WorldWideScience

Sample records for rat midbrain raphe

  1. Anti-Apoptotic Protein Bcl-xL Expression in the Midbrain Raphe Region Is Sensitive to Stress and Glucocorticoids.

    Science.gov (United States)

    Shishkina, Galina T; Kalinina, Tatyana S; Bulygina, Veta V; Lanshakov, Dmitry A; Babluk, Ekaterina V; Dygalo, Nikolay N

    2015-01-01

    Anti-apoptotic proteins are suggested to be important for the normal health of neurons and synapses as well as for resilience to stress. In order to determine whether stressful events may influence the expression of anti-apoptotic protein Bcl-xL in the midbrain and specifically in the midbrain serotonergic (5-HT) neurons involved in neurobehavioral responses to adverse stimuli, adult male rats were subjected to short-term or chronic forced swim stress. A short-term stress rapidly increased the midbrain bcl-xl mRNA levels and significantly elevated Bcl-xL immunoreactivity in the midbrain 5-HT cells. Stress-induced increase in glucocorticoid secretion was implicated in the observed effect. The levels of bcl-xl mRNA were decreased after stress when glucocorticoid elevation was inhibited by metyrapone (MET, 150 mg/kg), and this decrease was attenuated by glucocorticoid replacement with dexamethasone (DEX; 0.2 mg/kg). Both short-term stress and acute DEX administration, in parallel with Bcl-xL, caused a significant increase in tph2 mRNA levels and slightly enhanced tryptophan hydroxylase immunoreactivity in the midbrain. The increasing effect on the bcl-xl expression was specific to the short-term stress. Forced swim repeated daily for 2 weeks led to a decrease in bcl-xl mRNA in the midbrain without any effects on the Bcl-xL protein expression in the 5-HT neurons. In chronically stressed animals, an increase in tph2 gene expression was not associated with any changes in tryptophan hydroxylase protein levels. Our findings are the first to demonstrate that both short-term stress and acute glucocorticoid exposures induce Bcl-xL protein expression in the midbrain 5-HT neurons concomitantly with the activation of the 5-HT synthesis pathway in these neurons.

  2. Anti-Apoptotic Protein Bcl-xL Expression in the Midbrain Raphe Region Is Sensitive to Stress and Glucocorticoids.

    Directory of Open Access Journals (Sweden)

    Galina T Shishkina

    Full Text Available Anti-apoptotic proteins are suggested to be important for the normal health of neurons and synapses as well as for resilience to stress. In order to determine whether stressful events may influence the expression of anti-apoptotic protein Bcl-xL in the midbrain and specifically in the midbrain serotonergic (5-HT neurons involved in neurobehavioral responses to adverse stimuli, adult male rats were subjected to short-term or chronic forced swim stress. A short-term stress rapidly increased the midbrain bcl-xl mRNA levels and significantly elevated Bcl-xL immunoreactivity in the midbrain 5-HT cells. Stress-induced increase in glucocorticoid secretion was implicated in the observed effect. The levels of bcl-xl mRNA were decreased after stress when glucocorticoid elevation was inhibited by metyrapone (MET, 150 mg/kg, and this decrease was attenuated by glucocorticoid replacement with dexamethasone (DEX; 0.2 mg/kg. Both short-term stress and acute DEX administration, in parallel with Bcl-xL, caused a significant increase in tph2 mRNA levels and slightly enhanced tryptophan hydroxylase immunoreactivity in the midbrain. The increasing effect on the bcl-xl expression was specific to the short-term stress. Forced swim repeated daily for 2 weeks led to a decrease in bcl-xl mRNA in the midbrain without any effects on the Bcl-xL protein expression in the 5-HT neurons. In chronically stressed animals, an increase in tph2 gene expression was not associated with any changes in tryptophan hydroxylase protein levels. Our findings are the first to demonstrate that both short-term stress and acute glucocorticoid exposures induce Bcl-xL protein expression in the midbrain 5-HT neurons concomitantly with the activation of the 5-HT synthesis pathway in these neurons.

  3. Dorsal-to-Ventral Shift in Midbrain Dopaminergic Projections and Increased Thalamic/Raphe Serotonergic Function in Early Parkinson Disease.

    Science.gov (United States)

    Joutsa, Juho; Johansson, Jarkko; Seppänen, Marko; Noponen, Tommi; Kaasinen, Valtteri

    2015-07-01

    Loss of nigrostriatal neurons leading to dopamine depletion in the dorsal striatum is the pathologic hallmark of Parkinson disease contributing to the primary motor symptoms of the disease. However, Parkinson pathology is more widespread in the brain, affecting also other dopaminergic pathways and neurotransmitter systems, but these changes are less well characterized. This study aimed to investigate the mesencephalic striatal and extrastriatal dopaminergic projections together with extrastriatal serotonin transporter binding in Parkinson disease. Two hundred sixteen patients with Parkinson disease and 204 control patients (patients without neurodegenerative parkinsonism syndromes and normal SPECT imaging) were investigated with SPECT using the dopamine/serotonin transporter ligand (123)I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ((123)I-FP-CIT) in the clinical setting. The group differences and midbrain correlations were analyzed voxel by voxel over the entire brain. We found that Parkinson patients had lower (123)I-FP-CIT uptake in the striatum and ventral midbrain but higher uptake in the thalamus and raphe nuclei than control patients. In patients with Parkinson disease, the correlation of the midbrain tracer uptake was shifted from the putamen to widespread corticolimbic areas. All findings were highly significant at the voxel level familywise error-corrected P value of less than 0.05. Our findings show that Parkinson disease is associated not only with the degeneration of the nigrostriatal dopamine neurotransmission, but also with a parallel shift toward mesolimbic and mesocortical function. Furthermore, Parkinson disease patients seem to have upregulation of brain serotonin transporter function at the early phase of the disease. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  4. Harmane inhibits serotonergic dorsal raphe neurons in the rat.

    Science.gov (United States)

    Touiki, Khalid; Rat, Pascal; Molimard, Robert; Chait, Abderrahman; de Beaurepaire, Renaud

    2005-11-01

    Harmane and norharmane (two beta-carbolines) are tobacco components or products. The effects of harmane and norharmane on serotonergic raphe neurons remain unknown. Harmane and norharmane are inhibitors of the monoamine oxidases A (MAO-A) and B (MAO-B), respectively. To study the effects of harmane, norharmane, befloxatone (MAOI-A), and selegiline (MAOI-B) on the firing of serotonergic neurons. To compare the effects of these compounds to those of nicotine (whose inhibitory action on serotonergic neurons has been previously described). The effects of cotinine, a metabolite of nicotine known to interact with serotonergic systems, are also tested. In vivo electrophysiological recordings of serotonergic dorsal raphe neurons in the anaesthetized rat. Nicotine, harmane, and befloxatone inhibited serotonergic dorsal raphe neurons. The other compounds had no effects. The inhibitory effect of harmane (rapid and long-lasting inhibition) differed from that of nicotine (short and rapidly reversed inhibition) and from that of befloxatone (slow, progressive, and long-lasting inhibition). The inhibitory effects of harmane and befloxatone were reversed by the 5-HT1A antagonist WAY 100 635. Pretreatment of animals with p-chlorophenylalanine abolished the inhibitory effect of befloxatone, but not that of harmane. Nicotine, harmane, and befloxatone inhibit the activity of raphe serotonergic neurons. Therefore, at least two tobacco compounds, nicotine and harmane, inhibit the activity of serotonergic neurons. The mechanism by which harmane inhibits serotonergic dorsal raphe neurons is likely unrelated to a MAO-A inhibitory effect.

  5. Effect of MDMA-Induced Axotomy on the Dorsal Raphe Forebrain Tract in Rats: An In Vivo Manganese-Enhanced Magnetic Resonance Imaging Study.

    Directory of Open Access Journals (Sweden)

    Chuang-Hsin Chiu

    Full Text Available 3,4-Methylenedioxymethamphetamine (MDMA, also known as "Ecstasy", is a common recreational drug of abuse. Several previous studies have attributed the central serotonergic neurotoxicity of MDMA to distal axotomy, since only fine serotonergic axons ascending from the raphe nucleus are lost without apparent damage to their cell bodies. However, this axotomy has never been visualized directly in vivo. The present study examined the axonal integrity of the efferent projections from the midbrain raphe nucleus after MDMA exposure using in vivo manganese-enhanced magnetic resonance imaging (MEMRI. Rats were injected subcutaneously six times with MDMA (5 mg/kg or saline once daily. Eight days after the last injection, manganese ions (Mn2+ were injected stereotactically into the raphe nucleus, and a series of MEMRI images was acquired over a period of 38 h to monitor the evolution of Mn2+-induced signal enhancement across the ventral tegmental area, the medial forebrain bundle (MFB, and the striatum. The MDMA-induced loss of serotonin transporters was clearly evidenced by immunohistological staining consistent with the Mn2+-induced signal enhancement observed across the MFB and striatum. MEMRI successfully revealed the disruption of the serotonergic raphe-striatal projections and the variable effect of MDMA on the kinetics of Mn2+ accumulation in the MFB and striatum.

  6. Estradiol or fluoxetine alters depressive behavior and tryptophan hydroxylase in rat raphe.

    Science.gov (United States)

    Yang, Fu-Zhong; Wu, Yan; Zhang, Wei-Guo; Cai, Yi-Yun; Shi, Shen-Xun

    2010-03-10

    The effects of 17beta-estradiol and fluoxetine on behavior of ovariectomized rats subjected to the forced swimming test and the expression of tryptophan hydroxylase (TPH) in dorsal and median raphe were investigated, respectively through time sampling technique of behavior scoring and immunohistochemistry. Both estradiol and fluoxetine increased swimming and decreased immobility in the forced swimming test. The forced swimming stress decreased integrated optical density of TPH-positive regions in dorsal and median raphe. Both estradiol and fluoxetine administration prevented integrated optical density of TPH-positive regions from being decreased by forced swimming stress. These observations suggest that both estradiol and fluoxetine have protective bearing on ovariectomized rats enduring forced swimming stress.

  7. Single-prolonged stress induces apoptosis in dorsal raphe nucleus in the rat model of posttraumatic stress disorder

    Directory of Open Access Journals (Sweden)

    Liu Dongjuan

    2012-11-01

    Full Text Available Abstract Introduction Post-traumatic stress disorder (PTSD is an anxiety disorder that develops after exposure to a life-threatening traumatic experience. Meta-analyses of the brainstem showed that midsagittal area of the pons was significantly reduced in patients with PTSD, suggesting a potential apoptosis in dorsal raphe nucleus after single-prolonged stress (SPS. The aim of this study is to investigate whether SPS induces apoptosis in dorsal raphe nucleus in PTSD rats, which may be a possible mechanism of reduced volume of pons and density of gray matter. Methods In this study, rats were randomly divided into 1d, 7d and 14d groups after SPS along with the control group. The apoptosis rate was determined using annexin V-FITC/PI double-labeled flow cytometry (FCM. Levels of Cytochrome c (Cyt-C was examined by Western blotting. Expression of Cyt-C on mitochondria in the dorsal raphe nucleus neuron was determined by enzymohistochemistry under transmission electron microscopy (TEM. The change of thiamine monophosphatase (TMP levels was assessed by enzymohistochemistry under light microscope and TEM. Morphological changes of the ultrastructure of the dorsal raphe nucleus neuron were determined by TEM. Results Apoptotic morphological alterations were observed in dorsal raphe nucleus neuron for all SPS-stimulate groups of rats. The apoptosis rates were significantly increased in dorsal raphe nucleus neuron of SPS rats, along with increased release of cytochrome c from the mitochondria into the cytoplasm, increased expression of Cyt-C and TMP levels in the cytoplasm, which reached to the peak of increase 7 days of SPS. Conclusions The results indicate that SPS induced Cyt-C released from mitochondria into cytosol and apoptosis in dorsal raphe nucleus neuron of rats. Increased TMP in cytoplasm facilitated the clearance of apoptotic cells. We propose that this presents one of the mechanisms that lead to reduced volume of pons and gray matter associated

  8. Exposure to an open-field arena increases c-Fos expression in a subpopulation of neurons in the dorsal raphe nucleus, including neurons projecting to the basolateral amygdaloid complex

    DEFF Research Database (Denmark)

    Hale, M.W.; Hay-Schmidt, A.; Mikkelsen, J.D.

    2008-01-01

    Serotonergic systems in the dorsal raphe nucleus are thought to play an important role in the regulation of anxiety states. To investigate responses of neurons in the dorsal raphe nucleus to a mild anxiety-related stimulus, we exposed rats to an open-field, under low-light or high-light conditions....... Treatment effects on c-Fos expression in serotonergic and non-serotonergic cells in the midbrain raphe nuclei were determined 2 h following open-field exposure or home cage control (CO) conditions. Rats tested under both light conditions responded with increases in c-Fos expression in serotonergic neurons...... within subdivisions of the midbrain raphe nuclei compared with CO rats. However, the total numbers of serotonergic neurons involved were small suggesting that exposure to the open-field may affect a subpopulation of serotonergic neurons. To determine if exposure to the open-field activates a subset...

  9. Nitric oxide in the nucleus raphe magnus modulates cutaneous blood flow in rats during hypothermia

    Directory of Open Access Journals (Sweden)

    Masoumeh Kourosh Arami

    2015-10-01

    Full Text Available Objective(s: Nucleus Raphe Magnus (NRM that is involved in the regulation of body temperature contains nitric oxide (NO synthase. Considering the effect of NO on skin blood flow control, in this study, we assessed its thermoregulatory role within the raphe magnus. Materials and Methods: To this end, tail blood flow of male Wistar rats was measured by laser doppler following the induction of hypothermia. Results: Intra-NRM injection of SNP (exogenous NO donor, 0.1- 0.2 μl, 0.2 nM increased the blood flow. Similarly, unilateral microinjection of glutamate (0.1- 0.2 μl, 2.3 nM into the nucleus increased the blood flow. This effectof L-glutamate was reduced by prior intra NRM administrationof NO synthase inhibitor NG-methyl-L-arginine or NG-nitro-L-argininemethyl ester (L-NAME, 0.1 µl, 100 nM. Conclusion: It is concluded that NO modulates the thermoregulatory response of NRM to hypothermia and may interactwith excitatory amino acids in central skin blood flow regulation.

  10. Nitric oxide in the nucleus raphe magnus modulates cutaneous blood flow in rats during hypothermia.

    Science.gov (United States)

    Arami, Masoumeh Kourosh; Zade, Javad Mirnajafi; Komaki, Alireza; Amiri, Mahmood; Mehrpooya, Sara; Jahanshahi, Ali; Jamei, Behnam

    2015-10-01

    Nucleus Raphe Magnus (NRM) that is involved in the regulation of body temperature contains nitric oxide (NO) synthase. Considering the effect of NO on skin blood flow control, in this study, we assessed its thermoregulatory role within the raphe magnus. To this end, tail blood flow of male Wistar rats was measured by laser doppler following the induction of hypothermia. Intra-NRM injection of SNP (exogenous NO donor, 0.1- 0.2 μl, 0.2 nM) increased the blood flow. Similarly, unilateral microinjection of glutamate (0.1- 0.2 μl, 2.3 nM) into the nucleus increased the blood flow. This effect of L-glutamate was reduced by prior intra NRM administration of NO synthase inhibitor N(G)-methyl-L-arginine or N(G)-nitro-L-arginine methyl ester (L-NAME, 0.1 µl, 100 nM). It is concluded that NO modulates the thermoregulatory response of NRM to hypothermia and may interact with excitatory amino acids in central skin blood flow regulation.

  11. Tualang Honey Protects the Rat Midbrain and Lung against Repeated Paraquat Exposure

    Directory of Open Access Journals (Sweden)

    Suk Peng Tang

    2017-01-01

    Full Text Available Paraquat (PQ is a dopaminergic neurotoxin and a well-known pneumotoxicant that exerts its toxic effect via oxidative stress-mediated cellular injuries. This study investigated the protective effects of Tualang honey against PQ-induced toxicity in the midbrain and lungs of rats. The rats were orally treated with distilled water (2 mL/kg/day, Tualang honey (1.0 g/kg/day, or ubiquinol (0.2 g/kg/day throughout the experimental period. Two weeks after the respective treatments, the rats were injected intraperitoneally with saline (1 mL/kg/week or PQ (10 mg/kg/week once per week for four consecutive weeks. After four weekly exposures to PQ, the glutathione peroxidase activity and the number of tyrosine-hydroxylase immunopositive neurons in the midbrain were significantly decreased in animals from group PQ (p<0.05. The lungs of animals from group PQ showed significantly decreased activity of superoxide dismutase and glutathione-S-transferase. Treatment with Tualang honey ameliorated the toxic effects observed in the midbrain and lungs. The beneficial effects of Tualang honey were comparable to those of ubiquinol, which was used as a positive control. These findings suggest that treatment with Tualang honey may protect against PQ-induced toxicity in the rat midbrain and lung.

  12. Tualang Honey Protects the Rat Midbrain and Lung against Repeated Paraquat Exposure.

    Science.gov (United States)

    Tang, Suk Peng; Kuttulebbai Nainamohamed Salam, Sirajudeen; Jaafar, Hasnan; Gan, Siew Hua; Muzaimi, Mustapha; Sulaiman, Siti Amrah

    2017-01-01

    Paraquat (PQ) is a dopaminergic neurotoxin and a well-known pneumotoxicant that exerts its toxic effect via oxidative stress-mediated cellular injuries. This study investigated the protective effects of Tualang honey against PQ-induced toxicity in the midbrain and lungs of rats. The rats were orally treated with distilled water (2 mL/kg/day), Tualang honey (1.0 g/kg/day), or ubiquinol (0.2 g/kg/day) throughout the experimental period. Two weeks after the respective treatments, the rats were injected intraperitoneally with saline (1 mL/kg/week) or PQ (10 mg/kg/week) once per week for four consecutive weeks. After four weekly exposures to PQ, the glutathione peroxidase activity and the number of tyrosine-hydroxylase immunopositive neurons in the midbrain were significantly decreased in animals from group PQ ( p honey ameliorated the toxic effects observed in the midbrain and lungs. The beneficial effects of Tualang honey were comparable to those of ubiquinol, which was used as a positive control. These findings suggest that treatment with Tualang honey may protect against PQ-induced toxicity in the rat midbrain and lung.

  13. Tualang Honey Protects the Rat Midbrain and Lung against Repeated Paraquat Exposure

    Science.gov (United States)

    Sulaiman, Siti Amrah

    2017-01-01

    Paraquat (PQ) is a dopaminergic neurotoxin and a well-known pneumotoxicant that exerts its toxic effect via oxidative stress-mediated cellular injuries. This study investigated the protective effects of Tualang honey against PQ-induced toxicity in the midbrain and lungs of rats. The rats were orally treated with distilled water (2 mL/kg/day), Tualang honey (1.0 g/kg/day), or ubiquinol (0.2 g/kg/day) throughout the experimental period. Two weeks after the respective treatments, the rats were injected intraperitoneally with saline (1 mL/kg/week) or PQ (10 mg/kg/week) once per week for four consecutive weeks. After four weekly exposures to PQ, the glutathione peroxidase activity and the number of tyrosine-hydroxylase immunopositive neurons in the midbrain were significantly decreased in animals from group PQ (p honey ameliorated the toxic effects observed in the midbrain and lungs. The beneficial effects of Tualang honey were comparable to those of ubiquinol, which was used as a positive control. These findings suggest that treatment with Tualang honey may protect against PQ-induced toxicity in the rat midbrain and lung. PMID:28127418

  14. [Influence of estradiol on tryptophan hydroxylase and 5-hydroxytryptamine content in raphe nuclei of rats under forced swimming stress].

    Science.gov (United States)

    Yang, Fu-zhong; Wu, Yan; Zhang, Wei-guo; Cai, Yi-yun; Shi, Shen-xun

    2010-07-20

    To investigate the effect of estradiol (E2) on tryptophan hydroxylase (TPH) and 5-hydroxytryptamine (5-HT) content in raphe nuclei of rats under forced swimming stress and explore the role of estrogen and stress in disease mechanism of depression in women. At Week 3 post-ovariectomy, 35 ovariectomized (OVX) female SD rats were randomly divided into 5 groups (n = 7): non-stress group, control group, estradiol (E2) group and fluoxetine (FLX) group and E2 plus FLX group. Animals were administered with different drugs for 2 weeks. At Day 14, animals except those in the non-stress group were subjected to the 15 min forced swimming test (FST). At 2 hours post-FST, all animals including those in the non-stress group were perfused with 4% paraformaldehyde and brains removed for TPH and 5-HT immunofluorescence staining. We compared the content of TPH and 5-HT by observing and calculating the integrated optical density (IOD) of immunofluorescent-positive signals in raphe nuclei. (1) The IOD value of TPH- and 5-HT-positive region in raphe nuclei of rats in the control group was significantly lower than that of the non-stress group (P Forced swimming stress can decrease the TPH and 5-HT content in raphe nuclei. Such changes can be prevented by a pre-administration of estradiol. Similar results are observed with antidepressant fluoxetine. These effects may underlie the role of estradiol and stress in the disease mechanism of depression in women.

  15. Effect of arginine vasopressin in the nucleus raphe magnus on antinociception in the rat.

    Science.gov (United States)

    Yang, Jun; Chen, Jian-Min; Liu, Wen-Yan; Song, Cao-You; Wang, Cheng-Hai; Lin, Bao-Cheng

    2006-09-01

    Previous work has shown that arginine vasopressin (AVP) regulates antinociception through brain nuclei rather than the spinal cord and peripheral organs. The present study investigated the nociceptive effect of AVP in the nucleus raphe magnus (NRM) of the rat. Microinjection of AVP into the NRM increased pain threshold in a dose-dependent manner, while local administration of AVP-receptor antagonist-d(CH2)5Tyr(Et)DAVP decreased the pain threshold. Pain stimulation elevated AVP concentration in the NRM perfuse liquid. NRM pretreatment with AVP-receptor antagonist completely reversed AVP's effect on pain threshold in the NRM. The data suggest that AVP in the NRM is involved in antinociception.

  16. [Effects of perinatal exposure to bisphenol A inducing dopaminergic neuronal cell to apoptosis happening in midbrain of male rat offspring].

    Science.gov (United States)

    Lin, Yong; Zhang, Hao; Wang, Wen-dong; Wu, De-sheng; Jiang, Song-hui; Qu, Wei-dong

    2006-07-01

    To investigate the mechanism and effect of rat perinatal exposure to bisphenol A (BPA) resulting in midbrain dopaminergic neuronal cell apoptosis and tyrosine hydroxylase expression of male offspring. Rat dams were randomLy divided into 4 groups on gestational day(GD) 10 and given orally the bisphenol A doses as 0, 0.5, 5, 50 mg/kg x d from GD10 to weaning. The brains of male offspring were obtained for detecting, with immunohistochemistry protocol, the Caspase-3, Bcl-2 and tyrosine hydroxylase expression in the midbrain on postnatal day 21 or 30 respectively, and the midbrain apoptotic neuronal cell were detected by TUNEL on PND21. The expression of Caspase-3 in the midbrain of rat male offspring were increased but bcl-2 were decreased on PND21 and 30, respectively. On PND21, apoptotic neuronal cell were found in the midbrain of high and medium doses groups. TH protein expression was decreased. Perinatal exposure to bisphenol A can induce the apoptosis of midbrain dopaminergic neuron in the male rat offspring even after weaning, and concomitantly decrease the midbrain TH immunoreactivity, this may cause the abnormal function of dopaminergic pathway of rat male offspring.

  17. Opioid microinjection into raphe magnus modulates cardiorespiratory function in mice and rats.

    Science.gov (United States)

    Hellman, Kevin M; Mendelson, Scott J; Mendez-Duarte, Marco A; Russell, James L; Mason, Peggy

    2009-11-01

    The raphe magnus (RM) participates in opioid analgesia and contains pain-modulatory neurons with respiration-related discharge. Here, we asked whether RM contributes to respiratory depression, the most prevalent lethal effect of opioids. To investigate whether opioidergic transmission in RM produces respiratory depression, we microinjected a mu-opioid receptor agonist, DAMGO, or morphine into the RM of awake rodents. In mice, opioid microinjection produced sustained decreases in respiratory rate (170 to 120 breaths/min), as well as heart rate (520 to 400 beats/min). Respiratory sinus arrhythmia, indicative of enhanced parasympathetic activity, was prevalent in mice receiving DAMGO microinjection. We performed similar experiments in rats but observed no changes in breathing rate or heart rate. Both rats and mice experienced significantly more episodes of bradypnea, indicative of impaired respiratory drive, after opioid microinjection. During spontaneous arousals, rats showed less tachycardia after opioid microinjection than before microinjection, suggestive of an attenuated sympathetic tone. Thus, activation of opioidergic signaling within RM produces effects beyond analgesia, including the unwanted destabilization of cardiorespiratory function. These adverse effects on homeostasis consequent to opioid microinjection imply a role for RM in regulating the balance of sympathetic and parasympathetic tone.

  18. Electrolytic lesion of the nucleus raphe magnus reduced the antinociceptive effects of bilateral morphine microinjected into the nucleus cuneiformis in rats.

    Science.gov (United States)

    Haghparast, Abbas; Ordikhani-Seyedlar, Mehdi; Ziaei, Maryam

    2008-06-27

    Several lines of investigation show that the rostral ventromedial medulla is a critical relay for midbrain regions, including the nucleus cuneiformis (CnF), which control nociception at the spinal cord. There is some evidence that local stimulation or morphine administration into the CnF produces the effective analgesia through the nucleus raphe magnus (NRM). The present study tries to determine the effect of morphine-induced analgesia following microinjection into the CnF in the absence of NRM. Seven days after the cannulae implantation, morphine was microinjected bilaterally into the CnF at the doses of 0.25, 1, 2.5, 5, 7.5 and 10 microg/0.3 microl saline per side. The morphine-induced antinociceptive effect measured by tail-flick test at 30, 60, 90 and 120 min after microinjection. The results showed that bilateral microinjection of morphine into the CnF dose-dependently causes increase in tail-flick latency (TFL). The 50% effective dose of morphine was determined and microinjected into the CnF (2.5 microg/0.3 microl saline per side) in rats after NRM electrolytic lesion (1 mA, 30 s). Lesion of the NRM significantly decreased TFLs, 30 (Peffects through the opioid receptors in the CnF. It is also appeared that morphine-induced antinociception decreases following the NRM lesion but it seems that there are some other descending pain modulatory pathways that activate in the absence of NRM.

  19. Tualang Honey Protects the Rat Midbrain and Lung against Repeated Paraquat Exposure

    OpenAIRE

    Tang, Suk Peng; Kuttulebbai Nainamohamed Salam, Sirajudeen; Jaafar, Hasnan; Gan, Siew Hua; Muzaimi, Mustapha; Sulaiman, Siti Amrah

    2017-01-01

    Paraquat (PQ) is a dopaminergic neurotoxin and a well-known pneumotoxicant that exerts its toxic effect via oxidative stress-mediated cellular injuries. This study investigated the protective effects of Tualang honey against PQ-induced toxicity in the midbrain and lungs of rats. The rats were orally treated with distilled water (2?mL/kg/day), Tualang honey (1.0?g/kg/day), or ubiquinol (0.2?g/kg/day) throughout the experimental period. Two weeks after the respective treatments, the rats were i...

  20. Neurochemical differences between target-specific populations of rat dorsal raphe projection neurons.

    Science.gov (United States)

    Prouty, Eric W; Chandler, Daniel J; Waterhouse, Barry D

    2017-11-15

    Serotonin (5-HT)-containing neurons in the dorsal raphe (DR) nucleus project throughout the forebrain and are implicated in many physiological processes and neuropsychiatric disorders. Diversity among these neurons has been characterized in terms of their neurochemistry and anatomical organization, but a clear sense of whether these attributes align with specific brain functions or terminal fields is lacking. DR 5-HT neurons can co-express additional neuroactive substances, increasing the potential for individualized regulation of target circuits. The goal of this study was to link DR neurons to a specific functional role by characterizing cells according to both their neurotransmitter expression and efferent connectivity; specifically, cells projecting to the medial prefrontal cortex (mPFC), a region implicated in cognition, emotion, and responses to stress. Following retrograde tracer injection, brainstem sections from Sprague-Dawley rats were immunohistochemically stained for markers of serotonin, glutamate, GABA, and nitric oxide (NO). 98% of the mPFC-projecting serotonergic neurons co-expressed the marker for glutamate, while the markers for NO and GABA were observed in 60% and less than 1% of those neurons, respectively. To identify potential target-specific differences in co-transmitter expression, we also characterized DR neurons projecting to a visual sensory structure, the lateral geniculate nucleus (LGN). The proportion of serotonergic neurons co-expressing NO was greater amongst cells targeting the mPFC vs LGN (60% vs 22%). The established role of 5-HT in affective disorders and the emerging role of NO in stress signaling suggest that the impact of 5-HT/NO co-localization in DR neurons that regulate mPFC circuit function may be clinically relevant. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. NK3 Receptors mediate an increase in firing rate of midbrain dopamine neurons of the rat and the guinea pig

    NARCIS (Netherlands)

    Werkman, T.R.; McCreary, A.C.; Kruse, C.G.; Wadman, W.J.

    2011-01-01

    This in vitro study investigates and compares the effects of NK3 receptor ligands on the firing rate of rat and guinea pig midbrain dopamine neurons. The findings are discussed in the light of choosing suitable animal models for investigating pharmacological properties of NK3 receptor antagonists,

  2. Upregulation of the dorsal raphe nucleus-prefrontal cortex serotonin system by chronic treatment with escitalopram in hyposerotonergic Wistar-Kyoto rats

    NARCIS (Netherlands)

    Yamada, Makiko; Kawahara, Yukie; Kaneko, Fumi; Kishikawa, Yuki; Sotogaku, Naoki; Poppinga, Wilfred J.; Folgering, Joost H. A.; Dremencov, Eliyahu; Kawahara, Hiroshi; Nishi, Akinori

    Wistar-Kyoto (WKY) rats are sensitive to chronic stressors and exhibit depression-like behavior. Dorsal raphe nucleus (DRN) serotonin (5-HT) neurons projecting to the prefrontal cortex (PFC) comprise the important neurocircuitry underlying the pathophysiology of depression. To evaluate the DRN-PFC

  3. Hypothalamic projections to the ventral medulla oblongata in the rat, with special reference to the nucleus raphe pallidus: a study using autoradiographic and HRP techniques

    Energy Technology Data Exchange (ETDEWEB)

    Hosoya, Yasuhiko

    1985-10-07

    Hypothalamic descending projections to the medullary ventral surface were studied autoradiographically in the rat. A small amount of (/sup 3/H)leucine was injected unilaterally into various parts of the hypothalamus by air pressure. Abundant and characteristic terminal labelings were observed bilaterally in the nucleus raphe pallidus, the ventral surface to the pyramidal tract and the nucleus interfascicularis hypoglossi, after injections into the dorsal posterior hypothalamic area caudal to the paraventricular hypothalamic nucleus. Conspicuous, but less numerous labelings were observed in the nucleus raphe obscurus and the ipsilateral raphe magnus. After an injection of (/sup 3/H)leucine into the hypothalamus and injections of horseradish peroxidase (HRP) into the spinal cord in the same animal, silver grains were densely distributed around HRP-labeled neurons in the nucleus raphe pallidus including the nucleus interfascicularis hypoglossi. The present results suggest that the dorsal posterior hypothalamic area projects directly to the spinal-projecting neurons of the nucleus raphe pallidus. 53 refs.; 9 figs.

  4. Phosphorylation of CaMKII in the rat dorsal raphe nucleus plays an important role in sleep-wake regulation.

    Science.gov (United States)

    Cui, Su-Ying; Li, Sheng-Jie; Cui, Xiang-Yu; Zhang, Xue-Qiong; Yu, Bin; Sheng, Zhao-Fu; Huang, Yuan-Li; Cao, Qing; Xu, Ya-Ping; Lin, Zhi-Ge; Yang, Guang; Song, Jin-Zhi; Ding, Hui; Wang, Zi-Jun; Zhang, Yong-He

    2016-02-01

    The Ca(2+) modulation in the dorsal raphe nucleus (DRN) plays an important role in sleep-wake regulation. Calmodulin-dependent kinase II (CaMKII) is an important signal-transducing molecule that is activated by Ca(2+) . This study investigated the effects of intracellular Ca(2+) /CaMKII signaling in the DRN on sleep-wake states in rats. Maximum and minimum CaMKII phosphorylation was detected at Zeitgeber time 21 (ZT 21; wakefulness state) and ZT 3 (sleep state), respectively, across the light-dark rhythm in the DRN in rats. Six-hour sleep deprivation significantly reduced CaMKII phosphorylation in the DRN. Microinjection of the CAMKII activation inhibitor KN-93 (5 or 10 nmol) into the DRN suppressed wakefulness and enhanced rapid-eye-movement sleep (REMS) and non-REM sleep (NREMS). Application of a high dose of KN-93 (10 nmol) increased slow-wave sleep (SWS) time, SWS bouts, the mean duration of SWS, the percentage of SWS relative to total sleep, and delta power density during NREMS. Microinjection of CaCl2 (50 nmol) in the DRN increased CaMKII phosphorylation and decreased NREMS, SWS, and REMS. KN-93 abolished the inhibitory effects of CaCl2 on NREMS, SWS, and REMS. These data indicate a novel wake-promoting and sleep-suppressing role for the Ca(2+) /CaMKII signaling pathway in DRN neurons. We propose that the intracellular Ca(2+) /CaMKII signaling in the dorsal raphe nucleus (DRN) plays wake-promoting and sleep-suppressing role in rats. Intra-DRN application of KN-93 (CaMKII activation inhibitor) suppressed wakefulness and enhanced rapid-eye-movement sleep (REMS) and non-REMS (NREMS). Intra-DRN application of CaCl2 attenuated REMS and NREMS. We think these findings should provide a novel cellular and molecular mechanism of sleep-wake regulation. © 2015 International Society for Neurochemistry.

  5. Opioid receptors in midbrain dopaminergic regions of the rat. 1. Mu receptor autoradiography

    International Nuclear Information System (INIS)

    German, D.C.; Speciale, S.G.; Manaye, K.F.; Sadeq, M.

    1993-01-01

    Several lines of evidence indicate that an interaction exists between opioid peptides and midbrain dopaminergic neurons. The purpose of this study was to map and quantify the density of the mu opioid receptor subtype relative to the location of the dopaminergic (DA) neurons in the retrorubral field (nucleus A8), substantia nigra (nucleus A9), and ventral tegmental area and related nuclei (nucleus A10) in the rat. Sections through the rostral-caudal extent of the midbrain were stained with an antibody against tyrosine hydroxylase, as a DA cell marker, and comparable sections were processed for in vitro receptor autoradiography using the mu-selective ligand, 3 H-Tyr-D-Ala-N-MePhe-Gyl-ol enkephalin. In the nucleus A8 region, there were low levels of mu binding. In the rostral portion of nucleus A9, there was prominent mu binding both in the ventral pars compacta, which contains numerous DA neurons, and in regions that correspond to the location of the DA dendrites which project ventrally into the underlying substantia nigra pars reticulata. In the caudal portion of nucleus A9, mu binding was greatest in the substantia nigra pars reticulata, but also in the same region that contains DA neurons. In nucleus A10, mu receptor densities differed depending upon the nucleus A10 subdivision, and the rostral-caudal position in the nucleus. Low receptor densities were observed in rostral portions of the ventral tegmental area and interfascicular nucleus, and there was negligible binding in the parabrachial pigmented nucleus and paranigral nucleus at the level of the interpeduncular nucleus; all regions where there are high densities of DA somata. Mu binding was relatively high in the central linear nucleus, and in the dorsal and medial divisions of the medial terminal nucleus of the accessory optic system, which has been shown to contain DA dendrites. These data indicate that mu opioid receptors are located in certain regions occupied by all three midbrain DA nuclei, but in a

  6. Increased BOLD activation to predator stressor in subiculum and midbrain of amphetamine-sensitized maternal rats.

    Science.gov (United States)

    Febo, Marcelo; Pira, Ashley S

    2011-03-25

    Amphetamine, which is known to cause sensitization, potentiates the hormonal and neurobiological signatures of stress and may also increase sensitivity to stress-inducing stimuli in limbic areas. Trimethylthiazoline (5μL TMT) is a chemical constituent of fox feces that evokes innate fear and activates the neuronal and hormonal signatures of stress in rats. We used blood oxygen level dependent (BOLD) MRI to test whether amphetamine sensitization (1mg/kg, i.p. ×3days) in female rats has a lasting effect on the neural response to a stress-evoking stimulus, the scent of a predator, during the postpartum period. The subiculum and dopamine-enriched midbrain VTA/SN of amphetamine-sensitized but not control mothers showed a greater BOLD signal response to predator odor than a control putrid scent. The greater responsiveness of these two brain regions following stimulant sensitization might impact neural processing in response to stressors in the maternal brain. Copyright © 2010 Elsevier B.V. All rights reserved.

  7. Adolescence fluoxetine increases serotonergic activity in the raphe-hippocampus axis and improves depression-like behaviors in female rats that experienced neonatal maternal separation.

    Science.gov (United States)

    Yoo, Sang Bae; Kim, Bom-Taeck; Kim, Jin Young; Ryu, Vitaly; Kang, Dong-Won; Lee, Jong-Ho; Jahng, Jeong Won

    2013-06-01

    This study was conducted to examine if fluoxetine, a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor, would reverse adverse behavioral effects of neonatal maternal separation in female rats. Sprague-Dawley pups were separated from dam daily for 3h during postnatal day (PND) 1-14 (maternal separation; MS) or left undisturbed (non-handled; NH). Female NH and MS pups received intraperitoneal injection of fluoxetine (10mg/kg) or vehicle daily from PND 35 until the end of the whole experimental period. Rats were either subjected to behavioral tests during PND 44-54, or sacrificed for neurochemical analyses during PND 43-45. Daily food intake and weight gain of both NH and MS pups were suppressed by fluoxetine, with greater effects in MS pups. MS experience increased immobility and decrease swimming in forced swim test. Swimming was increased, although immobility was not significantly decreased, in MS females by adolescence fluoxetine. However, adolescence fluoxetine increased immobility during forced swim test and decreased time spent in open arms during elevated plus maze test in NH females. Fluoxetine normalized MS-induced decrease of the raphe 5-HT levels and increased 5-HT metabolism in the hippocampus in MS females, and increased the hypothalamic 5-HT both in NH and MS. Fluoxetine decreased the raphe 5-HT and increased the plasma corticosterone in NH females. Results suggest that decreased 5-HTergic activity in the raphe nucleus is implicated in the pathophysiology of depression-like behaviors, and increased 5-HTergic activities in the raphe-hippocampus axis may be a part of anti-depressant efficacy of fluoxetine, in MS females. Also, an extra-hypothalamic 5-HTergic activity may contribute to the increased anorectic efficacy of fluoxetine in MS females. Additionally, decreased 5-HT in the raphe and elevated plasma corticosterone may be related with fluoxetine-induced depression- and/or anxiety-like behaviors in NH females. Copyright © 2012 Elsevier Ltd

  8. Astrocyte Hypertrophy and Microglia Activation in the Rat Auditory Midbrain Is Induced by Electrical Intracochlear Stimulation.

    Science.gov (United States)

    Rosskothen-Kuhl, Nicole; Hildebrandt, Heika; Birkenhäger, Ralf; Illing, Robert-Benjamin

    2018-01-01

    Neuron-glia interactions contribute to tissue homeostasis and functional plasticity in the mammalian brain, but it remains unclear how this is achieved. The potential of central auditory brain tissue for stimulation-dependent cellular remodeling was studied in hearing-experienced and neonatally deafened rats. At adulthood, both groups received an intracochlear electrode into the left cochlea and were continuously stimulated for 1 or 7 days after waking up from anesthesia. Normal hearing and deafness were assessed by auditory brainstem responses (ABRs). The effectiveness of stimulation was verified by electrically evoked ABRs as well as immunocytochemistry and in situ hybridization for the immediate early gene product Fos on sections through the auditory midbrain containing the inferior colliculus (IC). Whereas hearing-experienced animals showed a tonotopically restricted Fos response in the IC contralateral to electrical intracochlear stimulation, Fos-positive neurons were found almost throughout the contralateral IC in deaf animals. In deaf rats, the Fos response was accompanied by a massive increase of GFAP indicating astrocytic hypertrophy, and a local activation of microglial cells identified by IBA1. These glia responses led to a noticeable increase of neuron-glia approximations. Moreover, staining for the GABA synthetizing enzymes GAD65 and GAD67 rose significantly in neuronal cell bodies and presynaptic boutons in the contralateral IC of deaf rats. Activation of neurons and glial cells and tissue re-composition were in no case accompanied by cell death as would have been apparent by a Tunel reaction. These findings suggest that growth and activity of glial cells is crucial for the local adjustment of neuronal inhibition to neuronal excitation.

  9. Activation of substantia gelatinosa by midbrain reticular stimulation demonstrated with 2-deoxyglucose in the rat spinal cord

    International Nuclear Information System (INIS)

    Gonzales-Lima, F.

    1986-01-01

    The autoradiographic ( 14 C)2-deoxyglucose (2-DG) method was used to map the descending effects of midbrain reticular stimulation on the rat cervical spinal cord. The stimulation evoked consistently a defensive 'freezing' reaction as well as a large and highly localized increase in 2-DG uptake in the substantia gelatinosa (SG)(Rexed laminae 2-3). No stimulus-induced changes in 2-DG uptake were produced in the other regions of the spinal cord. The findings represent the first anatomical demonstration of the activating effects of the spinal cord. The findings represent the first anatomical demonstration of the activating effects of midbrain reticular stimulation on the spinal cord. They also support the concept of an integrative role for the SG in descending reticular mechanisms at the spinal cord level. (author)

  10. Activation of substantia gelatinosa by midbrain reticular stimulation demonstrated with 2-deoxyglucose in the rat spinal cord

    Energy Technology Data Exchange (ETDEWEB)

    Gonzales-Lima, F

    1986-04-24

    The autoradiographic (/sup 14/C)2-deoxyglucose (2-DG) method was used to map the descending effects of midbrain reticular stimulation on the rat cervical spinal cord. The stimulation evoked consistently a defensive 'freezing' reaction as well as a large and highly localized increase in 2-DG uptake in the substantia gelatinosa (SG)(Rexed laminae 2-3). No stimulus-induced changes in 2-DG uptake were produced in the other regions of the spinal cord. The findings represent the first anatomical demonstration of the activating effects of the spinal cord. The findings represent the first anatomical demonstration of the activating effects of midbrain reticular stimulation on the spinal cord. They also support the concept of an integrative role for the SG in descending reticular mechanisms at the spinal cord level. 12 refs.

  11. Activation of GABAergic pathway by hypocretin in the median raphe nucleus (MRN) mediates stress-induced theta rhythm in rats.

    Science.gov (United States)

    Hsiao, Yi-Tse; Jou, Shuo-Bin; Yi, Pei-Lu; Chang, Fang-Chia

    2012-07-15

    The frequency of electroencephalograms (EEGs) is predominant in theta rhythm during stress (e.g., footshock) in rats. Median raphe nucleus (MRN) desynchronizes hippocampal theta waves via activation of GABAergic neurons in the medial septum-diagonal band of Broca (MS-DBB), a theta rhythm pacemaker. Increased hypocretin mediates stress responses in addition to the maintenance of wakefulness. Hypocretin receptors are abundant in the MRN, suggesting a possible role of hypocretin in modulating stress-induced theta rhythm. Our results indicated that the intensity of theta waves was enhanced by footshock and that a hypocretin receptor antagonist (TCS1102) suppressed the footshock-induced theta waves. Administration of hypocretin-1 (1 and 10 μg) and hypocretin-2 (10 μg) directly into the MRN simulated the effect of footshock and significantly increased theta waves. Co-administration of GABA(A) receptor antagonist, bicuculline, into the MRN blocked the increase of theta waves induced by hypocretins or footshock. These results suggested that stress enhances the release of hypocretins, activates GABAergic neurons in the MRN, blocks the ability of MRN to desynchronize theta waves, and subsequently increases the intensity of theta rhythm. Copyright © 2012 Elsevier B.V. All rights reserved.

  12. Agonist-dependent modulation of G-protein coupling and transduction of 5-HT1A receptors in rat dorsal raphe nucleus

    OpenAIRE

    Valdizán, Elsa M.; Castro, Elena; Pazos, Ángel

    2009-01-01

    5-HT1A receptors couple to different Go/Gi proteins in order to mediate a wide range of physiological actions. While activation of post-synaptic 5-HT1A receptors is mainly related to inhibition of adenylyl cyclase activity, functionality of autoreceptors located in raphe nuclei has been classically ascribed to modifications of the activity of potassium and calcium channels. In order to evaluate the possible existence of agonist-directed trafficking for 5-HT1A autoreceptors in the rat dorsal r...

  13. Effects of electroacupuncture on orphanin FQ immunoreactivity and preproorphanin FQ mRNA in nucleus of raphe magnus in the neuropathic pain rats.

    Science.gov (United States)

    Ma, Fei; Xie, Hong; Dong, Zhi-Qiang; Wang, Yan-Qing; Wu, Gen-Cheng

    2004-07-15

    Orphanin FQ (OFQ) is an endogenous ligand for opioid receptor-like-1 (ORL1) receptor. Previous studies have shown that both OFQ immunoreactivity and preproorphanin FQ (ppOFQ) mRNA expression could be observed in the brain regions involved in pain modulation, e.g., nucleus of raphe magnus (NRM), dorsal raphe nucleus (DRN), and ventrolateral periaqueductal gray (vlPAG). It was reported that electroacupuncture (EA) has analgesic effect on neuropathic pain, and the analgesic effect was mediated by the endogenous opioid peptides. In the present study, we investigated the effects of EA on the changes of OFQ in the neuropathic pain rats. In the sciatic nerve chronic constriction injury (CCI) model, we investigated the changes of ppOFQ mRNA and OFQ immunoreactivity in NRM after EA by in situ hybridization (ISH) and immunohistochemistry methods, respectively. Then, the ppOFQ mRNA-positive and OFQ immunoreactive cells were counted under a computerized image analysis system. The results showed that expression of ppOFQ mRNA decreased and OFQ immunoreactivity increased after EA treatment in the neuropathic pain rats. These results indicated that EA modulated OFQ synthesis and OFQ peptide level in NRM of the neuropathic pain rats. Copyright 2004 Elsevier Inc.

  14. CARDIOVASCULAR EFFECTS AND CHANGES IN MIDBRAIN PERIAQUEDUCTAL GRAY NEURONAL-ACTIVITY INDUCED BY ELECTRICAL-STIMULATION OF THE HYPOTHALAMUS IN THE RAT

    NARCIS (Netherlands)

    VANDERPLAS, J; WIERSINGAPOST, JEC; MAES, FW; BOHUS, B

    1995-01-01

    The effects of low-intensity electrical stimulation of sites in the hypothalamus and zona incerta (ZI) on mean blood pressure (MBP), heart rate (HR), and neuronal activity in the midbrain periaqueductal gray (FAG) were investigated in rats. Longlasting depressor responses were elicited from 67 sites

  15. Excitotoxic median raphe lesions aggravate working memory storage performance deficits caused by scopolamine infusion into the dentate gyrus of the hippocampus in the inhibitory avoidance task in rats

    Directory of Open Access Journals (Sweden)

    Babar E.

    2002-01-01

    Full Text Available The interactions between the median raphe nucleus (MRN serotonergic system and the septohippocampal muscarinic cholinergic system in the modulation of immediate working memory storage performance were investigated. Rats with sham or ibotenic acid lesions of the MRN were bilaterally implanted with cannulae in the dentate gyrus of the hippocampus and tested in a light/dark step-through inhibitory avoidance task in which response latency to enter the dark compartment immediately after the shock served as a measure of immediate working memory storage. MRN lesion per se did not alter response latency. Post-training intrahippocampal scopolamine infusion (2 and 4 µg/side produced a more marked reduction in response latencies in the lesioned animals compared to the sham-lesioned rats. Results suggest that the immediate working memory storage performance is modulated by synergistic interactions between serotonergic projections of the MRN and the muscarinic cholinergic system of the hippocampus.

  16. Interaction between estradiol and 5-HT1A receptors in the median raphe nucleus on acquisition of aversive information and association to the context in ovariectomized rats

    Directory of Open Access Journals (Sweden)

    Telma Gonçalves Carneiro Spera de Andrade

    2017-12-01

    Full Text Available The median raphe nucleus (MRN is related to stress resistance and defensive responses, a crucial source of serotonergic neurons that project to prosencephalic structures related to stress and anxiety. Estrogen receptors were identified in this mesencephalic structure. It is possible that the estrogen action is related to serotonin effect on somatodendritic 5-HT1A receptors, inhibiting the function of serotonergic neurons and thus preventing of the stress effect and inducing anxiolysis. So, in order to evaluate these aspects, female Wistar rats were ovariectomized and 21 days later were given a direct microinjection of estradiol benzoate (EB (1200 ng into the MRN, preceded by microinjections of saline or WAY100.635 (100 ng, a 5-HT1A receptor antagonist. Immediately after the two microinjections, the ovariectomized rats were conditioned with an aversive event (foot shock session in a Skinner box. Twenty-four hours later, they were exposed to the same context in a test session for 5 min for behavioral assessment: freezing, rearing, locomotion, grooming, and autonomic responses (fecal boluses and micturition. EB microinjection in the MRN prior to the exposure of animals to the foot shocks in the conditioning session did not alter their behavior in this session, but neutralized the association of the aversive experience to the context: there was a decrease in the expression of freezing and an increased rearing activity in the test session. This effect was reversed by prior microinjection of WAY100.635. In conclusion, EB acted on serotonergic neurons in the MRN of the ovariectomized rats, impairing the association of the aversive experience to the context, by co-modulating the functionality of somatodendritic 5-HT1A. Keywords: Contextual conditioning, Median raphe nucleus, Estradiol benzoate, 5-HT1A receptors, WAY100.635, Ovariectomized rats, Anxiety

  17. 5,7-DHT lesion of the dorsal raphe nuclei impairs object recognition but not affective behavior and corticosterone response to stressor in the rat.

    Science.gov (United States)

    Lieben, Cindy K J; Steinbusch, Harry W M; Blokland, Arjan

    2006-04-03

    Previous studies with acute tryptophan depletion, leading to transient central 5-HT reductions, showed no effects on affective behavior but impaired object memory. In the present study, the behavioral effects of a 5,7-dihydroxytryptamine (5,7-DHT) lesion in the dorsal raphe were evaluated in animal models of anxiety (open field test), depression (forced swimming test), behavioral inhibition (discrete fixed interval test) and cognition (object recognition task). The corticosterone response to a stress condition was examined at several intervals after 5,7-DHT treatment. The substantial reduction in neuronal 5-HT markers in the dorsal raphe did not affect anxiety-related, depressive-like or impulsive behavior. Compared to the SHAM group, the lesioned rats showed a lower response latency to obtain a reward, indicating a quick and accurate reaction to a stimulus. No differences were found in the progressive ratio test for food motivation. A marked impairment in object recognition was found. The 5,7-DHT treatment did not affect the corticosterone response to a stressful situation. Overall, these results corroborate studies with acute tryptophan depletion suggesting a role of 5-HT in object memory, but not affective behavior.

  18. How does early maternal separation and chronic stress in adult rats affect the immunoreactivity of serotonergic neurons within the dorsal raphe nucleus?

    Science.gov (United States)

    Pollano, Antonella; Trujillo, Verónica; Suárez, Marta M

    2018-01-01

    Vulnerability to emotional disorders like depression derives from interactions between early and late environments, including stressful conditions. The serotonin (5HT) system is strongly affected by stress and chronic unpredictable stress can alter the 5HT system. We evaluated the distribution of active serotonergic neurons in the dorsal raphe nucleus (DR) through immunohistochemistry in maternally separated and chronically stressed rats treated with an antidepressant, tianeptine, whose mechanism of action is still under review. Male Wistar rats were subjected to daily maternal separation (MS) for 4.5 h between postnatal days (PND) 1-21, or to animal facility rearing (AFR). Between (PND) days 50-74, rats were exposed to chronic unpredictable stress and were treated daily with tianeptine (10 mg/kg) or vehicle. We found an interaction between the effects of MS and chronic unpredictable stress on Fos-5HT immunoreactive cells at mid-caudal level of the DR. MS-chronically stressed rats showed an increase of Fos-5HT immunoreactive cells compared with AFR-chronically stressed rats. The ventrolateral (DRL/VLPAG) and dorsal (DRD) subdivisions of the DR were significantly more active than the ventral part (DRV). At the rostral level of the DR, tianeptine decreased the number of Fos-5HT cells in DR in the AFR groups, both unstressed and stressed. Overall, our results support the idea of a match in phenotype exhibited when the early and the adult environment correspond.

  19. Effect of morphine-induced antinociception is altered by AF64A-induced lesions on cholinergic neurons in rat nucleus raphe magnus.

    Science.gov (United States)

    Abe, Kenji; Ishida, Kota; Kato, Masatoshi; Shigenaga, Toshiro; Taguchi, Kyoji; Miyatake, Tadashi

    2002-11-01

    To examine the role of cholinergic neurons in the nucleus raphe magnus (NRM) in noxious heat stimulation and in the effects of morphine-induced antinociception by rats. After the cholinergic neuron selective toxin, AF64A, was microinjected into the NRM, we examined changes in the antinociceptive threshold and effects of morphine (5 mg/kg, ip) using the hot-plate (HP) and tail-flick (TF) tests. Systemic administration of morphine inhibited HP and TF responses in control rats. Microinjection of AF64A (2 nmol/site) into the NRM significantly decreased the threshold of HP response after 14 d, whereas the TF response was not affected. Morphine-induced antinociception was significantly attenuated in rats administered AF64A. Extracellular acetylcholine was attenuated after 14 d to below detectable levels in rats given AF64A. Naloxone (1 microg/site) microinjected into control rat NRM also antagonized the antinociceptive effect of systemic morphine. These findings suggest that cholinergic neuron activation in the NRM modulates the antinociceptive effect of morphine simultaneously with the opiate system.

  20. Anti-nociceptive effects of calcitonin gene-related peptide in nucleus raphe magnus of rats: an effect attenuated by naloxone.

    Science.gov (United States)

    Huang, Y; Brodda-Jansen, G; Lundeberg, T; Yu, L C

    2000-08-04

    The present study investigated the role of calcitonin gene-related peptide (CGRP) on nociception in nucleus raphe magnus (NRM) and the interaction between CGRP and opioid peptides in NRM of rats. CGRP-like immunoreactivity was found at a concentration of 6.0+/-0. 77 pmol/g in NRM tissue of ten samples of rats, suggesting that it may contribute to physiological responses orchestrated by the NRM. The hindpaw withdrawal latency (HWL) to thermal and mechanical stimulation increased significantly after intra-NRM administration of 0.5 or 1 nmol of CGRP in rats, but not 0.25 nmol. The anti-nociceptive effect induced by CGRP was antagonized by following intra-NRM injection of 1 nmol of the CGRP receptor antagonist CGRP8-37. Furthermore, the CGRP-induced anti-nociceptive effect was attenuated by following intra-NRM administration of 6 nmol of naloxone. The results indicate that CGRP and its receptors play an important role in anti-nociception, and there is a possible interaction between CGRP and opioid peptides in NRM of rats.

  1. Reversible inactivation and excitation of nucleus raphe magnus can modulate tail blood flow of male Wistar rats in response to hypothermia.

    Science.gov (United States)

    Malakouti, Seyed Mansour; Kourosh Arami, Masoomeh; Sarihi, Abdorahman; Hajizadeh, Sohrab; Behzadi, Gila; Shahidi, Siamak; Komaki, Alireza; Heshmatian, Behnam; Vahabian, Mehrangiz

    2008-10-01

    The nucleus raphe magnus (NRM) is involved in thermoregulatory processing. There is a correlation between changes in the firing rates of the cells in the NRM and the application of the peripheral thermal stimulus. we examined the effect of reversible inactivation and excitation of NRM on mechanisms involved in tail blood flow (TBF) regulation in hypothermia. Hypothermia was induced in Male Wistar rats and cannula was implanted above the NRM. To evaluate the effect of nucleus inactivation on TBF, the amount of TBF was measured by Laser Doppler in hypothermic rats, before and after lidocaine microinjection into NRM. TBF was also measured after glutamate microinjection to assess the effect of nucleus excitation in hypothermic rats. Results indicated that after dropping TBF by hypothermia, microinjection of lidocaine into NRM significantly decreased TBF from 54.43 +- 5.7 to 46.81 +- 3.4, whereas glutamate microinjection caused a significant increase from 44.194 +- 0.6 to 98 +- 10.0 CONCLUSION: These data suggest that NRM have thermoregulatory effect in response to hypothermia.

  2. Agonist-dependent modulation of G-protein coupling and transduction of 5-HT1A receptors in rat dorsal raphe nucleus.

    Science.gov (United States)

    Valdizán, Elsa Maria; Castro, Elena; Pazos, Angel

    2010-08-01

    5-HT1A receptors couple to different Go/Gi proteins in order to mediate a wide range of physiological actions. While activation of post-synaptic 5-HT1A receptors is mainly related to inhibition of adenylyl cyclase activity, functionality of autoreceptors located in raphe nuclei has been classically ascribed to modifications of the activity of potassium and calcium channels. In order to evaluate the possible existence of agonist-directed trafficking for 5-HT1A autoreceptors in the rat dorsal raphe nucleus, we studied their activation by two agonists with a different profile of efficacy [(+)8-OH-DPAT and buspirone], addressing simultaneously the identification of the specific Galpha subtypes ([35S]GTPgammaS labelling and immunoprecipitation) involved and the subsequent changes in cAMP formation. A significant increase (32%, plabelling of immunoprecipitates was obtained with anti-Galphai3 antibodies but not with anti-Galphao, anti-Galphai1, anti-Galphai2, anti-Galphaz or anti-Galphas antibodies. In contrast, in the presence of buspirone, significant [35S]GTPgammaS labelling of immunoprecipitates was obtained with anti-Galphai3 (50%, plabelling with anti-Galphai1, anti-Galphaz or anti-Galphas. The selective 5-HT1A antagonist WAY 100635 blocked the labelling induced by both agonists. Furthermore, (+)8-OH-DPAT failed to modify forskolin-stimulated cAMP accumulation, while buspirone induced a dose-dependent, WAY 100635-sensitive, inhibition of this response (Imax 30.8+/-4.9, pIC50 5.95+/-0.46). These results demonstrate the existence of an agonist-dependency pattern of G-protein coupling and transduction for 5-HT1A autoreceptors in native brain tissue. These data also open new perspectives for the understanding of the differential profiles of agonist efficacy in pre- vs. post-synaptic 5-HT1A receptor-associated responses.

  3. Distinct effect of orphanin FQ in nucleus raphe magnus and nucleus reticularis gigantocellularis on the rat tail flick reflex.

    Science.gov (United States)

    Yang, Z; Zhang, Y; Wu, G

    2001-06-22

    The aim of the present study is to investigate the effects of orphanin FQ (OFQ) microinjected into the nucleus raphe magnus (NRM) and the nucleus reticularis gigantocellularis (NGC) on pain modulation. The tail-flick latency (TFL) was used as a behavioral index of nociceptive responsiveness. The result showed microinjection of OFQ into the NRM significantly increased the TFL, whereas microinjection of OFQ into the NGC decreased the TFL, suggesting the analgesic effect of OFQ in the NRM and the hyperalgesic effect of OFQ in the NGC. As there are three classes of putative pain modulating neurons in the rostral ventromedial medulla (RVM), the hyperalgesic or analgesic effect of OFQ in the RVM might depend upon the different class of the neurons being acted.

  4. Multiple serotonin receptors: regional distribution and effect of raphe lesions

    International Nuclear Information System (INIS)

    Blackshear, M.A.; Sanders-Bush, E.; Steranka, L.R.

    1981-01-01

    These studies confirm and extend the recent work suggesting that [ 3 H]lysergic acid diethylamide (LSD) labels two distinct binding sites in rat brain resembling serotonin (5HT) receptors. Although Scatchard analyses of [ 3 H]LSD binding to membranes prepared from cortex/hippocampus were linear, the heterogeneity of the [ 3 H]LSD binding sites was clearly demonstrated in displacement studies. The displacement curves for both 5HT and spiperone were bisigmoidal with the concentration required to saturate the high affinity components nearly 3 orders of magnitude lower than the concentrations necessary to saturate the low affinity components. Additivity studies suggested that the sites with high affinity for 5HT and spiperone are different, independent sites. These sites are referred to as 5HT 1 and 5HT 2 respectively. Regional analyses showed, that in the frontal cortex, the density of the 5HT 2 site was slightly greater than the 5HT 1 site whereas the 5HT 1 site was predominant in all other brain areas, including the spinal cord. The pharmacological properties of the two sites have features in common with 5HT receptors; however, electrolytic lesions of the midbrain raphe nuclei did not change the densities or binding constants of the two apparent 5HT receptor subtypes, even though the number of high affinity 5HT uptake sites was markedly reduced. (Auth.)

  5. A New Subdivision Of The Rat Midbrain Periaqueductal Gray Based On Its Myeloarchitecture.

    NARCIS (Netherlands)

    Holstege, G.; Gerrits, P.O.; Croon, D.H.

    1993-01-01

    A new subdivision of the periaqueductal gray (PAG) based on its myelin content is described. Using a methacrylate-resin embedding technique for high resolution light microscopy, a myeloarchitectonic map of the normal rat PAG was made. Six main columns were distinguished. Column I is the central thin

  6. Corticotropin-releasing Factor in the Rat Dorsal Raphe Nucleus Promotes Different Forms of Behavioral Flexibility Depending on Social Stress History.

    Science.gov (United States)

    Snyder, Kevin P; Hill-Smith, Tiffany E; Lucki, Irwin; Valentino, Rita J

    2015-10-01

    The stress-related neuropeptide, corticotropin-releasing factor (CRF) regulates the dorsal raphe nucleus-serotonin (DRN-5-HT) system during stress and this may underlie affective and cognitive dysfunctions that characterize stress-related psychiatric disorders. CRF acts on both CRF1 and CRF2 receptor subtypes in the DRN that exert opposing inhibitory and excitatory effects on DRN-5-HT neuronal activity and 5-HT forebrain release, respectively. The current study first assessed the cognitive effects of intra-DRN microinfusion of CRF or the selective CRF2 agonist, urocortin II in stress-naive rats on performance of an operant strategy set-shifting task that is mediated by the medial prefrontal cortex (mPFC). CRF (30 ng) facilitated strategy set-shifting performance, whereas higher doses of CRF and urocortin II that would interact with CRF2 were without effect, consistent with a CRF1-mediated action. This dose decreased 5-HT extracellular levels in the mPFC, further supporting a role for CRF1. The effects of CRF were then assessed in rats exposed to repeated social stress using the resident-intruder model. Repeated social stress shifted the CRF effect from facilitation of strategy set shifting to facilitation of reversal learning and this was most prominent in a subpopulation of rats that resist defeat. Notably, in this subpopulation of rats 5-HT neuronal responses to CRF have been demonstrated to shift from CRF1-mediated inhibition to CRF2-mediated excitation. Because 5-HT facilitates reversal learning, the present results suggest that stress-induced changes in the cellular effects of CRF in the DRN translate to changes in cognitive effects of CRF. Together, the results underscore the potential for stress history to shift cognitive processing through changes in CRF neurotransmission in the DRN and the association of this effect with coping strategy.

  7. Effects of cocaine history on postsynaptic GABA receptors on dorsal raphe serotonin neurons in a stress-induced relapse model in rats.

    Science.gov (United States)

    Li, Chen; Kirby, Lynn G

    2016-01-01

    The serotonin (5-hydroxytryptamine, 5-HT) system plays an important role in stress-related psychiatric disorders and substance abuse. Stressors and stress hormones can inhibit the dorsal raphe nucleus (DRN)-5-HT system, which composes the majority of forebrain-projecting 5-HT. This inhibition is mediated via stimulation of GABA synaptic activity at DRN-5-HT neurons. Using swim stress-induced reinstatement of morphine conditioned place-preference, recent data from our laboratory indicate that morphine history sensitizes DRN-5-HT neurons to GABAergic inhibitory effects of stress. Moreover, GABAA receptor-mediated inhibition of the serotonergic DRN is required for this reinstatement. In our current experiment, we tested the hypothesis that GABAergic sensitization of DRN-5-HT neurons is a neuroadaptation elicited by multiple classes of abused drugs across multiple models of stress-induced relapse by applying a chemical stressor (yohimbine) to induce reinstatement of previously extinguished cocaine self-administration in Sprague-Dawley rats. Whole-cell patch-clamp recordings of GABA synaptic activity in DRN-5-HT neurons were conducted after the reinstatement. Behavioral data indicate that yohimbine triggered reinstatement of cocaine self-administration. Electrophysiology data indicate that 5-HT neurons in the cocaine group exposed to yohimbine had increased amplitude of inhibitory postsynaptic currents compared to yoked-saline controls exposed to yohimbine or unstressed animals in both drug groups. These data, together with previous findings, indicate that interaction between psychostimulant or opioid history and chemical or physical stressors may increase postsynaptic GABA receptor density and/or sensitivity in DRN-5-HT neurons. Such mechanisms may result in serotonergic hypofunction and consequent dysphoric mood states which confer vulnerability to stress-induced drug reinstatement. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  8. Excitatory amino acid receptor blockade within the caudal pressor area and rostral ventrolateral medulla alters cardiovascular responses to nucleus raphe obscurus stimulation in rats

    Directory of Open Access Journals (Sweden)

    Silva N.F.

    2002-01-01

    Full Text Available Pressor responses elicited by stimulation of the nucleus raphe obscurus (NRO depend on the integrity of the rostral ventrolateral medulla (RVLM. Therefore, to test the participation of excitatory amino acid (EAA receptors in the cardiovascular responses evoked by NRO stimulation (1 ms, 100 Hz, 40-70 µA, for 10 s, the EAA antagonist kynurenic acid (Kyn was microinjected at different sites in the ventrolateral medullar surface (2.7 nmol/200 nl of male Wistar rats (270-320 g, N = 39 and NRO stimulation was repeated. The effects of NRO stimulation were: hypertension (deltaMAP = +43 ± 1 mmHg, P<0.01, bradycardia (deltaHR = -30 ± 7 bpm, P<0.01 and apnea. Bilateral microinjection of Kyn into the RVLM, which did not change baseline parameters, almost abolished the bradycardia induced by NRO stimulation (deltaHR = -61 ± 3 before vs -2 ± 3 bpm after Kyn, P<0.01, N = 7. Unilateral microinjection of Kyn into the CVLM did not change baseline parameters or reduce the pressor response to NRO stimulation (deltaMAP = +46 ± 5 before vs +48 ± 5 mmHg after Kyn, N = 6. Kyn bilaterally microinjected into the caudal pressor area reduced blood pressure and heart rate and almost abolished the pressor response to NRO stimulation (deltaMAP = +46 ± 4 mmHg before vs +4 ± 2 mmHg after Kyn, P<0.01, N = 7. These results indicate that EAA receptors on the medullary ventrolateral surface play a role in the modulation of the cardiovascular responses induced by NRO stimulation, and also suggest that the RVLM participates in the modulation of heart rate responses and that the caudal pressor area modulates the pressor response following NRO stimulation.

  9. Role of glutamatergic receptors located in the nucleus raphe magnus on antinociceptive effect of morphine microinjected into the nucleus cuneiformis of rat.

    Science.gov (United States)

    Haghparast, Abbas; Soltani-Hekmat, Ava; Khani, Abbas; Komaki, Alireza

    2007-10-29

    Neurons in the nucleus cuneiformis (CnF), located just ventrolateral to the periaqueductal gray, project to medullary nucleus raphe magnus (NRM), which is a key medullary relay for descending pain modulation and is critically involved in opioid-induced analgesia. Previous studies have shown that antinociceptive response of CnF-microinjected morphine can be modulated by the specific subtypes of glutamatergic receptors within the CnF. In this study, we evaluated the role of NMDA and kainate/AMPA receptors that are widely distributed within the NRM on morphine-induced antinociception elicited from the CnF. Hundred and five male Wistar rats weighing 250-300 g were used. Morphine (10, 20 and 40 microg) and NMDA receptor antagonist, MK-801 (10 microg) or kainate/AMPA receptor antagonist, DNQX (0.5 microg) in 0.5 microl saline were stereotaxically microinjected into the CnF and NRM, respectively. The latency of tail-flick response was measured at set intervals (2, 7, 12, 17, 22, 27 min after microinjection) by using an automated tail-flick analgesiometer. The results showed that morphine microinjection into the CnF dose-dependently causes increase in tail-flick latency (TFL). MK-801 microinjected into the NRM, just 1 min before morphine injection into the CnF, significantly attenuated antinociceptive effects of morphine. On the other hand, DNQX microinjected into the NRM, significantly increased TFL after local application of morphine into the CnF. We suggest that morphine related antinociceptive effect elicited from the CnF is mediated, in part, by NMDA receptor at the level of the NRM whereas kainite/AMPA receptor has a net inhibitory influence at the same pathway.

  10. Tolerance to non-opioid analgesics is opioid-sensitive in nucleus raphe magnus

    Directory of Open Access Journals (Sweden)

    Merab G Tsagareli

    2011-07-01

    Full Text Available Repeated injection of opioid analgesics can lead to a progressive loss of its effect. This phenomenon is known as tolerance. Several lines of investigations have shown that systemic, intraperitoneal administration or the microinjection of non-opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs in the midbrain periaqueductal gray matter induces antinociception with some effects of tolerance. Our recent study has revealed that microinjection of three drugs analgin, ketorolac and xefocam into the central nucleus of amygdala produce tolerance to them and cross-tolerance to morphine. Here we report that repeated administrations of these NSAIDs into the nucleus raphe magnus (NRM in the following four days result in progressively less antinociception, i.e. produce the development of tolerance to these drugs in mail rats. Special control experiments showed that post-treatment with μ-opioid antagonist naloxone in NRM significantly decreased antinociceptive effects of NSAIDs at the first day in behavioral tail flick reflex (TF and hot plate (HP latencies. At the second day, naloxone generally had trend effects in both TF and HP tests impeded the development of tolerance to the antinociceptive effect of non-opioid analgesics. These findings strongly support the suggestion on endogenous opioid involvement in NSAIDs antinociception and tolerance in the descending pain control system. Moreover, repeated injections of NSAIDs progressively lead to tolerance to them, cross-tolerance to morphine and the risk of a withdrawal syndrome. Therefore, these results are important for human medicine too.

  11. [Effect of manual acupuncture stimulation of "Zusanli" (ST 36) on gastric motility, and SP and motilin activities in gastric antrum and nucleus raphe magnus in gastric hyperactivity and hypoactivity rats].

    Science.gov (United States)

    Yan, Chun-Chuan; Peng, Yan; Lin, Ya-Ping; Yi, Shou-Xiang; Chen, Ping; Hou, Yan-Ling; Shi, Dong-Mei

    2013-10-01

    To observe the changes of gastric motility and levels of substance P (SP) and motilin (MTL) in the gastric antrum and Nucleus Raphe Magnus (NRM) after manual acupuncture stimulation of "Zusanli" (ST 36) in gastric hyperactivity and hypoactivity rats, so as to analyze the role of NRM in acupuncture mediated adjustment of gastric motility. Fifty SD rats were randomly and equally divided into control, gastric hyperactivity (G-Hypera) model, gastric hypoactivity (G-Hypoa) model, acupuncture + G-Hypera and acupuncture + G-Hypoa groups (10 rats/group). G-Hypera model was established by intravenous (tail vein) injection of Maxolon (0.5 mL/200 g) and G-Hypoa model established by intravenous injection of Atropin (0.5 mL/200 g), respectively. After insertion of acupuncture needles into bilateral "Zusanli" (ST 36), the needles were repeatedly manipulated at a frequency of about 2 Hz for 5 min. The intragastric pressure was recorded and analyzed using a physiological signal analysis system. The SP and MTL contents of gastric antrum were measured by ELISA, and SP and MTL immunoactivity of NRM was determined by immunohistochemistry. In gastric hyperactivity rats, compared with the control group, the intragastric pressure (not systolic frequency), SP and MTL contents in the gastric antrum and MTL immunoactivity of NRM were significantly increased (P effect on gastric motility, which is closely associated with its functions in regulating gastric SP and MTL level and the expression of MTL and SP in the NRM of brainstem.

  12. Lipopolysaccharide-induced dopaminergic cell death in rat midbrain slice cultures: role of inducible nitric oxide synthase and protection by indomethacin.

    Science.gov (United States)

    Shibata, Haruki; Katsuki, Hiroshi; Nishiwaki, Mayumi; Kume, Toshiaki; Kaneko, Shuji; Akaike, Akinori

    2003-09-01

    Glial cell activation associated with inflammatory reaction may contribute to pathogenic processes of neurodegenerative disorders, through production of several cytotoxic molecules. We investigated the consequences of glial activation by interferon-gamma (IFN-gamma)/lipopolysaccharide (LPS) in rat midbrain slice cultures. Application of IFN-gamma followed by LPS caused dopaminergic cell death and accompanying increases in nitrite production and lactate dehydrogenase release. Aminoguanidine, an inhibitor of inducible nitric oxide synthase (iNOS), or SB203580, an inhibitor of p38 mitogen-activated protein kinase, prevented dopaminergic cell loss as well as nitrite production. SB203580 also suppressed expression of iNOS and cyclooxygenase-2 (COX-2) induced by IFN-gamma/LPS. A COX inhibitor indomethacin protected dopaminergic neurons from IFN-gamma/LPS-induced injury, whereas selective COX-2 inhibitors such as NS-398 and nimesulide did not. Notably, indomethacin was able to attenuate neurotoxicity of a nitric oxide (NO) donor. Neutralizing antibodies against tumour necrosis factor-alpha and interleukin-1beta did not inhibit dopaminergic cell death caused by IFN-gamma/LPS, although combined application of these antibodies blocked lactate dehydrogenase release and decrease in the number of non-dopaminergic neurons. These results indicate that iNOS-derived NO plays a crucial role in IFN-gamma/LPS-induced dopaminergic cell death, and that indomethacin exerts protective effect by mechanisms probably related to NO neurotoxicity rather than through COX inhibition.

  13. The effect of exercise frequency on neuropathic pain and pain-related cellular reactions in the spinal cord and midbrain in a rat sciatic nerve injury model

    Directory of Open Access Journals (Sweden)

    Sumizono M

    2018-02-01

    Full Text Available Megumi Sumizono,1,2 Harutoshi Sakakima,1 Shotaro Otsuka,1 Takuto Terashi,1 Kazuki Nakanishi,1,2 Koki Ueda,1,2 Seiya Takada,1,2 Kiyoshi Kikuchi3 1Course of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima University, Kagoshima, Japan; 2Kirishima Orthopedics, Kirishima, Japan; 3Division of Brain Science, Department of Physiology, Kurume University School of Medicine, Kurume, Japan Background: Exercise regimens are established methods that can relieve neuropathic pain. However, the relationship between frequency and intensity of exercise and multiple cellular responses of exercise-induced alleviation of neuropathic pain is still unclear. We examined the influence of exercise frequency on neuropathic pain and the intracellular responses in a sciatic nerve chronic constriction injury (CCI model. Materials and methods: Rats were assigned to four groups as follows: CCI and high-frequency exercise (HFE group, CCI and low-frequency exercise (LFE group, CCI and no exercise (No-Ex group, and naive animals (control group. Rats ran on a treadmill, at a speed of 20 m/min, for 30 min, for 5 (HFE or 3 (LFE days a week, for a total of 5 weeks. The 50% withdrawal threshold was evaluated for mechanical sensitivity. The activation of glial cells (microglia and astrocytes, expression of brain-derived neurotrophic factor (BDNF and μ-opioid receptor in the spinal dorsal horn and endogenous opioid in the midbrain were examined using immunohistochemistry. Opioid receptor antagonists (naloxone were administered using intraperitoneal injection. Results: The development of neuropathic pain was related to the activation of glial cells, increased BDNF expression, and downregulation of the μ-opioid receptor in the ipsilateral spinal dorsal horn. In the No-Ex group, neuropathic pain showed the highest level of mechanical hypersensitivity at 2 weeks, which improved slightly until 5 weeks after CCI. In both exercise groups, the alleviation of

  14. Retraction: Borroto-Escuela et al., The existence of FGFR1-5-HT1A receptor heterocomplexes in midbrain 5-HT neurons of the rat: relevance for neuroplasticity.

    Science.gov (United States)

    2013-07-10

    The Journal of Neuroscience has received a report describing an investigation by the Karolinska Institutet, which found substantial data misrepresentation in the article "The Existence of FGFR1-5-HT1A Receptor Heterocomplexes in Midbrain 5-HT Neurons of the Rat: Relevance for Neuroplasticity" by Dasiel O. Borroto-Escuela, Wilber Romero-Fernandez, Mileidys Pérez-Alea, Manuel Narvaez, Alexander O. Tarakanov, Giuseppa Mudó , Luigi F. Agnati, Francisco Ciruela, Natale Belluardo, and Kjell Fuxe, which appeared on pages 6295-6303 of the May 2, 2012 issue. Because the results cannot be considered reliable, the editors of The Journal are retracting the paper.

  15. PROJECTIONS OF DORSAL AND MEDIAN RAPHE NUCLEI TO DORSAL AND VENTRAL STRIATUM

    Directory of Open Access Journals (Sweden)

    G. R. Hassanzadeh G. Behzadi

    2007-08-01

    Full Text Available The ascending serotonergic projections are derived mainly from mesencephalic raphe nuclei. Topographical projections from mesencephalic raphe nuclei to the striatum were examined in the rat by the retrograde transport technique of HRP (horseradish peroxidase. In 29 rats stereotaxically injection of HRP enzyme were performed in dorsal and ventral parts of striatum separately. The extent of the injection sites and distribution of retrogradely labeled neuronal cell bodies were drawed on representative sections using a projection microscope. Following ipsilateral injection of HRP into the dorsal striatum, numerous labeled neurons were seen in rostral portion of dorsal raphe (DR nucleus. In the same level the cluster of labeled neurons were hevier through caudal parts of DR. A few neurons were also located in lateral wing of DR. More caudally some labeled neurons were found in lateral, medial line of DR. In median raphe nucleus (MnR the labeled neurons were scattered only in median portion of this nucleus. The ipsilateral injection of HRP into the ventral region of striatum resulted on labeling of numerous neurons in rostral, caudal and lateral portions of DR. Through the caudal extension of DR on 4th ventricle level, a large number of labeled neurons were distributed along the ventrocaudal parts of DR. In MnR, labeled neurons were observed only in median part of this nucleus. These findings suggest the mesencephalic raphe nuclei projections to caudo-putamen are topographically organized. In addition dorsal and median raphe nuclei have a stronger projection to the ventral striatum.

  16. Tolerance to Non-Opioid Analgesics is Opioid Sensitive in the Nucleus Raphe Magnus.

    Science.gov (United States)

    Tsagareli, Merab G; Nozadze, Ivliane; Tsiklauri, Nana; Gurtskaia, Gulnaz

    2011-01-01

    Repeated injection of opioid analgesics can lead to a progressive loss of effect. This phenomenon is known as tolerance. Several lines of investigations have shown that systemic, intraperitoneal administration or the microinjection of non-opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) into the midbrain periaqueductal gray matter induces antinociception with some effects of tolerance. Our recent study has revealed that microinjection of three drugs analgin, ketorolac, and xefocam into the central nucleus of amygdala produce tolerance to them and cross-tolerance to morphine. Here we report that repeated administrations of these NSAIDs into the nucleus raphe magnus (NRM) in the following 4 days result in progressively less antinociception compare to the saline control, i.e., tolerance develops to these drugs in male rats. Special control experiments showed that post-treatment with the μ-opioid antagonist naloxone into the NRM significantly decreased antinociceptive effects of NSAIDs on the first day of testing in the tail-flick (TF) reflex and hot plate (HP) latency tests. On the second day, naloxone generally had trend effects in both TF and HP tests and impeded the development of tolerance to the antinociceptive effect of non-opioid analgesics. These findings strongly support the suggestion of endogenous opioid involvement in NSAIDs antinociception and tolerance in the descending pain-control system. Moreover, repeated injections of NSAIDs progressively lead to tolerance to them, cross-tolerance to morphine, and the risk of a withdrawal syndrome. Therefore, these results are important for human medicine too.

  17. Physical Interactions and Functional Relationships of Neuroligin 2 and Midbrain Serotonin Transporters

    Directory of Open Access Journals (Sweden)

    Ran eYe

    2016-01-01

    Full Text Available The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT modulates many key brain functions including those subserving sensation, emotion, reward and cognition. Efficient clearance of 5-HT after release is achieved by the antidepressant-sensitive 5-HT transporter (SERT, SLC6A4. To identify novel SERT regulators, we pursued a proteomic analysis of mouse midbrain SERT complexes, evaluating findings in the context of prior studies that established a SERT-linked transcriptome. Remarkably, both efforts converged on a relationship of SERT with the synaptic adhesion protein neuroligin 2 (NLGN2, a postsynaptic partner for presynaptic neurexins, and a protein well known to organize inhibitory GABAergic synapses. Western blots of midbrain reciprocal immunoprecipitations confirmed SERT/NLGN2 associations, and also extended to other NLGN2 associated proteins (e.g. -neurexin (NRXN, gephyrin. Midbrain SERT/NLGN2 interactions were found to be Ca2+-independent, supporting cis versus trans-synaptic interactions, and were absent in hippocampal preparations, consistent with interactions arising in somatodendritic compartments. Dual color in situ hybridization confirmed co-expression of Tph2 and Nlgn2 mRNA in the dorsal raphe, with immunocytochemical studies confirming SERT:NLGN2 co-localization in raphe cell bodies but not axons. Consistent with correlative mRNA expression studies, loss of NLGN2 expression in Nlgn2 null mice produced significant reductions in midbrain and hippocampal SERT expression and function. Additionally, dorsal raphe 5-HT neurons from Nlgn2 null mice exhibit reduced excitability, a loss of GABAA receptor-mediated IPSCs, and increased 5-HT1A autoreceptor sensitivity. Finally, Nlgn2 null mice display significant changes in behaviors known to be responsive to SERT and/or 5-HT receptor manipulations. We discuss our findings in relation to the possible coordination of intrinsic and extrinsic regulation afforded by somatodendritic SERT:NLGN2

  18. Focal midbrain tumors in children

    NARCIS (Netherlands)

    Vandertop, W. P.; Hoffman, H. J.; Drake, J. M.; Humphreys, R. P.; Rutka, J. T.; Amstrong, D. C.; Becker, L. E.

    1992-01-01

    The clinical and neuroradiological features of focal midbrain tumors in 12 children are described, and the results of their surgical management are presented. Patients with a focal midbrain tumor usually exhibit either symptoms and signs of raised intracranial pressure caused by an obstructive

  19. Anxiogenic drug administration and elevated plus-maze exposure in rats activate populations of relaxin-3 neurons in the nucleus incertus and serotonergic neurons in the dorsal raphe nucleus.

    Science.gov (United States)

    Lawther, A J; Clissold, M L; Ma, S; Kent, S; Lowry, C A; Gundlach, A L; Hale, M W

    2015-09-10

    Anxiety is a complex and adaptive emotional state controlled by a distributed and interconnected network of brain regions, and disruption of these networks is thought to give rise to the behavioral symptoms associated with anxiety disorders in humans. The dorsal raphe nucleus (DR), which contains the majority of forebrain-projecting serotonergic neurons, is implicated in the control of anxiety states and anxiety-related behavior via neuromodulatory effects on these networks. Relaxin-3 is the native neuropeptide ligand for the Gi/o-protein-coupled receptor, RXFP3, and is primarily expressed in the nucleus incertus (NI), a tegmental region immediately caudal to the DR. RXFP3 activation has been shown to modulate anxiety-related behavior in rodents, and RXFP3 mRNA is expressed in the DR. In this study, we examined the response of relaxin-3-containing neurons in the NI and serotonergic neurons in the DR following pharmacologically induced anxiety and exposure to an aversive environment. We administered the anxiogenic drug FG-7142 or vehicle to adult male Wistar rats and, 30 min later, exposed them to either the elevated plus-maze or home cage control conditions. Immunohistochemical detection of c-Fos was used to determine activation of serotonergic neurons in the DR and relaxin-3 neurons in the NI, measured 2h following drug injection. Analysis revealed that FG-7142 administration and exposure to the elevated plus-maze are both associated with an increase in c-Fos expression in relaxin-3-containing neurons in the NI and in serotonergic neurons in dorsal and ventrolateral regions of the DR. These data are consistent with the hypothesis that relaxin-3 systems in the NI and serotonin systems in the DR interact to form part of a network involved in the control of anxiety-related behavior. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  20. Do dorsal raphe 5-HT neurons encode "beneficialness"?

    Science.gov (United States)

    Luo, Minmin; Li, Yi; Zhong, Weixin

    2016-11-01

    The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) affects numerous behavioral and physiological processes. Drugs that alter 5-HT signaling treat several major psychiatric disorders and may lead to widespread abuse. The dorsal raphe nucleus (DRN) in the midbrain provides a majority of 5-HT for the forebrain. The importance of 5-HT signaling propels the search for a general theoretical framework under which the diverse functions of the DRN 5-HT neurons can be interpreted and additional therapeutic solutions may be developed. However, experimental data so far support several seeming irreconcilable theories, suggesting that 5-HT neurons mediate behavioral inhibition, aversive processing, or reward signaling. Here, we review recent progresses and propose that DRN 5-HT neurons encode "beneficialness" - how beneficial the current environmental context represents for an individual. Specifically, we speculate that the activity of these neurons reflects the possible net benefit of the current context as determined by p·R-C, in which p indicates reward probability, R the reward value, and C the cost. Through the widespread projections of these neurons to the forebrain, the beneficialness signal may reconfigure neural circuits to bias perception, boost positive emotions, and switch behavioral choices. The "beneficialness" hypothesis can explain many conflicting observations, and at the same time raises new questions. We suggest additional experiments that will help elucidate the exact computational functions of the DRN 5-HT neurons. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. MRI characteristics of midbrain tumours

    International Nuclear Information System (INIS)

    Sun, B.; Wang, C.C.; Wang, J.

    1999-01-01

    We diagnosed 60 cases of midbrain tumours by MRI between 1993 to 1997. There were 39 males and 21 females, aged 2-64 years, mean 25.6 years. We found 38 patients with true intramedullary midbrain tumours, 11 predominantly in the tectum, 20 in the tegmentum and 7 with a downward extension to the pons; there were 7 within the cerebral aqueduct. There were 22 patients with infiltrating midbrain tumours extending from adjacent structures, 11 cases each from the thalamus and pineal region. All patients received surgical treatment. Gross total resection was achieved in 42 cases, subtotal (> 75 %) resection in 18. Pathological diagnoses included 16 low-grade and 15 high-grade astrocytomas; 5 oligodendroastrocytomas; 2 ependymomas; 11 glioblastomas; and 11 pineal parenchymal or germ-cell tumours. Midbrain tumours are a heterogeneous group of neoplasms, with wide variation in clinical and MRI features, related to the site and type of tumour. MRI not only allows precise analysis of their growth pattern, but also can lead to a correct preoperative diagnosis in the majority of cases. (orig.) (orig.)

  2. Absence of lateral palpebral raphe in Caucasians

    Directory of Open Access Journals (Sweden)

    Lucy Goold

    2009-07-01

    Full Text Available Lucy Goold1, Hirohiko Kakizaki1,2,3, Raman Malhotra3, Dinesh Selva11South Australian Institute of Ophthalmology and Discipline of Ophthalmology and Visual Sciences, University of Adelaide, Australia; 2Department of Ophthalmology, Aichi Medical University, Nagakute, Aichi, Japan; 3Corneoplastic Unit and Eye Bank, Queen Victoria Hospital NHS Trust, East Grinstead, West Sussex, United KingdomAbstract: Classical anatomical teaching reports the presence of the lateral palpebral raphe formed at the union in the preseptal and orbital parts of the orbicularis oculi muscle, or by the tendon adhering these to the underlying zygomatic bone. The lateral palpebral raphe has been shown to be absent in Asian cadavers. The current study uses both evidence from the anatomical dissection of five eyelids from three Caucasian cadavers, and histological assessment of the lateral canthus of 13 eyelids from seven Caucasian cadavers to illustrate the absence of the lateral palpebral raphe in Caucasian population.Keywords: lateral palpebral raphe, orbicularis oculi muscle, Caucasian, cadavers

  3. Analgesia induced by morphine microinjected into the nucleus raphe magnus: effects on tonic pain.

    Science.gov (United States)

    Dualé, Christian; Sierralta, Fernando; Dallel, Radhouane

    2007-07-01

    One of the possible sites of action of the analgesic effect of morphine is the Nucleus Raphe Magnus, as morphine injected into this structure induces analgesia in transient pain models. In order to test if morphine in the Nucleus Raphe Magnus is also analgesic in a tonic pain model, 5 microg of morphine or saline (control) were microinjected into the Nucleus Raphe Magnus of the rat. Analgesic effects were assessed following nociceptive stimulation using transient heating of the tail (phasic pain) and subcutaneous orofacial injection of 1.5 % formalin (tonic pain). While morphine was strongly analgesic for the tail-flick response (p <0.0001 compared to control), analgesia on the response to formalin was also observed for both early (p = 0.007) and late responses (p = 0.02). However, the response to formalin was not completely blunted. These results suggest that the Nucleus Raphe Magnus is not the exclusive site of action of morphine-induced analgesia in clinical conditions.

  4. Electrophysical properties, synaptic transmission and neuromodulation in serotonergic caudal raphe neurons.

    Science.gov (United States)

    Li, Y W; Bayliss, D A

    1998-06-01

    1. We studied electrophysiological properties, synaptic transmission and modulation by 5-hydroxytryptamine (5-HT) of caudal raphe neurons using whole-cell recording in a neonatal rat brain slice preparation; recorded neurons were identified as serotonergic by post-hoc immunohistochemical detection of tryptophan hydroxylase, the 5-HT-synthesizing enzyme. 2. Serotonergic neurons fired spontaneously (approximately 1 Hz), with maximal steady state firing rates of < 4 Hz. 5-Hydroxytryptamine caused hyperpolarization and cessation of spike activity in these neurons by activating inwardly rectifying K+ conductance via somatodendritic 5-HT1A receptors. 3. Unitary glutamatergic excitatory post-synaptic potentials (EPSP) and currents (EPSC) were evoked in serotonergic neurons by local electrical stimulation. Evoked EPSC were potently inhibited by 5-HT, an effect mediated by presynaptic 5-HT1B receptors. 4. In conclusion, serotonergic caudal raphe neurons are spontaneously active in vitro; they receive prominent glutamatergic synaptic inputs. 5-Hydroxytryptamine regulates serotonergic neuronal activity of the caudal raphe by decreasing spontaneous activity via somatodendritic 5-HT1A receptors and by inhibiting excitatory synaptic transmission onto these neurons via presynaptic 5-HT1B receptors. These local modulatory mechanisms provide multiple levels of feedback autoregulation of serotonergic raphe neurons by 5-HT.

  5. Isolated trochlear nerve palsy with midbrain hemorrhage

    Directory of Open Access Journals (Sweden)

    Raghavendra S

    2010-01-01

    Full Text Available Midbrain hemorrhage causing isolated fourth nerve palsy is extremely rare. Idiopathic, traumatic and congenital abnormalities are the most common causes of fourth nerve palsy. We report acute isolated fourth nerve palsy in an 18-year-old lady due to a midbrain hemorrhage probably due to a midbrain cavernoma. The case highlights the need for neuroimaging in selected cases of isolated trochlear nerve palsy.

  6. AAV-mediated gene transfer of the obesity-associated gene Etv5 in rat midbrain does not affect energy balance or motivated behavior.

    Directory of Open Access Journals (Sweden)

    Arjen J Boender

    Full Text Available Several genome-wide association studies have implicated the transcription factor E-twenty- six version 5 (Etv5 in the regulation of body mass index. Further substantiating the role of Etv5 in feeding behavior are the findings that targeted disruption of Etv5 in mice leads to decreased body weight gain and that expression of Etv5 is decreased in the ventral tegmental area and substantia nigra pars compacta (VTA/SNpc after food restriction. As Etv5 has been suggested to influence dopaminergic neurotransmission by driving the expression of genes that are responsible for the synthesis and release of dopamine, we investigated if expression levels of Etv5 are dependent on nutritional state and subsequently influence the expression levels of tyrosine hydroxylase. While it was shown that Etv5 expression in the VTA/SNpc increases after central administration of leptin and that Etv5 was able to drive expression of tyrosine hydroxylase in vitro, AAV-mediated gene transfer of Etv5 into the VTA/SNpc of rats did not alter expression of tyrosine hydroxylase in vivo. Moreover, AAV-mediated gene transfer of Etv5 in the VTA/SNpc did not affect measures of energy balance or performances in a progressive ratio schedule. Thus, these data do not support a role for increased expression of Etv5 in the VTA/SNpc in the regulation of feeding behavior.

  7. [Local GABA-ergic modulation of serotonergic neuron activity in the nucleus raphe magnus].

    Science.gov (United States)

    Iniushkin, A N; Merkulova, N A; Orlova, A O; Iniushkina, E M

    2009-07-01

    In voltage-clamp experimental on slices of the rat brainstem the effects of 5-HT and GABA on serotonergic neurons of nucleus raphe magnus were investigated. Local applications of 5-HT induced an increase in IPCSs frequency and amplitude in 45% of serotonergic cells. The effect suppressed by the blocker of fast sodium channels tetradotoxin. Antagonist of GABA receptor gabazine blocked IPSCs in neurons both sensitive and non-sensitive to 5-HT action. Applications of GABA induced a membrane current (I(GABA)), which was completely blocked by gabazine. The data suggest self-control of the activity of serotonergic neurons in nucleus raphe magnus by negative feedback loop via local GABAergic interneurons.

  8. Neuroglobin expression in the rat suprachiasmatic nucleus: colocalization, innervation, and response to light

    DEFF Research Database (Denmark)

    Hundahl, C A; Hannibal, J; Fahrenkrug, J

    2010-01-01

    Neuroglobin (Ngb) is a myoglobin-like (Mb) heme-globin, belonging the globin family located only in neuronal tissue of the central nervous system. Ngb has been shown to be upregulated in and to protect neurons from hypoxic and ischemic injury, but the function of Ngb-in particular how Ngb may...... protect neurons-remains largely elusive. We have previously described the localization of Ngb in the rat brain and found it to be expressed in areas primarily involved in sleep/wake, circadian, and food regulation. The present study was undertaken, using immunohistochemistry, to characterize......-containing cells received input from neuropeptide Y (NPY)-containing nerve fibers of the geniticulo-hypothalamic tract (GHT), whereas no direct input from the eye or the midbrain raphe system was demonstrated. The results indicate that the Ngb could be involved in both photic and nonphotic entrainment via input...

  9. Activity of Raphé Serotonergic Neurons Controls Emotional Behaviors

    Directory of Open Access Journals (Sweden)

    Anne Teissier

    2015-12-01

    Full Text Available Despite the well-established role of serotonin signaling in mood regulation, causal relationships between serotonergic neuronal activity and behavior remain poorly understood. Using a pharmacogenetic approach, we find that selectively increasing serotonergic neuronal activity in wild-type mice is anxiogenic and reduces floating in the forced-swim test, whereas inhibition has no effect on the same measures. In a developmental mouse model of altered emotional behavior, increased anxiety and depression-like behaviors correlate with reduced dorsal raphé and increased median raphé serotonergic activity. These mice display blunted responses to serotonergic stimulation and behavioral rescues through serotonergic inhibition. Furthermore, we identify opposing consequences of dorsal versus median raphé serotonergic neuron inhibition on floating behavior, together suggesting that median raphé hyperactivity increases anxiety, whereas a low dorsal/median raphé serotonergic activity ratio increases depression-like behavior. Thus, we find a critical role of serotonergic neuronal activity in emotional regulation and uncover opposing roles of median and dorsal raphé function.

  10. Activity of Raphé Serotonergic Neurons Controls Emotional Behaviors.

    Science.gov (United States)

    Teissier, Anne; Chemiakine, Alexei; Inbar, Benjamin; Bagchi, Sneha; Ray, Russell S; Palmiter, Richard D; Dymecki, Susan M; Moore, Holly; Ansorge, Mark S

    2015-12-01

    Despite the well-established role of serotonin signaling in mood regulation, causal relationships between serotonergic neuronal activity and behavior remain poorly understood. Using a pharmacogenetic approach, we find that selectively increasing serotonergic neuronal activity in wild-type mice is anxiogenic and reduces floating in the forced-swim test, whereas inhibition has no effect on the same measures. In a developmental mouse model of altered emotional behavior, increased anxiety and depression-like behaviors correlate with reduced dorsal raphé and increased median raphé serotonergic activity. These mice display blunted responses to serotonergic stimulation and behavioral rescues through serotonergic inhibition. Furthermore, we identify opposing consequences of dorsal versus median raphé serotonergic neuron inhibition on floating behavior, together suggesting that median raphé hyperactivity increases anxiety, whereas a low dorsal/median raphé serotonergic activity ratio increases depression-like behavior. Thus, we find a critical role of serotonergic neuronal activity in emotional regulation and uncover opposing roles of median and dorsal raphé function. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  11. Prognostic Implications of Raphe in Bicuspid Aortic Valve Anatomy.

    Science.gov (United States)

    Kong, William K F; Delgado, Victoria; Poh, Kian Keong; Regeer, Madelien V; Ng, Arnold C T; McCormack, Louise; Yeo, Tiong Cheng; Shanks, Miriam; Parent, Sarah; Enache, Roxana; Popescu, Bogdan A; Liang, Michael; Yip, James W; Ma, Lawrence C W; Kamperidis, Vasileios; van Rosendael, Philippe J; van der Velde, Enno T; Ajmone Marsan, Nina; Bax, Jeroen J

    2017-03-01

    Little is known about the association between bicuspid aortic valve (BAV) morphologic findings and the degree of valvular dysfunction, presence of aortopathy, and complications, including aortic valve surgery, aortic dissection, and all-cause mortality. To investigate the association between BAV morphologic findings (raphe vs nonraphe) and the degree of valve dysfunction, presence of aortopathy, and prognosis (including need for aortic valve surgery, aortic dissection, and all-cause mortality). In this large international multicenter registry of patients with BAV treated at tertiary referral centers, 2118 patients with BAV were evaluated. Patients referred for echocardiography from June 1, 1991, through November 31, 2015, were included in the study. Clinical and echocardiographic data were analyzed retrospectively. The morphologic BAV findings were categorized according to the Sievers and Schmidtke classification. Aortic valve function was divided into normal, regurgitation, or stenosis. Patterns of BAV aortopathy included the following: type 1, dilation of the ascending aorta and aortic root; type 2, isolated dilation of the ascending aorta; and type 3, isolated dilation of the sinus of Valsalva and/or sinotubular junction. Association between the presence and location of raphe and the risk of significant (moderate and severe) aortic valve dysfunction and aortic dilation and/or dissection. Of the 2118 patients (mean [SD] age, 47 [18] years; 1525 [72.0%] male), 1881 (88.8%) had BAV with fusion raphe, whereas 237 (11.2%) had BAV without raphe. Bicuspid aortic valves with raphe had a significantly higher prevalence of valve dysfunction, with a significantly higher frequency of aortic regurgitation (622 [33.1%] vs 57 [24.1%], P < .001) and aortic stenosis (728 [38.7%] vs 51 [21.5%], P < .001). Furthermore, aortic valve replacement event rates were significantly higher among patients with BAV with raphe (364 [19.9%] at 1 year, 393 [21.4%] at 2 years, and 447

  12. Pathological Laughter as a Symptom of Midbrain Infarction

    Science.gov (United States)

    Dabby, Ron; Watemberg, Nathan; Lampl, Yair; Eilam, Anda; Rapaport, Abraham; Sadeh, Menachem

    2004-01-01

    Pathological laughter is an uncommon symptom usually caused by bilateral, diffuse cerebral lesions. It has rarely been reported in association with isolated cerebral lesions. Midbrain involvement causing pathological laughter is extremely unusual. We describe three patients who developed pathological laughter after midbrain and pontine-midbrain infarction. In two patients a small infarction in the left paramedian midbrain was detected, whereas the third one sustained a massive bilateral pontine infarction extending to the midbrain. Laughter heralded stroke by one day in one patient and occurred as a delayed phenomenon three months after stroke in another. Pathological laughter ceased within a few days in two patients and was still present at a two year follow-up in the patient with delayed-onset laughter. Pathological laughter can herald midbrain infarction or follow stroke either shortly after onset of symptoms or as a delayed phenomenon. Furthermore, small unilateral midbrain infarctions can cause this rare complication. PMID:15706050

  13. Effects of obesogenic diet and estradiol on dorsal raphe gene expression in old female macaques.

    Directory of Open Access Journals (Sweden)

    Cynthia L Bethea

    Full Text Available The beneficial effects of bioidentical ovarian steroid hormone therapy (HT during the perimenopause are gaining recognition. However, the positive effects of estrogen (E plus or minus progesterone (P administration to ovariectomized (Ovx lab animals were recognized in multiple systems for years before clinical trials could adequately duplicate the results. Moreover, very large numbers of women are often needed to find statistically significant results in clinical trials of HT; and there are still opposing results being published, especially in neural and cardiovascular systems. One of the obvious differences between human and animal studies is diet. Laboratory animals are fed a diet that is low in fat and refined sugar, but high in micronutrients. In the US, a large portion of the population eats what is known as a "western style diet" or WSD that provides calories from 36% fat, 44% carbohydrates (includes 18.5% sugars and 18% protein. Unfortunately, obesity and diabetes have reached epidemic proportions and the percentage of obese women in clinical trials may be overlooked. We questioned whether WSD and obesity could decrease the positive neural effects of estradiol (E in the serotonin system of old macaques that were surgically menopausal. Old ovo-hysterectomized female monkeys were fed WSD for 2.5 years, and treated with placebo, Immediate E (ImE or Delayed E (DE. Compared to old Ovx macaques on primate chow and treated with placebo or E, the WSD-fed monkeys exhibited greater individual variance and blunted responses to E-treatment in the expression of genes related to serotonin neurotransmission, CRH components in the midbrain, synapse assembly, DNA repair, protein folding, ubiquitylation, transport and neurodegeneration. For many of the genes examined, transcript abundance was lower in WSD-fed than chow-fed monkeys. In summary, an obesogenic diet for 2.5 years in old surgically menopausal macaques blunted or increased variability in E

  14. The Effect of Short Moderate Stress on the Midbrain CRF System in a Macaque Model of Functional Hypothalamic Amenorrhea

    Science.gov (United States)

    Bethea, Cynthia L; Phu, Kenny; Reddy, Arubala P; Cameron, Judy L

    2014-01-01

    Objective To study the effect of moderate stress on CRF components in the serotonergic midbrain region in a monkey model of FHA. Design After characterization of stress sensitivity, monkeys were moved to a novel room and given 20% less chow for 5 days prior to euthanasia. Setting University of Pittsburgh nonhuman primate facility. Animals Female cynomolgus macaques (Macaca fascicularis) characterized as highly stress resilient (HSR, n=5), medium stress resilient (MSR, N=4) or stress sensitive (SS, n=4). Intervention 5 days of diet in a novel room with unfamiliar conspecifics. Main Outcome Measures Density of CRF axons in the serotonergic dorsal raphe nucleus; the number of UCN1 cells; the density of UCN1 axons; the expression of CRF-R1 and CRF-R2 in the dorsal raphe nucleus. Results CRF innervation was higher in HSR than SS animals; UCN1 cell number was higher in HSR than SS animals and UCN1 axon bouton density was not different, all opposite of non-stressed animals. CRF-R1 was not different between the sensitivity groups, but CRF-R2 was higher in HSR than SS animals. The relative expression of CRF-R1 and R2 was similar to non-stressed animals. Conclusions HSR animals respond to stress with an increase in CRF delivery to serotonin neurons. With stress, UCN1 transport decreases in HSR animals. CRF receptor expression was similar with or without stress. These changes may contribute to resilience in HSR animals. PMID:23849846

  15. Development of raphe serotonin neurons from specification to guidance.

    Science.gov (United States)

    Kiyasova, Vera; Gaspar, Patricia

    2011-11-01

    The main features of the development of the serotonin (5-HT) raphe neurons have been known for many years but more recent molecular studies, using mouse genetics, have since unveiled several intriguing aspects of the specification of the raphe serotonergic system. These studies indicated that, although all 5-HT neurons in the raphe follow the same general program for their specification, there are also clear regional differences in the way that these neurons are specified and are guided towards different brain targets. Here we overview recent progress made in the understanding of the developmental programming of serotonergic neurons in the mouse raphe, emphasizing data showing how heterogeneous subsets of 5-HT neurons may be generated. Serotonergic progenitors are produced in the brainstem in different rhombomeres under the influence of a set of secreted factors, sonic hedgehog and fibroblast growth factors, which determine their position in the neural tube. Two main transcriptional gene networks are involved in the specification of 5-HT identity, with Lmx1b and Pet1 transcription factors as main players. A differential requirement for Pet1 was, however, revealed, which underlies an anatomical and functional diversity. Transcriptional programs controlling 5-HT identity could also impact axon guidance mechanisms directing 5-HT neurons to their targets. Although no direct links have yet been established, a large set of molecular determinants have already been shown to be involved in the growth, axon guidance and targeting of 5-HT raphe neurons, particularly within the forebrain. Alterations in the molecular mechanisms involved in 5-HT development are likely to have significant roles in mood disease predisposition. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  16. A Neural Correlate of Predicted and Actual Reward-Value Information in Monkey Pedunculopontine Tegmental and Dorsal Raphe Nucleus during Saccade Tasks

    Science.gov (United States)

    Okada, Ken-ichi; Nakamura, Kae; Kobayashi, Yasushi

    2011-01-01

    Dopamine, acetylcholine, and serotonin, the main modulators of the central nervous system, have been proposed to play important roles in the execution of movement, control of several forms of attentional behavior, and reinforcement learning. While the response pattern of midbrain dopaminergic neurons and its specific role in reinforcement learning have been revealed, the role of the other neuromodulators remains rather elusive. Here, we review our recent studies using extracellular recording from neurons in the pedunculopontine tegmental nucleus, where many cholinergic neurons exist, and the dorsal raphe nucleus, where many serotonergic neurons exist, while monkeys performed eye movement tasks to obtain different reward values. The firing patterns of these neurons are often tonic throughout the task period, while dopaminergic neurons exhibited a phasic activity pattern to the task event. The different modulation patterns, together with the activity of dopaminergic neurons, reveal dynamic information processing between these different neuromodulator systems. PMID:22013541

  17. Optogenetic activation of dorsal raphe serotonin neurons enhances patience for future rewards.

    Science.gov (United States)

    Miyazaki, Kayoko W; Miyazaki, Katsuhiko; Tanaka, Kenji F; Yamanaka, Akihiro; Takahashi, Aki; Tabuchi, Sawako; Doya, Kenji

    2014-09-08

    Serotonin is a neuromodulator that is involved extensively in behavioral, affective, and cognitive functions in the brain. Previous recording studies of the midbrain dorsal raphe nucleus (DRN) revealed that the activation of putative serotonin neurons correlates with the levels of behavioral arousal [1], rhythmic motor outputs [2], salient sensory stimuli [3-6], reward, and conditioned cues [5-8]. The classic theory on serotonin states that it opposes dopamine and inhibits behaviors when aversive events are predicted [9-14]. However, the therapeutic effects of serotonin signal-enhancing medications have been difficult to reconcile with this theory [15, 16]. In contrast, a more recent theory states that serotonin facilitates long-term optimal behaviors and suppresses impulsive behaviors [17-21]. To test these theories, we developed optogenetic mice that selectively express channelrhodopsin in serotonin neurons and tested how the activation of serotonergic neurons in the DRN affects animal behavior during a delayed reward task. The activation of serotonin neurons reduced the premature cessation of waiting for conditioned cues and food rewards. In reward omission trials, serotonin neuron stimulation prolonged the time animals spent waiting. This effect was observed specifically when the animal was engaged in deciding whether to keep waiting and was not due to motor inhibition. Control experiments showed that the prolonged waiting times observed with optogenetic stimulation were not due to behavioral inhibition or the reinforcing effects of serotonergic activation. These results show, for the first time, that the timed activation of serotonin neurons during waiting promotes animals' patience to wait for a delayed reward. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. Receptor⁻Receptor Interactions in Multiple 5-HT1A Heteroreceptor Complexes in Raphe-Hippocampal 5-HT Transmission and Their Relevance for Depression and Its Treatment.

    Science.gov (United States)

    Borroto-Escuela, Dasiel O; Narváez, Manuel; Ambrogini, Patrizia; Ferraro, Luca; Brito, Ismel; Romero-Fernandez, Wilber; Andrade-Talavera, Yuniesky; Flores-Burgess, Antonio; Millon, Carmelo; Gago, Belen; Narvaez, Jose Angel; Odagaki, Yuji; Palkovits, Miklos; Diaz-Cabiale, Zaida; Fuxe, Kjell

    2018-06-03

    Due to the binding to a number of proteins to the receptor protomers in receptor heteromers in the brain, the term "heteroreceptor complexes" was introduced. A number of serotonin 5-HT1A heteroreceptor complexes were recently found to be linked to the ascending 5-HT pathways known to have a significant role in depression. The 5-HT1A⁻FGFR1 heteroreceptor complexes were involved in synergistically enhancing neuroplasticity in the hippocampus and in the dorsal raphe 5-HT nerve cells. The 5-HT1A protomer significantly increased FGFR1 protomer signaling in wild-type rats. Disturbances in the 5-HT1A⁻FGFR1 heteroreceptor complexes in the raphe-hippocampal 5-HT system were found in a genetic rat model of depression (Flinders sensitive line (FSL) rats). Deficits in FSL rats were observed in the ability of combined FGFR1 and 5-HT1A agonist cotreatment to produce antidepressant-like effects. It may in part reflect a failure of FGFR1 treatment to uncouple the 5-HT1A postjunctional receptors and autoreceptors from the hippocampal and dorsal raphe GIRK channels, respectively. This may result in maintained inhibition of hippocampal pyramidal nerve cell and dorsal raphe 5-HT nerve cell firing. Also, 5-HT1A⁻5-HT2A isoreceptor complexes were recently demonstrated to exist in the hippocampus and limbic cortex. They may play a role in depression through an ability of 5-HT2A protomer signaling to inhibit the 5-HT1A protomer recognition and signaling. Finally, galanin (1⁻15) was reported to enhance the antidepressant effects of fluoxetine through the putative formation of GalR1⁻GalR2⁻5-HT1A heteroreceptor complexes. Taken together, these novel 5-HT1A receptor complexes offer new targets for treatment of depression.

  19. Receptor–Receptor Interactions in Multiple 5-HT1A Heteroreceptor Complexes in Raphe-Hippocampal 5-HT Transmission and Their Relevance for Depression and Its Treatment

    Directory of Open Access Journals (Sweden)

    Dasiel O. Borroto-Escuela

    2018-06-01

    Full Text Available Due to the binding to a number of proteins to the receptor protomers in receptor heteromers in the brain, the term “heteroreceptor complexes” was introduced. A number of serotonin 5-HT1A heteroreceptor complexes were recently found to be linked to the ascending 5-HT pathways known to have a significant role in depression. The 5-HT1A–FGFR1 heteroreceptor complexes were involved in synergistically enhancing neuroplasticity in the hippocampus and in the dorsal raphe 5-HT nerve cells. The 5-HT1A protomer significantly increased FGFR1 protomer signaling in wild-type rats. Disturbances in the 5-HT1A–FGFR1 heteroreceptor complexes in the raphe-hippocampal 5-HT system were found in a genetic rat model of depression (Flinders sensitive line (FSL rats. Deficits in FSL rats were observed in the ability of combined FGFR1 and 5-HT1A agonist cotreatment to produce antidepressant-like effects. It may in part reflect a failure of FGFR1 treatment to uncouple the 5-HT1A postjunctional receptors and autoreceptors from the hippocampal and dorsal raphe GIRK channels, respectively. This may result in maintained inhibition of hippocampal pyramidal nerve cell and dorsal raphe 5-HT nerve cell firing. Also, 5-HT1A–5-HT2A isoreceptor complexes were recently demonstrated to exist in the hippocampus and limbic cortex. They may play a role in depression through an ability of 5-HT2A protomer signaling to inhibit the 5-HT1A protomer recognition and signaling. Finally, galanin (1–15 was reported to enhance the antidepressant effects of fluoxetine through the putative formation of GalR1–GalR2–5-HT1A heteroreceptor complexes. Taken together, these novel 5-HT1A receptor complexes offer new targets for treatment of depression.

  20. A novel dopamine transporter transgenic mouse line for identification and purification of midbrain dopaminergic neurons reveals midbrain heterogeneity

    DEFF Research Database (Denmark)

    Christiansen, Mia Apuschkin; Stilling, Sara; Rahbek-Clemmensen, Troels

    2015-01-01

    Midbrain dopaminergic (DAergic) neurons are a heterogeneous cell group, composed of functionally distinct cell populations projecting to the basal ganglia, prefrontal cortex and limbic system. Despite their functional significance, the midbrain population of DAergic neurons is sparse, constituting...... of the dopamine transporter (DAT) promoter was characterized. Confocal microscopy analysis of brain sections showed strong eGFP signal reporter in midbrain regions and striatal terminals that co-localized with the DAergic markers DAT and tyrosine hydroxylase (TH). Thorough quantification of co...

  1. Midbrain morphology reflects extent of brain damage in Krabbe disease

    Energy Technology Data Exchange (ETDEWEB)

    Zuccoli, Giulio; Narayanan, Srikala; Panigrahy, Ashok [Children' s Hospital of Pittsburgh of University of Pittsburgh Medical Center, Section of Neuroradiology, Pittsburgh, PA (United States); Poe, Michele D.; Escolar, Maria L. [University of Pittsburgh, Program for the Study of Neurodevelopment in Rare Disorders, Children' s Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA (United States)

    2015-07-15

    To study the relationships between midbrain morphology, Loes score, gross motor function, and cognitive function in infantile Krabbe disease. Magnetic resonance imaging (MRI) scans were evaluated by two neuroradiologists blinded to clinical status and neurodevelopmental function of children with early or late infantile Krabbe disease. A simplified qualitative 3-point scoring system based on midbrain morphology on midsagittal MRI was used. A score of 0 represented normal convex morphology of the midbrain, a score of 1 represented flattening of the midbrain, and a score of 3 represented concave morphology of the midbrain (hummingbird sign). Spearman correlations were estimated between this simplified MRI scoring system and the Loes score, gross motor score, and cognitive score. Forty-two MRIs of 27 subjects were reviewed. Analysis of the 42 scans showed normal midbrain morphology in 3 (7.1 %) scans, midbrain flattening in 11 (26.2 %) scans, and concave midbrain morphology (hummingbird sign) in 28 (66.7 %) scans. Midbrain morphology scores were positively correlated with the Loes score (r = 0.81, p < 0.001) and negatively correlated with both gross motor and cognitive scores (r = -.84, p < 0.001; r = -0.87, p < 0.001, respectively). The inter-rater reliability for the midbrain morphology scale was κ =.95 (95 % CI: 0.86-1.0), and the inter-rater reliability for the Loes scale was κ =.58 (95 % CI: 0.42-0.73). Midbrain morphology scores of midsagittal MRI images correlates with cognition and gross motor function in children with Krabbe disease. This MRI scoring system represents a simple but reliable method to assess disease progression in patients with infantile Krabbe disease. (orig.)

  2. Midbrain morphology reflects extent of brain damage in Krabbe disease

    International Nuclear Information System (INIS)

    Zuccoli, Giulio; Narayanan, Srikala; Panigrahy, Ashok; Poe, Michele D.; Escolar, Maria L.

    2015-01-01

    To study the relationships between midbrain morphology, Loes score, gross motor function, and cognitive function in infantile Krabbe disease. Magnetic resonance imaging (MRI) scans were evaluated by two neuroradiologists blinded to clinical status and neurodevelopmental function of children with early or late infantile Krabbe disease. A simplified qualitative 3-point scoring system based on midbrain morphology on midsagittal MRI was used. A score of 0 represented normal convex morphology of the midbrain, a score of 1 represented flattening of the midbrain, and a score of 3 represented concave morphology of the midbrain (hummingbird sign). Spearman correlations were estimated between this simplified MRI scoring system and the Loes score, gross motor score, and cognitive score. Forty-two MRIs of 27 subjects were reviewed. Analysis of the 42 scans showed normal midbrain morphology in 3 (7.1 %) scans, midbrain flattening in 11 (26.2 %) scans, and concave midbrain morphology (hummingbird sign) in 28 (66.7 %) scans. Midbrain morphology scores were positively correlated with the Loes score (r = 0.81, p < 0.001) and negatively correlated with both gross motor and cognitive scores (r = -.84, p < 0.001; r = -0.87, p < 0.001, respectively). The inter-rater reliability for the midbrain morphology scale was κ =.95 (95 % CI: 0.86-1.0), and the inter-rater reliability for the Loes scale was κ =.58 (95 % CI: 0.42-0.73). Midbrain morphology scores of midsagittal MRI images correlates with cognition and gross motor function in children with Krabbe disease. This MRI scoring system represents a simple but reliable method to assess disease progression in patients with infantile Krabbe disease. (orig.)

  3. Involvement of midbrain tectum neurokinin-mediated mechanisms in fear and anxiety

    International Nuclear Information System (INIS)

    Brenes, J.C.; Broiz, A.C.; Bassi, G.S.; Schwarting, R.K.W.; Brandão, M.L.

    2012-01-01

    Electrical stimulation of midbrain tectum structures, particularly the dorsal periaqueductal gray (dPAG) and inferior colliculus (IC), produces defensive responses, such as freezing and escape behavior. Freezing also ensues after termination of dPAG stimulation (post-stimulation freezing). These defensive reaction responses are critically mediated by Y -aminobutyric acid and 5-hydroxytryptamine mechanisms in the midbrain tectum. Neurokinins (NKs) also play a role in the mediation of dPAG stimulation-evoked fear, but how NK receptors are involved in the global processing and expression of fear at the level of the midbrain tectum is yet unclear. The present study investigated the role of NK-1 receptors in unconditioned defensive behavior induced by electrical stimulation of the dPAG and IC of male Wistar rats. Spantide (100 pmol/0.2 µL), a selective NK-1 antagonist, injected into these midbrain structures had anti-aversive effects on defensive responses and distress ultrasonic vocalizations induced by stimulation of the dPAG but not of the IC. Moreover, intra-dPAG injections of spantide did not influence post-stimulation freezing or alter exploratory behavior in rats subjected to the elevated plus maze. These results suggest that NK-1 receptors are mainly involved in the mediation of defensive behavior organized in the dPAG. Dorsal periaqueductal gray-evoked post-stimulation freezing was not affected by intra-dPAG injections of spantide, suggesting that NK-1-mediated mechanisms are only involved in the output mechanisms of defensive behavior and not involved in the processing of ascending aversive information from the dPAG

  4. Involvement of midbrain tectum neurokinin-mediated mechanisms in fear and anxiety

    Energy Technology Data Exchange (ETDEWEB)

    Brenes, J.C. [Experimental and Physiological Psychology, Philipps-University of Marburg, Marburg (Germany); Broiz, A.C.; Bassi, G.S. [Instituto de Neurociências e Comportamento, Campus USP, Ribeirão Preto, SP (Brazil); Laboratório de Psicobiologia, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Schwarting, R.K.W. [Experimental and Physiological Psychology, Philipps-University of Marburg, Marburg (Germany); Brandão, M.L. [Instituto de Neurociências e Comportamento, Campus USP, Ribeirão Preto, SP (Brazil); Laboratório de Psicobiologia, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil)

    2012-03-09

    Electrical stimulation of midbrain tectum structures, particularly the dorsal periaqueductal gray (dPAG) and inferior colliculus (IC), produces defensive responses, such as freezing and escape behavior. Freezing also ensues after termination of dPAG stimulation (post-stimulation freezing). These defensive reaction responses are critically mediated by {sub Y}-aminobutyric acid and 5-hydroxytryptamine mechanisms in the midbrain tectum. Neurokinins (NKs) also play a role in the mediation of dPAG stimulation-evoked fear, but how NK receptors are involved in the global processing and expression of fear at the level of the midbrain tectum is yet unclear. The present study investigated the role of NK-1 receptors in unconditioned defensive behavior induced by electrical stimulation of the dPAG and IC of male Wistar rats. Spantide (100 pmol/0.2 µL), a selective NK-1 antagonist, injected into these midbrain structures had anti-aversive effects on defensive responses and distress ultrasonic vocalizations induced by stimulation of the dPAG but not of the IC. Moreover, intra-dPAG injections of spantide did not influence post-stimulation freezing or alter exploratory behavior in rats subjected to the elevated plus maze. These results suggest that NK-1 receptors are mainly involved in the mediation of defensive behavior organized in the dPAG. Dorsal periaqueductal gray-evoked post-stimulation freezing was not affected by intra-dPAG injections of spantide, suggesting that NK-1-mediated mechanisms are only involved in the output mechanisms of defensive behavior and not involved in the processing of ascending aversive information from the dPAG.

  5. Distinct Contributions of Median Raphe Nucleus to Contextual Fear Conditioning and Fear-Potentiated Startle

    Science.gov (United States)

    Silva, R. C. B.; Cruz, A. P. M.; Avanzi, V.; Landeira-Fernandez, J.; Brandão, M. L.

    2002-01-01

    Ascending 5-HT projections from the median raphe nucleus (MRN), probably to the hippocampus, are implicated in the acquisition of contextual fear (background stimuli), as assessed by freezing behavior. Foreground cues like light, used as a conditioned stimulus (CS) in classical fear conditioning, also cause freezing through thalamic transmission to the amygdala. As the MRN projects to the hippocampus and amygdala, the role of this raphe nucleus in fear conditioning to explicit cues remains to be explained. Here we analyzed the behavior of rats with MRN electrolytic lesions in a contextual conditioning situation and in a fear-potentiated startle procedure. The animals received MRN electrolytic lesions either before or on the day after two consecutive training sessions in which they were submitted to 10 conditioning trials, each in an experimental chamber (same context) where they. received foot-shocks (0.6 mA, 1 sec) paired to a 4-sec light CS. Seven to ten days later, the animals were submitted to testing sessions for assessing conditioned fear when they were placed for five shocks, and the duration of contextual freezing was recorded. The animals were then submitted to a fear-potentiated startle in response to a 4-sec light-CS, followed by white noise (100 dB, 50 ms). Control rats (sham) tested in the same context showed more freezing than did rats with pre- or post-training MRN lesions. Startle was clearly potentiated in the presence of light CS in the sham-lesioned animals. Whereas pretraining lesions reduced both freezing and fear-potentiated startle, the post-training lesions reduced only freezing to context, without changing the fear-potentiated startle. In a second experiment, neurotoxic lesions of the MRN with local injections of N-methyl-D-aspartate or the activation of 5-HT1A somatodendritic auto-receptors of the MRN by microinjections of the 5-HT1A receptor agonist 8-hydroxy- 2-(di-n-propylamino)tetralin (8-OH-DPAT) before the training sessions also

  6. The role of serotoninergic neurons in rats agressive behaviour.

    Science.gov (United States)

    Czlonkowski, A; Kostowski, W; Markowska, L; Markiewicz, L; Wiśniewska, I

    1975-10-01

    Lesions of the dorsal and medial raphe nuclei that caused a marked decrease of the 5-HT level in the forebrain induced in groupped rats intraspecies aggressiveness but failed to increase mouse-killing behaviour. In rats isolated for 3 weeks lesions of the raphe nuclei did not change behaviour of "killers" and natural "non-killers". The role of 5-HT in mechanism of the aggressive behaviour is discussed.

  7. Inter- and intracellular relationship of substance P-containing neurons with serotonin and GABA in the dorsal raphe nucleus: combination of autoradiographic and immunocytochemical techniques

    International Nuclear Information System (INIS)

    Magoul, R.; Onteniente, B.; Oblin, A.; Calas, A.

    1986-01-01

    Double-labeling experiments were performed at the electron microscopic level in the dorsal raphe nucleus of rat, in order to study the inter- and intracellular relationship of substance P with gamma-aminobutyric acid (GABA) and serotonin. Autoradiography for either [ 3 H]serotonin or [ 3 H]GABA was coupled, on the same tissue section, with peroxidase-antiperoxidase immunocytochemistry for substance P in colchicine-treated animals. Intercellular relationships were represented by synaptic contacts made by [ 3 H]serotonin-labeled terminals on substance P-containing somata and dendrites, and by substance P-containing terminals on [ 3 H]GABA-labeled cells. Intracellular relationships were suggested by the occurrence of the peptide within [ 3 H]serotonin-containing and [ 3 H]GABA-containing cell bodies and fibers. Doubly labeled varicosities of the two kinds were also observed in the supraependymal plexus adjacent to the dorsal raphe nucleus. The results demonstrated that, in addition to reciprocal synaptic interactions made by substance P with serotonin and GABA, the dorsal raphe nucleus is the site of intracellular relationships between the peptide and either the amine or the amino acid

  8. The Effect of Citalopram on Midbrain CRF Receptors 1 and 2 in a Primate Model of Stress-Induced Amenorrhea

    Science.gov (United States)

    Senashova, Olga; Reddy, Arubala P.; Cameron, Judy L.; Bethea, Cynthia L.

    2012-01-01

    We have demonstrated marked differences in the neurobiology of the serotonin system between stress-sensitive (SS) and stress-resilient (SR) cynomolgus macaques characterized in a model of stress-induced amenorrhea, also called functional hypothalamic amenorrhea (FHA). Dysfunction of the serotonin system in SS monkeys suggested that administration of a selective serotonin reuptake inhibitor (SSRI) might correct FHA. This study examines the effect of escitalopram (CIT) administration to SS and SR monkeys on corticotrophin-releasing factor (CRF) receptor 1 (CRF-R1) and CRF receptor 2 (CRF-R2) gene expression in the serotonin cell body region of the midbrain dorsal raphe. CRF-R1 was not significantly different between groups. There was a significant effect of treatment and a significant interaction between treatment and stress sensitivity on the average CRF-R2-positive pixel area (P < .004 and P < .006, respectively) and on the average number of CRF-R2-positive cells (P < .023 and P < .025, respectively). CIT significantly increased CRF-R2-positive pixel area and cell number in the SS group (pixel area P < .001; cell number P < .01; Bonferoni) but not in the SR group. In summary, CIT administration tended to decrease CRF-R1, but the small animal number precluded significance. CIT administration significantly increased CRF-R2 only in SS animals. These data suggest that the administration of CIT reduces anxiogenic components and increases anxiolytic components of the CRF system in the midbrain serotonin network, which in turn leads to improved ovarian function. Moreover, these data raise the possibility that SSRIs may be effective in the treatment of stress-induced infertility. PMID:22412189

  9. Dorsal Raphe Dopamine Neurons Represent the Experience of Social Isolation

    Science.gov (United States)

    Matthews, Gillian A.; Nieh, Edward H.; Vander Weele, Caitlin M.; Halbert, Sarah A.; Pradhan, Roma V.; Yosafat, Ariella S.; Glober, Gordon F.; Izadmehr, Ehsan M.; Thomas, Rain E.; Lacy, Gabrielle D.; Wildes, Craig P.; Ungless, Mark A.; Tye, Kay M.

    2016-01-01

    Summary The motivation to seek social contact may arise from either positive or negative emotional states, as social interaction can be rewarding and social isolation can be aversive. While ventral tegmental area (VTA) dopamine (DA) neurons may mediate social reward, a cellular substrate for the negative affective state of loneliness has remained elusive. Here, we identify a functional role for DA neurons in the dorsal raphe nucleus (DRN), in which we observe synaptic changes following acute social isolation. DRN DA neurons show increased activity upon social contact following isolation, revealed by in vivo calcium imaging. Optogenetic activation of DRN DA neurons increases social preference but causes place avoidance. Furthermore, these neurons are necessary for promoting rebound sociability following an acute period of isolation. Finally, the degree to which these neurons modulate behavior is predicted by social rank, together supporting a role for DRN dopamine neurons in mediating a loneliness-like state. PaperClip PMID:26871628

  10. Mesopontine median raphe regulates hippocampal ripple oscillation and memory consolidation.

    Science.gov (United States)

    Wang, Dong V; Yau, Hau-Jie; Broker, Carl J; Tsou, Jen-Hui; Bonci, Antonello; Ikemoto, Satoshi

    2015-05-01

    Sharp wave-associated field oscillations (∼200 Hz) of the hippocampus, referred to as ripples, are believed to be important for consolidation of explicit memory. Little is known about how ripples are regulated by other brain regions. We found that the median raphe region (MnR) is important for regulating hippocampal ripple activity and memory consolidation. We performed in vivo simultaneous recording in the MnR and hippocampus of mice and found that, when a group of MnR neurons was active, ripples were absent. Consistently, optogenetic stimulation of MnR neurons suppressed ripple activity and inhibition of these neurons increased ripple activity. Notably, using a fear conditioning procedure, we found that photostimulation of MnR neurons interfered with memory consolidation. Our results demonstrate a critical role of the MnR in regulating ripples and memory consolidation.

  11. Electrical stimulation of the midbrain excites the auditory cortex asymmetrically.

    Science.gov (United States)

    Quass, Gunnar Lennart; Kurt, Simone; Hildebrandt, Jannis; Kral, Andrej

    2018-05-17

    Auditory midbrain implant users cannot achieve open speech perception and have limited frequency resolution. It remains unclear whether the spread of excitation contributes to this issue and how much it can be compensated by current-focusing, which is an effective approach in cochlear implants. The present study examined the spread of excitation in the cortex elicited by electric midbrain stimulation. We further tested whether current-focusing via bipolar and tripolar stimulation is effective with electric midbrain stimulation and whether these modes hold any advantage over monopolar stimulation also in conditions when the stimulation electrodes are in direct contact with the target tissue. Using penetrating multielectrode arrays, we recorded cortical population responses to single pulse electric midbrain stimulation in 10 ketamine/xylazine anesthetized mice. We compared monopolar, bipolar, and tripolar stimulation configurations with regard to the spread of excitation and the characteristic frequency difference between the stimulation/recording electrodes. The cortical responses were distributed asymmetrically around the characteristic frequency of the stimulated midbrain region with a strong activation in regions tuned up to one octave higher. We found no significant differences between monopolar, bipolar, and tripolar stimulation in threshold, evoked firing rate, or dynamic range. The cortical responses to electric midbrain stimulation are biased towards higher tonotopic frequencies. Current-focusing is not effective in direct contact electrical stimulation. Electrode maps should account for the asymmetrical spread of excitation when fitting auditory midbrain implants by shifting the frequency-bands downward and stimulating as dorsally as possible. Copyright © 2018 Elsevier Inc. All rights reserved.

  12. Orexin inputs to caudal raphé neurons involved in thermal, cardiovascular, and gastrointestinal regulation.

    Science.gov (United States)

    Berthoud, Hans-Rudolf; Patterson, Laurel M; Sutton, Gregory M; Morrison, Christopher; Zheng, Huiyuan

    2005-02-01

    Orexin-expressing neurons in the lateral hypothalamus with their wide projections throughout the brain are important for the regulation of sleep and wakefulness, ingestive behavior, and the coordination of these behaviors in the environmental context. To further identify downstream effector targets of the orexin system, we examined in detail orexin-A innervation of the caudal raphe nuclei in the medulla, known to harbor sympathetic preganglionic motor neurons involved in thermal, cardiovascular, and gastrointestinal regulation. All three components of the caudal raphe nuclei, raphe pallidus, raphe obscurus, and parapyramidal nucleus, are innervated by orexin-A-immunoreactive fibers. Using confocal microscopy, we demonstrate close anatomical appositions between varicose orexin-A immunoreactive axon profiles and sympathetic premotor neurons identified with either a transneuronal retrograde pseudorabies virus tracer injected into the interscapular brown fat pads, or with in situ hybridization of pro-TRH mRNA. Furthermore, orexin-A injected into the fourth ventricle induced c-Fos expression in the raphe pallidus and parapyramidal nucleus. These findings suggest that orexin neurons in the hypothalamus can modulate brown fat thermogenesis, cardiovascular, and gastrointestinal functions by acting directly on neurons in the caudal raphe nuclei, and support the idea that orexin's simultaneous stimulation of food intake and sympathetic activity might have evolved as a mechanism to stay alert while foraging.

  13. Chronic excitotoxic lesion of the dorsal raphe nucleus induces sodium appetite

    Directory of Open Access Journals (Sweden)

    Cavalcante-Lima H.R.

    2005-01-01

    Full Text Available We determined if the dorsal raphe nucleus (DRN exerts tonic control of basal and stimulated sodium and water intake. Male Wistar rats weighing 300-350 g were microinjected with phosphate buffer (PB-DRN, N = 11 or 1 µg/0.2 µl, in a single dose, ibotenic acid (IBO-DRN, N = 9 to 10 through a guide cannula into the DRN and were observed for 21 days in order to measure basal sodium appetite and water intake and in the following situations: furosemide-induced sodium depletion (20 mg/kg, sc, 24 h before the experiment and a low dose of dietary captopril (1 mg/g chow. From the 6th day after ibotenic acid injection IBO-DRN rats showed an increase in sodium appetite (12.0 ± 2.3 to 22.3 ± 4.6 ml 0.3 M NaCl intake whereas PB-DRN did not exceed 2 ml (P < 0.001. Water intake was comparable in both groups. In addition to a higher dipsogenic response, sodium-depleted IBO-DRN animals displayed an increase of 0.3 M NaCl intake compared to PB-DRN (37.4 ± 3.8 vs 21.6 ± 3.9 ml 300 min after fluid offer, P < 0.001. Captopril added to chow caused an increase of 0.3 M NaCl intake during the first 2 days (IBO-DRN, 33.8 ± 4.3 and 32.5 ± 3.4 ml on day 1 and day 2, respectively, vs 20.2 ± 2.8 ml on day 0, P < 0.001. These data support the view that DRN, probably via ascending serotonergic system, tonically modulates sodium appetite under basal and sodium depletion conditions and/or after an increase in peripheral or brain angiotensin II.

  14. Encoding of natural and artificial stimuli in the auditory midbrain

    Science.gov (United States)

    Lyzwa, Dominika

    How complex acoustic stimuli are encoded in the main center of convergence in the auditory midbrain is not clear. Here, the representation of neural spiking responses to natural and artificial sounds across this subcortical structure is investigated based on neurophysiological recordings from the mammalian midbrain. Neural and stimulus correlations of neuronal pairs are analyzed with respect to the neurons' distance, and responses to different natural communication sounds are discriminated. A model which includes linear and nonlinear neural response properties of this nucleus is presented and employed to predict temporal spiking responses to new sounds. Supported by BMBF Grant 01GQ0811.

  15. Effects of drugs of abuse on putative rostromedial tegmental neurons, inhibitory afferents to midbrain dopamine cells.

    Science.gov (United States)

    Lecca, Salvatore; Melis, Miriam; Luchicchi, Antonio; Ennas, Maria Grazia; Castelli, Maria Paola; Muntoni, Anna Lisa; Pistis, Marco

    2011-02-01

    Recent findings have underlined the rostromedial tegmental nucleus (RMTg), a structure located caudally to the ventral tegmental area, as an important site involved in the mechanisms of aversion. RMTg contains γ-aminobutyric acid neurons responding to noxious stimuli, densely innervated by the lateral habenula and providing a major inhibitory projection to reward-encoding midbrain dopamine (DA) neurons. One of the key features of drug addiction is the perseverance of drug seeking in spite of negative and unpleasant consequences, likely mediated by response suppression within neural pathways mediating aversion. To investigate whether the RMTg has a function in the mechanisms of addicting drugs, we studied acute effects of morphine, cocaine, the cannabinoid agonist WIN55212-2 (WIN), and nicotine on putative RMTg neurons. We utilized single unit extracellular recordings in anesthetized rats and whole-cell patch-clamp recordings in brain slices to identify and characterize putative RMTg neurons and their responses to drugs of abuse. Morphine and WIN inhibited both firing rate in vivo and excitatory postsynaptic currents (EPSCs) evoked by stimulation of rostral afferents in vitro, whereas cocaine inhibited discharge activity without affecting EPSC amplitude. Conversely, nicotine robustly excited putative RMTg neurons and enhanced EPSCs, an effect mediated by α7-containing nicotinic acetylcholine receptors. Our results suggest that activity of RMTg neurons is profoundly influenced by drugs of abuse and, as important inhibitory afferents to midbrain DA neurons, they might take place in the complex interplay between the neural circuits mediating aversion and reward.

  16. Ascending Midbrain Dopaminergic Axons Require Descending GAD65 Axon Fascicles for Normal Pathfinding

    Directory of Open Access Journals (Sweden)

    Claudia Marcela Garcia-Peña

    2014-06-01

    Full Text Available The Nigrostriatal pathway (NSP is formed by dopaminergic axons that project from the ventral midbrain to the dorsolateral striatum as part of the medial forebrain bundle. Previous studies have implicated chemotropic proteins in the formation of the NSP during development but little is known of the role of substrate-anchored signals in this process. We observed in mouse and rat embryos that midbrain dopaminergic axons ascend in close apposition to descending GAD65-positive axon bundles throughout their trajectory to the striatum. To test whether such interaction is important for dopaminergic axon pathfinding, we analyzed transgenic mouse embryos in which the GAD65 axon bundle was reduced by the conditional expression of the diphtheria toxin. In these embryos we observed dopaminergic misprojection into the hypothalamic region and abnormal projection in the striatum. In addition, analysis of Robo1/2 and Slit1/2 knockout embryos revealed that the previously described dopaminergic misprojection in these embryos is accompanied by severe alterations in the GAD65 axon scaffold. Additional studies with cultured dopaminergic neurons and whole embryos suggest that NCAM and Robo proteins are involved in the interaction of GAD65 and dopaminergic axons. These results indicate that the fasciculation between descending GAD65 axon bundles and ascending dopaminergic axons is required for the stereotypical NSP formation during brain development and that known guidance cues may determine this projection indirectly by instructing the pathfinding of the axons that are part of the GAD65 axon scaffold.

  17. Dorsal raphe nucleus projecting retinal ganglion cells: Why Y cells?

    Science.gov (United States)

    Pickard, Gary E.; So, Kwok-Fai; Pu, Mingliang

    2015-01-01

    Retinal ganglion Y (alpha) cells are found in retinas ranging from frogs to mice to primates. The highly conserved nature of the large, fast conducting retinal Y cell is a testament to its fundamental task, although precisely what this task is remained ill-defined. The recent discovery that Y-alpha retinal ganglion cells send axon collaterals to the serotonergic dorsal raphe nucleus (DRN) in addition to the lateral geniculate nucleus (LGN), medial interlaminar nucleus (MIN), pretectum and the superior colliculus (SC) has offered new insights into the important survival tasks performed by these cells with highly branched axons. We propose that in addition to its role in visual perception, the Y-alpha retinal ganglion cell provides concurrent signals via axon collaterals to the DRN, the major source of serotonergic afferents to the forebrain, to dramatically inhibit 5-HT activity during orientation or alerting/escape responses, which dis-facilitates ongoing tonic motor activity while dis-inhibiting sensory information processing throughout the visual system. The new data provide a fresh view of these evolutionarily old retinal ganglion cells. PMID:26363667

  18. File list: NoD.Neu.20.AllAg.Midbrain [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available NoD.Neu.20.AllAg.Midbrain mm9 No description Neural Midbrain ERX102458,ERX102459,ER...X102460,ERX102461,SRX002662 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/NoD.Neu.20.AllAg.Midbrain.bed ...

  19. File list: NoD.Neu.50.AllAg.Midbrain [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available NoD.Neu.50.AllAg.Midbrain mm9 No description Neural Midbrain ERX102458,ERX102459,ER...X102460,ERX102461,SRX002662 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/NoD.Neu.50.AllAg.Midbrain.bed ...

  20. File list: NoD.Neu.10.AllAg.Midbrain [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available NoD.Neu.10.AllAg.Midbrain mm9 No description Neural Midbrain SRX002662,ERX102458,ER...X102459,ERX102460,ERX102461 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/NoD.Neu.10.AllAg.Midbrain.bed ...

  1. File list: ALL.Neu.10.AllAg.Midbrain [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Neu.10.AllAg.Midbrain mm9 All antigens Neural Midbrain SRX002662,ERX102458,ERX1...02459,SRX332682,SRX317037,ERX102460,ERX102461,SRX332681 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/ALL.Neu.10.AllAg.Midbrain.bed ...

  2. File list: ALL.Neu.05.AllAg.Midbrain [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Neu.05.AllAg.Midbrain mm9 All antigens Neural Midbrain SRX002662,SRX332682,ERX1...02458,ERX102459,SRX317037,ERX102460,ERX102461,SRX332681 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/ALL.Neu.05.AllAg.Midbrain.bed ...

  3. File list: ALL.Neu.20.AllAg.Midbrain [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Neu.20.AllAg.Midbrain mm9 All antigens Neural Midbrain SRX332682,ERX102458,ERX1...02459,ERX102460,ERX102461,SRX317037,SRX002662,SRX332681 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/ALL.Neu.20.AllAg.Midbrain.bed ...

  4. File list: ALL.Neu.50.AllAg.Midbrain [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Neu.50.AllAg.Midbrain mm9 All antigens Neural Midbrain ERX102458,ERX102459,ERX1...02460,ERX102461,SRX317037,SRX002662,SRX332682,SRX332681 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/ALL.Neu.50.AllAg.Midbrain.bed ...

  5. VMAT2-mediated neurotransmission from midbrain leptin receptor neurons in feeding regulation

    Science.gov (United States)

    Leptin receptors (LepRs) expressed in the midbrain contribute to the action of leptin on feeding regulation. The midbrain neurons release a variety of neurotransmitters including dopamine (DA), glutamate and GABA. However, which neurotransmitter mediates midbrain leptin action on feeding remains unc...

  6. Fos expression in the midbrain periaqueductal grey after trigeminovascular stimulation

    NARCIS (Netherlands)

    Hoskin, KL; Bulmer, DCE; Lasalandra, M; Jonkman, A; Goadsby, PJ

    There is an accumulating body of evidence suggesting that the periaqueductal grey (PAG) is involved in the pathophysiology of migraine. Positron emission tomography (PET) studies in humans have shown that the caudal ventrolateral midbrain, encompassing the ventrolateral PAG, has activations during

  7. Obstructive sleep apnea is associated with altered midbrain chemical concentrations.

    Science.gov (United States)

    Macey, Paul M; Sarma, Manoj K; Prasad, Janani P; Ogren, Jennifer A; Aysola, Ravi; Harper, Ronald M; Thomas, M Albert

    2017-11-05

    Obstructive sleep apnea (OSA) is accompanied by altered structure and function in cortical, limbic, brainstem, and cerebellar regions. The midbrain is relatively unexamined, but contains many integrative nuclei which mediate physiological functions that are disrupted in OSA. We therefore assessed the chemistry of the midbrain in OSA in this exploratory study. We used a recently developed accelerated 2D magnetic resonance spectroscopy (2D-MRS) technique, compressed sensing-based 4D echo-planar J-resolved spectroscopic imaging (4D-EP-JRESI), to measure metabolites in the midbrain of 14 OSA (mean age±SD:54.6±10.6years; AHI:35.0±19.4; SAO 2 min:83±7%) and 26 healthy control (50.7±8.5years) subjects. High-resolution T1-weighted scans allowed voxel localization. MRS data were processed with custom MATLAB-based software, and metabolite ratios calculated with respect to the creatine peak using a prior knowledge fitting (ProFit) algorithm. The midbrain in OSA showed decreased N-acetylaspartate (NAA; OSA:1.24±0.43, Control:1.47±0.41; p=0.03; independent samples t-test), a marker of neuronal viability. Increased levels in OSA over control subjects appeared in glutamate (Glu; OSA:1.23±0.57, Control:0.98±0.33; p=0.03), ascorbate (Asc; OSA:0.56±0.28, Control:0.42±0.20; (50.7±8.5years; p=0.03), and myo-inositol (mI; OSA:0.96±0.48, Control:0.72±0.35; p=0.03). No differences between groups appeared in γ-aminobutyric acid (GABA) or taurine. The midbrain in OSA patients shows decreased NAA, indicating neuronal injury or dysfunction. Higher Glu levels may reflect excitotoxic processes and astrocyte activation, and higher mI is also consistent with glial activation. Higher Asc levels may result from oxidative stress induced by intermittent hypoxia in OSA. Additionally, Asc and Glu are involved with glutamatergic processes, which are likely upregulated in the midbrain nuclei of OSA patients. The altered metabolite levels help explain dysfunction and structural deficits in

  8. Reduced Serotonin Transporter Levels and Inflammation in the Midbrain Raphe of 12 month old APPswe/PSEN1dE9 Mice

    DEFF Research Database (Denmark)

    Metaxas, Athanasios; Vaitheeswaran, Ramanan; Jensen, Katrine T

    2018-01-01

    Background Although mood and sleep disturbances are nearly universal among patients with Alzheimer's disease (AD), brain structures involved in non-cognitive processing remain under characterized in terms of AD pathology. Objectives This study was designed to evaluate hallmarks of AD pathology...

  9. MicroRNA-326 acts as a molecular switch in the regulation of midbrain urocortin 1 expression

    Science.gov (United States)

    Aschrafi, Armaz; Verheijen, Jan M.; Gordebeke, Peter M.; Olde Loohuis, Nikkie F.; Menting, Kelly; Jager, Amanda; Palkovits, Miklos; Geenen, Bram; Kos, Aron; Martens, Gerard J.M.; Glennon, Jeffrey C.; Kaplan, Barry B.; Gaszner, Balázs; Kozicz, Tamas

    2016-01-01

    Background Altered levels of urocortin 1 (Ucn1) in the centrally projecting Edinger–Westphal nucleus (EWcp) of depressed suicide attempters or completers mediate the brain’s response to stress, while the mechanism regulating Ucn1 expression is unknown. We tested the hypothesis that microRNAs (miRNAs), which are vital fine-tuners of gene expression during the brain’s response to stress, have the capacity to modulate Ucn1 expression. Methods Computational analysis revealed that the Ucn1 3′ untranslated region contained a conserved binding site for miR-326. We examined miR-326 and Ucn1 levels in the EWcp of depressed suicide completers. In addition, we evaluated miR-326 and Ucn1 levels in the serum and the EWcp of a chronic variable mild stress (CVMS) rat model of behavioural despair and after recovery from CVMS, respectively. Gain and loss of miR-326 function experiments examined the regulation of Ucn1 by this miRNA in cultured midbrain neurons. Results We found reduced miR-326 levels concomitant with elevated Ucn1 levels in the EWcp of depressed suicide completers as well as in the EWcp of CVMS rats. In CVMS rats fully recovered from stress, both serum and EWcp miR-326 levels rebounded to nonstressed levels. While downregulation of miR-326 levels in primary midbrain neurons enhanced Ucn1 expression levels, miR-326 overexpression selectively reduced the levels of this neuropeptide. Limitations This study lacked experiments showing that in vivo alteration of miR-326 levels alleviate depression-like behaviours. We show only correlative data for miR-325 and cocaine- and amphetamine-regulated transcript levels in the EWcp. Conclusion We identified miR-326 dysregulation in depressed suicide completers and characterized this miRNA as an upstream regulator of the Ucn1 neuropeptide expression in midbrain neurons. PMID:27045550

  10. The effect of short moderate stress on the midbrain corticotropin-releasing factor system in a macaque model of functional hypothalamic amenorrhea.

    Science.gov (United States)

    Bethea, Cynthia L; Phu, Kenny; Reddy, Arubala P; Cameron, Judy L

    2013-10-01

    To study the effect of moderate stress on corticotropin-releasing factor (CRF) components in the serotonergic midbrain region in a monkey model of functional hypothalamic amenorrhea. After characterization of stress sensitivity, monkeys were moved to a novel room and given 20% less chow for 5 days before euthanasia. Primate research center. Female cynomolgus macaques (Macaca fascicularis) characterized as highly stress resilient (HSR, n = 5), medium stress resilient (n = 4), or stress sensitive (SS, n = 4). Five days of diet in a novel room with unfamiliar conspecifics. Density of CRF axons in the serotonergic dorsal raphe nucleus; the number of urocortin 1 (UCN1) cells; the density of UCN1 axons; the expression of CRF receptor 1 (CRF-R1) and CRF-R2 in the dorsal raphe nucleus. The CRF innervation was higher in HSR than in SS animals; UCN1 cell number was higher in HSR than in SS animals and UCN1 axon bouton density was not different; all opposite of nonstressed animals. The CRF-R1 was not different between the sensitivity groups, but CRF-R2 was higher in HSR than in SS animals. The relative expression of CRF-R1 and CRF-R2 was similar to nonstressed animals. The HSR animals respond to stress with an increase in CRF delivery to serotonin neurons. With stress, UCN1 transport decreases in HSR animals. The CRF receptor expression was similar with or without stress. These changes may contribute to resilience in HSR animals. Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  11. Effect of acupuncture on Lipopolysaccharide-induced anxiety-like behavioral changes: involvement of serotonin system in dorsal Raphe nucleus.

    Science.gov (United States)

    Yang, Tae Young; Jang, Eun Young; Ryu, Yeonhee; Lee, Gyu Won; Lee, Eun Byeol; Chang, Suchan; Lee, Jong Han; Koo, Jin Suk; Yang, Chae Ha; Kim, Hee Young

    2017-12-11

    Acupuncture has been used as a common therapeutic tool in many disorders including anxiety and depression. Serotonin transporter (SERT) plays an important role in the pathology of anxiety and other mood disorders. The aim of this study was to evaluate the effects of acupuncture on lipopolysaccharide (LPS)-induced anxiety-like behaviors and SERT in the dorsal raphe nuclei (DRN). Rats were given acupuncture at ST41 (Jiexi), LI11 (Quchi) or SI3 (Houxi) acupoint in LPS-treated rats. Anxiety-like behaviors of elevated plus maze (EPM) and open field test (OFT) were measured and expressions of SERT and/or c-Fos were also examined in the DRN using immunohistochemistry. The results showed that 1) acupuncture at ST41 acupoint, but neither LI11 nor SI3, significantly attenuated LPS-induced anxiety-like behaviors in EPM and OFT, 2) acupuncture at ST41 decreased SERT expression increased by LPS in the DRN. Our results suggest that acupuncture can ameliorate anxiety-like behaviors, possibly through regulation of SERT in the DRN.

  12. Reward and aversion in a heterogeneous midbrain dopamine system.

    Science.gov (United States)

    Lammel, Stephan; Lim, Byung Kook; Malenka, Robert C

    2014-01-01

    The ventral tegmental area (VTA) is a heterogeneous brain structure that serves a central role in motivation and reward processing. Abnormalities in the function of VTA dopamine (DA) neurons and the targets they influence are implicated in several prominent neuropsychiatric disorders including addiction and depression. Recent studies suggest that the midbrain DA system is composed of anatomically and functionally heterogeneous DA subpopulations with different axonal projections. These findings may explain a number of previously confusing observations that suggested a role for DA in processing both rewarding as well as aversive events. Here we will focus on recent advances in understanding the neural circuits mediating reward and aversion in the VTA and how stress as well as drugs of abuse, in particular cocaine, alter circuit function within a heterogeneous midbrain DA system. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Late onset arginase deficiency presenting with encephalopathy and midbrain hyperintensity

    Directory of Open Access Journals (Sweden)

    Boby Varkey Maramattom

    2016-01-01

    Full Text Available Urea cycle disorders (UCD are very rare metabolic disorders that present with encephalopathy and hyperammonemia. Of the UCDs, Arginase deficiency (ARD is the rarest and presents in childhood with a progressive spastic diplegia or seizures. Acute presentation in adulthood is extremely unusual. [1] We present the first case of adult onset ARD presenting with encephalopathy and diffusion weighted MRI findings that resembled a moustache in the midbrain.

  14. Ciliated Median Raphe Cyst of Perineum Presenting as Perianal Polyp: A Case Report with Immunohistochemical Study, Review of Literature, and Pathogenesis

    Directory of Open Access Journals (Sweden)

    Jayesh Sagar

    2006-01-01

    Full Text Available Median raphe cyst is a very rare, benign congenital lesion occurring mainly on the ventral aspect of the penis, but can develop anywhere in the midline between the external urethral meatus and anus. We report a case of median raphe cyst in the perineum presenting as a perianal polyp in a 65-year-old, English white male with exceptionally rare ciliated epithelium. According to our knowledge, this is the third such case of ciliated median raphe cyst in the English literature. This case, also the first case of ciliated median raphe cyst in the perineum location, focuses on pathogenesis of median raphe cyst.

  15. Ciliated median raphe cyst of perineum presenting as perianal polyp: a case report with immunohistochemical study, review of literature, and pathogenesis.

    Science.gov (United States)

    Sagar, Jayesh; Sagar, Bethani; Patel, Adam F; Shak, D K

    2006-03-05

    Median raphe cyst is a very rare, benign congenital lesion occurring mainly on the ventral aspect of the penis, but can develop anywhere in the midline between the external urethral meatus and anus. We report a case of median raphe cyst in the perineum presenting as a perianal polyp in a 65-year-old, English white male with exceptionally rare ciliated epithelium. According to our knowledge, this is the third such case of ciliated median raphe cyst in the English literature. This case, also the first case of ciliated median raphe cyst in the perineum location, focuses on pathogenesis of median raphe cyst.

  16. Reward Processing by the Dorsal Raphe Nucleus: 5-HT and Beyond

    Science.gov (United States)

    Luo, Minmin; Zhou, Jingfeng; Liu, Zhixiang

    2015-01-01

    The dorsal raphe nucleus (DRN) represents one of the most sensitive reward sites in the brain. However, the exact relationship between DRN neuronal activity and reward signaling has been elusive. In this review, we will summarize anatomical, pharmacological, optogenetics, and electrophysiological studies on the functions and circuit mechanisms of…

  17. The nucleus raphe interpositus in spinocerebellar ataxia type 3 (Machado-Joseph disease)

    NARCIS (Netherlands)

    Rub, U; Brunt, ER; Gierga, K; Schultz, C; Paulson, H; de Vos, RAI; Braak, H

    The nucleus raphe interpositus (RIP) plays an important role in the premotor network for saccades. Its omnipause neurons gate the activity of the burst neurons for vertical saccades lying within the rostral interstitial nucleus of the medial longitudinal fascicle and that for horizontal saccades

  18. Functional analysis of a novel human serotonin transporter gene promoter in immortalized raphe cells

    DEFF Research Database (Denmark)

    Mortensen, O V; Thomassen, M; Larsen, M B

    1999-01-01

    were found to possess the additional 379 bp fragment. The integrity of the promoter was furthermore confirmed by genomic Southern blotting. The promoter activity was analyzed by reporter gene assays in neuronal and non-neuronal serotonergic cell lines. In immortalized serotonergic raphe neurons, RN46A...

  19. GATA-3 is involved in the development of serotonergic neurons in the caudal raphe nuclei

    NARCIS (Netherlands)

    J. van der Wees (Jacqueline); A. Karis (Alar); E. Goedknegt; M. Rutteman; F.G. Grosveld (Frank); J.H. van Doorninck (Hikke); C.I. de Zeeuw (Chris)

    1999-01-01

    textabstractAbstract The GATA-3 transcription factor shows a specific and restricted expression pattern in the developing and adult mouse brain. In the present study we investigated the role of GATA-3 in the caudal raphe system, which is known to operate as a modulator of motor activity. We

  20. Neuromelanin imaging and midbrain volumetry in progressive supranuclear palsy and Parkinson's disease.

    Science.gov (United States)

    Taniguchi, Daisuke; Hatano, Taku; Kamagata, Koji; Okuzumi, Ayami; Oji, Yutaka; Mori, Akio; Hori, Masaaki; Aoki, Shigeki; Hattori, Nobutaka

    2018-05-14

    Background Nigral degeneration patterns differ between PSP and PD. However, the relationship between nigral degeneration and midbrain atrophy in PSP remains unclear. Objective We analyzed differences and relationships between nigral degeneration and midbrain atrophy in PSP and PD. Methods Neuromelanin-sensitive MRI and midbrain volumetry were performed in 11 PSP patients, 24 PD patients, and 10 controls to measure the neuromelanin-sensitive SNpc area and midbrain volume. Results The neuromelanin-sensitive SNpc area and midbrain volume were significantly smaller in PSP patients compared with PD patients and controls. Motor deficits were inversely correlated with neuromelanin-sensitive SNpc area in PD, but not PSP patients. There was no significant correlation between neuromelanin-sensitive SNpc area and midbrain volume in either disease group. Midbrain volumetry discriminated PSP from PD. Diagnostic accuracy was improved when neuromelanin-sensitive MRI analysis was added. Conclusions Neuromelanin-sensitive MRI and midbrain volumetry may reflect the clinical and pathological characteristics of PSP and PD. Combining neuromelanin-sensitive MRI and midbrain volumetry may be useful for differentiating PSP from PD. © 2018 International Parkinson and Movement Disorder Society. © 2018 International Parkinson and Movement Disorder Society.

  1. Hierarchical prediction errors in midbrain and septum during social learning.

    Science.gov (United States)

    Diaconescu, Andreea O; Mathys, Christoph; Weber, Lilian A E; Kasper, Lars; Mauer, Jan; Stephan, Klaas E

    2017-04-01

    Social learning is fundamental to human interactions, yet its computational and physiological mechanisms are not well understood. One prominent open question concerns the role of neuromodulatory transmitters. We combined fMRI, computational modelling and genetics to address this question in two separate samples (N = 35, N = 47). Participants played a game requiring inference on an adviser's intentions whose motivation to help or mislead changed over time. Our analyses suggest that hierarchically structured belief updates about current advice validity and the adviser's trustworthiness, respectively, depend on different neuromodulatory systems. Low-level prediction errors (PEs) about advice accuracy not only activated regions known to support 'theory of mind', but also the dopaminergic midbrain. Furthermore, PE responses in ventral striatum were influenced by the Met/Val polymorphism of the Catechol-O-Methyltransferase (COMT) gene. By contrast, high-level PEs ('expected uncertainty') about the adviser's fidelity activated the cholinergic septum. These findings, replicated in both samples, have important implications: They suggest that social learning rests on hierarchically related PEs encoded by midbrain and septum activity, respectively, in the same manner as other forms of learning under volatility. Furthermore, these hierarchical PEs may be broadcast by dopaminergic and cholinergic projections to induce plasticity specifically in cortical areas known to represent beliefs about others. © The Author (2017). Published by Oxford University Press.

  2. Activation of Midbrain Structures by Associative Novelty and the Formation of Explicit Memory in Humans

    Science.gov (United States)

    Schott, Bjorn H.; Sellner, Daniela B.; Lauer, Corinna-J.; Habib, Reza; Frey, Julietta U.; Guderian, Sebastian; Heinze, Hans-Jochen; Duzel, Emrah

    2004-01-01

    Recent evidence suggests a close functional relationship between memory formation in the hippocampus and dopaminergic neuromodulation originating in the ventral tegmental area and medial substantia nigra of the midbrain. Here we report midbrain activation in two functional MRI studies of visual memory in healthy young adults. In the first study,…

  3. The Transcription Factor Orthodenticle Homeobox 2 Influences Axonal Projections and Vulnerability of Midbrain Dopaminergic Neurons

    Science.gov (United States)

    Chung, Chee Yeun; Licznerski, Pawel; Alavian, Kambiz N.; Simeone, Antonio; Lin, Zhicheng; Martin, Eden; Vance, Jeffery; Isacson, Ole

    2010-01-01

    Two adjacent groups of midbrain dopaminergic neurons, A9 (substantia nigra pars compacta) and A10 (ventral tegmental area), have distinct projections and exhibit differential vulnerability in Parkinson's disease. Little is known about transcription factors that influence midbrain dopaminergic subgroup phenotypes or their potential role in disease.…

  4. Functional connectivity of the dorsal and median raphe nuclei at rest

    DEFF Research Database (Denmark)

    Beliveau, Vincent; Svarer, Claus; Frokjaer, Vibe G

    2015-01-01

    Serotonin (5-HT) is a neurotransmitter critically involved in a broad range of brain functions and implicated in the pathophysiology of neuropsychiatric illnesses including major depression, anxiety and sleep disorders. Despite being widely distributed throughout the brain, there is limited...... knowledge on the contribution of 5-HT to intrinsic brain activity. The dorsal raphe (DR) and median raphe (MR) nuclei are the source of most serotonergic neurons projecting throughout the brain and thus provide a compelling target for a seed-based probe of resting-state activity related to 5-HT. Here we...... implemented a novel multimodal neuroimaging approach for investigating resting-state functional connectivity (FC) between DR and MR and cortical, subcortical and cerebellar target areas. Using [(11)C]DASB positron emission tomography (PET) images of the brain serotonin transporter (5-HTT) combined...

  5. Extrasynaptic glycine receptors of rodent dorsal raphe serotonergic neurons:a sensitive target for ethanol

    OpenAIRE

    Maguire, Edward P.; Mitchell, Elizabeth A.; Greig, Scott J.; Corteen, Nicole; Balfour, David J. K.; Swinny, Jerome; Lambert, Jeremy J.; Belelli, Delia

    2014-01-01

    Alcohol abuse is a significant medical and social problem. Several neurotransmitter systems are implicated in ethanol's actions, with certain receptors and ion channels emerging as putative targets. The dorsal raphe (DR) nucleus is associated with the behavioral actions of alcohol, but ethanol actions on these neurons are not well understood. Here, using immunohistochemistry and electrophysiology we characterize DR inhibitory transmission and its sensitivity to ethanol. DR neurons exhibit inh...

  6. The influence of superlethal γ-radiation doses on the content and metabolism of serotonin in the rat brain

    International Nuclear Information System (INIS)

    Silina, A.G.; Sverdlov, A.G.

    1987-01-01

    As early as 60 min after γ-irradiation of Wistar rats with a dose of 150 Gy the content of serotonin and 5-hydroxyindoleacetic acid decreases in the midbrain, hippocampus, and cerebral hemisphere cortex. The decrease is most pronounced in the midbrain where serotoninergic neurons are located. The changes are accumulated during the first 24 h following irradiation h

  7. Glucose modulates food-related salience coding of midbrain neurons in humans.

    Science.gov (United States)

    Ulrich, Martin; Endres, Felix; Kölle, Markus; Adolph, Oliver; Widenhorn-Müller, Katharina; Grön, Georg

    2016-12-01

    Although early rat studies demonstrated that administration of glucose diminishes dopaminergic midbrain activity, evidence in humans has been lacking so far. In the present functional magnetic resonance imaging study, glucose was intravenously infused in healthy human male participants while seeing images depicting low-caloric food (LC), high-caloric food (HC), and non-food (NF) during a food/NF discrimination task. Analysis of brain activation focused on the ventral tegmental area (VTA) as the origin of the mesolimbic system involved in salience coding. Under unmodulated fasting baseline conditions, VTA activation was greater during HC compared with LC food cues. Subsequent to infusion of glucose, this difference in VTA activation as a function of caloric load leveled off and even reversed. In a control group not receiving glucose, VTA activation during HC relative to LC cues remained stable throughout the course of the experiment. Similar treatment-specific patterns of brain activation were observed for the hypothalamus. The present findings show for the first time in humans that glucose infusion modulates salience coding mediated by the VTA. Hum Brain Mapp 37:4376-4384, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  8. Contribution of Pro-Inflammatory Cytokine Signaling within Midbrain Periaqueductal Gray to Pain Sensitivity in Parkinson's disease via GABAergic Pathway

    Directory of Open Access Journals (Sweden)

    Xianbo Zhuang

    2016-07-01

    Full Text Available Background/Aims: Hypersensitive pain response is often observed in patients with Parkinson's disease (PD; however, the mechanisms responsible for hyperalgesia are not well understood. Chronic neuroinflammation is one of the hallmarks of PD pathophysiology. Since the midbrain periaqueductal gray (PAG is an important component of the descending inhibitory pathway controlling on central pain transmission, we examined the role for pro-inflammatory cytokines (PICs system of PAG in regulating exaggerated pain evoked by PD. Methods: We used a rat model of PD to perform the experimental protocols. PD was induced by microinjection of 6-hydroxydopamine to lesion the left medial forebrain bundle. Pain responses to mechanical and thermal stimulation were first examined in control rats and PD rats. Then, ELISA and Western Blot analysis were used to determine PIC levels and their receptors expression. Results: Protein expression of IL-1β, IL-6 and TNF-α receptors (namely, IL-1R, IL-6R and TNFR subtype TNFR1 in the plasma membrane PAG of PD rats was upregulated, whereas the total expression of PIC receptors was not significantly altered. The ratio of membrane protein and total protein (IL-1R, IL-6R and TNFR1 was 1.48±0.15, 1.59±0.18 and 1.67±0.16 in PAG of PD rats (P < 0.05 vs. their respective controls. This was accompanied with increases of PICs of PAG, and decreases of GABA (623±21 ng/mg in control rats and 418±18 ng/mg in PD rats; P < 0.05 vs. control rats and withdrawal thresholds to mechanical and thermal stimuli. Our data further showed that the concentrations of GABA and withdrawal thresholds were largely restored by blocking those PIC receptors in PAG of PD rats. Stimulation of GABA receptors in PAG of PD rats also blunted a decrease in withdrawal thresholds. Conclusions: Our data suggest that upregulation of the membrane PIC receptor in the PAG of PD rats is likely to impair the descending inhibitory pathways in regulating pain transmission

  9. Development and function of the midbrain dopamine system: what we know and what we need to

    OpenAIRE

    Bissonette, G. B.; Roesch, M. R.

    2015-01-01

    The past two decades have seen an explosion in our understanding of the origin and development of the midbrain dopamine system. Much of this work has been focused on the aspects of dopamine neuron development related to the onset of movement disorders such as Parkinson’s disease, with the intent of hopefully delaying, preventing or fixing symptoms. While midbrain dopamine degeneration is a major focus for treatment and research, many other human disorders are impacted by abnormal dopamine, in...

  10. Midbrain and forebrain patterning delivers immunocytochemically and functionally similar populations of neuropeptide Y containing GABAergic neurons.

    Science.gov (United States)

    Khaira, S K; Nefzger, C M; Beh, S J; Pouton, C W; Haynes, J M

    2011-09-01

    Neurons differentiated in vitro from embryonic stem cells (ESCs) have the potential to serve both as models of disease states and in drug discovery programs. In this study, we use sonic hedgehog (SHH) and fibroblast growth factor 8 (FGF-8) to enrich for forebrain and midbrain phenotypes from mouse ESCs. We then investigate, using Ca(2+) imaging and [(3)H]-GABA release studies, whether the GABAergic neurons produced exhibit distinct functional phenotypes. At day 24 of differentiation, reverse transcriptase-PCR showed the presence of both forebrain (Bf-1, Hesx1, Pgc-1α, Six3) and midbrain (GATA2, GATA3) selective mRNA markers in developing forebrain-enriched cultures. All markers were present in midbrain cultures except for Bf-1 and Pgc-1α. Irrespective of culture conditions all GABA immunoreactive neurons were also immunoreactive to neuropeptide Y (NPY) antibodies. Forebrain and midbrain GABAergic neurons responded to ATP (1 mM), L-glutamate (30 μM), noradrenaline (30 μM), acetylcholine (30 μM) and dopamine (30 μM), with similar elevations of intracellular Ca(2+)([Ca(2+)](i)). The presence of GABA(A) and GABA(B) antagonists, bicuculline (30 μM) and CGP55845 (1 μM), increased the elevation of [Ca(2+)](i) in response to dopamine (30 μM) in midbrain, but not forebrain GABAergic neurons. All agonists, except dopamine, elicited similar [(3)H]-GABA release from forebrain and midbrain cultures. Dopamine (30 μM) did not stimulate significant [(3)H]-GABA release in midbrain cultures, although it was effective in forebrain cultures. This study shows that differentiating neurons toward a midbrain fate restricts the expression of forebrain markers. Forebrain differentiation results in the expression of forebrain and midbrain markers. All GABA(+) neurons contain NPY, and show similar agonist-induced elevations of [Ca(2+)](i) and [(3)H]-GABA release. This study indicates that the pharmacological phenotype of these particular neurons may be independent of the addition of

  11. Projections from the raphe nuclei to the suprachiasmatic nucleus of the rat

    DEFF Research Database (Denmark)

    Hay-Schmidt, Anders; Vrang, N.; Larsen, P.J.

    2003-01-01

    Hypothalamus, Circadian rhythm, Serotonin, Nucleus, Neuronal connections, Phaseolus vulgaris-leucoagglutinin (PHA-L), Cholera toxin (ChB)......Hypothalamus, Circadian rhythm, Serotonin, Nucleus, Neuronal connections, Phaseolus vulgaris-leucoagglutinin (PHA-L), Cholera toxin (ChB)...

  12. Wnt5a regulates midbrain dopaminergic axon growth and guidance.

    Directory of Open Access Journals (Sweden)

    Brette D Blakely

    2011-03-01

    Full Text Available During development, precise temporal and spatial gradients are responsible for guiding axons to their appropriate targets. Within the developing ventral midbrain (VM the cues that guide dopaminergic (DA axons to their forebrain targets remain to be fully elucidated. Wnts are morphogens that have been identified as axon guidance molecules. Several Wnts are expressed in the VM where they regulate the birth of DA neurons. Here, we describe that a precise temporo-spatial expression of Wnt5a accompanies the development of nigrostriatal projections by VM DA neurons. In mice at E11.5, Wnt5a is expressed in the VM where it was found to promote DA neurite and axonal growth in VM primary cultures. By E14.5, when DA axons are approaching their striatal target, Wnt5a causes DA neurite retraction in primary cultures. Co-culture of VM explants with Wnt5a-overexpressing cell aggregates revealed that Wnt5a is capable of repelling DA neurites. Antagonism experiments revealed that the effects of Wnt5a are mediated by the Frizzled receptors and by the small GTPase, Rac1 (a component of the non-canonical Wnt planar cell polarity pathway. Moreover, the effects were specific as they could be blocked by Wnt5a antibody, sFRPs and RYK-Fc. The importance of Wnt5a in DA axon morphogenesis was further verified in Wnt5a-/- mice, where fasciculation of the medial forebrain bundle (MFB as well as the density of DA neurites in the MFB and striatal terminals were disrupted. Thus, our results identify a novel role of Wnt5a in DA axon growth and guidance.

  13. Serotonergic projections from the raphe nuclei to the subthalamic nucleus; a retrograde- and anterograde neuronal tracing study

    DEFF Research Database (Denmark)

    Reznitsky, Martin; Plenge, Per; Hay-Schmidt, Anders

    2016-01-01

    the 5-HT1A and 5-HT2A not were present. Retrograde tracer FluoroGold or Choleratoxin subunit B were iontophoretically delivered in the STN and combined with immunohistochemistry for 5-HT in order to map the topographic organization in the dorsal raphe system. The study showed that approximately 320...

  14. Movement disorders associated with focal midbrain lesion: correlation with clinical and I-123 IPT SPECT findings

    International Nuclear Information System (INIS)

    Kang, Ji Hoon; Im, Joo Hyuk; Kim, Jae Seung; Lee, Myoung Chong

    2001-01-01

    Midbrain lesion may produce a variety of movement disorders including tremor, dystonia, and parkinsonism. The anatomical and functional basis of the movement disorder associated with the midbrain lesion is still unclear. The purpose of this study was to correlate focal midbrain lesions with clinical and I-123 IPT SPECT findings. Five patients (aged 25 to 69 years, 3 men and 2 women) who presented with movement disorder associated with discrete focal midbrain lesion on the brain MRI were included. We reviewed the clinical characteristics of movement disorders and the brain MRI findings in all patients. I-123 IPT SPECT was performed in all patients and 9 normal controls to evaluate the integrity of the nigrostriatal dopaminergic system and specific binding ratios were also calculated. Patients consisted of 2 with parkinsonism, 1 with midbrain tremor, 1 with hemidystonia, and 1 with micrographia as the only manifestation. In all patients, movement disorders were confined to the limbs contralateral to the focal midbrain lesions. The causes of midbrain lesion were trauma (n=2), rupture of AVM (n=1), cerebral infarction (n=1), and encephalitis (n=1). The latency between the midbrain injury and the onset of movement disorder varied from 1.5 months to 2 years (mean 6.7 months). Specific binding ratios of ipsilateral striatum (1.6±1.4) were significantly lower than that of contralateral side (3.3±0.99) and normal control (3.5±0.5)(p<0.05). All of six patients had lesions involving substantia nigra on MRI and two of these with resting tremor had also lesions involving the red nucleus. Bradykinesia and rigidity were mild or absent in these two patients, despite severely decreased specific binding ratios (mean 0.55) of ipsilateral striatum. Movement disorders associated with focal midbrain lesion were partially related to the damage in the nigrostriatal dopaminergic system. However, the severity and nature of movement disorder were variable and not directly related to the

  15. Raphe serotonin neuron-specific oxytocin receptor knockout reduces aggression without affecting anxiety-like behavior in male mice only.

    Science.gov (United States)

    Pagani, J H; Williams Avram, S K; Cui, Z; Song, J; Mezey, É; Senerth, J M; Baumann, M H; Young, W S

    2015-02-01

    Serotonin and oxytocin influence aggressive and anxiety-like behaviors, though it is unclear how the two may interact. That the oxytocin receptor is expressed in the serotonergic raphe nuclei suggests a mechanism by which the two neurotransmitters may cooperatively influence behavior. We hypothesized that oxytocin acts on raphe neurons to influence serotonergically mediated anxiety-like, aggressive and parental care behaviors. We eliminated expression of the oxytocin receptor in raphe neurons by crossing mice expressing Cre recombinase under control of the serotonin transporter promoter (Slc6a4) with our conditional oxytocin receptor knockout line. The knockout mice generated by this cross are normal across a range of behavioral measures: there are no effects for either sex on locomotion in an open-field, olfactory habituation/dishabituation or, surprisingly, anxiety-like behaviors in the elevated O and plus mazes. There was a profound deficit in male aggression: only one of 11 raphe oxytocin receptor knockouts showed any aggressive behavior, compared to 8 of 11 wildtypes. In contrast, female knockouts displayed no deficits in maternal behavior or aggression. Our results show that oxytocin, via its effects on raphe neurons, is a key regulator of resident-intruder aggression in males but not maternal aggression. Furthermore, this reduction in male aggression is quite different from the effects reported previously after forebrain or total elimination of oxytocin receptors. Finally, we conclude that when constitutively eliminated, oxytocin receptors expressed by serotonin cells do not contribute to baseline anxiety-like behaviors or maternal care. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  16. Time-dependent effects of repeated THC treatment on dopamine D2/3 receptor-mediated signalling in midbrain and striatum.

    Science.gov (United States)

    Tournier, Benjamin B; Tsartsalis, Stergios; Dimiziani, Andrea; Millet, Philippe; Ginovart, Nathalie

    2016-09-15

    This study examined the time-course of alterations in levels and functional sensitivities of dopamine D2/3 receptors (D2/3R) during the course and up to 6 weeks following cessation of chronic treatment with Delta(9)-Tetrahydrocannabinol (THC) in rats. THC treatment led to an increase in D2/3R levels in striatum, as assessed using [(3)H]-(+)-PHNO, that was readily observable after one week of treatment, remained stably elevated during the subsequent 2 weeks of treatment, but fully reversed within 2 weeks of THC discontinuation. THC-induced D2/3R alterations were more pronounced and longer lasting in the dopamine cell body regions of the midbrain, wherein [(3)H]-(+)-PHNO binding was still elevated at 2 weeks but back to control values at 6 weeks after THC cessation. Parallel analyses of the psychomotor effects of pre- and post-synaptic doses of quinpirole also showed a pattern of D2/3R functional supersensitivity indicative of more rapid subsidence in striatum than in midbrain following drug cessation. These results indicate that chronic THC is associated with a biochemical and functional sensitization of D2/3R signaling, that these responses show a region-specific temporal pattern and are fully reversible following drug discontinuation. These results suggest that an increased post-synaptic D2/3R function and a decreased DA presynaptic signaling, mediated by increased D2/3R autoinhibition, may predominate during distinct phases of withdrawal and may contribute both to the mechanisms leading to relapse and to cannabinoid withdrawal symptoms. The different rates of normalization of D2/3R function in striatum and midbrain may be critical information for the development of new pharmacotherapies for cannabis dependence. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Disconnectivity between Dorsal Raphe Nucleus and Posterior Cingulate Cortex in Later Life Depression

    Directory of Open Access Journals (Sweden)

    Toshikazu Ikuta

    2017-08-01

    Full Text Available The dorsal raphe nucleus (DRN has been repeatedly implicated as having a significant relationship with depression, along with its serotoninergic innervation. However, functional connectivity of the DRN in depression is not well understood. The current study aimed to isolate functional connectivity of the DRN distinct in later life depression (LLD compared to a healthy age-matched population. Resting state functional magnetic resonance imaging (rsfMRI data from 95 participants (33 LLD and 62 healthy were collected to examine functional connectivity from the DRN to the whole brain in voxel-wise fashion. The posterior cingulate cortex (PCC bilaterally showed significantly smaller connectivity in the LLD group than the control group. The DRN to PCC connectivity did not show any association with the depressive status. The findings implicate that the LLD involves disruption of serotoninergic input to the PCC, which has been suggested to be a part of the reduced default mode network in depression.

  18. Specificity and impact of adrenergic projections to the midbrain dopamine system

    Science.gov (United States)

    Mejias-Aponte, Carlos A.

    2016-01-01

    Dopamine (DA) is a neuromodulator that regulates different brain circuits involved in cognitive functions, motor coordination, and emotions. Dysregulation of DA is associated with many neurological and psychiatric disorders such as Parkinson’s disease and substance abuse. Several lines of research have shown that the midbrain DA system is regulated by the central adrenergic system. This review focuses on adrenergic interactions with midbrain DA neurons. It discusses the current neuroanatomy including source of adrenergic innervation, type of synapses, and adrenoceptors expression. It also discusses adrenergic regulation of DA cell activity and neurotransmitter release. Finally, it reviews several neurological and psychiatric disorders where changes in adrenergic system are associated with dysregulation of the midbrain DA system. PMID:26820641

  19. Activation of midbrain structures by associative novelty and the formation of explicit memory in humans.

    Science.gov (United States)

    Schott, Björn H; Sellner, Daniela B; Lauer, Corinna-J; Habib, Reza; Frey, Julietta U; Guderian, Sebastian; Heinze, Hans-Jochen; Düzel, Emrah

    2004-01-01

    Recent evidence suggests a close functional relationship between memory formation in the hippocampus and dopaminergic neuromodulation originating in the ventral tegmental area and medial substantia nigra of the midbrain. Here we report midbrain activation in two functional MRI studies of visual memory in healthy young adults. In the first study, participants distinguished between familiar and novel configurations of pairs of items which had been studied together by either learning the location or the identity of the items. In the second study, participants studied words by either rating the words' pleasantness or counting syllables. The ventral tegmental area and medial substantia nigra showed increased activation by associative novelty (first study) and subsequent free recall performance (second study). In both studies, this activation accompanied hippocampal activation, but was unaffected by the study task. Thus midbrain regions seem to participate selectively in hippocampus-dependent processes of associative novelty and explicit memory formation, but appear to be unaffected by other task-relevant aspects.

  20. The effects of intracranial administration of hallucinogens on operant behavior in the rat. I. Lysergic acid diethylamide.

    Science.gov (United States)

    Mokler, D J; Stoudt, K W; Sherman, L C; Rech, R H

    1986-10-01

    Lysergic acid diethylamide (LSD) was infused in one microliter volumes into discrete brain regions of rats trained to press a bar for food reinforcement. The sites were chosen as major areas of the brain 5-hydroxytryptamine (5HT) system: the dorsal and median raphe nuclei, dorsal hippocampus, lateral habenular nuclei, and the prefrontal cortex. Following training in a fixed ratio-40 (FR-40) operant behavior rats were implanted for the lateral habenular nuclei, dorsal hippocampus and the prefrontal cortex. Following recovery from surgery, LSD (8.6 to 86 micrograms) or vehicle was infused immediately before a daily operant session. Infusion of vehicle was inactive. LSD produced a dose-dependent decrease in reinforcements and an increase in 10-sec periods of non-responding (pause intervals). LSD was significantly more potent when infused into the dorsal raphe nucleus than following intracerebroventricular (ICV) administration, whereas LSD was less potent when infused into the median raphe, lateral habenula or dorsal hippocampus. ED50s for increases in pause intervals were 9, 13, 23, 25, and 54 micrograms for infusion into the dorsal raphe, prefrontal cortex, dorsal hippocampus, median raphe, and lateral habenular nuclei, respectively. The ED50 for ICV administration in a previous study was 15 micrograms. The ED50 of LSD placed into the prefrontal cortex did not differ significantly from that of the ICV infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

  1. Enhanced midbrain response at 6-month follow-up in cocaine addiction, association with reduced drug-related choice: Midbrain in drug choice

    Energy Technology Data Exchange (ETDEWEB)

    Moeller, Scott J.; Tomasi, Dardo; Woicik, Patricia A.; Maloney, Thomas; Alia-Klein, Nelly; Honorio, Jean; Telang, Frank; Wang, Gene-Jack; Wang, Ruiliang; Sinha, Rajita; Carise, Deni; Astone-Twerell, Janetta; Bolger, Joy; Volkow, Nora D.; Goldstein, Rita Z.

    2012-03-28

    Drug addiction is characterized by dysregulated dopamine neurotransmission. Although dopamine functioning appears to partially recover with abstinence, the specific regions that recover and potential impact on drug seeking remain to be determined. Here we used functional magnetic resonance imaging (fMRI) to study an ecologically valid sample of 15 treatment-seeking cocaine addicted individuals at baseline and 6-month follow-up. At both study sessions, we collected fMRI scans during performance of a drug Stroop task, clinical self-report measures of addiction severity and behavioral measures of cocaine seeking (simulated cocaine choice); actual drug use in between the two study sessions was also monitored. At 6-month follow-up (compared with baseline), we predicted functional enhancement of dopaminergically innervated brain regions, relevant to the behavioral responsiveness toward salient stimuli. Consistent with predictions, whole-brain analyses revealed responses in the midbrain (encompassing the ventral tegmental area/substantia nigra complex) and thalamus (encompassing the mediodorsal nucleus) that were higher (and more positively correlated) at follow-up than baseline. Increased midbrain activity from baseline to follow-up correlated with reduced simulated cocaine choice, indicating that heightened midbrain activations in this context may be marking lower approach motivation for cocaine. Normalization of midbrain function at follow-up was also suggested by exploratory comparisons with active cocaine users and healthy controls (who were assessed only at baseline). Enhanced self-control at follow-up was suggested by a trend for the commonly hypoactive dorsal anterior cingulate cortex to increase response during a drug-related context. Together, these results suggest that fMRI could be useful in sensitively tracking follow-up outcomes in drug addiction.

  2. Self-transcendence trait and its relationship with in vivo serotonin transporter availability in brainstem raphe nuclei: An ultra-high resolution PET-MRI study.

    Science.gov (United States)

    Kim, Jong-Hoon; Son, Young-Don; Kim, Jeong-Hee; Choi, Eun-Jung; Lee, Sang-Yoon; Joo, Yo-Han; Kim, Young-Bo; Cho, Zang-Hee

    2015-12-10

    Self-transcendence is an inherent human personality trait relating to the experience of spiritual aspects of the self. We examined the relationship between self-transcendence and serotonin transporter (SERT) availability in brainstem raphe nuclei, which are collections of five different serotonergic nuclei with rostro-caudal extension, using ultra-high resolution magnetic resonance imaging (MRI) and positron emission tomography (PET) with (11)C-3-amino-4-(2-dimethylaminomethylphenylthio)benzonitrile ([(11)C]DASB) to elucidate potential roles of serotonergic neuronal activities in this personality trait. Sixteen healthy subjects completed 7.0T MRI and High Resolution Research Tomograph (HRRT) PET. The regions of interest (ROIs) included the dorsal raphe nucleus (R1), median raphe nucleus (R2), raphe pontis (R3), and the caudal raphe nuclei (R4 and R5). For the estimation of SERT availability, the binding potential (BPND) was derived using the simplified reference tissue model (SRTM2). The Temperament and Character Inventory was used to measure self-transcendence. The analysis revealed that the self-transcendence total score had a significant negative correlation with the [(11)C]DASB BPND in the caudal raphe (R5). The subscale score for spiritual acceptance was significantly negatively correlated with the [(11)C]DASB BPND in the median raphe nucleus (R2). The results indicate that the self-transcendence trait is associated with SERT availability in specific raphe subnuclei, suggesting that the serotonin system may serve as an important biological basis for human self-transcendence. Based on the connections of these nuclei with cortico-limbic and visceral autonomic structures, the functional activity of these nuclei and their related neural circuitry may play a crucial role in the manifestation of self-transcendence. Copyright © 2015. Published by Elsevier B.V.

  3. Fos and serotonin immunoreactivity in the raphe nuclei of the cat during carbachol-induced active sleep: a double-labeling study.

    Science.gov (United States)

    Yamuy, J; Sampogna, S; López-Rodríguez, F; Luppi, P H; Morales, F R; Chase, M H

    1995-07-01

    The microinjection of carbachol into the nucleus pontis oralis produces a state which is polygraphically and behaviorally similar to active sleep (rapid eye movement sleep). In the present study, using double-labeling techniques for serotonin and the protein product of c-fos (Fos), we sought to examine whether immunocytochemically identified serotonergic neurons of the raphe nuclei of the cat were activated, as indicated by their expression of c-fos, during this pharmacologically-induced behavioral state (active sleep-carbachol). Compared with control cats, which were injected with saline, active sleep-carbachol cats exhibited a significantly greater number of c-fos-expressing neurons in the raphe dorsalis, magnus and pallidus. Whereas most of the c-fos-expressing neurons in the raphe dorsalis were small, those in the raphe magnus were medium-sized and in the raphe pallidus they were small and medium-sized. The mean number of serotonergic neurons that expressed c-fos (i.e. double-labeled cells) was similar in control and active sleep-carbachol cats. These data indicate that there is an increased number of non-serotonergic, c-fos-expressing neurons in the raphe dorsalis, magnus and pallidus during the carbachol-induced state.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. FUSIMOTOR EFFECTS OF MIDBRAIN STIMULATION ON JAW MUSCLE-SPINDLES OF THE ANESTHETIZED CAT

    NARCIS (Netherlands)

    TAYLOR, A; JUCH, PJW

    The effects of electrical stimulation within the midbrain on fusimotor output to the jaw elevator muscles were studied in anaesthetized cats. Muscle spindle afferents recorded in the mesencephalic trigeminal nucleus were categorised as primary or secondary by their responses to succinylcholine

  5. Midbrain and medullary control of postinspiratory activity of the crural and costal diaphragm in vivo

    NARCIS (Netherlands)

    Subramanian, Hari H.; Holstege, Gert

    Subramanian HH, Holstege G. Midbrain and medullary control of postinspiratory activity of the crural and costal diaphragm in vivo. J Neurophysiol 105: 2852-2862, 2011. First published March 30, 2011; doi:10.1152/jn.00168.2011.-Studies on brain stem respiratory neurons suggest that eupnea consists of

  6. Development and function of the midbrain dopamine system: what we know and what we need to.

    Science.gov (United States)

    Bissonette, G B; Roesch, M R

    2016-01-01

    The past two decades have seen an explosion in our understanding of the origin and development of the midbrain dopamine system. Much of this work has been focused on the aspects of dopamine neuron development related to the onset of movement disorders such as Parkinson's disease, with the intent of hopefully delaying, preventing or fixing symptoms. While midbrain dopamine degeneration is a major focus for treatment and research, many other human disorders are impacted by abnormal dopamine, including drug addiction, autism and schizophrenia. Understanding dopamine neuron ontogeny and how dopamine connections and circuitry develops may provide us with key insights into potentially important avenues of research for other dopamine-related disorders. This review will provide a brief overview of the major molecular and genetic players throughout the development of midbrain dopamine neurons and what we know about the behavioral- and disease-related implications associated with perturbations to midbrain dopamine neuron development. We intend to combine the knowledge of two broad fields of neuroscience, both developmental and behavioral, with the intent on fostering greater discussion between branches of neuroscience in the service of addressing complex cognitive questions from a developmental perspective and identifying important gaps in our knowledge for future study. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  7. vox homeobox gene: a novel regulator of midbrain-hindbrain boundary development in medaka fish?

    Czech Academy of Sciences Publication Activity Database

    Fabian, Peter; Pantzartzi, Chrysoula; Kozmiková, Iryna; Kozmik, Zbyněk

    2016-01-01

    Roč. 226, č. 2 (2016), s. 99-107 ISSN 0949-944X R&D Projects: GA MŠk LO1419 Institutional support: RVO:68378050 Keywords : Midbrain-hindbrain boundary * vox * medaka * Heat shock element * fgf8 * Gene regulatory network Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.422, year: 2016

  8. The dorsal tectal longitudinal column (TLCd): a second longitudinal column in the paramedian region of the midbrain tectum.

    Science.gov (United States)

    Aparicio, M-Auxiliadora; Saldaña, Enrique

    2014-03-01

    The tectal longitudinal column (TLC) is a longitudinally oriented, long and narrow nucleus that spans the paramedian region of the midbrain tectum of a large variety of mammals (Saldaña et al. in J Neurosci 27:13108-13116, 2007). Recent analysis of the organization of this region revealed another novel nucleus located immediately dorsal, and parallel, to the TLC. Because the name "tectal longitudinal column" also seems appropriate for this novel nucleus, we suggest the TLC described in 2007 be renamed the "ventral tectal longitudinal column (TLCv)", and the newly discovered nucleus termed the "dorsal tectal longitudinal column (TLCd)". This work represents the first characterization of the rat TLCd. A constellation of anatomical techniques was used to demonstrate that the TLCd differs from its surrounding structures (TLCv and superior colliculus) cytoarchitecturally, myeloarchitecturally, neurochemically and hodologically. The distinct expression of vesicular amino acid transporters suggests that TLCd neurons are GABAergic. The TLCd receives major projections from various areas of the cerebral cortex (secondary visual mediomedial area, and granular and dysgranular retrosplenial cortices) and from the medial pretectal nucleus. It densely innervates the ipsilateral lateral posterior and laterodorsal nuclei of the thalamus. Thus, the TLCd is connected with vision-related neural centers. The TLCd may be unique as it constitutes the only known nucleus made of GABAergic neurons dedicated to providing massive inhibition to higher order thalamic nuclei of a specific sensory modality.

  9. Increased mRNA expression of cytochrome oxidase in dorsal raphe nucleus of depressive suicide victims

    Directory of Open Access Journals (Sweden)

    A Sanchez-Bahillo

    2008-04-01

    Full Text Available A Sanchez-Bahillo1, V Bautista-Hernandez1, Carlos Barcia Gonzalez1, R Bañon2, A Luna2, EC Hirsch3, Maria-Trinidad Herrero11Clinical and Experimental Neuroscience, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED; 2Department of Legal Medicine, Department of Human Anatomy, School of Medicine, University of Murcia, Campus de Espinardo, Murcia 30100, Spain; 3INSERM U679 Hôpital de la Salpêtrière, Boulevard de l’Hôpital, Paris, FranceAbstract: Suicidal behavior is a problem with important social repercussions. Some groups of the population show a higher risk of suicide; for example, depression, alcoholism, psychosis or drug abuse frequently precedes suicidal behavior. However, the relationship between metabolic alterations in the brain and premorbid clinical symptoms of suicide remains uncertain. The serotonergic and noradrenergic systems have frequently been, implicated in suicidal behavior and the amount of serotonin in the brain and CSF of suicide victims has been found to be low compared with normal subjects. However, there are contradictory results regarding the role of noradrenergic neurons in the mediation of suicide attempts, possibly reflecting the heterogeneity of conditions that lead to a common outcome. In the present work we focus on the subgroup of suicide victims that share a common diagnosis of major depression. Based on post-mortem studies analyzing mRNA expression by in situ hybridization, serotonergic neurons from the dorsal raphe nucleus (DRN from depressive suicide victims are seen to over-express cytochrome oxidase mRNA. However, no corresponding changes were found in the expression of tyrosine hydroxylase (TH mRNA in the noradrenergic neurons of the Locus Coeruleus (LC. These results suggest that, despite of the low levels of serotonin described in suicide victims, the activity of DRN neurons could increase in the suicidally depressed, probably due to the over activation of

  10. Positive regulation of raphe serotonin neurons by serotonin 2B receptors.

    Science.gov (United States)

    Belmer, Arnauld; Quentin, Emily; Diaz, Silvina L; Guiard, Bruno P; Fernandez, Sebastian P; Doly, Stéphane; Banas, Sophie M; Pitychoutis, Pothitos M; Moutkine, Imane; Muzerelle, Aude; Tchenio, Anna; Roumier, Anne; Mameli, Manuel; Maroteaux, Luc

    2018-06-01

    Serotonin is a neurotransmitter involved in many psychiatric diseases. In humans, a lack of 5-HT 2B receptors is associated with serotonin-dependent phenotypes, including impulsivity and suicidality. A lack of 5-HT 2B receptors in mice eliminates the effects of molecules that directly target serotonergic neurons including amphetamine derivative serotonin releasers, and selective serotonin reuptake inhibitor antidepressants. In this work, we tested the hypothesis that 5-HT 2B receptors directly and positively regulate raphe serotonin neuron activity. By ex vivo electrophysiological recordings, we report that stimulation by the 5-HT 2B receptor agonist, BW723C86, increased the firing frequency of serotonin Pet1-positive neurons. Viral overexpression of 5-HT 2B receptors in these neurons increased their excitability. Furthermore, in vivo 5-HT 2B -receptor stimulation by BW723C86 counteracted 5-HT 1A autoreceptor-dependent reduction in firing rate and hypothermic response in wild-type mice. By a conditional genetic ablation that eliminates 5-HT 2B receptor expression specifically and exclusively from Pet1-positive serotonin neurons (Htr2b 5-HTKO mice), we demonstrated that behavioral and sensitizing effects of MDMA (3,4-methylenedioxy-methamphetamine), as well as acute behavioral and chronic neurogenic effects of the antidepressant fluoxetine, require 5-HT 2B receptor expression in serotonergic neurons. In Htr2b 5-HTKO mice, dorsal raphe serotonin neurons displayed a lower firing frequency compared to control Htr2b lox/lox mice as assessed by in vivo extracellular recordings and a stronger hypothermic effect of 5-HT 1A -autoreceptor stimulation was observed. The increase in head-twitch response to DOI (2,5-dimethoxy-4-iodoamphetamine) further confirmed the lower serotonergic tone resulting from the absence of 5-HT 2B receptors in serotonin neurons. Together, these observations indicate that the 5-HT 2B receptor acts as a direct positive modulator of serotonin Pet1

  11. Auditory midbrain processing is differentially modulated by auditory and visual cortices: An auditory fMRI study.

    Science.gov (United States)

    Gao, Patrick P; Zhang, Jevin W; Fan, Shu-Juan; Sanes, Dan H; Wu, Ed X

    2015-12-01

    The cortex contains extensive descending projections, yet the impact of cortical input on brainstem processing remains poorly understood. In the central auditory system, the auditory cortex contains direct and indirect pathways (via brainstem cholinergic cells) to nuclei of the auditory midbrain, called the inferior colliculus (IC). While these projections modulate auditory processing throughout the IC, single neuron recordings have samples from only a small fraction of cells during stimulation of the corticofugal pathway. Furthermore, assessments of cortical feedback have not been extended to sensory modalities other than audition. To address these issues, we devised blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) paradigms to measure the sound-evoked responses throughout the rat IC and investigated the effects of bilateral ablation of either auditory or visual cortices. Auditory cortex ablation increased the gain of IC responses to noise stimuli (primarily in the central nucleus of the IC) and decreased response selectivity to forward species-specific vocalizations (versus temporally reversed ones, most prominently in the external cortex of the IC). In contrast, visual cortex ablation decreased the gain and induced a much smaller effect on response selectivity. The results suggest that auditory cortical projections normally exert a large-scale and net suppressive influence on specific IC subnuclei, while visual cortical projections provide a facilitatory influence. Meanwhile, auditory cortical projections enhance the midbrain response selectivity to species-specific vocalizations. We also probed the role of the indirect cholinergic projections in the auditory system in the descending modulation process by pharmacologically blocking muscarinic cholinergic receptors. This manipulation did not affect the gain of IC responses but significantly reduced the response selectivity to vocalizations. The results imply that auditory cortical

  12. Reduction in brain immunoreactive corticotropin-releasing factor (CRF) in spontaneously hypertensive rats

    International Nuclear Information System (INIS)

    Hashimoto, K.; Hattori, T.; Murakami, K.; Suemaru, S.; Kawada, Y.; Kageyama, J.; Ota, Z.

    1985-01-01

    The brain CRF concentration of spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) was examined by rat CRF radioimmunoassay. Anti-CRF serum was developed by immunizing rabbits with synthetic rat CRF. Synthetic rat CRF was also used as tracer and standard. The displacement of 125 I-rat CRF by serially diluted extracts of male Wistar rats hypothalamus, thalamus, midbrain, pons, medulla oblongata, cerebral cortex, cerebellum and neurointermediate lobe was parallel to the displacement of synthetic rat CRF. In both WKY and SHR the highest levels of CRF immunoreactivity were shown by the hypothalamus and neurointermediate lobe, and considerable CRF immunoreactivity was also detected in other brain regions. The CRF immunoreactivity in the hypothalamus, neurointermediate lobe, midbrain, medulla oblongata and cerebral cortex was significantly reduced in SHR and it may suggest that CRF abnormality may be implicated in the reported abnormalities in the pituitary-adrenal axis, autonomic response and behavior of SHR

  13. Serotonergic versus Nonserotonergic Dorsal Raphe Projection Neurons: Differential Participation in Reward Circuitry

    Directory of Open Access Journals (Sweden)

    Ross A. McDevitt

    2014-09-01

    Full Text Available The dorsal raphe nucleus (DRN contains the largest group of serotonin-producing neurons in the brain and projects to regions controlling reward. Although pharmacological studies suggest that serotonin inhibits reward seeking, electrical stimulation of the DRN strongly reinforces instrumental behavior. Here, we provide a targeted assessment of the behavioral, anatomical, and electrophysiological contributions of serotonergic and nonserotonergic DRN neurons to reward processes. To explore DRN heterogeneity, we used a simultaneous two-vector knockout/optogenetic stimulation strategy, as well as cre-induced and cre-silenced vectors in several cre-expressing transgenic mouse lines. We found that the DRN is capable of reinforcing behavior primarily via nonserotonergic neurons, for which the main projection target is the ventral tegmental area (VTA. Furthermore, these nonserotonergic projections provide glutamatergic excitation of VTA dopamine neurons and account for a large majority of the DRN-VTA pathway. These findings help to resolve apparent discrepancies between the roles of serotonin versus the DRN in behavioral reinforcement.

  14. Biophysical properties and computational modeling of calcium spikes in serotonergic neurons of the dorsal raphe nucleus.

    Science.gov (United States)

    Tuckwell, Henry C

    2013-06-01

    Serotonergic neurons of the dorsal raphe nuclei, with their extensive innervation of nearly the whole brain have important modulatory effects on many cognitive and physiological processes. They play important roles in clinical depression and other psychiatric disorders. In order to quantify the effects of serotonergic transmission on target cells it is desirable to construct computational models and to this end these it is necessary to have details of the biophysical and spike properties of the serotonergic neurons. Here several basic properties are reviewed with data from several studies since the 1960s to the present. The quantities included are input resistance, resting membrane potential, membrane time constant, firing rate, spike duration, spike and afterhyperpolarization (AHP) amplitude, spike threshold, cell capacitance, soma and somadendritic areas. The action potentials of these cells are normally triggered by a combination of sodium and calcium currents which may result in autonomous pacemaker activity. We here analyse the mechanisms of high-threshold calcium spikes which have been demonstrated in these cells the presence of TTX (tetrodotoxin). The parameters for calcium dynamics required to give calcium spikes are quite different from those for regular spiking which suggests the involvement of restricted parts of the soma-dendritic surface as has been found, for example, in hippocampal neurons. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  15. A pilot study on predictors of brainstem raphe abnormality in patients with major depressive disorder.

    Science.gov (United States)

    Kostić, Milutin; Munjiza, Ana; Pesic, Danilo; Peljto, Amir; Novakovic, Ivana; Dobricic, Valerija; Tosevski, Dusica Lecic; Mijajlovic, Milija

    2017-02-01

    Hypo/anechogenicity of the brainstem raphe (BR) structures has been suggested as a possible transcranial parenchymal sonography (TCS) marker associated with depression. The aim of this study was to analyze possible association of the abnormal BR echogenicity in patients with major depression when compared to healthy controls, and to evaluate its clinical and genetic correlates. TCS was performed in 53 patients diagnosed as major depressive disorder (MDD) without psychotic symptoms and in 54 healthy matched controls. The TCS detected BR abnormalities were significantly more frequent in MDD patients (35 out of 53; 66%) in comparison to matched controls (5 out of 56; 9%). The prevalence of short allele (s) homozygocity in the length polymorphism of the promoter region of the serotonin transporter gene (5-HTTLPR) was significantly higher in MDD patients relative to those with normal BR echogenicity. A stepwise statistical discriminant analysis revealed statistically significant separation between MDD patients with and without BR abnormalities groups based on the four predictors combined: the Hamilton Anxiety Rating Scale item 5 ("difficulty in concentration, poor memory"), presence of social phobia, s allele homozygocity of the 5-HTTLPR polymorphism, and presence of generalized anxiety disorder. Cross-sectional design and heterogenous treatment of depressed patients. Reduced BR echogenicity in at least a subgroup of MDD patients may reflect a particular phenotype, characterized by more prevalent comorbid anxiety disorders, associated with particular genetic polymorphisms and neurotransmitter(s) deficits, most probably altered serotonergic mechanisms. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Serotonin regulates the phase of the rat suprachiasmatic circadian pacemaker in vitro only during the subjective day.

    Science.gov (United States)

    Medanic, M; Gillette, M U

    1992-05-01

    1. The suprachiasmatic nucleus (SCN) of the hypothalamus is the primary pacemaker for circadian rhythms in mammals. The 24 h pacemaker is endogenous to the SCN and persists for multiple cycles in the suprachiasmatic brain slice. 2. While serotonin is not endogenous to the SCN, a major midbrain hypothalamic afferent pathway is serotonergic. Within this tract the dorsal raphe nucleus sends direct projections to the ventrolateral portions of the SCN. We investigated a possible regulatory role for serotonin in the mammalian circadian system by examining its effect, when applied at projection sites, on the circadian rhythm of neuronal activity in rat SCN in vitro. 3. Eight-week-old male rats from our inbred colony, housed on a 12 h light: 12 h dark schedule, were used. Hypothalamic brain slices containing the paired SCN were prepared in the day and maintained in glucose and bicarbonate-supplemented balanced salt solution for up to 53 h. 4. A 10(-11) ml drop of 10(-6) M-serotonin (5-hydroxytryptamine (5-HT) creatinine sulphate complex) in medium was applied to the ventrolateral portion of one of the SCN for 5 min on the first day in vitro. The effect of the treatment at each of seven time points across the circadian cycle was examined. The rhythm of spontaneous neuronal activity was recorded extracellularly on the second and third days in vitro. Phase shifts were determined by comparing the time-of-peak of neuronal activity in serotonin- vs. media-treated slices. 5. Application of serotonin during the subjective day induced significant advances in the phase of the electrical activity rhythm (n = 11). The most sensitive time of treatment was CT 7 (circadian time 7 is 7 h after 'lights on' in the animal colony), when a 7.0 +/- 0.1 h phase advance was observed (n = 3). This phase advance was perpetuated on day 3 in vitro without decrement. Serotonin treatment during the subjective night had no effect on the timing of the electrical activity rhythm (n = 9). 6. The

  17. Cooperative transcription activation by Nurr1 and Pitx3 induces embryonic stem cell maturation to the midbrain dopamine neuron phenotype

    DEFF Research Database (Denmark)

    Martinat, Cecile; Bacci, Jean-Jacques; Leete, Thomas

    2006-01-01

    's disease. We sought to identify genes that can potentiate maturation of ES cell cultures to the midbrain DA neuron phenotype. A number of transcription factors have been implicated in the development of midbrain DA neurons by expression analyses and loss-of-function knockout mouse studies, including Nurr1......Midbrain dopamine (DA) neurons play a central role in the regulation of voluntary movement, and their degeneration is associated with Parkinson's disease. Cell replacement therapies, and in particular embryonic stem (ES) cell-derived DA neurons, offer a potential therapeutic venue for Parkinson......, Pitx3, Lmx1b, Engrailed-1, and Engrailed-2. However, none of these factors appear sufficient alone to induce the mature midbrain DA neuron phenotype in ES cell cultures in vitro, suggesting a more complex regulatory network. Here we show that Nurr1 and Pitx3 cooperatively promote terminal maturation...

  18. Acute Psychosis Associated with Subcortical Stroke: Comparison between Basal Ganglia and Mid-Brain Lesions

    Directory of Open Access Journals (Sweden)

    Aaron McMurtray

    2014-01-01

    Full Text Available Acute onset of psychosis in an older or elderly individual without history of previous psychiatric disorders should prompt a thorough workup for neurologic causes of psychiatric symptoms. This report compares and contrasts clinical features of new onset of psychotic symptoms between two patients, one with an acute basal ganglia hemorrhagic stroke and another with an acute mid-brain ischemic stroke. Delusions and hallucinations due to basal ganglia lesions are theorized to develop as a result of frontal lobe dysfunction causing impairment of reality checking pathways in the brain, while visual hallucinations due to mid-brain lesions are theorized to develop due to dysregulation of inhibitory control of the ponto-geniculate-occipital system. Psychotic symptoms occurring due to stroke demonstrate varied clinical characteristics that depend on the location of the stroke within the brain. Treatment with antipsychotic medications may provide symptomatic relief.

  19. Midbrain adaptation may set the stage for the perception of musical beat

    Science.gov (United States)

    2017-01-01

    The ability to spontaneously feel a beat in music is a phenomenon widely believed to be unique to humans. Though beat perception involves the coordinated engagement of sensory, motor and cognitive processes in humans, the contribution of low-level auditory processing to the activation of these networks in a beat-specific manner is poorly understood. Here, we present evidence from a rodent model that midbrain preprocessing of sounds may already be shaping where the beat is ultimately felt. For the tested set of musical rhythms, on-beat sounds on average evoked higher firing rates than off-beat sounds, and this difference was a defining feature of the set of beat interpretations most commonly perceived by human listeners over others. Basic firing rate adaptation provided a sufficient explanation for these results. Our findings suggest that midbrain adaptation, by encoding the temporal context of sounds, creates points of neural emphasis that may influence the perceptual emergence of a beat. PMID:29118141

  20. Differences in Number of Midbrain Dopamine Neurons Associated with Summer and Winter Photoperiods in Humans.

    Directory of Open Access Journals (Sweden)

    Tim D Aumann

    Full Text Available Recent evidence indicates the number of dopaminergic neurons in the adult rodent hypothalamus and midbrain is regulated by environmental cues, including photoperiod, and that this occurs via up- or down-regulation of expression of genes and proteins that are important for dopamine (DA synthesis in extant neurons ('DA neurotransmitter switching'. If the same occurs in humans, it may have implications for neurological symptoms associated with DA imbalances. Here we tested whether there are differences in the number of tyrosine hydroxylase (TH, the rate-limiting enzyme in DA synthesis and DA transporter (DAT immunoreactive neurons in the midbrain of people who died in summer (long-day photoperiod, n = 5 versus winter (short-day photoperiod, n = 5. TH and DAT immunoreactivity in neurons and their processes was qualitatively higher in summer compared with winter. The density of TH immunopositive (TH+ neurons was significantly (~6-fold higher whereas the density of TH immunonegative (TH- neurons was significantly (~2.5-fold lower in summer compared with winter. The density of total neurons (TH+ and TH- combined was not different. The density of DAT+ neurons was ~2-fold higher whereas the density of DAT- neurons was ~2-fold lower in summer compared with winter, although these differences were not statistically significant. In contrast, midbrain nuclear volume, the density of supposed glia (small TH- cells, and the amount of TUNEL staining were the same in summer compared with winter. This study provides the first evidence of an association between environmental stimuli (photoperiod and the number of midbrain DA neurons in humans, and suggests DA neurotransmitter switching underlies this association.

  1. Genetic deletion of afadin causes hydrocephalus by destruction of adherens junctions in radial glial and ependymal cells in the midbrain.

    Directory of Open Access Journals (Sweden)

    Hideaki Yamamoto

    Full Text Available Adherens junctions (AJs play a role in mechanically connecting adjacent cells to maintain tissue structure, particularly in epithelial cells. The major cell-cell adhesion molecules at AJs are cadherins and nectins. Afadin binds to both nectins and α-catenin and recruits the cadherin-β-catenin complex to the nectin-based cell-cell adhesion site to form AJs. To explore the role of afadin in radial glial and ependymal cells in the brain, we generated mice carrying a nestin-Cre-mediated conditional knockout (cKO of the afadin gene. Newborn afadin-cKO mice developed hydrocephalus and died neonatally. The afadin-cKO brain displayed enlarged lateral ventricles and cerebral aqueduct, resulting from stenosis of the caudal end of the cerebral aqueduct and obliteration of the ventral part of the third ventricle. Afadin deficiency further caused the loss of ependymal cells from the ventricular and aqueductal surfaces. During development, radial glial cells, which terminally differentiate into ependymal cells, scattered from the ventricular zone and were replaced by neurons that eventually covered the ventricular and aqueductal surfaces of the afadin-cKO midbrain. Moreover, the denuded ependymal cells were only occasionally observed in the third ventricle and the cerebral aqueduct of the afadin-cKO midbrain. Afadin was co-localized with nectin-1 and N-cadherin at AJs of radial glial and ependymal cells in the control midbrain, but these proteins were not concentrated at AJs in the afadin-cKO midbrain. Thus, the defects in the afadin-cKO midbrain most likely resulted from the destruction of AJs, because AJs in the midbrain were already established before afadin was genetically deleted. These results indicate that afadin is essential for the maintenance of AJs in radial glial and ependymal cells in the midbrain and is required for normal morphogenesis of the cerebral aqueduct and ventral third ventricle in the midbrain.

  2. Response characteristics of vibration-sensitive neurons in the midbrain of the grassfrog, Rana temporaria

    DEFF Research Database (Denmark)

    Christensen-Dalsgaard, J; Jørgensen, M B

    1989-01-01

    European grassfrogs (Rana temporaria) were stimulated with pulsed sinusoidal, vertical vibrations (10-300 Hz) and the responses of 46 single midbrain neurons were recorded in awake, immobilized animals. Most units (40) had simple V-shaped excitatory vibrational tuning curves. The distribution of ...... stimuli probably play a role in communication and detection of predators and the vibration-sensitive midbrain neurons may be involved in the central processing of such behaviorally significant stimuli.......European grassfrogs (Rana temporaria) were stimulated with pulsed sinusoidal, vertical vibrations (10-300 Hz) and the responses of 46 single midbrain neurons were recorded in awake, immobilized animals. Most units (40) had simple V-shaped excitatory vibrational tuning curves. The distribution...... of best frequencies (BF's) was bimodal with peaks at 10 and 100 Hz and the thresholds ranged from 0.02 to 1.28 cm/s2 at the BF. Twenty-three neurons showed phasic-tonic and 11 neurons phasic responses. The dynamic range of seismic intensity for most neurons was 20-30 dB. In contrast to the sharp phase...

  3. Isolated Medial Rectus Nuclear Palsy as a Rare Presentation of Midbrain Infarction.

    Science.gov (United States)

    Al-Sofiani, Mohammed; Lee Kwen, Peterkin

    2015-10-08

    Diplopia is a common subjective complaint that can be the first manifestation of a serious pathology. Here, we report a rare case of midbrain infarction involving the lateral subnucleus of the oculomotor nuclear complex presenting as diplopia, with no other stroke manifestations. An 83-year-old right-handed white man with past medical history of diabetes mellitus, hypertension, dyslipidemia, and coronary artery disease presented to the emergency department (ED) with diplopia and unsteadiness. Two days prior to admission, the patient woke up with constant horizontal diplopia and unsteadiness, which limited his daily activities and led to a fall at home. He denied any weakness, clumsiness, nausea, vomiting, photophobia, fever, or chills. Ocular exam showed a disconjugate gaze at rest, weakness of the left medial rectus muscle, impaired convergence test, and bilateral 3-mm reactive pupils. The diplopia resolved by closing either eye. The remaining extraocular muscles and other cranial nerves were normal. There was no nystagmus, ptosis, or visual field deficit. Sensation, muscle tone, and strength were normal in all extremities. Magnetic resonance imaging (MRI) of the brain revealed a tiny focus of restricted diffusion in the left posterior lateral midbrain. A thorough history and physical examination is essential to diagnose and manage diplopia. Isolated extraocular palsy is usually thought to be caused by orbital lesions or muscular diseases. Here, we report a case of midbrain infarction manifested as isolated medial rectus palsy.

  4. Parkinson's disease-like midbrain hyperechogenicity is frequent in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Fathinia, Panteha; Hermann, Andreas; Reuner, Ulrike; Kassubek, Jan; Storch, Alexander; Ludolph, Albert C

    2013-02-01

    Clinical and neuroimaging data suggest impairment of the nigrostriatal system in amyotrophic lateral sclerosis (ALS). We thus hypothesized whether Parkinson's disease (PD)-like midbrain sonography findings are also present in ALS. Eighty-six patients with the diagnosis of possible or definite ALS according to revised El Escorial criteria were examined by transcranial B-mode sonography compared to 76 age- and gender-matched controls and 33 PD patients. Hyperechogenic areas of the midbrain representing the substantia nigra were measured planimetrically using standard protocols. In subjects with sufficient temporal acoustic bone windows, mean midbrain hyperechogenic areas were significantly higher in ALS (0.251 ± 0.104 cm(2)) and PD patients (0.286 ± 0.078 cm(2)) compared to controls (0.091 ± 0.054 cm(2)) with no significant difference between ALS and PD patients (one-way ANOVA: F value = 94.3; P diagnosis and differential diagnosis of PD and ALS alike.

  5. The role of the dorsal raphé nucleus in reward-seeking behavior

    Directory of Open Access Journals (Sweden)

    Kae eNakamura

    2013-08-01

    Full Text Available Pharmacological experiments have shown that the modulation of brain serotonin levels has a strong impact on value-based decision making. Anatomical and physiological evidence also revealed that the dorsal raphé nucleus (DRN, a major source of serotonin, and the dopamine system receive common inputs from brain regions associated with appetitive and aversive information processing. The serotonin and dopamine systems also have reciprocal functional influences on each other. However, the specific mechanism by which serotonin affects value-based decision making is not clear.To understand the information carried by the DRN for reward-seeking behavior, we measured single neuron activity in the primate DRN during the performance of saccade tasks to obtain different amounts of a reward. We found that DRN neuronal activity was characterized by tonic modulation that was altered by the expected and received reward value. Consistent reward-dependent modulation across different task periods suggested that DRN activity kept track of the reward value throughout a trial. The DRN was also characterized by modulation of its activity in the opposite direction by different neuronal subgroups, one firing strongly for the prediction and receipt of large rewards, with the other firing strongly for small rewards. Conversely, putative dopamine neurons showed positive phasic responses to reward-indicating cues and the receipt of an unexpected reward amount, which supports the reward prediction error signal hypothesis of dopamine.I suggest that the tonic reward monitoring signal of the DRN, possibly together with its interaction with the dopamine system, reports a continuous level of motivation throughout the performance of a task. Such a signal may provide reward context information to the targets of DRN projections, where it may be integrated further with incoming motivationally salient information.

  6. Impacts of brain serotonin deficiency following Tph2 inactivation on development and raphe neuron serotonergic specification.

    Directory of Open Access Journals (Sweden)

    Lise Gutknecht

    Full Text Available Brain serotonin (5-HT is implicated in a wide range of functions from basic physiological mechanisms to complex behaviors, including neuropsychiatric conditions, as well as in developmental processes. Increasing evidence links 5-HT signaling alterations during development to emotional dysregulation and psychopathology in adult age. To further analyze the importance of brain 5-HT in somatic and brain development and function, and more specifically differentiation and specification of the serotonergic system itself, we generated a mouse model with brain-specific 5-HT deficiency resulting from a genetically driven constitutive inactivation of neuronal tryptophan hydroxylase-2 (Tph2. Tph2 inactivation (Tph2-/- resulted in brain 5-HT deficiency leading to growth retardation and persistent leanness, whereas a sex- and age-dependent increase in body weight was observed in Tph2+/- mice. The conserved expression pattern of the 5-HT neuron-specific markers (except Tph2 and 5-HT demonstrates that brain 5-HT synthesis is not a prerequisite for the proliferation, differentiation and survival of raphe neurons subjected to the developmental program of serotonergic specification. Furthermore, although these neurons are unable to synthesize 5-HT from the precursor tryptophan, they still display electrophysiological properties characteristic of 5-HT neurons. Moreover, 5-HT deficiency induces an up-regulation of 5-HT(1A and 5-HT(1B receptors across brain regions as well as a reduction of norepinephrine concentrations accompanied by a reduced number of noradrenergic neurons. Together, our results characterize developmental, neurochemical, neurobiological and electrophysiological consequences of brain-specific 5-HT deficiency, reveal a dual dose-dependent role of 5-HT in body weight regulation and show that differentiation of serotonergic neuron phenotype is independent from endogenous 5-HT synthesis.

  7. Involvement of serotonin in the ventral tegmental area in thermoregulation of freely moving rats.

    Science.gov (United States)

    Ishiwata, Takayuki; Hasegawa, Hiroshi; Greenwood, Benjamin N

    2017-07-13

    We have recently reported that the serotonin (5-HT) projections from the midbrain's raphe nuclei that contains 5-HT cell bodies may play a role both in heat production and in heat loss. The purpose of the present study was to clarify the involvement of 5-HT in the ventral tegmental area (VTA), where 5-HT is suggested to participate in thermoregulation, using the combined methods of telemetry, microdialysis, and high performance liquid chromatography, with a special emphasis on regulation of the body temperature (T b ) in freely moving rats. First, we measured changes in T b , tail skin temperature (T tail ; an index of heat loss), heart rate (HR; an index of heat production), locomotor activity (Act), and levels of extracellular monoamines in the VTA during cold (5°C) or heat (35°C) exposure. Subsequently, we perfused citalopram (5-HT re-uptake inhibitor) into the VTA and measured the thermoregulatory parameters and monoamines release. Although T b , T tail , and HR changed during both exposures, significant changes in extracellular level of 5-HT (138.7±12.7% baseline, p<0.01), but not dopamine (DA) or noradrenaline (NA) were noted in the VTA only during heat exposure. In addition, perfusion of citalopram into the VTA increased extracellular 5-HT levels (221.0±52.2% baseline, p<0.01), but not DA or NA, while T b decreased from 37.4±0.1°C to 36.8±0.2°C (p<0.001),T tail increased from 26.3±0.4°C to 28.4±0.4°C (p<0.001), and HR and Act remained unchanged. Our results suggest that the VTA is a key area for thermoregulation, and 5-HT, but not DA or NA, modulates the heat loss system through action in the VTA. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Role of transforming growth factor-β in organogenesis: In vitro investigation using limb and midbrain cells

    International Nuclear Information System (INIS)

    Laflamme, D.; Faustman, E.

    1990-01-01

    Growth factors have been identified as important modulators of cellular growth and differentiation and alteration of these factors has been proposed as a mechanism for developmental toxicity. The aim of these studies is to understand the role of transforming growth factor-β(TGFβ-1) indifferentiation. For this purpose we have employed the differentiating micromass rat embryo midbrain (CNS) and limb bud (LB) primary culture systems. TFG-β-1 is added to the cultures 2 hours after plating on day 0 and differentiation and cytotoxicity is evaluated on day 5. Biochemical assays employed for differentiation are γ-[3H] aminobutyric acid uptake (CNS) and [35S] sulfate incorporation into sulfated proteoglycans (LB). Differentiation is also evaluated using image analysis of haematoxylin-stained neurons and alcian blue-stained chrondrocytes. The cultures are monitored for protein content and for cytotoxicity using the neural red uptake assay. Cultures exposed to 0.1, 0.5 and 1.0 μg/ml TGFβ-1 showed dose-dependent decreases in differentiation as measured by image analysis of stained foci and by γ-[3H] amino butyric acid uptake and [35S] sulphate incorporation but no changes were observed in total protein or cytotoxicity. Thus in these cultures, the exogenous addition of TGF-β-1 seems to selectively inhibit differentiation of both cell types. In other systems, the effects of TGFβ-1 have been shown to be multi-functional depending on concentration, location, growth conditions and timing. This preliminary study of these growth factor effects represents a further characterization of these widely used cell systems

  9. Autoradiographic visualization on the role of central 3H-5-hydroxytryptamine in acupuncture analgesia

    International Nuclear Information System (INIS)

    Zhu Shoupeng; Shi Fuxi; Liu Zhonghao; Jiang Ji

    1990-10-01

    The role played by central 5-hydroxytryptamine (5-HT) in electroacupuncture analgesia has been studied in rats by means of autoradiography with isotopic tracers 3 H-5-HT. The purpose of the study is to determine the localization of 3 H-5-HT in the midbrain raphe nuclei and in the mesencephalon aquaeduct as well as periaquaeductal gray matter. Parallel experiments were studied by freezing microautoradiographic method and histo-fixative microautoradiographic method. The analgesic effect of acupuncture can be enhanced or lowered by the increment or the decrement of the 5-HT level in the midbrain raphe nuclei and in the mesencephalon aquaeduct as well as periaquaeductal gray matter. The results show that when the rats were subjected to electro-acupuncture analgesia, the microautoradiographic intensities of 3 H-5-HT both in the midbrain raphe nuclei and in the areas of mesencephalon aqueduct were significantly increased. It may be observed that the release of 5-HT in these regions of the brain is accelerated during acupuncture analgesia. From this it can be concluded that the midbrain raphe nuclei and the mesencephalon aquaeduct as well as the periaquaeductal gray matter are closely related to acupuncture analgesia. The results imply that 5-HT in these areas may be one of the most important neurochemical agents mediating acupuncture analgesia

  10. Rats

    Directory of Open Access Journals (Sweden)

    Alexey Kondrashov

    2012-01-01

    Full Text Available We aimed to perform a chemical analysis of both Alibernet red wine and an alcohol-free Alibernet red wine extract (AWE and to investigate the effects of AWE on nitric oxide and reactive oxygen species production as well as blood pressure development in normotensive Wistar Kyoto (WKY and spontaneously hypertensive rats (SHRs. Total antioxidant capacity together with total phenolic and selected mineral content was measured in wine and AWE. Young 6-week-old male WKY and SHR were treated with AWE (24,2 mg/kg/day for 3 weeks. Total NOS and SOD activities, eNOS and SOD1 protein expressions, and superoxide production were determined in the tissues. Both antioxidant capacity and phenolic content were significantly higher in AWE compared to wine. The AWE increased NOS activity in the left ventricle, aorta, and kidney of SHR, while it did not change NOS activity in WKY rats. Similarly, increased SOD activity in the plasma and left ventricle was observed in SHR only. There were no changes in eNOS and SOD1 expressions. In conclusion, phenolics and minerals included in AWE may contribute directly to increased NOS and SOD activities of SHR. Nevertheless, 3 weeks of AWE treatment failed to affect blood pressure of SHR.

  11. Monorail/Foxa2 regulates floorplate differentiation and specification of oligodendrocytes, serotonergic raphé neurones and cranial motoneurones.

    Science.gov (United States)

    Norton, Will H; Mangoli, Maryam; Lele, Zsolt; Pogoda, Hans-Martin; Diamond, Brianne; Mercurio, Sara; Russell, Claire; Teraoka, Hiroki; Stickney, Heather L; Rauch, Gerd-Jörg; Heisenberg, Carl-Philipp; Houart, Corinne; Schilling, Thomas F; Frohnhoefer, Hans-Georg; Rastegar, Sepand; Neumann, Carl J; Gardiner, R Mark; Strähle, Uwe; Geisler, Robert; Rees, Michelle; Talbot, William S; Wilson, Stephen W

    2005-02-01

    In this study, we elucidate the roles of the winged-helix transcription factor Foxa2 in ventral CNS development in zebrafish. Through cloning of monorail (mol), which we find encodes the transcription factor Foxa2, and phenotypic analysis of mol-/- embryos, we show that floorplate is induced in the absence of Foxa2 function but fails to further differentiate. In mol-/- mutants, expression of Foxa and Hh family genes is not maintained in floorplate cells and lateral expansion of the floorplate fails to occur. Our results suggest that this is due to defects both in the regulation of Hh activity in medial floorplate cells as well as cell-autonomous requirements for Foxa2 in the prospective laterally positioned floorplate cells themselves. Foxa2 is also required for induction and/or patterning of several distinct cell types in the ventral CNS. Serotonergic neurones of the raphenucleus and the trochlear motor nucleus are absent in mol-/- embryos, and oculomotor and facial motoneurones ectopically occupy ventral CNS midline positions in the midbrain and hindbrain. There is also a severe reduction of prospective oligodendrocytes in the midbrain and hindbrain. Finally, in the absence of Foxa2, at least two likely Hh pathway target genes are ectopically expressed in more dorsal regions of the midbrain and hindbrain ventricular neuroepithelium, raising the possibility that Foxa2 activity may normally be required to limit the range of action of secreted Hh proteins.

  12. Brain SERT Expression of Male Rats Is Reduced by Aging and Increased by Testosterone Restitution

    Directory of Open Access Journals (Sweden)

    José Jaime Herrera-Pérez

    2013-01-01

    Full Text Available In preclinical and clinical studies aging has been associated with a deteriorated response to antidepressant treatment. We hypothesize that such impairment is explained by an age-related decrease in brain serotonin transporter (SERT expression associated with low testosterone (T levels. The objectives of this study were to establish (1 if brain SERT expression is reduced by aging and (2 if the SERT expression in middle-aged rats is increased by T-restitution. Intact young rats (3–5 months and gonad-intact middle-aged rats with or without T-restitution were used. The identification of the brain SERT expression was done by immunofluorescence in prefrontal cortex, lateral septum, hippocampus, and raphe nuclei. An age-dependent reduction of SERT expression was observed in all brain regions examined, while T-restitution recovered the SERT expression only in the dorsal raphe of middle-aged rats. This last action seems relevant since dorsal raphe plays an important role in the antidepressant action of selective serotonin reuptake inhibitors. All data suggest that this mechanism accounts for the T-replacement usefulness to improve the response to antidepressants in the aged population.

  13. Association of occlusal interference-induced masseter muscle hyperalgesia and P2X3 receptors in the trigeminal subnucleus caudalis and midbrain periaqueductal gray.

    Science.gov (United States)

    Sun, Shuzhen; Qi, Dong; Yang, Yingying; Ji, Ping; Kong, Jingjing; Wu, Qingting

    2016-03-02

    P2X3 receptor plays a role in nociception transmission of orofacial pain in temporomandibular disorder patients. A previous study found that P2X3 receptors in masseter muscle afferent neurons and the trigeminal ganglia were involved in masseter muscle pain induced by inflammation caused by chemical agents or eccentric muscle contraction. In this study, we attempted to investigate changes in P2X3 receptors in the trigeminal subnucleus caudalis (Vc) and midbrain periaqueductal gray (PAG) in relation to the hyperalgesia of masseter muscles induced by occlusal interference. Experimental occlusal interference by crown application was established in 30 rats and another 30 rats were treated as sham controls. On days 1, 3, 7, 14, and 28 after crown application, the mechanical pain threshold was examined by von-Frey filaments. The expression of the P2X3 receptor in Vc and PAG was investigated by immunohistochemistry and quantitative PCR. We found that mechanical pain threshold of bilateral masseter muscles decreased significantly after occlusal interference, which remained for the entire experimental period. The mRNA expression of the P2X3 receptor increased significantly and the number of P2X3R-positive neurons increased markedly in Vc and PAG accordingly. These results indicate that the upregulated expression of P2X3 receptors in Vc and PAG may contribute toward the development of orofacial pain induced by occlusal interference and P2X3 receptors in the PAG may play a key role in the supraspinal antiociception effect.

  14. Vertical diplopia and oscillopsia due to midbrain keyhole aqueduct syndrome associated with severe cough

    Directory of Open Access Journals (Sweden)

    Angela Jinsook Oh

    2018-06-01

    Full Text Available Purpose: Midline structural defects in the neural axis can give rise to neuro-ophthalmic symptoms. We report a rare case of keyhole aqueduct syndrome presenting after two years of severe cough due to gastroesophageal reflux disease. Observations: A 58-year-old woman with a 2-year history of daily, severe cough presented to the neuro-ophthalmology clinic with progressive diplopia and oscillopsia. Examination revealed a 1–2 Hz down-beating nystagmus in primary gaze that worsened with left, right, and down gazes. Gaze evoked nystagmus and mild paresis were also seen with up gaze. There was an incomitant left hypertropia due to skew deviation that worsened with right and up gazes and improved with down gaze. She also had a right-sided ptosis and a 3 mm anisocoria not due to cranial nerve 3 paresis or Horner's syndrome. Brain magnetic resonance imaging showed a 1.5 mm × 11.7 mm × 6 mm midline cleft in the ventral midbrain communicating with the cerebral aqueduct, consistent with keyhole aqueduct syndrome. Her nystagmus and diplopia improved with oral acetazolamide treatment, at high doses of 2500–3000 mg per day. Conclusions and importance: We report the first case of midbrain keyhole aqueduct syndrome with ocular motor and other neuro-ophthalmic manifestations associated with severe cough. Although her cough was effectively treated and intracranial pressure measurement was normal, her ophthalmic symptoms continued to progress, which is common in previous cases reported. Treatment with acetazolamide led to significant improvement, supporting the use of acetazolamide in this rare condition. Keywords: Keyhole aqueduct syndrome, Midbrain cleft, Mesencephalic cleft, Syrinx, Syringobulbia, Down-beating nystagmus, Cerebrospinal fluid

  15. Functional Plasticity after Unilateral Vestibular Midbrain Infarction in Human Positron Emission Tomography

    Science.gov (United States)

    Becker-Bense, Sandra; Buchholz, Hans-Georg; Baier, Bernhard; Schreckenberger, Mathias; Bartenstein, Peter; Zwergal, Andreas; Brandt, Thomas; Dieterich, Marianne

    2016-01-01

    The aim of the study was to uncover mechanisms of central compensation of vestibular function at brainstem, cerebellar, and cortical levels in patients with acute unilateral midbrain infarctions presenting with an acute vestibular tone imbalance. Eight out of 17 patients with unilateral midbrain infarctions were selected on the basis of signs of a vestibular tone imbalance, e.g., graviceptive (tilts of perceived verticality) and oculomotor dysfunction (skew deviation, ocular torsion) in F18-fluordeoxyglucose (FDG)-PET at two time points: A) in the acute stage, and B) after recovery 6 months later. Lesion-behavior mapping analyses with MRI verified the exact structural lesion sites. Group subtraction analyses and comparisons with healthy controls were performed with Statistic Parametric Mapping for the PET data. A comparison of PET A of acute-stage patients with that of healthy controls showed increases in glucose metabolism in the cerebellum, motion-sensitive visual cortex areas, and inferior temporal lobe, but none in vestibular cortex areas. At the supratentorial level bilateral signal decreases dominated in the thalamus, frontal eye fields, and anterior cingulum. These decreases persisted after clinical recovery in contrast to the increases. The transient activations can be attributed to ocular motor and postural recovery (cerebellum) and sensory substitution of vestibular function for motion perception (visual cortex). The persisting deactivation in the thalamic nuclei and frontal eye fields allows alternative functional interpretations of the thalamic nuclei: either a disconnection of ascending sensory input occurs or there is a functional mismatch between expected and actual vestibular activity. Our data support the view that both thalami operate separately for each hemisphere but receive vestibular input from ipsilateral and contralateral midbrain integration centers. Normally they have gatekeeper functions for multisensory input to the cortex and automatic

  16. Proliferation of murine midbrain neural stem cells depends upon an endogenous sonic hedgehog (Shh) source.

    Science.gov (United States)

    Martínez, Constanza; Cornejo, Víctor Hugo; Lois, Pablo; Ellis, Tammy; Solis, Natalia P; Wainwright, Brandon J; Palma, Verónica

    2013-01-01

    The Sonic Hedgehog (Shh) pathway is responsible for critical patterning events early in development and for regulating the delicate balance between proliferation and differentiation in the developing and adult vertebrate brain. Currently, our knowledge of the potential role of Shh in regulating neural stem cells (NSC) is largely derived from analyses of the mammalian forebrain, but for dorsal midbrain development it is mostly unknown. For a detailed understanding of the role of Shh pathway for midbrain development in vivo, we took advantage of mouse embryos with cell autonomously activated Hedgehog (Hh) signaling in a conditional Patched 1 (Ptc1) mutant mouse model. This animal model shows an extensive embryonic tectal hypertrophy as a result of Hh pathway activation. In order to reveal the cellular and molecular origin of this in vivo phenotype, we established a novel culture system to evaluate neurospheres (nsps) viability, proliferation and differentiation. By recreating the three-dimensional (3-D) microenvironment we highlight the pivotal role of endogenous Shh in maintaining the stem cell potential of tectal radial glial cells (RGC) and progenitors by modulating their Ptc1 expression. We demonstrate that during late embryogenesis Shh enhances proliferation of NSC, whereas blockage of endogenous Shh signaling using cyclopamine, a potent Hh pathway inhibitor, produces the opposite effect. We propose that canonical Shh signaling plays a central role in the control of NSC behavior in the developing dorsal midbrain by acting as a niche factor by partially mediating the response of NSC to epidermal growth factor (EGF) and fibroblast growth factor (FGF) signaling. We conclude that endogenous Shh signaling is a critical mechanism regulating the proliferation of stem cell lineages in the embryonic dorsal tissue.

  17. The value of midbrain morphology in predicting prognosis in chronic disorders of consciousness: A preliminary ultrasound study.

    Science.gov (United States)

    Chillura, Antonino; Naro, Antonino; Micchia, Katia; Bramanti, Alessia; Bramanti, Placido; Calabrò, Rocco Salvatore

    2017-09-15

    Transcranial sonography (TCS) of the brainstem is currently used to support the clinical diagnosis of movement disorders. The aim of the study was to assess the usefulness of midbrain TCS in assessing outcome in patients with Chronic Disorders of Consciousness (DOC). Eleven patients with Minimally Conscious State (MCS) and Unresponsive Wakefulness Syndrome (UWS) were included in the study. We measured the area and echogenicity of the midbrain by encoding and digitally analyzing the corresponding images from the orbitomeatal plane, the morphology of brain parenchyma from the thalamic and cella media plane, and the intracranial circulation. All the patients showed an increase of pulsatility index and numerous morphological alterations on all the scan planes. In particular, we found a loss of the characteristic butterfly-shape of the midbrain, which appeared hypoechoic in the UWS but not in the MCS patients. After six months, the patients were clinically assessed by using Glasgow Outcome Scale Extended (GOSE). We found that a higher increase in GOSE scoring at follow-up was correlated with larger area and higher echogenicity of the midbrain at baseline. The present study suggests that TCS data of the midbrain may support clinical assessment of patients with chronic DOC to estimate their outcome. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Midbrain serotonin transporter binding potential measured with [11C]DASB is affected by serotonin transporter genotype

    International Nuclear Information System (INIS)

    Reimold, M.; Bares, R.; Reischl, G.; Solbach, C.; Machulla, H.-J.; Smolka, M.N.; Mann, K.; Schumann, G.; Zimmer, A.; Wrase, J.; Hu, X.-Z.; Goldman, D.; Heinz, A.

    2007-01-01

    Homozygote carriers of two long (L) alleles of the serotonin transporter (5-HTT) regulatory region displayed in vitro a twofold increase in 5-HTT expression compared with carriers of one or two short (S) alleles. However, in vivo imaging studies yielded contradictory results. Recently, an A > G exchange leading to differential transcriptional activation of 5-HTT mRNA in lymphobalstoid cell lines was discovered in the 5-HTT regulatory region. In vitro and in vivo evidence suggests that [ 11 C]DASB, a new 5-HTT ligand offers some advantages over the ligands used in previous studies in measuring 5-HTT density independent of synaptic levels of serotonin. We assessed 5-HTT binding potential (BP 2) in the midbrain of 19 healthy subjects with positron emission tomography and [ 11 C]DASB. Accounting for the hypothesized functional similarity of L G and S in driving 5-HTT transcription, we assessed whether L A L A homozygotes display increased midbrain BP 2 compared with carriers of at least one S allele. BP 2 in the midbrain was significantly increased in L A L A homozygotes compared with carriers of at least one S allele. Interestingly, the genotype effect on the midbrain was significantly different from that on the thalamus and the amygdala where no group differences were detected. This in vivo study provides further evidence that subjects homozygous for the L A allele display increased expression of 5-HTT in the midbrain, the origin of central serotonergic projections. (author)

  19. Electrophysiological analysis of pathways connecting the medial preoptic area with the mesencephalic central grey matter in rats.

    Science.gov (United States)

    MacLeod, N K; Mayer, M L

    1980-01-01

    1. An electrophysiological study of ascending and descending connexions between the dorsal raphe region of the mesencephalic periaqueductal grey matter and the medial preoptic area has been performed in dioestrous female rats anaesthetized with urethane. 2. Extracellular action potentials recorded from 208 neurones in the medial preoptic area were analysed for a change in excitability following stimulation of the periaqueductal grey matter. 174 neurones were also tested for changes in excitability following stimulation of the mediobasal hypothalamus. 3. Stimulation of the periaqueductal grey matter at 1 Hz was rarely effective, but short trains of pulses (three at 100 Hz) usually caused an initial inhibition (62.5% of 208) of both projection identified and adjacent neurones of the medial preoptic area, at latencies of 5--90 msec (mean 34.1 +/- 1.4 msec). Inhibition following stimulation of the mediobasal hypothalamus occurred less frequently (34%) and at shorter latency (mean 12.0 +/- 1.8 msec; n = 48). 4. Less frequently (10.6%) periaqueductal grey matter stimulation caused an initial excitation of preoptic neurones at latencies of 15--180 msec, (mean 35.3 +/- 7.2). Initial excitation following mediobasal hypothalamus stimulation was stronger, occurred more frequently (29%) and at shorter latencies (range 3--60 msec, mean 13.1 +/- 1.5). Following such initial excitation, inhibition of spontaneous or ionophoretically evoked activity occurred more frequently following mediobasal hypothalamic stimulation, than after periaqueductal grey matter stimulation. 5. Twenty-four neurones displayed antidromic invasion following periaqueductal grey matter stimulation. Latencies for invasion ranged from 13 to 50 msec (mean 25.5 +/- 2.0 msec) and are suggestive of an unmyelinated projection. Occasionally an abrupt decrease in latency followed an increase in stimulus intensity. Antidromic invasion from mediobasal hypothalamus was characterized by a shorter latency (mean 12.5 +/- 0

  20. Diversity of bilateral synaptic assemblies for binaural computation in midbrain single neurons.

    Science.gov (United States)

    He, Na; Kong, Lingzhi; Lin, Tao; Wang, Shaohui; Liu, Xiuping; Qi, Jiyao; Yan, Jun

    2017-11-01

    Binaural hearing confers many beneficial functions but our understanding of its underlying neural substrates is limited. This study examines the bilateral synaptic assemblies and binaural computation (or integration) in the central nucleus of the inferior colliculus (ICc) of the auditory midbrain, a key convergent center. Using in-vivo whole-cell patch-clamp, the excitatory and inhibitory postsynaptic potentials (EPSPs/IPSPs) of single ICc neurons to contralateral, ipsilateral and bilateral stimulation were recorded. According to the contralateral and ipsilateral EPSP/IPSP, 7 types of bilateral synaptic assemblies were identified. These include EPSP-EPSP (EE), E-IPSP (EI), E-no response (EO), II, IE, IO and complex-mode (CM) neurons. The CM neurons showed frequency- and/or amplitude-dependent EPSPs/IPSPs to contralateral or ipsilateral stimulation. Bilateral stimulation induced EPSPs/IPSPs that could be larger than (facilitation), similar to (ineffectiveness) or smaller than (suppression) those induced by contralateral stimulation. Our findings have allowed our group to characterize novel neural circuitry for binaural computation in the midbrain. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Apc1 is required for maintenance of local brain organizers and dorsal midbrain survival.

    Science.gov (United States)

    Paridaen, Judith T M L; Danesin, Catherine; Elas, Abu Tufayal; van de Water, Sandra; Houart, Corinne; Zivkovic, Danica

    2009-07-15

    The tumor suppressor Apc1 is an intracellular antagonist of the Wnt/beta-catenin pathway, which is vital for induction and patterning of the early vertebrate brain. However, its role in later brain development is less clear. Here, we examined the mechanisms underlying effects of an Apc1 zygotic-effect mutation on late brain development in zebrafish. Apc1 is required for maintenance of established brain subdivisions and control of local organizers such as the isthmic organizer (IsO). Caudal expansion of Fgf8 from IsO into the cerebellum is accompanied by hyperproliferation and abnormal cerebellar morphogenesis. Loss of apc1 results in reduced proliferation and apoptosis in the dorsal midbrain. Mosaic analysis shows that Apc is required cell-autonomously for maintenance of dorsal midbrain cell fate. The tectal phenotype occurs independently of Fgf8-mediated IsO function and is predominantly caused by stabilization of beta-catenin and subsequent hyperactivation of Wnt/beta-catenin signalling, which is mainly mediated through LEF1 activity. Chemical activation of the Wnt/beta-catenin in wild-type embryos during late brain maintenance stages phenocopies the IsO and tectal phenotypes of the apc mutants. These data demonstrate that Apc1-mediated restriction of Wnt/beta-catenin signalling is required for maintenance of local organizers and tectal integrity.

  2. Electrosensory Midbrain Neurons Display Feature Invariant Responses to Natural Communication Stimuli.

    Directory of Open Access Journals (Sweden)

    Tristan Aumentado-Armstrong

    2015-10-01

    Full Text Available Neurons that respond selectively but in an invariant manner to a given feature of natural stimuli have been observed across species and systems. Such responses emerge in higher brain areas, thereby suggesting that they occur by integrating afferent input. However, the mechanisms by which such integration occurs are poorly understood. Here we show that midbrain electrosensory neurons can respond selectively and in an invariant manner to heterogeneity in behaviorally relevant stimulus waveforms. Such invariant responses were not seen in hindbrain electrosensory neurons providing afferent input to these midbrain neurons, suggesting that response invariance results from nonlinear integration of such input. To test this hypothesis, we built a model based on the Hodgkin-Huxley formalism that received realistic afferent input. We found that multiple combinations of parameter values could give rise to invariant responses matching those seen experimentally. Our model thus shows that there are multiple solutions towards achieving invariant responses and reveals how subthreshold membrane conductances help promote robust and invariant firing in response to heterogeneous stimulus waveforms associated with behaviorally relevant stimuli. We discuss the implications of our findings for the electrosensory and other systems.

  3. Electrosensory Midbrain Neurons Display Feature Invariant Responses to Natural Communication Stimuli.

    Science.gov (United States)

    Aumentado-Armstrong, Tristan; Metzen, Michael G; Sproule, Michael K J; Chacron, Maurice J

    2015-10-01

    Neurons that respond selectively but in an invariant manner to a given feature of natural stimuli have been observed across species and systems. Such responses emerge in higher brain areas, thereby suggesting that they occur by integrating afferent input. However, the mechanisms by which such integration occurs are poorly understood. Here we show that midbrain electrosensory neurons can respond selectively and in an invariant manner to heterogeneity in behaviorally relevant stimulus waveforms. Such invariant responses were not seen in hindbrain electrosensory neurons providing afferent input to these midbrain neurons, suggesting that response invariance results from nonlinear integration of such input. To test this hypothesis, we built a model based on the Hodgkin-Huxley formalism that received realistic afferent input. We found that multiple combinations of parameter values could give rise to invariant responses matching those seen experimentally. Our model thus shows that there are multiple solutions towards achieving invariant responses and reveals how subthreshold membrane conductances help promote robust and invariant firing in response to heterogeneous stimulus waveforms associated with behaviorally relevant stimuli. We discuss the implications of our findings for the electrosensory and other systems.

  4. Homozygous ARHGEF2 mutation causes intellectual disability and midbrain-hindbrain malformation.

    Directory of Open Access Journals (Sweden)

    Ethiraj Ravindran

    2017-04-01

    Full Text Available Mid-hindbrain malformations can occur during embryogenesis through a disturbance of transient and localized gene expression patterns within these distinct brain structures. Rho guanine nucleotide exchange factor (ARHGEF family members are key for controlling the spatiotemporal activation of Rho GTPase, to modulate cytoskeleton dynamics, cell division, and cell migration. We identified, by means of whole exome sequencing, a homozygous frameshift mutation in the ARHGEF2 as a cause of intellectual disability, a midbrain-hindbrain malformation, and mild microcephaly in a consanguineous pedigree of Kurdish-Turkish descent. We show that loss of ARHGEF2 perturbs progenitor cell differentiation and that this is associated with a shift of mitotic spindle plane orientation, putatively favoring more symmetric divisions. The ARHGEF2 mutation leads to reduction in the activation of the RhoA/ROCK/MLC pathway crucial for cell migration. We demonstrate that the human brain malformation is recapitulated in Arhgef2 mutant mice and identify an aberrant migration of distinct components of the precerebellar system as a pathomechanism underlying the midbrain-hindbrain phenotype. Our results highlight the crucial function of ARHGEF2 in human brain development and identify a mutation in ARHGEF2 as novel cause of a neurodevelopmental disorder.

  5. Homozygous ARHGEF2 mutation causes intellectual disability and midbrain-hindbrain malformation.

    Science.gov (United States)

    Ravindran, Ethiraj; Hu, Hao; Yuzwa, Scott A; Hernandez-Miranda, Luis R; Kraemer, Nadine; Ninnemann, Olaf; Musante, Luciana; Boltshauser, Eugen; Schindler, Detlev; Hübner, Angela; Reinecker, Hans-Christian; Ropers, Hans-Hilger; Birchmeier, Carmen; Miller, Freda D; Wienker, Thomas F; Hübner, Christoph; Kaindl, Angela M

    2017-04-01

    Mid-hindbrain malformations can occur during embryogenesis through a disturbance of transient and localized gene expression patterns within these distinct brain structures. Rho guanine nucleotide exchange factor (ARHGEF) family members are key for controlling the spatiotemporal activation of Rho GTPase, to modulate cytoskeleton dynamics, cell division, and cell migration. We identified, by means of whole exome sequencing, a homozygous frameshift mutation in the ARHGEF2 as a cause of intellectual disability, a midbrain-hindbrain malformation, and mild microcephaly in a consanguineous pedigree of Kurdish-Turkish descent. We show that loss of ARHGEF2 perturbs progenitor cell differentiation and that this is associated with a shift of mitotic spindle plane orientation, putatively favoring more symmetric divisions. The ARHGEF2 mutation leads to reduction in the activation of the RhoA/ROCK/MLC pathway crucial for cell migration. We demonstrate that the human brain malformation is recapitulated in Arhgef2 mutant mice and identify an aberrant migration of distinct components of the precerebellar system as a pathomechanism underlying the midbrain-hindbrain phenotype. Our results highlight the crucial function of ARHGEF2 in human brain development and identify a mutation in ARHGEF2 as novel cause of a neurodevelopmental disorder.

  6. Homozygous ARHGEF2 mutation causes intellectual disability and midbrain-hindbrain malformation

    Science.gov (United States)

    Yuzwa, Scott A.; Hernandez-Miranda, Luis R.; Musante, Luciana; Boltshauser, Eugen; Schindler, Detlev; Hübner, Angela; Reinecker, Hans-Christian; Ropers, Hans-Hilger; Miller, Freda D.; Hübner, Christoph; Kaindl, Angela M.

    2017-01-01

    Mid-hindbrain malformations can occur during embryogenesis through a disturbance of transient and localized gene expression patterns within these distinct brain structures. Rho guanine nucleotide exchange factor (ARHGEF) family members are key for controlling the spatiotemporal activation of Rho GTPase, to modulate cytoskeleton dynamics, cell division, and cell migration. We identified, by means of whole exome sequencing, a homozygous frameshift mutation in the ARHGEF2 as a cause of intellectual disability, a midbrain-hindbrain malformation, and mild microcephaly in a consanguineous pedigree of Kurdish-Turkish descent. We show that loss of ARHGEF2 perturbs progenitor cell differentiation and that this is associated with a shift of mitotic spindle plane orientation, putatively favoring more symmetric divisions. The ARHGEF2 mutation leads to reduction in the activation of the RhoA/ROCK/MLC pathway crucial for cell migration. We demonstrate that the human brain malformation is recapitulated in Arhgef2 mutant mice and identify an aberrant migration of distinct components of the precerebellar system as a pathomechanism underlying the midbrain-hindbrain phenotype. Our results highlight the crucial function of ARHGEF2 in human brain development and identify a mutation in ARHGEF2 as novel cause of a neurodevelopmental disorder. PMID:28453519

  7. Arterial blood supply to the thalamus and midbrain on CT sections, 2

    International Nuclear Information System (INIS)

    Takeshita, Gen; Ottomo, Michinori; Satoh, Nobuko; Yokoyama, Yoshiaki.

    1984-01-01

    The selective injection of a dyestuff into thalamoperforating arteries from the posterior part of the circle of Willis, using five postmortem brains, was performed. After fixation, sections parallel to the orbito-meatal line were obtained. In cases which showed a standard development of the posterior communicating arteries, the usual patterns were as follows: the area supplied by perforators of the posterior communicating artery (anterior thalamoperforating artery) was visualized in the hypothalamus and the antero-lateral part of the thalamus; the area supplied by perforators of the proximal segment of the posterior cerebral artery (interpeduncular thalamoperforating artery) was visualized in the midbrain and the medial part of thalamus; the area supplied by perforators of the ambient segment of the posterior cerebral artery (thalamogeniculate artery) was visualized in the medial part of the geniculate body and the posterior part of the thalamus. According to the development of the posterior communicating artery, the area supplied by each perforator was quite variable. Three CT sections were obtained containing three different patterns of the posterior communicating artery: 1) well-developed; 2) moderately developed; and 3) poorly developed. The identification of the area supplied by thalamoperforating arteries on CT sections was quite useful in the CT diagnosis of cerebrovascular disorders which involved the thalamus and the midbrain. (author)

  8. Midbrain adaptation may set the stage for the perception of musical beat.

    Science.gov (United States)

    Rajendran, Vani G; Harper, Nicol S; Garcia-Lazaro, Jose A; Lesica, Nicholas A; Schnupp, Jan W H

    2017-11-15

    The ability to spontaneously feel a beat in music is a phenomenon widely believed to be unique to humans. Though beat perception involves the coordinated engagement of sensory, motor and cognitive processes in humans, the contribution of low-level auditory processing to the activation of these networks in a beat-specific manner is poorly understood. Here, we present evidence from a rodent model that midbrain preprocessing of sounds may already be shaping where the beat is ultimately felt. For the tested set of musical rhythms, on-beat sounds on average evoked higher firing rates than off-beat sounds, and this difference was a defining feature of the set of beat interpretations most commonly perceived by human listeners over others. Basic firing rate adaptation provided a sufficient explanation for these results. Our findings suggest that midbrain adaptation, by encoding the temporal context of sounds, creates points of neural emphasis that may influence the perceptual emergence of a beat. © 2017 The Authors.

  9. Direct lineage reprogramming of mouse fibroblasts to functional midbrain dopaminergic neuronal progenitors

    Directory of Open Access Journals (Sweden)

    Han-Seop Kim

    2014-01-01

    Full Text Available The direct lineage reprogramming of somatic cells to other lineages by defined factors has led to innovative cell-fate-change approaches for providing patient-specific cells. Recent reports have demonstrated that four pluripotency factors (Oct4, Sox2, Klf4, and c-Myc are sufficient to directly reprogram fibroblasts to other specific cells, including induced neural stem cells (iNSCs. Here, we show that mouse fibroblasts can be directly reprogrammed into midbrain dopaminergic neuronal progenitors (DPs by temporal expression of the pluripotency factors and environment containing sonic hedgehog and fibroblast growth factor 8. Within thirteen days, self-renewing and functional induced DPs (iDPs were generated. Interestingly, the inhibition of both Jak and Gsk3β notably enhanced the iDP reprogramming efficiency. We confirmed the functionality of the iDPs by showing that the dopaminergic neurons generated from iDPs express midbrain markers, release dopamine, and show typical electrophysiological profiles. Our results demonstrate that the pluripotency factors-mediated direct reprogramming is an invaluable strategy for supplying functional and proliferating iDPs and may be useful for other neural progenitors required for disease modeling and cell therapies for neurodegenerative disorders.

  10. Midbrain dopamine neurons associated with reward processing innervate the neurogenic subventricular zone.

    Science.gov (United States)

    Lennington, Jessica B; Pope, Sara; Goodheart, Anna E; Drozdowicz, Linda; Daniels, Stephen B; Salamone, John D; Conover, Joanne C

    2011-09-14

    Coordinated regulation of the adult neurogenic subventricular zone (SVZ) is accomplished by a myriad of intrinsic and extrinsic factors. The neurotransmitter dopamine is one regulatory molecule implicated in SVZ function. Nigrostriatal and ventral tegmental area (VTA) midbrain dopamine neurons innervate regions adjacent to the SVZ, and dopamine synapses are found on SVZ cells. Cell division within the SVZ is decreased in humans with Parkinson's disease and in animal models of Parkinson's disease following exposure to toxins that selectively remove nigrostriatal neurons, suggesting that dopamine is critical for SVZ function and nigrostriatal neurons are the main suppliers of SVZ dopamine. However, when we examined the aphakia mouse, which is deficient in nigrostriatal neurons, we found no detrimental effect to SVZ proliferation or organization. Instead, dopamine innervation of the SVZ tracked to neurons at the ventrolateral boundary of the VTA. This same dopaminergic neuron population also innervated the SVZ of control mice. Characterization of these neurons revealed expression of proteins indicative of VTA neurons. Furthermore, exposure to the neurotoxin MPTP depleted neurons in the ventrolateral VTA and resulted in decreased SVZ proliferation. Together, these results reveal that dopamine signaling in the SVZ originates from a population of midbrain neurons more typically associated with motivational and reward processing.

  11. Elevated midbrain serotonin transporter availability in mixed mania: a case report

    Directory of Open Access Journals (Sweden)

    Kuikka Jyrki

    2004-09-01

    Full Text Available Abstract Background Results obtained from brain imaging studies indicate that serotonin transporter (SERT and dopamine transporter (DAT densities are altered in major depression. However, no such studies have been published on current mania or hypomania. Case presentation In this single photon emission computed tomography (SPECT study with [123I]nor-β-CIT we present a case with simultaneous symptoms of major depression and hypomania. She had an elevated serotonin transporter availability (SERT in the midbrain and elevated dopamine transporter availability (DAT in the striatum, which normalised in a one-year follow-up period during which she received eight months of psychodynamic psychotherapy. Conclusions To our knowledge, this is the first report on SERT and DAT associated with mania. In our case the availability of both SERT in the midbrain and DAT in the striatum were elevated at baseline and declined during psychotherapy, while the SERT and DAT of the depressed controls increased during psychotherapy. Symptoms of hypomania in the case were alleviated during psychotherapy. Clinical recovery was also reflected in the Hamilton Depression Rating Scale (HDRS scores.

  12. Hierarchical prediction errors in midbrain and basal forebrain during sensory learning.

    Science.gov (United States)

    Iglesias, Sandra; Mathys, Christoph; Brodersen, Kay H; Kasper, Lars; Piccirelli, Marco; den Ouden, Hanneke E M; Stephan, Klaas E

    2013-10-16

    In Bayesian brain theories, hierarchically related prediction errors (PEs) play a central role for predicting sensory inputs and inferring their underlying causes, e.g., the probabilistic structure of the environment and its volatility. Notably, PEs at different hierarchical levels may be encoded by different neuromodulatory transmitters. Here, we tested this possibility in computational fMRI studies of audio-visual learning. Using a hierarchical Bayesian model, we found that low-level PEs about visual stimulus outcome were reflected by widespread activity in visual and supramodal areas but also in the midbrain. In contrast, high-level PEs about stimulus probabilities were encoded by the basal forebrain. These findings were replicated in two groups of healthy volunteers. While our fMRI measures do not reveal the exact neuron types activated in midbrain and basal forebrain, they suggest a dichotomy between neuromodulatory systems, linking dopamine to low-level PEs about stimulus outcome and acetylcholine to more abstract PEs about stimulus probabilities. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. White noise improves learning by modulating activity in dopaminergic midbrain regions and right superior temporal sulcus.

    Science.gov (United States)

    Rausch, Vanessa H; Bauch, Eva M; Bunzeck, Nico

    2014-07-01

    In neural systems, information processing can be facilitated by adding an optimal level of white noise. Although this phenomenon, the so-called stochastic resonance, has traditionally been linked with perception, recent evidence indicates that white noise may also exert positive effects on cognitive functions, such as learning and memory. The underlying neural mechanisms, however, remain unclear. Here, on the basis of recent theories, we tested the hypothesis that auditory white noise, when presented during the encoding of scene images, enhances subsequent recognition memory performance and modulates activity within the dopaminergic midbrain (i.e., substantia nigra/ventral tegmental area, SN/VTA). Indeed, in a behavioral experiment, we can show in healthy humans that auditory white noise-but not control sounds, such as a sinus tone-slightly improves recognition memory. In an fMRI experiment, white noise selectively enhances stimulus-driven phasic activity in the SN/VTA and auditory cortex. Moreover, it induces stronger connectivity between SN/VTA and right STS, which, in addition, exhibited a positive correlation with subsequent memory improvement by white noise. Our results suggest that the beneficial effects of auditory white noise on learning depend on dopaminergic neuromodulation and enhanced connectivity between midbrain regions and the STS-a key player in attention modulation. Moreover, they indicate that white noise could be particularly useful to facilitate learning in conditions where changes of the mesolimbic system are causally related to memory deficits including healthy and pathological aging.

  14. Glutamate neurons are intermixed with midbrain dopamine neurons in nonhuman primates and humans

    Science.gov (United States)

    Root, David H.; Wang, Hui-Ling; Liu, Bing; Barker, David J.; Mód, László; Szocsics, Péter; Silva, Afonso C.; Maglóczky, Zsófia; Morales, Marisela

    2016-01-01

    The rodent ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) contain dopamine neurons intermixed with glutamate neurons (expressing vesicular glutamate transporter 2; VGluT2), which play roles in reward and aversion. However, identifying the neuronal compositions of the VTA and SNC in higher mammals has remained challenging. Here, we revealed VGluT2 neurons within the VTA and SNC of nonhuman primates and humans by simultaneous detection of VGluT2 mRNA and tyrosine hydroxylase (TH; for identification of dopamine neurons). We found that several VTA subdivisions share similar cellular compositions in nonhuman primates and humans; their rostral linear nuclei have a high prevalence of VGluT2 neurons lacking TH; their paranigral and parabrachial pigmented nuclei have mostly TH neurons, and their parabrachial pigmented nuclei have dual VGluT2-TH neurons. Within nonhuman primates and humans SNC, the vast majority of neurons are TH neurons but VGluT2 neurons were detected in the pars lateralis subdivision. The demonstration that midbrain dopamine neurons are intermixed with glutamate or glutamate-dopamine neurons from rodents to humans offers new opportunities for translational studies towards analyzing the roles that each of these neurons play in human behavior and in midbrain-associated illnesses such as addiction, depression, schizophrenia, and Parkinson’s disease. PMID:27477243

  15. Evidence of functional duplicity of Nestin expression in the adult mouse midbrain

    Directory of Open Access Journals (Sweden)

    Parisa Farzanehfar

    2017-03-01

    Full Text Available Whether or not neurogenesis occurs in the adult substantia nigra pars compacta (SNc is an important question relevant for developing better treatments for the motor symptoms of Parkinson's disease (PD. Although controversial, it is generally believed that dividing cells here remain undifferentiated or differentiate into glia, not neurons. However, there is a suggestion that Nestin-expressing neural precursor cells (NPCs in the adult SNc have a propensity to differentiate into neurons, which we sought to confirm in the present study. Adult (>8-weeks old transgenic NesCreERT2/GtROSA or NesCreERT2/R26eYFP mice were used to permanently label Nestin-expressing cells and their progeny with β-galactosidase (β-gal or enhanced yellow fluorescent protein (eYFP, respectively. Most β-gal+ or eYFP+ cells were found in the ependymal lining of the midbrain aqueduct (Aq and in the midline ventral to Aq. Smaller but significant numbers were in the periaqueductal gray (PAG, the ventral tegmental area (VTA, and in SNc. Low-level basal proliferation was evidenced by a modest increase in number of β-gal+ or eYFP+ cells over time, fewer β-gal+ or eYFP+ cells when mice were administered the anti-mitotic agent Cytarabine, and incorporation of the proliferation marker bromodeoxyuridine (BrdU in a very small number of β-gal+ cells. No evidence of migration was found, including no immunoreactivity against the migration markers doublecortin (DCX or polysialic acid neural cell adhesion molecule (PSA-NCAM, and no dispersal of β-gal+ or eYFP+ cells through the midbrain parenchyma over time. However, β-gal+ or eYFP+ cells did increase in size and express higher levels of mature neuronal genes over time, indicating growth and neuronal differentiation. In mice whose SNc dopamine neurons had been depleted with 6-hydroxy-dopamine, a model of PD, there were ~2-fold more β-gal+ cells in SNc specifically, although the proportion that were also NeuN+ was not affected

  16. Organization of Functional Long-Range Circuits Controlling the Activity of Serotonergic Neurons in the Dorsal Raphe Nucleus

    Directory of Open Access Journals (Sweden)

    Li Zhou

    2017-03-01

    Full Text Available Serotonergic neurons play key roles in various biological processes. However, circuit mechanisms underlying tight control of serotonergic neurons remain largely unknown. Here, we systematically investigated the organization of long-range synaptic inputs to serotonergic neurons and GABAergic neurons in the dorsal raphe nucleus (DRN of mice with a combination of viral tracing, slice electrophysiological, and optogenetic techniques. We found that DRN serotonergic neurons and GABAergic neurons receive largely comparable synaptic inputs from six major upstream brain areas. Upon further analysis of the fine functional circuit structures, we found both bilateral and ipsilateral patterns of topographic connectivity in the DRN for the axons from different inputs. Moreover, the upstream brain areas were found to bidirectionally control the activity of DRN serotonergic neurons by recruiting feedforward inhibition or via a push-pull mechanism. Our study provides a framework for further deciphering the functional roles of long-range circuits controlling the activity of serotonergic neurons in the DRN.

  17. Microangiographic study of the normal anatomy of the cerebral venous system in rats

    International Nuclear Information System (INIS)

    Schumacher, M.

    1984-01-01

    Microangiographic serial cuts were performed in 20 Sprague-Dawley rats for a systematic study of the normal anatomy of the cerebral veins. The draining pathways of the cerebral and cerebellar cortex, basal ganglia, hypothalamus, hippocampus and the midbrain are described and discussed with regard to their different functions. (orig.)

  18. Midbrain expression of Delta-like 1 homologue is regulated by GDNF and is associated with dopaminergic differentiation

    DEFF Research Database (Denmark)

    Christophersen, Nicolai S.; Gronborg, Mette; Petersen, Thomas Nordahl

    2007-01-01

    upregulation with increased positive staining of cell bodies in the SNc and fibers in the striatum. Analysis of the developmental regulation of Dlk1 in the murine ventral midbrain showed that the upregulation of Dlk1 mRNA correlated with the generation of tyrosine hydroxylase (TH)-positive neurons. Furthermore...

  19. [Role of the midbrain reticular formation in hormonal supply to the body in conditions of chronic emotional stress].

    Science.gov (United States)

    Amiragova, M G; Arakhangel'skaia, M I

    1983-08-01

    Chronic animal experiments were made to study the endocrine and electroencephalographic responses of the cortico-subcortical structures to stress before and after coagulation of the midbrain reticular formation. The operation entailed dramatic changes in both the bioelectrical responses and thyroid and adrenal responses, which were found to be differentiated.

  20. Midbrain Gene Screening Identifies a New Mesoaccumbal Glutamatergic Pathway and a Marker for Dopamine Cells Neuroprotected in Parkinson's Disease.

    Science.gov (United States)

    Viereckel, Thomas; Dumas, Sylvie; Smith-Anttila, Casey J A; Vlcek, Bianca; Bimpisidis, Zisis; Lagerström, Malin C; Konradsson-Geuken, Åsa; Wallén-Mackenzie, Åsa

    2016-10-20

    The ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) of the midbrain are associated with Parkinson's disease (PD), schizophrenia, mood disorders and addiction. Based on the recently unraveled heterogeneity within the VTA and SNc, where glutamate, GABA and co-releasing neurons have been found to co-exist with the classical dopamine neurons, there is a compelling need for identification of gene expression patterns that represent this heterogeneity and that are of value for development of human therapies. Here, several unique gene expression patterns were identified in the mouse midbrain of which NeuroD6 and Grp were expressed within different dopaminergic subpopulations of the VTA, and TrpV1 within a small heterogeneous population. Optogenetics-coupled in vivo amperometry revealed a previously unknown glutamatergic mesoaccumbal pathway characterized by TrpV1-Cre-expression. Human GRP was strongly detected in non-melanized dopaminergic neurons within the SNc of both control and PD brains, suggesting GRP as a marker for neuroprotected neurons in PD. This study thus unravels markers for distinct subpopulations of neurons within the mouse and human midbrain, defines unique anatomical subregions within the VTA and exposes an entirely new glutamatergic pathway. Finally, both TRPV1 and GRP are implied in midbrain physiology of importance to neurological and neuropsychiatric disorders.

  1. Wnt5a regulates ventral midbrain morphogenesis and the development of A9-A10 dopaminergic cells in vivo

    Czech Academy of Sciences Publication Activity Database

    Andersson, E.R.; Prakash, N.; Čajánek, L.; Minina, E.; Bryja, Vítězslav; Bryjová, Lenka; Yamaguchi, T.P.; Hall, A.C.; Wurst, W.; Arenas, E.

    2008-01-01

    Roč. 3, č. 10 (2008), s. 1-14 E-ISSN 1932-6203 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : Wnt 5a deficient mouse * ventral midbrain * planar cell polarity Subject RIV: BO - Biophysics

  2. The β-chemokines CCL2 and CCL7 are two novel differentiation factors for midbrain dopaminergic precursors and neurons

    International Nuclear Information System (INIS)

    Edman, Linda C.; Mira, Helena; Arenas, Ernest

    2008-01-01

    β-chemokines are secreted factors that regulate diverse functions in the adult brain, such as neuro-immune responses and neurotransmission, but their function in the developing brain is largely unknown. We recently found that the orphan nuclear receptor, Nurr1, up regulates CCL2 and CCL7 in neural stem cells, suggesting a possible function of β-chemokines in midbrain development. Here we report that two β-chemokines, CCL2 and CCL7, and two of their receptors, CCR1 and CCR2, are expressed and developmentally regulated in the ventral midbrain (VM). Moreover, we found that the expression of CCL7 was down regulated in the Nurr1 knockout mice, linking CCL7 to dopamine (DA) neuron development. When the function of CCL2 and CCL7 was examined, we found that they selectively enhanced the differentiation of Nurr1+ precursors into DA neurons, but not their survival or progenitor proliferation in primary precursor cultures. Moreover, both CCL2 and CCL7 promoted neuritogenesis in midbrain DA neuron cultures. Thus, our results show for the first time a function of β-chemokines in the developing brain and identify β-chemokines as novel class of pro-differentiation factors for midbrain DA neurons. These data also suggest that β-chemokines may become useful tools to enhance the differentiation of DA cell preparations for cell replacement therapy and drug discovery in Parkinson's disease (PD)

  3. Spumiform basement membrane aberrations in the microvasculature of the midbrain periaqueductal gray region in hamster : Rostro-caudal pathogenesis?

    NARCIS (Netherlands)

    Gerrits, P.O.; Kortekaas, R.; de Weerd, Heleen; Luiten, P.G.M.; van der Want, J.J.L.; Veening, Jan

    2013-01-01

    Spumiform basement membrane degeneration (sbmd) is a specific kind of aberration present in the capillaries of the midbrain periaqueductal gray (PAG) region of the senescent hamster. These capillaries, separated by the ependymal cell layer, are bordering the Sylvian cerebral aqueduct. The aqueduct,

  4. Spumiform basement membrane aberrations in the microvasculature of the midbrain periaqueductal gray region in hamster: rostro-caudal pathogenesis?

    NARCIS (Netherlands)

    Gerrits, P.O.; Kortekaas, R.; Weerd, H. de; Luiten, P.G.M.; Want, J.J. van der; Veening, J.G.

    2013-01-01

    Spumiform basement membrane degeneration (sbmd) is a specific kind of aberration present in the capillaries of the midbrain periaqueductal gray (PAG) region of the senescent hamster. These capillaries, separated by the ependymal cell layer, are bordering the Sylvian cerebral aqueduct. The aqueduct,

  5. Lipoma of the midbrain: post-mortem finding in a patient with breast cancer

    Directory of Open Access Journals (Sweden)

    Verônica Maia Gouvea

    1989-09-01

    Full Text Available Intracranial lipomas are rare, usually do not have clinical expression and are located mare frequently in the corpus callosum. Other locations include the spinal cord, midbrain tectum, superior vermis, tuber cinereum, infundibulum and more rarely cerebellopontine angle, hypothalamus, superior medullary velum and insula. We report the case of a lipoma of the left inferior colliculus which was a post-mortem finding in a woman who died of breast cancer. Although there are reports of intracranial lipomas in patients with malignant tumors there is no explanation for the co-existence of the two tumors. The present tumor also includes a segment of a nerve which is not uncommon, but a less common finding was the presence of nests of Schwann cells within it, shown by immunohistochemistry.

  6. A Case of Midbrain and Thalamic Infarction Involving Artery of Percheron

    Directory of Open Access Journals (Sweden)

    Muhammad Almamun

    2015-03-01

    Full Text Available Blood supply to the thalamus and brainstem have frequent anatomic variations. One of these is where all the perforators to the above areas arise from a single branch of the posterior cerebral artery commonly known as the artery of Percheron. Infarction involving this artery leading to bilateral thalamic and midbrain lesions is not uncommon, but can cause diagnostic difficulties due to the varying clinical presentations possible and the wide differentials. Early brain imaging and diagnosis is important for initiating appropriate treatment. In this case report, we discuss a patient who presented with an artery of Percheron related stroke affecting the mid brain and paramedian thalamic areas. We also discuss the differentials of presentations with similar symptoms.

  7. Surprised at all the entropy: hippocampal, caudate and midbrain contributions to learning from prediction errors.

    Directory of Open Access Journals (Sweden)

    Anne-Marike Schiffer

    Full Text Available Influential concepts in neuroscientific research cast the brain a predictive machine that revises its predictions when they are violated by sensory input. This relates to the predictive coding account of perception, but also to learning. Learning from prediction errors has been suggested for take place in the hippocampal memory system as well as in the basal ganglia. The present fMRI study used an action-observation paradigm to investigate the contributions of the hippocampus, caudate nucleus and midbrain dopaminergic system to different types of learning: learning in the absence of prediction errors, learning from prediction errors, and responding to the accumulation of prediction errors in unpredictable stimulus configurations. We conducted analyses of the regions of interests' BOLD response towards these different types of learning, implementing a bootstrapping procedure to correct for false positives. We found both, caudate nucleus and the hippocampus to be activated by perceptual prediction errors. The hippocampal responses seemed to relate to the associative mismatch between a stored representation and current sensory input. Moreover, its response was significantly influenced by the average information, or Shannon entropy of the stimulus material. In accordance with earlier results, the habenula was activated by perceptual prediction errors. Lastly, we found that the substantia nigra was activated by the novelty of sensory input. In sum, we established that the midbrain dopaminergic system, the hippocampus, and the caudate nucleus were to different degrees significantly involved in the three different types of learning: acquisition of new information, learning from prediction errors and responding to unpredictable stimulus developments. We relate learning from perceptual prediction errors to the concept of predictive coding and related information theoretic accounts.

  8. Arterial blood supply to midbrain, thalamus and internal capsule on CT, 3

    International Nuclear Information System (INIS)

    Takeshita, Gen; Ottomo, Michinori; Sasaki, Taisuke; Fukuda, Eiko.

    1984-01-01

    The selective injection of dye into the anterior choroidal artery (blue), the medial posterior choroidal artery (green), and the lateral posterior choroidal artery (red), using seven post-mortem brains, was performed. After fixation, sections parallel with the orbito-meatal line were obtained. The distribution of the anterior choroidal artery was visualized in the uncal region of the temporal lobe and the cerebral peduncle below the slice of the third ventricle. On the slice of the third ventricle, the lateral part of the geniculate region, the globus pallidus, and the posterior limb of the internal capsule were supplied by the anterior choroidal artery. The blood supply of the posterior limb of the internal capsule was also demonstrated on the slice of the anterior horn and on the body of the lateral ventricle. The distribution of the medial posterior choroidal artery was visualized in the tegmentum of the midbrain below the slice of the third ventricle, and on the slice of the anterior horn, the pineal body and the posterior part of the thalamus were also supplied. The distribution of the lateral posterior choroidal artery was visualized in the lateral part of the midbrain, around the red nucleus, below the slice of the third ventricle, and on the slice of the third ventricle, the upper part of the cerebral peduncle, the posterior part of the hypothalamus, and the medial part of the geniculate region were also supplied. Also, distribution to the medial and posterior parts of the thalamus was noted on the slice of the anterior horn. It was quite useful to identify the distribution of each choroidal artery on CT sections for the CT diagnosis of cerebrovascular disorders. (author)

  9. Discrimination of communication vocalizations by single neurons and groups of neurons in the auditory midbrain.

    Science.gov (United States)

    Schneider, David M; Woolley, Sarah M N

    2010-06-01

    Many social animals including songbirds use communication vocalizations for individual recognition. The perception of vocalizations depends on the encoding of complex sounds by neurons in the ascending auditory system, each of which is tuned to a particular subset of acoustic features. Here, we examined how well the responses of single auditory neurons could be used to discriminate among bird songs and we compared discriminability to spectrotemporal tuning. We then used biologically realistic models of pooled neural responses to test whether the responses of groups of neurons discriminated among songs better than the responses of single neurons and whether discrimination by groups of neurons was related to spectrotemporal tuning and trial-to-trial response variability. The responses of single auditory midbrain neurons could be used to discriminate among vocalizations with a wide range of abilities, ranging from chance to 100%. The ability to discriminate among songs using single neuron responses was not correlated with spectrotemporal tuning. Pooling the responses of pairs of neurons generally led to better discrimination than the average of the two inputs and the most discriminating input. Pooling the responses of three to five single neurons continued to improve neural discrimination. The increase in discriminability was largest for groups of neurons with similar spectrotemporal tuning. Further, we found that groups of neurons with correlated spike trains achieved the largest gains in discriminability. We simulated neurons with varying levels of temporal precision and measured the discriminability of responses from single simulated neurons and groups of simulated neurons. Simulated neurons with biologically observed levels of temporal precision benefited more from pooling correlated inputs than did neurons with highly precise or imprecise spike trains. These findings suggest that pooling correlated neural responses with the levels of precision observed in the

  10. Vertical diplopia and oscillopsia due to midbrain keyhole aqueduct syndrome associated with severe cough.

    Science.gov (United States)

    Oh, Angela Jinsook; Lanzman, Bryan Alexander; Liao, Yaping Joyce

    2018-06-01

    Midline structural defects in the neural axis can give rise to neuro-ophthalmic symptoms. We report a rare case of keyhole aqueduct syndrome presenting after two years of severe cough due to gastroesophageal reflux disease. A 58-year-old woman with a 2-year history of daily, severe cough presented to the neuro-ophthalmology clinic with progressive diplopia and oscillopsia. Examination revealed a 1-2 Hz down-beating nystagmus in primary gaze that worsened with left, right, and down gazes. Gaze evoked nystagmus and mild paresis were also seen with up gaze. There was an incomitant left hypertropia due to skew deviation that worsened with right and up gazes and improved with down gaze. She also had a right-sided ptosis and a 3 mm anisocoria not due to cranial nerve 3 paresis or Horner's syndrome. Brain magnetic resonance imaging showed a 1.5 mm × 11.7 mm × 6 mm midline cleft in the ventral midbrain communicating with the cerebral aqueduct, consistent with keyhole aqueduct syndrome. Her nystagmus and diplopia improved with oral acetazolamide treatment, at high doses of 2500-3000 mg per day. We report the first case of midbrain keyhole aqueduct syndrome with ocular motor and other neuro-ophthalmic manifestations associated with severe cough. Although her cough was effectively treated and intracranial pressure measurement was normal, her ophthalmic symptoms continued to progress, which is common in previous cases reported. Treatment with acetazolamide led to significant improvement, supporting the use of acetazolamide in this rare condition.

  11. Surprised at all the entropy: hippocampal, caudate and midbrain contributions to learning from prediction errors.

    Science.gov (United States)

    Schiffer, Anne-Marike; Ahlheim, Christiane; Wurm, Moritz F; Schubotz, Ricarda I

    2012-01-01

    Influential concepts in neuroscientific research cast the brain a predictive machine that revises its predictions when they are violated by sensory input. This relates to the predictive coding account of perception, but also to learning. Learning from prediction errors has been suggested for take place in the hippocampal memory system as well as in the basal ganglia. The present fMRI study used an action-observation paradigm to investigate the contributions of the hippocampus, caudate nucleus and midbrain dopaminergic system to different types of learning: learning in the absence of prediction errors, learning from prediction errors, and responding to the accumulation of prediction errors in unpredictable stimulus configurations. We conducted analyses of the regions of interests' BOLD response towards these different types of learning, implementing a bootstrapping procedure to correct for false positives. We found both, caudate nucleus and the hippocampus to be activated by perceptual prediction errors. The hippocampal responses seemed to relate to the associative mismatch between a stored representation and current sensory input. Moreover, its response was significantly influenced by the average information, or Shannon entropy of the stimulus material. In accordance with earlier results, the habenula was activated by perceptual prediction errors. Lastly, we found that the substantia nigra was activated by the novelty of sensory input. In sum, we established that the midbrain dopaminergic system, the hippocampus, and the caudate nucleus were to different degrees significantly involved in the three different types of learning: acquisition of new information, learning from prediction errors and responding to unpredictable stimulus developments. We relate learning from perceptual prediction errors to the concept of predictive coding and related information theoretic accounts.

  12. Involvement of 5-HT(2) serotonergic receptors of the nucleus raphe magnus and nucleus reticularis gigantocellularis/paragigantocellularis complex neural networks in the antinociceptive phenomenon that follows the post-ictal immobility syndrome.

    Science.gov (United States)

    de Oliveira, Rithiele Cristina; de Oliveira, Ricardo; Ferreira, Célio Marcos Dos Reis; Coimbra, Norberto Cysne

    2006-09-01

    The post-ictal immobility syndrome is followed by a significant increase in the nociceptive thresholds in animals and men. In this interesting post-ictal behavioral response, endogenous opioid peptides-mediated mechanisms, as well as cholinergic-mediated antinociceptive processes, have been suggested. However, considering that many serotonergic descending pathways have been implicated in antinociceptive reactions, the aim of the present work is to investigate the involvement of 5-HT(2)-serotonergic receptor subfamily in the post-ictal antinociception. The analgesia was measured by the tail-flick test in seven or eight Wistar rats per group. Convulsions were followed by statistically significant increase in the tail-flick latencies (TFL), at least for 120 min of the post-ictal period. Male Wistar rats were submitted to stereotaxic surgery for introduction of a guide-cannula in the rhombencephalon, aiming either the nucleus raphe magnus (NRM) or the gigantocellularis complex. In independent groups of animals, these nuclei were neurochemically lesioned with a unilateral microinjection of ibotenic acid (1.0 microg/0.2 microL). The neuronal damage of either the NRM or nucleus reticularis gigantocellularis/paragigantocellularis complex decreased the post-ictal analgesia. Also, in other independent groups, central administration of ritanserin (5.0 microg/0.2 microL) or physiological saline into each of the reticular formation nuclei studied caused a statistically significant decrease in the TFL of seizing animals, as compared to controls, in all post-ictal periods studied. These results indicate that serotonin input-connected neurons of the pontine and medullarly reticular nuclei may be involved in the post-ictal analgesia.

  13. Electrophysiological Assessment of Serotonin and GABA Neuron Function in the Dorsal Raphe during the Third Trimester Equivalent Developmental Period in Mice.

    Science.gov (United States)

    Morton, Russell A; Yanagawa, Yuchio; Valenzuela, C Fernando

    2015-01-01

    Alterations in the development of the serotonin system can have prolonged effects, including depression and anxiety disorders later in life. Serotonin axonal projections from the dorsal raphe undergo extensive refinement during the first 2 weeks of postnatal life in rodents (equivalent to the third trimester of human pregnancy). However, little is known about the functional properties of serotonin and GABA neurons in the dorsal raphe during this critical developmental period. We assessed the functional properties and synaptic connectivity of putative serotoninergic neurons and GABAergic neurons in the dorsal raphe during early [postnatal day (P) P5-P7] and late (P15-P17) stages of the third trimester equivalent period using electrophysiology. Our studies demonstrate that GABAergic neurons are hyperexcitable at P5-P7 relative to P15-P17. Furthermore, putative serotonin neurons exhibit an increase in both excitatory and GABAA receptor-mediated spontaneous postsynaptic currents during this developmental period. Our data suggest that GABAergic neurons and putative serotonin neurons undergo significant electrophysiological changes during neonatal development.

  14. Cadherin-13 Deficiency Increases Dorsal Raphe 5-HT Neuron Density and Prefrontal Cortex Innervation in the Mouse Brain

    Directory of Open Access Journals (Sweden)

    Andrea Forero

    2017-09-01

    Full Text Available Background: During early prenatal stages of brain development, serotonin (5-HT-specific neurons migrate through somal translocation to form the raphe nuclei and subsequently begin to project to their target regions. The rostral cluster of cells, comprising the median and dorsal raphe (DR, innervates anterior regions of the brain, including the prefrontal cortex. Differential analysis of the mouse 5-HT system transcriptome identified enrichment of cell adhesion molecules in 5-HT neurons of the DR. One of these molecules, cadherin-13 (Cdh13 has been shown to play a role in cell migration, axon pathfinding, and synaptogenesis. This study aimed to investigate the contribution of Cdh13 to the development of the murine brain 5-HT system.Methods: For detection of Cdh13 and components of the 5-HT system at different embryonic developmental stages of the mouse brain, we employed immunofluorescence protocols and imaging techniques, including epifluorescence, confocal and structured illumination microscopy. The consequence of CDH13 loss-of-function mutations on brain 5-HT system development was explored in a mouse model of Cdh13 deficiency.Results: Our data show that in murine embryonic brain Cdh13 is strongly expressed on 5-HT specific neurons of the DR and in radial glial cells (RGCs, which are critically involved in regulation of neuronal migration. We observed that 5-HT neurons are intertwined with these RGCs, suggesting that these neurons undergo RGC-guided migration. Cdh13 is present at points of intersection between these two cell types. Compared to wildtype controls, Cdh13-deficient mice display increased cell densities in the DR at embryonic stages E13.5, E17.5, and adulthood, and higher serotonergic innervation of the prefrontal cortex at E17.5.Conclusion: Our findings provide evidence for a role of CDH13 in the development of the serotonergic system in early embryonic stages. Specifically, we indicate that Cdh13 deficiency affects the cell

  15. Neonatal citalopram exposure decreases serotonergic fiber density in the olfactory bulb of male but not female adult rats

    Directory of Open Access Journals (Sweden)

    Junlin eZhang

    2013-05-01

    Full Text Available Manipulation of serotonin (5HT during early development has been shown to induce long-lasting morphological changes within the raphe nuclear complex and serotonergic circuitry throughout the brain. Recent studies have demonstrated altered raphe-derived 5HT transporter (SERT immunoreactive axonal expression in several cortical target sites after brief perinatal exposure to selective 5HT reuptake inhibitors such as citalopram (CTM. Since the serotonergic raphe nuclear complex projects to the olfactory bulb (OB and perinatal 5HT disruption has been shown to disrupt olfactory behaviors, the goal of this study was to further investigate such developmental effects in the OB of CTM exposed animals. Male and female rat pups were exposed to CTM from postnatal day 8-21. After animals reach adulthood (>90 days, OB tissue sections were processed immunohistochemically for SERT antiserum. Our data revealed that the density of the SERT immunoreactive fibers decreased ~40% in the OB of CTM exposed male rats, but not female rats. Our findings support a broad and long-lasting change throughout most of the 5HT system, including the OB, after early manipulation of 5HT. Because dysfunction of the early 5HT system has been implicated in the etiology of neurodevelopmental disorders such as autism spectrum disorders (ASDs, these new findings may offer insight into the abnormal olfactory perception often noted in patients with ASD.

  16. Epigenetic regulation of dorsal raphe GABA(B1a) associated with isolation-induced abnormal responses to social stimulation in mice.

    Science.gov (United States)

    Araki, Ryota; Hiraki, Yosuke; Nishida, Shoji; Kuramoto, Nobuyuki; Matsumoto, Kinzo; Yabe, Takeshi

    2016-02-01

    In isolation-reared mice, social encounter stimulation induces locomotor hyperactivity and activation of the dorsal raphe nucleus (DRN), suggesting that dysregulation of dorsal raphe function may be involved in abnormal behaviors. In this study, we examined the involvement of dorsal raphe GABAergic dysregulation in the abnormal behaviors of isolation-reared mice. We also studied an epigenetic mechanism underlying abnormalities of the dorsal raphe GABAergic system. Both mRNA and protein levels of GABA(B1a), a GABA(B) receptor subunit, were increased in the DRN of isolation-reared mice, compared with these levels in group-reared mice. In contrast, mRNA levels for other GABAergic system-related genes (GABA(A) receptor α1, β2 and γ2 subunits, GABA(B) receptor 1b and 2 subunits, and glutamate decarboxylase 67 and 65) were unchanged. Intra-DRN microinjection of 0.06 nmol baclofen (a GABA(B) receptor agonist) exacerbated encounter-induced hyperactivity and aggressive behavior, while microinjection of 0.3 nmol phaclofen (a GABA(B) receptor antagonist) attenuated encounter-induced hyperactivity and aggressive behavior in isolation-reared mice. Furthermore, microinjection of 0.06 nmol baclofen elicited encounter-induced hyperactivity in group-reared mice. Neither baclofen nor phaclofen affected immobility time in the forced swim test and hyperactivity in a novel environment of isolation reared mice. Bisulfite sequence analyses revealed that the DNA methylation level of the CpG island around the transcription start site (TSS) of GABA(B1a) was decreased in the DRN of isolation-reared mice. Chromatin immunoprecipitation analysis showed that histone H3 was hyperacetylated around the TSS of GABA(B1a) in the DRN of isolation-reared mice. These findings indicate that an increase in dorsal raphe GABA(B1a) expression via epigenetic regulation is associated with abnormal responses to social stimulation such as encounter-induced hyperactivity and aggressive behavior in isolation

  17. Organization of Functional Long-Range Circuits Controlling the Activity of Serotonergic Neurons in the Dorsal Raphe Nucleus.

    Science.gov (United States)

    Zhou, Li; Liu, Ming-Zhe; Li, Qing; Deng, Juan; Mu, Di; Sun, Yan-Gang

    2017-03-21

    Serotonergic neurons play key roles in various biological processes. However, circuit mechanisms underlying tight control of serotonergic neurons remain largely unknown. Here, we systematically investigated the organization of long-range synaptic inputs to serotonergic neurons and GABAergic neurons in the dorsal raphe nucleus (DRN) of mice with a combination of viral tracing, slice electrophysiological, and optogenetic techniques. We found that DRN serotonergic neurons and GABAergic neurons receive largely comparable synaptic inputs from six major upstream brain areas. Upon further analysis of the fine functional circuit structures, we found both bilateral and ipsilateral patterns of topographic connectivity in the DRN for the axons from different inputs. Moreover, the upstream brain areas were found to bidirectionally control the activity of DRN serotonergic neurons by recruiting feedforward inhibition or via a push-pull mechanism. Our study provides a framework for further deciphering the functional roles of long-range circuits controlling the activity of serotonergic neurons in the DRN. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  18. Adaptive Control of Dorsal Raphe by 5-HT4 in the Prefrontal Cortex Prevents Persistent Hypophagia following Stress

    Directory of Open Access Journals (Sweden)

    Alexandra Jean

    2017-10-01

    Full Text Available Transient reduced food intake (hypophagia following high stress could have beneficial effects on longevity, but paradoxically, hypophagia can persist and become anorexia-like behavior. The neural underpinnings of stress-induced hypophagia and the mechanisms by which the brain prevents the transition from transient to persistent hypophagia remain undetermined. In this study, we report the involvement of a network governing goal-directed behavior (decision. This network consists of the ascending serotonergic inputs from the dorsal raphe nucleus (DR to the medial prefrontal cortex (mPFC. Specifically, adult restoration of serotonin 4 receptor (5-HT4R expression in the mPFC rescues hypophagia and specific molecular changes related to depression resistance in the DR (5-HT release elevation, 5-HT1A receptor, and 5-HT transporter reductions of stressed 5-HT4R knockout mice. The adult mPFC-5-HT4R knockdown mimics the null phenotypes. When mPFC-5-HT4Rs are overexpressed and DR-5-HT1ARs are blocked in the DR, hypophagia following stress persists, suggesting an antidepressant action of early anorexia.

  19. Adaptive Control of Dorsal Raphe by 5-HT4 in the Prefrontal Cortex Prevents Persistent Hypophagia following Stress.

    Science.gov (United States)

    Jean, Alexandra; Laurent, Laetitia; Delaunay, Sabira; Doly, Stéphane; Dusticier, Nicole; Linden, David; Neve, Rachael; Maroteaux, Luc; Nieoullon, André; Compan, Valérie

    2017-10-24

    Transient reduced food intake (hypophagia) following high stress could have beneficial effects on longevity, but paradoxically, hypophagia can persist and become anorexia-like behavior. The neural underpinnings of stress-induced hypophagia and the mechanisms by which the brain prevents the transition from transient to persistent hypophagia remain undetermined. In this study, we report the involvement of a network governing goal-directed behavior (decision). This network consists of the ascending serotonergic inputs from the dorsal raphe nucleus (DR) to the medial prefrontal cortex (mPFC). Specifically, adult restoration of serotonin 4 receptor (5-HT 4 R) expression in the mPFC rescues hypophagia and specific molecular changes related to depression resistance in the DR (5-HT release elevation, 5-HT 1A receptor, and 5-HT transporter reductions) of stressed 5-HT 4 R knockout mice. The adult mPFC-5-HT 4 R knockdown mimics the null phenotypes. When mPFC-5-HT 4 Rs are overexpressed and DR-5-HT1ARs are blocked in the DR, hypophagia following stress persists, suggesting an antidepressant action of early anorexia. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Serotonin neurons in the dorsal raphe mediate the anticataplectic action of orexin neurons by reducing amygdala activity.

    Science.gov (United States)

    Hasegawa, Emi; Maejima, Takashi; Yoshida, Takayuki; Masseck, Olivia A; Herlitze, Stefan; Yoshioka, Mitsuhiro; Sakurai, Takeshi; Mieda, Michihiro

    2017-04-25

    Narcolepsy is a sleep disorder caused by the loss of orexin (hypocretin)-producing neurons and marked by excessive daytime sleepiness and a sudden weakening of muscle tone, or cataplexy, often triggered by strong emotions. In a mouse model for narcolepsy, we previously demonstrated that serotonin neurons of the dorsal raphe nucleus (DRN) mediate the suppression of cataplexy-like episodes (CLEs) by orexin neurons. Using an optogenetic tool, in this paper we show that the acute activation of DRN serotonin neuron terminals in the amygdala, but not in nuclei involved in regulating rapid eye-movement sleep and atonia, suppressed CLEs. Not only did stimulating serotonin nerve terminals reduce amygdala activity, but the chemogenetic inhibition of the amygdala using designer receptors exclusively activated by designer drugs also drastically decreased CLEs, whereas chemogenetic activation increased them. Moreover, the optogenetic inhibition of serotonin nerve terminals in the amygdala blocked the anticataplectic effects of orexin signaling in DRN serotonin neurons. Taken together, the results suggest that DRN serotonin neurons, as a downstream target of orexin neurons, inhibit cataplexy by reducing the activity of amygdala as a center for emotional processing.

  1. Ribosomal DNA transcription in the dorsal raphe nucleus is increased in residual but not in paranoid schizophrenia.

    Science.gov (United States)

    Krzyżanowska, Marta; Steiner, Johann; Brisch, Ralf; Mawrin, Christian; Busse, Stefan; Braun, Katharina; Jankowski, Zbigniew; Bernstein, Hans-Gert; Bogerts, Bernhard; Gos, Tomasz

    2015-03-01

    The central serotonergic system is implicated in the pathogenesis of schizophrenia, where the imbalance between dopamine, serotonin and glutamate plays a key pathophysiological role. The dorsal raphe nucleus (DRN) is the main source of serotonergic innervation of forebrain limbic structures disturbed in schizophrenia patients. The study was carried out on paraffin-embedded brains from 17 (8 paranoid and 9 residual) schizophrenia patients and 28 matched controls without mental disorders. The transcriptional activity of ribosomal DNA (rDNA) in DRN neurons was evaluated by the AgNOR silver-staining method. An increased rDNA transcriptional activity was found in schizophrenia patients in the cumulative analysis of all DRN subnuclei (t test, P = 0.02). Further subgroup analysis revealed that it was an effect specific for residual schizophrenia versus paranoid schizophrenia or control groups (ANOVA, P = 0.002). This effect was confounded neither by suicide nor by antipsychotic medication. Our findings suggest that increased activity of rDNA in DRN neurons is a distinct phenomenon in schizophrenia, particularly in residual patients. An activation of the rDNA transcription in DRN neurons may represent a compensatory mechanism to overcome the previously described prefrontal serotonergic hypofunction in this diagnostic subgroup.

  2. Wnt5a-treated midbrain neural stem cells improve dopamine cell replacement therapy in parkinsonian mice

    DEFF Research Database (Denmark)

    Parish, Clare L; Castelo-Branco, Gonçalo; Rawal, Nina

    2008-01-01

    have prevented their clinical application. We present here a method for generating large numbers of DA neurons based on expanding and differentiating ventral midbrain (VM) neural stem cells/progenitors in the presence of key signals necessary for VM DA neuron development. Mouse VM neurospheres (VMNs......Dopamine (DA) cell replacement therapy in Parkinson disease (PD) can be achieved using human fetal mesencephalic tissue; however, limited tissue availability has hindered further developments. Embryonic stem cells provide a promising alternative, but poor survival and risk of teratoma formation......) expanded with FGF2, differentiated with sonic hedgehog and FGF8, and transfected with Wnt5a (VMN-Wnt5a) generated 10-fold more DA neurons than did conventional FGF2-treated VMNs. VMN-Wnt5a cells exhibited the transcriptional and biochemical profiles and intrinsic electrophysiological properties of midbrain...

  3. Individual differences in the motivation to communicate relate to levels of midbrain and striatal catecholamine markers in male European starlings

    OpenAIRE

    Heimovics, Sarah A; Salvante, Katrina G; Sockman, Keith W; Riters, Lauren V

    2011-01-01

    Individuals display dramatic differences in social communication even within similar social contexts. Across vertebrates dopaminergic projections from the ventral tegmental area (VTA) and midbrain central gray (GCt) strongly influence motivated, reward-directed behaviors. Norepinephrine is also rich in these areas and may alter dopamine neuronal activity. The present study was designed to provide insight into the roles of dopamine and norepinephrine in VTA and GCt and their efferent striatal ...

  4. Wnt5a cooperates with canonical Wnts to generate midbrain dopaminergic neurons in vivo and in stem cells

    Czech Academy of Sciences Publication Activity Database

    Andersson, E.R.; Salto, C.; Villaescusa, J.C.; Cajanek, L.; Yang, S.; Bryjová, Lenka; Nagy, I.I.; Vainio, S.J.; Ramírez, C.; Bryja, Vítězslav; Arenas, E.

    2013-01-01

    Roč. 110, č. 7 (2013), E602-E610 ISSN 0027-8424 Grant - others:GA ČR(CZ) GA204/09/0498; GA ČR(CZ) GAP301/11/0747 Institutional research plan: CEZ:AV0Z50040702 Institutional support: RVO:68081707 Keywords : VENTRAL MIDBRAIN * PARKINSONS-DISEASE * BETA-CATENIN Subject RIV: BO - Biophysics Impact factor: 9.809, year: 2013

  5. Selective increase of in vivo firing frequencies in DA SN neurons after proteasome inhibition in the ventral midbrain.

    Science.gov (United States)

    Subramaniam, Mahalakshmi; Kern, Beatrice; Vogel, Simone; Klose, Verena; Schneider, Gaby; Roeper, Jochen

    2014-09-01

    The impairment of protein degradation via the ubiquitin-proteasome system (UPS) is present in sporadic Parkinson's disease (PD), and might play a key role in selective degeneration of vulnerable dopamine (DA) neurons in the substantia nigra pars compacta (SN). Further evidence for a causal role of dysfunctional UPS in familial PD comes from mutations in parkin, which results in a loss of function of an E3-ubiquitin-ligase. In a mouse model, genetic inactivation of an essential component of the 26S proteasome lead to widespread neuronal degeneration including DA midbrain neurons and the formation of alpha-synuclein-positive inclusion bodies, another hallmark of PD. Studies using pharmacological UPS inhibition in vivo had more mixed results, varying from extensive degeneration to no loss of DA SN neurons. However, it is currently unknown whether UPS impairment will affect the neurophysiological functions of DA midbrain neurons. To answer this question, we infused a selective proteasome inhibitor into the ventral midbrain in vivo and recorded single DA midbrain neurons 2 weeks after the proteasome challenge. We found a selective increase in the mean in vivo firing frequencies of identified DA SN neurons in anesthetized mice, while those in the ventral tegmental area (VTA) were unaffected. Our results demonstrate that a single-hit UPS inhibition is sufficient to induce a stable and selective hyperexcitability phenotype in surviving DA SN neurons in vivo. This might imply that UPS dysfunction sensitizes DA SN neurons by enhancing 'stressful pacemaking'. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  6. Mammal-like organization of the avian midbrain central gray and a reappraisal of the intercollicular nucleus.

    Directory of Open Access Journals (Sweden)

    Marcy A Kingsbury

    Full Text Available In mammals, rostrocaudal columns of the midbrain periaqueductal gray (PAG regulate diverse behavioral and physiological functions, including sexual and fight-or-flight behavior, but homologous columns have not been identified in non-mammalian species. In contrast to mammals, in which the PAG lies ventral to the superior colliculus and surrounds the cerebral aqueduct, birds exhibit a hypertrophied tectum that is displaced laterally, and thus the midbrain central gray (CG extends mediolaterally rather than dorsoventrally as in mammals. We therefore hypothesized that the avian CG is organized much like a folded open PAG. To address this hypothesis, we conducted immunohistochemical comparisons of the midbrains of mice and finches, as well as Fos studies of aggressive dominance, subordinance, non-social defense and sexual behavior in territorial and gregarious finch species. We obtained excellent support for our predictions based on the folded open model of the PAG and further showed that birds possess functional and anatomical zones that form longitudinal columns similar to those in mammals. However, distinguishing characteristics of the dorsal/dorsolateral PAG, such as a dense peptidergic innervation, a longitudinal column of neuronal nitric oxide synthase neurons, and aggression-induced Fos responses, do not lie within the classical avian CG, but in the laterally adjacent intercollicular nucleus (ICo, suggesting that much of the ICo is homologous to the dorsal PAG.

  7. Tiam1 Regulates the Wnt/Dvl/Rac1 Signaling Pathway and the Differentiation of Midbrain Dopaminergic Neurons

    Science.gov (United States)

    Čajánek, Lukáš; Ganji, Ranjani Sri; Henriques-Oliveira, Catarina; Theofilopoulos, Spyridon; Koník, Peter

    2013-01-01

    Understanding the mechanisms that drive the differentiation of dopaminergic (DA) neurons is crucial for successful development of novel therapies for Parkinson's disease, in which DA neurons progressively degenerate. However, the mechanisms underlying the differentiation-promoting effects of Wnt5a on DA precursors are poorly understood. Here, we present the molecular and functional characterization of a signaling pathway downstream of Wnt5a, the Wnt/Dvl/Rac1 pathway. First, we characterize the interaction between Rac1 and Dvl and identify the N-terminal part of Dvl3 as necessary for Rac1 binding. Next, we show that Tiam1, a Rac1 guanosine exchange factor (GEF), is expressed in the ventral midbrain, interacts with Dvl, facilitates Dvl-Rac1 interaction, and is required for Dvl- or Wnt5a-induced activation of Rac1. Moreover, we show that Wnt5a promotes whereas casein kinase 1 (CK1), a negative regulator of the Wnt/Dvl/Rac1 pathway, abolishes the interactions between Dvl and Tiam1. Finally, using ventral midbrain neurosphere cultures, we demonstrate that the generation of DA neurons in culture is impaired after Tiam1 knockdown, indicating that Tiam1 is required for midbrain DA differentiation. In summary, our data identify Tiam1 as a novel regulator of DA neuron development and as a Dvl-associated and Rac1-specific GEF acting in the Wnt/Dvl/Rac1 pathway. PMID:23109420

  8. Long-Term Impairment of Sound Processing in the Auditory Midbrain by Daily Short-Term Exposure to Moderate Noise

    Directory of Open Access Journals (Sweden)

    Liang Cheng

    2017-01-01

    Full Text Available Most citizen people are exposed daily to environmental noise at moderate levels with a short duration. The aim of the present study was to determine the effects of daily short-term exposure to moderate noise on sound level processing in the auditory midbrain. Sound processing properties of auditory midbrain neurons were recorded in anesthetized mice exposed to moderate noise (80 dB SPL, 2 h/d for 6 weeks and were compared with those from age-matched controls. Neurons in exposed mice had a higher minimum threshold and maximum response intensity, a longer first spike latency, and a higher slope and narrower dynamic range for rate level function. However, these observed changes were greater in neurons with the best frequency within the noise exposure frequency range compared with those outside the frequency range. These sound processing properties also remained abnormal after a 12-week period of recovery in a quiet laboratory environment after completion of noise exposure. In conclusion, even daily short-term exposure to moderate noise can cause long-term impairment of sound level processing in a frequency-specific manner in auditory midbrain neurons.

  9. Increased Fos expression among midbrain dopaminergic cell groups during birdsong tutoring.

    Science.gov (United States)

    Nordeen, E J; Holtzman, D A; Nordeen, K W

    2009-08-01

    During avian vocal learning, birds memorize conspecific song patterns and then use auditory feedback to match their vocal output to this acquired template. Some models of song learning posit that during tutoring, conspecific visual, social and/or auditory cues activate neuromodulatory systems that encourage acquisition of the tutor's song and attach incentive value to that specific acoustic pattern. This hypothesis predicts that stimuli experienced during social tutoring activate cell populations capable of signaling reward. Using immunocytochemistry for the protein product of the immediate early gene c-Fos, we found that brief exposure of juvenile male zebra finches to a live familiar male tutor increased the density of Fos+ cells within two brain regions implicated in reward processing: the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). This activation of Fos appears to involve both dopaminergic and non-dopaminergic VTA/SNc neurons. Intriguingly, a familiar tutor was more effective than a novel tutor in stimulating Fos expression within these regions. In the periaqueductal gray, a dopamine-enriched cell population that has been implicated in emotional processing, Fos labeling also was increased after tutoring, with a familiar tutor again being more effective than a novel conspecific. As several neural regions implicated in song acquisition receive strong dopaminergic projections from these midbrain nuclei, their activation in conjunction with hearing the tutor's song could help to establish sensory representations that later guide motor sequence learning.

  10. Threat of punishment motivates memory encoding via amygdala, not midbrain, interactions with the medial temporal lobe.

    Science.gov (United States)

    Murty, Vishnu P; Labar, Kevin S; Adcock, R Alison

    2012-06-27

    Neural circuits associated with motivated declarative encoding and active threat avoidance have both been described, but the relative contribution of these systems to punishment-motivated encoding remains unknown. The current study used functional magnetic resonance imaging in humans to examine mechanisms of declarative memory enhancement when subjects were motivated to avoid punishments that were contingent on forgetting. A motivational cue on each trial informed participants whether they would be punished or not for forgetting an upcoming scene image. Items associated with the threat of shock were better recognized 24 h later. Punishment-motivated enhancements in subsequent memory were associated with anticipatory activation of right amygdala and increases in its functional connectivity with parahippocampal and orbitofrontal cortices. On a trial-by-trial basis, right amygdala activation during the motivational cue predicted hippocampal activation during encoding of the subsequent scene; across participants, the strength of this interaction predicted memory advantages due to motivation. Of note, punishment-motivated learning was not associated with activation of dopaminergic midbrain, as would be predicted by valence-independent models of motivation to learn. These data are consistent with the view that motivation by punishment activates the amygdala, which in turn prepares the medial temporal lobe for memory formation. The findings further suggest a brain system for declarative learning motivated by punishment that is distinct from that for learning motivated by reward.

  11. Frequency-specific attentional modulation in human primary auditory cortex and midbrain.

    Science.gov (United States)

    Riecke, Lars; Peters, Judith C; Valente, Giancarlo; Poser, Benedikt A; Kemper, Valentin G; Formisano, Elia; Sorger, Bettina

    2018-07-01

    Paying selective attention to an audio frequency selectively enhances activity within primary auditory cortex (PAC) at the tonotopic site (frequency channel) representing that frequency. Animal PAC neurons achieve this 'frequency-specific attentional spotlight' by adapting their frequency tuning, yet comparable evidence in humans is scarce. Moreover, whether the spotlight operates in human midbrain is unknown. To address these issues, we studied the spectral tuning of frequency channels in human PAC and inferior colliculus (IC), using 7-T functional magnetic resonance imaging (FMRI) and frequency mapping, while participants focused on different frequency-specific sounds. We found that shifts in frequency-specific attention alter the response gain, but not tuning profile, of PAC frequency channels. The gain modulation was strongest in low-frequency channels and varied near-monotonically across the tonotopic axis, giving rise to the attentional spotlight. We observed less prominent, non-tonotopic spatial patterns of attentional modulation in IC. These results indicate that the frequency-specific attentional spotlight in human PAC as measured with FMRI arises primarily from tonotopic gain modulation, rather than adapted frequency tuning. Moreover, frequency-specific attentional modulation of afferent sound processing in human IC seems to be considerably weaker, suggesting that the spotlight diminishes toward this lower-order processing stage. Our study sheds light on how the human auditory pathway adapts to the different demands of selective hearing. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  12. Effects of organically bound tritium (OBT) on cultured midbrain cells from embryonic mice

    International Nuclear Information System (INIS)

    Wang Bing; Akihiro Shima; Takeshi Yamada; Keiko Watganabe

    1997-01-01

    Objective: Four kinds of organically bound tritium compounds (OBT s ) including 3 H-thymidine, 3 H-uridine, 3 H-arginine and 3 H-glutamic acid, were investigated on proliferation and differentiation of cultured mouse embryonic midbrain cells (MBCs). Methods: MBCs were isolated from day 11 embryos, cultured at a high concentration with the medium containing OBT. Results: Differentiation of MBC was more sensitive to radiation than proliferation. Dose-dependent decrease of DNA and protein contents were also observed. The RBE values, ranging from 4.6 to 8.7, of β rays from OBTs were obtained when compared with X-irradiation at their ID50s (inhibitory dose that reduced assessment value by 50% of the control) on inhibition of cell proliferation and differentiation, and on reduction of DNA and protein contents of the cultures. The mixed exposure to X-rays and one kind of OBTs or to any two kinds of OBTs resulted in more efficiently inhibitory effect on differentiation. Conclusions: MBC culture system was more sensitive to beta radiation from OBTs than to X-rays, which resulted in very high RBE values

  13. Long-Lasting Sound-Evoked Afterdischarge in the Auditory Midbrain.

    Science.gov (United States)

    Ono, Munenori; Bishop, Deborah C; Oliver, Douglas L

    2016-02-12

    Different forms of plasticity are known to play a critical role in the processing of information about sound. Here, we report a novel neural plastic response in the inferior colliculus, an auditory center in the midbrain of the auditory pathway. A vigorous, long-lasting sound-evoked afterdischarge (LSA) is seen in a subpopulation of both glutamatergic and GABAergic neurons in the central nucleus of the inferior colliculus of normal hearing mice. These neurons were identified with single unit recordings and optogenetics in vivo. The LSA can continue for up to several minutes after the offset of the sound. LSA is induced by long-lasting, or repetitive short-duration, innocuous sounds. Neurons with LSA showed less adaptation than the neurons without LSA. The mechanisms that cause this neural behavior are unknown but may be a function of intrinsic mechanisms or the microcircuitry of the inferior colliculus. Since LSA produces long-lasting firing in the absence of sound, it may be relevant to temporary or chronic tinnitus or to some other aftereffect of long-duration sound.

  14. Ventral medullary neurones excited from the hypothalamic and mid-brain defence areas.

    Science.gov (United States)

    Hilton, S M; Smith, P R

    1984-07-01

    In cats anaesthetised with chloralose, the ventral medulla was explored in and around the strip previously identified as the location of the efferent pathway from the hypothalamic and mid-brain defence areas to the spinal cord, in a search for neurones excited by electrical stimulation of the defence areas. Such units were found mostly in the caudal part of this strip, at a depth of not more than 500 microns from the surface. Nearly all were located in the ventral part of nucleus paragigantocellularis lateralis (PGL) at the level of the rostral pole of the inferior olive. There was evidence of temporal and spatial facilitation, indicating a convergent excitatory input from the defence areas onto neurones in PGL. This is consistent with earlier evidence of a synaptic relay in the efferent pathway at this site. When the pathway is blocked at this site, arterial blood pressure falls profoundly, so activity in these neurones may be essential for the normal level of sympathetic nerve activity.

  15. Neural Mobilization Treatment Decreases Glial Cells and Brain-Derived Neurotrophic Factor Expression in the Central Nervous System in Rats with Neuropathic Pain Induced by CCI in Rats

    Directory of Open Access Journals (Sweden)

    Aline Carolina Giardini

    2017-01-01

    Full Text Available Background. Glial cells are implicated in the development of chronic pain and brain-derived neurotropic factor (BDNF released from activated microglia contributes to the nociceptive transmission. Neural mobilization (NM technique is a method clinically effective in reducing pain sensitivity. Here we examined the involvement of glial cells and BDNF expression in the thalamus and midbrain after NM treatment in rats with chronic constriction injury (CCI. CCI was induced and rats were subsequently submitted to 10 sessions of NM, every other day, beginning 14 days after CCI. Thalamus and midbrain were analyzed for glial fibrillary acidic protein (GFAP, microglial cell OX-42, and BDNF using Immunohistochemistry and Western blot assays. Results. Thalamus and midbrain of CCI group showed increases in GFAP, OX-42, and BDNF expression compared with control group and, in contrast, showed decreases in GFAP, OX-42, and BDNF after NM when compared with CCI group. The decreased immunoreactivity for GFAP, OX-42, and BDNF in ventral posterolateral nucleus in thalamus and the periaqueductal gray in midbrain was shown by immunohistochemistry. Conclusions. These findings may improve the knowledge about the involvement of astrocytes, microglia, and BDNF in the chronic pain and show that NM treatment, which alleviates neuropathic pain, affects glial cells and BDNF expression.

  16. Treadmill exercise ameliorates social isolation-induced depression through neuronal generation in rat pups.

    Science.gov (United States)

    Cho, Jung-Wan; Jung, Sun-Young; Lee, Sang-Won; Lee, Sam-Jun; Seo, Tae-Beom; Kim, Young-Pyo; Kim, Dae-Young

    2017-12-01

    Social isolation is known to induce emotional and behavioral changes in animals and humans. The effect of treadmill exercise on depression was investigated using social isolated rat pups. The rat pups in the social isolation groups were housed individually. The rat pups in the exercise groups were forced to run on treadmill for 30 min once a day from postnatal day 21 to postnatal day 34. In order to evaluate depression state of rat pups, forced swimming test was performed. Newly generated cells in the hippocampal dentate gyrus were determined by 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry. We examined the expression of 5-hydroxytryptamine (5-HT) and tryptophan hydroxylase (TPH) in the dorsal raphe using immunofluorescence. The expression of brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) was detected by Western blot analysis. The present results demonstrated that social isolation increased resting time and decreased mobility time. Expression of 5-HT and TPH in the dorsal raphe and expression of BDNF and TrkB in the hippocampus were decreased by social isolation. The number of BrdU-positive cells in the hippocampal dentate gyrus was suppressed by social isolation. Treadmill exercise decreased resting time and increased mobility in the social isolated rat pups. Expression of 5-HT, TPH, BDNF, and TrkB was increased by treadmill exercise. The present results suggested that treadmill exercise may ameliorates social isolation-induced depression through increasing neuronal generation.

  17. Sex differences in corticotropin-releasing factor receptor-1 action within the dorsal raphe nucleus in stress responsivity.

    Science.gov (United States)

    Howerton, Alexis R; Roland, Alison V; Fluharty, Jessica M; Marshall, Anikò; Chen, Alon; Daniels, Derek; Beck, Sheryl G; Bale, Tracy L

    2014-06-01

    Women are twice as likely as men to suffer from stress-related affective disorders. Corticotropin-releasing factor (CRF) is an important link between stress and mood, in part through its signaling in the serotonergic dorsal raphe (DR). Development of CRF receptor-1 (CRFr1) antagonists has been a focus of numerous clinical trials but has not yet been proven efficacious. We hypothesized that sex differences in CRFr1 modulation of DR circuits might be key determinants in predicting therapeutic responses and affective disorder vulnerability. Male and female mice received DR infusions of the CRFr1 antagonist, NBI 35965, or CRF and were evaluated for stress responsivity. Sex differences in indices of neural activation (cFos) and colocalization of CRFr1 throughout the DR were examined. Whole-cell patch-clamp electrophysiology assessed sex differences in serotonin neuron membrane characteristics and responsivity to CRF. Males showed robust behavioral and hypothalamic-pituitary-adrenal axis responses to DR infusion of NBI 35965 and CRF, whereas females were minimally responsive. Sex differences were also found for both CRF-induced DR cFos and CRFr1 co-localization throughout the DR. Electrophysiologically, female serotonergic neurons showed blunted membrane excitability and divergent inhibitory postsynaptic current responses to CRF application. These studies demonstrate convincing sex differences in CRFr1 activity in the DR, where blunted female responses to NBI 35965 and CRF suggest unique stress modulation of the DR. These sex differences might underlie affective disorder vulnerability and differential sensitivity to pharmacologic treatments developed to target the CRF system, thereby contributing to a current lack of CRFr1 antagonist efficacy in clinical trials. © 2013 Published by Society of Biological Psychiatry on behalf of Society of Biological Psychiatry.

  18. Optogenetic modulation of descending prefrontocortical inputs to the dorsal raphe bidirectionally bias socioaffective choices after social defeat

    Directory of Open Access Journals (Sweden)

    Collin eChallis

    2014-02-01

    Full Text Available It has been well established that modulating serotonin (5-HT levels in humans and animals affects perception and response to social threats, however the circuit mechanisms that control 5-HT output during social interaction are not well understood. A better understanding of these systems could provide groundwork for more precise and efficient therapeutic interventions. Here we examined the organization and plasticity of microcircuits implicated in top-down control of 5-HT neurons in the dorsal raphe nucleus (DRN by excitatory inputs from the ventromedial prefrontal cortex (vmPFC and their role in social approach-avoidance decisions. We did this in the context of a social defeat model that induces a long lasting form of social aversion that is reversible by antidepressants. We first used viral tracing and Cre-dependent genetic identification of vmPFC glutamatergic synapses in the DRN to determine their topographic distribution in relation to 5-HT and GABAergic subregions and found that excitatory vmPFC projections primarily localized to GABA-rich areas of the DRN. We then used optogenetics in combination with cFos mapping and slice electrophysiology to establish the functional effects of repeatedly driving vmPFC inputs in DRN. We provide the first direct evidence that vmPFC axons drive synaptic activity and immediate early gene expression in genetically identified DRN GABA neurons through an AMPA receptor-dependent mechanism. In contrast, we did not detect vmPFC-driven synaptic activity in 5-HT neurons and cFos induction in 5-HT neurons was limited. Finally we show that optogenetically increasing or decreasing excitatory vmPFC input to the DRN during sensory exposure to an aggressor’s cues enhances or diminishes avoidance bias, respectively. These results clarify the functional organization of vmPFC-DRN pathways and identify GABAergic neurons as a key cellular element filtering top-down vmPFC influences on affect-regulating 5-HT output.

  19. Effects of GABA microinjection into dorsal raphe nucleus on behavior and activity of lateral habenular neurons in mice.

    Science.gov (United States)

    Xiao, Jinyu; Song, Meiying; Li, Fengdan; Liu, Xiaofeng; Anwar, Alinur; Zhao, Hua

    2017-12-01

    The dorsal raphe nucleus (DRN) is a key site for 5-hydroxytryptamine (5-HT) synthesis and release. DRN dysfunction has been implicated in several stress-related disorders, including depression and anxiety. The lateral habenular nucleus (LHb) has been shown to inhibit the activity of DRN 5-HT neurons, and thus the LHb-DRN pathway plays an important role in the pathogenesis of depression. Although it is known that the LHb also receives the projection from the 5-HT neuron in the DRN, whether 5-HT neurons in the DRN can influence activity of the LHb in vivo and whether this effect is related to the induced behavioral changes have not been investigated. In the current study, we determined how injecting γ-aminobutyric acid (GABA) into the DRN to inhibit 5-HT neurons affected behavior and the changes in the activity of LHb neurons in mice. We found that GABA injection into the DRN induced depression-like behavior in mice, as indicated by increased immobility time, and decreased climbing time in the forced swimming test and the tail suspension test, decreased time spent in the center and total distance moved in the open field test. Using extracellular single unit recording, we showed that the firing rate of LHb neurons decreased after GABA microinjection into the DRN. Further, c-Fos expression in LHb neurons was inhibited. Together our results indicate that inhibition of DRN 5-HT neurons can cause decreased LHb activity and depression-like behavior in mice, however this depression-like behavior could be independent of the LHb activity. The observed decrease in LHb activity is probably due to the presence of a negative feedback loop between the DRN and the LHb, which may play a role in maintaining emotional homeostasis. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Sound-by-sound thalamic stimulation modulates midbrain auditory excitability and relative binaural sensitivity in frogs.

    Science.gov (United States)

    Ponnath, Abhilash; Farris, Hamilton E

    2014-01-01

    Descending circuitry can modulate auditory processing, biasing sensitivity to particular stimulus parameters and locations. Using awake in vivo single unit recordings, this study tested whether electrical stimulation of the thalamus modulates auditory excitability and relative binaural sensitivity in neurons of the amphibian midbrain. In addition, by using electrical stimuli that were either longer than the acoustic stimuli (i.e., seconds) or presented on a sound-by-sound basis (ms), experiments addressed whether the form of modulation depended on the temporal structure of the electrical stimulus. Following long duration electrical stimulation (3-10 s of 20 Hz square pulses), excitability (spikes/acoustic stimulus) to free-field noise stimuli decreased by 32%, but returned over 600 s. In contrast, sound-by-sound electrical stimulation using a single 2 ms duration electrical pulse 25 ms before each noise stimulus caused faster and varied forms of modulation: modulation lasted sound-by-sound electrical stimulation varied between different acoustic stimuli, including for different male calls, suggesting modulation is specific to certain stimulus attributes. For binaural units, modulation depended on the ear of input, as sound-by-sound electrical stimulation preceding dichotic acoustic stimulation caused asymmetric modulatory effects: sensitivity shifted for sounds at only one ear, or by different relative amounts for both ears. This caused a change in the relative difference in binaural sensitivity. Thus, sound-by-sound electrical stimulation revealed fast and ear-specific (i.e., lateralized) auditory modulation that is potentially suited to shifts in auditory attention during sound segregation in the auditory scene.

  1. Short-Term Depression, Temporal Summation, and Onset Inhibition Shape Interval Tuning in Midbrain Neurons

    Science.gov (United States)

    Baker, Christa A.

    2014-01-01

    A variety of synaptic mechanisms can contribute to single-neuron selectivity for temporal intervals in sensory stimuli. However, it remains unknown how these mechanisms interact to establish single-neuron sensitivity to temporal patterns of sensory stimulation in vivo. Here we address this question in a circuit that allows us to control the precise temporal patterns of synaptic input to interval-tuned neurons in behaviorally relevant ways. We obtained in vivo intracellular recordings under multiple levels of current clamp from midbrain neurons in the mormyrid weakly electric fish Brienomyrus brachyistius during stimulation with electrosensory pulse trains. To reveal the excitatory and inhibitory inputs onto interval-tuned neurons, we then estimated the synaptic conductances underlying responses. We found short-term depression in excitatory and inhibitory pathways onto all interval-tuned neurons. Short-interval selectivity was associated with excitation that depressed less than inhibition at short intervals, as well as temporally summating excitation. Long-interval selectivity was associated with long-lasting onset inhibition. We investigated tuning after separately nullifying the contributions of temporal summation and depression, and found the greatest diversity of interval selectivity among neurons when both mechanisms were at play. Furthermore, eliminating the effects of depression decreased sensitivity to directional changes in interval. These findings demonstrate that variation in depression and summation of excitation and inhibition helps to establish tuning to behaviorally relevant intervals in communication signals, and that depression contributes to neural coding of interval sequences. This work reveals for the first time how the interplay between short-term plasticity and temporal summation mediates the decoding of temporal sequences in awake, behaving animals. PMID:25339741

  2. Activation of midbrain and ventral striatal regions implicates salience processing during a modified beads task.

    Directory of Open Access Journals (Sweden)

    Christine Esslinger

    Full Text Available INTRODUCTION: Metacognition, i.e. critically reflecting on and monitoring one's own reasoning, has been linked behaviorally to the emergence of delusions and is a focus of cognitive therapy in patients with schizophrenia. However, little is known about the neural processing underlying metacognitive function. To address this issue, we studied brain activity during a modified beads task which has been used to measure a "Jumping to Conclusions" (JTC bias in schizophrenia patients. METHODS: We used functional magnetic resonance imaging to identify neural systems active in twenty-five healthy subjects when solving a modified version of the "beads task", which requires a probabilistic decision after a variable amount of data has been requested by the participants. We assessed brain activation over the duration of a trial and at the time point of decision making. RESULTS: Analysis of activation during the whole process of probabilistic reasoning showed an extended network including the prefronto-parietal executive functioning network as well as medial parieto-occipital regions. During the decision process alone, activity in midbrain and ventral striatum was detected, as well as in thalamus, medial occipital cortex and anterior insula. CONCLUSIONS: Our data show that probabilistic reasoning shares neural substrates with executive functions. In addition, our finding that brain regions commonly associated with salience processing are active during probabilistic reasoning identifies a candidate mechanism that could underlie the behavioral link between dopamine-dependent aberrant salience and JTC in schizophrenia. Further studies with delusional schizophrenia patients will have to be performed to substantiate this link.

  3. CALBINDIN CONTENT AND DIFFERENTIAL VULNERABILITY OF MIDBRAIN EFFERENT DOPAMINERGIC NEURONS IN MACAQUES

    Directory of Open Access Journals (Sweden)

    Iria G Dopeso-Reyes

    2014-12-01

    Full Text Available Calbindin (CB is a calcium binding protein reported to protect dopaminergic neurons from degeneration. Although a direct link between CB content and differential vulnerability of dopaminergic neurons has long been accepted, factors other than CB have also been suggested, particularly those related to the dopamine transporter. Indeed, several studies have reported that CB levels are not causally related to the differential vulnerability of dopaminergic neurons against neurotoxins. Here we have used dual stains for tyrosine hydroxylase (TH and CB in 3 control and 3 MPTP-treated monkeys to visualize dopaminergic neurons in the ventral tegmental area (VTA and in the dorsal and ventral tiers of the substantia nigra pars compacta (SNcd and SNcv co-expressing TH and CB. In control animals, the highest percentages of co-localization were found in VTA (58.2%, followed by neurons located in the SNcd (34.7%. As expected, SNcv neurons lacked CB expression. In MPTP-treated animals, the percentage of CB-ir/TH-ir neurons in the VTA was similar to control monkeys (62.1%, whereas most of the few surviving neurons in the SNcd were CB-ir/TH-ir (88.6%. Next, we have elucidated the presence of CB within identified nigrostriatal and nigroextrastriatal midbrain dopaminergic projection neurons. For this purpose, two control monkeys received one injection of Fluoro-Gold into the caudate nucleus and one injection of cholera toxin (CTB into the postcommissural putamen, whereas two more monkeys were injected with CTB into the internal division of the globus pallidus. As expected, all the nigrocaudate- and nigroputamen-projecting neurons were TH-ir, although surprisingly, all of these nigrostriatal-projecting neurons were negative for CB. Furthermore, all the nigropallidal-projecting neurons co-expressed both TH and CB. In summary, although CB-ir dopaminergic neurons seem to be less prone to MPTP-induced degeneration, our data clearly demonstrated that these neurons are not

  4. Non-Monotonic Relation Between Noise Exposure Severity and Neuronal Hyperactivity in the Auditory Midbrain

    Directory of Open Access Journals (Sweden)

    Lara Li Hesse

    2016-08-01

    Full Text Available The occurrence of tinnitus can be linked to hearing loss in the majority of cases, but there is nevertheless a large degree of unexplained heterogeneity in the relation between hearing loss and tinnitus. Part of the problem might be that hearing loss is usually quantified in terms of increased hearing thresholds, which only provides limited information about the underlying cochlear damage. Moreover, noise exposure that does not cause hearing threshold loss can still lead to hidden hearing loss (HHL, i.e. functional deafferentation of auditory nerve fibres (ANFs through loss of synaptic ribbons in inner hair cells. Whilst it is known that increased hearing thresholds can trigger increases in spontaneous neural activity in the central auditory system, i.e. a putative neural correlate of tinnitus, the central effects of HHL have not yet been investigated. Here, we exposed mice to octave-band noise at 100 and 105 dB SPL, to generate HHL and permanent increases of hearing thresholds, respectively. Deafferentation of ANFs was confirmed through measurement of auditory brainstem responses and cochlear immunohistochemistry. Acute extracellular recordings from the auditory midbrain (inferior colliculus demonstrated increases in spontaneous neuronal activity (a putative neural correlate of tinnitus in both groups. Surprisingly the increase in spontaneous activity was most pronounced in the mice with HHL, suggesting that the relation between hearing loss and neuronal hyperactivity might be more complex than currently understood. Our computational model indicated that these differences in neuronal hyperactivity could arise from different degrees of deafferentation of low-threshold ANFs in the two exposure groups.Our results demonstrate that HHL is sufficient to induce changes in central auditory processing, and they also indicate a non-monotonic relationship between cochlear damage and neuronal hyperactivity, suggesting an explanation for why tinnitus might

  5. Ovarian steroid regulation of monoamine oxidase-A and -B mRNAs in the macaque dorsal raphe and hypothalamic nuclei.

    Science.gov (United States)

    Gundlah, Chrisana; Lu, Nick Z; Bethea, Cynthia L

    2002-03-01

    The serotonin neural system plays a pivotal role in mood, affective regulation and integrative cognition, as well as numerous autonomic functions. We have shown that ovarian steroids alter the expression of several genes in the dorsal raphe of macaques, which may increase serotonin synthesis and decrease serotonin autoinhibition. Another control point in aminergic neurotransmission involves degradation by MAO. This enzyme occurs in two isoforms, A and B, which have different substrate preferences. We questioned the effect of ovarian steroid hormones on MAO-A and MAO-B mRNA expression in the dorsal raphe nucleus and hypothalamus using in situ hybridization in non-human primates. Rhesus monkeys ( Macaca mulatta; n=5/group) were spayed and either placebo treated (controls), estrogen (E) treated (28 days), progesterone (P) treated (14 days placebo+14 days P), or E+P treated (14 days E+14 days E+P). Perfusion-fixed sections (25 microm) were hybridized with a 233 bp MAO-A, or a 373 bp MAO-B, radiolabeled-antisense monkey specific probes. Autoradiographic films were analyzed by densitometry, which was performed with NIH Image Software. MAO-A and -B mRNAs were detected in the dorsal raphe nucleus (DRN) and in the hypothalamic suprachiasmatic nucleus (SCN), preoptic area (POA), paraventricular nucleus (PVN), supraoptic nucleus (SON), lateral hypothalamus (LH) and ventromedial nucleus (VMN). MAO-A mRNA optical density was significantly decreased by E, P, and E+P in the DRN and in the hypothalamic PVN, LH and VMN. Ovarian hormones had no effect on MAO-B mRNA expression in the DRN. However, there was a significant decrease in MAO-B optical density in the hypothalamic POA, LH and VMN with E, P or E+P treatment. Pixel area generally reflected optical density. Ovarian steroids decreased MAO-A, but not B, in the raphe nucleus. However, both MAO-A and B were decreased in discrete hypothalamic nuclei by hormone replacement. These data suggest that the transcriptional regulation of

  6. Upper midbrain profile sign and cingulate sulcus sign. MRI findings on sagittal images in idiopathic normal-pressure hydrocephalus, Alzheimer's disease, and progressive supranuclear palsy

    International Nuclear Information System (INIS)

    Adachi, Michito; Ohshima, Fumi; Kawanami, Toru; Kato, Takeo

    2006-01-01

    On magnetic resonance imaging (MRI) sagittal sections, we sometimes encounter abnormal aspects of the superior profile of the midbrain and the cingulate sulcus in patients with dementia. In this preliminary study, we refer to these findings as the ''upper midbrain profile sign'' and the cingulate sulcus sign.'' We prospectively evaluated the usefulness of these signs for the diagnosis of idiopathic normal-pressure hydrocephalus (iNPH), Alzheimer's disease (AD) and progressive supranuclear palsy (PSP). We evaluated the upper midbrain profile sign and the cingulate sulcus sign on MRI sagittal images obtained from 21 people with headaches but no neurological deficit (controls), 10 iNPH patients, 11 AD patients, and 5 PSP patients. The upper midbrain profile sign indicated a concave shape to the superior profile of the midbrain on mid-sagittal images, and the cingulate sulcus sign indicated a narrow, tight aspect of the posterior part of the cingulate sulcus on paramedian-sagittal images. These signs were never seen in any images from the controls. The upper midbrain profile sign was seen in 7 of 10 patients with iNPH, 5 of 11 with AD, and 3 of 5 with PSP. The cingulate sulcus sign was seen in all 10 patients with iNPH but was never seen in any patient with AD or PSP. The upper midbrain profile sign could support a diagnosis of PSP but cannot discriminate among iNPH, AD, and PSP. In contrast, the cingulate sulcus sign has a very high sensitivity for iNPH and should facilitate the distinction of iNPH from other dementias. In the clinical setting, it is momentous to evaluate these signs easily by one simple MRI sequence. (author)

  7. MicroPET imaging of 5-HT{sub 1A} receptors in rat brain: a test-retest [{sup 18}F]MPPF study

    Energy Technology Data Exchange (ETDEWEB)

    Aznavour, Nicolas [McGill University, Department of Psychiatry, Montreal, QC (Canada)]|[Laboratory of Neuroenergetics and Cellular Dynamics, EPFL, SV, BMI, Lausanne (Switzerland); Benkelfat, Chawki; Gravel, Paul [McGill University, Department of Psychiatry, Montreal, QC (Canada)]|[McGill University, Department of Neurology and Neurosurgery, Montreal, QC (Canada); Aliaga, Antonio [McGill University, Department of Small Animal Imaging Laboratory, Montreal, QC (Canada); Rosa-Neto, Pedro [Douglas Hospital, Molecular NeuroImaging Laboratory, Montreal, QC (Canada); Bedell, Barry [McGill University, Department of Neurology and Neurosurgery, Montreal, QC (Canada)]|[McGill University, Department of Small Animal Imaging Laboratory, Montreal, QC (Canada); Zimmer, Luc [CERMEP, ANIMAGE Department, Lyon (France)]|[Universite Lyon 1 and CNRS, Lyon (France); Descarries, Laurent [Universite de Montreal, Department of Pathology and Cell Biology, Montreal, QC (Canada)]|[Universite de Montreal, Department of Physiology, Montreal, QC (Canada)]|[Universite de Montreal, GRSNC, Montreal, QC (Canada)

    2009-01-15

    Earlier studies have shown that positron emission tomography (PET) imaging with the radioligand [{sup 18}F]MPPF allows for measuring the binding potential of serotonin 5-hydroxytryptamine{sub 1A} (5-HT{sub 1A}) receptors in different regions of animal and human brain, including that of 5-HT{sub 1A} autoreceptors in the raphe nuclei. In the present study, we sought to determine if such data could be obtained in rat, with a microPET (R4, Concorde Microsystems). Scans from isoflurane-anaesthetised rats (n = 18, including six test-retest) were co-registered with magnetic resonance imaging data, and binding potential, blood to plasma ratio and radiotracer efflux were estimated according to a simplified reference tissue model. Values of binding potential for hippocampus (1.2), entorhinal cortex (1.1), septum (1.1), medial prefrontal cortex (1.0), amygdala (0.8), raphe nuclei (0.6), paraventricular hypothalamic nucleus (0.5) and raphe obscurus (0.5) were comparable to those previously measured with PET in cats, non-human primates or humans. Test-retest variability was in the order of 10% in the larger brain regions (hippocampus, medial prefrontal and entorhinal cortex) and less than 20% in small nuclei such as the septum and the paraventricular hypothalamic, basolateral amygdaloid and raphe nuclei. MicroPET brain imaging of 5-HT{sub 1A} receptors with [{sup 18}F]MPPF thus represents a promising avenue for investigating 5-HT{sub 1A} receptor function in rat. (orig.)

  8. CRISPR/Cas9-Mediated Zebrafish Knock-in as a Novel Strategy to Study Midbrain-Hindbrain Boundary Development.

    Science.gov (United States)

    Kesavan, Gokul; Chekuru, Avinash; Machate, Anja; Brand, Michael

    2017-01-01

    The midbrain-hindbrain boundary (MHB) acts as an organizer and controls the fate of neighboring cells to develop into either mesencephalic (midbrain) or metencephalic (hindbrain) cells by secreting signaling molecules like Wnt1 and Fgf8. The zebrafish is an excellent vertebrate model for studying MHB development due to the ease of gene manipulation and the possibility of following cellular dynamics and morphogenetic processes using live imaging. Currently, only very few reporter and/or Cre-driver lines are available to study gene expression at the MHB, hampering the understanding of MHB development, and traditional transgenic technologies using promoter/enhancer fragments or bacterial artificial chromosome (BAC)-mediated transgenesis often do not faithfully recapitulate endogenous expression patterns. In contrast, CRISPR/Cas9-mediated genome editing technology now provides a great opportunity to efficiently knock-in or knock-out genes. We have generated four CRISPR/Cas9-based knock-in fluorescent reporter lines for two crucial genes involved in MHB development, namely otx2 and pax2a . The coding sequences of the reporters were knocked-in upstream of the corresponding ATG and are, thus, under the control of the endogenous promoter/enhancer elements. Interestingly, this strategy does not disturb endogenous gene expression. Using the fast maturing fluorescent protein reporter, Venus, enabled us to follow MHB development using cell tracking and live imaging. In addition, we show that these reporter lines label various neuronal and glial cell types in the adult zebrafish brain, making them highly suitable for investigating embryonic and adult midbrain, hindbrain, and MHB development.

  9. Electrophysiological and gene expression characterization of the ontogeny of nestin-expressing cells in the adult mouse midbrain

    Directory of Open Access Journals (Sweden)

    Anupama Dey

    2017-08-01

    Full Text Available The birth of new neurons, or neurogenesis, in the adult midbrain is important for progressing dopamine cell-replacement therapies for Parkinson's disease. Most studies suggest newborn cells remain undifferentiated or differentiate into glia within the adult midbrain. However, some studies suggest nestin + neural precursor cells (NPCs have a propensity to generate new neurons here. We sought to confirm this by administering tamoxifen to adult NesCreERT2/R26eYFP transgenic mice, which permanently labelled adult nestin-expressing cells and their progeny with enhanced yellow fluorescent protein (eYFP. eYFP+ midbrain cells were then characterized 1–32 weeks later in acutely prepared brain slices using whole-cell patch clamp electrophysiology combined with single-cell RT-qPCR. Most eYFP+ cells exhibited a mature neuronal phenotype with large amplitude fast action potentials (APs, spontaneous post-synaptic currents (sPSCs, and expression of ‘mature’ neuronal genes (NeuN, Gad1, Gad2 and/or VGLUT2. This was the case even at the earliest time-point following tamoxifen (i.e. 1 week. In comparison to neighboring eYFP− (control cells, eYFP+ cells discharged more APs per unit current injection, and had faster AP time-to-peak, hyperpolarized resting membrane potential, smaller membrane capacitance and shorter duration sPSCs. eYFP+ cells were also differentiated from eYFP− cells by increased expression of ‘immature’ pro-neuronal genes (Pax6, Ngn2 and/or Msx1. However, further analyses failed to reveal evidence of a place of birth, neuronal differentiation, maturation and integration indicative of classical neurogenesis. Thus our findings do not support the notion that nestin + NPCs in the adult SNc and midbrain generate new neurons via classical neurogenesis. Rather, they raise the possibility that mature neurons express nestin under unknown circumstances, and that this is associated with altered physiology and gene expression.

  10. Differential regulation of serotonin-1A receptor-stimulated [35S]GTP gamma S binding in the dorsal raphe nucleus by citalopram and escitalopram.

    Science.gov (United States)

    Rossi, Dania V; Burke, Teresa F; Hensler, Julie G

    2008-03-31

    The effect of chronic citalopram or escitalopram administration on 5-HT1A receptor function in the dorsal raphe nucleus was determined by measuring [35S]GTP gamma S binding stimulated by the 5-HT1A receptor agonist (R)-(+)-8-OH-DPAT (1nM-10 microM). Although chronic administration of citalopram or escitalopram has been shown to desensitize somatodendritic 5-HT1A autoreceptors, we found that escitalopram treatment decreased the efficacy of 5-HT1A receptors to activate G proteins, whereas citalopram treatment did not. The binding of [3H]8-OH-DPAT to the coupled, high affinity agonist state of the receptor was not altered by either treatment. Interestingly, escitalopram administration resulted in greater occupancy of serotonin transporter sites as measured by the inhibition of [3H]cyanoimipramine binding. As the binding and action of escitalopram is limited by the inactive enantiomer R-citalopram present in racemic citalopram, we propose that the regulation of 5-HT1A receptor function in the dorsal raphe nucleus at the level of receptor-G protein interaction may be a result of greater inhibition of the serotonin transporter by escitalopram.

  11. Differential regulation of serotonin-1A receptor stimulated [35S]GTPγS binding in the dorsal raphe nucleus by citalopram and escitalopram

    Science.gov (United States)

    Rossi, Dania V.; Burke, Teresa F.; Hensler, Julie G.

    2008-01-01

    The effect of chronic citalopram or escitalopram administration on 5-HT1A receptor function in the dorsal raphe nucleus was determined by measuring [35S]GTPγS binding stimulated by the 5-HT1A receptor agonist (R)-(+)-8-OH-DPAT (1nM-10μM). Although chronic administration of citalopram or escitalopram has been shown to desensitize somatodendritic 5-HT1A autoreceptors, we found that escitalopram treatment decreased the efficacy of 5-HT1A receptors to activate G-proteins, whereas citalopram treatment did not. The binding of [3H]8-OH-DPAT to the coupled, high affinity agonist state of the receptor was not altered by either treatment. Interestingly, escitalopram administration resulted in greater occupancy of serotonin transporter sites as measured by the inhibition of [3H]cyanoimipramine binding. As the binding and action of escitalopram is limited by the inactive enantiomer R-citalopram present in racemic citalopram, we propose that the regulation of 5-HT1A receptor function in the dorsal raphe nucleus at the level of receptor-G protein interaction may be a result of greater inhibition of the serotonin transporter by escitalopram. PMID:18289523

  12. Differentiated human midbrain-derived neural progenitor cells express excitatory strychnine-sensitive glycine receptors containing α2β subunits.

    Directory of Open Access Journals (Sweden)

    Florian Wegner

    Full Text Available BACKGROUND: Human fetal midbrain-derived neural progenitor cells (NPCs may deliver a tissue source for drug screening and regenerative cell therapy to treat Parkinson's disease. While glutamate and GABA(A receptors play an important role in neurogenesis, the involvement of glycine receptors during human neurogenesis and dopaminergic differentiation as well as their molecular and functional characteristics in NPCs are largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here we investigated NPCs in respect to their glycine receptor function and subunit expression using electrophysiology, calcium imaging, immunocytochemistry, and quantitative real-time PCR. Whole-cell recordings demonstrate the ability of NPCs to express functional strychnine-sensitive glycine receptors after differentiation for 3 weeks in vitro. Pharmacological and molecular analyses indicate a predominance of glycine receptor heteromers containing α2β subunits. Intracellular calcium measurements of differentiated NPCs suggest that glycine evokes depolarisations mediated by strychnine-sensitive glycine receptors and not by D-serine-sensitive excitatory glycine receptors. Culturing NPCs with additional glycine, the glycine-receptor antagonist strychnine, or the Na(+-K(+-Cl(- co-transporter 1 (NKCC1-inhibitor bumetanide did not significantly influence cell proliferation and differentiation in vitro. CONCLUSIONS/SIGNIFICANCE: These data indicate that NPCs derived from human fetal midbrain tissue acquire essential glycine receptor properties during neuronal maturation. However, glycine receptors seem to have a limited functional impact on neurogenesis and dopaminergic differentiation of NPCs in vitro.

  13. Beyond the midbrain atrophy: wide spectrum of structural MRI finding in cases of pathologically proven progressive supranuclear palsy

    International Nuclear Information System (INIS)

    Sakurai, Keita; Tokumaru, Aya M.; Shimoji, Keigo; Murayama, Shigeo; Kanemaru, Kazutomi; Morimoto, Satoru; Aiba, Ikuko; Nakagawa, Motoo; Ozawa, Yoshiyuki; Shimohira, Masashi; Shibamoto, Yuta; Matsukawa, Noriyuki; Hashizume, Yoshio

    2017-01-01

    Recently, it has been recognized that pathologically proven progressive supranuclear palsy (PSP) cases are classified into various clinical subtypes with non-uniform symptoms and imaging findings. This article reviews essential imaging findings, general information, and advanced magnetic resonance imaging (MRI) techniques for PSP and presents these MRI findings of pathologically proven typical and atypical PSP cases for educational purposes. With the review of literatures, notably including atypical pathologically proven PSP cases, MRI and clinical information of 15 pathologically proven typical and atypical PSP cases were retrospectively evaluated. In addition to typical symptoms, PSP patients can exhibit atypical symptoms including levodopa-responsive parkinsonism, pure akinesia, non-fluent aphasia, corticobasal syndrome, and predominant cerebellar ataxia. As well as clinical symptoms, the degree of midbrain atrophy, a well-known imaging hallmark, is not consistent in atypical PSP cases. This fact has important implications for the limitation of midbrain atrophy as a diagnostic imaging biomarker of PSP pathology. Additional evaluation of other imaging findings including various regional atrophies of the globus pallidus, frontal lobe, cerebral peduncle, and superior cerebellar peduncle is essential for the diagnosis of atypical PSP cases. It is necessary for radiologists to recognize the wide clinical and radiological spectra of typical and atypical PSP cases. (orig.)

  14. Beyond the midbrain atrophy: wide spectrum of structural MRI finding in cases of pathologically proven progressive supranuclear palsy

    Energy Technology Data Exchange (ETDEWEB)

    Sakurai, Keita; Tokumaru, Aya M.; Shimoji, Keigo [Tokyo Metropolitan Medical Center of Gerontology, Department of Diagnostic Radiology, Tokyo (Japan); Murayama, Shigeo; Kanemaru, Kazutomi; Morimoto, Satoru [Tokyo Metropolitan Geriatric Hospital, Department of Neurology, Tokyo (Japan); Aiba, Ikuko [National Hospital Organization Higashi Nagoya National Hospital, Department of Neurology, Nagoya (Japan); Nakagawa, Motoo; Ozawa, Yoshiyuki; Shimohira, Masashi; Shibamoto, Yuta [Nagoya City University Graduate School of Medical Sciences, Department of Radiology, Nagoya (Japan); Matsukawa, Noriyuki [Nagoya City University Graduate School of Medical Sciences, Department of Neurology and Neuroscience, Nagoya (Japan); Hashizume, Yoshio [Fukushimura Hospital, Choju Medical Institute, Toyohashi (Japan)

    2017-05-15

    Recently, it has been recognized that pathologically proven progressive supranuclear palsy (PSP) cases are classified into various clinical subtypes with non-uniform symptoms and imaging findings. This article reviews essential imaging findings, general information, and advanced magnetic resonance imaging (MRI) techniques for PSP and presents these MRI findings of pathologically proven typical and atypical PSP cases for educational purposes. With the review of literatures, notably including atypical pathologically proven PSP cases, MRI and clinical information of 15 pathologically proven typical and atypical PSP cases were retrospectively evaluated. In addition to typical symptoms, PSP patients can exhibit atypical symptoms including levodopa-responsive parkinsonism, pure akinesia, non-fluent aphasia, corticobasal syndrome, and predominant cerebellar ataxia. As well as clinical symptoms, the degree of midbrain atrophy, a well-known imaging hallmark, is not consistent in atypical PSP cases. This fact has important implications for the limitation of midbrain atrophy as a diagnostic imaging biomarker of PSP pathology. Additional evaluation of other imaging findings including various regional atrophies of the globus pallidus, frontal lobe, cerebral peduncle, and superior cerebellar peduncle is essential for the diagnosis of atypical PSP cases. It is necessary for radiologists to recognize the wide clinical and radiological spectra of typical and atypical PSP cases. (orig.)

  15. α-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models.

    Science.gov (United States)

    Mazzulli, Joseph R; Zunke, Friederike; Isacson, Ole; Studer, Lorenz; Krainc, Dimitri

    2016-02-16

    Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the accumulation of protein aggregates comprised of α-synuclein (α-syn). A major barrier in treatment discovery for PD is the lack of identifiable therapeutic pathways capable of reducing aggregates in human neuronal model systems. Mutations in key components of protein trafficking and cellular degradation machinery represent important risk factors for PD; however, their precise role in disease progression and interaction with α-syn remains unclear. Here, we find that α-syn accumulation reduced lysosomal degradation capacity in human midbrain dopamine models of synucleinopathies through disrupting hydrolase trafficking. Accumulation of α-syn at the cell body resulted in aberrant association with cis-Golgi-tethering factor GM130 and disrupted the endoplasmic reticulum-Golgi localization of rab1a, a key mediator of vesicular transport. Overexpression of rab1a restored Golgi structure, improved hydrolase trafficking and activity, and reduced pathological α-syn in patient neurons. Our work suggests that enhancement of lysosomal hydrolase trafficking may prove beneficial in synucleinopathies and indicates that human midbrain disease models may be useful for identifying critical therapeutic pathways in PD and related disorders.

  16. Enduring, Sexually Dimorphic Impact of In Utero Exposure to Elevated Levels of Glucocorticoids on Midbrain Dopaminergic Populations

    Directory of Open Access Journals (Sweden)

    Glenda E. Gillies

    2016-12-01

    Full Text Available Glucocorticoid hormones (GCs released from the fetal/maternal glands during late gestation are required for normal development of mammalian organs and tissues. Accordingly, synthetic glucocorticoids have proven to be invaluable in perinatal medicine where they are widely used to accelerate fetal lung maturation when there is risk of pre-term birth and to promote infant survival. However, clinical and pre-clinical studies have demonstrated that inappropriate exposure of the developing brain to elevated levels of GCs, either as a result of clinical over-use or after stress-induced activation of the fetal/maternal adrenal cortex, is linked with significant effects on brain structure, neurological function and behaviour in later life. In order to understand the underlying neural processes, particular interest has focused on the midbrain dopaminergic systems, which are critical regulators of normal adaptive behaviours, cognitive and sensorimotor functions. Specifically, using a rodent model of GC exposure in late gestation (approximating human brain development at late second/early third trimester, we demonstrated enduring effects on the shape and volume of the ventral tegmental area (VTA and substantia nigra pars compacta (SNc (origins of the mesocorticolimbic and nigrostriatal dopaminergic pathways on the topographical organisation and size of the dopaminergic neuronal populations and astrocytes within these nuclei and on target innervation density and neurochemical markers of dopaminergic transmission (receptors, transporters, basal and amphetamine-stimulated dopamine release at striatal and prefrontal cortical sites that impact on the adult brain. The effects of antenatal GC treatment (AGT were both profound and sexually-dimorphic, not only in terms of quantitative change but also qualitatively, with several parameters affected in the opposite direction in males and females. Although such substantial neurobiological changes might presage marked

  17. Hypocretin/Orexin Peptides Alter Spike Encoding by Serotonergic Dorsal Raphe Neurons through Two Distinct Mechanisms That Increase the Late Afterhyperpolarization.

    Science.gov (United States)

    Ishibashi, Masaru; Gumenchuk, Iryna; Miyazaki, Kenichi; Inoue, Takafumi; Ross, William N; Leonard, Christopher S

    2016-09-28

    Orexins (hypocretins) are neuropeptides that regulate multiple homeostatic processes, including reward and arousal, in part by exciting serotonergic dorsal raphe neurons, the major source of forebrain serotonin. Here, using mouse brain slices, we found that, instead of simply depolarizing these neurons, orexin-A altered the spike encoding process by increasing the postspike afterhyperpolarization (AHP) via two distinct mechanisms. This orexin-enhanced AHP (oeAHP) was mediated by both OX1 and OX2 receptors, required Ca(2+) influx, reversed near EK, and decayed with two components, the faster of which resulted from enhanced SK channel activation, whereas the slower component decayed like a slow AHP (sAHP), but was not blocked by UCL2077, an antagonist of sAHPs in some neurons. Intracellular phospholipase C inhibition (U73122) blocked the entire oeAHP, but neither component was sensitive to PKC inhibition or altered PKA signaling, unlike classical sAHPs. The enhanced SK current did not depend on IP3-mediated Ca(2+) release but resulted from A-current inhibition and the resultant spike broadening, which increased Ca(2+) influx and Ca(2+)-induced-Ca(2+) release, whereas the slower component was insensitive to these factors. Functionally, the oeAHP slowed and stabilized orexin-induced firing compared with firing produced by a virtual orexin conductance lacking the oeAHP. The oeAHP also reduced steady-state firing rate and firing fidelity in response to stimulation, without affecting the initial rate or fidelity. Collectively, these findings reveal a new orexin action in serotonergic raphe neurons and suggest that, when orexin is released during arousal and reward, it enhances the spike encoding of phasic over tonic inputs, such as those related to sensory, motor, and reward events. Orexin peptides are known to excite neurons via slow postsynaptic depolarizations. Here we elucidate a significant new orexin action that increases and prolongs the postspike

  18. Wernekink Commissure Syndrome Secondary to Bilateral Caudal Paramedian Midbrain Infarction Presenting with a Unique “Heart or V” Appearance Sign: Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Chenguang Zhou

    2017-08-01

    Full Text Available Wernekink commissure syndrome secondary to caudal paramedian midbrain infarction (CPMI is a rare midbrain syndrome involving the decussation of the superior cerebellar peduncle in the caudal paramedian midbrain tegmentum. The central characteristics are constant bilateral cerebellar dysfunction, variable eye movement disorders, and rare delayed palatal myoclonus. Following is a description of the case of a 60-year-old man who presented with dizziness, slurred speech, and difficulty walking. Neurological examination revealed bilateral cerebellar dysfunction and bilateral internuclear ophthalmoplegia (bilateral INO. Serial magnetic resonance imaging (MRI revealed a lesion in the caudal paramedian midbrain with a “heart-shaped” sign on fluid-attenuation inversion recovery images and a “V-shaped” appearance on diffusion-weighted imaging (DWI. An acute CPMI with a “heart or V” appearance sign was diagnosed. Upon follow-up evaluation 3 months later, a palatal tremor accompanied by involuntary head tremor was discovered. Hypertrophy and increased signal of the bilateral inferior olivary nucleus, compatible with hypertropic olivary degeneration (HOD were revealed during a subsequent MRI study.

  19. Midbrain Gene Screening Identifies a New Mesoaccumbal Glutamatergic Pathway and a Marker for Dopamine Cells Neuroprotected in Parkinson’s Disease

    Science.gov (United States)

    Viereckel, Thomas; Dumas, Sylvie; Smith-Anttila, Casey J. A.; Vlcek, Bianca; Bimpisidis, Zisis; Lagerström, Malin C.; Konradsson-Geuken, Åsa; Wallén-Mackenzie, Åsa

    2016-01-01

    The ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) of the midbrain are associated with Parkinson’s disease (PD), schizophrenia, mood disorders and addiction. Based on the recently unraveled heterogeneity within the VTA and SNc, where glutamate, GABA and co-releasing neurons have been found to co-exist with the classical dopamine neurons, there is a compelling need for identification of gene expression patterns that represent this heterogeneity and that are of value for development of human therapies. Here, several unique gene expression patterns were identified in the mouse midbrain of which NeuroD6 and Grp were expressed within different dopaminergic subpopulations of the VTA, and TrpV1 within a small heterogeneous population. Optogenetics-coupled in vivo amperometry revealed a previously unknown glutamatergic mesoaccumbal pathway characterized by TrpV1-Cre-expression. Human GRP was strongly detected in non-melanized dopaminergic neurons within the SNc of both control and PD brains, suggesting GRP as a marker for neuroprotected neurons in PD. This study thus unravels markers for distinct subpopulations of neurons within the mouse and human midbrain, defines unique anatomical subregions within the VTA and exposes an entirely new glutamatergic pathway. Finally, both TRPV1 and GRP are implied in midbrain physiology of importance to neurological and neuropsychiatric disorders. PMID:27762319

  20. Widely scattered CT lesions in the midbrain and the pons in a case of neuro-Behcet's syndrome

    International Nuclear Information System (INIS)

    Kuroiwa, Yoshiyuki; Tohgi, Hideo; Kanayama, Hiroumi; Fujimori, Masaki; Aoki, Hidehiko

    1985-01-01

    We report on a 30-year-old man with neuro-Behcet's disease. His main neurologic symptoms and signs included headache, alternating hemiparesis, dysarthria, and truncal ataxia. Lumbar puncture demonstrated an elevated pressure, pleocytosis, and an increased protein concentration. Intravenous betamethasone produced a rapid and sustained improvement, without recurrence for two years. Widely scattered foci of small, low-density lesions were disclosed in the midbrain and the pons on a cranial CT scan with 2.5 mm thin-cut slices to enable us to focus on the brainstem. Such CT lesions are consistent with the neuropathological features of this illness, which shows a tendency for brainstem lesions to predominate; these lesions probably represent necrotic areas secondary to vasculitis. Brainstem CT studies with thin-cut slices may be an important diagnostic aid in patients suspected of having neuro-Behcet's disease. (author)

  1. Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of α-synuclein in midbrain dopamine neurons

    DEFF Research Database (Denmark)

    Decressac, M; Mattsson, Bente; Lundblad, M

    2012-01-01

    -synuclein, we have now been able to achieve increased levels of α-synuclein in the transduced midbrain dopamine neurons sufficient to induce profound deficits in motor function, accompanied by reduced expression of proteins involved in dopamine neurotransmission and a time-dependent loss of nigral dopamine......Parkinson's disease (PD) is characterised by the progressive loss of nigral dopamine neurons and the presence of synucleinopathy. Overexpression of α-synuclein in vivo using viral vectors has opened interesting possibilities to model PD-like pathology in rodents. However, the attempts made so far...... have failed to show a consistent behavioural phenotype and pronounced dopamine neurodegeneration. Using a more efficient adeno-associated viral (AAV) vector construct, which includes a WPRE enhancer element and uses the neuron-specific synapsin-1 promoter to drive the expression of human wild-type α...

  2. Dynamic representation of 3D auditory space in the midbrain of the free-flying echolocating bat

    Science.gov (United States)

    2018-01-01

    Essential to spatial orientation in the natural environment is a dynamic representation of direction and distance to objects. Despite the importance of 3D spatial localization to parse objects in the environment and to guide movement, most neurophysiological investigations of sensory mapping have been limited to studies of restrained subjects, tested with 2D, artificial stimuli. Here, we show for the first time that sensory neurons in the midbrain superior colliculus (SC) of the free-flying echolocating bat encode 3D egocentric space, and that the bat’s inspection of objects in the physical environment sharpens tuning of single neurons, and shifts peak responses to represent closer distances. These findings emerged from wireless neural recordings in free-flying bats, in combination with an echo model that computes the animal’s instantaneous stimulus space. Our research reveals dynamic 3D space coding in a freely moving mammal engaged in a real-world navigation task. PMID:29633711

  3. Response properties of neighboring neurons in the auditory midbrain for pure-tone stimulation: a tetrode study.

    Science.gov (United States)

    Seshagiri, Chandran V; Delgutte, Bertrand

    2007-10-01

    The complex anatomical structure of the central nucleus of the inferior colliculus (ICC), the principal auditory nucleus in the midbrain, may provide the basis for functional organization of auditory information. To investigate this organization, we used tetrodes to record from neighboring neurons in the ICC of anesthetized cats and studied the similarity and difference among the responses of these neurons to pure-tone stimuli using widely used physiological characterizations. Consistent with the tonotopic arrangement of neurons in the ICC and reports of a threshold map, we found a high degree of correlation in the best frequencies (BFs) of neighboring neurons, which were mostly binaural beats. However, the characteristic phases (CPs) of neighboring neurons revealed a significant correlation. Because the CP is related to the neural mechanisms generating the ITD sensitivity, this result is consistent with segregation of inputs to the ICC from the lateral and medial superior olives.

  4. Age-related hearing loss: Aquaporin 4 gene expression changes in the mouse cochlea and auditory midbrain

    Science.gov (United States)

    Christensen, Nathan; D'Souza, Mary; Zhu, Xiaoxia; Frisina, Robert D.

    2009-01-01

    Presbycusis – age-related hearing loss, is the number one communication disorder, and one of the top three chronic medical conditions of our aged population. Aquaporins, particularly aquaporin 4 (Aqp4), are membrane proteins with important roles in water and ion flux across cell membranes, including cells of the inner ear and pathways of the brain used for hearing. To more fully understand the biological bases of presbycusis, 39 CBA mice, a well-studied animal model of presbycusis, underwent non-invasive hearing testing as a function of sound frequency (auditory brainstem response – ABR thresholds, and distortion-product otoacoustic emission – DPOAE magnitudes), and were clustered into four groups based on age and hearing ability. Aqp4 gene expression, as determined by genechip microarray analysis and quantitative real-time PCR, was compared to the young adult control group in the three older groups: middle aged with good hearing, old age with mild presbycusis, and old age with severe presbycusis. Linear regression and ANOVA showed statistically significant changes in Aqp4 gene expression and ABR and DPOAE hearing status in the cochlea and auditory midbrain – inferior colliculus. Down-regulation in the cochlea was seen, and an initial down-, then up-regulation was discovered for the inferior colliculus Aqp4 expression. It is theorized that these changes in Aqp4 gene expression represent an age-related disruption of ion flux in the fluids of the cochlea that are responsible for ionic gradients underlying sound transduction in cochlear hair cells necessary for hearing. In regard to central auditory processing at the level of the auditory midbrain, aquaporin gene expression changes may affect neurotransmitter cycling involving supporting cells, thus impairing complex sound neural processing with age. PMID:19070604

  5. Effects of combined BDNF and GDNF treatment on cultured dopaminergic midbrain neurons

    DEFF Research Database (Denmark)

    Sautter, J; Meyer, Morten; Spenger, C

    1998-01-01

    Neural transplantation is an experimental therapy for Parkinson's disease. Pretreatment of fetal donor tissue with neurotrophic factors may improve survival of grafted dopaminergic neurons. Free-floating roller tube cultures of fetal rat ventral mesencephalon were treated with brain-derived neuro......Neural transplantation is an experimental therapy for Parkinson's disease. Pretreatment of fetal donor tissue with neurotrophic factors may improve survival of grafted dopaminergic neurons. Free-floating roller tube cultures of fetal rat ventral mesencephalon were treated with brain......-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), or a combination of both. Dopamine content of the culture medium, the number of tyrosine hydroxylase-immunoreactive neurons, and culture volumes were moderately increased in the BDNF- and GDNF-treated cultures but significantly...... increased by 6.8-, 3.2- and 2.4-fold, respectively after treatment with the combination of both factors. We conclude that pretreatment of dopaminergic tissue in culture with a combination of BDNF and GDNF may be an effective means to improve the quality of tissue prior to grafting....

  6. Postnatal Treadmill Exercise Alleviates Prenatal Stress-Induced Anxiety in Offspring Rats by Enhancing Cell Proliferation Through 5-Hydroxytryptamine 1A Receptor Activation

    Directory of Open Access Journals (Sweden)

    Sam Jun Lee

    2016-05-01

    Full Text Available Purpose: Stress during pregnancy is a risk factor for the development of anxiety-related disorders in offspring later in life. The effects of treadmill exercise on anxiety-like behaviors and hippocampal cell proliferation were investigated using rats exposed to prenatal stress. Methods: Exposure of pregnant rats to a hunting dog in an enclosed room was used to induce stress. Anxiety-like behaviors of offspring were evaluated using the elevated plus maze test. Immunohistochemistry for the detection of 5-bromo-2ʹ- deoxyuridine and doublecortin (DCX in the hippocampal dentate gyrus and 5-hydroxytryptamine 1A receptors (5-HT1A in the dorsal raphe was conducted. Brain-derived neurotrophic factor (BDNF and tyrosine kinase B (TrkB levels in the hippocampus were evaluated by western blot analysis. Results: Offspring of maternal rats exposed to stress during pregnancy showed anxiety-like behaviors. Offspring also showed reduced expression of BDNF, TrkB, and DCX in the dentate gyrus, decreased cell proliferation in the hippocampus, and reduced 5-HT1A expression in the dorsal raphe. Postnatal treadmill exercise by offspring, but not maternal exercise during pregnancy, enhanced cell proliferation and expression of these proteins. Conclusions: Postnatal treadmill exercise ameliorated anxiety-like behaviors in offspring of stressed pregnant rats, and the alleviating effect of exercise on these behaviors is hypothesized to result from enhancement of cell proliferation through 5-HT1A activation in offspring rats.

  7. Regulation of brain aromatase activity in rats

    International Nuclear Information System (INIS)

    Roselli, C.E.; Ellinwood, W.E.; Resko, J.A.

    1984-01-01

    The distribution and regulation of aromatase activity in the adult rat brain with a sensitive in vitro assay that measures the amount of 3 H 2 O formed during the conversion of [1 beta- 3 H]androstenedione to estrone. The rate of aromatase activity in the hypothalamus-preoptic area (HPOA) was linear with time up to 1 h, and with tissue concentrations up to 5 mgeq/200 microliters incubation mixture. The enzyme demonstrated a pH optimum of 7.4 and an apparent Michaelis-Menten constant (Km) of 0.04 microns. The greatest amount of aromatase activity was found in amygdala and HPOA from intact male rats. The hippocampus, midbrain tegmentum, cerebral cortex, cerebellum, and anterior pituitary all contained negligible enzymatic activity. Castration produced a significant decrease in aromatase activity in the HPOA, but not in the amygdala or cerebral cortex. The HPOAs of male rats contained significantly greater aromatase activity than the HPOAs of female rats. In females, this enzyme activity did not change during the estrous cycle or after ovariectomy. Administration of testosterone to gonadectomized male and female rats significantly enhanced HPOA aromatase activities to levels approximating those found in HPOA from intact males. Therefore, the results suggest that testosterone, or one of its metabolites, is a major steroidal regulator of HPOA aromatase activity in rats

  8. Neuroprotective and Therapeutic Effect of Caffeine on the Rat Model of Parkinson's Disease Induced by Rotenone.

    Science.gov (United States)

    Khadrawy, Yasser A; Salem, Ahmed M; El-Shamy, Karima A; Ahmed, Emad K; Fadl, Nevein N; Hosny, Eman N

    2017-09-03

    The present study aimed to investigate the protective and therapeutic effects of caffeine on rotenone-induced rat model of Parkinson's disease (PD). Rats were divided into control, PD model induced by rotenone (1.5 mg/kg intraperitoneally (i.p.) for 45 days), protected group injected with caffeine (30 mg/kg, i.p.) and rotenone for 45 days (during the development of PD model), and treated group injected with caffeine (30 mg/kg, i.p.) for 45 days after induction of PD model. The data revealed a state of oxidative and nitrosative stress in the midbrain and the striatum of animal model of PD as indicated from the increased lipid peroxidation and nitric oxide levels and the decreased reduced glutathione level and activities of glutathione-S-transferase and superoxide dismutase. Rotenone induced a decrease in acetylcholinesterase and Na + /K + -ATPase activities and an increase in tumor necrosis factor-α level in the midbrain and the striatum. Protection and treatment with caffeine ameliorated the oxidative stress and the changes in acetylcholinesterase and Na + /K + -ATPase activities induced by rotenone in the midbrain and the striatum. This was associated with improvement in the histopathological changes induced in the two areas of PD model. Caffeine protection and treatment restored the depletion of midbrain and striatal dopamine induced by rotenone and prevented decline in motor activities (assessed by open field test) and muscular strength (assessed by traction and hanging tests) and improved norepinephrine level in the two areas. The present study showed that caffeine offered a significant neuroprotection and treatment against neurochemical, histopathological, and behavioral changes in a rotenone-induced rat model of PD.

  9. Characteristics of central binding sites for [3H] DAMGO in spontaneously hypertensive rats

    International Nuclear Information System (INIS)

    Gulati, A.; Bhargava, H.N.

    1990-01-01

    The binding of [ 3 H] DAMGO, a highly selective ligand for μ-opiate receptors, to membranes of discrete brain regions and spinal cord of 10 week old spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats were determined. The brain regions examined were hypothalamus, amygdala, hippocampus, corpus striatum, pons and medulla, midbrain and cortex. [ 3 H] DAMGO bound to membranes of brain regions and spinal cord at a single high affinity site. The receptor density (B max value) and apparent dissociation constant (K d value) of [ 3 H] DAMGO to bind to membranes of hippocampus, corpus striatum, pons and medulla, cortex and spinal cord of WKY and SHR rats did not differ. The B max value of [ 3 H] DAMGO in membranes of hypothalamus and midbrain of SHR rats was significantly higher than in WKY rats but the K d values in the two strains did not differ. On the other hand, the B max value of [ 3 H] DAMGO in membranes of amygdala of SHR rats was lower than that of WKY rats but the K d values in the two strains were similar

  10. Characteristics of central binding sites for ( sup 3 H) DAMGO in spontaneously hypertensive rats

    Energy Technology Data Exchange (ETDEWEB)

    Gulati, A.; Bhargava, H.N. (Univ. of Illinois, Chicago (USA))

    1990-01-01

    The binding of ({sup 3}H) DAMGO, a highly selective ligand for {mu}-opiate receptors, to membranes of discrete brain regions and spinal cord of 10 week old spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats were determined. The brain regions examined were hypothalamus, amygdala, hippocampus, corpus striatum, pons and medulla, midbrain and cortex. ({sup 3}H) DAMGO bound to membranes of brain regions and spinal cord at a single high affinity site. The receptor density (B{sub max} value) and apparent dissociation constant (K{sub d} value) of ({sup 3}H) DAMGO to bind to membranes of hippocampus, corpus striatum, pons and medulla, cortex and spinal cord of WKY and SHR rats did not differ. The B{sub max} value of ({sup 3}H) DAMGO in membranes of hypothalamus and midbrain of SHR rats was significantly higher than in WKY rats but the K{sub d} values in the two strains did not differ. On the other hand, the B{sub max} value of ({sup 3}H) DAMGO in membranes of amygdala of SHR rats was lower than that of WKY rats but the K{sub d} values in the two strains were similar.

  11. Effects of protein restriction, melatonin administration, and short daylength on brain benzodiazepine receptors in prepubertal male rats

    International Nuclear Information System (INIS)

    Kennaway, D.J.; Royles, P.; Webb, H.; Carbone, F.

    1988-01-01

    The possibility that there are changes in brain benzodiazepine binding sites controlled by photoperiod was investigated in two strains of male rats. The hypothesis was tested by 3H-diazepam binding studies in various brain regions of prepubertal rats maintained in 14 or 10 h of light or treated with late-afternoon injections of melatonin (50 micrograms/day). Protein restriction was applied during the experiment to sensitize the animals to the treatments. Under the conditions employed, rats kept in short daylength throughout or kept on long photoperiod and given late-afternoon melatonin injections showed evidence of delayed puberty (seminal vesicle, ventral prostate, and testis weight decreased by 45%, 55%, and 60% respectively, compared to control rats). Binding measurements were made 1 h before and 2 and 5 h after the onset of darkness in the pubertal (42-day-old) or experimentally prepubertal rats. In the rats of the Porton strain (for which protein restriction was obligatory for the gonadal response) there was no consistent treatment or time effects on specific binding of 3H-diazepam to washed membranes of the hypothalamus, midbrain, or striatum. Similarly, there were no differences in the stimulation of 3H-diazepam binding by 100 microM GABA or the inhibition of binding by 50 microM N-acetyl 5 methoxy kynurenamine. By contrast, in Wistar rats, specific binding to midbrain membranes was reduced 5 h after dark compared to 2 h (37% saline; 20% melatonin) and the extent of stimulation by GABA in the hypothalamus was increased 5 h after darkness (35.6% to 46.7% saline; 37.4% to 50% melatonin). Melatonin treatment resulted in significantly higher specific binding in the hypothalamus 2 h after dark (10%, control fed; 20%, protein restricted) but reduced the GABA induced stimulation of binding in the midbrain (35.5% to 25%, control fed; 33.7% to 23.5%, protein restricted)

  12. Influence of neonatal and adult hyperthyroidism on behavior and biosynthetic capacity for norepinephrine, dopamine and 5-hydroxytryptamine in rat brain.

    Science.gov (United States)

    Rastogi, R B; Singhal, R L

    1976-09-01

    In neonatal rats, administration of l-triiodothyronine (10 mug/100 g/day) for 30 days presented signs of hyperthyroidism which included accelerated development of a variety of physical and behavioral characteristics accompanying maturation. The spontaneous motor activity was increased by 69%. Exposure of developing rats to thyroid hormone significantly increased the endogenous concentration of striatal tyrosine and the activity of tyrosine hydroxylase as well as the levels of dopamine in several brain regions. The concentration of striatal homovanillic acid and 3,4-dihydroxyphenylacetic acid, the chief metabolites of dopamine, was also increased and the magnitude of change was greater than the rise in dopamine. Despite increases in the activity of tyrosine hydroxylase and the availability of the substrate tyrosine, the steady-state levels of norepinephrine remained unaltered in various regions of brain except in cerebellum. Futhermore, neonatal hyperthyroidism significantly increased the levels of midbrain tryptophan and tryptophan hydroxylase activity but produced no change in 5-hydroxytryptamine levels of several discrete brain regions, except hypothalamus and cerebellum where its concentration was slightly decreased. However, the 5-hydroxyindoleacetic acid levels were enhanced in hypothalamus, ponsmedulla, midbrain, striatum and hippocampus. The elevated levels of 5-hydroxyindoleacetic acid did not seem to be due to increased intraneuronal deamination of 5-hydroxytryptamine since monoamine oxidase activity was not affected in cerebral cortex and midbrain of hyperthyroid rats. The data demonstrate that hyperthyroidism significantly increased the synthesis as well as the utilization of catecholamines and 5-hydroxytryptamine in maturing brain. Since the mature brain is known to respond differently to thyroid hormone action than does the developing brain, the effect of L-triiodothyronine treatment on various putative neurohumors also was examined in adult rats

  13. Midbrain Gene Screening Identifies a New Mesoaccumbal Glutamatergic Pathway and a Marker for Dopamine Cells Neuroprotected in Parkinson?s Disease

    OpenAIRE

    Viereckel, Thomas; Dumas, Sylvie; Smith-Anttila, Casey J. A.; Vlcek, Bianca; Bimpisidis, Zisis; Lagerstr?m, Malin C.; Konradsson-Geuken, ?sa; Wall?n-Mackenzie, ?sa

    2016-01-01

    The ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) of the midbrain are associated with Parkinson's disease (PD), schizophrenia, mood disorders and addiction. Based on the recently unraveled heterogeneity within the VTA and SNc, where glutamate, GABA and co-releasing neurons have been found to co-exist with the classical dopamine neurons, there is a compelling need for identification of gene expression patterns that represent this heterogeneity and that are of value for ...

  14. Safety and tolerability of MRI-guided infusion of AAV2-hAADC into the mid-brain of nonhuman primate

    Directory of Open Access Journals (Sweden)

    Waldy San Sebastian

    2014-01-01

    Full Text Available Aromatic L-amino acid decarboxylase (AADC deficiency is a rare, autosomal-recessive neurological disorder caused by mutations in the DDC gene that leads to an inability to synthesize catecholamines and serotonin. As a result, patients suffer compromised development, particularly in motor function. A recent gene replacement clinical trial explored putaminal delivery of recombinant adeno-associated virus serotype 2 vector encoding human AADC (AAV2-hAADC in AADC-deficient children. Unfortunately, patients presented only modest amelioration of motor symptoms, which authors acknowledged could be due to insufficient transduction of putamen. We hypothesize that, with the development of a highly accurate MRI-guided cannula placement technology, a more effective approach might be to target the affected mid-brain neurons directly. Transduction of AADC-deficient dopaminergic neurons in the substantia nigra and ventral tegmental area with locally infused AAV2-hAADC would be expected to lead to restoration of normal dopamine levels in affected children. The objective of this study was to assess the long-term safety and tolerability of bilateral AAV2-hAADC MRI-guided pressurized infusion into the mid-brain of nonhuman primates. Animals received either vehicle, low or high AAV2-hAADC vector dose and were euthanized 1, 3, or 9 months after surgery. Our data indicate that effective mid-brain transduction was achieved without untoward effects.

  15. Parkin and PINK1 Patient iPSC-Derived Midbrain Dopamine Neurons Exhibit Mitochondrial Dysfunction and α-Synuclein Accumulation

    Directory of Open Access Journals (Sweden)

    Sun Young Chung

    2016-10-01

    Full Text Available Parkinson's disease (PD is characterized by the selective loss of dopamine neurons in the substantia nigra; however, the mechanism of neurodegeneration in PD remains unclear. A subset of familial PD is linked to mutations in PARK2 and PINK1, which lead to dysfunctional mitochondria-related proteins Parkin and PINK1, suggesting that pathways implicated in these monogenic forms could play a more general role in PD. We demonstrate that the identification of disease-related phenotypes in PD-patient-specific induced pluripotent stem cell (iPSC-derived midbrain dopamine (mDA neurons depends on the type of differentiation protocol utilized. In a floor-plate-based but not a neural-rosette-based directed differentiation strategy, iPSC-derived mDA neurons recapitulate PD phenotypes, including pathogenic protein accumulation, cell-type-specific vulnerability, mitochondrial dysfunction, and abnormal neurotransmitter homeostasis. We propose that these form a pathogenic loop that contributes to disease. Our study illustrates the promise of iPSC technology for examining PD pathogenesis and identifying therapeutic targets.

  16. Parkin and PINK1 Patient iPSC-Derived Midbrain Dopamine Neurons Exhibit Mitochondrial Dysfunction and α-Synuclein Accumulation.

    Science.gov (United States)

    Chung, Sun Young; Kishinevsky, Sarah; Mazzulli, Joseph R; Graziotto, John; Mrejeru, Ana; Mosharov, Eugene V; Puspita, Lesly; Valiulahi, Parvin; Sulzer, David; Milner, Teresa A; Taldone, Tony; Krainc, Dimitri; Studer, Lorenz; Shim, Jae-Won

    2016-10-11

    Parkinson's disease (PD) is characterized by the selective loss of dopamine neurons in the substantia nigra; however, the mechanism of neurodegeneration in PD remains unclear. A subset of familial PD is linked to mutations in PARK2 and PINK1, which lead to dysfunctional mitochondria-related proteins Parkin and PINK1, suggesting that pathways implicated in these monogenic forms could play a more general role in PD. We demonstrate that the identification of disease-related phenotypes in PD-patient-specific induced pluripotent stem cell (iPSC)-derived midbrain dopamine (mDA) neurons depends on the type of differentiation protocol utilized. In a floor-plate-based but not a neural-rosette-based directed differentiation strategy, iPSC-derived mDA neurons recapitulate PD phenotypes, including pathogenic protein accumulation, cell-type-specific vulnerability, mitochondrial dysfunction, and abnormal neurotransmitter homeostasis. We propose that these form a pathogenic loop that contributes to disease. Our study illustrates the promise of iPSC technology for examining PD pathogenesis and identifying therapeutic targets. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  17. Laterotopic representation of left-right information onto the dorso-ventral axis of a zebrafish midbrain target nucleus.

    Science.gov (United States)

    Aizawa, Hidenori; Bianco, Isaac H; Hamaoka, Takanori; Miyashita, Toshio; Uemura, Osamu; Concha, Miguel L; Russell, Claire; Wilson, Stephen W; Okamoto, Hitoshi

    2005-02-08

    The habenulae are part of an evolutionarily highly conserved limbic-system conduction pathway that connects telencephalic nuclei to the interpeduncular nucleus (IPN) of the midbrain . In zebrafish, unilateral activation of the Nodal signaling pathway in the left brain specifies the laterality of the asymmetry of habenular size . We show "laterotopy" in the habenulo-interpeduncular projection in zebrafish, i.e., the stereotypic, topographic projection of left-sided habenular axons to the dorsal region of the IPN and of right-sided habenular axons to the ventral IPN. This asymmetric projection is accounted for by a prominent left-right (LR) difference in the size ratio of the medial and lateral habenular sub-nuclei, each of which specifically projects either to ventral or dorsal IPN targets. Asymmetric Nodal signaling directs the orientation of laterotopy but is dispensable for the establishment of laterotopy itself. Our results reveal a mechanism by which information distributed between left and right sides of the brain can be transmitted bilaterally without loss of LR coding, which may play a crucial role in functional lateralization of the vertebrate brain .

  18. Context-dependent fluctuation of serotonin in the auditory midbrain: the influence of sex, reproductive state and experience

    Science.gov (United States)

    Hanson, Jessica L.; Hurley, Laura M.

    2014-01-01

    In the face of changing behavioral situations, plasticity of sensory systems can be a valuable mechanism to facilitate appropriate behavioral responses. In the auditory system, the neurotransmitter serotonin is an important messenger for context-dependent regulation because it is sensitive to both external events and internal state, and it modulates neural activity. In male mice, serotonin increases in the auditory midbrain region, the inferior colliculus (IC), in response to changes in behavioral context such as restriction stress and social contact. Female mice have not been measured in similar contexts, although the serotonergic system is sexually dimorphic in many ways. In the present study, we investigated the effects of sex, experience and estrous state on the fluctuation of serotonin in the IC across contexts, as well as potential relationships between behavior and serotonin. Contrary to our expectation, there were no sex differences in increases of serotonin in response to a restriction stimulus. Both sexes had larger increases in second exposures, suggesting experience plays a role in serotonergic release in the IC. In females, serotonin increased during both restriction and interactions with males; however, the increase was more rapid during restriction. There was no effect of female estrous phase on the serotonergic change for either context, but serotonin was related to behavioral activity in females interacting with males. These results show that changes in behavioral context induce increases in serotonin in the IC by a mechanism that appears to be uninfluenced by sex or estrous state, but may depend on experience and behavioral activity. PMID:24198252

  19. Synaptic glutamate release by postnatal rat serotonergic neurons in microculture.

    Science.gov (United States)

    Johnson, M D

    1994-02-01

    Serotonergic neurons are thought to play a role in depression and obsessive compulsive disorder. However, their functional transmitter repertoire is incompletely known. To investigate this repertoire, intracellular recordings were obtained from 132 cytochemically identified rat mesopontine serotonergic neurons that had re-established synapses in microcultures. Approximately 60% of the neurons evoked excitatory glutamatergic potentials in themselves or in target neurons. Glutamatergic transmission was frequently observed in microcultures containing a solitary serotonergic neuron. Evidence for co-release of serotonin and glutamate from single raphe neurons was also obtained. However, evidence for gamma-aminobutyric acid release by serotonergic neurons was observed in only two cases. These findings indicate that many cultured serotonergic neurons form glutamatergic synapses and may explain several observations in slices and in vivo.

  20. A morphometric, immunohistochemical, and in situ hybridization study of the dorsal raphe nucleus in major depression, bipolar disorder, schizophrenia, and suicide.

    Science.gov (United States)

    Matthews, Paul R; Harrison, Paul J

    2012-03-01

    Several lines of evidence implicate 5-hydroxytryptamine (5-HT, serotonin) in the pathophysiology of mood disorders and suicide. However, it is unclear whether these conditions include morphological involvement of the dorsal raphe nucleus (DRN), the origin of most forebrain 5-HT innervation. We used morphometric, immunohistochemical, and molecular methods to compare the DRN in post-mortem tissue of 50 subjects (13 controls, 14 major depressive disorder [MDD], 13 bipolar disorder, 10 schizophrenia; 17 of the cases died by suicide). NeuN and PH8 antibodies were used to assess all neurons and serotonergic neurons respectively; 5-HT(1A) autoreceptor expression was investigated by regional and cellular in situ hybridization. Measurements were made at three rostrocaudal levels of the DRN. In MDD, the area of the DRN was decreased. In bipolar disorder, serotonergic neuronal size was decreased. Suicide was associated with an increased DRN area, and with a higher density but decreased size of serotonergic neurons. Total neuronal density and 5-HT(1A) receptor mRNA abundance were unaffected by diagnosis or suicide. No changes were seen in schizophrenia. The results show that mood disorders and suicide are associated with differential, limited morphological alterations of the DRN. The contrasting influences of MDD and suicide may explain some of the discrepancies between previous studies, since their design precluded detection of the effect. Copyright © 2011 Elsevier B.V. All rights reserved.

  1. [The relationships among raphe magnus nucleus, locus coeruleus and dorsal motor nucleus of vagus in the descending regulation of gastric motility].

    Science.gov (United States)

    Qiao, Hui; An, Shu-Cheng; Xu, Chang

    2011-02-01

    To explore the interrelationship among dorsal motor nucleus of the vagus (DMV), locus coeruleus (LC) and raphe magnus nucleus (NRM) in the mechanism of the descending regulation on gastric motility, which may constitute a parasympathetic local circuit, work as a neural center of gastric modulation in brainstem. Using nucleus location, electric stimulation and lesion, together with microinjection, and recording the inter-gastric pressure. (1) LC stimulation could inhibit the gastric motility significantly (P effect, while blocking the a receptor on DMV could reverse the effect. (2) NRM stimulation reduced the amplitude of gastric constriction (P effect, but blocking the 5-HT2A receptor on DMV depressed the gastric motility heavily (P effect of NRM stimulation, and microinjection of ritanserin into LC could likewise abolish it. (1) LC inhibit the gastric motility via a receptor in DMV, and meanwhile may excite it through 5-HT2A receptor in DMV, these two ways work together to keeping the gastric motility amplitude normally. (2) NRM inhibit the gastric motility via 5-HT2A receptor in LC.

  2. Brief pup exposure induces Fos expression in the lateral habenula and serotonergic caudal dorsal raphe nucleus of paternally experienced male California mice (Peromyscus californicus).

    Science.gov (United States)

    de Jong, T R; Measor, K R; Chauke, M; Harris, B N; Saltzman, W

    2010-09-01

    Fathers play a substantial role in infant care in a small but significant number of mammalian species, including humans. However, the neural circuitry controlling paternal behavior is much less understood than its female counterpart. In order to characterize brain areas activated by paternal care, male California mice were separated from their female mate and litter for 3 h and then exposed to a pup or a control object (a glass pebble with the approximate size and oblong shape of a newborn pup) for 10 min. All males receiving a pup showed a strong paternal response towards it, whereas males receiving a pebble interacted with it only occasionally. Despite the clear behavioral differences, exposure to a pup did not increase Fos-like immunoreactivity (Fos-LIR) compared to a pebble in brain areas previously found to be associated with parental care, including the medial preoptic nucleus and medial bed nucleus of the stria terminalis. Pup exposure did, however, significantly increase Fos-LIR in the lateral habenula (LHb) and in predominantly serotonergic neurons in the caudal dorsal raphe nucleus (DRC), as compared to pebble exposure. Both the LHb and DRC are known to be involved in the behavioral responses to strong emotional stimuli; therefore, these areas might play a role in controlling parental behavior in male California mice. Copyright (c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

  3. Stress-Induced Depression Is Alleviated by Aerobic Exercise Through Up-Regulation of 5-Hydroxytryptamine 1A Receptors in Rats

    Directory of Open Access Journals (Sweden)

    Tae Woon Kim

    2015-03-01

    Full Text Available Purpose: Stress is associated with depression, which induces many psychiatric disorders. Serotonin, also known as 5-hydroxy-tryptamine (5-HT, acts as a biochemical messenger and regulator in the brain. It also mediates several important physiological functions. Depression is closely associated with an overactive bladder. In the present study, we investigated the effect of treadmill exercise on stress-induced depression while focusing on the expression of 5-HT 1A (5-H1A receptors in the dorsal raphe. Methods: Stress was induced by applying a 0.2-mA electric foot shock to rats. Each set of electric foot shocks comprised a 6-second shock duration that was repeated 10 times with a 30-second interval. Three sets of electric foot shocks were applied each day for 7 days. For the confirmation of depressive state, a forced swimming test was performed. To visualize the expression of 5-HT and tryptophan hydroxylase (TPH, immunohistochemistry for 5-HT and TPH in the dorsal raphe was performed. Expression of 5-H1A receptors was determined by western blot analysis. Results: A depressive state was induced by stress, and treadmill exercise alleviated the depression symptoms in the stress-induced rats. Expressions of 5-HT, TPH, and HT 1A in the dorsal raphe were reduced by the induction of stress. Treadmill exercise increased 5-HT, TPH, and HT 1A expressions in the stress-induced rats. Conclusions: Treadmill exercise enhanced 5-HT synthesis through the up-regulation of 5-HT1A receptors, and improved the stress-induced depression. In the present study, treadmill exercise improved depression symptoms by enhancing 5-HT1A receptor expression. The present results suggest that treadmill exercise might be helpful for the alleviation of overactive bladder and improve sexual function.

  4. Stress-Induced Depression Is Alleviated by Aerobic Exercise Through Up-Regulation of 5-Hydroxytryptamine 1A Receptors in Rats.

    Science.gov (United States)

    Kim, Tae Woon; Lim, Baek Vin; Baek, Dongjin; Ryu, Dong-Soo; Seo, Jin Hee

    2015-03-01

    Stress is associated with depression, which induces many psychiatric disorders. Serotonin, also known as 5-hydroxy-tryptamine (5-HT), acts as a biochemical messenger and regulator in the brain. It also mediates several important physiological functions. Depression is closely associated with an overactive bladder. In the present study, we investigated the effect of treadmill exercise on stress-induced depression while focusing on the expression of 5-HT 1A (5-H1A) receptors in the dorsal raphe. Stress was induced by applying a 0.2-mA electric foot shock to rats. Each set of electric foot shocks comprised a 6-second shock duration that was repeated 10 times with a 30-second interval. Three sets of electric foot shocks were applied each day for 7 days. For the confirmation of depressive state, a forced swimming test was performed. To visualize the expression of 5-HT and tryptophan hydroxylase (TPH), immunohistochemistry for 5-HT and TPH in the dorsal raphe was performed. Expression of 5-H1A receptors was determined by western blot analysis. A depressive state was induced by stress, and treadmill exercise alleviated the depression symptoms in the stress-induced rats. Expressions of 5-HT, TPH, and HT 1A in the dorsal raphe were reduced by the induction of stress. Treadmill exercise increased 5-HT, TPH, and HT 1A expressions in the stress-induced rats. Treadmill exercise enhanced 5-HT synthesis through the up-regulation of 5-HT1A receptors, and improved the stress-induced depression. In the present study, treadmill exercise improved depression symptoms by enhancing 5-HT1A receptor expression. The present results suggest that treadmill exercise might be helpful for the alleviation of overactive bladder and improve sexual function.

  5. Functional reorganization of motor and limbic circuits after exercise training in a rat model of bilateral parkinsonism.

    Directory of Open Access Journals (Sweden)

    Zhuo Wang

    Full Text Available Exercise training is widely used for neurorehabilitation of Parkinson's disease (PD. However, little is known about the functional reorganization of the injured brain after long-term aerobic exercise. We examined the effects of 4 weeks of forced running wheel exercise in a rat model of dopaminergic deafferentation (bilateral, dorsal striatal 6-hydroxydopamine lesions. One week after training, cerebral perfusion was mapped during treadmill walking or at rest using [(14C]-iodoantipyrine autoradiography. Regional cerebral blood flow-related tissue radioactivity (rCBF was analyzed in three-dimensionally reconstructed brains by statistical parametric mapping. In non-exercised rats, lesions resulted in persistent motor deficits. Compared to sham-lesioned rats, lesioned rats showed altered functional brain activation during walking, including: 1. hypoactivation of the striatum and motor cortex; 2. hyperactivation of non-lesioned areas in the basal ganglia-thalamocortical circuit; 3. functional recruitment of the red nucleus, superior colliculus and somatosensory cortex; 4. hyperactivation of the ventrolateral thalamus, cerebellar vermis and deep nuclei, suggesting recruitment of the cerebellar-thalamocortical circuit; 5. hyperactivation of limbic areas (amygdala, hippocampus, ventral striatum, septum, raphe, insula. These findings show remarkable similarities to imaging findings reported in PD patients. Exercise progressively improved motor deficits in lesioned rats, while increasing activation in dorsal striatum and rostral secondary motor cortex, attenuating a hyperemia of the zona incerta and eliciting a functional reorganization of regions participating in the cerebellar-thalamocortical circuit. Both lesions and exercise increased activation in mesolimbic areas (amygdala, hippocampus, ventral striatum, laterodorsal tegmental n., ventral pallidum, as well as in related paralimbic regions (septum, raphe, insula. Exercise, but not lesioning, resulted

  6. Functional Reorganization of Motor and Limbic Circuits after Exercise Training in a Rat Model of Bilateral Parkinsonism

    Science.gov (United States)

    Wang, Zhuo; Myers, Kalisa G.; Guo, Yumei; Ocampo, Marco A.; Pang, Raina D.; Jakowec, Michael W.; Holschneider, Daniel P.

    2013-01-01

    Exercise training is widely used for neurorehabilitation of Parkinson’s disease (PD). However, little is known about the functional reorganization of the injured brain after long-term aerobic exercise. We examined the effects of 4 weeks of forced running wheel exercise in a rat model of dopaminergic deafferentation (bilateral, dorsal striatal 6-hydroxydopamine lesions). One week after training, cerebral perfusion was mapped during treadmill walking or at rest using [14C]-iodoantipyrine autoradiography. Regional cerebral blood flow-related tissue radioactivity (rCBF) was analyzed in three-dimensionally reconstructed brains by statistical parametric mapping. In non-exercised rats, lesions resulted in persistent motor deficits. Compared to sham-lesioned rats, lesioned rats showed altered functional brain activation during walking, including: 1. hypoactivation of the striatum and motor cortex; 2. hyperactivation of non-lesioned areas in the basal ganglia-thalamocortical circuit; 3. functional recruitment of the red nucleus, superior colliculus and somatosensory cortex; 4. hyperactivation of the ventrolateral thalamus, cerebellar vermis and deep nuclei, suggesting recruitment of the cerebellar-thalamocortical circuit; 5. hyperactivation of limbic areas (amygdala, hippocampus, ventral striatum, septum, raphe, insula). These findings show remarkable similarities to imaging findings reported in PD patients. Exercise progressively improved motor deficits in lesioned rats, while increasing activation in dorsal striatum and rostral secondary motor cortex, attenuating a hyperemia of the zona incerta and eliciting a functional reorganization of regions participating in the cerebellar-thalamocortical circuit. Both lesions and exercise increased activation in mesolimbic areas (amygdala, hippocampus, ventral striatum, laterodorsal tegmental n., ventral pallidum), as well as in related paralimbic regions (septum, raphe, insula). Exercise, but not lesioning, resulted in decreases

  7. Individual differences in the motivation to communicate relate to levels of midbrain and striatal catecholamine markers in male European starlings.

    Science.gov (United States)

    Heimovics, Sarah A; Salvante, Katrina G; Sockman, Keith W; Riters, Lauren V

    2011-11-01

    Individuals display dramatic differences in social communication even within similar social contexts. Across vertebrates dopaminergic projections from the ventral tegmental area (VTA) and midbrain central gray (GCt) strongly influence motivated, reward-directed behaviors. Norepinephrine is also rich in these areas and may alter dopamine neuronal activity. The present study was designed to provide insight into the roles of dopamine and norepinephrine in VTA and GCt and their efferent striatal target, song control region area X, in the regulation of individual differences in the motivation to sing. We used high pressure liquid chromatography with electrochemical detection to measure dopamine, norepinephrine and their metabolites in micropunched samples from VTA, GCt, and area X in male European starlings (Sturnus vulgaris). We categorized males as sexually motivated or non-sexually motivated based on individual differences in song produced in response to a female. Dopamine markers and norepinephrine in VTA and dopamine in area X correlated positively with sexually-motivated song. Norepinephrine in area X correlated negatively with non-sexually-motivated song. Dopamine in GCt correlated negatively with sexually-motivated song, and the metabolite DOPAC correlated positively with non-sexually-motivated song. Results highlight a role for evolutionarily conserved dopaminergic projections from VTA to striatum in the motivation to communicate and highlight novel patterns of catecholamine activity in area X, VTA, and GCt associated with individual differences in sexually-motivated and non-sexually-motivated communication. Correlations between dopamine and norepinephrine markers also suggest that norepinephrine may contribute to individual differences in communication by modifying dopamine neuronal activity in VTA and GCt. Copyright © 2011. Published by Elsevier Inc.

  8. Neural representation in the auditory midbrain of the envelope of vocalizations based on a peripheral ear model

    Directory of Open Access Journals (Sweden)

    Thilo eRode

    2013-10-01

    Full Text Available The auditory midbrain implant (AMI consists of a single shank array (20 sites for stimulation along the tonotopic axis of the central nucleus of the inferior colliculus (ICC and has been safely implanted in deaf patients who cannot benefit from a cochlear implant (CI. The AMI improves lip-reading abilities and environmental awareness in the implanted patients. However, the AMI cannot achieve the high levels of speech perception possible with the CI. It appears the AMI can transmit sufficient spectral cues but with limited temporal cues required for speech understanding. Currently, the AMI uses a CI-based strategy, which was originally designed to stimulate each frequency region along the cochlea with amplitude-modulated pulse trains matching the envelope of the bandpass-filtered sound components. However, it is unclear if this type of stimulation with only a single site within each frequency lamina of the ICC can elicit sufficient temporal cues for speech perception. At least speech understanding in quiet is still possible with envelope cues as low as 50 Hz. Therefore, we investigated how ICC neurons follow the bandpass-filtered envelope structure of natural stimuli in ketamine-anesthetized guinea pigs. We identified a subset of ICC neurons that could closely follow the envelope structure (up to ~100 Hz of a diverse set of species-specific calls, which was revealed by using a peripheral ear model to estimate the true bandpass-filtered envelopes observed by the brain. Although previous studies have suggested a complex neural transformation from the auditory nerve to the ICC, our data suggest that the brain maintains a robust temporal code in a subset of ICC neurons matching the envelope structure of natural stimuli. Clinically, these findings suggest that a CI-based strategy may still be effective for the AMI if the appropriate neurons are entrained to the envelope of the acoustic stimulus and can transmit sufficient temporal cues to higher

  9. Auditory and audio-visual processing in patients with cochlear, auditory brainstem, and auditory midbrain implants: An EEG study.

    Science.gov (United States)

    Schierholz, Irina; Finke, Mareike; Kral, Andrej; Büchner, Andreas; Rach, Stefan; Lenarz, Thomas; Dengler, Reinhard; Sandmann, Pascale

    2017-04-01

    There is substantial variability in speech recognition ability across patients with cochlear implants (CIs), auditory brainstem implants (ABIs), and auditory midbrain implants (AMIs). To better understand how this variability is related to central processing differences, the current electroencephalography (EEG) study compared hearing abilities and auditory-cortex activation in patients with electrical stimulation at different sites of the auditory pathway. Three different groups of patients with auditory implants (Hannover Medical School; ABI: n = 6, CI: n = 6; AMI: n = 2) performed a speeded response task and a speech recognition test with auditory, visual, and audio-visual stimuli. Behavioral performance and cortical processing of auditory and audio-visual stimuli were compared between groups. ABI and AMI patients showed prolonged response times on auditory and audio-visual stimuli compared with NH listeners and CI patients. This was confirmed by prolonged N1 latencies and reduced N1 amplitudes in ABI and AMI patients. However, patients with central auditory implants showed a remarkable gain in performance when visual and auditory input was combined, in both speech and non-speech conditions, which was reflected by a strong visual modulation of auditory-cortex activation in these individuals. In sum, the results suggest that the behavioral improvement for audio-visual conditions in central auditory implant patients is based on enhanced audio-visual interactions in the auditory cortex. Their findings may provide important implications for the optimization of electrical stimulation and rehabilitation strategies in patients with central auditory prostheses. Hum Brain Mapp 38:2206-2225, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  10. Dopamine D2/D3 receptor binding of [123I]epidepride in risperidone-treatment chronic MK-801-induced rat schizophrenia model using nanoSPECT/CT neuroimaging

    International Nuclear Information System (INIS)

    Huang, Y.R.; Pai, C.W.; Cheng, K.H.; Kuo, W.I.; Chen, M.W.; Chang, K.W.

    2014-01-01

    Introduction: Epidepride is a compound with an affinity in picomolar range for D 2 /D 3 receptors. The aim of this work was designed to investigate the diagnostic possibility of [ 123 I]epidepride imaging platform for risperidone-treatment chronic MK-801-induced rat schizophrenia model. Methods: Rats received repeated administration of MK-801 (dissolved in saline, i.p., 0.3 mg/kg/day) or saline for 4 weeks. After 1-week administration of MK-801, rats in MK-801 + risperidone group received risperidone (0.5 mg/kg/day) intraperitoneally 15 min prior to MK-801 administration for the rest of 3-week treatment. We obtained serial [ 123 I]epidepride neuroimages from nanoSPECT/CT and evaluated the alteration of specific binding in striatum and midbrain. Results: Risperidone reversed chronic MK-801-induced decrease in social interaction duration. IHC and ELISA analysis showed consistent results that chronic MK-801 treatment significantly decreased striatal and midbrain D 2 R expression but repeated risperidone administration reversed the effect of MK-801 treatment. In addition, [ 123 I]epidepride nanoSPECT/CT neuroimaging revealed that low specific [ 123 I]epidepride binding ratios caused by MK-801 in striatum and midbrain were statistically alleviated after 1- and 2-week risperidone administration, respectively. Conclusions: We established a rat schizophrenia model by chronic MK-801 administration for 4 weeks. [ 123 I]Epidepride nanoSPECT neuroimaging can trace the progressive alteration of D 2 R expression in striatum and midbrain caused by long-lasting MK-801 treatment. Besides diagnosing illness stage of disease, [ 123 I]epidepride can be a useful tool to evaluate therapeutic effects of antipsychotic drug in chronic MK-801-induced rat schizophrenia model

  11. Topography and collateralization of dopaminergic projections to primary motor cortex in rats.

    Science.gov (United States)

    Hosp, Jonas A; Nolan, Helen E; Luft, Andreas R

    2015-05-01

    Dopaminergic signaling within the primary motor cortex (M1) is necessary for successful motor skill learning. Dopaminergic neurons projecting to M1 are located in the ventral tegmental area (VTA, nucleus A10) of the midbrain. It is unknown which behavioral correlates are encoded by these neurons. The objective here is to investigate whether VTA-M1 fibers are collaterals of projections to prefrontal cortex (PFC) or nucleus accumbens (NAc) or if they form a distinct pathway. In rats, multiple-site retrograde fluorescent tracers were injected into M1, PFC and the core region of the NAc and VTA sections investigated for concomitant labeling of different tracers. Dopaminergic neurons projecting to M1, PFC and NAc were found in nucleus A10 and to a lesser degree in the medial nucleus A9. Neurons show high target specificity, minimal collateral branching to other than their target area and hardly cross the midline. Whereas PFC- and NAc-projecting neurons are indistinguishably intermingled within the ventral portion of dopaminergic nuclei in middle and caudal midbrain, M1-projecting neurons are only located within the dorsal part of the rostral midbrain. Within M1, the forelimb representation receives sevenfold more dopaminergic projections than the hindlimb representation. This strong rostro-caudal gradient as well as the topographical preference to dorsal structures suggest that projections to M1 emerged late in the development of the dopaminergic systems in and form a functionally distinct system.

  12. An Lmx1b-miR135a2 regulatory circuit modulates Wnt1/Wnt signaling and determines the size of the midbrain dopaminergic progenitor pool.

    Directory of Open Access Journals (Sweden)

    Angela Anderegg

    Full Text Available MicroRNAs regulate gene expression in diverse physiological scenarios. Their role in the control of morphogen related signaling pathways has been less studied, particularly in the context of embryonic Central Nervous System (CNS development. Here, we uncover a role for microRNAs in limiting the spatiotemporal range of morphogen expression and function. Wnt1 is a key morphogen in the embryonic midbrain, and directs proliferation, survival, patterning and neurogenesis. We reveal an autoregulatory negative feedback loop between the transcription factor Lmx1b and a newly characterized microRNA, miR135a2, which modulates the extent of Wnt1/Wnt signaling and the size of the dopamine progenitor domain. Conditional gain of function studies reveal that Lmx1b promotes Wnt1/Wnt signaling, and thereby increases midbrain size and dopamine progenitor allocation. Conditional removal of Lmx1b has the opposite effect, in that expansion of the dopamine progenitor domain is severely compromised. Next, we provide evidence that microRNAs are involved in restricting dopamine progenitor allocation. Conditional loss of Dicer1 in embryonic stem cells (ESCs results in expanded Lmx1a/b+ progenitors. In contrast, forced elevation of miR135a2 during an early window in vivo phenocopies the Lmx1b conditional knockout. When En1::Cre, but not Shh::Cre or Nes::Cre, is used for recombination, the expansion of Lmx1a/b+ progenitors is selectively reduced. Bioinformatics and luciferase assay data suggests that miR135a2 targets Lmx1b and many genes in the Wnt signaling pathway, including Ccnd1, Gsk3b, and Tcf7l2. Consistent with this, we demonstrate that this mutant displays reductions in the size of the Lmx1b/Wnt1 domain and range of canonical Wnt signaling. We posit that microRNA modulation of the Lmx1b/Wnt axis in the early midbrain/isthmus could determine midbrain size and allocation of dopamine progenitors. Since canonical Wnt activity has recently been recognized as a key

  13. Hypocretin-1 levels in the cerebrospinal fluid of patients with Percheron artery infarction with or without midbrain involvement: A case series.

    Science.gov (United States)

    Suzuki, Keisuke; Miyamoto, Tomoyuki; Miyamoto, Masayuki; Maeda, Hiroto; Nokura, Kazuya; Tohyama, Jun; Hirata, Koichi; Shimizu, Tetsuo; Kanbayashi, Takashi

    2016-07-01

    Bilateral paramedian thalamic infarctions (BPTIs) due to artery of Percheron occlusion are known to cause hypersomnia. However, the role of hypocretin-1, a wake-promoting peptide that is located at the lateral hypothalamus, in hypersomnia in these patients remains unclear. To clarify the role of hypocretin-1 in hypersomnia in patients with BPTIs, hypocretin-1 levels in the cerebrospinal fluid (CSF) were measured in 6 patients with BPTIs: 2 with rostral midbrain involvement (BPT+RMI) and 4 without midbrain involvement (BPT-MI). CSF hypocretin-1 levels were decreased in 2 patients with BPT+RMI and were within normal ranges in 4 patients with BPT-MI. Hypersomnia was noted in all the patients. In one BPT+RMI patient, hypersomnia was improved within 2 weeks and decreased CSF hypocretin-1 levels were reversed (acute phase (on day 9), 109.2 pg/mL; chronic phase (at 3 months), 323 pg/mL), whereas another BPT+RMI patient who displayed coma in the acute phase had decreased CSF orexin levels (107 pg/mL) at day 49 and exhibited severe disability. Hypocretin deficiency was not involved in hypersomnia observed in BPT-MI patients; however, CSF hypocretin-1 levels were reduced in BPT+RMI patients. Reduced CSF hypocretin-1 levels in the chronic phase may possibly predict a poor clinical outcome in patients with Percheron artery infarction.

  14. Isthmin is a novel secreted protein expressed as part of the Fgf-8 synexpression group in the Xenopus midbrain-hindbrain organizer.

    Science.gov (United States)

    Pera, Edgar M; Kim, James I; Martinez, Sarah L; Brechner, Mariel; Li, Su Yu; Wessely, Oliver; De Robertis, E M

    2002-08-01

    Patterning of the central nervous system is regulated by a signaling center located at the midbrain-hindbrain boundary (MHB), or isthmus organizer. Fibroblast growth factors secreted from the MHB are required and sufficient to direct the ordered growth and regionalization of the midbrain and anterior hindbrain. In an unbiased secretion cloning screen of Xenopus gastrula embryos we identified a novel gene, which we designated as Isthmin (xIsm) due to its prominent expression at the MHB. xIsm encodes a secreted protein of 449 amino acids containing one copy of the thrombospondin type 1 repeat (TSR). We also found orthologous Isthmin genes in human (hIsm) and mouse (mIsm), as well as a gene encoding an Isthmin-like human unknown protein (hIsm-l). The conservation of a unique carboxy-terminal region between hIsm and hIsm-l suggests that Isthmin is the founding member of a new family of secreted proteins. xIsm was strongly expressed maternally in the Xenopus egg and showed zygotic expression in the ventral blastopore lip, notochord, and MHB. Additional expression domains were detected in neural crest, ear vesicle, and developing blood islands. Interestingly, xIsm was co-expressed with Fibroblast growth factor-8 (xFgf-8) at multiple sites including the MHB, indicating that these two genes are part of a synexpression group which also includes sprouty and sef homologs.

  15. Activin A Inhibits MPTP and LPS-Induced Increases in Inflammatory Cell Populations and Loss of Dopamine Neurons in the Mouse Midbrain In Vivo.

    Science.gov (United States)

    Stayte, Sandy; Rentsch, Peggy; Tröscher, Anna R; Bamberger, Maximilian; Li, Kong M; Vissel, Bryce

    2017-01-01

    Parkinson's disease is a chronic neurodegenerative disease characterized by a significant loss of dopaminergic neurons within the substantia nigra pars compacta region and a subsequent loss of dopamine within the striatum. A promising avenue of research has been the administration of growth factors to promote the survival of remaining midbrain neurons, although the mechanism by which they provide neuroprotection is not understood. Activin A, a member of the transforming growth factor β superfamily, has been shown to be a potent anti-inflammatory following acute brain injury and has been demonstrated to play a role in the neuroprotection of midbrain neurons against MPP+-induced degeneration in vitro. We hypothesized that activin A may offer similar anti-inflammatory and neuroprotective effects in in vivo mouse models of Parkinson's disease. We found that activin A significantly attenuated the inflammatory response induced by both MPTP and intranigral administration of lipopolysaccharide in C57BL/6 mice. We found that administration of activin A promoted survival of dopaminergic and total neuron populations in the pars compacta region both 8 days and 8 weeks after MPTP-induced degeneration. Surprisingly, no corresponding protection of striatal dopamine levels was found. Furthermore, activin A failed to protect against loss of striatal dopamine transporter expression in the striatum, suggesting the neuroprotective action of activin A may be localized to the substantia nigra. Together, these results provide the first evidence that activin A exerts potent neuroprotection and anti-inflammatory effects in the MPTP and lipopolysaccharide mouse models of Parkinson's disease.

  16. Regulation of Hippocampal 5-HT Release by P2X7 Receptors in Response to Optogenetic Stimulation of Median Raphe Terminals of Mice

    Directory of Open Access Journals (Sweden)

    Flóra Gölöncsér

    2017-10-01

    Full Text Available Serotonergic and glutamatergic neurons of median raphe region (MRR play a pivotal role in the modulation of affective and cognitive functions. These neurons synapse both onto themselves and remote cortical areas. P2X7 receptors (P2rx7 are ligand gated ion channels expressed by central presynaptic excitatory nerve terminals and involved in the regulation of neurotransmitter release. P2rx7s are implicated in various neuropsychiatric conditions such as schizophrenia and depression. Here we investigated whether 5-HT release released from the hippocampal terminals of MRR is subject to modulation by P2rx7s. To achieve this goal, an optogenetic approach was used to selectively activate subpopulation of serotonergic terminals derived from the MRR locally, and one of its target area, the hippocampus. Optogenetic activation of neurons in the MRR with 20 Hz was correlated with freezing and enhanced locomotor activity of freely moving mice and elevated extracellular levels of 5-HT, glutamate but not GABA in vivo. Similar optical stimulation (OS significantly increased [3H]5-HT and [3H]glutamate release in acute MRR and hippocampal slices. We examined spatial and temporal patterns of [3H]5-HT release and the interaction between the serotonin and glutamate systems. Whilst [3H]5-HT release from MRR neurons was [Ca2+]o-dependent and sensitive to TTX, CNQX and DL-AP-5, release from hippocampal terminals was not affected by the latter drugs. Hippocampal [3H]5-HT released by electrical but not OS was subject to modulation by 5- HT1B/D receptors agonist sumatriptan (1 μM, whereas the selective 5-HT1A agonist buspirone (0.1 μM was without effect. [3H]5-HT released by electrical and optical stimulation was decreased in mice genetically deficient in P2rx7s, and after perfusion with selective P2rx7 antagonists, JNJ-47965567 (0.1 μM, and AZ-10606120 (0.1 μM. Optical and electrical stimulation elevated the extracellular level of ATP. Our results demonstrate for the

  17. A description of the lumbar interfascial triangle and its relation with the lateral raphe: anatomical constituents of load transfer through the lateral margin of the thoracolumbar fascia

    Science.gov (United States)

    Schuenke, M D; Vleeming, A; Van Hoof, T; Willard, F H

    2012-01-01

    rib to the iliac crest. This triangle results in the unification of different fascial sheaths along the lateral border of the TLF, creating a ridged-union of dense connective tissue that has been termed the lateral raphe (Spine, 9,1984, 163). This triangle may function in the distribution of laterally mediated tension to balance different viscoelastic moduli, along either the middle or posterior layers of the TLF. PMID:22582887

  18. Differentiation in boron distribution in adult male and female rats' normal brain: A BNCT approach

    International Nuclear Information System (INIS)

    Goodarzi, Samereh; Pazirandeh, Ali; Jameie, Seyed Behnamedin; Baghban Khojasteh, Nasrin

    2012-01-01

    Boron distribution in adult male and female rats' normal brain after boron carrier injection (0.005 g Boric Acid+0.005 g Borax+10 ml distilled water, pH: 7.4) was studied in this research. Coronal sections of control and trial animal tissue samples were irradiated with thermal neutrons. Using alpha autoradiography, significant differences in boron concentration were seen in forebrain, midbrain and hindbrain sections of male and female animal groups with the highest value, four hours after boron compound injection. - Highlights: ► Boron distribution in male and female rats' normal brain was studied in this research. ► Coronal sections of animal tissue samples were irradiated with thermal neutrons. ► Alpha and Lithium tracks were counted using alpha autoradiography. ► Different boron concentration was seen in brain sections of male and female rats. ► The highest boron concentration was seen in 4 h after boron compound injection.

  19. Effects of chronic lead intoxication on rat serotoninergic system and anxiety behavior.

    Science.gov (United States)

    Sansar, Wafa; Bouyatas, My Mustapha; Ahboucha, Samir; Gamrani, Halima

    2012-01-01

    Chronic lead exposure has been shown to produce behavioral disturbances in human and animal models. These disturbances are associated with alterations in monoaminergic neurotransmission in the central nervous system (CNS), some of which have been attributed to serotonin (5-HT). This study was undertaken to investigate the chronic effects of lead exposure on the serotoninergic system in the dorsal raphe nucleus (DRN) and the consequences of its toxicity on rat behavior. Adult male Wistar rats were chronically exposed for 3 months to 0.5% lead acetate in drinking water. The serotoninergic system was evaluated using immunohistochemistry and the anxiety behavior was assessed by the light/dark box test. The results show that chronic lead exposure induces a significant increase of blood and brain lead levels in treated rats compared with controls. The density of the immunoreactive serotoninergic cell bodies was significantly higher in treated rats in all parts of the DRN. Assessment of animal behavior using the light/dark box test showed that lead-treated rats spent significantly more time in the light chamber compared with controls (P=0.001). These findings suggest that lead exposure may possibly induce increased anxiety as a consequence of changes in neuronal 5-HT content in the DRN. Copyright © 2011 Elsevier GmbH. All rights reserved.

  20. [Changes of neurotransmitter, lipid peroxide and their metabolic related enzyme activities in the brain of rats exposed to noise and vitamin E].

    Science.gov (United States)

    Sakuma, N

    1984-09-01

    Effects of noise on locomotor activities were analysed in rat. In addition, changes in lipid peroxide (LPX), their metabolic related enzyme activities, and neurotransmitter in the rat brain due to noise exposure and the effects of vitamin E on the rats were studied. The results obtained were as follows: After white noise exposure of 95 dB (A), the locomotor activities of rat increased. But 3 weeks after noise exposure, the activities began to decrease. LPX and glutathione peroxidase (GSH-Px) activities in hypothalamus and cortex increased at the 14th day after noise exposure or at the 21st day after noise exposure. Superoxide dismutase (SOD) activities increased in hippocampus at the 4th day after noise exposure, and decreased in midbrain and thalamus at the 14th day and the 21th day after noise exposure. Norepinephrine (NE) increased in hypothalamus at the 1st day, the 2nd day and the 7th day after noise exposure, and increased in striatum at the 7th day after noise exposure, in cortex at the 4th day and the 7th day after exposure. At the 14th day after noise exposure, NE decreased in cerebellum, in medulla and pons, in midbrain and thalamus, and in cortex. In cortex NE also decreased at the 21st day after noise exposure. Serotonin increased in hypothalamus and in midbrain and thalamus at the 1st and 4th day after noise exposure, and increased in striatum at the 7th day after noise exposure. Decrease in serotonin was observed in cerebellum at the 14th day after noise exposure. Vitamin E decreased LPX in rat brain and the liver.

  1. Differential numbers of foci of lymphocytes within the brains of Lewis rats exposed to weak complex nocturnal magnetic fields during development of experimental allergic encephalomyelitis.

    Science.gov (United States)

    Persinger, Michael A

    2009-01-01

    To discern if specific structures of the rat brain contained more foci of lymphocytes following induction of experimental allergic encephalomyelitis and exposures to weak, amplitude-modulated magnetic fields for 6 min once per hour during the scotophase, the residuals between the observed and predicted values for the numbers of foci for 320 structures were obtained. Compared to the brains of sham-field exposed rats, the brains of rats exposed to 7-Hz 50 nT (0.5 mG) amplitude-modulated fields showed more foci within hippocampal structures and the dorsal central grey of the midbrain while those exposed to 7-Hz 500 nT (5 mG) fields showed greater densities within the hypothalamus and optic chiasm. The brains of rats exposed to either the 50 nT or 500 nT amplitude-modulated 40-Hz fields displayed greater densities of foci within the midbrain structures related to rapid eye movement. Most of the enhancements of infiltrations within the magnetic field-exposed rats occurred in structures within periventricular or periaqueductal regions and were both frequency- and intensity-dependent. The specificity and complexity of the configurations of the residuals of the numbers of infiltrated foci following exposures to the different fields suggest that the brain itself may be a "sensory organ" for the detection of these stimuli.

  2. DIRECT VISUALIZATION OF THE DOPAMINE TRANSPORTER IN CULTURED NEWBORN RAT MIDBRAIN NEURONS USING THE FLUORESCENT COCAINE ANALOGUE JHC 1-64

    DEFF Research Database (Denmark)

    Rasmussen, Søren; Vægter, Christian Bjerggaard; Cha, J

    In this study we have established methods for visualization and tracking of the dopamine transporter (DAT) in cultured dopaminergic neurons in real time using a fluorescent cocaine analogue JHC 1-64 and confocal fluorescence microscopy. The initial binding experiments in HEK 293 cells stably...... 1-64 was prevented by excess concentrations of dopamine, cocaine, mazindol, or RTI-55, whereas the norepinephrine and/or serotonin transporter specific inhibitors desmethylimipramine and citalopram did not affect fluorescent labeling of the neurons. This strongly supports that JHC 1-64 specifically...

  3. Dickkopf 3 Promotes the Differentiation of a Rostrolateral Midbrain Dopaminergic Neuronal Subset In Vivo and from Pluripotent Stem Cells In Vitro in the Mouse.

    Science.gov (United States)

    Fukusumi, Yoshiyasu; Meier, Florian; Götz, Sebastian; Matheus, Friederike; Irmler, Martin; Beckervordersandforth, Ruth; Faus-Kessler, Theresa; Minina, Eleonora; Rauser, Benedict; Zhang, Jingzhong; Arenas, Ernest; Andersson, Elisabet; Niehrs, Christof; Beckers, Johannes; Simeone, Antonio; Wurst, Wolfgang; Prakash, Nilima

    2015-09-30

    Wingless-related MMTV integration site 1 (WNT1)/β-catenin signaling plays a crucial role in the generation of mesodiencephalic dopaminergic (mdDA) neurons, including the substantia nigra pars compacta (SNc) subpopulation that preferentially degenerates in Parkinson's disease (PD). However, the precise functions of WNT1/β-catenin signaling in this context remain unknown. Stem cell-based regenerative (transplantation) therapies for PD have not been implemented widely in the clinical context, among other reasons because of the heterogeneity and incomplete differentiation of the transplanted cells. This might result in tumor formation and poor integration of the transplanted cells into the dopaminergic circuitry of the brain. Dickkopf 3 (DKK3) is a secreted glycoprotein implicated in the modulation of WNT/β-catenin signaling. Using mutant mice, primary ventral midbrain cells, and pluripotent stem cells, we show that DKK3 is necessary and sufficient for the correct differentiation of a rostrolateral mdDA neuron subset. Dkk3 transcription in the murine ventral midbrain coincides with the onset of mdDA neurogenesis and is required for the activation and/or maintenance of LMX1A (LIM homeobox transcription factor 1α) and PITX3 (paired-like homeodomain transcription factor 3) expression in the corresponding mdDA precursor subset, without affecting the proliferation or specification of their progenitors. Notably, the treatment of differentiating pluripotent stem cells with recombinant DKK3 and WNT1 proteins also increases the proportion of mdDA neurons with molecular SNc DA cell characteristics in these cultures. The specific effects of DKK3 on the differentiation of rostrolateral mdDA neurons in the murine ventral midbrain, together with its known prosurvival and anti-tumorigenic properties, make it a good candidate for the improvement of regenerative and neuroprotective strategies in the treatment of PD. Significance statement: We show here that Dickkopf 3 (DKK3), a

  4. [Role of the Periaqueductal Gray Matter of the Midbrain in Regulation of Somatic Pain Sensitivity During Stress: Participation of Corticotropin-Releasing Factor and Glucocorticoid Hormones].

    Science.gov (United States)

    Yarushkina, N I; Filaretova, L P

    2015-01-01

    Periaqueductal gray matter of the midbrain (PAGM) plays a crucial role in the regulation of pain sensitivity under stress, involving in the stress-induced analgesia. A key hormonal system of adaptation under stress is the hypothalamic-pituitary-adrenocortical (HPA) axis. HPA axis's hormones, corticotropin-releasing factor (CRF) and glucocorticoids, are involved in stress-induced analgesia. Exogenous hormones of the HPA axis, similarly to the hormones produced under stress, may cause an analgesic effect. CRF-induced analgesia may be provided by glucocorticoid hormones. CRF and glucocorticoids-induced effects on somatic pain sensitivity may be mediated by PAGM. The aim of the review was to analyze the data of literature on the role of PAGM in the regulation of somatic pain sensitivity under stress and in providing of CRF and glucocorticoid-induced analgesia.

  5. Activity-based anorexia activates nesfatin-1 immunoreactive neurons in distinct brain nuclei of female rats.

    Science.gov (United States)

    Scharner, Sophie; Prinz, Philip; Goebel-Stengel, Miriam; Lommel, Reinhard; Kobelt, Peter; Hofmann, Tobias; Rose, Matthias; Stengel, Andreas

    2017-12-15

    Activity-based anorexia (ABA) is an established animal model for the eating disorder anorexia nervosa (AN). The pathophysiology of AN and the involvement of food intake-regulatory peptides is still poorly understood. Nesfatin-1, an anorexigenic peptide also involved in the mediation of stress, anxiety and depression might be a likely candidate involved in the pathogenesis of AN. Therefore, activation of nesfatin-1 immunoreactive (ir) brain nuclei was investigated under conditions of ABA. Female Sprague-Dawley rats were used and divided into four groups (n=6/group): activity-based anorexia (ABA), restricted feeding (RF), activity (AC) and ad libitum fed (AL). After the 21-day experimental period and development of ABA, brains were processed for c-Fos/nesfatin-1 double labeling immunohistochemistry. ABA increased the number of nesfatin-1 immunopositive neurons in the paraventricular nucleus, arcuate nucleus, dorsomedial hypothalamic nucleus, locus coeruleus and in the rostral part of the nucleus of the solitary tract compared to AL and AC groups (p0.05). Moreover, we observed significantly more c-Fos and nesfatin-1 ir double-labeled cells in ABA rats compared to RF, AL and AC in the supraoptic nucleus (p<0.05) and compared to AL and AC in the paraventricular nucleus, arcuate nucleus, dorsomedial hypothalamic nucleus, dorsal raphe nucleus and the rostral raphe pallidus (p<0.05). Since nesfatin-1 plays a role in the inhibition of food intake and the response to stress, we hypothesize that the observed changes of brain nesfatin-1 might play a role in the pathophysiology and symptomatology under conditions of ABA and potentially also in patients with AN. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Effects of anpirtoline on regional serotonin synthesis in the rat brain: an autoradiographic study

    International Nuclear Information System (INIS)

    Watanabe, Arata; Nakai, Akio; Tohyama, Yoshihiro; Nguyen, Khnah Q.; Diksic, Mirko

    2006-01-01

    Anpirtoline has been described as an agonist at 5-HT 1B receptors with a relatively high potency. It also acts as an agonist at 5-HT 1A receptors, but has a lower potency than at the 5-HT 1B sites. There is very little known about the mechanism by which anpirtoline influences regional 5-HT synthesis. The aim of the present study was to investigate the effects of acutely and chronically administered anpirtoline on 5-HT synthesis in the rat brain using the autoradiographic α-[ 14 C]methyl-L-tryptophan method. In the acute study, anpirtoline (2.0 mg/kg) was administered intraperitoneally 30 min before the tracer injection. The control rats were injected with the same volume of saline. In the chronic study, anpirtoline (2 mg/kg per day) was injected subcutaneously in saline once a day for 10 days. There were no significant differences between the plasma-free and total tryptophan concentrations between the anpirtoline treatment and the respective control groups. In the acute experiment, 5-HT synthesis rates in all of the brain areas investigated were significantly decreased by anpirtoline when compared to the saline-treated group. In the chronic anpirtoline experiment, 5-HT synthesis rates of almost all of the projection areas, as well as the raphe nuclei, were normalized or had a tendency to be normalized. These results suggest that it is likely that the terminal 5-HT 1B receptors are involved in the regulation of 5-HT synthesis in the projection areas and that 5-HT synthesis, in the raphe, is likely influenced by anpirtoline's 5-HT 1A and/or 5-HT 1B agonistic properties

  7. Acute treatment with fluvoxamine elevates rat brain serotonin synthesis in some terminal regions: An autoradiographic study

    International Nuclear Information System (INIS)

    Muck-Seler, Dorotea; Pivac, Nela; Diksic, Mirko

    2012-01-01

    Introduction: A considerable body of evidence indicates the involvement of the neurotransmitter serotonin (5-HT) in the pathogenesis and treatment of depression. Methods: The acute effect of fluvoxamine, on 5-HT synthesis rates was investigated in rat brain regions, using α- 14 C-methyl-L-tryptophan as a tracer. Fluvoxamine (25 mg/kg) and saline (control) were injected intraperitoneally, one hour before the injection of the tracer (30 μCi). Results: There was no significant effect of fluvoxamine on plasma free tryptophan. After Benjamini–Hochberg False Discovery Rate correction, a significant decrease in the 5-HT synthesis rate in the fluvoxamine treated rats, was found in the raphe magnus (− 32%), but not in the median (− 14%) and dorsal (− 3%) raphe nuclei. In the regions with serotonergic axon terminals, significant increases in synthesis rates were observed in the dorsal (+ 41%) and ventral (+ 43%) hippocampus, visual (+ 38%), auditory (+ 65%) and parietal (+ 37%) cortex, and the substantia nigra pars compacta (+ 56%). There were no significant changes in the 5-HT synthesis rates in the median (+ 11%) and lateral (+ 24%) part of the caudate-putamen, nucleus accumbens (+ 5%), VTA (+ 16%) or frontal cortex (+ 6%). Conclusions: The data show that the acute administration of fluvoxamine affects 5-HT synthesis rates in a regionally specific pattern, with a general elevation of the synthesis in the terminal regions and a reduction in some cell body structures. The reasons for the regional specific effect of fluvoxamine on 5-HT synthesis are unclear, but may be mediated by the presynaptic serotonergic autoreceptors.

  8. Wnt/B-Catenin Signaling is Required to Rescue Midbrain Dopaminergic Progenitors and Promote Neurorepair in Ageing Mouse Model of Parkinson’s Disease

    Science.gov (United States)

    L’Episcopo, Francesca; Tirolo, Cataldo; Testa, Nunzio; Caniglia, Salvatore; Morale, Maria Concetta; Serapide, Maria Francesca; Pluchino, Stefano; Marchetti, Bianca

    2014-01-01

    SUMMARY Wnt/β-catenin signaling is required for specification and neurogenesis of midbrain dopaminergic (mDA) neurons, the pivotal neuronal population that degenerates in Parkinson’s disease (PD) and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Wnt/β-catenin signaling plays a vital role in adult neurogenesis but whether it might engage DA neurogenesis/neurorepair in the affected PD brain is yet unresolved. Recently, the adult midbrain aqueduct periventricular regions (Aq-PVRs) were shown to harbor neural stem/progenitor cells (mNPCs) with DA potential in vitro, but restrictive mechanisms in vivo are believed to limit their DA regenerative capacity. Using in vitro mNPC culture systems we herein demonstrate that aging is one most critical factor restricting mNPC neurogenic potential via dysregulation of Wnt/β-catenin signaling. Cococulture paradigms between young/aged (Y/A) mNPCs and Y/A astrocytes identified glial age and a decline of glial-derived factors including Wnts as key determinants of impaired neurogenic potential, whereas Wnt activation regimens efficiently reversed the diminished proliferative, neuronal and DA differentiation potential of A-mNPCs. Next, in vivo studies in wild (Wt) and transgenic β-catenin reporter mice uncovered Wnt/β-catenin signaling activation and remarkable astrocyte remodeling of Aq-PVR in response to MPTP-induced DA neuron death. Spatio-temporal analyses unveiled β-catenin signaling in predopaminergic (Nurr1+/TH−) and imperiled or rescuing DAT+ neurons during MPTP-induced DA neuron injury and self-repair. Aging inhibited Wnt signaling, whereas β-catenin activation in situ with a specific GSK-3β antagonist promoted a significant degree of DA neurorestoration associated with reversal of motor deficit, with implications for neurorestorative approaches in PD. PMID:24648001

  9. A potential role for the midbrain in integrating fat-free mass determined energy needs: An H2 (15) O PET study.

    Science.gov (United States)

    Weise, Christopher M; Thiyyagura, Pradeep; Reiman, Eric M; Chen, Kewei; Krakoff, Jonathan

    2015-06-01

    Little is known on how sensing of energy needs is centrally represented, integrated, and translated into the behavioral aspects of energy homeostasis. Fat free mass (FFM) is the major determinant of energy expenditure. We investigated how interindividual variances in FFM relate to neuronal activity in humans. Healthy adults (n = 64, 21F/43M; age 31.3 ± 9.1y; percentage of body fat [PFAT] 25.6 ± 10.7%; BMI 30.4 ± 9) underwent a 36h fast and subsequent H(2) (15) O positron emission tomographic (PET) measurement of regional cerebral blood flow (rCBF). Multiple variable regression analysis revealed significant associations of FFM with rCBF within the midbrain [including parts of the periaqueductal gray (PAG), ventral tegmental area (VTA), thalamic and hypothalamic regions], the bilateral parahippocampal region, left anterior cingulate, left insular cortex, right cerebellum, and distinct regions within the temporal and occipital cortex. In contrast, no significant associations were found for fat mass (FM). We investigated the potential functional-anatomical link between FFM and central regulation of food intake by performing a conjunction analysis of FFM and the perceived hunger feelings. This showed a significant overlap within the midbrain PAG. Mediation analysis demonstrated a significant indirect effect of FFM on hunger with PAG rCBF as mediator. Most regions we found to be associated with FFM form part in ascending homeostatic pathways and cortical circuitries implicated in the regulation of basic bodily functions indicating a potential role of these central networks in the integration of FFM determined energy needs. © 2015 Wiley Periodicals, Inc.

  10. Eel calcitonin binding site distribution and antinociceptive activity in rats

    International Nuclear Information System (INIS)

    Guidobono, F.; Netti, C.; Sibilia, V.; Villa, I.; Zamboni, A.; Pecile, A.

    1986-01-01

    The distribution of binding site for [ 125 I]-eel-calcitonin (ECT) to rat central nervous system, studied by an autoradiographic technique, showed concentrations of binding in the diencephalon, the brain stem and the spinal cord. Large accumulations of grains were seen in the hypothalamus, the amygdala, in the fasciculus medialis prosencephali, in the fasciculus longitudinalis medialis, in the ventrolateral part of the periventricular gray matter, in the lemniscus medialis and in the raphe nuclei. The density of grains in the reticular formation and in the nucleus tractus spinalis nervi trigemini was more moderate. In the spinal cord, grains were scattered throughout the dorsal horns. Binding of the ligand was displaced equally by cold ECT and by salmon CT(sCT), indicating that both peptides bind to the same receptors. Human CT was much weaker than sCT in displacing [ 125 I]-ECT binding. The administration of ECT into the brain ventricles of rats dose-dependently induced a significant and long-lasting enhancement of hot-plate latencies comparable with that obtained with sCT. The antinociceptive activity induced by ECT is compatible with the topographical distribution of binding sites for the peptide and is a further indication that fish CTs are active in the mammalian brain

  11. Fluoxetine Exerts Age-Dependent Effects on Behavior and Amygdala Neuroplasticity in the Rat

    Science.gov (United States)

    Homberg, Judith R.; Olivier, Jocelien D. A.; Blom, Tom; Arentsen, Tim; van Brunschot, Chantal; Schipper, Pieter; Korte-Bouws, Gerdien; van Luijtelaar, Gilles; Reneman, Liesbeth

    2011-01-01

    The selective serotonin reuptake inhibitor (SSRI) Prozac® (fluoxetine) is the only registered antidepressant to treat depression in children and adolescents. Yet, while the safety of SSRIs has been well established in adults, serotonin exerts neurotrophic actions in the developing brain and thereby may have harmful effects in adolescents. Here we treated adolescent and adult rats chronically with fluoxetine (12 mg/kg) at postnatal day (PND) 25 to 46 and from PND 67 to 88, respectively, and tested the animals 7–14 days after the last injection when (nor)fluoxetine in blood plasma had been washed out, as determined by HPLC. Plasma (nor)fluoxetine levels were also measured 5 hrs after the last fluoxetine injection, and matched clinical levels. Adolescent rats displayed increased behavioral despair in the forced swim test, which was not seen in adult fluoxetine treated rats. In addition, beneficial effects of fluoxetine on wakefulness as measured by electroencephalography in adults was not seen in adolescent rats, and age-dependent effects on the acoustic startle response and prepulse inhibition were observed. On the other hand, adolescent rats showed resilience to the anorexic effects of fluoxetine. Exploratory behavior in the open field test was not affected by fluoxetine treatment, but anxiety levels in the elevated plus maze test were increased in both adolescent and adult fluoxetine treated rats. Finally, in the amygdala, but not the dorsal raphe nucleus and medial prefrontal cortex, the number of PSA-NCAM (marker for synaptic remodeling) immunoreactive neurons was increased in adolescent rats, and decreased in adult rats, as a consequence of chronic fluoxetine treatment. No fluoxetine-induced changes in 5-HT1A receptor immunoreactivity were observed. In conclusion, we show that fluoxetine exerts both harmful and beneficial age-dependent effects on depressive behavior, body weight and wakefulness, which may relate, in part, to differential fluoxetine

  12. Fluoxetine exerts age-dependent effects on behavior and amygdala neuroplasticity in the rat.

    Directory of Open Access Journals (Sweden)

    Judith R Homberg

    Full Text Available The selective serotonin reuptake inhibitor (SSRI Prozac® (fluoxetine is the only registered antidepressant to treat depression in children and adolescents. Yet, while the safety of SSRIs has been well established in adults, serotonin exerts neurotrophic actions in the developing brain and thereby may have harmful effects in adolescents. Here we treated adolescent and adult rats chronically with fluoxetine (12 mg/kg at postnatal day (PND 25 to 46 and from PND 67 to 88, respectively, and tested the animals 7-14 days after the last injection when (norfluoxetine in blood plasma had been washed out, as determined by HPLC. Plasma (norfluoxetine levels were also measured 5 hrs after the last fluoxetine injection, and matched clinical levels. Adolescent rats displayed increased behavioral despair in the forced swim test, which was not seen in adult fluoxetine treated rats. In addition, beneficial effects of fluoxetine on wakefulness as measured by electroencephalography in adults was not seen in adolescent rats, and age-dependent effects on the acoustic startle response and prepulse inhibition were observed. On the other hand, adolescent rats showed resilience to the anorexic effects of fluoxetine. Exploratory behavior in the open field test was not affected by fluoxetine treatment, but anxiety levels in the elevated plus maze test were increased in both adolescent and adult fluoxetine treated rats. Finally, in the amygdala, but not the dorsal raphe nucleus and medial prefrontal cortex, the number of PSA-NCAM (marker for synaptic remodeling immunoreactive neurons was increased in adolescent rats, and decreased in adult rats, as a consequence of chronic fluoxetine treatment. No fluoxetine-induced changes in 5-HT(1A receptor immunoreactivity were observed. In conclusion, we show that fluoxetine exerts both harmful and beneficial age-dependent effects on depressive behavior, body weight and wakefulness, which may relate, in part, to differential

  13. An HPLC tracing of the enhancer regulation in selected discrete brain areas of food-deprived rats.

    Science.gov (United States)

    Miklya, I; Knoll, B; Knoll, J

    2003-05-09

    The recent discovery of the enhancer regulation in the mammalian brain brought a different perspective to the brain-organized realization of goal-oriented behavior, which is the quintessence of plastic behavioral descriptions such as drive or motivation. According to this new approach, 'drive' means that special endogenous enhancer substances enhance the impulse-propagation-mediated release of transmitters in a proper population of enhancer-sensitive neurons, and keep these neurons in the state of enhanced excitability until the goal is reached. However, to reach any goal needs the participation of the catecholaminergic machinery, the engine of the brain. We developed a method to detect the specific enhancer effect of synthetic enhancer substances [(-)-deprenyl, (-)-PPAP, (-)-BPAP] by measuring the release of transmitters from freshly isolated selected discrete brain areas (striatum, substantia nigra, tuberculum olfactorium, locus coeruleus, raphe) by the aid of HPLC with electrochemical detection. To test the validity of the working hypothesis that in any form of goal-seeking behavior the catecholaminergic and serotonergic neurons work on a higher activity level, we compared the amount of norepinephrine, dopamine, and serotonin released from selected discrete brain areas isolated from the brain of sated and food-deprived rats. Rats were deprived of food for 48 and 72 hours, respectively, and the state of excitability of their catecholaminergic and serotonergic neurons in comparison to that of sated rats was measured. We tested the orienting-searching reflex activity of the rats in a special open field, isolated thereafter selected discrete brain areas and measured the release of norepinephrine, dopamine, and serotonin from the proper tissue samples into the organ bath. The orienting-searching reflex activity of the rats increased proportionally to the time elapsed from the last feed and the amount of dopamine released from the striatum, substantia nigra and

  14. The hTH-GFP reporter rat model for the study of Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Lorraine Iacovitti

    Full Text Available Parkinson disease (PD is the second leading neurodegenerative disease in the US. As there is no known cause or cure for PD, researchers continue to investigate disease mechanisms and potential new therapies in cell culture and in animal models of PD. In PD, one of the most profoundly affected neuronal populations is the tyrosine hydroxylase (TH-expressing dopaminergic (DA neurons of the substantia nigra pars compacta (SNpc. These DA-producing neurons undergo degeneration while neighboring DA-producing cells of the ventral tegmental area (VTA are largely spared. To aid in these studies, The Michael J. Fox Foundation (MJFF partnered with Thomas Jefferson University and Taconic Inc. to generate new transgenic rat lines carrying the human TH gene promoter driving EGFP using a 11 kb construct used previously to create a hTH-GFP mouse reporter line. Of the five rat founder lines that were generated, three exhibited high level specific GFP fluorescence in DA brain structures (ie. SN, VTA, striatum, olfactory bulb, hypothalamus. As with the hTH-GFP mouse, none of the rat lines exhibit reporter expression in adrenergic structures like the adrenal gland. Line 12141, with its high levels of GFP in adult DA brain structures and minimal ectopic GFP expression in non-DA structures, was characterized in detail. We show here that this line allows for anatomical visualization and microdissection of the rat midbrain into SNpc and/or VTA, enabling detailed analysis of midbrain DA neurons and axonal projections after toxin treatment in vivo. Moreover, we further show that embryonic SNpc and/or VTA neurons, enriched by microdissection or FACS, can be used in culture or transplant studies of PD. Thus, the hTH-GFP reporter rat should be a valuable tool for Parkinson's disease research.

  15. Rapid decrease in brain enkephalin content after low-dose whole-body X-irradiation of the rat

    Energy Technology Data Exchange (ETDEWEB)

    Miyachi, Yukihisa (Central Research Inst. of Electric Power Industry, Komae, Tokyo (Japan). Komae Research Lab.); Ogawa, Norio; Mori, Akitane

    1992-03-01

    Methionine-eckephalin (ME) contents in the hypothalamus and other rat brain structures were measured immediately after 10 or 20 cGy whole-body X-irradiation. The ME contents of homogenates of the striatum, hypothalamus, midbrain + thalamus, hindbrain and pituitary were assayed radioimmunologically with {sup 125}I. The contents of all the structure, except the pituitary, decreased significantly after 20 cGy irradiation. The reduction in the hypothalamus was transient, ME content gradually recovering with time. These results suggest that the central nervous system of mammals is one of the most radiosensitive organs as judged by changes in stress-induced mediators such as ME. (author).

  16. Morphine regulates Argonaute 2 and TH expression and activity but not miR-133b in midbrain dopaminergic neurons.

    Science.gov (United States)

    García-Pérez, Daniel; López-Bellido, Roger; Hidalgo, Juana M; Rodríguez, Raquel E; Laorden, Maria Luisa; Núñez, Cristina; Milanés, Maria Victoria

    2015-01-01

    Epigenetic changes such as microRNAs (miRs)/Ago2-induced gene silencing represent complex molecular signature that regulate cellular plasticity. Recent studies showed involvement of miRs and Ago2 in drug addiction. In this study, we show that changes in gene expression induced by morphine and morphine withdrawal occur with concomitant epigenetic modifications in the mesolimbic dopaminergic (DA) pathway [ventral tegmental area (VTA)/nucleus accumbens (NAc) shell], which is critically involved in drug-induced dependence. We found that acute or chronic morphine administration as well as morphine withdrawal did not modify miR-133b messenger RNA (mRNA) expression in the VTA, whereas Ago2 protein levels were decreased and increased in morphine-dependent rats and after morphine withdrawal, respectively. These changes were paralleled with enhanced and decreased NAc tyrosine hydroxylase (TH) protein (an early DA marker) in morphine-dependent rats and after withdrawal, respectively. We also observed changes in TH mRNA expression in the VTA that could be related to Ago2-induced translational repression of TH mRNA during morphine withdrawal. However, the VTA number of TH-positive neurons suffered no alterations after the different treatment. Acute morphine administration produced a marked increase in TH activity and DA turnover in the NAc (shell). In contrast, precipitated morphine withdrawal decreased TH activation and did not change DA turnover. These findings provide new information into the possible correlation between Ago2/miRs complex regulation and DA neurons plasticity during opiate addiction. © 2013 Society for the Study of Addiction.

  17. Early-life Social Isolation Impairs the Gonadotropin-Inhibitory Hormone Neuronal Activity and Serotonergic System in Male Rats

    Directory of Open Access Journals (Sweden)

    Tomoko eSoga

    2015-11-01

    Full Text Available Social isolation in early life deregulates the serotonergic system of the brain, compromising reproductive function. Gonadotropin-inhibitory hormone (GnIH neurons in the dorsomedial hypothalamic nucleus are critical to the inhibitory regulation of gonadotropin-releasing hormone neuronal activity in the brain and release of luteinising hormone by the pituitary gland. Although GnIH responds to stress, the role of GnIH in social isolation-induced deregulation of the serotonin system and reproductive function remains unclear. We investigated the effect of social isolation in early life on the serotonergic–GnIH neuronal system using enhanced green fluorescent protein (EGFP-tagged GnIH-transgenic rats. Socially isolated rats were observed for anxious and depressive behaviours. Using immunohistochemistry, we examined c-Fos protein expression in EGFP–GnIH neurons in 9-week-old adult male rats after 6 weeks post-weaning isolation or group -housing. We also inspected serotonergic fibre juxtapositions in EGFP–GnIH neurons in control and socially isolated male rats. Socially isolated rats exhibited anxious and depressive behaviours. The total number of EGFP–GnIH neurons was the same in control and socially isolated rats, but c-Fos expression in GnIH neurons was significantly reduced in socially isolated rats. Serotonin fibre juxtapositions on EGFP–GnIH neurons was also lower in socially isolated rats. In addition, levels of tryptophan hydroxylase mRNA expression in the dorsal raphe nucleus were significantly attenuated in these rats. These results suggest that social isolation in early life results in lower serotonin levels, which reduce GnIH neuronal activity and may lead to reproductive failure.

  18. Early-Life Social Isolation Impairs the Gonadotropin-Inhibitory Hormone Neuronal Activity and Serotonergic System in Male Rats.

    Science.gov (United States)

    Soga, Tomoko; Teo, Chuin Hau; Cham, Kai Lin; Idris, Marshita Mohd; Parhar, Ishwar S

    2015-01-01

    Social isolation in early life deregulates the serotonergic system of the brain, compromising reproductive function. Gonadotropin-inhibitory hormone (GnIH) neurons in the dorsomedial hypothalamic nucleus are critical to the inhibitory regulation of gonadotropin-releasing hormone neuronal activity in the brain and release of luteinizing hormone by the pituitary gland. Although GnIH responds to stress, the role of GnIH in social isolation-induced deregulation of the serotonin system and reproductive function remains unclear. We investigated the effect of social isolation in early life on the serotonergic-GnIH neuronal system using enhanced green fluorescent protein (EGFP)-tagged GnIH transgenic rats. Socially isolated rats were observed for anxious and depressive behaviors. Using immunohistochemistry, we examined c-Fos protein expression in EGFP-GnIH neurons in 9-week-old adult male rats after 6 weeks post-weaning isolation or group housing. We also inspected serotonergic fiber juxtapositions in EGFP-GnIH neurons in control and socially isolated male rats. Socially isolated rats exhibited anxious and depressive behaviors. The total number of EGFP-GnIH neurons was the same in control and socially isolated rats, but c-Fos expression in GnIH neurons was significantly reduced in socially isolated rats. Serotonin fiber juxtapositions on EGFP-GnIH neurons were also lower in socially isolated rats. In addition, levels of tryptophan hydroxylase mRNA expression in the dorsal raphe nucleus were significantly attenuated in these rats. These results suggest that social isolation in early-life results in lower serotonin levels, which reduce GnIH neuronal activity and may lead to reproductive failure.

  19. Neurons in the monoaminergic nuclei of the rat and human central nervous system express FA1/dlk

    DEFF Research Database (Denmark)

    Jensen, Charlotte Harken; Meyer, M; Schrøder, Henrik Daa

    2001-01-01

    The gene DLK1 encodes a member of the epidermal growth factor (EGF) superfamily, delta-like (dlk). When exposed in vivo to the action of an unknown protease, this type 1 membrane protein generates a soluble peptide referred to as Fetal antigen 1 (FA1). By acting in juxtacrine as well as paracrine....../autocrine manners, both forms have been shown to be active in the differentiation/proliferation process of various cell types. In adults, FA1/dlk has been demonstrated mainly within (neuro) endocrine tissues. In this study we investigated the presence of FA1/dlk in other parts of the developing and adult rat...... and human CNS. Using immunocytochemistry and in situ hybridization we found that in both species FA1/dlk was expressed in neurons of the Edinger-Westphal's nucleus as well as in substantia nigra, ventral tegmental area (VTA), locus coeruleus and in certain parts of the raphe nuclei....

  20. Autoradiographic localization of glucocorticosteriod binding sites in rat brain after in vivo injection of [3H]RU 28362

    International Nuclear Information System (INIS)

    Sarrieau, Alain; Dussaillant, Monique; Rostene, William

    1988-01-01

    The autoradiographic distribution of glucocorticosteriod binding sites in the brain of adrenalectomized rats was studied following in vivo injection of a potent synthetic glucocorticosteriod agonist [ 3 H]RU 28362. Analysis of the autoradiograms revealed a specific and dense labelling in the pyramidal cell layer of the Ammon's horn and in the granular cell layer of the dentate gyrus of the hippocampus. In the hypothalmus, the labelling was particularly high in the paraventricular nucleus (site of CRF synthesis), the arcuate, periventricular and the supraoptic nuclei as well as in the median eminence. Autoradiograms also revealed the presence of[ 3 H]RU 28362 binding sites in several brain regions including the amygdala, the pineal gland, the entorhinal cortex, the interpeduncular, interfascicular and dorsal raphe nuclei, the central grey and the substantia nigra suggesting possible effects of glucocorticosteriods in these structures (author)

  1. Serotonin depletion results in a decrease of the neuronal activation caused by rivastigmine in the rat hippocampus

    DEFF Research Database (Denmark)

    Kornum, Birgitte R; Weikop, Pia; Moller, Arne

    2006-01-01

    nicotinic receptors located at nerve terminals. The aim of the present study was to determine in which areas and to what extent 5-HT mediates the neuronal response to ACh release. For this purpose, neuronal activity was measured in rats with rivastigmine-induced elevated ACh levels after a 95% 5-HT...... depletion obtained by dosing p-chlorophenylalanine followed by D,L-fenfluramine. Neuronal activation was quantified by stereological measurements of c-Fos immunoreactivity. The brain areas examined were medial prefrontal cortex, septum, dorsal hippocampus, and dorsal raphe nucleus. Rivastigmine...... brain areas examined. It is concluded that 5-HT mediates part of the ACh-induced hippocampal neuronal activation, possibly mediated via locally released 5-HT....

  2. DNA microarray unravels rapid changes in transcriptome of MK-801 treated rat brain

    Science.gov (United States)

    Kobayashi, Yuka; Kulikova, Sofya P; Shibato, Junko; Rakwal, Randeep; Satoh, Hiroyuki; Pinault, Didier; Masuo, Yoshinori

    2015-01-01

    AIM: To investigate the impact of MK-801 on gene expression patterns genome wide in rat brain regions. METHODS: Rats were treated with an intraperitoneal injection of MK-801 [0.08 (low-dose) and 0.16 (high-dose) mg/kg] or NaCl (vehicle control). In a first series of experiment, the frontoparietal electrocorticogram was recorded 15 min before and 60 min after injection. In a second series of experiments, the whole brain of each animal was rapidly removed at 40 min post-injection, and different regions were separated: amygdala, cerebral cortex, hippocampus, hypothalamus, midbrain and ventral striatum on ice followed by DNA microarray (4 × 44 K whole rat genome chip) analysis. RESULTS: Spectral analysis revealed that a single systemic injection of MK-801 significantly and selectively augmented the power of baseline gamma frequency (30-80 Hz) oscillations in the frontoparietal electroencephalogram. DNA microarray analysis showed the largest number (up- and down- regulations) of gene expressions in the cerebral cortex (378), midbrain (376), hippocampus (375), ventral striatum (353), amygdala (301), and hypothalamus (201) under low-dose (0.08 mg/kg) of MK-801. Under high-dose (0.16 mg/kg), ventral striatum (811) showed the largest number of gene expression changes. Gene expression changes were functionally categorized to reveal expression of genes and function varies with each brain region. CONCLUSION: Acute MK-801 treatment increases synchrony of baseline gamma oscillations, and causes very early changes in gene expressions in six individual rat brain regions, a first report. PMID:26629322

  3. Daily Dose effect of Valerian root extract on some Neurotransmitter contents in different Brain areas of male Albino Rats

    International Nuclear Information System (INIS)

    Waggas, Abeer M

    2007-01-01

    The aim of the present study was to investigate the daily effect of valerian (Valeriana officinalis L .) root extract on epinephrine (E), norepinephrine (NE), dopamine (DA), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) , and gamma-aminobutyric acid (GABA) contents in different brain areas (cerebellum , pons plus medulla oblongata , striatum , cerebral cortex, hypothalamus, midbrain and hippocampus) of male albino rats .The daily intraperitoneal ( i.p.) injection of 300 mg/kg body wt valerian for 30 days caused a significant increase in epinephrine ( E ) content in pons plus medulla oblongata, cerebral cortex , hypothalamus and in midbrain . Norepinephrine (NE ) content was significantly increased in all brain areas tested except in cerebellum and cerebral cortex . Dopamine (DA) content was significantly increased in all tested brain areas except in cerebral cortex and hippocampus . moreover , there was also a significant increase in serotonin (5-HT ) and 5-hydroxyindol acetic acid (5-HIAA) contents in all tested brain areas . However, gamma-aminobutyric acid (GABA) content was significantly decreased in all tested brain areas . After the extract withdrawal, the increase in ( E, NE, DA , 5-HT ) contents and the decrease in GABA content persisted in pons plus medulla oblongata , striatum , midbrain and hippocampus , and this might be due to regional differences toward the effect. The increase in E, NE, DA , 5-HT and 5-HIAA contents, at the same time the decrease in GABA content in the different brain areas of albino rats may be due to the presence of both valepotriates and valerenic acid in the extract which mediated the GABA ergic mechanisms including the inhibition of GABA metabolism and the increase in GABA synthesis and release , although agonized the GABAA receptors which led to the inhibit of the neurotransmitter release. Valerian root extract may be useful as a herbal medicine having sedative effect and it is safe. (author)

  4. Cell type-specific gene expression of midbrain dopaminergic neurons reveals molecules involved in their vulnerability and protection.

    Science.gov (United States)

    Chung, Chee Yeun; Seo, Hyemyung; Sonntag, Kai Christian; Brooks, Andrew; Lin, Ling; Isacson, Ole

    2005-07-01

    Molecular differences between dopamine (DA) neurons may explain why the mesostriatal DA neurons in the A9 region preferentially degenerate in Parkinson's disease (PD) and toxic models, whereas the adjacent A10 region mesolimbic and mesocortical DA neurons are relatively spared. To characterize innate physiological differences between A9 and A10 DA neurons, we determined gene expression profiles in these neurons in the adult mouse by laser capture microdissection, microarray analysis and real-time PCR. We found 42 genes relatively elevated in A9 DA neurons, whereas 61 genes were elevated in A10 DA neurons [> 2-fold; false discovery rate (FDR) neurotoxic or protective biochemical pathways. Three A9-elevated molecules [G-protein coupled inwardly rectifying K channel 2 (GIRK2), adenine nucleotide translocator 2 (ANT-2) and the growth factor IGF-1] and three A10-elevated peptides (GRP, CGRP and PACAP) were further examined in both alpha-synuclein overexpressing PC12 (PC12-alphaSyn) cells and rat primary ventral mesencephalic (VM) cultures exposed to MPP+ neurotoxicity. GIRK2-positive DA neurons were more vulnerable to MPP+ toxicity and overexpression of GIRK2 increased the vulnerability of PC12-alphaSyn cells to the toxin. Blocking of ANT decreased vulnerability to MPP+ in both cell culture systems. Exposing cells to IGF-1, GRP and PACAP decreased vulnerability of both cell types to MPP+, whereas CGRP protected PC12-alphaSyn cells but not primary VM DA neurons. These results indicate that certain differentially expressed molecules in A9 and A10 DA neurons may play key roles in their relative vulnerability to toxins and PD.

  5. Maternal and developmental toxicity of the hallucinogenic plant-based beverage ayahuasca in rats.

    Science.gov (United States)

    da Motta, Luciana Gueiros; de Morais, Juliana Alves; Tavares, Ana Carolina A M; Vianna, Leonora Maciel Sousa; Mortari, Marcia Renata; Amorim, Rivadávio Fernandes Batista; Carvalho, Rosângela R; Paumgartten, Francisco José R; Pic-Taylor, Aline; Caldas, Eloisa Dutra

    2018-04-01

    Rats were treated orally with ayahuasca (AYA) on gestation days (GD) 6-20 at doses corresponding to one-(1X) to eight-fold (8X) the average dose taken by a human adult in a religious ritual, and the pregnancy outcome evaluated on GD21. Rats treated with 4X and 8X doses died during the treatment period (44 and 52%), and those that survived showed kidney injury. Rats surviving the 8X dose showed neuronal loss in hippocampal regions and in the raphe nuclei, and those from the 2X dose neuronal loss in CA1. Delayed intrauterine growth, induced embryo deaths and increased occurrence of foetal anomalies were observed at the 8X dose. At non-lethal doses, AYA enhanced embryolethality and the incidence of foetal soft-tissue and skeleton anomalies. This study suggested that AYA is developmentally toxic and that its daily use by pregnant women may pose risks for the conceptus. Copyright © 2018 Elsevier Inc. All rights reserved.

  6. Immunohistochemical Mapping of TRK-Fused Gene Products in the Rat Brainstem

    International Nuclear Information System (INIS)

    Takeuchi, Shigeko; Masuda, Chiaki; Maebayashi, Hisae; Tooyama, Ikuo

    2012-01-01

    The TRK-fused gene (TFG in human, Tfg in rat) was originally identified in human papillary thyroid cancer as a chimeric form of the NTRK1 gene. It was since reported that the gene product (TFG) plays a role in regulating phosphotyrosine-specific phosphatase-1 activity. As shown in the accompanying paper, we produced an antibody to rat TFG and used it to localize TFG to selected neurons in specific regions. In the present study, we mapped the TFG-positive neurons in the brainstem, cerebellum, and spinal cord of rats. In the brainstem, neurons intensely positive for TFG were distributed in the raphe nuclei, the gigantocellular reticular nucleus, the reticulotegmental nucleus of the pons, and some cranial nerve nuclei such as the trigeminal nuclei, the vestibulocochlear nuclei, and the dorsal motor nucleus of the vagus. Purkinje cells in the cerebellum and motor neurons in the spinal anterior horn were also positive for TFG. These results provide fundamental data for studying the functions of TFG in the brain

  7. A well-refined in vitro model derived from human embryonic stem cell for screening phytochemicals with midbrain dopaminergic differentiation-boosting potential for improving Parkinson's disease.

    Science.gov (United States)

    Hsieh, Wen-Ting; Chiang, Been-Huang

    2014-07-09

    Stimulation of endogenous neurogenesis is a potential approach to compensate for loss of dopaminergic neurons of substantia nigra compacta nigra (SNpc) in patients with Parkinson's disease (PD). This objective was to establish an in vitro model by differentiating pluripotent human embryonic stem cells (hESCs) into midbrain dopaminergic (mDA) neurons for screening phytochemicals with mDA neurogenesis-boosting potentials. Consequently, a five-stage differentiation process was developed. The derived cells expressed many mDA markers including tyrosine hydroxylase (TH), β-III tubulin, and dopamine transporter (DAT). The voltage-gated ion channels and dopamine release were also examined for verifying neuron function, and the dopamine receptor agonists bromocriptine and 7-hydroxy-2-(dipropylamino)tetralin (7-OH-DPAT) were used to validate our model. Then, several potential phytochemicals including green tea catechins and ginsenosides were tested using the model. Finally, ginsenoside Rb1 was identified as the most potent phytochemical which is capable of upregulating neurotrophin expression and inducing mDA differentiation.

  8. Hemispheric Asymmetries in Striatal Reward Responses Relate to Approach-Avoidance Learning and Encoding of Positive-Negative Prediction Errors in Dopaminergic Midbrain Regions.

    Science.gov (United States)

    Aberg, Kristoffer Carl; Doell, Kimberly C; Schwartz, Sophie

    2015-10-28

    Some individuals are better at learning about rewarding situations, whereas others are inclined to avoid punishments (i.e., enhanced approach or avoidance learning, respectively). In reinforcement learning, action values are increased when outcomes are better than predicted (positive prediction errors [PEs]) and decreased for worse than predicted outcomes (negative PEs). Because actions with high and low values are approached and avoided, respectively, individual differences in the neural encoding of PEs may influence the balance between approach-avoidance learning. Recent correlational approaches also indicate that biases in approach-avoidance learning involve hemispheric asymmetries in dopamine function. However, the computational and neural mechanisms underpinning such learning biases remain unknown. Here we assessed hemispheric reward asymmetry in striatal activity in 34 human participants who performed a task involving rewards and punishments. We show that the relative difference in reward response between hemispheres relates to individual biases in approach-avoidance learning. Moreover, using a computational modeling approach, we demonstrate that better encoding of positive (vs negative) PEs in dopaminergic midbrain regions is associated with better approach (vs avoidance) learning, specifically in participants with larger reward responses in the left (vs right) ventral striatum. Thus, individual dispositions or traits may be determined by neural processes acting to constrain learning about specific aspects of the world. Copyright © 2015 the authors 0270-6474/15/3514491-10$15.00/0.

  9. Reduced connectivity and inter-hemispheric symmetry of the sensory system in a rat model of vulnerability to developing depression.

    Science.gov (United States)

    Ben-Shimol, E; Gass, N; Vollmayr, B; Sartorius, A; Goelman, G

    2015-12-03

    Defining the markers corresponding to a high risk of developing depression in humans would have major clinical significance; however, few studies have been conducted since they are not only complex but also require homogeneous groups. This study compared congenital learned helpless (cLH) rats, selectively bred for high stress sensitivity and learned helplessness (LH) behavior, to congenital non-learned helpless (cNLH) rats that were bred for resistance to uncontrollable stress. Naïve cLH rats show some depression-like behavior but full LH behavior need additional stress, making this model ideal for studying vulnerability to depression. Resting-state functional connectivity obtained from seed correlation analysis was calculated for multiple regions that were selected by anatomy AND by a data-driven approach, independently. Significance was determined by t-statistic AND by permutation analysis, independently. A significant reduction in functional connectivity was observed by both analyses in the cLH rats in the sensory, motor, cingulate, infralimbic, accumbens and the raphe nucleus. These reductions corresponded primarily to reduced inter-hemispheric connectivity. The main reduction however was in the sensory system. It is argued that reduced connectivity and inter-hemispheric connectivity of the sensory system reflects an internal convergence state which may precede other depressive symptomatology and therefore could be used as markers for vulnerability to the development of depression. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  10. Alteration of CNS dopamine transporter and D2 receptor in aged and scopolamine induced amnestic rats

    International Nuclear Information System (INIS)

    Lin Yansong; Ding Shiyu; Chen Zhengping; Zhou Xiang; Fang Ping; Wang Bocheng; Zhang Manda

    2002-01-01

    Objective: To evaluate the effect of aging and scopolamine (Sco) induced amnesia on central dopamine transporter (DAT), D 2 receptor in rats. Methods: The 3 month old amnestic rat models were made by peritoneal injection of the muscarinic receptor antagonist Sco (5 mg/kg) for 10 d. Passive avoidance task was carried out to evaluate the recent learning and memory of rats. The biodistribution of 125 I-2-β-carbomethoxy-3-β(4-iodophenyl)-tropan ( 125 I-β-CIT) and 125 I-s-3-iodo-N-(1-ethyl-2-pyrolidinyl) methyl-2-hydroxy-6-methoxybenzamide (IBZM) in the brain was used to evaluate the DAT and D 2 receptor. Results: During 10 d passive avoidance task testing, no difference was found for the first day among 3 month control, 26 month old and Sco group rats, on the 10th day the entry number of aged and Sco group rats was (1.33 +- 0.82)/10 min, (3.00 +- 0.63)/10 min, respectively, higher than that of the control rats (t was 5.682 and 6.372, respectively, P 125 I-β-CIT binding were found in the striatum (ST), hippocampus (HIP) and frontal cortex (FC) of the aged and Sco group rats (t was 4.151, 5.416, 4.871, 6.922, 7.331 and 3.990, respectively, P 125 I-IBZM binding in ST was found in both Sco and old rats (t was 6.021 and 3.227, respectively, P 2 receptor, was found in ST, HIP and cortex of the aged and Sco group suggesting a gradual degeneration of dopaminergic neurons in aged rats. The decreased levels of 125 I-β-CIT and 125 I-IBZM binding in cortex area might be responsible for the amnesia in he Sco group through the dopaminergic pathway of midbrain-frontal cortex

  11. Neuroanatomy-based matrix-guided trimming protocol for the rat brain.

    Science.gov (United States)

    Defazio, Rossella; Criado, Ana; Zantedeschi, Valentina; Scanziani, Eugenio

    2015-02-01

    Brain trimming through defined neuroanatomical landmarks is recommended to obtain consistent sections in rat toxicity studies. In this article, we describe a matrix-guided trimming protocol that uses channels to reproduce coronal levels of anatomical landmarks. Both setup phase and validation study were performed on Han Wistar male rats (Crl:WI(Han)), 10-week-old, with bodyweight of 298 ± 29 (SD) g, using a matrix (ASI-Instruments(®), Houston, TX) fitted for brains of rats with 200 to 400 g bodyweight. In the setup phase, we identified eight channels, that is, 6, 8, 10, 12, 14, 16, 19, and 21, matching the recommended landmarks midway to the optic chiasm, frontal pole, optic chiasm, infundibulum, mamillary bodies, midbrain, middle cerebellum, and posterior cerebellum, respectively. In the validation study, we trimmed the immersion-fixed brains of 60 rats using the selected channels to determine how consistently the channels reproduced anatomical landmarks. Percentage of success (i.e., presence of expected targets for each level) ranged from 89 to 100%. Where 100% success was not achieved, it was noted that the shift in brain trimming was toward the caudal pole. In conclusion, we developed and validated a trimming protocol for the rat brain that allow comparable extensiveness, homology, and relevance of coronal sections as the landmark-guided trimming with the advantage of being quickly learned by technicians. © 2014 by The Author(s).

  12. A role for galanin N-terminal fragment (1-15) in anxiety- and depression-related behaviors in rats.

    Science.gov (United States)

    Millón, Carmelo; Flores-Burgess, Antonio; Narváez, Manuel; Borroto-Escuela, Dasiel O; Santín, Luis; Parrado, Concepción; Narváez, José Angel; Fuxe, Kjell; Díaz-Cabiale, Zaida

    2014-10-31

    Galanin (GAL) plays a role in mood regulation. In this study we analyzed the action of the active N-terminal fragment [GAL(1-15)] in anxiety- and depression-related behavioral tests in rats. The effect of GAL(1-15) was analyzed in the forced swimming test, tail suspension test, open field test, and light/dark test. The proximity of GAL1 and GAL2 receptors was examined with the proximity ligation assay (PLA). We tested the GAL receptors involved in GAL(1-15) effects with the GAL2 receptor antagonist M871 and with an in vivo model of siRNA GAL2 receptor knockdown or siRNA GAL1 receptor knockdown rats. The effects of GAL(1-15) were also studied in the cell line RN33B. GAL(1-15) induced strong depression-like and anxiogenic-like effects in all the tests. These effects were stronger than the ones induced by GAL. The involvement of the GAL2 receptor was demonstrated with M871 and with the siRNA GAL2 receptor knockdown rats. The PLA indicated the possible existence of GAL1 and GAL2 heteroreceptor complexes in the dorsal hippocampus and especially in the dorsal raphe nucleus. In the siRNA GAL1 receptor knockdown rats the behavioral actions of GAL(1-15) disappeared, and in the siRNA GAL2 receptor knockdown rats the reductions of the behavioral actions of GAL(1-15) was linked to a disappearance of PLA. In the cell line RN33B, GAL(1-15) decreased 5-HT immunoreactivity more strongly than GAL. Our results indicate that GAL(1-15) exerts strong depression-related and anxiogenic-like effects and may give the basis for the development of drugs targeting GAL1 and GAL2 heteroreceptor complexes in the raphe-limbic system for the treatment of depression and anxiety. © The Author 2015. Published by Oxford University Press on behalf of CINP.

  13. A Role for Galanin N-Terminal Fragment (1–15) in Anxiety- and Depression-Related Behaviors in Rats

    Science.gov (United States)

    Millón, Carmelo; Flores-Burgess, Antonio; Narváez, Manuel; Borroto-Escuela, Dasiel O.; Santín, Luis; Parrado, Concepción; Narváez, José Angel; Fuxe, Kjell

    2015-01-01

    Background: Galanin (GAL) plays a role in mood regulation. In this study we analyzed the action of the active N-terminal fragment [GAL(1–15)] in anxiety- and depression-related behavioral tests in rats. Methods: The effect of GAL(1–15) was analyzed in the forced swimming test, tail suspension test, open field test, and light/dark test. The proximity of GAL1 and GAL2 receptors was examined with the proximity ligation assay (PLA). We tested the GAL receptors involved in GAL(1–15) effects with the GAL2 receptor antagonist M871 and with an in vivo model of siRNA GAL2 receptor knockdown or siRNA GAL1 receptor knockdown rats. The effects of GAL(1–15) were also studied in the cell line RN33B. Results: GAL(1–15) induced strong depression-like and anxiogenic-like effects in all the tests. These effects were stronger than the ones induced by GAL. The involvement of the GAL2 receptor was demonstrated with M871 and with the siRNA GAL2 receptor knockdown rats. The PLA indicated the possible existence of GAL1 and GAL2 heteroreceptor complexes in the dorsal hippocampus and especially in the dorsal raphe nucleus. In the siRNA GAL1 receptor knockdown rats the behavioral actions of GAL(1–15) disappeared, and in the siRNA GAL2 receptor knockdown rats the reductions of the behavioral actions of GAL(1–15) was linked to a disappearance of PLA. In the cell line RN33B, GAL(1–15) decreased 5-HT immunoreactivity more strongly than GAL. Conclusions: Our results indicate that GAL(1–15) exerts strong depression-related and anxiogenic-like effects and may give the basis for the development of drugs targeting GAL1 and GAL2 heteroreceptor complexes in the raphe-limbic system for the treatment of depression and anxiety. PMID:25522404

  14. Hypoxia-induced increases in serotonin-immunoreactive nerve fibers in the medulla oblongata of the rat.

    Science.gov (United States)

    Morinaga, Ryosuke; Nakamuta, Nobuaki; Yamamoto, Yoshio

    2016-10-01

    Hypoxia induces respiratory responses in mammals and serotonergic neurons in the medulla oblongata participate in respiratory control. However, the morphological changes in serotonergic neurons induced by hypoxia have not yet been examined and respiratory controls of serotonergic neurons have not been clarified. We herein investigated the distribution of immunoreactivity for serotonin (5-hydroxytryptamine; 5-HT) in the medulla oblongata of control rats and rats exposed to 1-6h of hypoxia (10% O 2 ). We also examined the medulla oblongata by multiple immunofluorescence labeling for 5-HT, neurokinin 1 receptors (NK1R), a marker for some respiratory neurons in the pre-Bötzinger complex (PBC), and dopamine β-hydroxylase (DBH), a marker for catecholaminergic neurons. The number of 5-HT-immunoreactive nerve cell bodies in the raphe nuclei was higher in rats exposed to hypoxia than in control rats. The number of 5-HT-immunoreactive nerve fibers significantly increased in the rostral ventrolateral medulla of rats exposed to 1-6h of hypoxia, caudal ventrolateral medulla of rats exposed to 2-6h of hypoxia, and lateral part of the nucleus of the solitary tract and dorsal motor nucleus of the vagus nerve of rats exposed to 1-2h of hypoxia. Multiple immunofluorescence labeling showed that 5-HT-immunoreactive nerve fibers were close to NK1R-immunoreactive neurons in ventrolateral medulla and to DBH-immunoreactive neurons in the medulla. These results suggest that serotonergic neurons partly regulate respiratory control under hypoxic conditions by modulating the activity of NK1R-expressing and catecholaminergic neurons. Copyright © 2016 Elsevier GmbH. All rights reserved.

  15. Top-Down Effect of Direct Current Stimulation on the Nociceptive Response of Rats.

    Directory of Open Access Journals (Sweden)

    Luiz Fabio Dimov

    Full Text Available Transcranial direct current stimulation (tDCS is an emerging, noninvasive technique of neurostimulation for treating pain. However, the mechanisms and pathways involved in its analgesic effects are poorly understood. Therefore, we investigated the effects of direct current stimulation (DCS on thermal and mechanical nociceptive thresholds and on the activation of the midbrain periaqueductal gray (PAG and the dorsal horn of the spinal cord (DHSC in rats; these central nervous system areas are associated with pain processing. Male Wistar rats underwent cathodal DCS of the motor cortex and, while still under stimulation, were evaluated using tail-flick and paw pressure nociceptive tests. Sham stimulation and naive rats were used as controls. We used a randomized design; the assays were not blinded to the experimenter. Immunoreactivity of the early growth response gene 1 (Egr-1, which is a marker of neuronal activation, was evaluated in the PAG and DHSC, and enkephalin immunoreactivity was evaluated in the DHSC. DCS did not change the thermal nociceptive threshold; however, it increased the mechanical nociceptive threshold of both hind paws compared with that of controls, characterizing a topographical effect. DCS decreased the Egr-1 labeling in the PAG and DHSC as well as the immunoreactivity of spinal enkephalin. Altogether, the data suggest that DCS disinhibits the midbrain descending analgesic pathway, consequently inhibiting spinal nociceptive neurons and causing an increase in the nociceptive threshold. This study reinforces the idea that the motor cortex participates in the neurocircuitry that is involved in analgesia and further clarifies the mechanisms of action of tDCS in pain treatment.

  16. Atypical dopamine transporter inhibitors R-modafinil and JHW 007 differentially affect D2 autoreceptor neurotransmission and the firing rate of midbrain dopamine neurons.

    Science.gov (United States)

    Avelar, Alicia J; Cao, Jianjing; Newman, Amy Hauck; Beckstead, Michael J

    2017-09-01

    Abuse of psychostimulants like cocaine that inhibit dopamine (DA) reuptake through the dopamine transporter (DAT) represents a major public health issue, however FDA-approved pharmacotherapies have yet to be developed. Recently a class of ligands termed "atypical DAT inhibitors" has gained attention due to their range of effectiveness in increasing extracellular DA levels without demonstrating significant abuse liability. These compounds not only hold promise as therapeutic agents to treat stimulant use disorders but also as experimental tools to improve our understanding of DAT function. Here we used patch clamp electrophysiology in mouse brain slices to explore the effects of two atypical DAT inhibitors (R-modafinil and JHW 007) on the physiology of single DA neurons in the substantia nigra and ventral tegmental area. Despite their commonalities of being DAT inhibitors that lack cocaine-like behavioral profiles, these compounds exhibited surprisingly divergent cellular effects. Similar to cocaine, R-modafinil slowed DA neuron firing in a D2 receptor-dependent manner and rapidly enhanced the amplitude and duration of D2 receptor-mediated currents in the midbrain. In contrast, JHW 007 exhibited little effect on firing, slow DAT blockade, and an unexpected inhibition of D2 receptor-mediated currents that may be due to direct D2 receptor antagonism. Furthermore, pretreatment with JHW 007 blunted the cellular effects of cocaine, suggesting that it may be valuable to investigate similar DAT inhibitors as potential therapeutic agents. Further exploration of these and other atypical DAT inhibitors may reveal important cellular effects of compounds that will have potential as pharmacotherapies for treating cocaine use disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. A possible role of midbrain dopamine neurons in short- and long-term adaptation of saccades to position-reward mapping.

    Science.gov (United States)

    Takikawa, Yoriko; Kawagoe, Reiko; Hikosaka, Okihide

    2004-10-01

    Dopamine (DA) neurons respond to sensory stimuli that predict reward. To understand how DA neurons acquire such ability, we trained monkeys on a one-direction-rewarded version of memory-guided saccade task (1DR) only when we recorded from single DA neurons. In 1DR, position-reward mapping was changed across blocks of trials. In the early stage of training of 1DR, DA neurons responded to reward delivery; in the later stages, they responded predominantly to the visual cue that predicted reward or no reward (reward predictor) differentially. We found that such a shift of activity from reward to reward predictor also occurred within a block of trials after position-reward mapping was altered. A main effect of long-term training was to accelerate the within-block reward-to-predictor shift of DA neuronal responses. The within-block shift appeared first in the intermediate stage, but was slow, and DA neurons often responded to the cue that indicated reward in the preceding block. In the advanced stage, the reward-to-predictor shift occurred quickly such that the DA neurons' responses to visual cues faithfully matched the current position-reward mapping. Changes in the DA neuronal responses co-varied with the reward-predictive differentiation of saccade latency both in short-term (within-block) and long-term adaptation. DA neurons' response to the fixation point also underwent long-term changes until it occurred predominantly in the first trial within a block. This might trigger a switch between the learned sets. These results suggest that midbrain DA neurons play an essential role in adapting oculomotor behavior to frequent switches in position-reward mapping.

  18. Role of IL-1 beta and 5-HT2 receptors in midbrain periaqueductal gray (PAG) in potentiating defensive rage behavior in cat.

    Science.gov (United States)

    Bhatt, Suresh; Bhatt, Rekha; Zalcman, Steven S; Siegel, Allan

    2008-02-01

    Feline defensive rage, a form of aggressive behavior that occurs in response to a threat can be elicited by electrical stimulation of the medial hypothalamus or midbrain periaqueductal gray (PAG). Our laboratory has recently begun a systematic examination of the role of cytokines in the regulation of rage and aggressive behavior. It was shown that the cytokine, interleukin-2 (IL-2), differentially modulates defensive rage when microinjected into the medial hypothalamus and PAG by acting through separate neurotransmitter systems. The present study sought to determine whether a similar relationship exists with respect to interleukin 1-beta (IL-1 beta), whose receptor activation in the medial hypothalamus potentiates defensive rage. Thus, the present study identified the effects of administration of IL-1 beta into the PAG upon defensive rage elicited from the medial hypothalamus. Microinjections of IL-1 beta into the dorsal PAG significantly facilitated defensive rage behavior elicited from the medial hypothalamus in a dose and time dependent manner. In addition, the facilitative effects of IL-1 beta were blocked by pre-treatment with anti-IL-1 beta receptor antibody, while IL-1 beta administration into the PAG had no effect upon predatory attack elicited from the lateral hypothalamus. The findings further demonstrated that IL-1 beta's effects were mediated through 5-HT(2) receptors since pretreatment with a 5-HT(2C) receptors antagonist blocked the facilitating effects of IL-1 beta. An extensive pattern of labeling of IL-1 beta and 5-HT(2C) receptors in the dorsal PAG supported these findings. The present study demonstrates that IL-beta in the dorsal PAG, similar to the medial hypothalamus, potentiates defensive rage behavior and is mediated through a 5-HT(2C) receptor mechanism.

  19. Electro-acupuncture stimulation acts on the basal ganglia output pathway to ameliorate motor impairment in Parkinsonian model rats.

    Science.gov (United States)

    Jia, Jun; Li, Bo; Sun, Zuo-Li; Yu, Fen; Wang, Xuan; Wang, Xiao-Min

    2010-04-01

    The role of electro-acupuncture (EA) stimulation on motor symptoms in Parkinson's disease (PD) has not been well studied. In a rat hemiparkinsonian model induced by unilateral transection of the medial forebrain bundle (MFB), EA stimulation improved motor impairment in a frequency-dependent manner. Whereas EA stimulation at a low frequency (2 Hz) had no effect, EA stimulation at a high frequency (100 Hz) significantly improved motor coordination. However, neither low nor high EA stimulation could significantly enhance dopamine levels in the striatum. EA stimulation at 100 Hz normalized the MFB lesion-induced increase in midbrain GABA content, but it had no effect on GABA content in the globus pallidus. These results suggest that high-frequency EA stimulation improves motor impairment in MFB-lesioned rats by increasing GABAergic inhibition in the output structure of the basal ganglia.

  20. Effects of chronic fluoxetine treatment on neurogenesis and tryptophan hydroxylase expression in adolescent and adult rats.

    Science.gov (United States)

    Klomp, Anne; Václavů, Lena; Meerhoff, Gideon F; Reneman, Liesbeth; Lucassen, Paul J

    2014-01-01

    The antidepressant drug fluoxetine (Prozac) has been increasingly prescribed to children and adolescents with depressive disorders despite a lack of thorough understanding of its therapeutic effects in the paediatric population and of its putative neurodevelopmental effects. Within the framework of PRIOMEDCHILD ERA-NET, we investigated; a) effects of chronic fluoxetine treatment on adult hippocampal neurogenesis, a structural readout relevant for antidepressant action and hippocampal development; b) effects on tryptophan hydroxylase (TPH) expression, a measure of serotonin synthesis; c) whether treatment effects during adolescence differed from treatment at an adult age, and d) whether they were subregion-specific. Stereological quantification of the number of proliferating (Ki-67+) cells and of the number of young migratory neurons (doublecortin+), revealed a significant age-by-treatment interaction effect, indicating that fluoxetine affects both proliferation and neurogenesis in adolescent-treated rats differently than it does in adult-treated rats. In terms of subregional differences, fluoxetine enhanced proliferation mainly in the dorsal parts of the hippocampus, and neurogenesis in both the suprapyramidal and infrapyramidal blades of the dentate gyrus in adolescent-treated rats, while no such differences were seen in adult-treated rats. Fluoxetine exerted similar age-by-treatment interaction effects on TPH cells mainly in the ventral portion of the dorsal raphe nucleus. We conclude that fluoxetine exerts divergent effects on structural plasticity and serotonin synthesis in adolescent versus adult-treated rats. These preliminary data indicate a differential sensitivity of the adolescent brain to this drug and thus warrant further research into their behavioural and translational aspects. Together with recent related findings, they further call for caution in prescribing these drugs to the adolescent population.

  1. Effects of chronic fluoxetine treatment on neurogenesis and tryptophan hydroxylase expression in adolescent and adult rats.

    Directory of Open Access Journals (Sweden)

    Anne Klomp

    Full Text Available The antidepressant drug fluoxetine (Prozac has been increasingly prescribed to children and adolescents with depressive disorders despite a lack of thorough understanding of its therapeutic effects in the paediatric population and of its putative neurodevelopmental effects. Within the framework of PRIOMEDCHILD ERA-NET, we investigated; a effects of chronic fluoxetine treatment on adult hippocampal neurogenesis, a structural readout relevant for antidepressant action and hippocampal development; b effects on tryptophan hydroxylase (TPH expression, a measure of serotonin synthesis; c whether treatment effects during adolescence differed from treatment at an adult age, and d whether they were subregion-specific. Stereological quantification of the number of proliferating (Ki-67+ cells and of the number of young migratory neurons (doublecortin+, revealed a significant age-by-treatment interaction effect, indicating that fluoxetine affects both proliferation and neurogenesis in adolescent-treated rats differently than it does in adult-treated rats. In terms of subregional differences, fluoxetine enhanced proliferation mainly in the dorsal parts of the hippocampus, and neurogenesis in both the suprapyramidal and infrapyramidal blades of the dentate gyrus in adolescent-treated rats, while no such differences were seen in adult-treated rats. Fluoxetine exerted similar age-by-treatment interaction effects on TPH cells mainly in the ventral portion of the dorsal raphe nucleus. We conclude that fluoxetine exerts divergent effects on structural plasticity and serotonin synthesis in adolescent versus adult-treated rats. These preliminary data indicate a differential sensitivity of the adolescent brain to this drug and thus warrant further research into their behavioural and translational aspects. Together with recent related findings, they further call for caution in prescribing these drugs to the adolescent population.

  2. The 5-HT(1A) receptor agonist, 8-OH-DPAT, attenuates stress-induced anorexia in conjunction with the suppression of hypothalamic serotonin release in rats.

    Science.gov (United States)

    Shimizu, N; Hori, T; Ogino, C; Kawanishi, T; Hayashi, Y

    2000-12-22

    The effect of the selective 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) on stress-induced anorexia and serotonin (5-HT) release in the rat hypothalamus was studied with brain microdialysis. Subcutaneous injection of 8-OH-DPAT (1 mg/kg) significantly attenuated the immobilization-induced anorexia for 3 h, but had no effect during the following 9 h. Injection of 8-OH-DPAT itself had no effect on basal release of 5-HT, while it significantly blocked the immobilization-induced 5-HT release in the lateral hypothalamus. The results suggest that 8-OH-DPAT attenuated the stress-induced anorexia through the activation of 5-HT(1A) autoreceptors in dorsal raphe nucleus.

  3. A blunted anxiolytic like effect of curcumin against acute lead induced anxiety in rat: involvement of serotonin.

    Science.gov (United States)

    Benammi, Hind; El Hiba, Omar; Romane, Abderrahmane; Gamrani, Halima

    2014-06-01

    Anxiety is one of the most common mental disorders sharing extreme or pathological anxiety states as the primary disturbance in mood or emotional tone, with increased fear and exaggerated acute stress responses. Medicinal plants are very variable, but some of them are used as a spice such as curcumin (Curcuma longa). Curcumin shows a wide range of pharmacological potentialities, however, little is known about its anxiolytic properties. The aim of our study was to assess the anti-anxiety potential of curcumin extract against experimental lead induced-anxiety in rats. Experiments were carried out on male Wistar rats intoxicated acutely with an intraperitoneal injection of Pb (25mg/kg B.W.) and/or concomitantly with administration of curcumin (30 mg/kg B.W.) for 3 days. Using immunohistochemistry and anxiety assessment tests (dark light box and elevated plus maze), we evaluated, respectively, the expression of serotonin (5HT) in the dorsal raphe nucleus (DRN) and the anxiety state in our animals. Our results showed, for the first time, a noticeable anxiolytic effect of curcumin against lead induced anxiety in rats and this may possibly result from modulation of central neuronal monoaminergic neurotransmission, especially serotonin, which has shown a significant reduction of the immunoreactivity within the DRN. Copyright © 2014 Elsevier GmbH. All rights reserved.

  4. Cortico-pontine theta carrier frequency phase shift across sleep/wake states following monoaminergic lesion in rat.

    Science.gov (United States)

    Kalauzi, Aleksandar; Spasic, Sladjana; Petrovic, Jelena; Ciric, Jelena; Saponjic, Jelena

    2012-06-01

    This study was aimed to explore the sleep/wake states related cortico-pontine theta carrier frequency phase shift following a systemically induced chemical axotomy of the monoaminergic afferents within a brain of the freely moving rats. Our experiments were performed in 14 adult, male Sprague Dawley rats, chronically implanted for sleep recording. We recorded sleep during baseline condition, following sham injection (saline i.p. 1 ml/kg), and every week for 5 weeks following injection of the systemic neurotoxins (DSP-4 or PCA; 1 ml/kg, i.p.) for chemical axotomy of the locus coeruleus (LC) and dorsal raphe (DR) axon terminals. After sleep/wake states identification, FFT analysis was performed on 5 s epochs. Theta carrier frequency phase shift (∆Φ) was calculated for each epoch by averaging theta Fourier component phase shifts, and the ∆Φ values were plotted for each rat in control condition and 28 days following the monoaminergic lesions, as a time for permanently established DR or LC chemical axotomy. Calculated group averages have shown that ∆Φ increased between pons and cortex significantly in all sleep/wake states (Wake, NREM and REM) following the monoaminergic lesions, with respect to controls. Monoaminergic lesions established the pontine leading role in the brain theta oscillations during all sleep/wake states.

  5. Expression of TASK-1 in brainstem and the occurrence of central sleep apnea in rats.

    Science.gov (United States)

    Wang, Jing; Zhang, Cheng; Li, Nan; Su, Li; Wang, Guangfa

    2008-03-20

    Recent studies revealed that unstable ventilation control is one of mechanisms underlying the occurrence of sleep apnea. Thus, we investigated whether TASK-1, an acid-sensitive potassium channel, plays a role in the occurrence of sleep apnea. First, the expression of TASK-1 transcriptions on brainstem was checked by in situ hybridization. Then, the correlation between the central apneic episodes and protein contents of TASK-1 measured by western blot was analyzed from 27 male rats. Results showed that TASK-1 mRNAs were widely distributed on the putative central chemoreceptors such as locus coeruleus, nucleus tractus solitarius and medullary raphe, etc. Both the total spontaneous apnea index (TSAI) and spontaneous apnea index in NREM sleep (NSAI) were positively correlated with TASK-1 protein contents (r=0.547 and 0.601, respectively, p<0.01). However, the post-sigh sleep apnea index (PAI) had no relationship with TASK-1 protein. Thus, we concluded that TASK-1 channels may function as central chemoreceptors that play a role in spontaneous sleep apneas in rats.

  6. The Effects of Insulin-Induced Hypoglycaemia on Tyrosine Hydroxylase Phosphorylation in Rat Brain and Adrenal Gland.

    Science.gov (United States)

    Senthilkumaran, Manjula; Johnson, Michaela E; Bobrovskaya, Larisa

    2016-07-01

    In this study we investigated the effects of insulin-induced hypoglycaemia on tyrosine hydroxylase (TH) protein and TH phosphorylation in the adrenal gland, C1 cell group, locus coeruleus (LC) and midbrain dopaminergic cell groups that are thought to play a role in response to hypoglycaemia and compared the effects of different concentrations of insulin in rats. Insulin (1 and 10 U/kg) treatment caused similar reductions in blood glucose concentration (from 7.5-9 to 2-3 mmol/L); however, plasma adrenaline concentration was increased 20-30 fold in response to 10 U/kg insulin and only 14 fold following 1 U/kg. Time course studies (at 10 U/kg insulin) revealed that in the adrenal gland, Ser31 phosphorylation was increased between 30 and 90 min (4-5 fold), implying that TH was activated to increase catecholamine synthesis in adrenal medulla to replenish the stores. In the brain, Ser19 phosphorylation was limited to certain dopaminergic groups in the midbrain, while Ser31 phosphorylation was increased in most catecholaminergic regions at 60 min (1.3-2 fold), suggesting that Ser31 phosphorylation may be an important mechanism to maintain catecholamine synthesis in the brain. Comparing the effects of 1 and 10 U/kg insulin revealed that Ser31 phosphorylation was increased to similar extent in the adrenal gland and C1 cell group in response to both doses whereas Ser31 and Ser19 phosphorylation were only increased in response to 1 U/kg insulin in LC and in response to 10 U/kg insulin in most midbrain regions. Thus, the adrenal gland and some catecholaminergic brain regions become activated in response to insulin administration and brain catecholamines may be important for initiation of physiological defences against insulin-induced hypoglycaemia.

  7. The rostromedial tegmental nucleus is essential for non-rapid eye movement sleep.

    Directory of Open Access Journals (Sweden)

    Su-Rong Yang

    2018-04-01

    Full Text Available The rostromedial tegmental nucleus (RMTg, also called the GABAergic tail of the ventral tegmental area, projects to the midbrain dopaminergic system, dorsal raphe nucleus, locus coeruleus, and other regions. Whether the RMTg is involved in sleep-wake regulation is unknown. In the present study, pharmacogenetic activation of rat RMTg neurons promoted non-rapid eye movement (NREM sleep with increased slow-wave activity (SWA. Conversely, rats after neurotoxic lesions of 8 or 16 days showed decreased NREM sleep with reduced SWA at lights on. The reduced SWA persisted at least 25 days after lesions. Similarly, pharmacological and pharmacogenetic inactivation of rat RMTg neurons decreased NREM sleep. Electrophysiological experiments combined with optogenetics showed a direct inhibitory connection between the terminals of RMTg neurons and midbrain dopaminergic neurons. The bidirectional effects of the RMTg on the sleep-wake cycle were mimicked by the modulation of ventral tegmental area (VTA/substantia nigra compacta (SNc dopaminergic neuronal activity using a pharmacogenetic approach. Furthermore, during the 2-hour recovery period following 6-hour sleep deprivation, the amount of NREM sleep in both the lesion and control rats was significantly increased compared with baseline levels; however, only the control rats showed a significant increase in SWA compared with baseline levels. Collectively, our findings reveal an essential role of the RMTg in the promotion of NREM sleep and homeostatic regulation.

  8. Application of the Physical Disector Principle for Quantification of Dopaminergic Neuronal Loss in a Rat 6-Hydroxydopamine Nigral Lesion Model of Parkinson's Disease

    Directory of Open Access Journals (Sweden)

    Katrine Fabricius

    2017-12-01

    Full Text Available Stereological analysis is the optimal tool for quantitative assessment of brain morphological and cellular changes induced by neurotoxic lesions or treatment interventions. Stereological methods based on random sampling techniques yield unbiased estimates of particle counts within a defined volume, thereby providing a true quantitative estimate of the target cell population. Neurodegenerative diseases involve loss of specific neuron types, such as the midbrain tyrosine hydroxylase-positive dopamine neurons in Parkinson's disease and in animal models of nigrostriatal degeneration. Therefore, we applied an established automated physical disector principle in a fractionator design for efficient stereological quantitative analysis of tyrosine hydroxylase (TH-positive dopamine neurons in the substantia nigra pars compacta of hemiparkinsonian rats with unilateral 6-hydroxydopamine (6-OHDA lesions. We obtained reliable estimates of dopamine neuron numbers, and established the relationship between behavioral asymmetry and dopamine neuron loss on the lesioned side. In conclusion, the automated physical disector principle provided a useful and efficient tool for unbiased estimation of TH-positive neurons in rat midbrain, and should prove valuable for investigating neuroprotective strategies in 6-OHDA model of parkinsonism, while generalizing to other immunohistochemically-defined cell populations.

  9. Dorsal periaqueductal gray stimulation facilitates anxiety-, but not panic-related, defensive responses in rats tested in the elevated T-maze

    International Nuclear Information System (INIS)

    Camplesi, M. Jr.; Bortoli, V.C. de; Paula Soares, V. de; Nogueira, R.L.; Zangrossi, H. Jr.

    2012-01-01

    The escape response to electrical or chemical stimulation of the dorsal periaqueductal gray matter (DPAG) has been associated with panic attacks. In order to explore the validity of the DPAG stimulation model for the study of panic disorder, we determined if the aversive consequences of the electrical or chemical stimulation of this midbrain area can be detected subsequently in the elevated T-maze. This animal model, derived from the elevated plus-maze, permits the measurement in the same rat of a generalized anxiety- and a panic-related defensive response, i.e., inhibitory avoidance and escape, respectively. Facilitation of inhibitory avoidance, suggesting an anxiogenic effect, was detected in male Wistar rats (200-220 g) tested in the elevated T-maze 30 min after DPAG electrical stimulation (current generated by a sine-wave stimulator, frequency at 60 Hz) or after local microinjection of the GABA A receptor antagonist bicuculline (5 pmol). Previous electrical (5, 15, 30 min, or 24 h before testing) or chemical stimulation of this midbrain area did not affect escape performance in the elevated T-maze or locomotion in an open-field. No change in the two behavioral tasks measured by the elevated T-maze was observed after repetitive (3 trials) electrical stimulation of the DPAG. The results indicate that activation of the DPAG caused a short-lived, but selective, increase in defensive behaviors associated with generalized anxiety

  10. Dorsal periaqueductal gray stimulation facilitates anxiety-, but not panic-related, defensive responses in rats tested in the elevated T-maze

    Energy Technology Data Exchange (ETDEWEB)

    Camplesi, M. Jr. [Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, GO (Brazil); Bortoli, V.C. de [Departamento de Ciências da Saúde, Centro Universitário Norte do Espírito Santo, Universidade Federal do Espírito Santo, São Mateus, ES (Brazil); Paula Soares, V. de [Departamento de Biofísica e Farmacologia, Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, RN (Brazil); Nogueira, R.L. [Laboratório de Psicologia Comparada, Universidade Estácio de Sá, Rio de Janeiro, RJ (Brazil); Zangrossi, H. Jr. [Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil)

    2012-08-03

    The escape response to electrical or chemical stimulation of the dorsal periaqueductal gray matter (DPAG) has been associated with panic attacks. In order to explore the validity of the DPAG stimulation model for the study of panic disorder, we determined if the aversive consequences of the electrical or chemical stimulation of this midbrain area can be detected subsequently in the elevated T-maze. This animal model, derived from the elevated plus-maze, permits the measurement in the same rat of a generalized anxiety- and a panic-related defensive response, i.e., inhibitory avoidance and escape, respectively. Facilitation of inhibitory avoidance, suggesting an anxiogenic effect, was detected in male Wistar rats (200-220 g) tested in the elevated T-maze 30 min after DPAG electrical stimulation (current generated by a sine-wave stimulator, frequency at 60 Hz) or after local microinjection of the GABA{sub A} receptor antagonist bicuculline (5 pmol). Previous electrical (5, 15, 30 min, or 24 h before testing) or chemical stimulation of this midbrain area did not affect escape performance in the elevated T-maze or locomotion in an open-field. No change in the two behavioral tasks measured by the elevated T-maze was observed after repetitive (3 trials) electrical stimulation of the DPAG. The results indicate that activation of the DPAG caused a short-lived, but selective, increase in defensive behaviors associated with generalized anxiety.

  11. Effect of salvia Egyptiaca extract on cholinergic system in adult male albino rats

    International Nuclear Information System (INIS)

    Abdel Kader, S.M.

    2004-01-01

    The daily oral administrations of Salvia aegyptiaca extract, equivalent to 2 g/kg body weight for 4 weeks, caused significant decrease in acetylcholine esterase activity in whole blood and in all tested brain areas (cerebellum, pons + medulla oblongata, striatum, cerebral cortex, hypothalamus, midbrain and hippocampus) of male albino rat nearly all over the experimental period. Treatment with Salvia aegyptiaca extract also resulted in significant increase in acetylcholine content in the cerebral cortex and hippocampus' nearly throughout the whole experimental period. It could be concluded from the present results that the extract of Salvia aegyptiaca caused an increase in acetylcholine content and this increase may be due to the decrease in the activity of acetylcholine esterase enzyme which play an important role in the treatment of Alzheimer's disease

  12. Omega-3 fatty acid deficient male rats exhibit abnormal behavioral activation in the forced swim test following chronic fluoxetine treatment: association with altered 5-HT1A and alpha2A adrenergic receptor expression.

    Science.gov (United States)

    Able, Jessica A; Liu, Yanhong; Jandacek, Ronald; Rider, Therese; Tso, Patrick; McNamara, Robert K

    2014-03-01

    Omega-3 fatty acid deficiency during development leads to enduing alterations in central monoamine neurotransmission in rat brain. Here we investigated the effects of omega-3 fatty acid deficiency on behavioral and neurochemical responses to chronic fluoxetine (FLX) treatment. Male rats were fed diets with (CON, n = 34) or without (DEF, n = 30) the omega-3 fatty acid precursor alpha-linolenic acid (ALA) during peri-adolescent development (P21-P90). A subset of CON (n = 14) and DEF (n = 12) rats were administered FLX (10 mg/kg/d) through their drinking water for 30 d beginning on P60. The forced swimming test (FST) was initiated on P90, and regional brain mRNA markers of serotonin and noradrenaline neurotransmission were determined. Dietary ALA depletion led to significant reductions in frontal cortex docosahexaenoic acid (DHA, 22:6n-3) composition in DEF (-26%, p = 0.0001) and DEF + FLX (-32%, p = 0.0001) rats. Plasma FLX and norfluoxetine concentrations did not different between FLX-treated DEF and CON rats. During the 15-min FST pretest, DEF + FLX rats exhibited significantly greater climbing behavior compared with CON + FLX rats. During the 5-min test trial, FLX treatment reduced immobility and increased swimming in CON and DEF rats, and only DEF + FLX rats exhibited significant elevations in climbing behavior. DEF + FLX rats exhibited greater midbrain, and lower frontal cortex, 5-HT1A mRNA expression compared with all groups including CON + FLX rats. DEF + FLX rats also exhibited greater midbrain alpha2A adrenergic receptor mRNA expression which was positively correlated with climbing behavior in the FST. These preclinical data demonstrate that low omega-3 fatty acid status leads to abnormal behavioral and neurochemical responses to chronic FLX treatment in male rats. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Opiate antagonist binding sites in discrete brain regions of spontaneously hypertensive and normotensive Wistar-Kyoto rats

    International Nuclear Information System (INIS)

    Rahmani, N.H.; Gulati, A.; Bhargava, H.N.

    1991-01-01

    The binding of 3 H-naltrexone, an opiate receptor antagonist, to membranes of discrete brain regions and spinal cord of 10 week old spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats was determined. The brain regions examined were hypothalamus, amygdala, hippocampus, corpus striatum, pons and medulla, midbrain and cortex. 3 H-Naltrexone bound to membranes of brain regions and spinal cord at a single high affinity site with an apparent dissociation constant value of 3 nM. The highest density of 3 H-naltrexone binding sites were in hippocampus and lowest in the cerebral cortex. The receptor density (B max value) and apparent dissociation constant (K d value) values of 3 H-naltrexone to bind to opiate receptors on the membranes of amygdala, hippocampus, corpus striatum, pons and medulla, midgrain, cortex and spinal cord of WKY and SHR rates did not differ. The B max value of 3 H-naltrexone binding to membranes of hypothalamus of SHR rates was 518% higher than WKY rats but the K d values in the two strains did not differ. It is concluded that SHR rats have higher density of opiate receptors labeled with 3 H-naltrexone in the hypothalamus only, in comparison with WKY rats, and that such a difference in the density of opiate receptors may be related to the elevated blood pressure in SHR rats

  14. Opiate antagonist binding sites in discrete brain regions of spontaneously hypertensive and normotensive Wistar-Kyoto rats

    Energy Technology Data Exchange (ETDEWEB)

    Rahmani, N.H.; Gulati, A.; Bhargava, H.N. (Univ. of Illinois, Chicago (USA))

    1991-01-01

    The binding of {sup 3}H-naltrexone, an opiate receptor antagonist, to membranes of discrete brain regions and spinal cord of 10 week old spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats was determined. The brain regions examined were hypothalamus, amygdala, hippocampus, corpus striatum, pons and medulla, midbrain and cortex. {sup 3}H-Naltrexone bound to membranes of brain regions and spinal cord at a single high affinity site with an apparent dissociation constant value of 3 nM. The highest density of {sup 3}H-naltrexone binding sites were in hippocampus and lowest in the cerebral cortex. The receptor density (B{sub max}value) and apparent dissociation constant (K{sub d} value) values of {sup 3}H-naltrexone to bind to opiate receptors on the membranes of amygdala, hippocampus, corpus striatum, pons and medulla, midgrain, cortex and spinal cord of WKY and SHR rates did not differ. The B{sub max} value of {sup 3}H-naltrexone binding to membranes of hypothalamus of SHR rates was 518% higher than WKY rats but the K{sub d} values in the two strains did not differ. It is concluded that SHR rats have higher density of opiate receptors labeled with {sup 3}H-naltrexone in the hypothalamus only, in comparison with WKY rats, and that such a difference in the density of opiate receptors may be related to the elevated blood pressure in SHR rats.

  15. Early life stress elicits visceral hyperalgesia and functional reorganization of pain circuits in adult rats

    Directory of Open Access Journals (Sweden)

    D.P. Holschneider

    2016-06-01

    Full Text Available Early life stress (ELS is a risk factor for developing functional gastrointestinal disorders, and has been proposed to be related to a central amplification of sensory input and resultant visceral hyperalgesia. We sought to characterize ELS-related changes in functional brain responses during acute noxious visceral stimulation. Neonatal rats (males/females were exposed to limited bedding (ELS or standard bedding (controls on postnatal days 2–9. Age 10–11 weeks, animals were implanted with venous cannulas and transmitters for abdominal electromyography (EMG. Cerebral blood flow (rCBF was mapped during colorectal distension (CRD using [14C]-iodoantipyrine autoradiography, and analyzed in three-dimensionally reconstructed brains by statistical parametric mapping and functional connectivity. EMG responses to CRD were increased after ELS, with no evidence of a sex difference. ELS rats compared to controls showed a greater significant positive correlation of EMG with amygdalar rCBF. Factorial analysis revealed a significant main effect of ‘ELS’ on functional activation of nodes within the pain pathway (somatosensory, insular, cingulate and prefrontal cortices, locus coeruleus/lateral parabrachial n. [LC/LPB], periaqueductal gray, sensory thalamus, as well as in the amygdala, hippocampus and hypothalamus. In addition, ELS resulted in an increase in the number of significant functional connections (i.e. degree centrality between regions within the pain circuit, including the amygdala, LC/LPB, insula, anterior ventral cingulate, posterior cingulate (retrosplenium, and stria terminalis, with decreases noted in the sensory thalamus and the hippocampus. Sex differences in rCBF were less broadly expressed, with significant differences noted at the level of the cortex, amygdala, dorsal hippocampus, raphe, sensory thalamus, and caudate-putamen. ELS showed a sexually dimorphic effect (‘Sex x ELS’ interaction at the LC/LPB complex, globus pallidus

  16. [123I]Epidepride neuroimaging of dopamine D2/D3 receptor in chronic MK-801-induced rat schizophrenia model

    International Nuclear Information System (INIS)

    Huang, Yuan-Ruei; Shih, Jun-Ming; Chang, Kang-Wei; Huang, Chieh; Wu, Yu-Lung; Chen, Chia-Chieh

    2012-01-01

    Purpose: [ 123 I]Epidepride is a radio-tracer with very high affinity for dopamine D 2 /D 3 receptors in brain. The importance of alteration in dopamine D 2 /D 3 receptor binding condition has been wildly verified in schizophrenia. In the present study we set up a rat schizophrenia model by chronic injection of a non-competitive NMDA receptor antagonist, MK-801, to examine if [ 123 I]epidepride could be used to evaluate the alterations of dopamine D 2 /D 3 receptor binding condition in specific brain regions. Method: Rats were given repeated injection of MK-801 (dissolved in saline, 0.3 mg/kg) or saline for 1 month. Afterwards, total distance traveled (cm) and social interaction changes were recorded. Radiochemical purity of [ 123 I]epidepride was analyzed by Radio-Thin-Layer Chromatography (chloroform: methanol, 9:1, v/v) and [ 123 I]epidepride neuroimages were obtained by ex vivo autoradiography and small animal SPECT/CT. Data obtained were then analyzed to determine the changes of specific binding ratio. Result: Chronic MK-801 treatment for a month caused significantly increased local motor activity and induced an inhibition of social interaction. As shown in [ 123 I]epidepride ex vivo autoradiographs, MK-801 induced a decrease of specific binding ratio in the striatum (24.01%), hypothalamus (35.43%), midbrain (41.73%) and substantia nigra (37.93%). In addition, [ 123 I]epidepride small animal SPECT/CT neuroimaging was performed in the striatum and midbrain. There were statistically significant decreases in specific binding ratio in both the striatum (P 123 I]epidepride is a useful radio-tracer to reveal the alterations of dopamine D 2 /D 3 receptor binding in a rat schizophrenia model and is also helpful to evaluate therapeutic effects of schizophrenia in the future.

  17. Bilateral lesions of the medial frontal cortex disrupt recognition of social hierarchy during antiphonal communication in naked mole-rats (Heterocephalus glaber).

    Science.gov (United States)

    Yosida, Shigeto; Okanoya, Kazuo

    2012-02-01

    Generation of the motor patterns of emotional sounds in mammals occurs in the periaqueductal gray matter of the midbrain and is not directly controlled by the cortex. The medial frontal cortex indirectly controls vocalizations, based on the recognition of social context. We examined whether the medial frontal cortex was responsible for antiphonal vocalization, or turn-taking, in naked mole-rats. In normal turn-taking, naked mole-rats vocalize more frequently to dominant individuals than to subordinate ones. Bilateral lesions of the medial frontal cortex disrupted differentiation of call rates to the stimulus animals, which had varied social relationships to the subject. However, medial frontal cortex lesions did not affect either the acoustic properties of the vocalizations or the timing of the vocal exchanges. This suggests that the medial frontal cortex may be involved in social cognition or decision making during turn-taking, while other regions of the brain regulate when animals vocalize and the vocalizations themselves.

  18. treated rats

    African Journals Online (AJOL)

    aghomotsegin

    2014-01-08

    Jan 8, 2014 ... nucleus, bizarre segmentation; (I) shows hypersegmentation, bizarre segmentation of neutrophils in the shape of ring nucleus with polychromatophilic RBCs. 1998; Muller and Tobin, 1980). The current study shows that rats administered C. edulis hydro-ethanol extract, orally for 28 days, developed anemia, ...

  19. Studies on the role of serotonin receptor subtypes in the effect of sibutramine in various feeding paradigms in rats

    Science.gov (United States)

    Grignaschi, G; Fanelli, E; Scagnol, I; Samanin, R

    1999-01-01

    The effect of the 5-hydroxytryptamine (5-HT) and noradrenaline (NA) reuptake inhibitor sibutramine was studied in food deprived, neuropeptide Y (NPY)- or muscimol-injected rats. Sibutramine dose-dependently reduced feeding caused by food-deprivation (ED50=5.1±0.8 mg kg−1) or by NPY injection into the paraventricular nucleus of the hypothalamus (ED50=6.0±0.5 mg kg−1). The increase in food intake caused by muscimol injected into the dorsal raphe was not modified by sibutramine (1–10 mg kg−1). The hypophagic effect of 5.1 mg kg−1 sibutramine in food-deprived rats was studied in rats pretreated with different serotonin receptor antagonists. Metergoline (non-selective, 0.3 and 1.0 mg kg−1), ritanserin (5-HT2A/2C, 0.5 and 1.0 mg kg−1) and GR127935 (5-HT1B/1D, 0.5 and 1.0 mg kg−1) did not modify the hypophagic effect of sibutramine, while SB206553 (5-HT2B/2C, 5 and 10 mg kg−1) slightly but significantly reduced it (Fint(2.53)=3.4; Psibutramine in NPY-injected rats was not modified by GR127935 (1.0 mg kg−1). The results suggest that, with the possible exception of a partial involvement of 5-HT2B/2C receptors in sibutramine's hypophagia in food-deprived rats, 5-HT1 and 5-HT2 receptor subtypes do not play an important role in the hypophagic effect of sibutramine, at least in the first 2 h after injection. PMID:10455265

  20. Differentiated cells derived from fetal neural stem cells improve motor deficits in a rat model of Parkinson’s disease

    Institute of Scientific and Technical Information of China (English)

    Wei Wang; Hao Song; Aifang Shen; Chao Chen; Yanming Liu; Yabing Dong; Fabin Han

    2015-01-01

    Objective: Parkinson’s disease(PD), which is one of the most common neuro‐degenerative disorders, is characterized by the loss of dopamine(DA) neurons in the substantia nigra in the midbrain. Experimental and clinical studies have shown that fetal neural stem cells(NSCs) have therapeutic effects in neurological disorders. The aim of this study was to examine whether cells that were differentiated from NSCs had therapeutic effects in a rat model of PD. Methods: NSCs were isolated from 14‐week‐old embryos and induced to differentiate into neurons, DA neurons, and glial cells, and these cells were characterized by their expression of the following markers: βⅢ‐tubulin and microtubule‐associated protein 2(neurons), tyrosine hydroxylase(DA neurons), and glial fibrillary acidic protein(glial cells). After a 6‐hydroxydopamine(6‐OHDA)‐lesioned rat model of PD was generated, the differentiated cells were transplanted into the striata of the 6‐OHDA‐lesioned PD rats. Results: The motor behaviors of the PD rats were assessed by the number of apomorphine‐induced rotation turns. The results showed that the NSCs differentiated in vitro into neurons and DA neurons with high efficiencies. After transplantation into the striata of the PD rats, the differentiated cells significantly improved the motor deficits of the transplanted PD rats compared to those of the control nontransplanted PD rats by decreasing the apomorphine‐induced turn cycles as early as 4 weeks after transplantation. Immunofluorescence analyses showed that the differentiated DA neurons survived more than 16 weeks. Conclusions: Our results showed that cells that were differentiated from NSCs had therapeutic effects in a rat PD model, which suggests that differentiated cells may be an effective treatment for patients with PD.

  1. ECoG sleep-waking rhythms and bodily activity in the cerveau isolé rat.

    Science.gov (United States)

    Nakata, K; Kawamura, H

    1986-01-01

    In rats with a high mesencephalic transection, isolating both the locus coeruleus and raphe nuclei from the forebrain, Electrocorticogram (ECoG) and Electromyogram (EMG) of the neck muscles were continuously recorded. Normal sleep-waking ECoG changes with a significant circadian rhythm reappeared in 4 to 9 days after transection. Neck muscle EMG and bodily movements were independent of the ECoG changes and did not show any significant circadian rhythm. In these high mesencephalic rats with sleep-waking ECoG changes, large bilateral hypothalamic lesions were made by passing DC current either in the preoptic area or in the posterior hypothalamus. After the preoptic area lesions the amount of low voltage fast ECoG per day markedly increased, whereas after the posterior hypothalamic lesions, the total amount of low voltate fast wave per day decreased showing long-lasting slow wave sleep pattern. These results support an idea that the forebrain, especially in the hypothalamus including the preoptic area, a mechanism inducing sleep-waking ECoG changes is localized.

  2. Regional brain distribution of toluene in rats and in a human autopsy

    Energy Technology Data Exchange (ETDEWEB)

    Ameno, Kiyoshi; Kiriu, Takahiro; Fuke, Chiaki; Ameno, Setsuko; Shinohara, Toyohiko; Ijiri, Iwao (Kagawa Medical School (Japan). Dept. of Forensic Medicine)

    1992-02-01

    Toluene concentrations in 9 brain regions of acutely exposed rats and that in 11 brain regions of a human case who inhaled toluene prior to death are described. After exposure to toluene by inhalation (2000 or 10 000 ppm) for 0.5 h or by oral dosing (400 mg/kg.), rats were killed by decapitation 0.5 and 4 h after onset of inhalation and 2 and 10 h after oral ingestion. After each experimental condition the highest range of brain region/blood toluene concentration ratio (BBCR) was in the brain stem regions (2.85-3.22) such as the pons and medulla oblongata, the middle range (1.77-2.12) in the midbrain, thalamus, caudate-putamen, hypothalamus and cerebellum, and the lowest range (1.22-1.64) in the hippocampus and cerebral cortex. These distribution patterns were quite constant. Toluene concentration in various brain regions were unevenly distributed and directly related blood levels. In a human case who had inhaled toluene vapor, the distribution among brain regions was relatively similar to that in rats, the highest concentration ratios being in the corpus callosum (BBCR:2.66) and the lowest in the hippocampus (BBCR:1.47). (orig.).

  3. Effect of cadmium exposure on lipids, lipid peroxidation and metal distribution in rat brain regions

    Energy Technology Data Exchange (ETDEWEB)

    Hussain, T; Ali, M M; Chandra, S V

    1985-01-01

    Effect of cadmium treatment on brain lipids, lipid peroxidation and distribution of Zn, Cu and Fe in rat brain regions was investigated. Adult male rats were exposed to Cd (100 ppm Cd as cadmium acetate) in drinking water for 30 days. The Cd exposure resulted in a significant decrease in the phospholipid content and an increase in the lipid peroxidation in the cerebral cortex and cerebellum. The total lipid content was not affected in any of the regions but a significant decrease in cholesterol and cerebroside contents were observed only in the cerebral cortex. A positive correlation between the increase in lipid peroxidation and decrease in the phospholipid content in the cerebral cortex and cerebellum was observed. A maximum accumulation of Cd occurred in the cerebral cortex. The Cu and Fe contents were significantly increased but the Zn levels decreased in the Cd-treated rats in all but the midbrain region. Results suggest that the increased peroxidation decomposition of structural lipids and the altered distribution of the essential trace metals in brain may play a significant role in Cd-induced neurotoxicity. 27 references, 2 tables.

  4. Behavioural and neurotoxic effects of ayahuasca infusion (Banisteriopsis caapi and Psychotria viridis) in female Wistar rat.

    Science.gov (United States)

    Pic-Taylor, Aline; da Motta, Luciana Gueiros; de Morais, Juliana Alves; Junior, Willian Melo; Santos, Alana de Fátima Andrade; Campos, Leandro Ambrósio; Mortari, Marcia Renata; von Zuben, Marcus Vinicius; Caldas, Eloisa Dutra

    2015-09-01

    Ayahuasca, a psychoactive beverage used by indigenous and religious groups, is generally prepared by the coction of Psychotria viridis and Banisteriopsis caapi plants containing N,N-dimethyltryptamine (DMT) and β-carboline alkaloids, respectively. To investigate the acute toxicity of ayahuasca, the infusion was administered by gavage to female Wistar rats at doses of 30X and 50X the dose taken during a religious ritual, and the animals observed for 14 days. Behavioural functions were investigated one hour after dosing at 15X and 30X using the open field, elevated plus maze, and forced swimming tests. Neuronal activation (c-fos marked neurons) and toxicity (Fluoro-Jade B and Nissl/Cresyl staining) were investigated in the dorsal raphe nuclei (DRN), amygdaloid nucleus, and hippocampal formation brain areas of rats treated with a 30X ayahuasca dose. The actual lethal oral dose in female Wistar rats could not be determined in this study, but was shown to be higher than the 50X (which corresponds to 15.1mg/kg bw DMT). The ayahuasca and fluoxetine treated groups showed a significant decrease in locomotion in the open field and elevated plus-maze tests compared to controls. In the forced swimming test, ayahuasca treated animals swam more than controls, a behaviour that was not significant in the fluoxetine group. Treated animals showed higher neuronal activation in all brain areas involved in serotoninergic neurotransmission. Although this led to some brain injury, no permanent damage was detected. These results suggest that ayahuasca has antidepressant properties in Wistar female at high doses, an effect that should be further investigated. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Autoradiographic localization of 3H-paroxetine-labeled serotonin uptake sites in rat brain

    International Nuclear Information System (INIS)

    De Souza, E.B.; Kuyatt, B.L.

    1987-01-01

    Paroxetine is a potent and selective inhibitor of serotonin uptake into neurons. Serotonin uptake sites have been identified, localized, and quantified in rat brain by autoradiography with 3H-paroxetine; 3H-paroxetine binding in slide-mounted sections of rat forebrain was of high affinity (KD = 10 pM) and the inhibition affinity constant (Ki) values of various drugs in competing 3H-paroxetine binding significantly correlated with their reported potencies in inhibiting synaptosomal serotonin uptake. Serotonin uptake sites labeled by 3H-paroxetine were highly concentrated in the dorsal and median raphe nuclei, central gray, superficial layer of the superior colliculus, lateral septal nucleus, paraventricular nucleus of the thalamus, and the islands of Calleja. High concentrations of 3H-paroxetine binding sites were found in brainstem areas containing dopamine (substantia nigra and ventral tegmental area) and norepinephrine (locus coeruleus) cell bodies. Moderate concentrations of 3H-paroxetine binding sites were present in laminae I and IV of the frontal parietal cortex, primary olfactory cortex, olfactory tubercle, regions of the basal ganglia, septum, amygdala, thalamus, hypothalamus, hippocampus, and some brainstem areas including the interpeduncular, trigeminal, and parabrachial nuclei. Lower densities of 3H-paroxetine binding sites were found in other regions of the neocortex and very low to nonsignificant levels of binding were present in white matter tracts and in the cerebellum. Lesioning of serotonin neurons with 3,4-methylenedioxyamphetamine caused large decreases in 3H-paroxetine binding. The autoradiographic distribution of 3H-paroxetine binding sites in rat brain corresponds extremely well to the distribution of serotonin terminals and cell bodies as well as with the pharmacological sites of action of serotonin

  6. Significance of local cerebral glucose utilization determined by the autoradiographic (/sup 14/C)deoxyglucose method in experimentally induced coma

    Energy Technology Data Exchange (ETDEWEB)

    Sakurada, O.; Kobayashi, M.; Ueno, H.; Ishii, S. (Juntendo Univ., Tokyo (Japan). School of Medicine)

    1982-01-01

    Bilateral lesions made in the midbrain reticular formation of the rat produced behavioral akinesia. These animals neither ate nor drank. EEGs of these animals usually showed high voltage slow waves at rest. Slight EEG arousal response was demonstrated by clapping, touching and pinching only in rats with moderate impairment. Concerning the rates of local cerebral glucose utilization (LCGU) measured by means of the autoradiographic (/sup 14/C) deoxyglucose method, 13 structures exhibited significant reductions in 28 gray structures examined when compared with sham operated rats. Lesions in the midbrain reticular formation resulted in reduction of LCGU in the neocortex, ventral nucleus of the thalamus, subthalamic nucleus, and medial and lateral geniculated bodies, mamillary body, septal nucleus and caudateputamen. Structures which did not show any significant change in LCGU were those related to the paleo and archi-cortices. These findings suggest the existence of two types of ascending activating systems. Administration of 30 mg/kg of pentobarbital reduced LCGU diffusely throughout the brain. When thyrotropin releasing hormone (TRH) was administered to rats with lesions in the midbrain reticular formation, reversal of the reduction of LCGU was observed in the dorsomedial nucleus of the thalamus and the mamillary body. Reversal of LCGU in the dorsomedial nucleus of thalamus was especially significant and its level exceeded the level of the sham control value. This suggests TRH might exert its function through the dorsomedial nucleus of the thalamus and mamillary body. When TRH was administered to rats treated with pentobarbital, significant reversal was observed in the following structures: the lateral and ventral nucleus of the thalamus, dentate gyrus, caudate-putamen, nucleus accumbens, pontine gray matter, and raphe nucleus.

  7. Acute administration of fluoxetine normalizes rapid eye movement sleep abnormality, but not depressive behaviors in olfactory bulbectomized rats.

    Science.gov (United States)

    Wang, Yi-Qun; Tu, Zhi-Cai; Xu, Xing-Yuan; Li, Rui; Qu, Wei-Min; Urade, Yoshihiro; Huang, Zhi-Li

    2012-01-01

    In humans, depression is associated with altered rapid eye movement (REM) sleep. However, the exact nature of the relationship between depressive behaviors and sleep abnormalities is debated. In this study, bilateral olfactory bulbectomy (OBX) was carried out to create a model of depression in rats. The sleep-wake profiles were assayed using a cutting-edge sleep bioassay system, and depressive behaviors were evaluated by open field and forced swimming tests. The monoamine content and monoamine metabolite levels in the brain were determined by a HPLC-electrochemical detection system. OBX rats exhibited a significant increase in REM sleep, especially between 15:00 and 18:00 hours during the light period. Acute treatment with fluoxetine (10 mg/kg, i.p.) immediately abolished the OBX-induced increase in REM sleep, but hyperactivity in the open field test and the time spent immobile in the forced swimming test remained unchanged. Neurochemistry studies revealed that acute administration of fluoxetine increased serotonin (5-HT) levels in the hippocampus, thalamus, and midbrain and decreased levels of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA). The ratio of 5-HIAA to 5-HT decreased in almost all regions of the brain. These results indicate that acute administration of fluoxetine can reduce the increase in REM sleep but does not change the depressive behaviors in OBX rats, suggesting that there was no causality between REM sleep abnormalities and depressive behaviors in OBX rats. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

  8. The role of melatonin in radiation induced biochemical disturbances in brain and thyroid gland in adult male albino rats

    International Nuclear Information System (INIS)

    Abdel Kader, S.M.; EI-Sherbiny, E.M.

    2007-01-01

    Radiation induced changes in adult male albino male rats before and after melatonin administration were monitored to detect some biochemical changes in brain and thyroid gland. The parameters monitored were dopamine (DA), norepinephdne (NE) and gamma aminobutyric acid (GABA) in brain and triiodothyronine (T 3 ) thyroxine (T 4 ) and thyroid stimulating hormone (TSH) in serum of irradiated adult male albino rats before and after intraperitoneal injection of melatonin. Results indicated that 6.0 Gy whole body γ-irradiated rats showed gradual and significant decrease in DA, NE and GABA contents in different brain areas under investigation (cerebellum, pons+medulla oblongata, corpus striatum, cerebral cortex, hypothalamus, midbrain and hippocampus). The maximum effect of whole body γ-irradiation was observed after 21 days. Moreover, gradual and significant decrease in serum T 3 and T 4 levels were recorded after γ-irradiation. However, TSH level showed significant elevation throughout the experimental period. Melatonin at a dose level of 15 mg/kg b.wt. was intraperitoneally injected daily 30 minutes after 6.0 Gy whole body γ-irradiation, ameliorated DA, NE and GABA contents in different brain areas compared to those measured in irradiated rats. Moreover, melatonin gradually attenuated the effect of γ-irradiation on serum T 3 and T 4 levels to reach nearly the control level at day 21 after melatonin injection. However, melatonin ameliorated the elevated TSH level induced by γ-irradiation to reach its corresponding control value at day 21

  9. The progestin etonogestrel enhances the respiratory response to metabolic acidosis in newborn rats. Evidence for a mechanism involving supramedullary structures.

    Science.gov (United States)

    Loiseau, Camille; Osinski, Diane; Joubert, Fanny; Straus, Christian; Similowski, Thomas; Bodineau, Laurence

    2014-05-01

    Central congenital hypoventilation syndrome is a neuro-respiratory disease characterized by the dysfunction of the CO2/H(+) chemosensitive neurons of the retrotrapezoid nucleus/parafacial respiratory group. A recovery of CO2/H(+) chemosensitivity has been observed in some central congenital hypoventilation syndrome patients coincidental with contraceptive treatment by a potent progestin, desogestrel (Straus et al., 2010). The mechanisms of this progestin effect remain unknown, although structures of medulla oblongata, midbrain or diencephalon are known to be targets for progesterone. In the present study, on ex vivo preparations of central nervous system of newborn rats, we show that acute exposure to etonogestrel (active metabolite of desogestrel) enhanced the increased respiratory frequency induced by metabolic acidosis via a mechanism involving supramedullary structures located in pontine, mesencephalic or diencephalic regions. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  10. Visualization of μ1 opiate receptors in rat brain by using a computerized autoradiographic subtraction technique

    International Nuclear Information System (INIS)

    Goodman, R.R.; Pasternak, G.W.

    1985-01-01

    The authors have developed a quantitative computerized subtraction technique to demonstrate in rat brain the regional distribution of μ 1 sites, a common very-high-affinity binding site for both morphine and the enkephalins. Low concentrations of [D-Ala 2 , D-Leu 5 ]enkephalin selectively inhibit the μ 1 binding of [ 3 H]dihydromorphine, leaving μ 2 -sites, while low morphine concentrations eliminate the μ 1 binding of [ 3 H][D-Ala 2 , D-Leu 5 ]enkephalin, leaving sigma sites. Thus, quantitative differences between images of sections incubated in the presence and absence of these low concentrations of unlabeled opioid represent μ 1 binding sites. The regional distributions of μ 1 sites labeled with [ 3 H]dihydromorphine were quite similar to those determined by using [ 3 H][D-Ala 2 , D-Leu 5 ]enkephalin. High levels of μ 1 binding were observed in the periaqueductal gray, medial thalamus, and median raphe, consistent with the previously described role of μ 1 sites in analgesia. Other regions with high levels of μ 1 binding include the nucleus accumbens, the clusters and subcallosal streak of the striatum, hypothalamus, medial habenula, and the medial septum/diagonal band region. The proportion of total specific binding corresponding to μ 1 sites varied among the regions, ranging from 14% to 75% for [ 3 H][D-Ala 2 , D-Leu 5 ]enkephalin and 20% to 52% for [ 3 H]dihydromorphine

  11. Localization of glucocorticoid receptor mRNA in the male rat brain by in situ hybridization

    International Nuclear Information System (INIS)

    Aronsson, M.; Fuxe, K.; Dong, Y.; Agnati, L.F.; Okret, S.; Gustafsson, J.A.

    1988-01-01

    The localization and distribution of mRNA encoding the glucocorticoid receptor (GR) was investigated in tissue sections of the adult male rat brain by in situ hybridization and RNA blot analysis. GR mRNA levels were measured by quantitative autoradiography with 35S- and 32P-labeled RNA probes, respectively. Strong labeling was observed within the pyramidal nerve cells of the CA1 and CA2 areas of the hippocampal formation, in the granular cells of the dentate gyrus, in the parvocellular nerve cells of the paraventricular hypothalamic nucleus, and in the cells of the arcuate nucleus, especially the parvocellular part. Moderate labeling of a large number of nerve cells was observed within layers II, III, and VI of the neocortex and in many thalamic nuclei, especially the anterior and ventral nuclear groups as well as several midline nuclei. Within the cerebellar cortex, strong labeling was observed all over the granular layer. In the lower brainstem, strong labeling was found within the entire locus coeruleus and within the mesencephalic raphe nuclei rich in noradrenaline and 5-hydroxytryptamine cell bodies, respectively. A close correlation was found between the distribution of GR mRNA and the distribution of previously described GR immunoreactivity. These studies open the possibility of obtaining additional information on in vivo regulation of GR synthesis and how the brain may alter its sensitivity to circulating glucocorticoids

  12. Anatomical Inputs From the Sensory and Value Structures to the Tail of the Rat Striatum

    Directory of Open Access Journals (Sweden)

    Haiyan Jiang

    2018-05-01

    Full Text Available The caudal region of the rodent striatum, called the tail of the striatum (TS, is a relatively small area but might have a distinct function from other striatal subregions. Recent primate studies showed that this part of the striatum has a unique function in encoding long-term value memory of visual objects for habitual behavior. This function might be due to its specific connectivity. We identified inputs to the rat TS and compared those with inputs to the dorsomedial striatum (DMS in the same animals. The TS directly received anatomical inputs from both sensory structures and value-coding regions, but the DMS did not. First, inputs from the sensory cortex and sensory thalamus to the TS were found; visual, auditory, somatosensory and gustatory cortex and thalamus projected to the TS but not to the DMS. Second, two value systems innervated the TS; dopamine and serotonin neurons in the lateral part of the substantia nigra pars compacta (SNc and dorsal raphe nucleus projected to the TS, respectively. The DMS received inputs from the separate group of dopamine neurons in the medial part of the SNc. In addition, learning-related regions of the limbic system innervated the TS; the temporal areas and the basolateral amygdala selectively innervated the TS, but not the DMS. Our data showed that both sensory and value-processing structures innervated the TS, suggesting its plausible role in value-guided sensory-motor association for habitual behavior.

  13. 5HT-1A receptors and anxiety-like behaviours: studies in rats with constitutionally upregulated/downregulated serotonin transporter.

    Science.gov (United States)

    Bordukalo-Niksic, Tatjana; Mokrovic, Gordana; Stefulj, Jasminka; Zivin, Marko; Jernej, Branimir; Cicin-Sain, Lipa

    2010-12-01

    Altered activity of brain serotonergic (5HT) system has been implicated in a wide range of behaviours and behavioural disorders, including anxiety. Functioning of 5HT-1A receptor has been suggested as a modulator of emotional balance in both, normal and pathological forms of anxiety. Here, we studied serotonergic modulation of anxiety-like behaviour using a genetic rat model with constitutional differences in 5HT homeostasis, named Wistar-Zagreb 5HT (WZ-5HT) rats. The model, consisting of high-5HT and low-5HT sublines, was developed by selective breeding of animals for extreme activities of peripheral (platelet) 5HT transporter, but selection process had affected also central 5HT homeostasis, as evidenced from neurochemical and behavioural studies. Anxiety-like behaviour in WZ-5HT rats was evaluated by two commonly used paradigms: open field and elevated-plus maze. The involvement of 5HT-1A receptors in behavioural response was assessed by measuring mRNA expression in cell bodies (raphe nuclei) and projection regions (frontal cortex, hippocampus) by use of RT-PCR and in situ hybridization, and by measuring functionality of cortical 5HT-1A receptors by use of [(3)H]8-OH-DPAT radioligand binding. Animals from the high-5HT subline exhibit increased anxiety-like behaviour and decreased exploratory activity when exposed to novel environment. No measurable differences in constitutional (baseline) functionality or expression of 5HT-1A receptors between sublines were found. The results support contribution of increased serotonergic functioning to the anxiety-like behaviour. They also validate the high-5HT subline of WZ-5HT rats as a potential model to study mechanisms of anxiety, especially of its nonpathological form, while the low-5HT subline may be useful to model sensation seeking phenotype. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  14. Mitogen-activated protein kinase phosphatase (MKP)-1 as a neuroprotective agent: promotion of the morphological development of midbrain dopaminergic neurons.

    Science.gov (United States)

    Collins, Louise M; O'Keeffe, Gerard W; Long-Smith, Caitriona M; Wyatt, Sean L; Sullivan, Aideen M; Toulouse, André; Nolan, Yvonne M

    2013-06-01

    A greater understanding of the mechanisms that promote the survival and growth of dopaminergic neurons is essential for the advancement of cell replacement therapies for Parkinson's disease (PD). Evidence supports a role for the mitogen-activated protein kinase p38 in the demise of dopaminergic neurons, while mitogen-activated protein kinase phosphatase-1 (MKP-1), which negatively regulates p38 activity, has not yet been investigated in this context. Here, we show that MKP-1 is expressed in dopaminergic neurons cultured from E14 rat ventral mesencephalon (VM). When dopaminergic neurons were transfected to overexpress MKP-1, they displayed a more complex morphology than their control counterparts in vitro. Specifically, MKP-1-transfection induced significant increases in neurite length and branching with a maximum increase observed in primary branches. We demonstrate that inhibition of dopaminergic neurite growth induced by treatment of rat VM neurons with the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) in vitro is mediated by p38 and is concomitant with a significant and selective decrease in MKP-1 expression in these neurons. We further show that overexpression of MKP-1 in dopaminergic neurons contributes to neuroprotection against the effects of 6-OHDA. Collectively, we report that MKP-1 can promote the growth and elaboration of dopaminergic neuronal processes and can help protect them from the neurotoxic effects of 6-OHDA. Thus, we propose that strategies aimed at augmenting MKP-1 expression or activity may be beneficial in protecting dopaminergic neurons and may provide potential therapeutic approaches for PD.

  15. Effect of ethanol on enkephalinergic opioid system of rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Belyayev, N.A.; Balakireva, N.N.; Brusov, O.S.; Panchenko, L.F.

    1983-10-13

    Specific binding of /sup 3/H-morphine and /sup 3/H-(D-Ala/sup 2/, D-Leu/sup 5/)-enkephalin (H-EN) with opiatic receptors was studied on white rats along with the content of Met- and Leu-enkephalin and the activity of enkephalinase in various brain segments after single dose (20% solution in 0.9% NaCl, IP; 1.5-4.5 g/kg body weight) and chronic injection (20% EtOH substituted for drinking water) of ethanol. The single injection of EtOH (1.5-4.5 g/kg) resulted in a depression of the specific binding of H-EN with opiate receptors. Doses of 1.5 and 2.5 g/kg led to a lower content of Leu-enkephalin in mid-brain but to an increase of Met-enkephalin; the 4.5 g/kg dose had no effect on the striatum. With chronic administration of EtOH, most of the values obtained on the experimental animals were similar to the control data. 23 references.

  16. miR-16 and Fluoxetine Both Reverse Autophagic and Apoptotic Change in Chronic Unpredictable Mild Stress Model Rats

    Directory of Open Access Journals (Sweden)

    Yang Yang

    2017-07-01

    Full Text Available In the clinic selective serotonin reuptake inhibitors (SSRIs, like Fluoxetine, remain the primary treatment for major depression. It has been suggested that miR-16 regulates serotonin transporters (SERT via raphe nuclei and hippocampal responses to antidepressants. However, the underlying mechanism and regulatory pathways are still obtuse. Here, a chronic unpredicted mild stress (CUMS depression model in rats was established, and then raphe nuclei miR-16 and intragastric Fluoxetine injections were administered for a duration of 3 weeks. An open field test and sucrose preference quantification displayed a significant decrease in the CUMS groups when compare to the control groups, however these changes were attenuated by both miR-16 and Fluoxetine treatments. A dual-luciferase reporter assay system verified that hsa-miR-16 inhibitory effects involve the targeting of 3′UTR on the 5-HTT gene. Expression levels of miR-16 and BDNF in the hippocampus were examined with RT-PCR, and it was found that increased 5-HT2a receptor expression induced by CUMS can be decreased by miR-16 and Fluoxetine administration. Immunofluorescence showed that expression levels of neuron NeuN and MAP-2 in CUMS rats were lower. Apoptosis and autophagy levels were evaluated separately through relative expression of Bcl-2, Caspase-3, Beclin-1, and LC3II. Furthermore, CUMS was found to decrease levels of hippocampal mTOR, PI3K, and AKT. These findings indicate that apoptosis and autophagy related pathways could be involved in the effectiveness of antidepressants, in which miR-16 participates in the regulation of, and is likely to help integrate rapid therapeutic strategies to alleviate depression clinically. These findings indicate that miR-16 participates in the regulation of apoptosis and autophagy and could account for some part of the therapeutic effect of SSRIs. This discovery has the potential to further the understanding of SSRIs and accelerate the development of new

  17. RatMap--rat genome tools and data.

    Science.gov (United States)

    Petersen, Greta; Johnson, Per; Andersson, Lars; Klinga-Levan, Karin; Gómez-Fabre, Pedro M; Ståhl, Fredrik

    2005-01-01

    The rat genome database RatMap (http://ratmap.org or http://ratmap.gen.gu.se) has been one of the main resources for rat genome information since 1994. The database is maintained by CMB-Genetics at Goteborg University in Sweden and provides information on rat genes, polymorphic rat DNA-markers and rat quantitative trait loci (QTLs), all curated at RatMap. The database is under the supervision of the Rat Gene and Nomenclature Committee (RGNC); thus much attention is paid to rat gene nomenclature. RatMap presents information on rat idiograms, karyotypes and provides a unified presentation of the rat genome sequence and integrated rat linkage maps. A set of tools is also available to facilitate the identification and characterization of rat QTLs, as well as the estimation of exon/intron number and sizes in individual rat genes. Furthermore, comparative gene maps of rat in regard to mouse and human are provided.

  18. Quantitative autoradiographic localization of cholecystokinin receptors in rat and guinea pig brain using 125I-Bolton-Hunter-CCK8

    International Nuclear Information System (INIS)

    Niehoff, D.L.

    1989-01-01

    The autoradiographic localization of receptors for the brain-gut peptide cholecystokinin (CCK) has shown differences in receptor distribution between rat and guinea pig brain. However the full anatomical extent of the differences has not been determined quantitatively. In the present study, 125 I-Bolton-Hunter-CCK8 ( 125 I-BH-CCK8) was employed in a comparative quantitative autoradiographic analysis of the distribution of CCK receptors in these two species. The pharmacological profile of 125 I-BH-CCK8 binding in guinea pig forebrain sections was comparable to those previously reported for rat and human. Statistically significant differences in receptor binding between rat and guinea pig occurred in olfactory bulb, caudate-putamen, amygdala, several cortical areas, ventromedial hypothalamus, cerebellum, and a number of midbrain and brainstem nuclei. The results of this study confirm the presence of extensive species-specific variation in the distribution of CCK receptors, suggesting possible differences in the physiological roles of this peptide in different mammalian species

  19. Differentiation in boron distribution in adult male and female rats' normal brain: A BNCT approach

    Energy Technology Data Exchange (ETDEWEB)

    Goodarzi, Samereh, E-mail: samere.g@gmail.com [Department of Nuclear Engineering, Science and Research Branch, Islamic Azad University, PO Box 19395-1943, Tehran (Iran, Islamic Republic of); Pazirandeh, Ali, E-mail: paziran@yahoo.com [Department of Nuclear Engineering, Science and Research Branch, Islamic Azad University, PO Box 19395-1943, Tehran (Iran, Islamic Republic of); Jameie, Seyed Behnamedin, E-mail: behnamjameie@tums.ac.ir [Basic Science Department, Faculty of Allied Medicine, Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of); Department of Anatomy, Faculty of Medicine, Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of); Baghban Khojasteh, Nasrin, E-mail: khojasteh_n@yahoo.com [Department of Nuclear Engineering, Science and Research Branch, Islamic Azad University, PO Box 19395-1943, Tehran (Iran, Islamic Republic of)

    2012-06-15

    Boron distribution in adult male and female rats' normal brain after boron carrier injection (0.005 g Boric Acid+0.005 g Borax+10 ml distilled water, pH: 7.4) was studied in this research. Coronal sections of control and trial animal tissue samples were irradiated with thermal neutrons. Using alpha autoradiography, significant differences in boron concentration were seen in forebrain, midbrain and hindbrain sections of male and female animal groups with the highest value, four hours after boron compound injection. - Highlights: Black-Right-Pointing-Pointer Boron distribution in male and female rats' normal brain was studied in this research. Black-Right-Pointing-Pointer Coronal sections of animal tissue samples were irradiated with thermal neutrons. Black-Right-Pointing-Pointer Alpha and Lithium tracks were counted using alpha autoradiography. Black-Right-Pointing-Pointer Different boron concentration was seen in brain sections of male and female rats. Black-Right-Pointing-Pointer The highest boron concentration was seen in 4 h after boron compound injection.

  20. Effect of deltamethrin on transmission of gamma aminobutyric acid (GABA) and thyroid hormones in adult male albino rats

    International Nuclear Information System (INIS)

    Abdel-kader, S.M.; Abdel-Rahman, M.

    2005-01-01

    The oral administration of 1/5 LD 5 0 of deltamethrin for 15 days produced an increase in GABA content and a decrease in Cl - ions concentration in all tested brain areas (cerebellum, pons + medulla oblongata, striatum, cerebral cortex, hypothalamus, midbrain and hippocampus) of adult male albino rats, almost at most time intervals. Deltamethrin also resulted in a significant decrease in serum TSH and increase in T 3 and T 4 levels in the treated rats. From the present results, it was found that deltamethrin decreased the passage of Cl - ions in the cells which might be, in part, due to a decrease of the transmission of GABA and an increase of the circulating thyroid hormones (triiodothyronine and thyroxine). Accordingly, deltamethrin may act as GABA antagonist and may act on the hypothalamus pituitary thyroid axis. In conclusion the elevation of thyroid hormones as well as the decrease in both CL - ions and GABA transmission which could be all together responsible for the impairment of motor activity, hyper excitability and seizure that occurred in rats treated with the pyrethroid insecticide deltamethrin

  1. Autoradiographic localization of (125I-Tyr4)bombesin-binding sites in rat brain

    International Nuclear Information System (INIS)

    Zarbin, M.A.; Kuhar, M.J.; O'Donohue, T.L.; Wolf, S.S.; Moody, T.W.

    1985-01-01

    The binding of ( 125 I-Tyr 4 )bombesin to rat brain slices was investigated. Radiolabeled (Tyr 4 )bombesin bound with high affinity (K/sub d/ . 4 nM) to a single class of sites (B/sub max/ . 130 fmol/mg of protein); the ratio of specific to nonspecific binding was 6/1. Also, pharmacology studies indicated that the C-terminal of bombesin was important for the high affinity binding activity. Autoradiographic studies indicated that the ( 125 I-Tyr4)bombesin-binding sites were discretely distributed in certain gray but not white matter regions of rat brain. Highest grain densities were present in the olfactory bulb and tubercle, nucleus accumbens, suprachiasmatic and periventricular nuclei of the hypothalamus, central medial thalamic nucleus, medial amygdaloid nucleus, hippocampus, dentate gyrus, subiculum, nucleus of the solitary tract, and substantia gelatinosa. Moderate grain densities were present in the parietal cortex, deep layers of the neocortex, rhinal cortex, caudate putamen, stria terminalis, locus ceruleus, parabrachial nucleus, and facial nucleus. Low grain densities were present in the globus pallidus, lateral thalamus, and midbrain. Negligible grain densities were present in the cerebellum, corpus callosum, and all regions treated with 1 microM unlabeled bombesin. The discrete regional distribution of binding suggests that endogenous bombesin-like peptides may function as important regulatory agents in certain brain loci

  2. Enhanced catecholaminergic and serotoninergic activity in rat brain from weaning to sexual maturity: rationale for prophylactic (-)deprenyl (selegiline) medication.

    Science.gov (United States)

    Knoll, J; Miklya, I

    1995-01-01

    Food deprived rats in the late developmental phase of life (2 months of age) are significantly more active than those in the early postdevelopmental phase (4 months of age), pointing to enhanced catecholaminergic activity during the developmental phase. We therefore measured the resting release of dopamine from the striatum, substantia nigra and tuberculum olfactorium, and of noradrenaline from the locus coeruleus, as an indicator of the basic activity of catecholaminergic neurons in the brain, in 2,4,8,16 and 32 weeks old male and female rats. We also measured the release of serotonin from the raphe. Both in male and female rats, the resting release of transmitters from brain catecholaminergic and serotoninergic neurons between weaning and the end of the 2nd month of age, i.e. during the crucial developmental phase of their life, was significantly higher than either before or after that period, signalling a transition from a developmental to a postdevelopmental (aging) phase of life and indicating that safe and effective measures are needed to maintain the catecholaminergic system at a higher activity level during the postdevelopmental phase. Daily administration of low doses (0.01-0.25 mg/kg) of (-)deprenyl for 21 days significantly enhances the resting release of catecholamines and diminishes that of serotonin, providing a rationale for prophylactic medication with this drug during the postdevelopmental lifespan. We also show that (-)methamphetamine, the parent compound of (-)deprenyl and (-)1-phenyl-2-propylaminopentane (PPAP), a deprenyl analogue free of MAO-B inhibitory potency but otherwise possessing the same pharmacological profile as (-)deprenyl, act similarly, furnishing direct evidence that enhancement of catecholaminergic activity in the brain by multiple, small dose administration of (-)deprenyl is unrelated to MAO-B inhibition.

  3. Mesolimbic effects of the antidepressant fluoxetine in Holtzman rats, a genetic strain with increased vulnerability to stress

    Science.gov (United States)

    Padilla, Eimeira; Shumake, Jason; Barrett, Douglas W.; Sheridan, Eva C.; Gonzalez-Lima, F.

    2011-01-01

    This is the first metabolic mapping study of the effects of fluoxetine after learned helplessness training. Antidepressants are the most commonly prescribed medications, but the regions underlying treatment effects in affectively disordered brains are poorly understood. We hypothesized the antidepressant action of fluoxetine would produce adaptations in mesolimbic regions after two weeks of treatment. We used Holtzman rats, a genetic strain showing susceptibility to novelty-evoked hyperactivity and stress-evoked helplessness, to map regional brain metabolic effects caused by fluoxetine treatment. Animals underwent learned helplessness, and subsequently immobility time was scored in the forced swim test (FST). On the next day, animals began receiving two weeks of fluoxetine (5 mg/kg/day) or vehicle and were retested in the FST at the end of drug treatment. Antidepressant behavioral effects of fluoxetine were analyzed using a ratio of immobility during pre- and post-treatment FST sessions. Brains were analyzed for regional metabolic activity using quantitative cytochrome oxidase histochemistry as in our previous study using congenitally helpless rats. Fluoxetine exerted a protective effect against FST-induced immobility behavior in Holtzman rats. Fluoxetine also caused a significant reduction in the mean regional metabolism of the nucleus accumbens shell and the ventral hippocampus as compared to vehicle-treated subjects. Additional networks affected by fluoxetine treatment included the prefrontal-cingulate cortex and brainstem nuclei linked to depression (e.g. habenula, dorsal raphe and interpeduncular nucleus). We concluded that corticolimbic regions such as the prefrontal-cingulate cortex, nucleus accumbens, ventral hippocampus and key brainstem nuclei represent important contributors to the neural network mediating fluoxetine antidepressant action. PMID:21376019

  4. A novel therapeutic approach to 6-OHDA-induced Parkinson's disease in rats via supplementation of PTD-conjugated tyrosine hydroxylase.

    Science.gov (United States)

    Wu, Shao Ping; Fu, Ai Ling; Wang, Yu Xia; Yu, Lei Ping; Jia, Pei Yuan; Li, Qian; Jin, Guo Zhang; Sun, Man Ji

    2006-07-21

    The present study aimed to evaluate whether the protein transduction domain (PTD)-conjugated human tyrosine hydroxylase (TH) fusion protein was effective on the 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease (PD) model rats. An expression vector pET-PTD-TH harbouring the PTD-TH gene was constructed and transformed to the Escherichia coli BL21 cells for expression. The expressed recombinant PTD-TH with a molecular weight of 61 kD was successfully transduced (1 microM) into the dopaminergic SH-sy5y human neuroblastoma cells in vitro and visualized by immunohistochemical assay. An in vivo experiment in rats showed that the iv administered PTD-TH protein (8 mg/kg) permeated across the blood-brain barrier, penetrated into the striatum and midbrain, and peaked at 5-8 h after the injection. The behavioral effects of PTD-TH on the apomorphine-induced rotations in the PD model rats 8 weeks after the 6-OHDA lesion showed that a single bolus of PTD-TH (8 mg/kg) iv injection caused a decrement of 60% of the contralateral turns on day 1 and 40% on days 5-17. The results imply that iv delivery of PTD-TH is therapeutically effective on the 6-OHDA-induced PD in rats, the PTD-mediated human TH treatment opening a promising therapeutic direction in treatment of PD.

  5. A novel therapeutic approach to 6-OHDA-induced Parkinson's disease in rats via supplementation of PTD-conjugated tyrosine hydroxylase

    International Nuclear Information System (INIS)

    Wu Shaoping; Fu Ailing; Wang Yuxia; Yu Leiping; Jia Peiyuan; Li Qian; Jin Guozhang; Sun Manji

    2006-01-01

    The present study aimed to evaluate whether the protein transduction domain (PTD)-conjugated human tyrosine hydroxylase (TH) fusion protein was effective on the 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease (PD) model rats. An expression vector pET-PTD-TH harbouring the PTD-TH gene was constructed and transformed to the Escherichia coli BL21 cells for expression. The expressed recombinant PTD-TH with a molecular weight of 61 kD was successfully transduced (1 μM) into the dopaminergic SH-sy5y human neuroblastoma cells in vitro and visualized by immunohistochemical assay. An in vivo experiment in rats showed that the iv administered PTD-TH protein (8 mg/kg) permeated across the blood-brain barrier, penetrated into the striatum and midbrain, and peaked at 5-8 h after the injection. The behavioral effects of PTD-TH on the apomorphine-induced rotations in the PD model rats 8 weeks after the 6-OHDA lesion showed that a single bolus of PTD-TH (8 mg/kg) iv injection caused a decrement of 60% of the contralateral turns on day 1 and 40% on days 5-17. The results imply that iv delivery of PTD-TH is therapeutically effective on the 6-OHDA-induced PD in rats, the PTD-mediated human TH treatment opening a promising therapeutic direction in treatment of PD

  6. The N-Methyl-d-Aspartate Receptor Antagonist MK-801 Prevents Thallium-Induced Behavioral and Biochemical Alterations in the Rat Brain.

    Science.gov (United States)

    Osorio-Rico, Laura; Villeda-Hernández, Juana; Santamaría, Abel; Königsberg, Mina; Galván-Arzate, Sonia

    2015-01-01

    Thallium (Tl(+)) is a toxic heavy metal capable of increasing oxidative damage and disrupting antioxidant defense systems. Thallium invades the brain cells through potassium channels, increasing neuronal excitability, although until now the possible role of glutamatergic transmission in this event has not been investigated. Here, we explored the possible involvement of a glutamatergic component in the Tl(+)-induced toxicity through the N-methyl-d-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) in rats. The effects of MK-801 (1 mg/kg, intraperitoneally [ip]) on early (24 hours) motor alterations, lipid peroxidation, reduced glutathione (GSH) levels, and GSH peroxidase activity induced by Tl(+) acetate (32 mg/kg, ip) were evaluated in adult rats. MK-801 attenuated the Tl(+)-induced hyperactivity and lipid peroxidation in the rat striatum, hippocampus and midbrain, and produced mild effects on other end points. Our findings suggest that glutamatergic transmission via NMDA receptors might be involved in the Tl(+)-induced altered regional brain redox activity and motor performance in rats. © The Author(s) 2015.

  7. Rat Genome Database (RGD)

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Rat Genome Database (RGD) is a collaborative effort between leading research institutions involved in rat genetic and genomic research to collect, consolidate,...

  8. Effect of ginsenoside Rg3 on tyrosine hydroxylase and related mechanisms in the forced swimming-induced fatigue rats.

    Science.gov (United States)

    Xu, Yuxia; Zhang, Peng; Wang, Chu; Shan, Ye; Wang, Dandan; Qian, Fenglei; Sun, Mengwei; Zhu, Cuiqing

    2013-10-28

    Ginsenoside Rg3 has shown multiple pharmacological activities and been considered as one of the most promising approaches for fatigue treatment. However, little is known about the cellular and molecular mechanisms of Rg3 on anti-fatigue and the effect of Rg3 on dopaminergic system has not been reported yet. The major aim of this study is to investigate the effect of Rg3 on TH expression and the related biochemical parameters, such as PKAα, ERK1/2, Akt and α-synuclein in brain of fatigue rats. Weight-loaded forced swimming was performed to establish an animal model of fatigue. Rg3 (10mg/kg, 50mg/kg and 100mg/kg) was intragastrically administrated before swimming. The effect of Rg3 on the expression and phosphorylation of TH and TH-related proteins in fatigue rats or in SH-SY5Y cells was assessed with western blotting. HPLC was used to examine the level of DA and DOPAC in the fatigue rats tissues. TH and phosphorylated TH were decreased in different brain regions of which ventral midbrain were less affected in weight-loaded forced swimming rats. Pretreatment with Rg3 significantly suppressed fatigue-induced decrease expression of TH and TH phosphorylation. Also treatment with Rg3 reversed the decrease expression of PKAα as well as the phosphorylation of ERK1/2 and Akt which were induced by weight-loaded forced swimming. Moreover, weight-loaded swimming could induce the increase expression of α-synuclein in hippocampus and midbrain, while suppressed α-synuclein expression in striatum and prefrontal cortex. Furthermore, Rg3 could induce the increase of TH expression and phosphorylation which was accompanied with elevated expression and phosphorylation of related kinase proteins in vitro, while the inhibitors of kinase proteins could suppress these effects of Rg3. In addition, HPLC results showed that Rg3 could reverse the weight-loaded swimming-induced increase of DOPAC/DA ratio. Our data suggest that fatigue can induce the decrease of DA which might partially

  9. (3H)-dihydrotestosterone in catecholamine neurons of rat brain stem: combined localization by autoradiography and formaldehyde-induced fluorescence

    International Nuclear Information System (INIS)

    Heritage, A.S.; Stumpf, W.E.; Sar, M.; Grant, L.D.

    1981-01-01

    A combined formaldehyde-induced fluorescence (FIF)-autoradiography procedure was used to determine how and where the androgen, dihydrotestosterone (DHT), is associated with catecholamine systems in the rat brain. With this dual localization method, ( 3 H)-DHT target sites can be visualized in relation to catecholamine perikarya and terminals. In the hindbrain, catecholamine neurons adjacent to the fourth ventricle (group A4), the nucleus (n.) olivaris superior (group A5), the n. parabranchialis medialis (group A7), and in the locus coeruleus (group A6) and subcoeruleal regions, as well as in the substantia grisea centralis, concentrate ( 3 H)-DHT in their nuclei. ( 3 H)-DHT target neurons appear to be innervated by numerous catecholamine terminals in the following hindbrain regions: n. motorius dorsalis nervi vagi, n. tractus solitarii, n. commissuralis, n. raphe pallidus, n. olivaris inferior, the ventrolateral portion of the substantia grisea centralis, n. cuneiformis, and the ventrolateral reticular formation in the caudal mesencephalon. In the forebrain, ( 3 H)-DHT concentrates in nuclei of catecholamine neurons located in the n. arcuatus and n. periventricularis (group A12). In addition, ( 3 H)-DHT target neurons appear to be innervated by numerous catecholamine terminals in the following forebrain regions: n. periventricularis rotundocellularis, n. paraventricularis, n. dorsomedialis, n. periventricularis, area retrochiasmatica, n. interstititalis striae terminalis (ventral portion), and n. amygdaloideus centralis. The disclosure of a morphologic association between ( 3 H)-DHT target sites and certain brain catecholamine systems suggests a close functional interdependence between androgens and catecholamines

  10. Autoradiographic localization and characterization of atrial natriuretic peptide binding sites in the rat central nervous system and adrenal gland

    International Nuclear Information System (INIS)

    Gibson, T.R.; Wildey, G.M.; Manaker, S.; Glembotski, C.C.

    1986-01-01

    Atrial natriuretic peptides (ANP) have recently been identified in both heart and CNS. These peptides possess potent natriuretic, diuretic, and vasorelaxant activities, and are all apparently derived from a single prohormone. Specific ANP binding sites have been characterized in the adrenal zona glomerulosa and kidney cortex, and one study reported ANP binding sites in the CNS. However, a detailed examination of the localization of ANP binding sites throughout the brain has not been reported. In this study, quantitative autoradiography was employed to examine the distribution of ANP receptors in the rat CNS. The binding of (3- 125 I-iodotyrosyl28) rat ANP-28 to binding sites in the rat CNS was saturable, specific for ANP-related peptides, and displayed high affinity (Kd = 600 pM). When the relative concentrations of ANP binding sites were determined throughout the rat brain, the highest levels of ANP binding were localized to the circumventricular organs, including the area postrema and subfornical organ, and the olfactory apparatus. Moderate levels of ANP binding sites were present throughout the midbrain and brain stem, while low levels were found in the forebrain, diencephalon, basal ganglia, cortex, and cerebellum. The presence of ANP binding sites in the subfornical organ and the area postrema, regions considered to be outside the blood-brain barrier, suggests that peripheral ANP levels may regulate some aspects of CNS control of salt and water balance. The possible functions of ANP binding sites in other regions of the rat brain are not known, but, like many other peptides, ANP may act as a neurotransmitter or neuromodulator at these loci

  11. Region specific regulation of glutamic acid decarboxylase mRNA expression by dopamine neurons in rat brain.

    Science.gov (United States)

    Lindefors, N; Brene, S; Herrera-Marschitz, M; Persson, H

    1989-01-01

    In situ hybridization histochemistry and RNA blots were used to study the expression of glutamic acid decarboxylase (GAD) mRNA in rats with or without a unilateral lesion of midbrain dopamine neurons. Two populations of GAD mRNA positive neurons were found in the intact caudate-putamen, substantia nigra and fronto-parietal cortex. In caudate-putamen, only one out of ten of the GAD mRNA positive neurons expressed high levels, while in substantia nigra every second of the positive neurons expressed high levels of GAD mRNA. Relatively few, but intensively labelled neurons were found in the intact fronto-parietal cerebral cortex. In addition, one out of six of the GAD mRNA positive neurons in the fronto-parietal cortex showed a low labeling. On the ipsilateral side, the forebrain dopamine deafferentation induced an increase in the number of neurons expressing high levels of GAD mRNA in caudate-putamen, and a decrease in fronto-parietal cortex. A smaller decrease was also seen in substantia nigra. However, the total number of GAD mRNA positive neurons were not significantly changed in any of these brain regions. The changes in the levels of GAD mRNA after the dopamine lesion were confirmed by RNA blot analysis. Hence, midbrain dopamine neurons appear to control neuronal expression of GAD mRNA by a tonic down-regulation in a fraction of GAD mRNA positive neurons in caudate-putamen, and a tonic up-regulation in a fraction of GAD mRNA positive neurons in fronto-parietal cortex and substantia nigra.

  12. The anorexic agents, sibutramine and fenfluramine, depress GABAB-induced inhibitory postsynaptic potentials in rat mesencephalic dopaminergic cells

    Science.gov (United States)

    Ledonne, Ada; Sebastianelli, Luca; Federici, Mauro; Bernardi, Giorgio; Mercuri, Nicola Biagio

    2009-01-01

    Background and purpose Nutrition is the result of a complex interaction among environmental, homeostatic and reward-related processes. Accumulating evidence supports key roles for the dopaminergic neurons of the ventral midbrain in regulating feeding behaviour. For this reason, in the present study, we have investigated the electrophysiological effects of two centrally acting anorexic agents, fenfluramine and sibutramine, on these cells. Experimental approach Rat midbrain slices were used to make intracellular recordings from dopaminergic neurons of the substantia nigra and the ventral tegmental area. Gamma-aminobutyric acid (GABA)-mediated synaptic transmission was assessed from the inhibitory postsynaptic potentials (IPSPs) mediated by GABAA and GABAB receptors. Key results Fenfluramine and sibutramine reduced, concentration-dependently, the GABAB IPSPs, without affecting the GABAA-mediated potentials. This effect is presynaptic, as postsynaptic membrane responses induced by application of a GABAB receptor agonist, baclofen, were not affected by the two drugs. Furthermore, the selective 5-hydroxytriptamine 1B (5-HT1B) receptor antagonist, SB216641, blocked the reduction of GABAB IPSPs caused by fenfluramine and sibutramine, indicating that the receptor mediating this effect is 5-HT1B. Conclusions and implications Two anorexic agents, fenfluramine and sibutramine, induced the activation of 5-HT1B receptors located on presynaptic GABAergic terminals, thus reducing the release of GABA. This action can alter the strength of synaptic afferents that modify the activity of dopaminergic neurons, inducing neuronal excitation. Our results reveal an additional mechanism of action for fenfluramine and sibutramine that might contribute to reducing food intake, by influencing the pleasurable and motor aspects of feeding behaviour. PMID:19298257

  13. Regional specificity in deltamethrin induced cytochrome P450 expression in rat brain

    International Nuclear Information System (INIS)

    Yadav, Sanjay; Johri, Ashu; Dhawan, Alok; Seth, Prahlad K.; Parmar, Devendra

    2006-01-01

    Oral administration of deltamethrin (5 mg/kg x 7 or 15 or 21 days) was found to produce a time-dependent increase in the mRNA expression of xenobiotic metabolizing cytochrome P450 1A1 (CYP1A1), 1A2 and CYP2B1, 2B2 isoenzymes in rat brain. RT-PCR studies further showed that increase in the mRNA expression of these CYP isoenzymes observed after 21 days of exposure was region specific. Hippocampus exhibited maximum increase in the mRNA expression of CYP1A1, which was followed by pons-medulla, cerebellum and hypothalamus. The mRNA expression of CYP2B1 also exhibited maximum increase in the hypothalamus and hippocampus followed by almost similar increase in midbrain and cerebellum. In contrast, mRNA expression of CYP1A2 and CYP2B2, the constitutive isoenzymes exhibited relatively higher increase in pons-medulla, cerebellum and frontal cortex. Immunoblotting studies carried out with polyclonal antibody raised against rat liver CYP1A1/1A2 or CYP2B1/2B2 isoenzymes also showed increase in immunoreactivity comigrating with CYP1A1/1A2 or 2B1/2B2 in the microsomal fractions isolated from hippocampus, hypothalamus and cerebellum of rat treated with deltamethrin. Though the exact relationship of the xenobiotic metabolizing CYPs with the physiological function of the brain is yet to be clearly understood, the increase in the mRNA expression of the CYPs in the brain regions that regulate specific brain functions affected by deltamethrin have further indicated that modulation of these CYPs could be associated with the various endogenous functions of the brain

  14. Immuno-localization of galanin receptor-1 (GALR1) in rat brain

    International Nuclear Information System (INIS)

    Larm, J.M.; Gundlach, A.L.

    2002-01-01

    Full text: Galanin is expressed in discrete areas throughout the central nervous system and has several putative physiological actions including effects on hormone secretion, reproduction and cognition, via actions at multiple G-protein-coupled receptors. Currently, three galanin receptors - GalR1, -R2, -R3 - have been identified that differ in pharmacology, signalling and distribution. The distribution of [ 125 I]-galanin binding sites presumably represents multiple receptors and so the precise regional and cellular localization of each receptor subtype is unknown. This study examined the distribution in rat brain of GalR1 receptors by immunohistochemistry, using polyclonal antibodies raised against short peptide sequences from the third intracellular loop and the proximal C-terminal. Adult rats were deeply anaesthetized (pentobarbitone 60 mg/kg, ip.) and perfusion-fixed with 4% paraformaldehyde. Specific GalR1 immunoreactivity (IR) was detected in neurons in various brain regions including cells within the olfactory bulb, piriform cortex, dorsomedial thalamus, hypothalamus (PVN, SON, ARC), midbrain/pons (intense staining in ventrolateral/medial PAG) and medulla. The localization pattern was qualitatively similar with both antisera and was consistent with that observed for GalR1 mRNA in normal rat brain. Recent evidence also reveals that GalR1- mRNA and -IR levels are coordinately altered after neuronal stimulation. These studies demonstrate a method for the identification of GalR1-containing cells that should assist in better differentiating the phenotype of galanin-receptive neurons. Copyright (2002) Australian Neuroscience Society

  15. Specific binding of 125I-salmon calcitonin to rat brain

    International Nuclear Information System (INIS)

    Nakamuta, Hiromichi; Furukawa, Shinichi; Koida, Masao; Yajima, Haruaki; Orlowski, R.C.

    1981-01-01

    Rat brain particulate fraction was found to contain binding sites for 125 I-Salmon Calcitonin-I ( 125 I-SCT). Maximum binding occurred in the physiological pH range of 7.25 - 7.5. The binding reaction proceeded in a temperature-dependent manner. Binding sites were broadly distributed among the various rat brain regions and considerable regional differences existed in the affinity and density as detected by Scatchard analysis. The highest affinity was recorded in the case of the hypothalamus and the lowest in the case of the cerebellum. The KD (nM) and Bmax (pmole/mg protein) estimated for the binding to four regions were as follows: hypothalamus: 1.4 and 0.19, midbrain, hippocampus plus striatum: 1.5 and 0.08, pon plus medulla oblongata: 3.0 and 0.15 and cerebellum: 8.3 and 0.20. Using a particulate fraction of rat brain void of cerebellum and cortices, a binding assay for calcitonins was developed. Binding of 125 I-SCT was inhibited by unlabeled salmon, [Asu sup(1,7)]-eel and porcine calcitonins in a dose-dependent manner and the IC50s were 2.0, 8.0 and 30 nM, respectively. The IC50s were comparable to those estimated using a kidney particulate fraction. Human calcitonin, β-endorphin and substance P were weak inhibitors of the binding. Other peptides, drugs and putative neurotransmitters tested (totally 23 substances) failed to inhibit the binding at concentrations of 1.0 μM. The physiological significance of brain binding sites for calcitonin, with the possibility that the brain may possess endogenous ligands for these sites are discussed. (author)

  16. Afferent projections to the deep mesencephalic nucleus in the rat

    International Nuclear Information System (INIS)

    Veazey, R.B.; Severin, C.M.

    1982-01-01

    Afferent projections to the deep mesencephalic nucleus (DMN) of the rat were demonstrated with axonal transport techniques. Potential sources for projections to the DMN were first identified by injecting the nucleus with HRP and examining the cervical spinal cord, brain stem, and cortex for retrogradely labeled neurons. Areas consistently labeled were then injected with a tritiated radioisotope, the tissue processed for autoradiography, and the DMN examined for anterograde labeling. Afferent projections to the medial and/or lateral parts of the DMN were found to originate from a number of spinal, bulbar, and cortical centers. Rostral brain centers projecting to both medial and lateral parts of the DMN include the ipsilateral motor and somatosensory cortex, the entopeduncular nucleus, and zona incerta. at the level of the midbrain, the ipsilateral substantia nigra and contralateral DMN likewise project to the DMN. Furthermore, the ipsilateral superior colliculus projects to the DMN, involving mainly the lateral part of the nucleus. Afferents from caudal centers include bilateral projections from the sensory nucleus of the trigeminal complex and the nucleus medulla oblongata centralis, as well as from the contralateral dentate nucleus. The projections from the trigeminal complex and nucleus medullae oblongatae centralis terminate in the intermediate and medial parts of the DMN, whereas projections from the contralateral dentate nucleus terminate mainly in its lateral part. In general, the afferent connections of the DMN arise from diverse areas of the brain. Although most of these projections distribute throughout the entire extent of the DMN, some of them project mainly to either medial or lateral parts of the nucleus, thus suggesting that the organization of the DMN is comparable, at least in part, to that of the reticular formation of the pons and medulla, a region in which hodological differences between medial and lateral subdivisions are known to exist

  17. Running Reduces Uncontrollable Stress-Evoked Serotonin and Potentiates Stress-Evoked Dopamine Concentrations in the Rat Dorsal Striatum.

    Directory of Open Access Journals (Sweden)

    Peter J Clark

    Full Text Available Accumulating evidence from both the human and animal literature indicates that exercise reduces the negative consequences of stress. The neurobiological etiology for this stress protection, however, is not completely understood. Our lab reported that voluntary wheel running protects rats from expressing depression-like instrumental learning deficits on the shuttle box escape task after exposure to unpredictable and inescapable tail shocks (uncontrollable stress. Impaired escape behavior is a result of stress-sensitized serotonin (5-HT neuron activity in the dorsal raphe (DRN and subsequent excessive release of 5-HT into the dorsal striatum following exposure to a comparatively mild stressor. However, the possible mechanisms by which exercise prevents stress-induced escape deficits are not well characterized. The purpose of this experiment was to test the hypothesis that exercise blunts the stress-evoked release of 5-HT in the dorsal striatum. Changes to dopamine (DA levels were also examined, since striatal DA signaling is critical for instrumental learning and can be influenced by changes to 5-HT activity. Adult male F344 rats, housed with or without running wheels for 6 weeks, were either exposed to tail shock or remained undisturbed in laboratory cages. Twenty-four hours later, microdialysis was performed in the medial (DMS and lateral (DLS dorsal striatum to collect extracellular 5-HT and DA before, during, and following 2 mild foot shocks. We report wheel running prevents foot shock-induced elevation of extracellular 5-HT and potentiates DA concentrations in both the DMS and DLS approximately 24 h following exposure to uncontrollable stress. These data may provide a possible mechanism by which exercise prevents depression-like instrumental learning deficits following exposure to acute stress.

  18. Dopamine D1-like receptor in lateral habenula nucleus affects contextual fear memory and long-term potentiation in hippocampal CA1 in rats.

    Science.gov (United States)

    Chan, Jiangping; Guan, Xin; Ni, Yiling; Luo, Lilu; Yang, Liqiang; Zhang, Pengyue; Zhang, Jichuan; Chen, Yanmei

    2017-03-15

    The Lateral Habenula (LHb) plays an important role in emotion and cognition. Recent experiments suggest that LHb has functional interaction with the hippocampus and plays an important role in spatial learning. LHb is reciprocally connected with midbrain monoaminergic brain areas such as the ventral tegmental area (VTA). However, the role of dopamine type 1 receptor (D1R) in LHb in learning and memory is not clear yet. In the present study, D1R agonist or antagonist were administered bilaterally into the LHb in rats. We found that both D1R agonist and antagonist impaired the acquisition of contextual fear memory in rats. D1R agonist or antagonist also impaired long term potentiation (LTP) in hippocampal CA3-CA1 synapses in freely moving rats and attenuated learning induced phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) subunit 1 (GluA1) at Ser831 and Ser845 in hippocampus. Taken together, our results suggested that dysfunction of D1R in LHb affected the function of hippocampus. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Quantitative autoradiographic localization of cholecystokinin receptors in rat and guinea pig brain using sup 125 I-Bolton-Hunter-CCK8

    Energy Technology Data Exchange (ETDEWEB)

    Niehoff, D.L. (Abbott Laboratories, Abbott Park, IL (USA))

    1989-03-01

    The autoradiographic localization of receptors for the brain-gut peptide cholecystokinin (CCK) has shown differences in receptor distribution between rat and guinea pig brain. However the full anatomical extent of the differences has not been determined quantitatively. In the present study, {sup 125}I-Bolton-Hunter-CCK8 ({sup 125}I-BH-CCK8) was employed in a comparative quantitative autoradiographic analysis of the distribution of CCK receptors in these two species. The pharmacological profile of {sup 125}I-BH-CCK8 binding in guinea pig forebrain sections was comparable to those previously reported for rat and human. Statistically significant differences in receptor binding between rat and guinea pig occurred in olfactory bulb, caudate-putamen, amygdala, several cortical areas, ventromedial hypothalamus, cerebellum, and a number of midbrain and brainstem nuclei. The results of this study confirm the presence of extensive species-specific variation in the distribution of CCK receptors, suggesting possible differences in the physiological roles of this peptide in different mammalian species.

  20. GABA(A) receptor antagonism in the ventrocaudal periaqueductal gray increases anxiety in the anxiety-resistant postpartum rat.

    Science.gov (United States)

    Miller, Stephanie M; Piasecki, Christopher C; Peabody, Mitchell F; Lonstein, Joseph S

    2010-06-01

    Postpartum mammals show suppressed anxiety, which is necessary for their ability to appropriately care for offspring. It is parsimonious to suggest that the neurobiological basis of this reduced anxiety is similar to that of non-parturient animals, involving GABA(A) receptor activity in sites including the midbrain periaqueductal gray (PAG). In Experiment 1, postpartum and diestrous virgin female rats received an intraperitoneal injection of the GABA(A) receptor antagonist (+)-bicuculline (0, 2 and 4 mg/kg) and anxiety-related behavior was assessed with an elevated plus maze. The 4 mg/kg dose of (+)-bicuculline significantly increased anxiety-related behavior, particularly in the postpartum females. Experiment 2 revealed that bicuculline's action was within the central nervous system, because anxiety in neither dams nor virgins was significantly affected by intraperitoneal injection of bicuculline methiodide (0, 2 and 6 mg/kg), which does not readily cross the blood-brain-barrier. In Experiment 3, bicuculline methiodide (2.5 ng/side) was directly infused into the ventrocaudal PAG (cPAGv) and significantly increased dams' anxiety compared to saline-infused controls. These studies expand our knowledge of how GABA(A) receptor modulators affect anxiety behaviors in postpartum rats to the widely-used elevated plus maze, and indicate that the postpartum suppression of anxiety is in part a consequence of elevated GABAergic neurotransmission in the cPAGv. Copyright 2010 Elsevier Inc. All rights reserved.

  1. Immunology taught by rats

    OpenAIRE

    Klenerman, P; Barnes, EJ

    2017-01-01

    Immunology may be best taught by viruses, and possibly by humans, but the rats of New York City surprisingly also have plenty to offer. A survey published in 2014 of the pathogens carried by rats trapped in houses and parks in Manhattan identified a huge burden of infectious agents in these animals, including several novel viruses. Among these are Norway rat hepaciviruses (NrHVs), which belong to the same family as hepatitis C virus (HCV). NrHVs were found in rat livers, raising the possibili...

  2. The effects of the selective 5-HT(2C) receptor antagonist SB 242084 on learned helplessness in male Fischer 344 rats.

    Science.gov (United States)

    Strong, Paul V; Greenwood, Benjamin N; Fleshner, Monika

    2009-05-01

    Rats exposed to an uncontrollable stressor demonstrate a constellation of behaviors such as exaggerated freezing and deficits in shuttle box escape learning. These behaviors in rats have been called learned helplessness and have been argued to model human stress-related mood disorders. Learned helplessness is thought to be caused by hyperactivation of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) and a subsequent exaggerated release of 5-HT in DRN projection sites. Blocking 5-HT(2C) receptors in the face of an increase in serotonin can alleviate anxiety behaviors in some animal models. However, specific 5-HT receptor subtypes involved in learned helplessness remain unknown. The current experiments tested the hypothesis that 5-HT(2C) receptor activation is necessary and sufficient for the expression of learned helplessness. The selective 5-HT(2C) receptor antagonist SB 242084 (1.0 mg/kg) administered i.p. to adult male Fischer 344 rats prior to shuttle box behavioral testing, but not before stress, blocked stress-induced deficits in escape learning but had no effect on the exaggerated shock-elicited freezing. The selective 5-HT(2C) receptor agonist CP-809101 was sufficient to produce learned helplessness-like behaviors in the absence of prior stress and these effects were blocked by pretreatment with SB 242084. Results implicate the 5-HT(2C) receptor subtype in mediating the shuttle box escape deficits produced by exposure to uncontrollable stress and suggest that different postsynaptic 5-HT receptor subtypes underlie the different learned helplessness behaviors.

  3. Adenoviral vectors for highly selective gene expression in central serotonergic neurons reveal quantal characteristics of serotonin release in the rat brain

    Directory of Open Access Journals (Sweden)

    Teschemacher Anja G

    2009-03-01

    Full Text Available Abstract Background 5-hydroxytryptamine (5 HT, serotonin is one of the key neuromodulators in mammalian brain, but many fundamental properties of serotonergic neurones and 5 HT release remain unknown. The objective of this study was to generate an adenoviral vector system for selective targeting of serotonergic neurones and apply it to study quantal characteristics of 5 HT release in the rat brain. Results We have generated adenoviral vectors which incorporate a 3.6 kb fragment of the rat tryptophan hydroxylase-2 (TPH-2 gene which selectively (97% co-localisation with TPH-2 target raphe serotonergic neurones. In order to enhance the level of expression a two-step transcriptional amplification strategy was employed. This allowed direct visualization of serotonergic neurones by EGFP fluorescence. Using these vectors we have performed initial characterization of EGFP-expressing serotonergic neurones in rat organotypic brain slice cultures. Fluorescent serotonergic neurones were identified and studied using patch clamp and confocal Ca2+ imaging and had features consistent with those previously reported using post-hoc identification approaches. Fine processes of serotonergic neurones could also be visualized in un-fixed tissue and morphometric analysis suggested two putative types of axonal varicosities. We used micro-amperometry to analyse the quantal characteristics of 5 HT release and found that central 5 HT exocytosis occurs predominantly in quanta of ~28000 molecules from varicosities and ~34000 molecules from cell bodies. In addition, in somata, we observed a minority of large release events discharging on average ~800000 molecules. Conclusion For the first time quantal release of 5 HT from somato-dendritic compartments and axonal varicosities in mammalian brain has been demonstrated directly and characterised. Release from somato-dendritic and axonal compartments might have different physiological functions. Novel vectors generated in this

  4. Revealing the cerebral regions and networks mediating vulnerability to depression: oxidative metabolism mapping of rat brain.

    Science.gov (United States)

    Harro, Jaanus; Kanarik, Margus; Kaart, Tanel; Matrov, Denis; Kõiv, Kadri; Mällo, Tanel; Del Río, Joaquin; Tordera, Rosa M; Ramirez, Maria J

    2014-07-01

    The large variety of available animal models has revealed much on the neurobiology of depression, but each model appears as specific to a significant extent, and distinction between stress response, pathogenesis of depression and underlying vulnerability is difficult to make. Evidence from epidemiological studies suggests that depression occurs in biologically predisposed subjects under impact of adverse life events. We applied the diathesis-stress concept to reveal brain regions and functional networks that mediate vulnerability to depression and response to chronic stress by collapsing data on cerebral long term neuronal activity as measured by cytochrome c oxidase histochemistry in distinct animal models. Rats were rendered vulnerable to depression either by partial serotonergic lesion or by maternal deprivation, or selected for a vulnerable phenotype (low positive affect, low novelty-related activity or high hedonic response). Environmental adversity was brought about by applying chronic variable stress or chronic social defeat. Several brain regions, most significantly median raphe, habenula, retrosplenial cortex and reticular thalamus, were universally implicated in long-term metabolic stress response, vulnerability to depression, or both. Vulnerability was associated with higher oxidative metabolism levels as compared to resilience to chronic stress. Chronic stress, in contrast, had three distinct patterns of effect on oxidative metabolism in vulnerable vs. resilient animals. In general, associations between regional activities in several brain circuits were strongest in vulnerable animals, and chronic stress disrupted this interrelatedness. These findings highlight networks that underlie resilience to stress, and the distinct response to stress that occurs in vulnerable subjects. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Hindbrain Catecholamine Neurons Activate Orexin Neurons During Systemic Glucoprivation in Male Rats.

    Science.gov (United States)

    Li, Ai-Jun; Wang, Qing; Elsarelli, Megan M; Brown, R Lane; Ritter, Sue

    2015-08-01

    Hindbrain catecholamine neurons are required for elicitation of feeding responses to glucose deficit, but the forebrain circuitry required for these responses is incompletely understood. Here we examined interactions of catecholamine and orexin neurons in eliciting glucoprivic feeding. Orexin neurons, located in the perifornical lateral hypothalamus (PeFLH), are heavily innervated by hindbrain catecholamine neurons, stimulate food intake, and increase arousal and behavioral activation. Orexin neurons may therefore contribute importantly to appetitive responses, such as food seeking, during glucoprivation. Retrograde tracing results showed that nearly all innervation of the PeFLH from the hindbrain originated from catecholamine neurons and some raphe nuclei. Results also suggested that many catecholamine neurons project collaterally to the PeFLH and paraventricular hypothalamic nucleus. Systemic administration of the antiglycolytic agent, 2-deoxy-D-glucose, increased food intake and c-Fos expression in orexin neurons. Both responses were eliminated by a lesion of catecholamine neurons innervating orexin neurons using the retrogradely transported immunotoxin, anti-dopamine-β-hydroxylase saporin, which is specifically internalized by dopamine-β-hydroxylase-expressing catecholamine neurons. Using designer receptors exclusively activated by designer drugs in transgenic rats expressing Cre recombinase under the control of tyrosine hydroxylase promoter, catecholamine neurons in cell groups A1 and C1 of the ventrolateral medulla were activated selectively by peripheral injection of clozapine-N-oxide. Clozapine-N-oxide injection increased food intake and c-Fos expression in PeFLH orexin neurons as well as in paraventricular hypothalamic nucleus neurons. In summary, catecholamine neurons are required for the activation of orexin neurons during glucoprivation. Activation of orexin neurons may contribute to appetitive responses required for glucoprivic feeding.

  6. RatMap—rat genome tools and data

    Science.gov (United States)

    Petersen, Greta; Johnson, Per; Andersson, Lars; Klinga-Levan, Karin; Gómez-Fabre, Pedro M.; Ståhl, Fredrik

    2005-01-01

    The rat genome database RatMap (http://ratmap.org or http://ratmap.gen.gu.se) has been one of the main resources for rat genome information since 1994. The database is maintained by CMB–Genetics at Göteborg University in Sweden and provides information on rat genes, polymorphic rat DNA-markers and rat quantitative trait loci (QTLs), all curated at RatMap. The database is under the supervision of the Rat Gene and Nomenclature Committee (RGNC); thus much attention is paid to rat gene nomenclature. RatMap presents information on rat idiograms, karyotypes and provides a unified presentation of the rat genome sequence and integrated rat linkage maps. A set of tools is also available to facilitate the identification and characterization of rat QTLs, as well as the estimation of exon/intron number and sizes in individual rat genes. Furthermore, comparative gene maps of rat in regard to mouse and human are provided. PMID:15608244

  7. Effects of autoshaping procedures on 3H-8-OH-DPAT-labeled 5-HT1a binding and 125I-LSD-labeled 5-HT2a binding in rat brain.

    Science.gov (United States)

    Tomie, Arthur; Di Poce, Jason; Aguado, Allison; Janes, Amy; Benjamin, Daniel; Pohorecky, Larissa

    2003-06-13

    Effects of experience with Pavlovian autoshaping procedures on lever-press autoshaping conditioned response (CR) performance and 3H-8-OH-DPAT-labeled binding of 5-HT(1a) receptors as well as 125I-LSD-labeled binding of 5-HT(2a) receptors were evaluated in four groups of male Long-Evans hooded rats. Two groups of rats (Group Paired High CR and Group Paired Low CR) received Pavlovian autoshaping procedures wherein the presentation of a lever (conditioned stimulus, CS) was followed by the response-independent presentation of food (unconditioned stimulus, US). Rats in Group Paired High CR (n=12) showed more rapid CR acquisition and higher asymptotic levels of lever-press autoshaping CR performance relative to rats in Group Low CR (n=12). Group Omission (n=9) received autoshaping with an omission contingency, such that performing the lever-press autoshaping CR resulted in the cancellation the food US, while Group Random (n=9) received presentations of lever CS and food US randomly with respect to one another. Though Groups Omission and Random did not differ in lever-press autoshaping CR performance, Group Omission showed significantly lower levels of 3H-8-OH-DPAT-labeled 5-HT(1a) binding in post-synaptic areas (frontal cortex, septum, caudate putamen), as well as significantly higher plasma corticosterone levels than Group Random. In addition, Group Random showed higher levels of 3H-8-OH-DPAT-labeled 5-HT(1a) binding in pre-synaptic somatodendritic autoreceptors on dorsal raphe nucleus relative to each of the other three groups. Autoradiographic analysis of 125I-LSD-labeled 5-HT(2a) receptor binding revealed no significant differences between Groups Paired High CR and Paired Low CR or between Groups Omission and Random in any brain regions.

  8. SWEEP Project RAT

    DEFF Research Database (Denmark)

    Ibsen, Lars Bo; Madsen, Søren; Petersen, L. B.

    This report presents the results from the design analyses made for the clustered suction caisson used as foundation for a Riser Access Tower (RAT). The RAT is intended built next to the K15-FA-1 Platform in the Dutch Sector of the North Sea....

  9. Colon of the rat

    International Nuclear Information System (INIS)

    Lindstroem, C.G.; Rosengren, J.-E.; Fork, F.-T.

    1979-01-01

    The anatomy and radiologic appearance of the colon in rats are described on the basis of 300 animals treated with carcinogenic agents and 40 normal rats. The macroscopic and microscopic appearance of the mucosa varies in the different parts of the colon. Lymphoid plaques are normal structures. The results justify a new anatomic nomenclature. (Auth.)

  10. Expression of neuropeptide W in rat stomach mucosa: regulation by nutritional status, glucocorticoids and thyroid hormones.

    Science.gov (United States)

    Caminos, Jorge E; Bravo, Susana B; García-Rendueles, María E R; Ruth González, C; Garcés, Maria F; Cepeda, Libia A; Lage, Ricardo; Suárez, Miguel A; López, Miguel; Diéguez, Carlos

    2008-02-07

    Neuropeptide W (NPW) is a recently identified neuropeptide that binds to G-protein-coupled receptor 7 (GPR7) and 8 (GPR8). In rodent brain, NPW mRNA is confined to specific nuclei in hypothalamus, midbrain and brainstem. Expression of NPW mRNA has also been confirmed in peripheral organs such as stomach. Several reports suggested that brain NPW is implicated in the regulation of energy and hormonal homeostasis, namely the adrenal and thyroid axes; however the precise physiological role and regulation of peripheral NPW remains unclear. In this study, we examined the effects of nutritional status on the regulation of NPW in stomach mucosa. Our results show that in this tissue, NPW mRNA and protein expression is negatively regulated by fasting and food restriction, in all the models we studied: males, females and pregnant females. Next, we examined the effect of glucocorticoids and thyroid hormones on NPW mRNA expression in the stomach mucosa. Our data showed that NPW expression is decreased in this tissue after glucocorticoid treatment or hyperthyroidism. Conversely, hypothyroidism induces a marked increase in the expression of NPW in rat stomach. Overall, these data indicate that stomach NPW is regulated by nutritional and hormonal status.

  11. Utility of a tripolar stimulating electrode for eliciting dopamine release in the rat striatum.

    Science.gov (United States)

    Bergstrom, B P; Garris, P A

    1999-03-01

    The present study evaluated tripolar stimulating electrodes for eliciting dopamine release in the rat brain in vivo. Stimulating electrodes were placed either in the medial forebrain bundle or in the ventral mesencephalon associated with the ventral tegmental area and substantia nigra. The concentration of extracellular dopamine was monitored in dopamine terminal fields at 100-ms intervals using fast-scan cyclic voltammetry at carbon-fiber microelectrodes. To characterize the stimulated area, recordings were collected in several striatal regions including the caudate putamen and the core and shell of the nucleus accumbens. The tripolar electrode was equally effective in stimulating dopamine release in medial and lateral regions of the striatum. In contrast, responses evoked by a bipolar electrode were typically greater in one mediolateral edge versus the other. The added size of the tripolar electrode did not appear to cause complications as signals were stable over the course of the experiment (3 h). Subsets of mesostriatal dopamine neurons could also be selectively activated using the tripolar electrode in excellent agreement with previously described topography. Taken together, these results suggested that the tripolar stimulating electrode is well suited for studying the regulation of midbrain dopamine neurons in vivo.

  12. Haloperidol-induced changes in neuronal activity in the striatum of the freely moving rat

    Directory of Open Access Journals (Sweden)

    Dorin eYael

    2013-12-01

    Full Text Available The striatum is the main input structure of the basal ganglia, integrating input from the cerebral cortex and the thalamus, which is modulated by midbrain dopaminergic input. Dopamine modulators, including agonists and antagonists, are widely used to relieve motor and psychiatric symptoms in a variety of pathological conditions. Haloperidol, a dopamine D2 antagonist, is commonly used in multiple psychiatric conditions and motor abnormalities. This article reports the effects of haloperidol on the activity of three major striatal subpopulations: medium spiny projection neurons (MSNs, fast spiking interneurons (FSIs and tonically active neurons (TANs. We implanted multi-wire electrode arrays in the rat dorsal striatum and recorded the activity of multiple single units in freely moving animals before and after systemic haloperidol injection. Haloperidol decreased the firing rate of FSIs and MSNs while increasing their tendency to fire in an oscillatory manner in the high voltage spindle (HVS frequency range of 7-9 Hz. Haloperidol led to an increased firing rate of TANs but did not affect their non-oscillatory firing pattern and their typical correlated firing activity. Our results suggest that dopamine plays a key role in tuning both single unit activity and the interactions within and between different subpopulations in the striatum in a differential manner. These findings highlight the heterogeneous striatal effects of tonic dopamine regulation via D2 receptors which potentially enable the treatment of diverse pathological states associated with basal ganglia dysfunction.

  13. Manganese-enhanced magnetic resonance imaging (MEMRI) reveals brain circuitry involved in responding to an acute novel stress in rats with a history of repeated social stress.

    Science.gov (United States)

    Bangasser, Debra A; Lee, Catherine S; Cook, Philip A; Gee, James C; Bhatnagar, Seema; Valentino, Rita J

    2013-10-02

    Responses to acute stressors are determined in part by stress history. For example, a history of chronic stress results in facilitated responses to a novel stressor and this facilitation is considered to be adaptive. We previously demonstrated that repeated exposure of rats to the resident-intruder model of social stress results in the emergence of two subpopulations that are characterized by different coping responses to stress. The submissive subpopulation failed to show facilitation to a novel stressor and developed a passive strategy in the Porsolt forced swim test. Because a passive stress coping response has been implicated in the propensity to develop certain psychiatric disorders, understanding the unique circuitry engaged by exposure to a novel stressor in these subpopulations would advance our understanding of the etiology of stress-related pathology. An ex vivo functional imaging technique, manganese-enhanced magnetic resonance imaging (MEMRI), was used to identify and distinguish brain regions that are differentially activated by an acute swim stress (15 min) in rats with a history of social stress compared to controls. Specifically, Mn(2+) was administered intracerebroventricularly prior to swim stress and brains were later imaged ex vivo to reveal activated structures. When compared to controls, all rats with a history of social stress showed greater activation in specific striatal, hippocampal, hypothalamic, and midbrain regions. The submissive subpopulation of rats was further distinguished by significantly greater activation in amygdala, bed nucleus of the stria terminalis, and septum, suggesting that these regions may form a circuit mediating responses to novel stress in individuals that adopt passive coping strategies. The finding that different circuits are engaged by a novel stressor in the two subpopulations of rats exposed to social stress implicates a role for these circuits in determining individual strategies for responding to stressors

  14. Dynamic plasticity in coupled avian midbrain maps

    Science.gov (United States)

    Atwal, Gurinder Singh

    2004-12-01

    Internal mapping of the external environment is carried out using the receptive fields of topographic neurons in the brain, and in a normal barn owl the aural and visual subcortical maps are aligned from early experiences. However, instantaneous misalignment of the aural and visual stimuli has been observed to result in adaptive behavior, manifested by functional and anatomical changes of the auditory processing system. Using methods of information theory and statistical mechanics a model of the adaptive dynamics of the aural receptive field is presented and analyzed. The dynamics is determined by maximizing the mutual information between the neural output and the weighted sensory neural inputs, admixed with noise, subject to biophysical constraints. The reduced costs of neural rewiring, as in the case of young barn owls, reveal two qualitatively different types of receptive field adaptation depending on the magnitude of the audiovisual misalignment. By letting the misalignment increase with time, it is shown that the ability to adapt can be increased even when neural rewiring costs are high, in agreement with recent experimental reports of the increased plasticity of the auditory space map in adult barn owls due to incremental learning. Finally, a critical speed of misalignment is identified, demarcating the crossover from adaptive to nonadaptive behavior.

  15. Participation of the dorsal periaqueductal grey matter in the hypoxic ventilatory response in unanaesthetized rats.

    Science.gov (United States)

    Lopes, L T; Biancardi, V; Vieira, E B; Leite-Panissi, C; Bícego, K C; Gargaglioni, L H

    2014-07-01

    Although periaqueductal grey matter activation is known to elicit respiratory and cardiovascular responses, the role of this midbrain area in the compensatory responses to hypoxia is still unknown. To test the participation of the periaqueductal grey matter in cardiorespiratory and thermal responses to hypoxia in adult male Wistar rats, we performed a chemical lesion of the dorsolateral/dorsomedial or the ventrolateral/lateral periaqueductal grey matter using ibotenic acid. Pulmonary ventilation, mean arterial pressure, heart rate and body temperature were measured in unanaesthetized rats during normoxic and hypoxic exposure (5, 15, 30 min, 7% O2). An ibotenic acid lesion of the dorsolateral/dorsomedial periaqueductal grey matter caused a higher increase in pulmonary ventilation (67.1%, 1730±282.5 mL kg(-1) min(-1)) compared to the Sham group (991.4±194 mL kg(-1) min(-1)) after 15 min in hypoxia, whereas for the ventrolateral/Lateral periaqueductal grey matter lesion, no differences were observed between groups. Mean arterial pressure, heart rate and body temperature were not affected by a dorsolateral/dorsomedial or ventrolateral/lateral periaqueductal grey matter lesion. Middle to caudal portions of the dorsolateral/dorsomedial periaqueductal grey matter neurones modulate the hypoxic ventilatory response, exerting an inhibitory modulation during low O2 situations. In addition, the middle to caudal portions of the dorsolateral/dorsomedial or ventrolateral/lateral periaqueductal grey matter do not appear to exert a tonic role on cardiovascular or thermal parameters during normoxic and hypoxic conditions. © 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

  16. Human olfactory bulb neural stem cells mitigate movement disorders in a rat model of Parkinson's disease.

    Science.gov (United States)

    Marei, Hany E S; Lashen, Samah; Farag, Amany; Althani, Asmaa; Afifi, Nahla; A, Abd-Elmaksoud; Rezk, Shaymaa; Pallini, Roberto; Casalbore, Patrizia; Cenciarelli, Carlo

    2015-07-01

    Parkinson's disease (PD) is a neurological disorder characterized by the loss of midbrain dopaminergic (DA) neurons. Neural stem cells (NSCs) are multipotent stem cells that are capable of differentiating into different neuronal and glial elements. The production of DA neurons from NSCs could potentially alleviate behavioral deficits in Parkinsonian patients; timely intervention with NSCs might provide a therapeutic strategy for PD. We have isolated and generated highly enriched cultures of neural stem/progenitor cells from the human olfactory bulb (OB). If NSCs can be obtained from OB, it would alleviate ethical concerns associated with the use of embryonic tissue, and provide an easily accessible cell source that would preclude the need for invasive brain surgery. Following isolation and culture, olfactory bulb neural stem cells (OBNSCs) were genetically engineered to express hNGF and GFP. The hNFG-GFP-OBNSCs were transplanted into the striatum of 6-hydroxydopamin (6-OHDA) Parkinsonian rats. The grafted cells survived in the lesion environment for more than eight weeks after implantation with no tumor formation. The grafted cells differentiated in vivo into oligodendrocyte-like (25 ± 2.88%), neuron-like (52.63 ± 4.16%), and astrocyte -like (22.36 ± 1.56%) lineages, which we differentiated based on morphological and immunohistochemical criteria. Transplanted rats exhibited a significant partial correction in stepping and placing in non-pharmacological behavioral tests, pole and rotarod tests. Taken together, our data encourage further investigations of the possible use of OBNSCs as a promising cell-based therapeutic strategy for Parkinson's disease. © 2014 Wiley Periodicals, Inc.

  17. Testosterone regulation of sex steroid-related mRNAs and dopamine-related mRNAs in adolescent male rat substantia nigra

    Directory of Open Access Journals (Sweden)

    Purves-Tyson Tertia D

    2012-08-01

    Full Text Available Abstract Background Increased risk of schizophrenia in adolescent males indicates that a link between the development of dopamine-related psychopathology and testosterone-driven brain changes may exist. However, contradictions as to whether testosterone increases or decreases dopamine neurotransmission are found and most studies address this in adult animals. Testosterone-dependent actions in neurons are direct via activation of androgen receptors (AR or indirect by conversion to 17β-estradiol and activation of estrogen receptors (ER. How midbrain dopamine neurons respond to sex steroids depends on the presence of sex steroid receptor(s and the level of steroid conversion enzymes (aromatase and 5α-reductase. We investigated whether gonadectomy and sex steroid replacement could influence dopamine levels by changing tyrosine hydroxylase (TH protein and mRNA and/or dopamine breakdown enzyme mRNA levels [catechol-O-methyl transferase (COMT and monoamine oxygenase (MAO A and B] in the adolescent male rat substantia nigra. We hypothesized that adolescent testosterone would regulate sex steroid signaling through regulation of ER and AR mRNAs and through modulation of aromatase and 5α-reductase mRNA levels. Results We find ERα and AR in midbrain dopamine neurons in adolescent male rats, indicating that dopamine neurons are poised to respond to circulating sex steroids. We report that androgens (T and DHT increase TH protein and increase COMT, MAOA and MAOB mRNAs in the adolescent male rat substantia nigra. We report that all three sex steroids increase AR mRNA. Differential action on ER pathways, with ERα mRNA down-regulation and ERβ mRNA up-regulation by testosterone was found. 5α reductase-1 mRNA was increased by AR activation, and aromatase mRNA was decreased by gonadectomy. Conclusions We conclude that increased testosterone at adolescence can shift the balance of sex steroid signaling to favor androgenic responses through promoting

  18. Individually reared rats

    International Nuclear Information System (INIS)

    Kraeuchi, K.; Gentsch, C.; Feer, H.

    1981-01-01

    The influence of social isolation in rats on postsynaptic alpha 1 - and beta-adrenergic receptors, on the cAMP generating system and on the presynaptic uptake mechanism in the central noradrenergic system was examined in different brain regions. Rearing rats in isolation from the 19th day of life for 12 weeks leads in all regions to a general tendency for a reduction in 3 H-DHA binding, to an enhanced 3 H-WB4101 binding and to a decreased responsiveness of the noradrenaline sensitive cAMP generating system. These changes reach significance only in the pons-medulla-thallamusregion. Isolated rats showed an increased synaptosomal uptake of noradrenaline, most pronounced and significant in the hypothalamus. Our data provide further support for a disturbance in central noradrenergic function in isolated rats. (author)

  19. Evolution of extra-nigral damage predicts behavioural deficits in a rat proteasome inhibitor model of Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Anthony C Vernon

    2011-02-01

    Full Text Available Establishing the neurological basis of behavioural dysfunction is key to provide a better understanding of Parkinson's disease (PD and facilitate development of effective novel therapies. For this, the relationships between longitudinal structural brain changes associated with motor behaviour were determined in a rat model of PD and validated by post-mortem immunohistochemistry. Rats bearing a nigrostriatal lesion induced by infusion of the proteasome inhibitor lactacystin into the left-medial forebrain bundle and saline-injected controls underwent magnetic resonance imaging (MRI at baseline (prior to surgery and 1, 3 and 5 weeks post-surgery with concomitant motor assessments consisting of forelimb grip strength, accelerating rotarod, and apormorphine-induced rotation. Lactacystin-injected rats developed early motor deficits alongside decreased ipsilateral cortical volumes, specifically thinning of the primary motor (M1 and somatosensory cortices and lateral ventricle hypertrophy (as determined by manual segmentation and deformation-based morphometry. Although sustained, motor dysfunction and nigrostriatal damage were maximal by 1 week post-surgery. Additional volume decreases in the ipsilateral ventral midbrain; corpus striatum and thalamus were only evident by week 3 and 5. Whilst cortical MRI volume changes best predicted the degree of motor impairment, post-mortem tyrosine hydroxylase immunoreactivity in the striatum was a better predictor of motor behaviour overall, with the notable exception of performance in the accelerating rotarod, in which, M1 cortical thickness remained the best predictor. These results highlight the importance of identifying extra-nigral regions of damage that impact on behavioural dysfunction from damage to the nigrostriatal system.

  20. Effect of time period after boric acid injection on {sup 10}B absorption in different regions of adult male rat's brain

    Energy Technology Data Exchange (ETDEWEB)

    Baghban Khojasteh, Nasrin, E-mail: khojasteh.nasrin@gmail.com [Nuclear Engineering Department, Science and Research Branch, Islamic Azad University, Poonak Sq. PO Box 14515-775, Tehran (Iran, Islamic Republic of); Pazirandeh, Ali [Nuclear Engineering Department, Science and Research Branch, Islamic Azad University, Poonak Sq. PO Box 14515-775, Tehran (Iran, Islamic Republic of); Jameie, Behnam [Nuclear Engineering Department, Science and Research Branch, Islamic Azad University, Poonak Sq. PO Box 14515-775, Tehran (Iran, Islamic Republic of); Laboratory of Basic Science and Neuroscience, Basic Science Dept, Faculty of Allied Medicine, Cellular and Molecular Research Center, Tehran University of Medical Science, Pardis-e-Hemmat,Tehran (Iran, Islamic Republic of); Goodarzi, Samereh [Nuclear Engineering Department, Science and Research Branch, Islamic Azad University, Poonak Sq. PO Box 14515-775, Tehran (Iran, Islamic Republic of)

    2012-06-15

    Distribution of {sup 10}B in different regions of rat normal brain was studied. Two groups were chosen as control and trial. Trial group received 2 ml of neutral boron compound. 2, 4 and 6 h after the injection brain removed, coronal sections of forebrain, midbrain and hindbrain were sandwiched between two pieces of polycarbonate. Autoradiography plots of {sup 10}B distribution showed significant differences in three regions with the highest {sup 10}B concentration in the forebrain during 4 h after injection. - Highlights: Black-Right-Pointing-Pointer Normal tissue tolerance is very important in BNCT. Black-Right-Pointing-Pointer This study has been done to determine {sup 10}B distribution in three anatomical regions of rat normal brain. Black-Right-Pointing-Pointer These specific regions of brain have not been studied in previous BNCT projects. Black-Right-Pointing-Pointer We found significant differences in {sup 10}B distribution between these three regions. Black-Right-Pointing-Pointer In different time periods after neutral boron compound injection, there has been a significant difference in boron absorption.

  1. New Insights on Different Response of MDMA-Elicited Serotonin Syndrome to Systemic and Intracranial Administrations in the Rat Brain.

    Science.gov (United States)

    Shokry, Ibrahim M; Callanan, John J; Sousa, John; Tao, Rui

    2016-01-01

    In spite of the fact that systemic administration of MDMA elicits serotonin syndrome, direct intracranial administration fails to reproduce the effect. To reconcile these findings, it has been suggested that the cause of serotonin syndrome is attributed mainly to MDMA hepatic metabolites, and less likely to MDMA itself. Recently, however, this explanation has been challenged, and alternative hypotheses need to be explored. Here, we tested the hypothesis that serotonin syndrome is the result of excessive 5HT simultaneously in many brain areas, while MDMA administered intracranially fails to cause serotonin syndrome because it produces only a localized effect at the delivery site and not to other parts of the brain. This hypothesis was examined using adult male Sprague Dawley rats by comparing 5HT responses in the right and left hemispheric frontal cortices, right and left hemispheric diencephalons, and medullar raphe nucleus. Occurrence of serotonin syndrome was confirmed by measuring change in body temperature. Administration routes included intraperitoneal (IP), intracerebroventricular (ICV) and reverse microdialysis. First, we found that IP administration caused excessive 5HT in all five sites investigated and induced hypothermia, suggesting the development of the serotonin syndrome. In contrast, ICV and reverse microdialysis caused excessive 5HT only in regions of delivery sites without changes in body-core temperature, suggesting the absence of the syndrome. Next, chemical dyes were used to trace differences in distribution and diffusion patterns between administration routes. After systemic administration, the dyes were found to be evenly distributed in the brain. However, the dyes administered through ICV or reverse microdialysis injection still remained in the delivery sites, poorly diffusing to the brain. In conclusion, intracranial MDMA administration in one area has no or little effect on other areas, which must be considered a plausible reason for the

  2. New Insights on Different Response of MDMA-Elicited Serotonin Syndrome to Systemic and Intracranial Administrations in the Rat Brain.

    Directory of Open Access Journals (Sweden)

    Ibrahim M Shokry

    Full Text Available In spite of the fact that systemic administration of MDMA elicits serotonin syndrome, direct intracranial administration fails to reproduce the effect. To reconcile these findings, it has been suggested that the cause of serotonin syndrome is attributed mainly to MDMA hepatic metabolites, and less likely to MDMA itself. Recently, however, this explanation has been challenged, and alternative hypotheses need to be explored. Here, we tested the hypothesis that serotonin syndrome is the result of excessive 5HT simultaneously in many brain areas, while MDMA administered intracranially fails to cause serotonin syndrome because it produces only a localized effect at the delivery site and not to other parts of the brain. This hypothesis was examined using adult male Sprague Dawley rats by comparing 5HT responses in the right and left hemispheric frontal cortices, right and left hemispheric diencephalons, and medullar raphe nucleus. Occurrence of serotonin syndrome was confirmed by measuring change in body temperature. Administration routes included intraperitoneal (IP, intracerebroventricular (ICV and reverse microdialysis. First, we found that IP administration caused excessive 5HT in all five sites investigated and induced hypothermia, suggesting the development of the serotonin syndrome. In contrast, ICV and reverse microdialysis caused excessive 5HT only in regions of delivery sites without changes in body-core temperature, suggesting the absence of the syndrome. Next, chemical dyes were used to trace differences in distribution and diffusion patterns between administration routes. After systemic administration, the dyes were found to be evenly distributed in the brain. However, the dyes administered through ICV or reverse microdialysis injection still remained in the delivery sites, poorly diffusing to the brain. In conclusion, intracranial MDMA administration in one area has no or little effect on other areas, which must be considered a plausible

  3. Anatomical and electrophysiological characterization of presumed dopamine-containing neurons within the supramammillary region of the rat.

    Science.gov (United States)

    Shepard, P D; Mihailoff, G A; German, D C

    1988-03-01

    A combination of immunocytochemical, electrophysiological and pharmacological techniques were employed to study the properties of neurons within the supramammillary (SUM) complex of the rat. The SUM region contains a small, but dense, population of tyrosine hydroxylase immunoreactive neurons. Following injection of the orthograde neuroanatomical tracer, Phaseolus Vulgaris leucoagglutinin, into the SUM region, heavy terminal labeling was observed in the lateral septal nucleus, diagonal band of Broca and bed nucleus of the stria terminalis. The electrophysiological and pharmacological properties of antidromically-activated SUM neurons revealed evidence of two neuronal populations. Both groups of neurons exhibited long duration action potentials (greater than 2 msec) and slow conduction velocities (less than 0.5 m/sec). However, cells in one group were characterized by slow and erratic firing rates and insensitivity to dopamine (DA) autoreceptor agonists. Cells in the other group typically exhibited no spontaneous activity but could be induced to discharge by iontophoretic application of glutamate. These latter cells were sensitive to DA autoreceptor stimulation. Of the two populations of mammilloseptal SUM neurons, the silent population exhibited several properties similar to those of midbrain DA neurons.

  4. 5-HT1A receptor gene silencers Freud-1 and Freud-2 are differently expressed in the brain of rats with genetically determined high level of fear-induced aggression or its absence.

    Science.gov (United States)

    Kondaurova, Elena M; Ilchibaeva, Tatiana V; Tsybko, Anton S; Kozhemyakina, Rimma V; Popova, Nina K; Naumenko, Vladimir S

    2016-09-01

    Serotonin 5-HT1A receptor is known to play a crucial role in the mechanisms of genetically defined aggression. In its turn, 5-HT1A receptor functional state is under control of multiple factors. Among others, transcriptional factors Freud-1 and Freud-2 are known to be involved in the repression of 5-HT1A receptor gene expression. However, implication of these factors in the regulation of behavior is unclear. Here, we investigated the expression of 5-HT1A receptor and silencers Freud-1 and Freud-2 in the brain of rats selectively bred for 85 generations for either high level of fear-induced aggression or its absence. It was shown that Freud-1 and Freud-2 levels were different in aggressive and nonaggressive animals. Freud-1 protein level was decreased in the hippocampus, whereas Freud-2 protein level was increased in the frontal cortex of highly aggressive rats. There no differences in 5-HT1A receptor gene expression were found in the brains of highly aggressive and nonaggressive rats. However, 5-HT1A receptor protein level was decreased in the midbrain and increased in the hippocampus of highly aggressive rats. These data showed the involvement of Freud-1 and Freud-2 in the regulation of genetically defined fear-induced aggression. However, these silencers do not affect transcription of the 5-HT1A receptor gene in the investigated rats. Our data indicate the implication of posttranscriptional rather than transcriptional regulation of 5-HT1A receptor functional state in the mechanisms of genetically determined aggressive behavior. On the other hand, the implication of other transcriptional regulators for 5-HT1A receptor gene in the mechanisms of genetically defined aggression could be suggested. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Structure of the vitreoretinal border region in spontaneously hypertensive rats (SHR rats)

    DEFF Research Database (Denmark)

    Heegaard, Steffen

    1993-01-01

    Øjenpatologi, vitreoretinal border region, inner limiting membrane of the retina, spontaneously hypertensive rats, SHR rats, ultrastructure......Øjenpatologi, vitreoretinal border region, inner limiting membrane of the retina, spontaneously hypertensive rats, SHR rats, ultrastructure...

  6. Rat bite fever.

    NARCIS (Netherlands)

    Gaastra, W.; Boot, R.G.A.; Ho, H.; Lipman, L.J.A.

    2009-01-01

    Rat bite fever (RBF) is a bacterial zoonosis for which two causal bacterial species have been identified: Streptobacillis moniliformis and Spirillum minus. Haverhill fever (HF) is a form of S. moniliformis infection believed to develop after ingestion of contaminated food or water. Here the

  7. Neuroanatomical patterns of the mu, delta, and kappa opioid receptors of rat brain as determined by quantitative in vitro autoradiography

    International Nuclear Information System (INIS)

    Tempel, A.; Zukin, R.S.

    1987-01-01

    Highly specific radioligands and quantitative autoradiography reveal strikingly different neuroanatomical patterns for the mu, delta, and kappa opioid receptors of rat brain. The mu receptors are most densely localized in patches in the striatum, layers I and III of the cortex, the pyramidal cell layer of the hippocampal formation, specific nuclei of the thalamus, the pars reticulata of the substantia nigra, the interpeduncular nucleus, and the locus coeruleus. In contrast, delta receptors are highly confined, exhibiting selective localization in layers I, II, and VIa of the neocortex, a diffuse pattern in the striatum, and moderate concentration in the pars reticulata of the substantia nigra and in the interpeduncular nucleus. delta receptors are absent in most other brain structures. This distribution is unexpected in that the enkephalins, the putative endogenous ligands of the delta receptor, occur essentially throughout the brain. The kappa receptors of rat brain exhibit a third pattern distinct from that of the mu and delta receptors. kappa receptors occur at low density in patches in the striatum and at particularly high density in the nucleus accumbens, along the pyramidal and molecular layers of the hippocampus, in the granular cell layer of the dentate gyrus, specific midline nuclei of the thalamus, and hindbrain regions. kappa receptors appear to be uniformly distributed across regions in the neocortex with the exception of layer III, which revealed only trace levels of binding. An important conclusion of the present study is that delta receptors occur at high density only in the forebrain and in two midbrain structures, whereas mu and kappa receptors exhibit discrete patterns in most major brain regions

  8. Biochemical changes in tissue catecholamines and serotonin in duodenal ulceration caused by cysteamine or propionitrile in the rat

    International Nuclear Information System (INIS)

    Szabo, S.; Horner, H.C.; Maull, H.; Schnoor, J.; Chiueh, C.C.; Palkovits, M.

    1987-01-01

    Previous structure-activity and pharmacologic studies with duodenal ulcerogens cysteamine and propionitrile implicating catecholamines in the pathogenesis of duodenal ulceration have now been followed up by dose- and time-response biochemical investigations to assess the importance of monoamines in the development of duodenal ulcers. The concentrations of norepinephrine (noradrenaline), dopamine, serotonin and their metabolites were measured in total brain, brain regions, stomach, duodenum, pancreas and adrenals in the rat. Turnover of catecholamines was determined in rats pretreated with the inhibitor of tyrosine hydroxylase alpha-methyl-p-tyrosine. The duodenal ulcerogens caused a dose- and time-dependent depletion of norepinephrine in virtually all the tissues examined. The effect was maximal 4 or 7 hr after cysteamine or propionitrile, and norepinephrine levels returned to normal in 24 hr. Dopamine changes were selective and often biphasic, e.g., elevation in adrenals, biphasic in brain cortex, hippocampus and midbrain, but uniformly decreasing in glandular stomach and duodenum. In the median eminence dopamine levels decreased by 181 and 324% at 15 and 30 min, respectively, after cysteamine, but neither dopamine nor 3,4-dihydroxyphenylacetic acid was modified in the periventricular nucleus. Serotonin levels were relatively stable, revealing slight elevations or no changes in most of the tissues. The turnover of norepinephrine was accelerated by both chemicals in virtually all brain regions, but dopamine turnover was affected only in a few areas, e.g., in the corpus striatum and medulla oblongata cysteamine decreased dopamine turnover, whereas propionitrile first (at 1 hr) accelerated then (at 8 hr) significantly suppressed it.(ABSTRACT TRUNCATED AT 250 WORDS)

  9. Formation of multinucleated giant cells and microglial degeneration in rats expressing a mutant Cu/Zn superoxide dismutase gene

    Directory of Open Access Journals (Sweden)

    Streit Wolfgang J

    2007-02-01

    Full Text Available Abstract Background Microglial neuroinflammation is thought to play a role in the pathogenesis of amyotrophic lateral sclerosis (ALS. The purpose of this study was to provide a histopathological evaluation of the microglial neuroinflammatory response in a rodent model of ALS, the SOD1G93A transgenic rat. Methods Multiple levels of the CNS from spinal cord to cerebral cortex were studied in SOD1G93A transgenic rats during three stages of natural disease progression, including presymptomatic, early symptomatic (onset, and late symptomatic (end stage, using immuno- and lectin histochemical markers for microglia, such as OX-42, OX-6, and Griffonia simplicifolia isolectin B4. Results Our studies revealed abnormal aggregates of microglia forming in the spinal cord as early as the presymptomatic stage. During the symptomatic stages there was prominent formation of multinucleated giant cells through fusion of microglial cells in the spinal cord, brainstem, and red nucleus of the midbrain. Other brain regions, including substantia nigra, cranial nerve nuclei, hippocampus and cortex showed normal appearing microglia. In animals during end stage disease at 4–5 months of age virtually all microglia in the spinal cord gray matter showed extensive fragmentation of their cytoplasm (cytorrhexis, indicative of widespread microglial degeneration. Few microglia exhibiting nuclear fragmentation (karyorrhexis indicative of apoptosis were identified at any stage. Conclusion The current findings demonstrate the occurrence of severe abnormalities in microglia, such as cell fusions and cytorrhexis, which may be the result of expression of mutant SOD1 in these cells. The microglial changes observed are different from those that accompany normal microglial activation, and they demonstrate that aberrant activation and degeneration of microglia is part of the pathogenesis of motor neuron disease.

  10. Effect of background noise on neuronal coding of interaural level difference cues in rat inferior colliculus.

    Science.gov (United States)

    Mokri, Yasamin; Worland, Kate; Ford, Mark; Rajan, Ramesh

    2015-07-01

    Humans can accurately localize sounds even in unfavourable signal-to-noise conditions. To investigate the neural mechanisms underlying this, we studied the effect of background wide-band noise on neural sensitivity to variations in interaural level difference (ILD), the predominant cue for sound localization in azimuth for high-frequency sounds, at the characteristic frequency of cells in rat inferior colliculus (IC). Binaural noise at high levels generally resulted in suppression of responses (55.8%), but at lower levels resulted in enhancement (34.8%) as well as suppression (30.3%). When recording conditions permitted, we then examined if any binaural noise effects were related to selective noise effects at each of the two ears, which we interpreted in light of well-known differences in input type (excitation and inhibition) from each ear shaping particular forms of ILD sensitivity in the IC. At high signal-to-noise ratios (SNR), in most ILD functions (41%), the effect of background noise appeared to be due to effects on inputs from both ears, while for a large percentage (35.8%) appeared to be accounted for by effects on excitatory input. However, as SNR decreased, change in excitation became the dominant contributor to the change due to binaural background noise (63.6%). These novel findings shed light on the IC neural mechanisms for sound localization in the presence of continuous background noise. They also suggest that some effects of background noise on encoding of sound location reported to be emergent in upstream auditory areas can also be observed at the level of the midbrain. © 2015 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  11. GABAB-receptor activation alters the firing pattern of dopamine neurons in the rat substantia nigra.

    Science.gov (United States)

    Engberg, G; Kling-Petersen, T; Nissbrandt, H

    1993-11-01

    Previous electrophysiological experiments have emphasized the importance of the firing pattern for the functioning of midbrain dopamine (DA) neurons. In this regard, excitatory amino acid receptors appear to constitute an important modulatory control mechanism. In the present study, extracellular recording techniques were used to investigate the significance of GABAB-receptor activation for the firing properties of DA neurons in the substantia nigra (SN) in the rat. Intravenous administration of the GABAB-receptor agonist baclofen (1-16 mg/kg) was associated with a dose-dependent regularization of the firing pattern, concomitant with a reduction in burst firing. At higher doses (16-32 mg/kg), the firing rate of the DA neurons was dose-dependently decreased. Also, microiontophoretic application of baclofen regularized the firing pattern of nigral DA neurons, including a reduction of burst firing. Both the regularization of the firing pattern and inhibition of firing rate produced by systemic baclofen administration was antagonized by the GABAB-receptor antagonist CGP 35348 (200 mg/kg, i.v.). The GABAA-receptor agonist muscimol produced effects on the firing properties of DA neurons that were opposite to those observed following baclofen, i.e., an increase in firing rate accompanied by a decreased regularity. The NMDA receptor antagonist MK 801 (0.4-3.2 mg/kg, i.v.) produced a moderate, dose-dependent increase in the firing rate of the nigral DA neurons as well as a slightly regularized firing pattern. Pretreatment with MK 801 (3.2 mg/kg, i.v., 3-10 min) did neither promote nor prevent the regularization of the firing pattern or inhibition of firing rate on the nigral DA neurons produced by baclofen. The present results clearly show that GABAB-receptors can alter the firing pattern of nigral DA neurons, hereby counterbalancing the previously described ability of glutamate to induce burst firing activity on these neurons.

  12. A sodium afterdepolarization in rat superior colliculus neurons and its contribution to population activity.

    Science.gov (United States)

    Ghitani, Nima; Bayguinov, Peter O; Basso, Michele A; Jackson, Meyer B

    2016-07-01

    The mammalian superior colliculus (SC) is a midbrain structure that integrates multimodal sensory inputs and computes commands to initiate rapid eye movements. SC neurons burst with the sudden onset of a visual stimulus, followed by persistent activity that may underlie shifts of attention and decision making. Experiments in vitro suggest that circuit reverberations play a role in the burst activity in the SC, but the origin of persistent activity is unclear. In the present study we characterized an afterdepolarization (ADP) that follows action potentials in slices of rat SC. Population responses seen with voltage-sensitive dye imaging consisted of rapid spikes followed immediately by a second distinct depolarization of lower amplitude and longer duration. Patch-clamp recordings showed qualitatively similar behavior: in nearly all neurons throughout the SC, rapid spikes were followed by an ADP. Ionic and pharmacological manipulations along with experiments with current and voltage steps indicated that the ADP of SC neurons arises from Na(+) current that either persists or resurges following Na(+) channel inactivation at the end of an action potential. Comparisons of pharmacological properties and frequency dependence revealed a clear parallel between patch-clamp recordings and voltage imaging experiments, indicating a common underlying membrane mechanism for the ADP in both single neurons and populations. The ADP can initiate repetitive spiking at intervals consistent with the frequency of persistent activity in the SC. These results indicate that SC neurons have intrinsic membrane properties that can contribute to electrical activity that underlies shifts of attention and decision making. Copyright © 2016 the American Physiological Society.

  13. Laughing rats are optimistic.

    Directory of Open Access Journals (Sweden)

    Rafal Rygula

    Full Text Available Emotions can bias human decisions- for example depressed or anxious people tend to make pessimistic judgements while those in positive affective states are often more optimistic. Several studies have reported that affect contingent judgement biases can also be produced in animals. The animals, however, cannot self-report; therefore, the valence of their emotions, to date, could only be assumed. Here we present the results of an experiment where the affect-contingent judgement bias has been produced by objectively measured positive emotions. We trained rats in operant Skinner boxes to press one lever in response to one tone to receive a food reward and to press another lever in response to a different tone to avoid punishment by electric foot shock. After attaining a stable level of discrimination performance, the animals were subjected to either handling or playful, experimenter-administered manual stimulation - tickling. This procedure has been confirmed to induce a positive affective state in rats, and the 50-kHz ultrasonic vocalisations (rat laughter emitted by animals in response to tickling have been postulated to index positive emotions akin to human joy. During the tickling and handling sessions, the numbers of emitted high-frequency 50-kHz calls were scored. Immediately after tickling or handling, the animals were tested for their responses to a tone of intermediate frequency, and the pattern of their responses to this ambiguous cue was taken as an indicator of the animals' optimism. Our findings indicate that tickling induced positive emotions which are directly indexed in rats by laughter, can make animals more optimistic. We demonstrate for the first time a link between the directly measured positive affective state and decision making under uncertainty in an animal model. We also introduce innovative tandem-approach for studying emotional-cognitive interplay in animals, which may be of great value for understanding the emotional

  14. Evidence that the periaqueductal gray matter mediates the facilitation of panic-like reactions in neonatally-isolated adult rats.

    Directory of Open Access Journals (Sweden)

    Jeyce Willig Quintino-dos-Santos

    Full Text Available Plenty of evidence suggests that childhood separation anxiety (CSA predisposes the subject to adult-onset panic disorder (PD. As well, panic is frequently comorbid with both anxiety and depression. The brain mechanisms whereby CSA predisposes to PD are but completely unknown in spite of the increasing evidence that panic attacks are mediated at midbrain's dorsal periaqueductal gray matter (DPAG. Accordingly, here we examined whether the neonatal social isolation (NSI, a model of CSA, facilitates panic-like behaviors produced by electrical stimulations of DPAG of rats as adults. Eventual changes in anxiety and depression were also assessed in the elevated plus-maze (EPM and forced-swimming test (FST respectively. Male pups were subjected to 3-h daily isolations from post-natal day 2 (PN2 until weaning (PN21 allotting half of litters in individual boxes inside a sound-attenuated chamber (NSI, n = 26 whilst siblings (sham-isolated rats, SHAM, n = 27 and dam were moved to another box in a separate room. Non-handled controls (CTRL, n = 18 remained undisturbed with dams until weaning. As adults, rats were implanted with electrodes into the DPAG (PN60 and subjected to sessions of intracranial stimulation (PN65, EPM (PN66 and FST (PN67-PN68. Groups were compared by Fisher's exact test (stimulation sites, likelihood ratio chi-square tests (stimulus-response threshold curves and Bonferroni's post hoc t-tests (EPM and FST, for P<0.05. Notably, DPAG-evoked panic-like responses of immobility, exophthalmus, trotting, galloping and jumping were markedly facilitated in NSI rats relative to both SHAM and CTRL groups. Conversely, anxiety and depression scores either did not change or were even reduced in neonatally-handled groups relative to CTRL, respectively. Data are the first behavioral evidence in animals that early-life separation stress produces the selective facilitation of panic-like behaviors in adulthood. Most importantly, results implicate

  15. Distribution of Fos-Like Immunoreactivity, Catecholaminergic and Serotoninergic Neurons Activated by the Laryngeal Chemoreflex in the Medulla Oblongata of Rats.

    Science.gov (United States)

    Wang, Xiaolu; Guo, Ruichen; Zhao, Wenjing

    2015-01-01

    The laryngeal chemoreflex (LCR) induces apnea, glottis closure, bradycardia and hypertension in young and maturing mammals. We examined the distribution of medullary nuclei that are activated by the LCR and used immunofluorescent detection of Fos protein as a cellular marker for neuronal activation to establish that the medullary catecholaminergic and serotoninergic neurons participate in the modulation of the LCR. The LCR was elicited by the infusion of KCl-HCl solution into the laryngeal lumen of adult rats in the experimental group, whereas the control group received the same surgery but no infusion. In comparison, the number of regions of Fos-like immunoreactivity (FLI) that were activated by the LCR significantly increased in the nucleus of the solitary tract (NTS), the vestibular nuclear complex (VNC), the loose formation of the nucleus ambiguus (AmbL), the rostral ventral respiratory group (RVRG), the ventrolateral reticular complex (VLR), the pre-Bötzinger complex (PrBöt), the Bötzinger complex (Böt), the spinal trigeminal nucleus (SP5), and the raphe obscurus nucleus (ROb) bilaterally from the medulla oblongata. Furthermore, 12.71% of neurons with FLI in the dorsolateral part of the nucleus of the solitary tract (SolDL) showed tyrosine hydroxylase-immunoreactivity (TH-ir, catecholaminergic), and 70.87% of neurons with FLI in the ROb were serotoninergic. Our data demonstrated the distribution of medullary nuclei that were activated by the LCR, and further demonstrated that catecholaminergic neurons of the SolDL and serotoninergic neurons of the ROb were activated by the LCR, indicating the potential central pathway of the LCR.

  16. Distribution of Fos-Like Immunoreactivity, Catecholaminergic and Serotoninergic Neurons Activated by the Laryngeal Chemoreflex in the Medulla Oblongata of Rats.

    Directory of Open Access Journals (Sweden)

    Xiaolu Wang

    Full Text Available The laryngeal chemoreflex (LCR induces apnea, glottis closure, bradycardia and hypertension in young and maturing mammals. We examined the distribution of medullary nuclei that are activated by the LCR and used immunofluorescent detection of Fos protein as a cellular marker for neuronal activation to establish that the medullary catecholaminergic and serotoninergic neurons participate in the modulation of the LCR. The LCR was elicited by the infusion of KCl-HCl solution into the laryngeal lumen of adult rats in the experimental group, whereas the control group received the same surgery but no infusion. In comparison, the number of regions of Fos-like immunoreactivity (FLI that were activated by the LCR significantly increased in the nucleus of the solitary tract (NTS, the vestibular nuclear complex (VNC, the loose formation of the nucleus ambiguus (AmbL, the rostral ventral respiratory group (RVRG, the ventrolateral reticular complex (VLR, the pre-Bötzinger complex (PrBöt, the Bötzinger complex (Böt, the spinal trigeminal nucleus (SP5, and the raphe obscurus nucleus (ROb bilaterally from the medulla oblongata. Furthermore, 12.71% of neurons with FLI in the dorsolateral part of the nucleus of the solitary tract (SolDL showed tyrosine hydroxylase-immunoreactivity (TH-ir, catecholaminergic, and 70.87% of neurons with FLI in the ROb were serotoninergic. Our data demonstrated the distribution of medullary nuclei that were activated by the LCR, and further demonstrated that catecholaminergic neurons of the SolDL and serotoninergic neurons of the ROb were activated by the LCR, indicating the potential central pathway of the LCR.

  17. The Serotonin Receptor 6 Antagonist Idalopirdine and Acetylcholinesterase Inhibitor Donepezil Have Synergistic Effects on Brain Activity—A Functional MRI Study in the Awake Rat

    Directory of Open Access Journals (Sweden)

    Craig F. Ferris

    2017-06-01

    Full Text Available The 5-HT6 receptor is a promising target for cognitive disorders, in particular for Alzheimer's disease (AD and other CNS disorders. The high-affinity and selective 5-HT6 receptor antagonist idalopirdine (Lu AE58054 is currently in development for mild-moderate AD as adjunct therapy to acetylcholinesterase inhibitors (AChEIs. We studied the effects of idalopirdine alone and in combination with the AChEI donepezil on brain activity using BOLD (Blood Oxygen Level Dependent functional magnetic resonance imaging (fMRI in the awake rat. Idalopirdine (2 mg/kg, i.v. alone had a modest effect on brain activity, resulting in activation of eight brain regions at the peak response. Of these, the cholinergic diagonal band of Broca, the infralimbic cortex, the ventral pallidum, the nucleus accumbens shell, and the magnocellular preoptic area were shared with the effects of donepezil (0.3 mg/kg, i.v.. Donepezil alone activated 19 brain regions at the peak response, including several cortical regions, areas of the septo-hippocampal system and the serotonergic raphe nucleus. When idalopirdine and donepezil were combined, there was a robust stimulation pattern with activation of 36 brain regions spread across the extended-amygdala-, striato-pallidal, and septo-hippocampal networks as well as the cholinergic system. These findings indicate that, whilst idalopirdine and donepezil recruit a number of overlapping regions including one of the forebrain cholinergic nuclei, the synergistic effect of both compounds extends beyond the cholinergic system and the effects of donepezil alone toward recruitment of multiple neural circuits and neurotransmitter systems. These data provide new insight into the mechanisms via which idalopirdine might improve cognition in donepezil-treated AD patients.

  18. Local connections between the columns of the periaqueductal gray matter: a case for intrinsic neuromodulation.

    Science.gov (United States)

    Jansen, A S; Farkas, E; Mac Sams, J; Loewy, A D

    1998-02-16

    Chemical stimulation of the lateral or ventrolateral columns of the midbrain periaqueductal gray matter (PAG) in conscious animals produces opposite responses (viz., defensive behavior and pressor responses from the lateral column vs. quiescence and depressor responses from the ventrolateral column), raising the possibility that the two columns are interconnected. To test this hypothesis, two types of anatomical experiments were performed in rats. First, the anterograde axonal marker Phaseolus vulgaris leuco-agglutinin (PHA-L) was injected into individual PAG columns or adjoining regions which included the Edinger-Westphal, dorsal raphe, and precommissural nuclei. The results shows that each column projects bilaterally to all of the other PAG columns, and also provides local connections within its own column. Furthermore, the Edinger-Westphal and precommissural nuclei project to all four PAG columns, while the dorsal raphe nucleus projects only to the ventrolateral and lateral columns. In a second experiment, we found that cardiovascular-related PAG projection neurons of both the lateral and ventrolateral columns receive an input from the reciprocal PAG column. This was demonstrated by a double tracer neuroanatomical study in which PHA-L was first iontophoretically ejected into either the lateral or ventrolateral PAG columns and then, several days later the retrograde transneuronal viral tracer, pseudorabies virus, was injected into the stellate sympathetic ganglion. Intra-PAG circuits were visualized by a dual immunohistochemical procedure. These results suggest that during the fight-or-flight response when the 'fight' program is activated, inhibition of the 'flight' PAG network may occur and the converse situation may occur during the flight response. Copyright 1997 Elsevier Science B.V.

  19. A method based on Monte Carlo simulations and voxelized anatomical atlases to evaluate and correct uncertainties on radiotracer accumulation quantitation in beta microprobe studies in the rat brain

    Science.gov (United States)

    Pain, F.; Dhenain, M.; Gurden, H.; Routier, A. L.; Lefebvre, F.; Mastrippolito, R.; Lanièce, P.

    2008-10-01

    The β-microprobe is a simple and versatile technique complementary to small animal positron emission tomography (PET). It relies on local measurements of the concentration of positron-labeled molecules. So far, it has been successfully used in anesthetized rats for pharmacokinetics experiments and for the study of brain energetic metabolism. However, the ability of the technique to provide accurate quantitative measurements using 18F, 11C and 15O tracers is likely to suffer from the contribution of 511 keV gamma rays background to the signal and from the contribution of positrons from brain loci surrounding the locus of interest. The aim of the present paper is to provide a method of evaluating several parameters, which are supposed to affect the quantification of recordings performed in vivo with this methodology. We have developed realistic voxelized phantoms of the rat whole body and brain, and used them as input geometries for Monte Carlo simulations of previous β-microprobe reports. In the context of realistic experiments (binding of 11C-Raclopride to D2 dopaminergic receptors in the striatum; local glucose metabolic rate measurement with 18F-FDG and H2O15 blood flow measurements in the somatosensory cortex), we have calculated the detection efficiencies and corresponding contribution of 511 keV gammas from peripheral organs accumulation. We confirmed that the 511 keV gammas background does not impair quantification. To evaluate the contribution of positrons from adjacent structures, we have developed β-Assistant, a program based on a rat brain voxelized atlas and matrices of local detection efficiencies calculated by Monte Carlo simulations for several probe geometries. This program was used to calculate the 'apparent sensitivity' of the probe for each brain structure included in the detection volume. For a given localization of a probe within the brain, this allows us to quantify the different sources of beta signal. Finally, since stereotaxic accuracy is

  20. Chemogenetic activation of dopamine neurons in the ventral tegmental area, but not substantia nigra, induces hyperactivity in rats

    NARCIS (Netherlands)

    Boekhoudt, Linde; Omrani, Azar; Luijendijk, Mieneke C M; Wolterink-Donselaar, Inge G; Wijbrans, Ellen C; van der Plasse, Geoffrey; Adan, Roger A H

    2016-01-01

    Hyperactivity is a core symptom in various psychiatric disorders, including attention-deficit/hyperactivity disorder, schizophrenia, bipolar disorders, and anorexia nervosa. Although hyperactivity has been linked to dopaminergic  signalling, the causal relationship between midbrain dopamine neuronal

  1. Tubuloglomerular feedback in Dahl rats

    DEFF Research Database (Denmark)

    Karlsen, F M; Leyssac, P P; Holstein-Rathlou, N H

    1998-01-01

    in both Dahl-S and salt-resistant Dahl rats on high- and low-salt diets. TGF was investigated in the closed-loop mode with a videometric technique, in which the response in late proximal flow rate to perturbations in Henle flow rate was measured. All Dahl rats showed a similar compensatory response...

  2. Neutron radiography of osteopetrotic rat

    International Nuclear Information System (INIS)

    Graf, B.; Renard, G.; Le Gall, J.; Laporte, A.

    1983-01-01

    The osteopetrotic disease is characterized by bone and cartilage tissue coexistence in the medullary space of long bones. The authors have studied ''congenital osteopetrosis'' of ''op'' rats. Comparing radiography, neutrography and histology, the evolution of the ''osteopetrotic disease'' and the healing of the ill rats by a single injection of bone marrow from normal animals is shown. (Auth.)

  3. The three-kidney rat

    International Nuclear Information System (INIS)

    Provoost, A.P.; Van Aken, M.

    1984-01-01

    In contrast to the numerous research into the adaption of renal function when nephons are lost, much less attention has been paid to the effects of an extra kidney. Through the availability of inbred rat strains, techniques to transplant rat kidneys, and methods to measure total and individual kidney function repeatedly in the same animal, it became possible to study the renal function in rats with three kidneys. Adult male rats of a highly inbred Wistar strain were used. Nine recipients of a third kidney (3-K) were compared with 5 sham operated control (2-K) rats. The total GFR, as measured by the plasma clearance of Cr-5l EDTA, was taken 1,3,6,9, and 15 weeks after operation. The contribution of each kidney to the total renal function was determined by a Tc-99m DTPA scan performed at weeks 10 and 16. After transplantation the total GFR of 3-K rats was, in general, not different from the value before transplantation or from that of 2-K rats. The lack of increase of the GFR of 3-K rats was not the result of a non-functioning graft

  4. Developmental exposure to terbutaline alters cell signaling in mature rat brain regions and augments the effects of subsequent neonatal exposure to the organophosphorus insecticide chlorpyrifos

    International Nuclear Information System (INIS)

    Meyer, Armando; Seidler, Frederic J.; Aldridge, Justin E.; Slotkin, Theodore A.

    2005-01-01

    Exposure to apparently unrelated neurotoxicants can nevertheless converge on common neurodevelopmental events. We examined the long-term effects of developmental exposure of rats to terbutaline, a β-adrenoceptor agonist used to arrest preterm labor, and the organophosphorus insecticide chlorpyrifos (CPF) separately and together. Treatments mimicked the appropriate neurodevelopmental stages for human exposures: terbutaline on postnatal days (PN) 2-5 and CPF on PN11-14, with assessments conducted on PN45. Although neither treatment affected growth or viability, each elicited alterations in CNS cell signaling mediated by adenylyl cyclase (AC), a transduction pathway shared by numerous neuronal and hormonal signals. Terbutaline altered signaling in the brainstem and cerebellum, with gender differences particularly notable in the cerebellum (enhanced AC in males, suppressed in females). By itself, CPF exposure elicited deficits in AC signaling in the midbrain, brainstem, and striatum. However, sequential exposure to terbutaline followed by CPF produced larger alterations and involved a wider spectrum of brain regions than were obtained with either agent alone. In the cerebral cortex, adverse effects of the combined treatment intensified between PN45 and PN60, suggesting that exposures alter the long-term program for development of synaptic communication, leading to alterations in AC signaling that emerge even after adolescence. These findings indicate that terbutaline, like CPF, is a developmental neurotoxicant, and reinforce the idea that its use in preterm labor may create a subpopulation that is sensitized to long-term CNS effects of organophosphorus insecticides

  5. Do rats have orgasms?

    Science.gov (United States)

    Pfaus, James G.; Scardochio, Tina; Parada, Mayte; Gerson, Christine; Quintana, Gonzalo R.; Coria-Avila, Genaro A.

    2016-01-01

    Background Although humans experience orgasms with a degree of statistical regularity, they remain among the most enigmatic of sexual responses; difficult to define and even more difficult to study empirically. The question of whether animals experience orgasms is hampered by similar lack of definition and the additional necessity of making inferences from behavioral responses. Method Here we define three behavioral criteria, based on dimensions of the subjective experience of human orgasms described by Mah and Binik, to infer orgasm-like responses (OLRs) in other species: 1) physiological criteria that include pelvic floor and anal muscle contractions that stimulate seminal emission and/or ejaculation in the male, or that stimulate uterine and cervical contractions in the female; 2) short-term behavioral changes that reflect immediate awareness of a pleasurable hedonic reward state during copulation; and 3) long-term behavioral changes that depend on the reward state induced by the OLR, including sexual satiety, the strengthening of patterns of sexual arousal and desire in subsequent copulations, and the generation of conditioned place and partner preferences for contextual and partner-related cues associated with the reward state. We then examine whether physiological and behavioral data from observations of male and female rats during copulation, and in sexually-conditioned place- and partner-preference paradigms, are consistent with these criteria. Results Both male and female rats display behavioral patterns consistent with OLRs. Conclusions The ability to infer OLRs in rats offers new possibilities to study the phenomenon in neurobiological and molecular detail, and to provide both comparative and translational perspectives that would be useful for both basic and clinical research. PMID:27799081

  6. Do rats have orgasms?

    Directory of Open Access Journals (Sweden)

    James G. Pfaus

    2016-10-01

    Full Text Available Background: Although humans experience orgasms with a degree of statistical regularity, they remain among the most enigmatic of sexual responses; difficult to define and even more difficult to study empirically. The question of whether animals experience orgasms is hampered by similar lack of definition and the additional necessity of making inferences from behavioral responses. Method: Here we define three behavioral criteria, based on dimensions of the subjective experience of human orgasms described by Mah and Binik, to infer orgasm-like responses (OLRs in other species: 1 physiological criteria that include pelvic floor and anal muscle contractions that stimulate seminal emission and/or ejaculation in the male, or that stimulate uterine and cervical contractions in the female; 2 short-term behavioral changes that reflect immediate awareness of a pleasurable hedonic reward state during copulation; and 3 long-term behavioral changes that depend on the reward state induced by the OLR, including sexual satiety, the strengthening of patterns of sexual arousal and desire in subsequent copulations, and the generation of conditioned place and partner preferences for contextual and partner-related cues associated with the reward state. We then examine whether physiological and behavioral data from observations of male and female rats during copulation, and in sexually-conditioned place- and partner-preference paradigms, are consistent with these criteria. Results: Both male and female rats display behavioral patterns consistent with OLRs. Conclusions: The ability to infer OLRs in rats offers new possibilities to study the phenomenon in neurobiological and molecular detail, and to provide both comparative and translational perspectives that would be useful for both basic and clinical research.

  7. Functional and ultrastructural neuroanatomy of interactive intratectal/tectonigral mesencephalic opioid inhibitory links and nigrotectal GABAergic pathways: involvement of GABAA and mu1-opioid receptors in the modulation of panic-like reactions elicited by electrical stimulation of the dorsal midbrain.

    Science.gov (United States)

    Ribeiro, S J; Ciscato, J G; de Oliveira, R; de Oliveira, R C; D'Angelo-Dias, R; Carvalho, A D; Felippotti, T T; Rebouças, E C C; Castellan-Baldan, L; Hoffmann, A; Corrêa, S A L; Moreira, J E; Coimbra, N C

    2005-12-01

    In the present study, the functional neuroanatomy of nigrotectal-tectonigral pathways as well as the effects of central administration of opioid antagonists on aversive stimuli-induced responses elicited by electrical stimulation of the midbrain tectum were determined. Central microinjections of naloxonazine, a selective mu(1)-opiod receptor antagonist, in the mesencephalic tectum (MT) caused a significant increase in the escape thresholds elicited by local electrical stimulation. Furthermore, either naltrexone or naloxonazine microinjected in the substantia nigra, pars reticulata (SNpr), caused a significant increase in the defensive thresholds elicited by electrical stimulation of the continuum comprised by dorsolateral aspects of the periaqueductal gray matter (dlPAG) and deep layers of the superior colliculus (dlSC), as compared with controls. These findings suggest an opioid modulation of GABAergic inhibitory inputs controlling the defensive behavior elicited by MT stimulation, in cranial aspects. In fact, iontophoretic microinjections of the neurotracer biodextran into the SNpr, a mesencephalic structure rich in GABA-containing neurons, show outputs to neural substrate of the dlSC/dlPAG involved with the generation and organization of fear- and panic-like reactions. Neurochemical lesion of the nigrotectal pathways increased the sensitivity of the MT to electrical (at alertness, freezing and escape thresholds) and chemical (blockade of GABA(A) receptors) stimulation, suggesting a tonic modulatory effect of the nigrotectal GABAergic outputs on the neural networks of the MT involved with the organization of the defensive behavior and panic-like reactions. Labeled neurons of the midbrain tectum send inputs with varicosities to ipsi and contralateral dlSC/dlPAG and ipsilateral substantia nigra, pars reticulata and compacta, in which the anterograde and retrograde tracing from a single injection indicates that the substantia nigra has reciprocal connections with

  8. The academic rat race

    DEFF Research Database (Denmark)

    Landes, Xavier; Andersen, Martin Marchman; Nielsen, Morten Ebbe Juul

    2012-01-01

    : an increased pressure to produce articles (in peer-reviewed journals) has created an unbalanced emphasis on the research criterion at the expense of the latter two. More fatally, this pressure has turned academia into a rat race, leading to a deep change in the fundamental structure of academic behaviour......, and entailing a self-defeating and hence counter-productive pattern, where more publications is always better and where it becomes increasingly difficult for researchers to keep up with the new research in their field. The article identifies the pressure to publish as a problem of collective action. It ends up...

  9. The Rat Race

    CERN Multimedia

    Stephen Haywood

    Dear Muriel, Being an animal, you are probably more familiar with rats than most of us. Yet it seems to me that our Community (not just ATLAS) is stuck in a huge "rat race". I am somewhat mystified as to how we have got ourselves into this and I wonder whether you or your readers could explain this - I give my own observations below. In HEP and ATLAS specifically, we are all working long hours and we are all becoming exhausted. There are people at Point 1 who are working day and night, every day of the week; there are people writing software who send emails round the clock, including weekends. It is one thing to have bursts of activity which require us to put in some longer hours, but in ATLAS, the bursts last months or years. I have been on ATLAS 14 years and it has felt like one endless rush. Why do we do this? We are all highly motivated, we love our work and want to succeed individually and collectively. We are parts of various teams, and we do not want to let the side down. We worked hard at school an...

  10. Long-term effects on biotransformation of labelled choline in different parts of the rat brain induced by single choline injections

    Energy Technology Data Exchange (ETDEWEB)

    Nordberg, A.; Wahlstroem, G.

    1988-01-01

    The long-term effects of single choline (Ch) injections on the uptake and metabolism of a tracer dose of /sup 3/H-Ch were studied in male rats. Choline was administered as a threshold infusion to obtain convulsions 10 and 4 weeks before sacrific (group 1). At a single threshold infusion of choline 4 weeks before sacrifice no convulsions were induced in 50% of the animals in a second group (group 2-) whereas convulsions were induced in the remainder of the animals in this group (group 2+). Group 3 contained control animals. One min. after administration of a tracer dose of /sup 3/H-Ch the animals were sacrificed and examined for /sup 3/H-total activity, /sup 3/H-Ch, /sup 3/H-acetylcholine (/sup 3/H-ACh) and /sup 3/H-phosphorylcholine (/sup 3/-H-PhCh). These activities were determined in three parts of the brain (cortex, striatum, midbrain + medulla oblongata). In the cortex a significant negative correlation between brain weight and /sup 3/H-ACh synthesis was seen in group 1. A comparison between group 2+ and group 2- indicated that induced convulsions were not critical for this effect. In the striatum there was a significant reduction in the total uptake of radioactivity in group 1 and group 2- when values were compared to the control group. Furthermore a significant positive correlation was detected between the concentration of radiolabel and /sup 3/H-ACh synthesis and a negative relationship with the level of /sup 3/H-Ch. In the midbrain preparation the synthesis of /sup 3/H-ACh was reduced in group 1 where a significant negative correlation was found between the average threshold dose of choline and both /sup 3/H-Ach and /sup 3/H-PhCh synthesis. Thus the Ch threshold doses given several weeks before testing seem to have long term effects on the uptake and utilization of a tracer dose of /sup 3/H-Ch in the cortex and striatum.

  11. The Significance of Brain Transcranial Sonography in Burning Mouth Syndrome: a Pilot Study.

    Science.gov (United States)

    Zavoreo, Iris; Vučićević, Vanja; Boras; Zadravec, Dijana; Bašić, Vanja; Kes; Ciliga, Dubravka; Gabrić, Dragana

    2017-03-01

    Burning mouth syndrome (BMS) is a chronic disorder which is affecting mostly postmenopausal women and is characterized by burning symptoms in the oral cavity on the clinically healthy oral mucosa. Also, the results of previous studies suggested a possible role of peripheral and/or central neurological disturbances in these patients. The aim of this study was to analyze patients with burning mouth syndrome using transcranial sonography. By use of transcranial sonography of the brain parenchyma, substantia nigra , midbrain raphe and brain nucleus were evaluated in 20 patients with BMS (64.7±12.3 years) and 20 controls with chronic pain in the lumbosacral region (61.5±15). Statistical analysis was performed by use of Student t test with significance set at pburning mouth syndrome might reflect central disturbances within this syndrome. Burning Mouth Syndrome; Transcranial Sonography; substantia nigra; Midbrain Raphe Nuclei; Red Nucleus.

  12. Serotonin metabolism in rat brain

    International Nuclear Information System (INIS)

    Schutte, H.H.

    1976-01-01

    The metabolism of serotonin in rat brain was studied by measuring specific activities of tryptophan in plasma and of serotonin, 5-hydroxyindole acetic acid and tryptophan in the brain after intravenous injection of tritiated tryptophan. For a detailed analysis of the specific activities, a computer simulation technique was used. It was found that only a minor part of serotonin in rat brain is synthesized from tryptophan rapidly transported from the blood. It is suggested that the brain tryptophan originates from brain proteins. It was also found that the serotonin in rat brain is divided into more than one metabolic compartment

  13. Evaluation of brain SERT occupancy by resveratrol against MDMA-induced neurobiological and behavioral changes in rats: A 4-[¹⁸F]-ADAM/small-animal PET study.

    Science.gov (United States)

    Shih, Jui-Hu; Ma, Kuo-Hsing; Chen, Chien-Fu F; Cheng, Cheng-Yi; Pao, Li-Heng; Weng, Shao-Ju; Huang, Yuahn-Sieh; Shiue, Chyng-Yann; Yeh, Ming-Kung; Li, I-Hsun

    2016-01-01

    The misuse of 3,4-methylenedioxymethamphetamine (MDMA) has drawn a growing concern worldwide for its psychophysiological impacts on humans. MDMA abusers are often accompanied by long-term serotonergic neurotoxicity, which is associated with reduced density of cerebral serotonin transporters (SERT) and depressive disorders. Resveratrol (RSV) is a natural polyphenolic phytoalexin that has been known for its antidepressant and neuroprotective effects. However, biological targets of RSV as well as its neuroprotective effects against MDMA remained largely unknown. In this study, we examined binding potency of RSV and MDMA to SERT using small-animal positron emission tomography (PET) with the SERT radioligand, N,N-dimethyl-2-(2-amino-4-[(18)F]fluorophenylthio)benzylamine (4-[(18)F]-ADAM) and investigated the protection of RSV against the acute and long-term adverse effects of MDMA. We found that RSV exhibit binding potentials to SERT in vivo in a dose-dependent manner with variation among brain regions. When the MDMA-treated rats (10mg/kg, s.c.) were co-injected with RSV (20mg/kg, i.p.) twice daily for 4 consecutive days, MDMA-induced acute elevation in plasma corticosterone was significantly reduced. Further, 4-[(18)F]-ADAM PET imaging revealed that RSV protected against the MDMA-induced decrease in SERT availability in the midbrain and the thalamus 2 weeks following the co-treatment. The PET data were comparable to the observation from the forced swim test that RSV sufficiently ameliorated the depressive-like behaviors of the MDMA-treated rats. Together, these findings suggest that RSV is a potential antidepressant and may confer protection against neurobiological and behavioral changes induced by MDMA. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  14. Origin and neurochemical properties of bulbospinal neurons projecting to the rat lumbar spinal cord via the medal longitudinal fasciculus and caudal ventrolateral medulla

    Directory of Open Access Journals (Sweden)

    Zilli eHuma

    2014-04-01

    Full Text Available Bulbospinal systems (BS originate from various regions of the brainstem and influence spinal neurons by classical synaptic and modulatory mechanisms. Our aim was to determine the brainstem locations of cells of origin of BS pathways passing through the medial longitudinal fasciculus (MLF and the caudal ventrolateral medulla (CVLM. We also examined the transmitter content of spinal terminations of the CVLM pathway. Six adult rats received Fluorogold (FG injections to the right intermediate grey matter of the lumbar cord (L1-L2 and the b-subunit of cholera toxin (CTb was injected either into the MLF or the right CVLM (3 animals each. Double-labelled cells were identified within brainstem structures with confocal microscopy and mapped onto brainstem diagrams. An additional 3 rats were injected with CTb in the CVLM to label axon terminals in the lumbar spinal cord. Double-labelled cells projecting via the MLF or CVLM were found principally in reticular regions of the medulla and pons but small numbers of cells were also located within the midbrain. CVLM projections to the lumbar cord were almost exclusively ipsilateral and concentrated within the intermediate grey matter. Most (62% of terminals were immunoreactive for the vesicular glutamate transporter 2 while 23% contained the vesicular GABA transporter. The inhibitory subpopulation was glycinergic, GABAergic or contained both transmitters. The proportions of excitatory and inhibitory axons projecting via the CVLM to the lumbar cord are similar to those projecting via the MLF. Unlike the MLF pathway, CVLM projections are predominantly ipsilateral and concentrated within intermediate grey but do not extend into motor nuclei or laminia VIII. Terminations of the CVLM pathway are located in a region of the grey matter that is rich in premotor interneurons; thus its primary function may be to coordinate activity of premotor networks.

  15. Beta-endorphin in genetically hypoprolactinemic rat: IPL nude rat

    International Nuclear Information System (INIS)

    Cohen, H.; Sabbagh, I.; Abou-Samra, A.B.; Bertrand, J.

    1986-01-01

    Beta-endorphin has been reported to regulate not only stress- and suckling-induced but also basal prolactin secretion. In the aim to better evaluate the endogenous beta-endorphin-prolactin interrelation, the authors measured beta-endorphin levels in a new rat strain, genetically hypoprolactinemic and characterized by a total lack of lactation: IPL nude rat. Beta-endorphin was measured using a specific anti-h-β endorphin in plasma and extracts of anterior and neurointermediate lobes of the pituitary, hypothalamus and brain. Pituitary extracts were also chromatographed on Sephadex G50 column. Results obtained showed that in IPL nude females on diestrus and males, the beta-endorphin contents of the neurointermediate lobe was significantly lower than in normal rats, while the values found in the other organs and plasma were similar. However, elution pattern of the anterior pituitary extracts from male rats showed greater immunoactivity eluting as I 125 h-beta-endorphin than in normal rat; this was not the case for the female rat. These results are consistent with a differential regulation of beta-endorphin levels of anterior and neurointermediate lobe by catecholamines. Moreover they suggest that PRL secretion was more related to neurointermediate beta-endorphin. 40 references, 2 figures, 4 tables

  16. Beta-endorphin in genetically hypoprolactinemic rat: IPL nude rat

    Energy Technology Data Exchange (ETDEWEB)

    Cohen, H.; Sabbagh, I.; Abou-Samra, A.B.; Bertrand, J.

    1986-01-20

    Beta-endorphin has been reported to regulate not only stress- and suckling-induced but also basal prolactin secretion. In the aim to better evaluate the endogenous beta-endorphin-prolactin interrelation, the authors measured beta-endorphin levels in a new rat strain, genetically hypoprolactinemic and characterized by a total lack of lactation: IPL nude rat. Beta-endorphin was measured using a specific anti-h-..beta.. endorphin in plasma and extracts of anterior and neurointermediate lobes of the pituitary, hypothalamus and brain. Pituitary extracts were also chromatographed on Sephadex G50 column. Results obtained showed that in IPL nude females on diestrus and males, the beta-endorphin contents of the neurointermediate lobe was significantly lower than in normal rats, while the values found in the other organs and plasma were similar. However, elution pattern of the anterior pituitary extracts from male rats showed greater immunoactivity eluting as I/sup 125/ h-beta-endorphin than in normal rat; this was not the case for the female rat. These results are consistent with a differential regulation of beta-endorphin levels of anterior and neurointermediate lobe by catecholamines. Moreover they suggest that PRL secretion was more related to neurointermediate beta-endorphin. 40 references, 2 figures, 4 tables.

  17. Intramitochondrial autonomy in rat tissues

    International Nuclear Information System (INIS)

    Subramanian, M.; Rajwade, M.S.; Satav, J.G.; Katyare, S.S.; Fatterpaker, P.; Sreenivasan, A.

    1974-01-01

    The biogenesis of mitochondria in rat liver and their protein turnover has been investigated using 1- 14 C leucine. The results indicate that intramitochondrial autonomy exists both with respect to their genesis and turnover. (M.G.B.)

  18. Autoshaping in micrencephalic rats

    International Nuclear Information System (INIS)

    Goldstein, L.H.; Oakley, D.A.

    1989-01-01

    An autoshaping procedure in which the illumination of a lever was predictive of food reinforcement was used to compare learning in rats with micrencephaly induced by irradiation on the 16th day of gestation and in sham-irradiated controls. Both groups showed equivalent levels of lever-directed activity, and the micrencephalic animals differentiated as well as the control animals between the predictive lever and a nonpredictive lever. The micrencephalic animals were able to redistribute their lever-directed activity when the significance of the levers was reversed and did so more readily than the control animals. Results support the claim that association learning survives either traumatic or developmental neocortical damage and have implications for remedial procedures following both head injury and developmental cerebral pathology in humans

  19. Autoshaping in micrencephalic rats.

    Science.gov (United States)

    Goldstein, L H; Oakley, D A

    1989-06-01

    An autoshaping procedure in which the illumination of a lever was predictive of food reinforcement was used to compare learning in rats with micrencephaly induced by irradiation on the 16th day of gestation and in sham-irradiated controls. Both groups showed equivalent levels of lever-directed activity, and the micrencephalic animals differentiated as well as the control animals between the predictive lever and a nonpredictive lever. The micrencephalic animals were able to redistribute their lever-directed activity when the significance of the levers was reversed and did so more readily than the control animals. Results support the claim that association learning survives either traumatic or developmental neocortical damage and have implications for remedial procedures following both head injury and developmental cerebral pathology in humans.

  20. High-Frequency Stimulation of the Subthalamic Nucleus Activates Motor Cortex Pyramidal Tract Neurons by a Process Involving Local Glutamate, GABA and Dopamine Receptors in Hemi-Parkinsonian Rats.

    Science.gov (United States)

    Chuang, Chi-Fen; Wu, Chen-Wei; Weng, Ying; Hu, Pei-San; Yeh, Shin-Rung; Chang, Yen-Chung

    2018-04-30

    Deep brain stimulation (DBS) is widely used to treat advanced Parkinson’s disease (PD). Here, we investigated how DBS applied on the subthalamic nucleus (STN) influenced the neural activity in the motor cortex. Rats, which had the midbrain dopaminergic neurons partially depleted unilaterally, called the hemi-Parkinsonian rats, were used as a study model. c-Fos expression in the neurons was used as an indicator of neural activity. Application of high-frequency stimulation (HFS) upon the STN was used to mimic the DBS treatment. The motor cortices in the two hemispheres of hemi-Parkinsonian rats were found to contain unequal densities of c-Fos-positive (Fos+) cells, and STN-HFS rectified this bilateral imbalance. In addition, STN-HFS led to the intense c-Fos expression in a group of motor cortical neurons which exhibited biochemical and anatomical characteristics resembling those of the pyramidal tract (PT) neurons sending efferent projections to the STN. The number of PT neurons expressing high levels of c-Fos was significantly reduced by local application of the antagonists of non-N-methyl-D-aspartate (non-NMDA) glutamate receptors, gammaaminobutyric acid A (GABAA) receptors and dopamine receptors in the upper layers of the motor cortex. The results indicate that the coincident activations of synapses and dopamine receptors in the motor cortex during STN-HFS trigger the intense expression of c-Fos of the PT neurons. The implications of the results on the cellular mechanism underlying the therapeutic effects of STN-DBS on the movement disorders of PD are also discussed.

  1. Long-lasting pathological consequences of overexpression-induced α-synuclein spreading in the rat brain.

    Science.gov (United States)

    Rusconi, Raffaella; Ulusoy, Ayse; Aboutalebi, Helia; Di Monte, Donato A

    2018-04-01

    Increased expression of α-synuclein can initiate its long-distance brain transfer, representing a potential mechanism for pathology spreading in age-related synucleinopathies, such as Parkinson's disease. In this study, the effects of overexpression-induced α-synuclein transfer were assessed over a 1-year period after injection of viral vectors carrying human α-synuclein DNA into the rat vagus nerve. This treatment causes targeted overexpression within neurons in the dorsal medulla oblongata and subsequent diffusion of the exogenous protein toward more rostral brain regions. Protein advancement and accumulation in pontine, midbrain, and forebrain areas were contingent upon continuous overexpression, because death of transduced medullary neurons resulted in cessation of spreading. Lack of sustained spreading did not prevent the development of long-lasting pathological changes. Particularly remarkable were findings in the locus coeruleus, a pontine nucleus with direct connections to the dorsal medulla oblongata and greatly affected by overexpression-induced transfer in this model. Data revealed progressive degeneration of catecholaminergic neurons that proceeded long beyond the time of spreading cessation. Neuronal pathology in the locus coeruleus was accompanied by pronounced microglial activation and, at later times, astrocytosis. Interestingly, microglial activation was also featured in another region reached by α-synuclein transfer, the central amygdala, even in the absence of frank neurodegeneration. Thus, overexpression-induced spreading, even if temporary, causes long-lasting pathological consequences in brain regions distant from the site of overexpression but anatomically connected to it. Neurodegeneration may be a consequence of severe protein burden, whereas even a milder α-synuclein accumulation in tissues affected by protein transfer could induce sustained microglial activation. © 2018 The Authors. Aging Cell published by the Anatomical Society and

  2. Connections of the superior paraolivary nucleus of the rat: II. Reciprocal connections with the tectal longitudinal column

    Directory of Open Access Journals (Sweden)

    Antonio eViñuela

    2011-02-01

    Full Text Available The superior paraolivary nucleus (SPON, a prominent GABAergic center of the mammalian auditory brainstem, projects to the ipsilateral inferior colliculus (IC and sends axons through the commissure of the IC (CoIC. Herein we demonstrate that the SPON is reciprocally connected with the recently discovered tectal longitudinal column (TLC. The TLC is a long and narrow structure that spans nearly the entire midbrain tectum longitudinally, immediately above the periaqueductal gray matter (PAG and very close to the midline.Unilateral injections of biotinylated dextran into the SPON of the rat label abundant terminal fibers in the TLC of both sides, with an ipsilateral predominance. The SPON provides a dense innervation of the entire rostrocaudal extent of the ipsilateral TLC, and a relatively sparser innervation of the caudal and rostral portions of the contralateral TLC. SPON fibers reach the TLC by two routes: as collaterals of axons of the CoIC, and as axons that circumvent the ipsilateral IC before traveling in the deep layers of the superior colliculus.The density of these projections identifies