Sample records for central cholinergic activation

  1. Central cholinergic activation of a vagus nerve - to spleen circuit alleviates experimental colitis (United States)

    Ji, Hong; Rabbi, Mohammad F; Labis, Benoit; Pavlov, Valentin A; Tracey, Kevin J; Ghia, Jean-Eric


    The cholinergic anti-inflammatory pathway is an efferent vagus nerve-based mechanism that regulates immune responses and cytokine production through α7nicotinic-acetylcholinereceptor (α7nAChR) signaling. Decreased efferent vagus nerve activity is observed in inflammatory bowel disease (IBD). We determined whether central activation of this pathway alters inflammation in mice with colitis and the mediating role of a vagus nerve-to spleen circuit and α7nAChR signaling. Two experimental models of colitis were used in C57BL/6 mice. Central cholinergic activation induced by the acetylcholinesterase inhibitor galantamine or a muscarinic acetylcholine receptor agonist treatments resulted in reduced mucosal inflammation associated with decreased MHC II level and pro-inflammatory cytokine secretion by splenic CD11c+ cells mediated by α7nAChR signaling. The cholinergic anti-inflammatory efficacy was abolished in mice with vagotomy, splenic neurectomy or splenectomy. In conclusion, central cholinergic activation of a vagus nerve–to spleen circuit controls intestinal inflammation and this regulation can be explored to develop novel therapeutic strategies. PMID:23881354

  2. Central cholinergic activation of a vagus nerve-to-spleen circuit alleviates experimental colitis. (United States)

    Ji, H; Rabbi, M F; Labis, B; Pavlov, V A; Tracey, K J; Ghia, J E


    The cholinergic anti-inflammatory pathway is an efferent vagus nerve-based mechanism that regulates immune responses and cytokine production through α7 nicotinic acetylcholine receptor (α7nAChR) signaling. Decreased efferent vagus nerve activity is observed in inflammatory bowel disease. We determined whether central activation of this pathway alters inflammation in mice with colitis and the mediating role of a vagus nerve-to-spleen circuit and α7nAChR signaling. Two experimental models of colitis were used in C57BL/6 mice. Central cholinergic activation induced by the acetylcholinesterase inhibitor galantamine or a muscarinic acetylcholine receptor agonist treatments resulted in reduced mucosal inflammation associated with decreased major histocompatibility complex II level and pro-inflammatory cytokine secretion by splenic CD11c⁺ cells mediated by α7nAChR signaling. The cholinergic anti-inflammatory efficacy was abolished in mice with vagotomy, splenic neurectomy, or splenectomy. In conclusion, central cholinergic activation of a vagus nerve-to-spleen circuit controls intestinal inflammation and this regulation can be explored to develop novel therapeutic strategies.

  3. Aldrin-induced locomotor activity: possible involvement of the central GABAergic-cholinergic-dopaminergic interaction. (United States)

    Jamaluddin, S; Poddar, M K


    Aldrin (5 mg/kg/day, p.o.) under nontolerant condition, administered either for a single day or for 12 consecutive days, enhanced locomotor activity (LA) of rats. The increase in LA was greater in rats treated with aldrin for 12 consecutive days than that observed with a single dose. The aim of the present study is to evaluate the involvement of possible interactions of central GABAergic, cholinergic and dopaminergic systems using their agonist(s) and antagonist(s) in the regulation of LA in aldrin nontolerant rats. Administration of either L-DOPA along with carbidopa or bicuculline potentiated aldrin-induced increase in LA under nontolerant condition as well as LA of the control rats. Treatment with muscimol, haloperidol, atropine or physostigmine all decreased the LA of both aldrin nontolerant and control rats. Further, the application of (a) haloperidol along with bicuculline, atropine or physostigmine and (b) physostigmine along with bicuculline or L-DOPA + carbidopa significantly reduced LA but L-DOPA + carbidopa along with atropine or bicuculline increased LA of the control rats. These agonist(s)/antagonist(s)-induced decrease or increase in LA of the control rats were attenuated or potentiated, respectively, when those agonist(s)/antagonist(s) under abovementioned condition were administered to aldrin nontolerant rats. The attenuating or potentiating effects of aldrin on agonist(s)/antagonist(s) (either individually or in different combinations)-induced change in LA were greater in rats treated with aldrin for 12 consecutive days than that observed with a single-dose aldrin treatment. These results suggest that aldrin, under nontolerant condition, reduces central GABAergic activity and increases LA by activating dopaminergic system via inhibition of cholinergic activity. The treatment with aldrin for 12 consecutive days produces greater effect than that caused by a single-day treatment.

  4. Anticholinesterase Effects on Number and Function of Brain Muscarinic Receptors and Central Cholinergic Activity: Drug Intervention. (United States)


    the near future. In addition, since the entire cerebral cortex projects to many nuclei throughout the brain through excitatory fibers it appears even...Florentini, F., Forloni, G.L. and Ladinsky, H.: Frontal decortication and adaptive changes in striatal cholinergic neurons in the rat, Brain...Research, 363, 128-134, 1986. 2) Consolo, Silvana: Frontal decortication and adaptive changes in striatal cholinergic neurons: Neuropharmacological and

  5. Probing peripheral and central cholinergic system responses. (United States)

    Naranjo, C A; Fourie, J; Herrmann, N; Lanctôt, K L; Birt, C; Yau, K K


    OBJECTIVE: The pharmacological response to drugs that act on the cholinergic system of the iris has been used to predict deficits in central cholinergic functioning due to diseases such as Alzheimer's disease, yet correlations between central and peripheral responses have not been properly studied. This study assessed the effect of normal aging on (1) the tropicamide-induced increase in pupil diameter, and (2) the reversal of this effect with pilocarpine. Scopolamine was used as a positive control to detect age-dependent changes in central cholinergic functioning in the elderly. DESIGN: Randomized double-blind controlled trial. PARTICIPANTS: Ten healthy elderly (mean age 70) and 9 young (mean age 33) volunteers. INTERVENTIONS: Pupil diameter was monitored using a computerized infrared pupillometer over 4 hours. The study involved 4 sessions. In 1 session, tropicamide (20 microL, 0.01%) was administered to one eye and placebo to the other. In another session, tropicamide (20 microL, 0.01%) was administered to both eyes, followed 23 minutes later by the application of pilocarpine (20 microL, 0.1%) to one eye and placebo to the other. All eye drops were given in a randomized order. In 2 separate sessions, a single dose of scopolamine (0.5 mg, intravenously) or placebo was administered, and the effects on word recall were measured using the Buschke Selective Reminding Test over 2 hours. OUTCOME MEASURES: Pupil size at time points after administration of tropicamide and pilocarpine; scopolamine-induced impairment in word recall. RESULTS: There was no significant difference between elderly and young volunteers in pupillary response to tropicamide at any time point (p > 0.05). The elderly group had a significantly greater pilocarpine-induced net decrease in pupil size 85, 125, 165 and 215 minutes after administration, compared with the young group (p tropicamide. Thus, pilocarpine may be useful to assess variations in central cholinergic function in elderly patients. PMID

  6. [The role of central cholinergic system in epilepsy]. (United States)

    Wang, Ying; Wang, Yi; Chen, Zhong


    Epilepsy is a chronic neurological disorder, which is not only related to the imbalance between excitatory glutamic neurons and inhibitory GABAergic neurons, but also related to abnormal central cholinergic regulation. This article summarizes the scientific background and experimental data about cholinergic dysfunction in epilepsy from both cellular and network levels, further discusses the exact role of cholinergic system in epilepsy. In the cellular level, several types of epilepsy are believed to be associated with aberrant metabotropic muscarinic receptors in several different brain areas, while the mutations of ionotropic nicotinic receptors have been reported to result in a specific type of epilepsy-autosomal dominant nocturnal frontal lobe epilepsy. In the network level, cholinergic projection neurons as well as their interaction with other neurons may regulate the development of epilepsy, especially the cholinergic circuit from basal forebrain to hippocampus, while cholinergic local interneurons have not been reported to be associated with epilepsy. With the development of optogenetics and other techniques, dissect and regulate cholinergic related epilepsy circuit has become a hotspot of epilepsy research.

  7. Sex differences in brain cholinergic activity in MSG-obese rats submitted to exercise. (United States)

    Sagae, Sara Cristina; Grassiolli, Sabrina; Raineki, Charlis; Balbo, Sandra Lucinei; Marques da Silva, Ana Carla


    Obesity is an epidemic disease most commonly caused by a combination of increased energy intake and lack of physical activity. The cholinergic system has been shown to be involved in the regulation of food intake and energy expenditure. Moreover, physical exercise promotes a reduction of fat pads and body mass by increasing energy expenditure, but also influences the cholinergic system. The aim of this study is to evaluate the interaction between physical exercise (swimming) and central cholinergic activity in rats treated with monosodium glutamate (MSG, a model for obesity) during infancy. Our results show that MSG treatment is able to induce obesity in male and female rats. Specifically, MSG-treated rats presented a reduced body mass and nasoanal length, and increased perigonadal and retroperitoneal fat pads in relation to the body mass. Physical exercise was able to reduce body mass in both male and female rats, but did not change the fat pads in MSG-treated rats. Increased food intake was only seen in MSG-treated females submitted to exercise. Cholinergic activity was increased in the cortex of MSG-treated females and physical exercise was able to reduce this activity. Thalamic cholinergic activity was higher in sedentary MSG-treated females and exercised MSG-treated males. Hypothalamic cholinergic activity was higher in male and female MSG-treated rats, and was not reduced by exercise in the 2 sexes. Taken together, these results show that MSG treatment and physical exercise have different effects in the cholinergic activity of males and females.

  8. The involvement of the central cholinergic system in the pressor and bradycardic effects of centrally administrated melittin in normotensive conscious rats. (United States)

    Yalcin, Murat; Erturk, Melih


    Recently we demonstrated that centrally administrated melittin, a phospholipase A(2) (PLA(2)) activator, caused pressor and bradycardic effect in the normotensive conscious rats. In the current study we aimed to determine the mediation of central cholinergic system in the pressor and bradycardic effect of centrally administrated melittin. Studies were performed in normotensive male Sprague-Dawley rats. 1.5, 3.0 or 6.0microg/5.0microl doses of melittin were injected intracerebroventricularly (i.c.v.). Melittin caused dose- and time-dependent increases in mean arterial pressure (MAP) and decrease in heart rate (HR). In order to test the mediation of central cholinergic system on the pressor and bradycardic effect of melittin, the rats were pretreated with mecamylamine (50microg; i.c.v.), cholinergic nonselective nicotinic receptor antagonist, atropine sulfate (10microg; i.c.v.), a cholinergic nonselective muscarinic receptor antagonist, hemicholinium-3 (20microg; i.c.v.), a high affinity neuronal choline uptake inhibitor, methyllycaconitine (10 and 25microg; i.c.v.) or alpha-bungarotoxin (10 and 25microg; i.c.v.), selective antagonists of alpha-7 subtype nicotinic acetylcholine receptors (alpha7nAChRs), 15min prior to melittin (3.0microg) injection. Pretreatment with mecamylamine, hemicholinium-3, methyllycaconitine or alpha-bungarotoxin partially attenuated the pressor and bradicardia effect of elicited by melittin in the normotensive conscious rats whereas pretreatment with atropine had no effect. In conclusion, i.c.v. administration of melittin increases MAP and decreases HR in conscious rats. The activation of central nicotinic cholinergic receptors, predominantly alpha7nAChRs, partially acts as a mediator in the pressor responses to i.c.v. injection of melittin in the normotensive conscious rats. Moreover, decreased uptake of choline to the cholinergic terminals may consider that melittin activates central choline and acetylcholine release, as well.

  9. Central cholinergic pathway involvement in the regulation of pupil diameter, blink rate and cognitive function. (United States)

    Naicker, Preshanta; Anoopkumar-Dukie, Shailendra; Grant, Gary D; Neumann, David L; Kavanagh, Justin J


    Anticholinergic medications can exert their effects by acting on muscarinic receptors, which mediates the function of acetylcholine in the central nervous system. Acetylcholine plays a number of roles, particularly in regard to the control of muscle activity and normal cognitive functioning. Eighteen subjects were recruited into the human, double-blind, placebo-controlled, four-way crossover study. Pupil diameter and blink rate were assessed at rest while eye tracking technology recorded eye characteristics. Thereafter a cognitive task was performed, where pupil size and blink rate were once again measured. Assessments were performed pre-ingestion, 0.5h and 2h following the ingestion of a strong centrally acting anticholinergic (promethazine hydrochloride), a moderate centrally acting anticholinergic (hyoscine hydrobromide), an anticholinergic devoid of central effects (hyoscine butylbromide) and placebo. At rest, hyoscine hydrobromide was the only medication to increase pupil diameter and no drug intervention influenced blink rate. During performance of the cognitive task, hyoscine hydrobromide increased pupil diameter and promethazine increased blink rate. Promethazine was the only medication to influence the modified attention network test (ANT) by increasing the conflict effect and grand mean reaction time (RT). Pupil diameter and blink rate were both influenced by the central anticholinergics during performance of the cognitive test, thus highlighting the importance of central cholinergic pathways in the control of pupil diameter and blink rate. The collective effects of central anticholinergics on the modified ANT and on pupil diameter and blink rate during its performance, conveys the importance of central cholinergic pathways in cognitive function. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  10. Cholinergic-opioidergic interaction in the central amygdala induces antinociception in the guinea pig

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    Leite-Panissi C.R.A.


    Full Text Available Several studies have demonstrated the involvement of the central nucleus of the amygdala (CEA in the modulation of defensive behavior and in antinociceptive regulation. In a previous study, we demonstrated the existence of a cholinergic-opioidergic interaction in the CEA, modulating the defensive response of tonic immobility in guinea pigs. In the present study, we investigated a similar interaction in the CEA, but now involved in the regulation of the nociceptive response. Microinjection of carbachol (2.7 nmol and morphine (2.2 nmol into the CEA promoted antinociception up to 45 min after microinjection in guinea pigs as determined by a decrease in the vocalization index in the vocalization test. This test consists of the application of a peripheral noxious stimulus (electric shock into the subcutaneous region of the thigh that provokes the emission of a vocalization response by the animal. Furthermore, the present results demonstrated that the antinociceptive effect of carbachol (2.7 nmol; N = 10 was blocked by previous administration of atropine (0.7 nmol; N = 7 or naloxone (1.3 nmol; N = 7 into the same site. In addition, the decrease in the vocalization index induced by the microinjection of morphine (2.2 nmol; N = 9 into the CEA was prevented by pretreatment with naloxone (1.3 nmol; N = 11. All sites of injection were confirmed by histology. These results indicate the involvement of the cholinergic and opioidergic systems of the CEA in the modulation of antinociception in guinea pigs. In addition, the present study suggests that cholinergic transmission may activate the release of endorphins/enkephalins from interneurons of the CEA, resulting in antinociception.

  11. Monitoring the Right Collection: The Central Cholinergic Neurons as an Instructive Example

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    Balázs Hangya


    Full Text Available Some neurons are more equal than others: neuroscience relies heavily on the notion that there is a division of labor among different subtypes of brain cells. Therefore, it is important to recognize groups of neurons that participate in the same computation or share similar tasks. However, what the best ways are to identify such collections is not yet clear. Here, we argue that monitoring the activity of genetically defined cell types will lead to new insights about neural mechanisms and improve our understanding of disease vulnerability. Through highlighting how central cholinergic neurons encode reward and punishment that can be captured by a unified framework of reinforcement surprise, we hope to provide an instructive example of how studying a genetically defined cell type may further our understanding of neural function.

  12. Metabolic changes in deafferented central neurons of an insect, Acheta domesticus. II. Effects on cholinergic binding sites and acetylcholinesterase. (United States)

    Meyer, M R; Reddy, G R; Edwards, J S


    Following the finding that cercal deafferentation of developing giant interneurons in the terminal abdominal ganglion (TG) of the cricket Acheta domesticus reduces TG protein metabolism within target interneuron dendrites and somata (Meyer and Edwards, 1982), it is now shown that deafferentation alters the turnover of three macromolecules associated with cholinergic transmission in the cercal sensory-giant interneuron pathway. The labeled specific ligands 3H-quinuclidinyl benzilate and 125I-alpha-bungarotoxin were used to assay populations of putative TG muscarinic and nicotinic cholinergic receptors, respectively, in control and deafferented groups of ganglia. The AChE activity of TG was also determined by assay and histochemical methods. Long-term deafferentation sustained throughout postembryonic development markedly reduces the densities of both muscarinic and nicotinic binding sites in the TG; short-term deafferentation of adult TG also leads to characteristic alterations in the properties of all three cholinergic markers within several days. Rapid changes seen in adults thus correlate with ultrastructural data demonstrating loss of afferent terminals within hours of sensory appendage removal. We propose that peripheral innervation-dependent regulatory mechanisms operate in both the developing and adult insect nervous system. Such mechanisms may influence transsynaptically the synthesis and turnover of specific macromolecules, some of which may reside on the cell surface of insect central neurons that are part of the cercal sensory-giant interneuron system.

  13. Central cholinergic dysfunction could be associated with oropharyngeal dysphagia in early Parkinson's disease. (United States)

    Lee, Kyung Duck; Koo, Jung Hoi; Song, Sun Hong; Jo, Kwang Deog; Lee, Moon Kyu; Jang, Wooyoung


    Dysphagia is an important issue in the prognosis of Parkinson's disease (PD). Although several studies have reported that oropharyngeal dysphagia may be associated with cognitive dysfunction, the exact relationship between cortical function and swallowing function in PD patients is unclear. Therefore, we investigated the association between an electrophysiological marker of central cholinergic function, which reflected cognitive function, and swallowing function, as measured by videofluoroscopic studies (VFSS). We enrolled 29 early PD patients. Using the Swallowing Disturbance Questionnaire (SDQ), we divided the enrolled patients into two groups: PD with dysphagia and PD without dysphagia. The videofluoroscopic dysphagia scale (VDS) was applied to explore the nature of the dysphagia. To assess central cholinergic dysfunction, short latency afferent inhibition (SAI) was evaluated. We analyzed the relationship between central cholinergic dysfunction and oropharyngeal dysphagia and investigated the characteristics of the dysphagia. The SAI values were significantly different between the two groups. The comparison of each VFSS component between the PD with dysphagia group and the PD without dysphagia group showed statistical significance for most of the oral phase components and for a single pharyngeal phase component. The total score on the VDS was higher in the PD with dysphagia group than in the PD without dysphagia group. The Mini-Mental State Examination and SAI values showed significant correlations with the total score of the oral phase components. According to binary logistic regression analysis, SAI value independently contributed to the presence of dysphagia in PD patients. Our findings suggest that cholinergic dysfunction is associated with dysphagia in early PD and that an abnormal SAI value is a good biomarker for predicting the risk of dysphagia in PD patients.

  14. Functional role of cholinergic drugs on spontaneous muscular activity in the amphistome Gastrothylax crumenifer from ruminants. (United States)

    Verma, P K; Kumar, D; Tandan, S K


    Acetylcholine is the major endogenous classical neurotransmitter in the central and peripheral nervous system of trematodes and mammals. This study investigates the effects of cholinergic drugs on muscle activity in the amphistome, Gastrothylax crumenifer. In the present investigation, acetylcholine (10- 7-10- 3 m) did not produce any marked effect, whereas carbachol (10- 7-10- 3 m) elicited a concentration-dependent decrease in amplitude, baseline tension and frequency of contractions as compared to the control. Nicotine (10- 7-10- 3 m) produced a significant decrease in the amplitude and frequency of spontaneous muscular activity in a concentration-dependent manner, as compared to control amplitude (0.5 +/- 0.01 g) and frequency (58.5 +/- 3.45 per 5 min). However, the baseline tension was also reduced significantly by 10- 3 m nicotine. Atropine (10- 7-10- 3 m) elicited a concentration-dependent increase in amplitude and baseline tension, whereas there was no significant effect on the frequency of the spontaneous contractions of rumen flukes. These observations indicate that G. crumenifer has an inhibitory cholinergic system and that the inhibitory activity of nicotine is more pronounced than that of carbachol or acetylcholine.

  15. Effects of Ginkgo biloba Extract EGb 761, Donepezil and their Combination on Central Cholinergic Function in Aged Rats. (United States)

    Stein, Christoph; Hopfeld, Julia; Lau, Helene; Klein, Jochen


    Ginkgo extract EGb 761 and cholinesterase inhibitors have been shown to be effective in the treatment of dementia patients. In addition to neuroprotective effects, Ginkgo extract EGb 761 has been reported to elevate brain levels of certain neurotransmitters such as dopamine, noradrenaline, and acetylcholine. In the present study, we investigated the impact of EGb 761, donepezil and the combination of both drugs on the central cholinergic system in aged rats. 24 month old rats received EGb 761 (100 mg/kg/day), donepezil (1.5 mg/kg/day), the combination of both drugs or vehicle control by oral gavage for 14 days. We used microdialysis in rat hippocampus to monitor extracellular concentrations of acetylcholine (ACh), choline, glucose and lactate. Brain homogenates were prepared to measure activities of acetylcholinesterase (AChE), choline acetyltransferase (ChAT) and high affinity choline uptake (HACU). While EGb 761 alone had no effect, donepezil and the combination of donepezil and EGb 761 increased basal ACh levels by 2- to 3-fold. Concomitantly, significant reductions of AChE and HACU were measured in both groups. No differences were seen between donepezil and the combination in these parameters. Treatment with EGb 761 decreased extracellular choline release and showed a tendency to moderately elevate ChAT activity. We found that donepezil and EGb 761 do not display a pharmacological interaction when given together. Adding EGb 761 did not modify the effects of donepezil on the hippocampal cholinergic system. Reduced choline levels indicate neuroprotective properties of EGb 761. Therefore, the combination of EGb 761 and donepezil may be beneficial in the treatment of Alzheimer's disease (AD). This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

  16. Selective Activation of Cholinergic Interneurons Enhances Accumbal Phasic Dopamine Release: Setting the Tone for Reward Processing

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    Roger Cachope


    Full Text Available Dopamine plays a critical role in motor control, addiction, and reward-seeking behaviors, and its release dynamics have traditionally been linked to changes in midbrain dopamine neuron activity. Here, we report that selective endogenous cholinergic activation achieved via in vitro optogenetic stimulation of nucleus accumbens, a terminal field of dopaminergic neurons, elicits real-time dopamine release. This mechanism occurs via direct actions on dopamine terminals, does not require changes in neuron firing within the midbrain, and is dependent on glutamatergic receptor activity. More importantly, we demonstrate that in vivo selective activation of cholinergic interneurons is sufficient to elicit dopamine release in the nucleus accumbens. Therefore, the control of accumbal extracellular dopamine levels by endogenous cholinergic activity results from a complex convergence of neurotransmitter/neuromodulator systems that may ultimately synergize to drive motivated behavior.

  17. Upregulating Nonneuronal Cholinergic Activity Decreases TNF Release from Lipopolysaccharide-Stimulated RAW264.7 Cells

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    Yi Lv


    Full Text Available Nonneuronal cholinergic system plays a primary role in maintaining homeostasis. It has been proved that endogenous neuronal acetylcholine (ACh could play an anti-inflammatory role, and exogenous cholinergic agonists could weaken macrophages inflammatory response to lipopolysaccharide (LPS stimulation through activation of α7 subunit-containing nicotinic acetylcholine receptor (α7nAChR. We assumed that nonneuronal cholinergic system existing in macrophages could modulate inflammation through autocrine ACh and expressed α7nAChR on the cells. Therefore, we explored whether LPS continuous stimulation could upregulate the nonneuronal cholinergic activity in macrophages and whether increasing autocrine ACh could decrease TNF release from the macrophages. The results showed that, in RAW264.7 cells incubated with LPS for 20 hours, the secretion of ACh was significantly decreased at 4 h and then gradually increased, accompanied with the enhancement of α7nAChR expression level. The release of TNF was greatly increased from RAW264.7 cells at 4 h and 8 h exposure to LPS; however, it was suppressed at 20 h. Upregulating choline acetyltransferase (ChAT expression through ChAT gene transfection could enhance ACh secretion and reduce TNF release from the infected RAW264. 7cells. The results indicated that LPS stimulation could modulate the activity of nonneuronal cholinergic system of RAW264.7 cells. Enhancing autocrine ACh production could attenuate TNF release from RAW264.7 cells.

  18. Pathogen-induced heart rate changes associated with cholinergic nervous system activation. (United States)

    Fairchild, Karen D; Srinivasan, Varadamurthy; Moorman, J Randall; Gaykema, Ronald P A; Goehler, Lisa E


    The autonomic nervous system plays a central role in regulation of host defense and in physiological responses to sepsis, including changes in heart rate and heart rate variability. The cholinergic anti-inflammatory response, whereby infection triggers vagal efferent signals that dampen production of proinflammatory cytokines, would be predicted to result in increased vagal signaling to the heart and increased heart rate variability. In fact, decreased heart rate variability is widely described in humans with sepsis. Our studies elucidate this apparent paradox by showing that mice injected with pathogens demonstrate transient bradyarrhythmias of vagal origin in a background of decreased heart rate variability (HRV). Intraperitoneal injection of a large inoculum of Gram-positive or Gram-negative bacteria or Candida albicans rapidly induced bradyarrhythmias of sinus and AV nodal block, characteristic of cardiac vagal firing and dramatically increased short-term HRV. These pathogen-induced bradycardias were immediately terminated by atropine, an antagonist of muscarinic cholinergic receptors, demonstrating the role of vagal efferent signaling in this response. Vagal afferent signaling following pathogen injection was demonstrated by intense nuclear c-Fos activity in neurons of the vagal sensory ganglia and brain stem. Surprisingly, pathogen-induced bradycardia demonstrated rapid and prolonged desensitization and did not recur on repeat injection of the same organism 3 h or 3 days after the initial exposure. After recovery from the initial bradycardia, depressed heart rate variability developed in some mice and was correlated with elevated plasma cytokine levels and mortality. Our findings of decreased HRV and transient heart rate decelerations in infected mice are similar to heart rate changes described by our group in preterm neonates with sepsis. Pathogen sensing and signaling via the vagus nerve, and the desensitization of this response, may account for periods of

  19. Alterations in brain activation during cholinergic enhancement with rivastigmine in Alzheimer's disease


    Rombouts, S.; Barkhof, F; van Meel, C S; Scheltens, P


    Background: Rivastigmine enhances cholinergic activity and has been shown in clinical trials to decrease the rate of deterioration in Alzheimer's disease. It remains unclear where in the brain it exerts its effect. Functional magnetic resonance imaging (fMRI) can be used to measure changes in brain function and relate these to cognition.

  20. Libidibia ferrea Mature Seeds Promote Antinociceptive Effect by Peripheral and Central Pathway: Possible Involvement of Opioid and Cholinergic Receptors

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    Luis Armando Sawada


    Full Text Available Libidibia ferrea (LF is a medicinal plant that holds many pharmacological properties. We evaluated the antinociceptive effect in the LF aqueous seed extract and Lipidic Portion of Libidibia ferrea (LPLF, partially elucidating their mechanisms. Histochemical tests and Gas chromatography of the LPLF were performed to characterize its fatty acids. Acetic acid-induced abdominal constriction, formalin-induced pain, and hot-plate test in mice were employed in the study. In all experiments, aqueous extract or LPLF was administered systemically at the doses of 1, 5, and 10 mg/kg. LF aqueous seed extract and LPLF demonstrated a dose-dependent antinociceptive effect in all tests indicating both peripheral anti-inflammatory and central analgesia properties. Also, the use of atropine (5 mg/kg, naloxone (5 mg/kg in the abdominal writhing test was able to reverse the antinociceptive effect of the LPLF, indicating that at least one of LF lipids components is responsible for the dose related antinociceptive action in chemical and thermal models of nociception in mice. Together, the present results suggested that Libidibia ferrea induced antinociceptive activity is possibly related to its ability to inhibit opioid, cholinergic receptors, and cyclooxygenase-2 pathway, since its main component, linoleic acid, has been demonstrated to produce such effect in previous studies.

  1. Libidibia ferrea mature seeds promote antinociceptive effect by peripheral and central pathway: possible involvement of opioid and cholinergic receptors. (United States)

    Sawada, Luis Armando; Monteiro, Vanessa Sâmia da Conçeição; Rabelo, Guilherme Rodrigues; Dias, Germana Bueno; Da Cunha, Maura; do Nascimento, José Luiz Martins; Bastos, Gilmara de Nazareth Tavares


    Libidibia ferrea (LF) is a medicinal plant that holds many pharmacological properties. We evaluated the antinociceptive effect in the LF aqueous seed extract and Lipidic Portion of Libidibia ferrea (LPLF), partially elucidating their mechanisms. Histochemical tests and Gas chromatography of the LPLF were performed to characterize its fatty acids. Acetic acid-induced abdominal constriction, formalin-induced pain, and hot-plate test in mice were employed in the study. In all experiments, aqueous extract or LPLF was administered systemically at the doses of 1, 5, and 10 mg/kg. LF aqueous seed extract and LPLF demonstrated a dose-dependent antinociceptive effect in all tests indicating both peripheral anti-inflammatory and central analgesia properties. Also, the use of atropine (5 mg/kg), naloxone (5 mg/kg) in the abdominal writhing test was able to reverse the antinociceptive effect of the LPLF, indicating that at least one of LF lipids components is responsible for the dose related antinociceptive action in chemical and thermal models of nociception in mice. Together, the present results suggested that Libidibia ferrea induced antinociceptive activity is possibly related to its ability to inhibit opioid, cholinergic receptors, and cyclooxygenase-2 pathway, since its main component, linoleic acid, has been demonstrated to produce such effect in previous studies.

  2. Eye Movements and Abducens Motoneuron Behavior after Cholinergic Activation of the Nucleus Reticularis Pontis Caudalis (United States)

    Márquez-Ruiz, Javier; Escudero, Miguel


    Study Objectives: The aim of this work was to characterize eye movements and abducens (ABD) motoneuron behavior after cholinergic activation of the nucleus reticularis pontis caudalis (NRPC). Methods: Six female adult cats were prepared for chronic recording of eye movements (using the scleral search-coil technique), electroencephalography, electromyography, ponto-geniculo-occipital (PGO) waves in the lateral geniculate nucleus, and ABD motoneuron activities after microinjections of the cholinergic agonist carbachol into the NRPC. Results: Unilateral microinjections of carbachol in the NRPC induced tonic and phasic phenomena in the oculomotor system. Tonic effects consisted of ipsiversive rotation to the injected side, convergence, and downward rotation of the eyes. Phasic effects consisted of bursts of rhythmic rapid eye movements directed contralaterally to the injected side along with PGO-like waves in the lateral geniculate and ABD nuclei. Although tonic effects were dependent on the level of drowsiness, phasic effects were always present and appeared along with normal saccades when the animal was vigilant. ABD motoneurons showed phasic activities associated with ABD PGO-like waves during bursts of rapid eye movements, and tonic and phasic activities related to eye position and velocity during alertness. Conclusion The cholinergic activation of the NRPC induces oculomotor phenomena that are somewhat similar to those described during REM sleep. A precise comparison of the dynamics and timing of the eye movements further suggests that a temporal organization of both NRPCs is needed to reproduce the complexity of the oculomotor behavior during REM sleep. Citation: Márquez-Ruiz J; Escudero M. Eye movements and abducens motoneuron behavior after cholinergic activation of the nucleus reticularis pontis caudalis. SLEEP 2010;33(11):1517-1527. PMID:21102994

  3. Dopamine D₂-agonist rotigotine effects on cortical excitability and central cholinergic transmission in Alzheimer's disease patients. (United States)

    Martorana, Alessandro; Di Lorenzo, Francesco; Esposito, Zaira; Lo Giudice, Temistocle; Bernardi, Giorgio; Caltagirone, Carlo; Koch, Giacomo


    Dopamine is a neurotransmitter involved in several brain functions ranging from emotions control, movement organization to memory formation. It is also involved in the regulation of mechanisms of synaptic plasticity. However, its role in Alzheimer's disease (AD) pathogenesis is still puzzling. Several recent line of research instead indicates a clear role for dopamine in both amyloid β formation as well as in cognitive decline progression. In particular it has been shown that dopamine D₂-like receptors (namely D₃ and D₂) could be mostly responsible for dopamine dysfunction in AD. Here we aimed to study the effects of the dopamine agonist Rotigotine on cortical excitability and on central cholinergic transmission in cases of AD. Rotigotine is a dopamine agonist with a pharmacological profile with high affinity for D₃ and D₂ receptors. We used paired pulse protocols assessing short intracortical inhibition (SICI) and intracortical facilitation (ICF) to asses cortical excitability over the primary motor cortex and Short Latency Afferent Inhibition (SLAI) protocols, to verify the effects of the drug on central cholinergic transmission in a group of AD patients compared to age-matched controls. We observed that rotigotine induces unexpected changes in both cortical excitability (increased) and central cholinergic transmission (restored) of AD patients. These unexpected effects might depend on the dopamine D₂-like receptors dysfunction previously described in AD brains. The current findings could indicate that future strategies aimed to ameliorate symptoms of the related AD cognitive decline could also involve some dopaminergic drugs. This article is part of a Special Issue entitled 'Cognitive Enhancers'. Copyright © 2012 Elsevier Ltd. All rights reserved.

  4. Modulation of cholinergic systems by manganese. (United States)

    Finkelstein, Yoram; Milatovic, Dejan; Aschner, Michael


    Information on changes in the central nervous system (CNS) cholinergic systems following exposure to manganese are considerably less extensive than that associated with other neurotransmitter systems. However, experimental and clinical evidence support the notion that cholinergic activity plays a key role in the pathophysiology of manganese-induced neurotoxicity. Manganese acts as a chemical stressor in cholinergic neurons in a region-specific manner causing breakdown of the cellular homeostatic mechanisms. In fact, a number of cholinergic synaptic mechanisms are putative targets for manganese activity: presynaptic choline uptake, quantal release of acetylcholine into the synaptic cleft, postsynaptic binding of acetylcholine to receptors and its synaptic degradation by acetylcholinesterase. Moreover, manganese significantly influences astrocytic choline transport systems and astrocytic acetylcholine-binding proteins. Thus, manganese exerts its effect on the highly dynamic reciprocal relationship between astrocytes and cholinergic neurons. Cholinergic afferents are crucial in the physiology of locomotion, cognition, emotion and behavioral response, and therefore, it is not surprising that the anatomical selectivity of most manganese-induced cholinergic effects is compatible with the clinical correlates of manganism, which involves impairment of emotional response, decline in higher cortical functions and movement disorder. Manganism, also referred to as Parkinson's-like disorder, is initially manifested by a neuropsychiatric syndrome (locura manganica), the most frequent symptoms and signs of which are compulsive behavior, emotional lability, visual hallucinations and flight of ideas, cognitive decline and memory loss. These signs and symptoms are followed by an extrapyramidal syndrome, which shares numerous clinical and pathophysiological characteristics with idiopathic Parkinson's disease (PD). This natural history of disease could be a clinical reflection of the

  5. Cholinergic activity and levodopa-induced dyskinesia: a multitracer molecular imaging study. (United States)

    Brumberg, Joachim; Küsters, Sebastian; Al-Momani, Ehab; Marotta, Giorgio; Cosgrove, Kelly P; van Dyck, Christopher H; Herrmann, Ken; Homola, György A; Pezzoli, Gianni; Buck, Andreas K; Volkmann, Jens; Samnick, Samuel; Isaias, Ioannis U


    To investigate the association between levodopa-induced dyskinesias and striatal cholinergic activity in patients with Parkinson's disease. This study included 13 Parkinson's disease patients with peak-of-dose levodopa-induced dyskinesias, 12 nondyskinetic patients, and 12 healthy controls. Participants underwent 5-[123I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine single-photon emission computed tomography, a marker of nicotinic acetylcholine receptors, [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane single-photon emission computed tomography, to measure dopamine reuptake transporter density and 2-[18F]fluoro-2-deoxyglucose positron emission tomography to assess regional cerebral metabolic activity. Striatal binding potentials, uptake values at basal ganglia structures, and correlations with clinical variables were analyzed. Density of nicotinic acetylcholine receptors in the caudate nucleus of dyskinetic subjects was similar to that of healthy controls and significantly higher to that of nondyskinetic patients, in particular, contralaterally to the clinically most affected side. Our findings support the hypothesis that the expression of dyskinesia may be related to cholinergic neuronal excitability in a dopaminergic-depleted striatum. Cholinergic signaling would play a role in maintaining striatal dopaminergic responsiveness, possibly defining disease phenotype and progression.

  6. Cardiovascular effects of the intracerebroventricular injection of adrenomedullin: roles of the peripheral vasopressin and central cholinergic systems

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    B. Cam-Etoz


    Full Text Available Our objective was to investigate in conscious Sprague-Dawley (6-8 weeks, 250-300 g female rats (N = 7 in each group the effects of intracerebroventricularly (icv injected adrenomedullin (ADM on blood pressure and heart rate (HR, and to determine if ADM and calcitonin gene-related peptide (CGRP receptors, peripheral V1 receptors or the central cholinergic system play roles in these cardiovascular effects. Blood pressure and HR were observed before and for 30 min following drug injections. The following results were obtained: 1 icv ADM (750 ng/10 µL caused an increase in both blood pressure and HR (DMAP = 11.8 ± 2.3 mmHg and ΔHR = 39.7 ± 4.8 bpm. 2 Pretreatment with a CGRP receptor antagonist (CGRP8-37 and ADM receptor antagonist (ADM22-52 blocked the effect of central ADM on blood pressure and HR. 3 The nicotinic receptor antagonist mecamylamine (25 µg/10 µL, icv and the muscarinic receptor antagonist atropine (5 µg/10 µL, icv prevented the stimulating effect of ADM on blood pressure. The effect of ADM on HR was blocked only by atropine (5 µg/10 µL, icv. 4 The V1 receptor antagonist [β-mercapto-β-β-cyclopentamethylenepropionyl¹, O-me-Tyr²,Arg8]-vasopressin (V2255; 10 µg/kg, that was applied intravenously, prevented the effect of ADM on blood pressure and HR. This is the first study reporting the role of specific ADM and CGRP receptors, especially the role of nicotinic and muscarinic central cholinergic receptors and the role of peripheral V1 receptors in the increasing effects of icv ADM on blood pressure and HR.

  7. Cardiovascular effects of the intracerebroventricular injection of adrenomedullin: roles of the peripheral vasopressin and central cholinergic systems

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    Cam-Etoz, B.; Isbil-Buyukcoskun, N.; Ozluk, K. [Department of Physiology, Uludag University Medical Faculty, Gorukle/Bursa (Turkey)


    Our objective was to investigate in conscious Sprague-Dawley (6-8 weeks, 250-300 g) female rats (N = 7 in each group) the effects of intracerebroventricularly (icv) injected adrenomedullin (ADM) on blood pressure and heart rate (HR), and to determine if ADM and calcitonin gene-related peptide (CGRP) receptors, peripheral V{sub 1} receptors or the central cholinergic system play roles in these cardiovascular effects. Blood pressure and HR were observed before and for 30 min following drug injections. The following results were obtained: 1) icv ADM (750 ng/10 µL) caused an increase in both blood pressure and HR (ΔMAP = 11.8 ± 2.3 mmHg and ΔHR = 39.7 ± 4.8 bpm). 2) Pretreatment with a CGRP receptor antagonist (CGRP{sub 8-37}) and ADM receptor antagonist (ADM{sub 22-52}) blocked the effect of central ADM on blood pressure and HR. 3) The nicotinic receptor antagonist mecamylamine (25 µg/10 µL, icv) and the muscarinic receptor antagonist atropine (5 µg/10 µL, icv) prevented the stimulating effect of ADM on blood pressure. The effect of ADM on HR was blocked only by atropine (5 µg/10 µL, icv). 4) The V{sub 1} receptor antagonist [β-mercapto-β-β-cyclopentamethylenepropionyl{sup 1}, O-me-Tyr{sup 2},Arg{sup 8}]-vasopressin (V2255; 10 µg/kg), that was applied intravenously, prevented the effect of ADM on blood pressure and HR. This is the first study reporting the role of specific ADM and CGRP receptors, especially the role of nicotinic and muscarinic central cholinergic receptors and the role of peripheral V{sub 1} receptors in the increasing effects of icv ADM on blood pressure and HR.

  8. Potentiation by cholinesterase inhibitors of cholinergic activity in rat isolated stomach and colon. (United States)

    Jarvie, Emma M; Cellek, Selim; Sanger, Gareth J


    Acetylcholinesterase (AChE) inhibitors stimulate gastrointestinal (GI) motility and are potential treatments of conditions associated with inadequate GI motility. The ability of itopride to facilitate neuronally (predominantly cholinergic) mediated contractions of rat isolated stomach, evoked by electrical field stimulation (EFS), has been compared with other cholinesterase inhibitors and with tegaserod, a clinically effective prokinetic and non-selective 5-HT(4) receptor agonist which also facilitates GI cholinergic function. Neostigmine greatly increased EFS-evoked contractions over a narrow concentration range (0.01-1 microM; 754+/-337% facilitation at 1 microM); higher concentrations (1, 3 microM) also increased muscle tension. Donepezil increased EFS-evoked contractions gradually over the full range of concentrations (0.01-10 microM; maximum increase 516+/-20% at 10 microM). Itopride increased the contractions even more gradually, rising to 188+/-84% at 10 microM. The butyrylcholinesterase inhibitor iso-OMPA 0.01-10 microM also increased EFS-evoked contractions, to a maximum of 36+/-5.0% at 10 microM, similar to that caused by tegaserod (35+/-5.2% increase at 1 microM). The effects of tegaserod, but not itopride were inhibited by the 5-HT(4) receptor antagonist SB-204070A 0.3 microM. In rat isolated colon, neostigmine was again the most efficacious, causing a defined maximum increase in EFS-evoked contractions (343+/-82% at 10 microM), without changing muscle tension. Maximum increases caused by donepezil and itopride were, respectively, 57.6+/-20 and 43+/-15% at 10 microM. These data indicate that the abilities of different AChE inhibitors to increase GI cholinergic activity differ markedly. Understanding the reasons is essential if AChE inhibitors are to be optimally developed as GI prokinetics.

  9. Antinociception induced by systemic administration of local anaesthetics depends on a central cholinergic mechanism. (United States)

    Bartolini, A; Galli, A; Ghelardini, C; Giotti, A; Malcangio, M; Malmberg-Aiello, P; Zucchi, P L


    1 The antinociceptive effects of systemically-administered procaine, lignocaine and bupivacaine were examined in mice and rats by using the hot-plate, writhing and tail flick tests. 2 In both species all three local anaesthetics produced significant antinociception which was prevented by atropine (5 mg kg-1, i.p.) and by hemicholinium-3 (1 microgram per mouse, i.c.v.), but not by naloxone (3 mg kg-1, i.p.), alpha-methyl-p-tyrosine (100 mg kg-1, s.c.), reserpine (2 mg kg-1, i.p.) or atropine methylbromide (5.5 mg kg-1, i.p.). 3 Atropine (5 mg kg-1, i.p.) which totally antagonized oxotremorine (40 micrograms kg-1, s.c.) antinociception did not modify morphine (5 mg kg-1, s.c.) or baclofen (4 mg kg-1, s.c.) antinociception. On the other hand, hemicholinium, which antagonized local anaesthetic antinociception, did not prevent oxotremorine, morphine or baclofen antinociception. 4 Intracerebroventricular injection in mice of procaine (200 micrograms), lignocaine (150 microgram) and bupivacaine (25 micrograms), doses which were largely ineffective by parenteral routes, induced an antinociception whose intensity equalled that obtainable subcutaneously. Moreover, the i.c.v. injection of antinociceptive doses did not impair performance on the rota-rod test. 5 Concentrations below 10(-10) M of procaine, lignocaine and bupivacaine did not evoke any response on the isolated longitudinal muscle strip of guinea-pig ileum, or modify acetylcholine (ACh)-induced contractions. On the other hand, they always increased electrically-evoked twitches. 6 The same concentrations of local anaesthetics which induced antinociception did not inhibit acetylcholinesterase (AChE) in vitro. 7 On the basis of the above findings and the existing literature, a facilitation of cholinergic transmission by the local anaesthetics is postulated; this could be due to blockade of presynaptic muscarinic receptors.

  10. Activation of the cholinergic antiinflammatory pathway reduces ricin-induced mortality and organ failure in mice. (United States)

    Mabley, Jon G; Pacher, Pal; Szabo, Csaba


    Exposure to ricin, either by accident through ingestion of castor oil plant seeds or intentionally through its use as a bioweapon, invariably leads to multiple organ damage and death. Currently there is only a vaccine in advanced development to ricin, but no other antidote. Ricin causes systemic inflammation with increased proinflammatory cytokine release and subsequent multiple organ failure, particularly kidney and liver dysfunction. Activation of the cholinergic antiinflammatory pathway, specifically through the alpha7 nicotinic acetylcholine receptor (either indirectly through vagus nerve stimulation or directly through nicotine treatment) reduces proinflammatory gene expression. This activation also increases release of proinflammatory chemokines and cytokines, and has proven effective in a variety of inflammatory diseases. The aim of this study was to investigate whether nicotine treatment protected against ricin toxicity in mice. Male Balb/c mice exposed to ricin had increased serum levels of the inflammatory cytokine tumor necrosis factor-alpha and markers of both kidney (blood urea nitrogen, creatine) and liver (alanine tranaminase) dysfunction, with a subsequent increase in mortality. Nicotine administration 2 h after ricin injection significantly delayed and reduced ricin-induced mortality, an effect coupled with reduced serum levels of tumor necrosis factor-alpha and markers of kidney and liver dysfunction. Both the kidney and liver had markedly increased cellular oxidative stress following ricin exposure, an effect attenuated by nicotine administration. In conclusion, these data demonstrate that in cases of ricin poisoning, activation of the cholinergic antiinflammatory pathway may prove beneficial by reducing organ damage, delaying mortality, and allowing for a greater chance of survival.

  11. Rosmarinus officinalis polyphenols activate cholinergic activities in PC12 cells through phosphorylation of ERK1/2. (United States)

    El Omri, Abdelfatteh; Han, Junkyu; Yamada, Parida; Kawada, Kiyokazu; Ben Abdrabbah, Manef; Isoda, Hiroko


    This paper aimed to elucidate the traditional use of Rosmarinus officinalis through the investigation of cholinergic activities and neuronal differentiation in rat pheochromocytoma PC12 cells. These effects were examined in relation to the plant's habitat, the extraction procedure, and the major active compounds of R. officinalis. Cell viability, cell differentiation, acetylcholinesterase (AChE) activity, total choline, acetylcholine (ACh) and extracellular signal-regulated kinases (ERK1/2) were determined in PC12 cells treated with extracts and HPLC-identified polyphenols of R. officinalis originated from Tunisian semi-arid and subhumid area in comparison with nerve growth factor (NGF). R. officinalis extracts potentiated cell differentiation and significantly enhanced AChE activity in PC12 cells. The highest AChE activity was induced by semi-arid hydro-ethanolic extract (137% of control). Among HPLC-identified and screened polyphenols, carnosic acid (CA) and rosmarinic acid (RA) significantly induced cell differentiation, increased ACh level, and enhanced AChE activity in PC12 cells. U0126, inhibitor of ERK1/2, significantly reduced CA and RA effects on cell differentiation and AChE activity. R. officinalis' CA and RA exhibited neurotrophic effects in PC12 cells through cell differentiation induction and cholinergic activities enhancement. These effects could be regulated by mitogen-activated protein kinase (MAPK), ERK1/2 signaling pathway. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

  12. Tyrosine hydroxylase activity decreases with induction of cholinergic properties in cultured sympathetic neurons


    Wolinsky, Eve; Patterson, Paul H.


    Establishment of transmitter phenotype is an essential step in neuronal development. Studies on rat sympathetic neurons both in vivo and in vitro have provided evidence that mature cholinergic sympathetic neurons arise from previously noradrenergic neurons. Cultured rat superior cervical ganglion neurons can be influenced by their environment to remain noradrenergic, to acquire dual transmitter function, or to become predominantly cholinergic. Several other neuronal traits, such as a variety ...

  13. Cholinergic pairing with visual activation results in long-term enhancement of visual evoked potentials.

    Directory of Open Access Journals (Sweden)

    Jun Il Kang

    Full Text Available Acetylcholine (ACh contributes to learning processes by modulating cortical plasticity in terms of intensity of neuronal activity and selectivity properties of cortical neurons. However, it is not known if ACh induces long term effects within the primary visual cortex (V1 that could sustain visual learning mechanisms. In the present study we analyzed visual evoked potentials (VEPs in V1 of rats during a 4-8 h period after coupling visual stimulation to an intracortical injection of ACh analog carbachol or stimulation of basal forebrain. To clarify the action of ACh on VEP activity in V1, we individually pre-injected muscarinic (scopolamine, nicotinic (mecamylamine, alpha7 (methyllycaconitine, and NMDA (CPP receptor antagonists before carbachol infusion. Stimulation of the cholinergic system paired with visual stimulation significantly increased VEP amplitude (56% during a 6 h period. Pre-treatment with scopolamine, mecamylamine and CPP completely abolished this long-term enhancement, while alpha7 inhibition induced an instant increase of VEP amplitude. This suggests a role of ACh in facilitating visual stimuli responsiveness through mechanisms comparable to LTP which involve nicotinic and muscarinic receptors with an interaction of NMDA transmission in the visual cortex.

  14. Two polypeptides from Dendroaspis angusticeps venom selectively inhibit the binding of central muscarinic cholinergic receptor ligands. (United States)

    Jerusalinsky, D; Cerveñasky, C; Peña, C; Raskovsky, S; Dajas, F


    Two new polypeptides were isolated and purified from the venom of the snake Dendroaspis angusticeps, which also contains other neuroactive peptides such as Dendrotoxins and Fasciculins. The amino acid composition of the peptides was determined and the first 10 amino acids from the MTX2 N-terminal fragment were sequenced. The so-called muscarinic toxins (MTX1 and MTX2) have been shown to inhibit the specific binding of [3H]QNB (0.15 nM), [3H]PZ (2.5 nM) and [3H]oxoM (2 nM) to bovine cerebral cortex membranes by 60, 88 and 82% respectively. In contrast, they caused only a 30% blockade of the [3H]QNB specific binding to similar membrane preparations from the brainstem. The Hill number for the [3H]PZ binding inhibition by the putative muscarinic toxin MTX2 was 0.95 suggesting homogeneity in the behaviour of the sites involved. The data from [3H]oxoM binding gave a Hill number of 0.83. The decreases in the specific binding involved increases in KD for the three different ligands (8-fold for [3H]QNB, 4-fold for [3H]PZ and 3.5-fold for [3H]oxoM) without significant changes in Bmax, except for a slight decrease in the [3H]oxoM binding sites (-19%); such results suggest that there may be a competitive inhibition between the MTXs and these ligands. The Ki for MTX2/[3H]PZ was 22.58 +/- 3.52 nM; for MTX2/[3H]oxoM, 144.9 +/- 21.07 nM and for MTX2/[3H]QNB, 134.98 +/- 18.35 nM. The labelling of MTX2 with 125I allowed direct demonstration of specific and saturable binding to bovine cerebral cortex synaptosomal membranes. In conclusion, the results reported in this study strongly support the hypotheses that the two polypeptides isolated from D. angusticeps venom selectively inhibit specific ligand binding to central muscarinic receptors, in a competitive manner at least for the antagonist [3H]PZ and that the MTX2 specifically binds to a central site that is suggested to be a muscarinic receptor of the M1 subtype.

  15. [Hypolipidemic activity of N-cholinergic antagonist Benzohexonium in the experiments ]. (United States)

    Khnychenko, L K; Okunevich, I V; Losev, N A; Sapronov, N S


    Methods: Experiments were carried out on outbred albino male rats (n = 150, 230-250 g). For modeling dislipoproteinemia (DLP) we used 3 models: single intraperitoneal injection of the detergent triton WR-1339; administration of ethanol; maintenance on a special hypercholesterolaemic diet (HD) during 21 days. Animals were divided into four groups: normal control, model group, gemfibrozil (Gfb) group, benzohexonium (Benz) group. Rats received per os benzohexonium (20mg/kg), reference drug gemfibrozil (50 mg/kg). We determined content of total cholesterol (TCh), triglycerides (TG) in samples of blood serum and liver, TCh in aorta. TCh, TG and Ch-HDL were analyzed spectrophotometrically using of standardized methods. Results: Compared with model group the contents of TCh, TG in serum and liver were significantly decreased in model + Benz group, whereas Ch-HDL was raised in rats fed special HD (P<0.05). Calculated index of atherogenity (TCh - Ch-HDL) / (Ch-HDL) showed the positive effect. Conclusion: The results obtained were shown the hypolipidemic activity of N-cholinergic antagonist Benzohexonium (20 mg/kg) lowered the content of lipids in blood, liver, and aorta.

  16. Cholinergic Enhancement of Brain Activation in Mild Cognitive Impairment (MCI during Episodic Memory Encoding

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    Shannon L Risacher


    Full Text Available Objective: To determine the physiological impact of treatment with donepezil (Aricept on neural circuitry supporting episodic memory encoding in patients with amnestic mild cognitive impairment (MCI using functional MRI (fMRI. Methods: 18 patients with MCI and 20 age-matched healthy controls (HC were scanned twice while performing an event-related verbal episodic encoding task. MCI participants were scanned before treatment and after approximately 3 months on donepezil; HC were untreated but rescanned at the same interval. Voxel-level analyses assessed treatment effects in activation profile relative to retest changes in non-treated HC. Changes in task-related connectivity in medial temporal circuitry were also evaluated, as were associations between brain activation pattern, task-related functional connectivity, task performance, and clinical measures of cognition.Results: At baseline, the MCI group showed reduced activation during encoding relative to HC in the right medial temporal lobe (MTL; hippocampal/parahippocampal and additional regions, as well as attenuated task-related deactivation, relative to rest, in a medial parietal lobe cluster. After treatment, the MCI group showed normalized MTL activation and improved parietal deactivation. These changes were associated with cognitive performance. After treatment, the MCI group also demonstrated increased task-related functional connectivity from the right MTL cluster seed region to a network of other sites including the basal nucleus/caudate and bilateral frontal lobes. Increased functional connectivity was associated with improved task performance.Conclusions: Pharmacologic enhancement of cholinergic function in amnestic MCI is associated with changes in brain activation pattern and functional connectivity during episodic memory processing which are in turn related to increased cognitive performance. fMRI is a promising biomarker for assessing treatment related changes in brain function.

  17. Cracking the Betel Nut: Cholinergic Activity of Areca Alkaloids and Related Compounds. (United States)

    Horenstein, Nicole A; Quadri, Marta; Stokes, Clare; Shoaib, Mohammed; Papke, Roger L


    The use of betel quid is the most understudied major addiction in the world. The neuropsychological activity of betel quid has been attributed to alkaloids of Areca catechu. With the goal of developing novel addiction treatments, we evaluate the muscarinic and nicotinic activity of the four major Areca alkaloids: arecoline, arecaidine, guvacoline, and guvacine and four structurally related compounds. Acetylcholine receptors were expressed in Xenopus oocytes and studied with two-electrode voltage clamp. Both arecoline- and guvacoline-activated muscarinic acetylcholine receptors (mAChR), while only arecoline produced significant activation of nicotinic AChR (nAChR). We characterized four additional arecoline-related compounds, seeking an analog that would retain selective activity for a α4* nAChR, with diminished effects on mAChR and not be a desensitizer of α7 nAChR. We show that this profile is largely met by isoarecolone. Three additional arecoline analogs were characterized. While the quaternary dimethyl analog had a broad range of activities, including activation of mAChR and muscle-type nAChR, the methyl analog only activated a range of α4* nAChR, albeit with low potency. The ethyl analog had no detectable cholinergic activity. Evidence indicates that α4* nAChR are at the root of nicotine addiction, and this may also be the case for betel addiction. Our characterization of isoarecolone and 1-(4-methylpiperazin-1-yl) ethanone as truly selective α4*nAChR selective partial agonists with low muscarinic activity may point toward a promising new direction for the development of drugs to treat both nicotine and betel addiction. Nearly 600 million people use Areca nut, often with tobacco. Two of the Areca alkaloids are muscarinic acetylcholine receptor agonists, and one, arecoline, is a partial agonist for the α4* nicotinic acetylcholine receptors (nAChR) associated with tobacco addiction. The profile of arecoline activity suggested its potential to be used as a

  18. Medications influencing central cholinergic pathways affect fixation stability, saccadic response time and associated eye movement dynamics during a temporally-cued visual reaction time task. (United States)

    Naicker, Preshanta; Anoopkumar-Dukie, Shailendra; Grant, Gary D; Modenese, Luca; Kavanagh, Justin J


    Anticholinergic medications largely exert their effects due to actions on the muscarinic receptor, which mediates the functions of acetylcholine in the peripheral and central nervous systems. In the central nervous system, acetylcholine plays an important role in the modulation of movement. This study investigated the effects of over-the-counter medications with varying degrees of central anticholinergic properties on fixation stability, saccadic response time and the dynamics associated with this eye movement during a temporally-cued visual reaction time task, in order to establish the significance of central cholinergic pathways in influencing eye movements during reaction time tasks. Twenty-two participants were recruited into the placebo-controlled, human double-blind, four-way crossover investigation. Eye tracking technology recorded eye movements while participants reacted to visual stimuli following temporally informative and uninformative cues. The task was performed pre-ingestion as well as 0.5 and 2 h post-ingestion of promethazine hydrochloride (strong centrally acting anticholinergic), hyoscine hydrobromide (moderate centrally acting anticholinergic), hyoscine butylbromide (anticholinergic devoid of central properties) and a placebo. Promethazine decreased fixation stability during the reaction time task. In addition, promethazine was the only drug to increase saccadic response time during temporally informative and uninformative cued trials, whereby effects on response time were more pronounced following temporally informative cues. Promethazine also decreased saccadic amplitude and increased saccadic duration during the temporally-cued reaction time task. Collectively, the results of the study highlight the significant role that central cholinergic pathways play in the control of eye movements during tasks that involve stimulus identification and motor responses following temporal cues.

  19. Paying attention to smell: cholinergic signaling in the olfactory bulb (United States)

    D’Souza, Rinaldo D.; Vijayaraghavan, Sukumar


    The tractable, layered architecture of the olfactory bulb (OB), and its function as a relay between odor input and higher cortical processing, makes it an attractive model to study how sensory information is processed at a synaptic and circuit level. The OB is also the recipient of strong neuromodulatory inputs, chief among them being the central cholinergic system. Cholinergic axons from the basal forebrain modulate the activity of various cells and synapses within the OB, particularly the numerous dendrodendritic synapses, resulting in highly variable responses of OB neurons to odor input that is dependent upon the behavioral state of the animal. Behavioral, electrophysiological, anatomical, and computational studies examining the function of muscarinic and nicotinic cholinergic receptors expressed in the OB have provided valuable insights into the role of acetylcholine (ACh) in regulating its function. We here review various studies examining the modulation of OB function by cholinergic fibers and their target receptors, and provide putative models describing the role that cholinergic receptor activation might play in the encoding of odor information. PMID:25309421

  20. Urotensin II modulates rapid eye movement sleep through activation of brainstem cholinergic neurons

    DEFF Research Database (Denmark)

    Huitron-Resendiz, Salvador; Kristensen, Morten Pilgaard; Sánchez-Alavez, Manuel


    administration of UII into the PPT nucleus increases REM sleep without inducing changes in the cortical blood flow. Intracerebroventricular injection of UII enhances both REM sleep and wakefulness and reduces slow-wave sleep 2. Intracerebroventricular, but not local, administration of UII increases cortical...... blood flow. Moreover, whole-cell recordings from rat-brain slices show that UII selectively excites cholinergic PPT neurons via an inward current and membrane depolarization that were accompanied by membrane conductance decreases. This effect does not depend on action potential generation or fast...

  1. Melanocortin 4 receptor stimulation decreases pancreatitis severity in rats by activation of the cholinergic anti-inflammatory pathway. (United States)

    Minutoli, Letteria; Squadrito, Francesco; Nicotina, Piero Antonio; Giuliani, Daniela; Ottani, Alessandra; Polito, Francesca; Bitto, Alessandra; Irrera, Natasha; Guzzo, Giuseppe; Spaccapelo, Luca; Fazzari, Carmine; Macrì, Antonio; Marini, Herbert; Guarini, Salvatore; Altavilla, Domenica


    Acute pancreatitis is an inflammatory condition that may lead to multisystemic organ failure. Melanocortin peptides have been successfully used in experimental models of organ failure and shock, and their protective effect occurs through the activation of a vagus nerve-mediated cholinergic anti-inflammatory pathway by acting at brain melanocortin 4 receptors. In the light of these observations, we studied the effects of the selective melanocortin 4 receptor agonist RO27-3225 in an experimental model of cerulein-induced pancreatitis. Randomized experiment. Research laboratory at a university hospital. Experimental pancreatitis in rats. Acute pancreatitis was induced in male Sprague-Dawley rats by intraperitoneal injections of cerulein (80 μg/kg, four injections at hourly intervals). Before pancreatitis induction, groups of animals were subjected to bilateral cervical vagotomy, pretreated with the nicotinic acetylcholine receptor antagonist chlorisondamine or the selective melanocortin 4 receptor antagonist HS024, or not pretreated. Thirty minutes after the first cerulein injection, rats were intraperitoneally treated with a nanomolar dose of RO27-3225 or vehicle. Some experimental groups were prepared for neural efferent activity recording along the vagus nerve starting 30 mins after treatment with RO27-3225 or vehicle, and for a 30-min period. Serum lipase and amylase activity, tumor necrosis factor-α and interleukin-6 expression, pancreatic myeloperoxidase activity, and histologic damage were evaluated; neural efferent activity of vagal fibers was also assessed. RO27-3225 reduced cerulein-induced serum lipase and amylase activity, blunted the expression of tumor necrosis factor-α and interleukin-6, abated the increase in pancreatic myeloperoxidase activity, and protected against histologic damage. Furthermore, RO27-3225 markedly increased neural efferent activity along the vagus nerve. Vagotomy, chlorisondamine, and HS024 abated these protective effects of RO27

  2. Cholinergic modulation of the medial prefrontal cortex: the role of nicotinic receptors in attention and regulation of neuronal activity

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    Bernard eBloem


    Full Text Available Acetylcholine release in the medial prefrontal cortex is (mPFC crucial for normal cognitive performance. Despite the fact that many have studied how acetylcholine affects neuronal processing in the mPFC and thereby influences attention behavior, there is still a lot unknown about how this occurs. Here we will review the evidence that cholinergic modulation of the mPFC plays a role in attention and we will summarize the current knowledge about the role between acetylcholine receptors and behavior and how acetylcholine receptor activation changes processing in the cortical microcircuitry. Recent evidence implicates fast phasic release of acetylcholine in cue detection and attention. This review will focus mainly on the fast ionotropic nicotinic receptors and less on the metabotropic muscarinic receptors. Finally, we will review limitations of the existing studies and address how innovative technologies might push the field forward in order to gain understanding into the relation between acetylcholine, neuronal activity and behavior.

  3. Evidence for activation of both adrenergic and cholinergic nervous pathways by yohimbine, an alpha 2-adrenoceptor antagonist. (United States)

    Bagheri, H; Chale, J J; Guyen, L N; Tran, M A; Berlan, M; Montastruc, J L


    Adrenoceptors are involved in the control of the activity of the autonomic nervous system and especially the sympathetic nervous system. Activation of alpha 2-adrenoceptors decreases sympathetic tone whereas their blockade has an opposite effect. However, previous investigations have shown that yohimbine (a potent alpha 2-adrenoceptor antagonist) increases salivary secretion through activation of cholinergic pathways. The aim of the present experiment was to investigate the involvement of both the sympathetic and the parasympathetic system in several pharmacological effects of yohimbine. For this purpose, salivary secretion and various endocrino-metabolic parameters (noradrenaline and insulin secretions, lipomobilization) were evaluated in conscious fasting dogs before and after blockade of either the sympathetic (with the beta-adrenoceptor antagonist agent nadolol) or the parasympathetic (with the anticholinergic agent atropine) systems. Yohimbine alone (0.4, i.v.) increased within 5-15 minutes, plasma noradrenaline (600%), insulin levels (300%), free-fatty acids (79%) and salivary secretion (143%). Atropine (0.2, i.v.) suppressed yohimbine-induced salivary secretion (90%) but did not significantly modify the yohimbine induced changes in noradrenaline (312%), insulin (277%) and free-fatty acids (102%) plasma levels. Administration of nadolol (1, i.v.) did not change the magnitude of the increase in both noradrenaline plasma levels (550%) and salivary secretion (300%) induced by yohimbine. However, nadolol totally blunted the increase in insulin (15%) and free-fatty acids (4%) plasma levels. These results show that yohimbine-induced increase in salivary secretion is a cholinergic effect whereas the increase in insulin and free fatty acids can be explained by an increase in sympathetic tone.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. The cholinergic system, circadian rhythmicity, and time memory

    NARCIS (Netherlands)

    Hut, R. A.; Van der Zee, E. A.


    This review provides an overview of the interaction between the mammalian cholinergic system and circadian system, and its possible role in time memory. Several studies made clear that circadian (daily) fluctuations in acetylcholine (ACh) release, cholinergic enzyme activity and cholinergic receptor

  5. Evaluating the evidence surrounding pontine cholinergic involvement in REM sleep generation

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    Kevin P Grace


    Full Text Available Rapid eye movement (REM sleep - characterized by vivid dreaming, motor paralysis, and heightened neural activity - is one of the fundamental states of the mammalian central nervous system. Initial theories of rapid eye movement (REM sleep generation posited that induction of the state required activation of the ‘pontine REM sleep generator’ by cholinergic inputs. Here we review and evaluate the evidence surrounding cholinergic involvement in REM sleep generation. We submit that: (i the capacity of pontine cholinergic neurotransmission to generate REM sleep has been firmly established by gain-of-function experiments, (ii the function of endogenous cholinergic input to REM sleep generating sites cannot be determined by gain-of-function experiments; rather, loss-of-function studies are required, (iii loss-of-function studies show that endogenous cholinergic input to the PFT is not required for REM sleep generation, and (iv Cholinergic input to the pontine REM sleep generating sites serve an accessory role in REM sleep generation: reinforcing non-REM-to-REM sleep transitions making them quicker and less likely to fail.

  6. Evaluating the Evidence Surrounding Pontine Cholinergic Involvement in REM Sleep Generation (United States)

    Grace, Kevin P.; Horner, Richard L.


    Rapid eye movement (REM) sleep – characterized by vivid dreaming, motor paralysis, and heightened neural activity – is one of the fundamental states of the mammalian central nervous system. Initial theories of REM sleep generation posited that induction of the state required activation of the “pontine REM sleep generator” by cholinergic inputs. Here, we review and evaluate the evidence surrounding cholinergic involvement in REM sleep generation. We submit that: (i) the capacity of pontine cholinergic neurotransmission to generate REM sleep has been firmly established by gain-of-function experiments, (ii) the function of endogenous cholinergic input to REM sleep generating sites cannot be determined by gain-of-function experiments; rather, loss-of-function studies are required, (iii) loss-of-function studies show that endogenous cholinergic input to the PTF is not required for REM sleep generation, and (iv) cholinergic input to the pontine REM sleep generating sites serve an accessory role in REM sleep generation: reinforcing non-REM-to-REM sleep transitions making them quicker and less likely to fail. PMID:26388832

  7. Change of central cholinergic receptors following lesions of nucleus basalis magnocellularis in rats: search for an imaging index suitable for the early detection of Alzheimer's disease

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    Ogawa, Mikako [Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501 (Japan); Photon Medical Research Center, Hamamatsu Medical University, Hamamatsu, Shizuoka 431-3192 (Japan); Iida, Yasuhiko [Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501 (Japan); School of Medicine, Gunma University, Maebashi, Gunma 371-8511 (Japan); Nakagawa, Masaki [Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501 (Japan); Kuge, Yugi [Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501 (Japan); Kawashima, Hidekazu [Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501 (Japan); Tominaga, Akiko [Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501 (Japan); Ueda, Masashi [Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501 (Japan); Magata, Yasuhiro [Photon Medical Research Center, Hamamatsu Medical University, Hamamatsu, Shizuoka 431-3192 (Japan); Saji, Hideo [Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501 (Japan)]. E-mail:


    Cholinergic system in the central nervous system is involved in the memory function. Thus, because the dysfunction of cholinergic system that project to the cerebral cortex from nucleus basalis of Meynert (nbM) would be implicated in the memory function deficits in Alzheimer's disease (AD), evaluating cholinergic function may be useful for the early detection of AD. In this study, because the nucleus basalis magnocellularis (NBM) in rats is equivalent to nbM in human, we investigated the change in cholinergic receptors in the frontal cortex of rats with unilateral lesion to the NBM to find an appropriate index for the early detection of AD using techniques of nuclear medicine. The right NBM was injected with ibotenic acid. [{sup 18}F]FDG-PET images were obtained 3 days later. Some rats were sacrificed at 1 week, whereas others were subjected to a second [{sup 18}F]FDG-PET at 4 weeks then sacrificed for membrane preparation. The prepared membranes were subjected to radioreceptor assays to measure the density of nicotinic and muscarinic acetylcholine receptors. Glucose metabolism had decreased on the damaged side compared to the control side at 3 days, but at 4 weeks, there was no difference between the sides. Nicotinic acetylcholine receptors had significantly decreased in density compared to the control side at both 1 and 4 weeks. However, muscarinic receptors were not affected. These results suggested that neuronal dysfunction in AD could be diagnosed at an early stage by imaging nicotinic acetylcholine receptors.

  8. Cholinergic innervation of human mesenteric lymphatic vessels. (United States)

    D'Andrea, V; Bianchi, E; Taurone, S; Mignini, F; Cavallotti, C; Artico, M


    The cholinergic neurotransmission within the human mesenteric lymphatic vessels has been poorly studied. Therefore, our aim is to analyse the cholinergic nerve fibres of lymphatic vessels using the traditional enzymatic techniques of staining, plus the biochemical modifications of acetylcholinesterase (AChE) activity. Specimens obtained from human mesenteric lymphatic vessels were subjected to the following experimental procedures: 1) drawing, cutting and staining of tissues; 2) staining of total nerve fibres; 3) enzymatic staining of cholinergic nerve fibres; 4) homogenisation of tissues; 5) biochemical amount of proteins; 6) biochemical amount of AChE activity; 6) quantitative analysis of images; 7) statistical analysis of data. The mesenteric lymphatic vessels show many AChE positive nerve fibres around their wall with an almost plexiform distribution. The incubation time was performed at 1 h (partial activity) and 6 h (total activity). Moreover, biochemical dosage of the same enzymatic activity confirms the results obtained with morphological methods. The homogenates of the studied tissues contain strong AChE activity. In our study, the lymphatic vessels appeared to contain few cholinergic nerve fibres. Therefore, it is expected that perivascular nerve stimulation stimulates cholinergic nerves innervating the mesenteric arteries to release the neurotransmitter AChE, which activates muscarinic or nicotinic receptors to modulate adrenergic neurotransmission. These results strongly suggest, that perivascular cholinergic nerves have little or no effect on the adrenergic nerve function in mesenteric arteries. The cholinergic nerves innervating mesenteric arteries do not mediate direct vascular responses.

  9. Activation of the mouse primary visual cortex by medial prefrontal subregion stimulation is not mediated by cholinergic basalo-cortical projections

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    Hoang Nam eNguyen


    Full Text Available The medial prefrontal cortex (mPFC exerts top-down control of primary visual cortex (V1 activity. As there is no direct neuronal projection from mPFC to V1, this functional connection may use an indirect route, i.e., via basalo-cortical cholinergic projections. The cholinergic projections to V1 originate from neurons in the horizontal limb of the diagonal band of Broca (HDB, which receive neuronal projections from the ventral part of the mPFC, composed of prelimbic (PrL and infralimbic cortices (IL. Therefore, the objective of this study was to determine whether electrical stimulation of mice mPFC subregions activate 1 V1 neurons and 2 HDB cholinergic neurons, suggesting that the HDB serves as a relay point in the mPFC-V1 interaction. Neuronal activation was quantified using c-Fos immunocytochemistry or thallium autometallography for each V1 layer using automated particle analysis tools and optical density measurement. Stimulation of IL and PrL induced significantly higher c-Fos expression or thallium labelling in layers II/III and V of V1 in the stimulated hemisphere only. A HDB cholinergic neuron-specific lesion by saporin administration reduced IL-induced c-Fos expression in layers II/III of V1 but not in layer V. However, there was no c-Fos expression or thallium labelling in the HDB neurons, suggesting that this area was not activated by IL stimulation. Stimulation of another mPFC subarea, the anterior cingulate cortex (AC, which is involved in attention and receives input from V1, activated neither V1 nor HDB. The present results indicate that IL and PrL, but not AC, stimulation activates V1 with the minor involvement of the HDB cholinergic projections. These results suggest a functional link between the ventral mPFC and V1, but this function is only marginally supported by HDB cholinergic neurons and may involve other brain regions.

  10. Cholinergic regulation of fear learning and extinction. (United States)

    Wilson, Marlene A; Fadel, Jim R


    Cholinergic activation regulates cognitive function, particularly long-term memory consolidation. This Review presents an overview of the anatomical, neurochemical, and pharmacological evidence supporting the cholinergic regulation of Pavlovian contextual and cue-conditioned fear learning and extinction. Basal forebrain cholinergic neurons provide inputs to neocortical regions and subcortical limbic structures such as the hippocampus and amygdala. Pharmacological manipulations of muscarinic and nicotinic receptors support the role of cholinergic processes in the amygdala, hippocampus, and prefrontal cortex in modulating the learning and extinction of contexts or cues associated with threat. Additional evidence from lesion studies and analysis of in vivo acetylcholine release with microdialysis similarly support a critical role of cholinergic neurotransmission in corticoamygdalar or corticohippocampal circuits during acquisition of fear extinction. Although a few studies have suggested a complex role of cholinergic neurotransmission in the cellular plasticity essential for extinction learning, more work is required to elucidate the exact cholinergic mechanisms and physiological role of muscarinic and nicotinic receptors in these fear circuits. Such studies are important for elucidating the role of cholinergic neurotransmission in disorders such as posttraumatic stress disorder that involve deficits in extinction learning as well as for developing novel therapeutic approaches for such disorders. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  11. Nicotinic Cholinergic System in the Hypothalamus Modulates the Activity of the Hypothalamic Neuropeptides during the Stress Response (United States)

    Balkan, Burcu; Pogun, Sakire


    The hypothalamus harbors high levels of cholinergic neurons and axon terminals. Nicotinic acetylcholine receptors, which play an important role in cholinergic neurotransmission, are expressed abundantly in the hypothalamus. Accumulating evidence reveals a regulatory role for nicotine in diverse functions mediated by the hypothalamus, including the regulation of the stress responses. The nicotinic cholinergic system lies at the intersection of homeostatic and reward pathways and shows sex differences in some of its effects. Furthermore, nicotinic acetylcholine receptor modulation offers significant potential for future drug development targeting pathologies related to hypothalamic functions. The present review will discuss the hypothalamic neuropeptides and their interaction with the nicotinic cholinergic system. The anatomical distribution of the cholinergic neurons, axon terminals and nicotinic receptors in discrete hypothalamic nuclei will be described. The effect of nicotinic cholinergic neurotransmission and nicotine exposure on HPA axis regulation at the hypothalamic level will be analyzed in view of the different neuropeptides involved. Copyright© Bentham Science Publishers; For any queries, please email at

  12. Opposing Roles of Cholinergic and GABAergic Activity in the Insular Cortex and Nucleus Basalis Magnocellularis during Novel Recognition and Familiar Taste Memory Retrieval. (United States)

    Rodríguez-García, Gabriela; Miranda, María Isabel


    Acetylcholine (ACh) is thought to facilitate cortical plasticity during memory formation and its release is regulated by the nucleus basalis magnocellularis (NBM). Questions remain regarding which neuronal circuits and neurotransmitters trigger activation or suppression of cortical cholinergic activity. During novel, but not familiar, taste consumption, there is a significant increase in ACh release in the insular cortex (IC), a highly relevant structure for taste learning. Here, we evaluate how GABA inhibition modulates cholinergic transmission and its involvement during taste novelty processing and familiar taste memory retrieval. Using saccharin as a taste stimulus in a taste preference paradigm, we examined the effects of injecting the GABAA receptor agonist muscimol or the GABAA receptor antagonist bicuculline into the IC or NBM during learning or retrieval of an appetitive taste memory on taste preference in male Sprague Dawley rats. GABAA receptor agonism and antagonism had opposite effects on cortical ACh levels in novel taste presentation versus familiar taste recognition and ACh levels were associated with the propensity to acquire or retrieve a taste memory. These results indicate that the pattern of cortical cholinergic and GABAergic neuroactivity during novel taste exposure is the opposite of that which occurs during familiar taste recognition and these differing neurotransmitter system states may enable different behavioral consequences. Divergences in ACh and GABA levels may produce differential alterations in excitatory and inhibitory neural processes within the cortex during acquisition and retrieval. During learning and recall, several brain structures act together. This work demonstrates interactions between cortical cholinergic and GABAergic systems during taste learning and memory retrieval. We found that the neuroactivity pattern during novel taste exposure is opposite that which occurs during familiar taste recognition. GABAA receptors must

  13. Nicotinic α4 Receptor-Mediated Cholinergic Influences on Food Intake and Activity Patterns in Hypothalamic Circuits.

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    Ana P García

    Full Text Available Nicotinic acetylcholine receptors (nAChRs play an important role in regulating appetite and have been shown to do so by influencing neural activity in the hypothalamus. To shed light on the hypothalamic circuits governing acetylcholine's (ACh regulation of appetite this study investigated the influence of hypothalamic nAChRs expressing the α4 subunit. We found that antagonizing the α4β2 nAChR locally in the lateral hypothalamus with di-hydro-ß-erythroidine (DHβE, an α4 nAChR antagonist with moderate affinity, caused an increase in food intake following free access to food after a 12 hour fast, compared to saline-infused animals. Immunocytochemical analysis revealed that orexin/hypocretin (HO, oxytocin, and tyrosine hydroxylase (TH-containing neurons in the A13 and A12 of the hypothalamus expressed the nAChR α4 subunit in varying amounts (34%, 42%, 50%, and 51%, respectively whereas melanin concentrating hormone (MCH neurons did not, suggesting that DHβE-mediated increases in food intake may be due to a direct activation of specific hypothalamic circuits. Systemic DHβE (2 mg/kg administration similarly increased food intake following a 12 hour fast. In these animals a subpopulation of orexin/hypocretin neurons showed elevated activity compared to control animals and MCH neuronal activity was overall lower as measured by expression of the immediate early gene marker for neuronal activity cFos. However, oxytocin neurons in the paraventricular hypothalamus and TH-containing neurons in the A13 and A12 did not show differential activity patterns. These results indicate that various neurochemically distinct hypothalamic populations are under the influence of α4β2 nAChRs and that cholinergic inputs to the lateral hypothalamus can affect satiety signals through activation of local α4β2 nAChR-mediated transmission.

  14. Nicotinic α4 Receptor-Mediated Cholinergic Influences on Food Intake and Activity Patterns in Hypothalamic Circuits. (United States)

    García, Ana P; Aitta-aho, Teemu; Schaaf, Laura; Heeley, Nicholas; Heuschmid, Lena; Bai, Yunjing; Barrantes, Francisco J; Apergis-Schoute, John


    Nicotinic acetylcholine receptors (nAChRs) play an important role in regulating appetite and have been shown to do so by influencing neural activity in the hypothalamus. To shed light on the hypothalamic circuits governing acetylcholine's (ACh) regulation of appetite this study investigated the influence of hypothalamic nAChRs expressing the α4 subunit. We found that antagonizing the α4β2 nAChR locally in the lateral hypothalamus with di-hydro-ß-erythroidine (DHβE), an α4 nAChR antagonist with moderate affinity, caused an increase in food intake following free access to food after a 12 hour fast, compared to saline-infused animals. Immunocytochemical analysis revealed that orexin/hypocretin (HO), oxytocin, and tyrosine hydroxylase (TH)-containing neurons in the A13 and A12 of the hypothalamus expressed the nAChR α4 subunit in varying amounts (34%, 42%, 50%, and 51%, respectively) whereas melanin concentrating hormone (MCH) neurons did not, suggesting that DHβE-mediated increases in food intake may be due to a direct activation of specific hypothalamic circuits. Systemic DHβE (2 mg/kg) administration similarly increased food intake following a 12 hour fast. In these animals a subpopulation of orexin/hypocretin neurons showed elevated activity compared to control animals and MCH neuronal activity was overall lower as measured by expression of the immediate early gene marker for neuronal activity cFos. However, oxytocin neurons in the paraventricular hypothalamus and TH-containing neurons in the A13 and A12 did not show differential activity patterns. These results indicate that various neurochemically distinct hypothalamic populations are under the influence of α4β2 nAChRs and that cholinergic inputs to the lateral hypothalamus can affect satiety signals through activation of local α4β2 nAChR-mediated transmission.

  15. Electroacupuncture at Zusanli Prevents Severe Scalds-Induced Gut Ischemia and Paralysis by Activating the Cholinergic Pathway

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    Huan Wang


    Full Text Available Severe burn injuries may result in gastrointestinal paralysis, and barrier dysfunction due to gut ischemia and lowered vagus excitability. In this study we investigate whether electroacupuncture (EA at Zusanli (ST36 could prevent severe scalds-induced gut ischemia, paralysis, and barrier dysfunction and whether the protective role of EA at ST36 is related to the vagus nerve. 35% burn area rats were divided into six groups: (a EAN: EA nonchannel acupoints followed by scald injury; (b EA: EA at ST36 after scald injury; (c VGX/EA: vagotomy (VGX before EA at ST36 and scald injury; (d VGX/EAN: VGX before EAN and scald injury; (e atropine/EA: applying atropine before scald injury and then EA at ST36; (f atropine/EAN: applying atropine before scald injury and then EA at nonchannel acupoints. EA at the Zusanli point significantly promoted the intestinal impelling ratio and increased the amount of mucosal blood flow after scald injury. The plasma diamine oxidase (DAO and intestinal permeability decreased significantly after scald injury in the EA group compared with others. However, EA after atropine injection or cervical vagotomy failed to improve intestinal motility and mucosa blood flow suggesting that the mechanism of EA may be related to the activation of the cholinergic nerve pathway.

  16. Activation of the cholinergic anti-inflammatory system by nicotine attenuates arthritis via suppression of macrophage migration (United States)

    Li, Sha; Zhou, Bin; Liu, Ben; Zhou, Yaou; Zhang, Huali; Li, Tong; Zuo, Xiaoxia


    Activation of the cholinergic anti-inflammatory pathway (CAP), which relies on the alpha-7 nicotinic acetylcholine receptor, has been reported to reduce proinflammatory cytokine levels in experimental arthritis. To gain more insight regarding the role of the CAP in the pathogenesis of arthritis, the present study focused on the modulation of macrophage infiltration. In a mouse model of collagen-induced arthritis (CIA), nicotine and vagotomy were used to stimulate and inhibit the CAP, respectively. Subsequently, arthritic scores were measured and histopathological assessment of joint sections was conducted. Cluster of differentiation (CD)11b-positive macrophages in the synovium were studied by immunofluorescence histochemistry. The serum levels of chemokines, including macrophage inflammatory protein (MIP)-1α, monocyte chemoattractant protein (MCP)-1 and MIP-2 were evaluated by ELISA. Furthermore, the expression levels of C-C chemokine receptor (CCR)2 and intercellular adhesion molecule (ICAM)-1 in the synovium were evaluated by immunohistochemical staining. The results indicated that treatment with nicotine significantly attenuated the clinical and histopathological changes associated with arthritis, reduced CD11b-positive macrophages in the synovium, and downregulated the serum expression levels of MIP-1α and MCP-1. Conversely, vagotomy aggravated arthritis and upregulated the expression levels of MCP-1. However, MIP-2 expression did not differ among the control, CIA, vagotomy and nicotine groups. In addition, the expression levels of CCR2 were reduced in the nicotine group; however, they were increased in the vagotomy group compared with in the untreated CIA group. The expression levels of ICAM-1 in the synovium were also influenced by activation of the CAP. Taken together, the present results indicated that nicotine-induced activation of the CAP in mice with CIA may reduce the number of macrophages in the synovium, which may serve a role in alleviating

  17. Melanocortin 4 receptor activation protects against testicular ischemia-reperfusion injury by triggering the cholinergic antiinflammatory pathway. (United States)

    Minutoli, Letteria; Bitto, Alessandra; Squadrito, Francesco; Irrera, Natasha; Rinaldi, Mariagrazia; Nicotina, Piero Antonio; Arena, Salvatore; Magno, Carlo; Marini, Herbert; Spaccapelo, Luca; Ottani, Alessandra; Giuliani, Daniela; Romeo, Carmelo; Guarini, Salvatore; Antonuccio, Pietro; Altavilla, Domenica


    Melanocortins (MC) trigger a vagus nerve-mediated cholinergic-antiinflammatory pathway projecting to the testis. We tested whether pharmacological activation of brain MC receptors might protect the testis from the damage induced by ischemia-reperfusion. Adult male rats were subjected to 1-h testicular ischemia, followed by 24-h reperfusion [testicular ischemia-reperfusion (TI/R)]. Before TI/R, groups of animals were subjected to bilateral cervical vagotomy, or pretreated with the nicotinic acetylcholine receptor antagonist chlorisondamine or the selective MC(4) receptor antagonist HS024. Immediately after reperfusion, rats were ip treated with saline or the MC analog [Nle(4),D-Phe(7)]α-melanocyte-stimulating hormone (NDP-α-MSH) (340 μg/kg). We evaluated testicular IL-6 and TNF-α by Western blot analysis and organ damage by light microscopy. Some experimental groups were prepared for neural efferent activity recording along the vagus nerve starting 30 min after treatment with NDP-α-MSH or saline, and for a 30-min period. Additional groups of TI/R rats were treated for 30 d with saline, NDP-α-MSH, chlorisondamine plus NDP-α-MSH, or HS024 plus NDP-α-MSH to evaluate spermatogenesis, organ damage, and the apoptosis machinery. After a 24-h reperfusion, in TI/R saline-treated rats, there was an increase in IL-6 and TNF-α expression and a marked damage in both testes. NDP-α-MSH inhibited IL-6 and TNF-α expression, decreased histological damage, and increased neural efferent activity. Furthermore, NDP-α-MSH administration for 30 d greatly improved spermatogenesis, reduced organ damage, and inhibited apoptosis. All positive NDP-α-MSH effects were abrogated by vagotomy, chlorisondamine, or HS024. Our data suggest that selective MC(4) receptor agonists might be therapeutic candidates for the management of testicular torsion.

  18. PET study of cholinergic system in the brain

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    Shinotoh, Hitoshi [Chiba Univ. (Japan). School of Medicine


    Recently, we have developed a method to measure acetylcholinesterase (AChE) activity, a functional marker for cholinergic system, by positron emission tomography (PET) and carbon-11 labeled N-methyl-4-piperidyl acetate. Kinetic analysis of the radioactivity in the brain and the plasma yielded a rate constant ``k 3`` as an index of AChE activity. The ratios for the k 3 values for the cerebral cortex/thalamus/cerebellum/striatum found in healthy participants were 1/ 3/ 8/ 10, respectively, corresponding well with AChE activity ratios in the brain at necropsy (1/ 3/ 8/ 38), except for the striatum. In 23 healthy volunteers (age range: 24-89 years), there was no age-related decline of k 3 values in the cerebral cortex, suggesting AChE activity is preserved in aged cerebral cortex. In 11 patients with Alzheimer`s disease, there was a significant reduction (-24%) of k 3 values in the cerebral cortex and hippocampus, suggesting a loss of ascending cholinergic system from the basal forebrain to the cerebral cortex and hippocampus. In 16 patients with Parkinson`s disease, there was a significant reduction (-18%) of k 3 values in the cerebral cortex. In 10 patients with progressive supra nuclear palsy, there was a significant reduction (-38%) of k 3 values in the thalamus. This technique is useful for investigating central cholinergic system in neuro degenerative disorders with dementia. (author)

  19. Illuminating the role of cholinergic signaling in circuits of attention and emotionally salient behaviors. (United States)

    Luchicchi, Antonio; Bloem, Bernard; Viaña, John Noel M; Mansvelder, Huibert D; Role, Lorna W


    Acetylcholine (ACh) signaling underlies specific aspects of cognitive functions and behaviors, including attention, learning, memory and motivation. Alterations in ACh signaling are involved in the pathophysiology of multiple neuropsychiatric disorders. In the central nervous system, ACh transmission is mainly guaranteed by dense innervation of select cortical and subcortical regions from disperse groups of cholinergic neurons within the basal forebrain (BF; e.g., diagonal band, medial septal, nucleus basalis) and the pontine-mesencephalic nuclei, respectively. Despite the fundamental role of cholinergic signaling in the CNS and the long standing knowledge of the organization of cholinergic circuitry, remarkably little is known about precisely how ACh release modulates cortical and subcortical neural activity and the behaviors these circuits subserve. Growing interest in cholinergic signaling in the CNS focuses on the mechanism(s) of action by which endogenously released ACh regulates cognitive functions, acting as a neuromodulator and/or as a direct transmitter via nicotinic and muscarinic receptors. The development of optogenetic techniques has provided a valuable toolbox with which we can address these questions, as it allows the selective manipulation of the excitability of cholinergic inputs to the diverse array of cholinergic target fields within cortical and subcortical domains. Here, we review recent papers that use the light-sensitive opsins in the cholinergic system to elucidate the role of ACh in circuits related to attention and emotionally salient behaviors. In particular, we highlight recent optogenetic studies which have tried to disentangle the precise role of ACh in the modulation of cortical-, hippocampal- and striatal-dependent functions.

  20. Cholinergic Mechanisms in Spinal Locomotion - Potential Target for Rehabilitation Approaches

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    L M Jordan


    Full Text Available Previous experiments implicate cholinergic brainstem and spinal systems in the control of locomotion. Our results demonstrate that the endogenous cholinergic propriospinal system, acting via M2 and M3 muscarinic receptors, is capable of consistently producing well-coordinated locomotor activity in the in vitro neonatal preparation, placing it in a position to contribute to normal locomotion and to provide a basis for recovery of locomotor capability in the absence of descending pathways. Tests of these suggestions, however, reveal that the spinal cholinergic system plays little if any role in the induction of locomotion, because MLR-evoked locomotion in decerebrate cats is not prevented by cholinergic antagonists. Furthermore, it is not required for the development of stepping movements after spinal cord injury, because cholinergic agonists do not facilitate the appearance of locomotion after spinal cord injury, unlike the dramatic locomotion-promoting effects of clonidine, a noradrenergic α-2 agonist. Furthermore, cholinergic antagonists actually improve locomotor activity after spinal cord injury, suggesting that plastic changes in the spinal cholinergic system interfere with locomotion rather than facilitating it. Changes that have been observed in the cholinergic innervation of motoneurons after spinal cord injury do not decrease motoneuron excitability, as expected. Instead, the development of a hyper-cholinergic state after spinal cord injury appears to enhance motoneuron output and suppress locomotion. A cholinergic suppression of afferent input from the limb after spinal cord injury is also evident from our data, and this may contribute to the ability of cholinergic antagonists to improve locomotion. Not only is a role for the spinal cholinergic system in supressing locomotion after SCI suggested by our results, but an obligatory contribution of a brainstem cholinergic relay to reticulospinal locomotor command systems is not confirmed

  1. Central Asia Active Fault Database (United States)

    Mohadjer, Solmaz; Ehlers, Todd A.; Kakar, Najibullah


    The ongoing collision of the Indian subcontinent with Asia controls active tectonics and seismicity in Central Asia. This motion is accommodated by faults that have historically caused devastating earthquakes and continue to pose serious threats to the population at risk. Despite international and regional efforts to assess seismic hazards in Central Asia, little attention has been given to development of a comprehensive database for active faults in the region. To address this issue and to better understand the distribution and level of seismic hazard in Central Asia, we are developing a publically available database for active faults of Central Asia (including but not limited to Afghanistan, Tajikistan, Kyrgyzstan, northern Pakistan and western China) using ArcGIS. The database is designed to allow users to store, map and query important fault parameters such as fault location, displacement history, rate of movement, and other data relevant to seismic hazard studies including fault trench locations, geochronology constraints, and seismic studies. Data sources integrated into the database include previously published maps and scientific investigations as well as strain rate measurements and historic and recent seismicity. In addition, high resolution Quickbird, Spot, and Aster imagery are used for selected features to locate and measure offset of landforms associated with Quaternary faulting. These features are individually digitized and linked to attribute tables that provide a description for each feature. Preliminary observations include inconsistent and sometimes inaccurate information for faults documented in different studies. For example, the Darvaz-Karakul fault which roughly defines the western margin of the Pamir, has been mapped with differences in location of up to 12 kilometers. The sense of motion for this fault ranges from unknown to thrust and strike-slip in three different studies despite documented left-lateral displacements of Holocene and late

  2. The hallucinogenic herb Salvia divinorum and its active ingredient salvinorin A inhibit enteric cholinergic transmission in the guinea-pig ileum. (United States)

    Capasso, R; Borrelli, F; Capasso, F; Siebert, D J; Stewart, D J; Zjawiony, J K; Izzo, A A


    Salvia divinorum is a widespread hallucinogenic herb traditionally employed for divination, as well as a medicament for several disorders including disturbances of gastrointestinal motility. In the present study we evaluated the effect of a standardized extract from the leaves of S. divinorum (SDE) on enteric cholinergic transmission in the guinea-pig ileum. SDE reduced electrically evoked contractions without modifying the contractions elicited by exogenous acetylcholine, thus suggesting a prejunctional site of action. The inhibitory effect of SDE on twitch response was abolished by the opioid receptor antagonist naloxone and by the kappa-opioid antagonist nor-binaltorphimine, but not by naltrindole (a delta-opioid receptor antagonist), CTOP (a mu-opioid receptor antagonist), thioperamide (a H(3) receptor antagonist), yohimbine (an alpha(2)-receptor antagonist), methysergide (a 5-hydroxytryptamine receptor antagonist), N(G)-nitro-L-arginine methyl ester (an inhibitor of NO synthase) or apamin (a blocker of Ca(2+)-activated K(+) channels). Salvinorin A, the main active ingredient of S. divinorum, inhibited in a nor-binaltorphimine- and naloxone-sensitive manner electrically induced contractions. It is concluded that SDE depressed enteric cholinergic transmission likely through activation of kappa-opioid receptors and this may provide the pharmacological basis underlying its traditional antidiarrhoeal use. Salvinorin A might be the chemical ingredient responsible for this activity.

  3. Acute low-level microwave exposure and central cholinergic activity: studies on irradiation parameters

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    Lai, H.; Horita, A.; Guy, A.W.


    Sodium-dependent high-affinity choline uptake was measured in the striatum, frontal cortex, hippocampus, and hypothalamus of rats after acute exposure (45 min) to pulsed (2 microseconds, 500 pps) or continuous-wave 2,450-MHz microwaves in cylindrical waveguides or miniature anechoic chambers. In all exposure conditions, the average whole-body specific absorption rate was at 0.6 W/kg. Decrease in choline uptake was observed in the frontal cortex after microwave exposure in all of the above irradiation conditions. Regardless of the exposure system used, hippocampal choline uptake was decreased after exposure to pulsed but not continuous-wave microwaves. Striatal choline uptake was decreased after exposure to either pulsed or continuous-wave microwaves in the miniature anechoic chamber. No significant change in hypothalamic choline uptake was observed under any of the exposure conditions studied. We conclude that depending on the parameters of the radiation, microwaves can elicit specific and generalized biological effects.

  4. Severe Organophosphate Poisoning with Delayed Cholinergic ...

    African Journals Online (AJOL)

    ... junction and Autonomic Synapses is clinically important. After exposure these agents cause acute and sub acute manifestations depending on the type and severity of the agents like Acute Cholinergic Manifestations, Intermediate Syndrome with Nicotinic features and Delayed Central Nervous System Complications.

  5. The Input-Output Relationship of the Cholinergic Basal Forebrain

    Directory of Open Access Journals (Sweden)

    Matthew R. Gielow


    Full Text Available Basal forebrain cholinergic neurons influence cortical state, plasticity, learning, and attention. They collectively innervate the entire cerebral cortex, differentially controlling acetylcholine efflux across different cortical areas and timescales. Such control might be achieved by differential inputs driving separable cholinergic outputs, although no input-output relationship on a brain-wide level has ever been demonstrated. Here, we identify input neurons to cholinergic cells projecting to specific cortical regions by infecting cholinergic axon terminals with a monosynaptically restricted viral tracer. This approach revealed several circuit motifs, such as central amygdala neurons synapsing onto basolateral amygdala-projecting cholinergic neurons or strong somatosensory cortical input to motor cortex-projecting cholinergic neurons. The presence of input cells in the parasympathetic midbrain nuclei contacting frontally projecting cholinergic neurons suggest that the network regulating the inner eye muscles are additionally regulating cortical state via acetylcholine efflux. This dataset enables future circuit-level experiments to identify drivers of known cortical cholinergic functions.

  6. Effect of galantamine on the human α7 neuronal nicotinic acetylcholine receptor, the Torpedo nicotinic acetylcholine receptor and spontaneous cholinergic synaptic activity (United States)

    Texidó, Laura; Ros, Esteve; Martín-Satué, Mireia; López, Susana; Aleu, Jordi; Marsal, Jordi; Solsona, Carles


    Various types of anticholinesterasic agents have been used to improve the daily activities of Alzheimer's disease patients. It was recently demonstrated that Galantamine, described as a molecule with anticholinesterasic properties, is also an allosteric enhancer of human α4β2 neuronal nicotinic receptor activity. We explored its effect on the human α7 neuronal nicotinic acetylcholine receptor (nAChR) expressed in Xenopus oocytes. Galantamine, at a concentration of 0.1 μM, increased the amplitude of acetylcholine (ACh)-induced ion currents in the human α7 nAChR expressed in Xenopus oocytes, but caused inhibition at higher concentrations. The maximum effect of galantamine, an increase of 22% in the amplitude of ACh-induced currents, was observed at a concentration of 250 μM Ach. The same enhancing effect was obtained in oocytes transplanted with Torpedo nicotinic acetylcholine receptor (AChR) isolated from the electric organ, but in this case the optimal concentration of galantamine was 1 μM. In this case, the maximum effect of galantamine, an increase of 35% in the amplitude of ACh-induced currents, occurred at a concentration of 50 μM ACh. Galantamine affects not only the activity of post-synaptic receptors but also the activity of nerve terminals. At a concentration of 1 μM, quantal spontaneous events, recorded in a cholinergic synapse, increased their amplitude, an effect which was independent of the anticholinesterasic activity associated with this compound. The anticholinesterasic effect was recorded in preparations treated with a galantamine concentration of 10 μM. In conclusion, our results show that galantamine enhances human α7 neuronal nicotinic ACh receptor activity. It also enhances muscular AChRs and the size of spontaneous cholinergic synaptic events. However, only a very narrow range of galantamine concentrations can be used for enhancing effects. PMID:15834443

  7. The basal forebrain cholinergic system in aging and dementia : Rescuing cholinergic neurons from neurotoxic amyloid-beta 42 with memantine

    NARCIS (Netherlands)

    Nyakas, Csaba; Granic, Ivica; Halmy, Laszlo G.; Banerjee, Pradeep; Luiten, Paul G. M.


    The dysfunction and loss of basal forebrain cholinergic neurons and their cortical projections are among the earliest pathological events in the pathogenesis of Alzheimer's disease (AD). The evidence pointing to cholinergic impairments come from studies that report a decline in the activity of

  8. Activation of the cholinergic anti-inflammatory pathway by nicotine ameliorates lipopolysaccharide-induced preeclampsia-like symptoms in pregnant rats. (United States)

    Liu, Yuanyuan; Yang, Jinying; Bao, Junjie; Li, Xiaolan; Ye, Aihua; Zhang, Guozheng; Liu, Huishu


    Preeclampsia (PE) exerts a more intense systemic inflammatory response than normal pregnancy. Recently, the role of the cholinergic anti-inflammatory pathway (CAP) in regulating inflammation has been extensively studied. The aim of this study was to investigate the effect of nicotine, a selective cholinergic agonist, on lipopolysaccharide (LPS)-induced preeclampsia-like symptoms in pregnant rats and to determine the molecular mechanism underlying it. Rats were administered LPS (1.0 μg/kg) via tail vein injection on gestational day 14 to induce preeclampsia-like symptoms. Nicotine (1.0 mg/kg/d) and α-bungarotoxin (1.0 μg/kg/d) were injected subcutaneously into the rats from gestational day 14-19. Clinical symptoms were recorded. Serum and placentas were collected to determine cytokine levels using Luminex. The mRNA and protein expression levels of α7 nicotinic acetylcholine receptor (α7nAChR) were determined using Real time-PCR and Western blot analysis. Immunohistochemistry was performed to determine the level of activation of nuclear factor-κB (NF-κB) in placentas. Nicotine significantly ameliorated LPS-induced preeclampsia-like symptoms in pregnant rats (P treatment decreased the levels of LPS-induced pro-inflammatory cytokines in the serum (P preeclampsia (P preeclampsia rats. Our findings suggest that the activation of α7nAChR by nicotine attenuates preeclampsia-like symptoms, and this protective effect is likely the result of the inhibition of inflammation via the NF-κB p65 pathway. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. A cholinergic basal forebrain feeding circuit modulates appetite suppression. (United States)

    Herman, Alexander M; Ortiz-Guzman, Joshua; Kochukov, Mikhail; Herman, Isabella; Quast, Kathleen B; Patel, Jay M; Tepe, Burak; Carlson, Jeffrey C; Ung, Kevin; Selever, Jennifer; Tong, Qingchun; Arenkiel, Benjamin R


    Atypical food intake is a primary cause of obesity and other eating and metabolic disorders. Insight into the neural control of feeding has previously focused mainly on signalling mechanisms associated with the hypothalamus, the major centre in the brain that regulates body weight homeostasis. However, roles of non-canonical central nervous system signalling mechanisms in regulating feeding behaviour have been largely uncharacterized. Acetylcholine has long been proposed to influence feeding owing in part to the functional similarity between acetylcholine and nicotine, a known appetite suppressant. Nicotine is an exogenous agonist for acetylcholine receptors, suggesting that endogenous cholinergic signalling may play a part in normal physiological regulation of feeding. However, it remains unclear how cholinergic neurons in the brain regulate food intake. Here we report that cholinergic neurons of the mouse basal forebrain potently influence food intake and body weight. Impairment of cholinergic signalling increases food intake and results in severe obesity, whereas enhanced cholinergic signalling decreases food consumption. We found that cholinergic circuits modulate appetite suppression on downstream targets in the hypothalamus. Together our data reveal the cholinergic basal forebrain as a major modulatory centre underlying feeding behaviour.

  10. Nematode cholinergic pharmacology

    Energy Technology Data Exchange (ETDEWEB)

    Segerberg, M.A.


    Nematode acetylcholine (ACh) receptors were characterized using both biochemical and electrophysiological techniques, including: (1) receptor binding studies in crude homogenates of the free-living nematode Caenorhabditis elegans and the parasitic nematode Ascaris lumbricoides with the high-affinity probe ({sup 3}H)N-methylscopolamine (({sup 3}H)NMS) which binds to muscarinic receptors in many vertebrate and invertebrate tissues (2) measurement of depolarization and contraction induced by a variety of cholinergic agents, including N-methylscopolamine (NMS), in an innervated dorsal muscle strip preparation of Ascaris; (3) examination of the antagonistic actions of d-tubocurarine (dTC) and NMS at dorsal neuromuscular junction; (4) measurement of input resistance changes in Ascaris commissural motorneurons induced by ACh, dTC, NMS, pilocarpine and other cholinergic drugs.

  11. Serum Anticholinergic Activity: A Possible Peripheral Marker of the Anticholinergic Burden in the Central Nervous System in Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Koji Hori


    Full Text Available We review the utility of serum anticholinergic activity (SAA as a peripheral marker of anticholinergic activity (AA in the central nervous system (CAA. We hypothesize that the compensatory mechanisms of the cholinergic system do not contribute to SAA if their system is intact and that if central cholinergic system deteriorates alone in conditions such as Alzheimer’s disease or Lewy body dementia, CAA and SAA are caused by way of hyperactivity of inflammatory system and SAA is a marker of the anticholinergic burden in CNS. Taking into account the diurnal variations in the plasma levels of corticosteroids, which are thought to affect SAA, it should be measured at noon or just afterward.

  12. Cholinergic depletion and basal forebrain volume in primary progressive aphasia

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    Jolien Schaeverbeke


    In the PPA group, only LV cases showed decreases in AChE activity levels compared to controls. Surprisingly, a substantial number of SV cases showed significant AChE activity increases compared to controls. BF volume did not correlate with AChE activity levels in PPA. To conclude, in our sample of PPA patients, LV but not SV was associated with cholinergic depletion. BF atrophy in PPA does not imply cholinergic depletion.

  13. Astrocytes mediate in vivo cholinergic-induced synaptic plasticity.

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    Marta Navarrete


    Full Text Available Long-term potentiation (LTP of synaptic transmission represents the cellular basis of learning and memory. Astrocytes have been shown to regulate synaptic transmission and plasticity. However, their involvement in specific physiological processes that induce LTP in vivo remains unknown. Here we show that in vivo cholinergic activity evoked by sensory stimulation or electrical stimulation of the septal nucleus increases Ca²⁺ in hippocampal astrocytes and induces LTP of CA3-CA1 synapses, which requires cholinergic muscarinic (mAChR and metabotropic glutamate receptor (mGluR activation. Stimulation of cholinergic pathways in hippocampal slices evokes astrocyte Ca²⁺ elevations, postsynaptic depolarizations of CA1 pyramidal neurons, and LTP of transmitter release at single CA3-CA1 synapses. Like in vivo, these effects are mediated by mAChRs, and this cholinergic-induced LTP (c-LTP also involves mGluR activation. Astrocyte Ca²⁺ elevations and LTP are absent in IP₃R2 knock-out mice. Downregulating astrocyte Ca²⁺ signal by loading astrocytes with BAPTA or GDPβS also prevents LTP, which is restored by simultaneous astrocyte Ca²⁺ uncaging and postsynaptic depolarization. Therefore, cholinergic-induced LTP requires astrocyte Ca²⁺ elevations, which stimulate astrocyte glutamate release that activates mGluRs. The cholinergic-induced LTP results from the temporal coincidence of the postsynaptic activity and the astrocyte Ca²⁺ signal simultaneously evoked by cholinergic activity. Therefore, the astrocyte Ca²⁺ signal is necessary for cholinergic-induced synaptic plasticity, indicating that astrocytes are directly involved in brain storage information.

  14. Hypoglycemia induced changes in cholinergic receptor expression in the cerebellum of diabetic rats

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    Anju TR


    Full Text Available Abstract Glucose homeostasis in humans is an important factor for the functioning of nervous system. Hypoglycemia and hyperglycemia is found to be associated with central and peripheral nerve system dysfunction. Changes in acetylcholine receptors have been implicated in the pathophysiology of many major diseases of the central nervous system (CNS. In the present study we showed the effects of insulin induced hypoglycemia and streptozotocin induced diabetes on the cerebellar cholinergic receptors, GLUT3 and muscle cholinergic activity. Results showed enhanced binding parameters and gene expression of Muscarinic M1, M3 receptor subtypes in cerebellum of diabetic (D and hypoglycemic group (D + IIH and C + IIH. α7nAchR gene expression showed a significant upregulation in diabetic group and showed further upregulated expression in both D + IIH and C + IIH group. AchE expression significantly upregulated in hypoglycemic and diabetic group. ChAT showed downregulation and GLUT3 expression showed a significant upregulation in D + IIH and C + IIH and diabetic group. AchE activity enhanced in the muscle of hypoglycemic and diabetic rats. Our studies demonstrated a functional disturbance in the neuronal glucose transporter GLUT3 in the cerebellum during insulin induced hypoglycemia in diabetic rats. Altered expression of muscarinic M1, M3 and α7nAchR and increased muscle AchE activity in hypoglycemic rats in cerebellum is suggested to cause cognitive and motor dysfunction. Hypoglycemia induced changes in ChAT and AchE gene expression is suggested to cause impaired acetycholine metabolism in the cerebellum. Cerebellar dysfunction is associated with seizure generation, motor deficits and memory impairment. The results shows that cerebellar cholinergic neurotransmission is impaired during hyperglycemia and hypoglycemia and the hypoglycemia is causing more prominent imbalance in cholinergic neurotransmission which is suggested to be a cause of cerebellar

  15. Diverse Roads to Relapse: A Discriminative Cue Signaling Cocaine Availability Is More Effective in Renewing Cocaine Seeking in Goal Trackers Than Sign Trackers and Depends on Basal Forebrain Cholinergic Activity. (United States)

    Pitchers, Kyle K; Phillips, Kyra B; Jones, Jonte L; Robinson, Terry E; Sarter, Martin


    Stimuli associated with taking drugs are notorious instigators of relapse. There is, however, considerable variation in the motivational properties of such stimuli, both as a function of the individual and the nature of the stimulus. The behavior of some individuals (sign trackers, STs) is especially influenced by cues paired with reward delivery, perhaps because they are prone to process information via dopamine-dependent, cue-driven, incentive salience systems. Other individuals (goal trackers, GTs) are better able to incorporate higher-order contextual information, perhaps because of better executive/attentional control over behavior, which requires frontal cortical cholinergic activity. We hypothesized, therefore, that a cue that "sets the occasion" for drug taking (a discriminative stimulus, DS) would reinstate cocaine seeking more readily in GTs than STs and that this would require intact cholinergic neurotransmission. To test this, male STs and GTs were trained to self-administer cocaine using an intermittent access schedule with periods of cocaine availability and unavailability signaled by a DS(+) and a DS(-), respectively. Thereafter, half of the rats received an immunotoxic lesion that destroyed 40-50% of basal forebrain cholinergic neurons and later, after extinction training, were tested for the ability of noncontingent presentations of the DS(+) to reinstate cocaine seeking behavior. The DS(+) was much more effective in reinstating cocaine seeking in GTs than STs and this effect was abolished by cholinergic losses despite the fact that all rats continued to orient to the DS(+) We conclude that vulnerability to relapse involves interactions between individual cognitive-motivational biases and the form of the drug cue encountered.SIGNIFICANCE STATEMENT The most predictable outcome of a diagnosis of addiction is a high chance for relapse. When addicts encounter cues previously associated with drug, their attention may be unduly attracted to such cues and

  16. Fetal rat sympathetic neurons maintained in a serum-free medium retain induced cholinergic characteristics. (United States)

    Higgins, D; Iacovitti, L; Burton, H


    When maintained in some serum-containing media, fetal rat sympathetic neurons acquire substantial choline acetyltransferase activity and form cholinergic synapses in vitro. However, when they are maintained in a serum-free, defined culture medium, choline acetyltransferase activity is not detected and cholinergic synapses are not observed. In this study, we have examined the effects of various times of exposure to a medium inducing cholinergic function on the properties of neurons subsequently maintained in defined medium. We report that 2-day, but not 2-h, exposure to this inducing medium causes a long-lasting (greater than 6 weeks) increase (7-10-fold) in the activity of choline acetyltransferase and that, under these conditions, sympathetic neurons in vitro form cholinergic, electrical and mixed function cholinergic and electrical synapses. We conclude that a relatively brief exposure to media inducing cholinergic function can cause long-lasting changes in the functional properties of sympathetic neurons in vitro.

  17. The nicotinic cholinergic system function in the human brain. (United States)

    Nees, Frauke


    Research on the nicotinic cholinergic system function in the brain was previously mainly derived from animal studies, yet, research in humans is growing. Up to date, findings allow significant advances on the understanding of nicotinic cholinergic effects on human cognition, emotion and behavior using a range of functional brain imaging approaches such as pharmacological functional magnetic resonance imaging or positron emission tomography. Studies provided insights across various mechanistic psychological domains using different tasks as well as at rest in both healthy individuals and patient populations, with so far partly mixed results reporting both enhancements and decrements of neural activity related to the nicotinic cholinergic system. Moreover, studies on the relation between brain structure and the nicotinic cholinergic system add important information in this context. The present review summarizes the current status of human brain imaging studies and presents the findings within a theoretical and clinical perspective as they may be useful not only for an advancement of the understanding of basic nicotinic cholinergic-related mechanisms, but also for the development and integration of psychological and pharmacological treatment approaches. Patterns of functional neuroanatomy and neural circuitry across various cognitive and emotional domains may be used as neuropsychological markers of mental disorders such as addiction, Alzheimer's disease, Parkinson disease or schizophrenia, where nicotinic cholinergic system changes are characteristic. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. Glucocorticoid programming of the mesopontine cholinergic system

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    Sónia eBorges


    Full Text Available Stress perception, response, adaptation and coping strategies are individually distinct, and the sequel of stress and/or glucocorticoids is also distinct between subjects. In the last years, it has become clear that early life stress is a powerful modulator of neuroendocrine stress-responsive circuits, programming intrinsic susceptibility to stress, and potentiating the appearance of stress-related disorders such as depression, anxiety and addiction. Herein we were interested in understanding how early life experiences reset the normal processing of negative stimuli, leading to emotional dysfunction. Animals prenatally exposed to glucocorticoids (iuGC present hyperanxiety, increased fear behaviour and hyper-reactivity to negative stimuli. In parallel, we found a remarkable increase in the number of aversive 22kHz ultrasonic vocalizations in response to an aversive cue. Considering the suggested role of the mesopontine tegmentum cholinergic pathway, arising from the laterodorsal tegmental nucleus (LDT and pedunculopontine tegmental nucleus (PPT, in the initiation of 22kHz vocalizations and hypothetically in the control of emotional arousal and tone, we decided to evaluate the condition of this circuit in iuGC animals. Notably, in a basal situation, iuGC animals present increased choline acetyltransferase (ChAT expression in the LDT and PPT, but not in other cholinergic nuclei, namely in the nucleus basalis of Meynert. In addition, and in accordance with the amplified response to an adverse stimulus of iuGC animals, we found marked changes in the cholinergic activation pattern of LDT and PPT regions. Altogether, our results suggest a specific cholinergic pathway programing by prenatal GC, and hint that this may be of relevance in setting individuals stress vulnerability threshold.

  19. Pharmacological identification of cholinergic receptor subtypes on Drosophila melanogaster larval heart. (United States)

    Malloy, Cole A; Ritter, Kyle; Robinson, Jonathan; English, Connor; Cooper, Robin L


    The Drosophila melanogaster heart is a popular model in which to study cardiac physiology and development. Progress has been made in understanding the role of endogenous compounds in regulating cardiac function in this model. It is well characterized that common neurotransmitters act on many peripheral and non-neuronal tissues as they flow through the hemolymph of insects. Many of these neuromodulators, including acetylcholine (ACh), have been shown to act directly on the D. melanogaster larval heart. ACh is a primary neurotransmitter in the central nervous system (CNS) of vertebrates and at the neuromuscular junctions on skeletal and cardiac tissue. In insects, ACh is the primary excitatory neurotransmitter of sensory neurons and is also prominent in the CNS. A full understanding regarding the regulation of the Drosophila cardiac physiology by the cholinergic system remains poorly understood. Here we use semi-intact D. melanogaster larvae to study the pharmacological profile of cholinergic receptor subtypes, nicotinic acetylcholine receptors (nAChRs) and muscarinic acetylcholine receptors (mAChRs), in modulating heart rate (HR). Cholinergic receptor agonists, nicotine and muscarine both increase HR, while nAChR agonist clothianidin exhibits no significant effect when exposed to an open preparation at concentrations as low as 100 nM. In addition, both nAChR and mAChR antagonists increase HR as well but also display capabilities of blocking agonist actions. These results provide evidence that both of these receptor subtypes display functional significance in regulating the larval heart's pacemaker activity.

  20. Cholinergic neurons in the dorsomedial hypothalamus regulate mouse brown adipose tissue metabolism

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    Jae Hoon Jeong


    Conclusion: DMH cholinergic neurons directly send efferent signals to sympathetic premotor neurons in the Rpa. Elevated cholinergic input to this area reduces BAT activity through activation of M2 mAChRs on serotonergic neurons. Therefore, the direct DMHACh–Rpa5-HT pathway may mediate physiological heat-defense responses to elevated environmental temperature.

  1. Vectorised Spreading Activation algorithm for centrality measurement

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    Alexander Troussov


    Full Text Available Spreading Activation is a family of graph-based algorithms widely used in areas such as information retrieval, epidemic models, and recommender systems. In this paper we introduce a novel Spreading Activation (SA method that we call Vectorised Spreading Activation (VSA. VSA algorithms, like “traditional” SA algorithms, iteratively propagate the activation from the initially activated set of nodes to the other nodes in a network through outward links. The level of the node’s activation could be used as a centrality measurement in accordance with dynamic model-based view of centrality that focuses on the outcomes for nodes in a network where something is flowing from node to node across the edges. Representing the activation by vectors allows the use of the information about various dimensionalities of the flow and the dynamic of the flow. In this capacity, VSA algorithms can model multitude of complex multidimensional network flows. We present the results of numerical simulations on small synthetic social networks and multi­dimensional network models of folksonomies which show that the results of VSA propagation are more sensitive to the positions of the initial seed and to the community structure of the network than the results produced by traditional SA algorithms. We tentatively conclude that the VSA methods could be instrumental to develop scalable and computationally efficient algorithms which could achieve synergy between computation of centrality indexes with detection of community structures in networks. Based on our preliminary results and on improvements made over previous studies, we foresee advances and applications in the current state of the art of this family of algorithms and their applications to centrality measurement.

  2. Activation of Muscarinic Acetylcholine Receptor Subtype 4 is Essential for Cholinergic Stimulation of Gastric Acid Secretion - Relation To D Cell/Somatostatin -

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    Koji Takeuchi


    Full Text Available AbstractBackground/Aim: Muscarinic acetylcholine receptors exist in five subtypes (M1~M5, and they are widely expressed in various tissues to mediate diverse autonomic functions, including gastric secretion. In the present study, we demonstrated, using M1~M5 KO mice, the importance of M4 receptors in carbachol (CCh stimulation of acid secretion and investigated how the secretion is modulated by the activation of M4 receptors. Methods: C57BL/6J mice of wild-type (WT and M1-M5 KO were used. Under urethane anesthesia, acid secretion was measured in the stomach equipped with an acute fistula. CCh (30 µg/kg was given s.c. to stimulate acid secretion. Atropine or octreotide (a somatostatin analogue was given s.c. 20 min before the administration of CCh. CYN154806 (a somatostatin SST2 receptor antagonist was given i.p. 20 min before the administration of octreotide or CCh. Results: CCh caused an increase of acid secretion in WT mice, and the effect was totally inhibited by prior administration of atropine. The effect of CCh was similarly observed in the animals lacking M1, M2 or M5 receptors but significantly decreased in M3 or M4 KO mice. CYN154806, the SST2 receptor antagonist, dose-dependently and significantly reversed the decreased acid response to CCh in M4 but not M3 KO mice. Octreotide, the somatostatin analogue, inhibited the secretion of acid under CCh-stimulated conditions in WT mice. The immunohistochemical study showed the localization of M4 receptors on D cells in the stomach. Serum somatostatin levels in M4 KO mice were higher than WT mice under basal conditions, while those in WT mice were significantly decreased in response to CCh. Conclusions: These results suggest that under cholinergic stimulation the acid secretion is directly mediated by M3 receptors and indirectly modified by M4 receptors. It is assumed that the activation of M4 receptors inhibits the release of somatostatin from D cells and minimizes the acid inhibitory effect

  3. Adenosine inhibits glutamatergic input to basal forebrain cholinergic neurons (United States)

    Hawryluk, J. M.; Ferrari, L. L.; Keating, S. A.


    Adenosine has been proposed as an endogenous homeostatic sleep factor that accumulates during waking and inhibits wake-active neurons to promote sleep. It has been specifically hypothesized that adenosine decreases wakefulness and promotes sleep recovery by directly inhibiting wake-active neurons of the basal forebrain (BF), particularly BF cholinergic neurons. We previously showed that adenosine directly inhibits BF cholinergic neurons. Here, we investigated 1) how adenosine modulates glutamatergic input to BF cholinergic neurons and 2) how adenosine uptake and adenosine metabolism are involved in regulating extracellular levels of adenosine. Our experiments were conducted using whole cell patch-clamp recordings in mouse brain slices. We found that in BF cholinergic neurons, adenosine reduced the amplitude of AMPA-mediated evoked glutamatergic excitatory postsynaptic currents (EPSCs) and decreased the frequency of spontaneous and miniature EPSCs through presynaptic A1 receptors. Thus we have demonstrated that in addition to directly inhibiting BF cholinergic neurons, adenosine depresses excitatory inputs to these neurons. It is therefore possible that both direct and indirect inhibition may synergistically contribute to the sleep-promoting effects of adenosine in the BF. We also found that blocking the influx of adenosine through the equilibrative nucleoside transporters or inhibiting adenosine kinase and adenosine deaminase increased endogenous adenosine inhibitory tone, suggesting a possible mechanism through which adenosine extracellular levels in the basal forebrain are regulated. PMID:22357797

  4. Brain Cholinergic Function and Response to Rivastigmine in Patients With Chronic Sequels of Traumatic Brain Injury

    DEFF Research Database (Denmark)

    Östberg, Anna; Virta, Jere; Rinne, Juha O


    subjects for more than 1 year after at least moderate traumatic brain injury. Ten of the subjects were respondents and 7 nonrespondents to cholinergic medication. DESIGN:: Cholinergic function was assessed with [methyl-C] N-methylpiperidyl-4-acetate-PET (C-MP4A-PET), which reflects the activity...

  5. Delirium Accompanied by Cholinergic Deficiency and Organ Failure in a 73-Year-Old Critically Ill Patient: Physostigmine as a Therapeutic Option

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    Benedikt Zujalovic


    Full Text Available Delirium is a common problem in ICU patients, resulting in prolonged ICU stay and increased mortality. A cholinergic deficiency in the central nervous system is supposed to be a relevant pathophysiologic process in delirium. Acetylcholine is a major transmitter of the parasympathetic nervous system influencing several organs (e.g., heart and kidneys and the inflammatory response too. This perception might explain that delirium is not an individual symptom, but rather a part of a symptom complex with various disorders of the whole organism. The cholinergic deficiency could not be quantified up to now. Using the possibility of bedside determination of the acetylcholinesterase activity (AChE activity, we assumed to objectify the cholinergic homeostasis within minutes. As reported here, the postoperative delirium was accompanied by a massive hemodynamic and renal deterioration of unclear genesis. We identified the altered AChE activity as a plausible pathophysiological mechanism. The pharmacological intervention with the indirect parasympathomimetic physostigmine led to a quick and lasting improvement of the patient’s cognitive, hemodynamic, and renal status. In summary, severe delirium is not always an attendant phenomenon of critical illness. It might be causal for multiple organ deterioration if it is based on cholinergic deficiency and has to be treated at his pathophysiological roots whenever possible.

  6. Long-term relationships between cholinergic tone, synchronous bursting and synaptic remodeling.

    Directory of Open Access Journals (Sweden)

    Maya Kaufman

    Full Text Available Cholinergic neuromodulation plays key roles in the regulation of neuronal excitability, network activity, arousal, and behavior. On longer time scales, cholinergic systems play essential roles in cortical development, maturation, and plasticity. Presumably, these processes are associated with substantial synaptic remodeling, yet to date, long-term relationships between cholinergic tone and synaptic remodeling remain largely unknown. Here we used automated microscopy combined with multielectrode array recordings to study long-term relationships between cholinergic tone, excitatory synapse remodeling, and network activity characteristics in networks of cortical neurons grown on multielectrode array substrates. Experimental elevations of cholinergic tone led to the abrupt suppression of episodic synchronous bursting activity (but not of general activity, followed by a gradual growth of excitatory synapses over hours. Subsequent blockage of cholinergic receptors led to an immediate restoration of synchronous bursting and the gradual reversal of synaptic growth. Neither synaptic growth nor downsizing was governed by multiplicative scaling rules. Instead, these occurred in a subset of synapses, irrespective of initial synaptic size. Synaptic growth seemed to depend on intrinsic network activity, but not on the degree to which bursting was suppressed. Intriguingly, sustained elevations of cholinergic tone were associated with a gradual recovery of synchronous bursting but not with a reversal of synaptic growth. These findings show that cholinergic tone can strongly affect synaptic remodeling and synchronous bursting activity, but do not support a strict coupling between the two. Finally, the reemergence of synchronous bursting in the presence of elevated cholinergic tone indicates that the capacity of cholinergic neuromodulation to indefinitely suppress synchronous bursting might be inherently limited.

  7. In vivo cholinergic circuit evaluation in frontotemporal and Alzheimer dementias. (United States)

    Di Lazzaro, V; Pilato, F; Dileone, M; Saturno, E; Oliviero, A; Marra, C; Daniele, A; Ranieri, F; Gainotti, G; Tonali, P A


    The test of short latency afferent inhibition (SAI) of the motor cortex is helpful in demonstrating dysfunction of central cholinergic circuits in Alzheimer disease (AD). The authors evaluated SAI in 20 patients with frontotemporal dementia (FTD) and compared data with those from 20 patients with AD and 20 controls. SAI was normal in FTD, whereas it was reduced in AD. SAI may represent an additional tool to discriminate FTD from AD.

  8. Overnight fasting regulates inhibitory tone to cholinergic neurons of the dorsomedial nucleus of the hypothalamus. (United States)

    Groessl, Florian; Jeong, Jae Hoon; Talmage, David A; Role, Lorna W; Jo, Young-Hwan


    The dorsomedial nucleus of the hypothalamus (DMH) contributes to the regulation of overall energy homeostasis by modulating energy intake as well as energy expenditure. Despite the importance of the DMH in the control of energy balance, DMH-specific genetic markers or neuronal subtypes are poorly defined. Here we demonstrate the presence of cholinergic neurons in the DMH using genetically modified mice that express enhanced green florescent protein (eGFP) selectively in choline acetyltransferase (Chat)-neurons. Overnight food deprivation increases the activity of DMH cholinergic neurons, as shown by induction of fos protein and a significant shift in the baseline resting membrane potential. DMH cholinergic neurons receive both glutamatergic and GABAergic synaptic input, but the activation of these neurons by an overnight fast is due entirely to decreased inhibitory tone. The decreased inhibition is associated with decreased frequency and amplitude of GABAergic synaptic currents in the cholinergic DMH neurons, while glutamatergic synaptic transmission is not altered. As neither the frequency nor amplitude of miniature GABAergic or glutamatergic postsynaptic currents is affected by overnight food deprivation, the fasting-induced decrease in inhibitory tone to cholinergic neurons is dependent on superthreshold activity of GABAergic inputs. This study reveals that cholinergic neurons in the DMH readily sense the availability of nutrients and respond to overnight fasting via decreased GABAergic inhibitory tone. As such, altered synaptic as well as neuronal activity of DMH cholinergic neurons may play a critical role in the regulation of overall energy homeostasis.

  9. Overnight fasting regulates inhibitory tone to cholinergic neurons of the dorsomedial nucleus of the hypothalamus.

    Directory of Open Access Journals (Sweden)

    Florian Groessl

    Full Text Available The dorsomedial nucleus of the hypothalamus (DMH contributes to the regulation of overall energy homeostasis by modulating energy intake as well as energy expenditure. Despite the importance of the DMH in the control of energy balance, DMH-specific genetic markers or neuronal subtypes are poorly defined. Here we demonstrate the presence of cholinergic neurons in the DMH using genetically modified mice that express enhanced green florescent protein (eGFP selectively in choline acetyltransferase (Chat-neurons. Overnight food deprivation increases the activity of DMH cholinergic neurons, as shown by induction of fos protein and a significant shift in the baseline resting membrane potential. DMH cholinergic neurons receive both glutamatergic and GABAergic synaptic input, but the activation of these neurons by an overnight fast is due entirely to decreased inhibitory tone. The decreased inhibition is associated with decreased frequency and amplitude of GABAergic synaptic currents in the cholinergic DMH neurons, while glutamatergic synaptic transmission is not altered. As neither the frequency nor amplitude of miniature GABAergic or glutamatergic postsynaptic currents is affected by overnight food deprivation, the fasting-induced decrease in inhibitory tone to cholinergic neurons is dependent on superthreshold activity of GABAergic inputs. This study reveals that cholinergic neurons in the DMH readily sense the availability of nutrients and respond to overnight fasting via decreased GABAergic inhibitory tone. As such, altered synaptic as well as neuronal activity of DMH cholinergic neurons may play a critical role in the regulation of overall energy homeostasis.

  10. Donepezil ? biological activity nad evaluation of its efficiency.


    Drábková, Markéta


    1 Summary Title: Donepezil - biological activity and evaluation of its efficiency Author: Markéta Drábková Supervisor: Doc. MUDr. Josef Herink, DrSc. Department: Department of biological and medicinal sciences Cognitive enhancers are drugs which preferentially affect cholinergic transmission in the central nervous system. The cholinergic system in the brain is the most seriously damaged neurotransmitter system in Alzheimer, s disease and dementia with Lewy bodies. Donepezil is a new cognitive...

  11. IL-4 Induces Cholinergic Differentiation of Retinal Cells In Vitro. (United States)

    Granja, Marcelo Gomes; Braga, Luis Eduardo Gomes; Carpi-Santos, Raul; de Araujo-Martins, Leandro; Nunes-Tavares, Nilson; Calaza, Karin C; Dos Santos, Aline Araujo; Giestal-de-Araujo, Elizabeth


    Interleukin-4 (IL-4) is a pleiotropic cytokine that regulates several phenomena, among them survival and differentiation of neuronal and glial cells. The aim of this work was to investigate the effect of IL-4 on the cholinergic differentiation of neonatal rat retinal cells in vitro, evaluating its effect on the levels of cholinergic markers (CHT1-high-affinity choline transporter; VAChT-vesicular acetylcholine transporter, ChAT-choline acetyltransferase, AChE-acetylcholinesterase), muscarinic receptors, and on the signaling pathways involved. Lister Hooded rat pups were used in postnatal days 0-2 (P0-P2). Our results show that IL-4 treatment (50 U/mL) for 48 h increases the levels of the cholinergic transporters VAChT and CHT1, the acetylcholinesterase activity, and the number of ChAT-positive cells. It also induces changes in muscarinic receptor levels, leading to a small decrease in M1 levels and a significant increase in M3 and M5 levels after 48 h of treatment. We also showed that IL-4 effect on M3 receptors is dependent on type I IL-4 receptor and on an increase in NFκB phosphorylation. These results indicate that IL-4 stimulates cholinergic differentiation of retinal cells.

  12. The catecholaminergic-cholinergic balance hypothesis of bipolar disorder revisited (United States)

    van Enkhuizen, Jordy; Janowsky, David S; Olivier, Berend; Minassian, Arpi; Perry, William; Young, Jared W; Geyer, Mark A


    Bipolar disorder is a unique illness characterized by fluctuations between mood states of depression and mania. Originally, an adrenergic-cholinergic balance hypothesis was postulated to underlie these different affective states. In this review, we update this hypothesis with recent findings from human and animal studies, suggesting that a catecholaminergic-cholinergic hypothesis may be more relevant. Evidence from neuroimaging studies, neuropharmacological interventions, and genetic associations support the notion that increased cholinergic functioning underlies depression, whereas increased activations of the catecholamines (dopamine and norepinephrine) underlie mania. Elevated functional acetylcholine during depression may affect both muscarinic and nicotinic acetylcholine receptors in a compensatory fashion. Increased functional dopamine and norepinephrine during mania on the other hand may affect receptor expression and functioning of dopamine reuptake transporters. Despite increasing evidence supporting this hypothesis, a relationship between these two neurotransmitter systems that could explain cycling between states of depression and mania is missing. Future studies should focus on the influence of environmental stimuli and genetic susceptibilities that may affect the catecholaminergic-cholinergic balance underlying cycling between the affective states. Overall, observations from recent studies add important data to this revised balance theory of bipolar disorder, renewing interest in this field of research. PMID:25107282

  13. Cellular mechanisms underlying spatiotemporal features of cholinergic retinal waves (United States)

    Ford, Kevin J.; Félix, Aude L.; Feller, Marla B.


    Prior to vision, a transient network of recurrently connected cholinergic interneurons, called starburst amacrine cells (SACs), generates spontaneous retinal waves. Despite an absence of robust inhibition, cholinergic retinal waves initiate infrequently and propagate within finite boundaries. Here we combine a variety of electrophysiological and imaging techniques and computational modeling to elucidate the mechanisms underlying these spatial and temporal properties of waves in developing mouse retina. Waves initiate via rare spontaneous depolarizations of SACs. Waves propagate through recurrent cholinergic connections between SACs and volume release of ACh as demonstrated using paired recordings and a cell-based ACh optical sensor. Perforated patch recordings and two-photon calcium imaging reveal that individual SACs have slow afterhyperpolarizations that induce SACs to have variable depolarizations during sequential waves. Using a computational model in which the properties of SACs are based on these physiological measurements, we reproduce the slow frequency, speed, and finite size of recorded waves. This study represents a detailed description of the circuit that mediates cholinergic retinal waves and indicates that variability of the interneurons that generate this network activity may be critical for the robustness of waves across different species and stages of development. PMID:22262883

  14. Cholinergic modulation of dopamine pathways through nicotinic acetylcholine receptors. (United States)

    de Kloet, Sybren F; Mansvelder, Huibert D; De Vries, Taco J


    Nicotine addiction is highly prevalent in current society and is often comorbid with other diseases. In the central nervous system, nicotine acts as an agonist for nicotinic acetylcholine receptors (nAChRs) and its effects depend on location and receptor composition. Although nicotinic receptors are found in most brain regions, many studies on addiction have focused on the mesolimbic system and its reported behavioral correlates such as reward processing and reinforcement learning. Profound modulatory cholinergic input from the pedunculopontine and laterodorsal tegmentum to dopaminergic midbrain nuclei as well as local cholinergic interneuron projections to dopamine neuron axons in the striatum may play a major role in the effects of nicotine. Moreover, an indirect mesocorticolimbic feedback loop involving the medial prefrontal cortex may be involved in behavioral characteristics of nicotine addiction. Therefore, this review will highlight current understanding of the effects of nicotine on the function of mesolimbic and mesocortical dopamine projections in the mesocorticolimbic circuit. Copyright © 2015. Published by Elsevier Inc.

  15. Lack of correlation between cholinergic-induced changes in chemosensory activity and dopamine release from the cat carotid body in vitro. (United States)

    Iturriaga, R; Alcayaga, J; Zapata, P


    We studied the effects of nicotine, acetylcholine (ACh) and dopamine (DA) on the frequency of chemosensory discharges (f(x)) and catecholamine (CA) efflux in the cat carotid body superfused in vitro. CA efflux was measured by changes in CA concentration (DeltaCA) determined by chronoamperometry with nafionated carbon-fiber microelectrodes inserted in the carotid body, while f(x) was recorded simultaneously from the carotid (sinus) nerve. Nicotine (10-20 microg) and ACh (>100 microg) increased f(x) in all carotid bodies (n=16), but produced a delayed DeltaCA ( approximately 0.65 microM) in only half of them. Eserine potentiated ACh-evoked increases in f(x) and CA effluxes. Nicotine and ACh-induced DeltaCA were rapidly reduced upon repeated administration. While f(x) increases evoked by low doses of nicotine or ACh were reduced or abolished by prior administration of exogenous DA (>100 microg), CA effluxes were enhanced and hastened. Thus, cholinergic-induced changes in f(x) are dissociated from CA efflux.

  16. TASK Channels on Basal Forebrain Cholinergic Neurons Modulate Electrocortical Signatures of Arousal by Histamine (United States)

    Vu, Michael T.; Du, Guizhi; Bayliss, Douglas A.


    Basal forebrain cholinergic neurons are the main source of cortical acetylcholine, and their activation by histamine elicits cortical arousal. TWIK-like acid-sensitive K+ (TASK) channels modulate neuronal excitability and are expressed on basal forebrain cholinergic neurons, but the role of TASK channels in the histamine-basal forebrain cholinergic arousal circuit is unknown. We first expressed TASK channel subunits and histamine Type 1 receptors in HEK cells. Application of histamine in vitro inhibited the acid-sensitive K+ current, indicating a functionally coupled signaling mechanism. We then studied the role of TASK channels in modulating electrocortical activity in vivo using freely behaving wild-type (n = 12) and ChAT-Cre:TASKf/f mice (n = 12), the latter lacking TASK-1/3 channels on cholinergic neurons. TASK channel deletion on cholinergic neurons significantly altered endogenous electroencephalogram oscillations in multiple frequency bands. We then identified the effect of TASK channel deletion during microperfusion of histamine into the basal forebrain. In non-rapid eye movement sleep, TASK channel deletion on cholinergic neurons significantly attenuated the histamine-induced increase in 30–50 Hz activity, consistent with TASK channels contributing to histamine action on basal forebrain cholinergic neurons. In contrast, during active wakefulness, histamine significantly increased 30–50 Hz activity in ChAT-Cre:TASKf/f mice but not wild-type mice, showing that the histamine response depended upon the prevailing cortical arousal state. In summary, we identify TASK channel modulation in response to histamine receptor activation in vitro, as well as a role of TASK channels on cholinergic neurons in modulating endogenous oscillations in the electroencephalogram and the electrocortical response to histamine at the basal forebrain in vivo. SIGNIFICANCE STATEMENT Attentive states and cognitive function are associated with the generation of γ EEG activity

  17. Assessment of Cholinergic Properties of Ashwagandha Leaf-Extract in the Amnesic Mouse Brain. (United States)

    Gautam, Akash; Wadhwa, Renu; Thakur, Mahendra K


    In our earlier study, we have shown the memory enhancing and scopolamine-induced amnesia recovery properties of Ashwagandha leaf extract using behavioral paradigm and expression analysis of synaptic plasticity genes. However, the exact mechanism through which Ashwagandha demonstrates these effects is still unknown. In the present study, we hypothesized that the alcoholic extract of Ashwagandha leaves (i-Extract) possesses cholinergic properties, which in turn inhibit the anti-cholinergic nature of scopolamine. Therefore, the potential of i-Extract to recover from the scopolamine-induced cholinergic deficits was assessed by measuring acetylcholine (neurotransmitter) and Arc (synaptic activity-related gene) expression level in the mouse brain. The enzymatic activity of acetyl cholinesterase and choline acetyltransferase was assessed through colorimetric assays, and expression level of Arc protein was examined by Western blotting. Furthermore, mRNA level of these genes was examined by semi-quantitative reverse-transcriptase PCR. We observed that the treatment of i-Extract in scopolamine-induced amnesic mouse attenuates scopolamine-induced detrimental alterations in the cholinergic system. Thus, our study provided biochemical and molecular evidence of cholinergic properties of Ashwagandha leaf extract during brain disorders associated with cholinergic dysfunction.

  18. A cholinergic hypothesis of the unconscious in affective disorders.

    Directory of Open Access Journals (Sweden)

    Costa eVakalopoulos


    Full Text Available The interactions between distinct pharmacological systems are proposed as a key dynamic in the formation of unconscious memories underlying rumination and mood disorder, but also reflect the plastic capacity of neural networks that can aid recovery. An inverse and reciprocal relationship is postulated between cholinergic and monoaminergic receptor subtypes. M1-type muscarinic receptor transduction facilitates encoding of unconscious, prepotent behavioural repertoires at the core of affective disorders and ADHD. Behavioural adaptation to new contingencies is mediated by the classic prototype receptor: 5-HT1A (Gi/o and its modulation of m1-plasticity. Reversal of learning is dependent on increased phasic activation of midbrain monoaminergic nuclei and is a function of hippocampal theta. Acquired hippocampal dysfunction due to abnormal activation of the hypothalamic-pituitary-adrenal (HPA axis predicts deficits in hippocampal-dependent memory and executive function and further impairments to cognitive inhibition. Encoding of explicit memories is mediated by Gq/11 and Gs signalling of monoamines only. A role is proposed for the phasic activation of the basal forebrain cholinergic nucleus by cortical projections from the complex consisting of the insula and claustrum. Although controversial. recent studies suggest a common ontogenetic origin of the two structures and a functional coupling. Lesions of the region result in loss of motivational behaviour and familiarity based judgements. A major hypothesis of the paper is that these lost faculties result indirectly, from reduced cholinergic tone.

  19. Striatal cholinergic interneuron regulation and circuit effects

    Directory of Open Access Journals (Sweden)

    Sean Austin Lim


    Full Text Available The striatum plays a central role in motor control and motor learning. Appropriate responses to environmental stimuli, including pursuit of reward or avoidance of aversive experience all require functional striatal circuits. These pathways integrate synaptic inputs from limbic and cortical regions including sensory, motor and motivational information to ultimately connect intention to action. Although many neurotransmitters participate in striatal circuitry, one critically important player is acetylcholine (ACh. Relative to other brain areas, the striatum contains exceptionally high levels of ACh, the enzymes that catalyze its synthesis and breakdown, as well as both nicotinic and muscarinic receptor types that mediate its postsynaptic effects. The principal source of striatal ACh is the cholinergic interneuron (ChI, which comprises only about 1-2% of all striatal cells yet sends dense arbors of projections throughout the striatum. This review summarizes recent advances in our understanding of the factors affecting the excitability of these neurons through acute effects and long term changes in their synaptic inputs. In addition, we discuss the physiological effects of ACh in the striatum, and how changes in ACh levels may contribute to disease states during striatal dysfunction.

  20. severe organophosphate poisoning with delayed cholinergic crisis

    African Journals Online (AJOL)




  1. Atopic predisposition in cholinergic urticaria patients and its implications. (United States)

    Altrichter, S; Koch, K; Church, M K; Maurer, M


    Cholinergic urticaria (CholU) is a frequent chronic urticaria disorder with itchy weal and flare-type skin reactions in response to physical exercise or passive warming. A higher frequency of atopy among CholU patients has been reported, but the significance of this observation is unclear. To assess the prevalence and relevance of atopy in CholU patients. Thirty CholU patients were assessed for atopic skin diathesis (atopic predisposition) by use of the Erlangen Atopy Score and divided into atopic and non-atopic predisposed CholU individuals. Both groups were assessed for disease severity (CholUSI) and activity (CholUAS7), quality of life impairment [Dermatology Life Quality Index (DLQI) and CU-Q2 OL], seasonal exacerbation, total and specific serum IgE and comorbidities. CholU patients were found to exhibit high rates of atopic predisposition (57%), with higher prevalence and scores in female than in male patients. High Erlangen Atopy Scores were linked to high CholU severity, activity and impact on QoL. Atopic predisposed CholU patients show different seasonal exacerbation patterns, IgE specificity and comorbidity profiles as compared to non-atopic CholU patients. Atopic predisposition and cholinergic urticaria appear to be linked more closely than previously thought, which suggests shared pathogenetic mechanisms. Atopic patients with cholinergic urticaria have more severe disease and poorer quality of life than those who do not. Thus, all cholinergic urticaria patients should be assessed for atopic predisposition. © 2016 European Academy of Dermatology and Venereology.

  2. Cholinergic Urticaria with Anaphylaxis: An Underrecognized Clinical Entity. (United States)

    Vadas, Peter; Sinilaite, Angela; Chaim, Marcus


    Cholinergic urticaria is a form of physical urticaria triggered by high ambient temperature, strenuous physical activity, and strong emotion. These same triggers may cause multisystem reactions that can be life-threatening. A study of patients with cholinergic urticaria with anaphylaxis was undertaken to describe the demographic and clinical features of this form of anaphylaxis. To describe a cohort of patients with anaphylaxis triggered by high ambient temperature, exertion, and stress. Patients from an academic allergy practice in a university teaching hospital were identified by retrospective chart review. A total of 19 patients with recurrent episodes of anaphylaxis due to cholinergic triggers were identified. The female:male ratio was 15:4 (79% females). The mean age of onset was 27.5 years. Patients experienced a mean of 9.41 episodes per year. All 19 patients (100%) reported anaphylaxis triggered by high ambient temperature, 89.5% reported anaphylaxis triggered by strenuous exertion, and 78.9% reported anaphylaxis triggered by stress. Cutaneous involvement was present in 94.7%; 78.9% had upper airway obstructive symptoms, 78.9% had lower airway involvement, 57.9% had gastrointestinal involvement, and 78.9% had cardiovascular manifestations. Anaphylaxis severity scores were grade 1 (mild) in 11.1%, grade 2 (moderate) in 44.4%, and grade 3 (severe) in 44.4%. Baseline tryptase levels were normal in all but 1 patient. Anaphylaxis due to cholinergic triggers is underreported, with only several case reports in the literature. Reactions are multisystem with cutaneous, upper and lower airway, and cardiovascular involvement in most patients. Manifestations may be life-threatening, and reactions are often severe. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  3. Cholinergic mechanism involved in the nociceptive modulation of dentate gyrus. (United States)

    Jiao, Runsheng; Yang, Chunxiao; Zhang, Ying; Xu, Manying; Yang, Xiaofang


    Acetylcholine (ACh) causes a wide variety of anti-nociceptive effects. The dentate gyrus (DG) region of the hippocampal formation (HF) has been demonstrated to be involved in nociceptive perception. However, the mechanisms underlying this anti-nociceptive role have not yet been elucidated in the cholinergic pain-related neurons of DG. The electrical activities of pain-related neurons of DG were recorded by a glass microelectrode. Two kinds of pain-related neurons were found: pain-excited neurons (PEN) and pain-inhibited neurons (PIN). The experimental protocol involved intra-DG administration of muscarinic cholinergic receptor (mAChR) agonist or antagonist. Intra-DG microinjection of 1 microl of ACh (0.2 microg/microl) or 1 microl of pilocarpine (0.4 microg/microl) decreased the discharge frequency of PEN and prolonged firing latency, but increased the discharge frequency of PIN and shortened PIN inhibitory duration (ID). Intra-DG administration of 1 microl of atropine (1.0 microg/microl) showed exactly the opposite effects. According to the above experimental results, we can presume that cholinergic pain-related neurons in DG are involved in the modulation of the nociceptive response by affecting the discharge of PEN and PIN.

  4. Cholinergic neuromodulation controls directed temporal communication in neocortex in vitro

    Directory of Open Access Journals (Sweden)

    Anita K Roopun


    Full Text Available Acetylcholine is the primary neuromodulator involved in cortical arousal in mammals. Cholinergic modulation is involved in conscious awareness, memory formation and attention – processes that involve intercommunication between different cortical regions. Such communication is achieved in part through temporal structuring of neuronal activity by population rhythms, particularly in the beta and gamma frequency ranges (12 – 80 Hz. Here we demonstrate, using in vitro and in silico models, that spectrally identical patterns of beta2 and gamma rhythms are generated in primary sensory areas and polymodal association areas by fundamentally different local circuit mechanisms: Glutamatergic excitation induced beta2 frequency population rhythms only in layer 5 association cortex whereas cholinergic neuromodulation induced this rhythm only in layer 5 primary sensory cortex. This region-specific sensitivity of local circuits to cholinergic modulation allowed for control of the extent of cortical temporal interactions. Furthermore, the contrasting mechanisms underlying these beta2 rhythms produced a high degree of directionality, favouring an influence of association cortex over primary auditory cortex.

  5. Cholinergic components of nervous system of Schistosoma mansoni and S. haematobium (Digenea: Schistosomatidae). (United States)

    Reda, Enayat S; El-Shabasy, Eman A; Said, Ashraf E; Mansour, Mohamed F A; Saleh, Mai A


    A comparison has been made for the first time between the cholinergic components of the nervous system of important human digeneans namely Schistosoma mansoni and Schistosoma haematobium from infected hamster (Cricentus auratus) in Egypt. In each parasite, the central nervous system consists of two cerebral ganglia and three pairs of nerve cords (ventral, lateral, and dorsal) linked together by some transverse connectives and numerous ring commissures. Peripheral cholinergic innervation was detected in oral and ventral suckers and in some parts of female reproductive system in both species, but there were some differences. The possible functions of some of these nervous components are discussed.

  6. Cholinergic receptor subtypes and their role in cognition, emotion, and vigilance control: an overview of preclinical and clinical findings. (United States)

    Graef, Susanne; Schönknecht, Peter; Sabri, Osama; Hegerl, Ulrich


    The cholinergic system has long been linked to cognitive processes. Two main classes of acetylcholine (ACh) receptors exist in the human brain, namely muscarinic and nicotinic receptors, of which several subtypes occur. This review seeks to provide an overview of previous findings on the influence of cholinergic receptor manipulations on cognition in animals and humans, with particular emphasis on the role of selected cholinergic receptor subtypes. Furthermore, the involvement of these receptor subtypes in the regulation of emotion and brain electrical activity as measured by electroencephalography (EEG) shall be addressed since these domains are considered to be important modulators of cognitive functioning. In regard to cognition, the muscarinic receptor subtypes have been implicated mainly in memory functions, but have also been linked to attentional processes. The nicotinic α7 receptor subtype is involved in working memory, whereas the α4β2* subtype has been linked to tests of attention. Both muscarinic and nicotinic cholinergic mechanisms play a role in modulating brain electrical activity. Nicotinic receptors have been strongly associated with the modulation of depression and anxiety. Cholinergic receptor manipulations have an effect on cognition, emotion, and brain electrical activity as measured by EEG. Changes in cognition can result from direct cholinergic receptor manipulation or from cholinergically induced changes in vigilance or affective state.

  7. Asynchronous Cholinergic Drive Correlates with Excitation-Inhibition Imbalance via a Neuronal Ca2+ Sensor Protein

    Directory of Open Access Journals (Sweden)

    Keming Zhou


    Full Text Available Excitation-inhibition imbalance in neural networks is widely linked to neurological and neuropsychiatric disorders. However, how genetic factors alter neuronal activity, leading to excitation-inhibition imbalance, remains unclear. Here, using the C. elegans locomotor circuit, we examine how altering neuronal activity for varying time periods affects synaptic release pattern and animal behavior. We show that while short-duration activation of excitatory cholinergic neurons elicits a reversible enhancement of presynaptic strength, persistent activation results to asynchronous and reduced cholinergic drive, inducing imbalance between endogenous excitation and inhibition. We find that the neuronal calcium sensor protein NCS-2 is required for asynchronous cholinergic release in an activity-dependent manner and dampens excitability of inhibitory neurons non-cell autonomously. The function of NCS-2 requires its Ca2+ binding and membrane association domains. These results reveal a synaptic mechanism implicating asynchronous release in regulation of excitation-inhibition balance.

  8. Cholinergic induced mesenteric vasorelaxation in response to head-up tilt

    DEFF Research Database (Denmark)

    Perko, M J; Madsen, P; Perko, G


    resistance as expressed by analogous elevations in the diastolic blood velocity (to 62 +/- 9 vs. 56 +/- 7 cm s-1 with placebo). Throughout the normotensive and hypotensive phases of head-up tilt, cholinergic blockade reduced mesenteric artery mean blood velocity by 39 and 42%, respectively, corresponding......Central hypovolaemia induced by head-up tilt evokes a reduction in superior mesenteric artery resistance resulting in maintenance of regional blood flow. Mechanisms of importance for this response are not known, but a parasympathetic contribution could be expected. To evaluate this hypothesis......, superior mesenteric artery blood flow and resistance were evaluated by duplex ultrasound in eight healthy volunteers during postprandial head-up tilt with and without cholinergic blockade. During supine rest, cholinergic blockade did not influence the postprandial reduction in peripheral mesenteric artery...

  9. Cytokinins are central regulators of cambial activity. (United States)

    Matsumoto-Kitano, Miho; Kusumoto, Takami; Tarkowski, Petr; Kinoshita-Tsujimura, Kaori; Václavíková, Katerina; Miyawaki, Kaori; Kakimoto, Tatsuo


    The roots and stems of dicotyledonous plants thicken by the cell proliferation in the cambium. Cambial proliferation changes in response to environmental factors; however, the molecular mechanisms that regulate cambial activity are largely unknown. The quadruple Arabidopsis thaliana mutant atipt1;3;5;7, in which 4 genes encoding cytokinin biosynthetic isopentenyltransferases are disrupted by T-DNA insertion, was unable to form cambium and showed reduced thickening of the root and stem. The atipt3 single mutant, which has moderately decreased levels of cytokinins, exhibited decreased root thickening without any other recognizable morphological changes. Addition of exogenously supplied cytokinins to atipt1;3;5;7 reactivated the cambium in a dose-dependent manner. When an atipt1;3;5;7 shoot scion was grafted onto WT root stock, both the root and shoot grew normally and trans-zeatin-type (tZ-type) cytokinins in the shoot were restored to WT levels, but isopentenyladenine-type cytokinins in the shoot remained unchanged. Conversely, when a WT shoot was grafted onto an atipt1;3;5;7 root, both the root and shoot grew normally and isopentenyladenine-type cytokinins in the root were restored to WT levels, but tZ-type cytokinins were only partially restored. Collectively, it can be concluded that cytokinins are important regulators of cambium development and that production of cytokinins in either the root or shoot is sufficient for normal development of both the root and shoot.

  10. Urban activism in Central and Eastern Europe: A theoretical framework

    Directory of Open Access Journals (Sweden)

    Alexandra Bitušíková


    Full Text Available The study brings an overview of selected transdisciplinary theoretical approaches to the study of urban movements and activism placed within the framework of civil society and social movements, focused on the region of Central and Eastern Europe, and seen from a social anthropological perspective. It attempts to challenge older academic writings that described civil society in Central and Eastern Europe as underdeveloped and weak, and presents research that points out a specific nature of activism in the countries of the region. It builds primarily on the concepts of civil society, social movements, urban movements and urban activism as presented by scholars both from “Western” and “Central and Eastern” European countries and demonstrates that after more than two decades since the fall of communism it is still important to take different historic, political, economic, social and cultural contexts into account when comparing urban movements and activism within Europe.

  11. Some Central Nervous System Activities of Nerium Oleander Linn ...

    African Journals Online (AJOL)

    Purpose: The purpose of the study was to evaluate the activity of 50 % hydroalcohol flower extract of Nerium oleander Linn. on the central nervous system (CNS) of mice. Methods: The effect of the 50 % hydroalcohol extract of N. oleander flowers at dosage levels of 100 and 200 mg/kg p.o. on the locomotor activity of mice ...

  12. Cholinergic Neurotransmission in the Posterior Insular Cortex Is Altered in Preclinical Models of Neuropathic Pain: Key Role of Muscarinic M2 Receptors in Donepezil-Induced Antinociception (United States)

    Ferrier, Jérémy; Bayet-Robert, Mathilde; Dalmann, Romain; El Guerrab, Abderrahim; Aissouni, Youssef; Graveron-Demilly, Danielle; Chalus, Maryse; Pinguet, Jérémy; Eschalier, Alain; Richard, Damien; Daulhac, Laurence; Balayssac, David


    Neuropathic pain is one of the most debilitating pain conditions, yet no therapeutic strategy has been really effective for its treatment. Hence, a better understanding of its pathophysiological mechanisms is necessary to identify new pharmacological targets. Here, we report important metabolic variations in brain areas involved in pain processing in a rat model of oxaliplatin-induced neuropathy using HRMAS 1H-NMR spectroscopy. An increased concentration of choline has been evidenced in the posterior insular cortex (pIC) of neuropathic animal, which was significantly correlated with animals' pain thresholds. The screening of 34 genes mRNA involved in the pIC cholinergic system showed an increased expression of the high-affinity choline transporter and especially the muscarinic M2 receptors, which was confirmed by Western blot analysis in oxaliplatin-treated rats and the spared nerve injury model (SNI). Furthermore, pharmacological activation of M2 receptors in the pIC using oxotremorine completely reversed oxaliplatin-induced mechanical allodynia. Consistently, systemic treatment with donepezil, a centrally active acetylcholinesterase inhibitor, prevented and reversed oxaliplatin-induced cold and mechanical allodynia as well as social interaction impairment. Intracerebral microdialysis revealed a lower level of acetylcholine in the pIC of oxaliplatin-treated rats, which was significantly increased by donepezil. Finally, the analgesic effect of donepezil was markedly reduced by a microinjection of the M2 antagonist, methoctramine, within the pIC, in both oxaliplatin-treated rats and spared nerve injury rats. These findings highlight the crucial role of cortical cholinergic neurotransmission as a critical mechanism of neuropathic pain, and suggest that targeting insular M2 receptors using central cholinomimetics could be used for neuropathic pain treatment. SIGNIFICANCE STATEMENT Our study describes a decrease in cholinergic neurotransmission in the posterior insular

  13. Cholinergic regulation of the vasopressin neuroendocrine system

    Energy Technology Data Exchange (ETDEWEB)

    Michels, K.M.


    To clarify the physical and functional relationship between the cholinergic system, and the neurodocrine cells of the supraoptic nucleus, a combination of experiments on receptor binding, localization and function were carried out. The putative nicotinic receptor probe (/sup 125/I)alpha bungarotoxin ((/sup 125/I)alpha BTX) bound with high affinity and specificity to the vasopressin and oxytocin magnocellular neurons of the supraoptic nucleus, nucleus circularis, and paraventricular nucleus. Binding of (/sup 125/I)alpha BTX within the neural lobe was very low. In contrast, the muscarinic cholinergic receptor probe (/sup 3/H)quinuclidinylbenzilate ((/sup 3/H)QNB) did not bind to magnocellular vasopressin and oxytocin cell groups. The median eminence, which contains the neurosecretory axons, and the neural lobe of the pituitary contain low levels of (/sup 3/H)QNB binding. The physiological significance of these cholinergic receptors in regulation of vasopressin release was tested using an in vitro preparation of the supraoptic - neural lobe system.

  14. Cholinergic Modulation of Type 2 Immune Responses

    Directory of Open Access Journals (Sweden)

    Goele Bosmans


    Full Text Available In recent years, the bidirectional relationship between the nervous and immune system has become increasingly clear, and its role in both homeostasis and inflammation has been well documented over the years. Since the introduction of the cholinergic anti-inflammatory pathway, there has been an increased interest in parasympathetic regulation of both innate and adaptive immune responses, including T helper 2 responses. Increasing evidence has been emerging suggesting a role for the parasympathetic nervous system in the pathophysiology of allergic diseases, including allergic rhinitis, asthma, food allergy, and atopic dermatitis. In this review, we will highlight the role of cholinergic modulation by both nicotinic and muscarinic receptors in several key aspects of the allergic inflammatory response, including barrier function, innate and adaptive immune responses, and effector cells responses. A better understanding of these cholinergic processes mediating key aspects of type 2 immune disorders might lead to novel therapeutic approaches to treat allergic diseases.

  15. [The cholinergic non-excitability phenomenon in the atrial myocardium of lower vertebrates]. (United States)

    Abramochkin, D V; Kuz'min, V S; Sukhova, G S; Rozenshtraukh, L V


    Changes of electric activity induced by acetylcholine were studied in atrial myocardium of fishes (cod and carp) and reptilians (lizard and grass-snake). Standart microelectrode technique and novel method of optical mapping were used in the study. Acetylcholine (1-50 microM) provoked decrease of the action potential amplitude down to full inhibition of electrical activity in wide regions of atrium of cod and carp. We define this phenomenon as cholinergic inexcitability. In other regions excitation persisted even during action of 500 microM acetylcholine. In atria of lizard and grass-snake acetylcholine caused shortening of action potential without changes in it's amplitude. Local cholinergic inexcitability, shown in the atrial myocardium of fishes, is quite similar to the phenomenon, that was described earlier in the atria of frogs. It presents the heart of fish as an interesting model for study of mechanisms of cholinergic atrial arrhythmias initiation.

  16. Neonicotinoid insecticides inhibit cholinergic neurotransmission in a molluscan (Lymnaea stagnalis) nervous system. (United States)

    Vehovszky, Á; Farkas, A; Ács, A; Stoliar, O; Székács, A; Mörtl, M; Győri, J


    Neonicotinoids are highly potent and selective systemic insecticides, but their widespread use also has a growing impact on non-target animals and contaminates the environment, including surface waters. We tested the neonicotinoid insecticides commercially available in Hungary (acetamiprid, Mospilan; imidacloprid, Kohinor; thiamethoxam, Actara; clothianidin, Apacs; thiacloprid, Calypso) on cholinergic synapses that exist between the VD4 and RPeD1 neurons in the central nervous system of the pond snail Lymnaea stagnalis. In the concentration range used (0.01-1 mg/ml), neither chemical acted as an acetylcholine (ACh) agonist; instead, both displayed antagonist activity, inhibiting the cholinergic excitatory components of the VD4-RPeD1 connection. Thiacloprid (0.01 mg/ml) blocked almost 90% of excitatory postsynaptic potentials (EPSPs), while the less effective thiamethoxam (0.1 mg/ml) reduced the synaptic responses by about 15%. The ACh-evoked membrane responses of the RPeD1 neuron were similarly inhibited by the neonicotinoids, confirming that the same ACh receptor (AChR) target was involved. We conclude that neonicotinoids act on nicotinergic acetylcholine receptors (nAChRs) in the snail CNS. This has been established previously in the insect CNS; however, our data indicate differences in the background mechanism or the nAChR binding site in the snail. Here, we provide the first results concerning neonicotinoid-related toxic effects on the neuronal connections in the molluscan nervous system. Aquatic animals, including molluscs, are at direct risk while facing contaminated surface waters, and snails may provide a suitable model for further studies of the behavioral/neuronal consequences of intoxication by neonicotinoids. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. A Reaction-Diffusion Model of Cholinergic Retinal Waves (United States)

    Lansdell, Benjamin; Ford, Kevin; Kutz, J. Nathan


    Prior to receiving visual stimuli, spontaneous, correlated activity in the retina, called retinal waves, drives activity-dependent developmental programs. Early-stage waves mediated by acetylcholine (ACh) manifest as slow, spreading bursts of action potentials. They are believed to be initiated by the spontaneous firing of Starburst Amacrine Cells (SACs), whose dense, recurrent connectivity then propagates this activity laterally. Their inter-wave interval and shifting wave boundaries are the result of the slow after-hyperpolarization of the SACs creating an evolving mosaic of recruitable and refractory cells, which can and cannot participate in waves, respectively. Recent evidence suggests that cholinergic waves may be modulated by the extracellular concentration of ACh. Here, we construct a simplified, biophysically consistent, reaction-diffusion model of cholinergic retinal waves capable of recapitulating wave dynamics observed in mice retina recordings. The dense, recurrent connectivity of SACs is modeled through local, excitatory coupling occurring via the volume release and diffusion of ACh. In addition to simulation, we are thus able to use non-linear wave theory to connect wave features to underlying physiological parameters, making the model useful in determining appropriate pharmacological manipulations to experimentally produce waves of a prescribed spatiotemporal character. The model is used to determine how ACh mediated connectivity may modulate wave activity, and how parameters such as the spontaneous activation rate and sAHP refractory period contribute to critical wave size variability. PMID:25474327

  18. GABAergic terminals are a source of galanin to modulate cholinergic neuron development in the neonatal forebrain. (United States)

    Keimpema, Erik; Zheng, Kang; Barde, Swapnali Shantaram; Berghuis, Paul; Dobszay, Márton B; Schnell, Robert; Mulder, Jan; Luiten, Paul G M; Xu, Zhiqing David; Runesson, Johan; Langel, Ülo; Lu, Bai; Hökfelt, Tomas; Harkany, Tibor


    The distribution and (patho-)physiological role of neuropeptides in the adult and aging brain have been extensively studied. Galanin is an inhibitory neuropeptide that can coexist with γ-aminobutyric acid (GABA) in the adult forebrain. However, galanin's expression sites, mode of signaling, impact on neuronal morphology, and colocalization with amino acid neurotransmitters during brain development are less well understood. Here, we show that galaninergic innervation of cholinergic projection neurons, which preferentially express galanin receptor 2 (GalR2) in the neonatal mouse basal forebrain, develops by birth. Nerve growth factor (NGF), known to modulate cholinergic morphogenesis, increases GalR2 expression. GalR2 antagonism (M871) in neonates reduces the in vivo expression and axonal targeting of the vesicular acetylcholine transporter (VAChT), indispensable for cholinergic neurotransmission. During cholinergic neuritogenesis in vitro, GalR2 can recruit Rho-family GTPases to induce the extension of a VAChT-containing primary neurite, the prospective axon. In doing so, GalR2 signaling dose-dependently modulates directional filopodial growth and antagonizes NGF-induced growth cone differentiation. Galanin accumulates in GABA-containing nerve terminals in the neonatal basal forebrain, suggesting its contribution to activity-driven cholinergic development during the perinatal period. Overall, our data define the cellular specificity and molecular complexity of galanin action in the developing basal forebrain. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail:

  19. Internal cholinergic regulation of learning and recall in a model of olfactory processing

    Directory of Open Access Journals (Sweden)

    Licurgo Benemann Almeida


    Full Text Available In the olfactory system, cholinergic modulation has been associated with contrast modulation and changes in receptive fields in the olfactory bulb, as well the learning of odor associations in olfactory cortex. Computational modeling and behavioral studies suggest that cholinergic modulation could improve sensory processing and learning while preventing pro-active interference when task demands are high. However, how sensory inputs and/or learning regulate incoming modulation has not yet been elucidated. We here use a computational model of the olfactory bulb, piriform cortex (PC and horizontal limb of the diagonal band of Broca (HDB to explore how olfactory learning could regulate cholinergic inputs to the system in a closed feedback loop. In our model, the novelty of an odor is reflected in firing rates and sparseness of cortical neurons in response to that odor and these firing rates can directly regulate learning in the system by modifying cholinergic inputs to the system. In the model, cholinergic neurons reduce their firing in response to familiar odors – reducing plasticity in the PC, but increase their firing in response to novel odor – increasing PC plasticity. Recordings from HDB neurons in awake behaving rats reflect predictions from the model by showing that a subset of neurons decrease their firing as an odor becomes familiar.

  20. Central nervous system depressant activity of Russelia equisetiformis

    African Journals Online (AJOL)

    A significant reduction (p< 0.05) in amphetamine – induced stereotype behavior was observed with 200mg/kg REC, but there was no protection against amphetamine – induced mortality. The results of this study suggest that Russelia equisetiformis methanol extract possesses central nervous system depressant activities.

  1. Modeling the Interaction between β-Amyloid Aggregates and Choline Acetyltransferase Activity and Its Relation with Cholinergic Dysfunction through Two-Enzyme/Two-Compartment Model

    Directory of Open Access Journals (Sweden)

    Hedia Fgaier


    Full Text Available The effect of β-amyloid aggregates on activity of choline acetyltransferase (ChAT which is responsible for synthesizing acetylcholine (ACh in human brain is investigated through the two-enzyme/two-compartment (2E2C model where the presynaptic neuron is considered as compartment 1 while both the synaptic cleft and the postsynaptic neuron are considered as compartment 2 through suggesting three different kinetic mechanisms for the inhibition effect. It is found that the incorporation of ChAT inhibition by β-amyloid aggregates into the 2E2C model is able to yield dynamic solutions for concentrations of generated β-amyloid, ACh, choline, acetate, and pH in addition to the rates of ACh synthesis and ACh hydrolysis in compartments 1 and 2. It is observed that ChAT activity needs a high concentration of β-amyloid aggregates production rate. It is found that ChAT activity is reduced significantly when neurons are exposed to high levels of β-amyloid aggregates leading to reduction in levels of ACh which is one of the most significant physiological symptoms of AD. Furthermore, the system of ACh neurocycle is dominated by the oscillatory behavior when ChAT enzyme is completely inhibited by β-amyloid. It is observed that the direct inactivation of ChAT by β-amyloid aggregates may be a probable mechanism contributing to the development of AD.

  2. Case of cholinergic urticaria accompanied by anaphylaxis. (United States)

    Iijima, Shigeruko; Kojo, Kazumi; Takayama, Noriko; Hiragun, Makiko; Kan, Takanobu; Hide, Michihiro


    Cholinergic urticaria occasionally occurs in combination with anaphylactic symptoms. However, this has not been widely reported. Herein, we report the case of a 14-year-old Japanese male who was diagnosed with cholinergic urticaria accompanied by anaphylaxis. The patient, who was suffering from atopic dermatitis and bronchial asthma, had developed wheals after exercising or bathing, which would have increased his core body temperature, since summer 2014. He experienced two episodes of severe systemic symptoms and wheal development when he took a bath after eating in December 2014 and the following January. His symptoms included wheezing, numbness of the lips, respiratory distress, blindness and fainting. Laboratory tests revealed the following results: serum IgE level, 7060 IU/mL; titers of specific immunoglobulin E antibodies against Malassezia and MGL_1304, 31.70 UA/mL and 112.5 ng/mL, respectively. A histamine release test against human sweat revealed a class 4 response. Skin prick and intradermal tests against autologous sweat produced immediate-type positive reactions. According to these findings, we diagnosed him with the sweat-hypersensitivity type of cholinergic urticaria accompanied by anaphylaxis. He was successfully treated with lafutidine, a histamine H2 receptor antagonist, in combination with fexofenadine. It is important for dermatologists to be aware that cholinergic urticaria can progress to anaphylaxis. © 2017 Japanese Dermatological Association.

  3. Cholinergic Modulation of Restraint Stress Induced Neurobehavioral ...

    African Journals Online (AJOL)

    The involvement of the cholinergic system in restraint stress induced neurobehavioral alterations was investigated in rodents using the hole board, elevated plus maze, the open field and the light and dark box tests. Restraint stress (3h) reduced significantly (p<0.05) the number of entries and time spent in the open arm, ...

  4. APOE-Sensitive Cholinergic Sprouting Compensates for Hippocampal Dysfunctions Due to Reduced Entorhinal Input. (United States)

    Bott, Jean-Bastien; Héraud, Céline; Cosquer, Brigitte; Herbeaux, Karine; Aubert, Julien; Sartori, Maxime; Goutagny, Romain; Mathis, Chantal


    most promising therapeutic targets, but the underlying mechanisms are still unclear. Here, we show that the mammalian brain is able to manage several deleterious consequences of the loss of entorhinal neurons on hippocampal activity and cognitive performance through a fast cholinergic sprouting followed by a slower glutamatergic reinnervation. The cholinergic sprouting is gender dependent and highly sensitive to the genetic risk factor APOE4 Our findings highlight the specific impact of early loss of entorhinal input on hippocampal hyperactivity and cognitive deficits characterizing early stages of AD, especially in APOE4 carriers. Copyright © 2016 the authors 0270-6474/16/3610473-15$15.00/0.

  5. In vitro antiplasmodial activity of Central American medicinal plants. (United States)

    Jenett-Siems, K; Mockenhaupt, F P; Bienzle, U; Gupta, M P; Eich, E


    The in vitro antiplasmodial activities of 14 plant species traditionally used in Central America for the treatment of malaria or fever were evaluated. Lipophilic extracts of Piper hispidum, Siparuna andina, S. pauciflora, S. tonduziana, and Xylopia cf. frutescens, proved to be active against both a chloroquine-sensitive and a resistant strain of Plasmodium falciparum. IC50 values ranged between 3.0 microg/ml and 21.9 microg/ml; however, moderate cytotoxicity of active extracts was observed. Bioactivity-guided fractionation of Piper hispidum yielded 2',4, 6'-trihydroxy-4'-methoxydihydrochalcone (asebogenin) as an active compound.

  6. Central Cholinesterase Inhibition Enhances Glutamatergic Synaptic Transmission


    Kozhemyakin, Maxim; Rajasekaran, Karthik; Kapur, Jaideep


    Central cholinergic overstimulation results in prolonged seizures of status epilepticus in humans and experimental animals. Cellular mechanisms of underlying seizures caused by cholinergic stimulation remain uncertain, but enhanced glutamatergic transmission is a potential mechanism. Paraoxon, an organophosphate cholinesterase inhibitor, enhanced glutamatergic transmission on hippocampal granule cells synapses by increasing the frequency and amplitude of spontaneous excitatory postsynaptic cu...

  7. Opposite effects of moderate heat stress and hyperthermia on cholinergic system of soil nematodes Caenorhabditis elegans and Caenorhabditis briggsae. (United States)

    Kalinnikova, Tatiana B; Kolsanova, Rufina R; Belova, Evgenia B; Shagidullin, Rifgat R; Gainutdinov, Marat Kh


    Cholinergic system plays important role in all functions of organisms of free-living soil nematodes C. elegans and C. briggsae. Using pharmacological analysis we showed the existence of two opposite responses of nematodes cholinergic system to moderate and extreme heat stress. Short-term (15min) noxious heat (31-32°C) caused activation of cholinergic synaptic transmission in C. elegans and C. briggsae organisms by sensitization of nicotinic ACh receptors. In contrast, hyperthermia blocked cholinergic synaptic transmission by inhibition of ACh secretion by neurons. The resistance of behavior to extreme high temperature (36-37°C) was significantly higher in C. briggsae than in C. elegans, and thermostability of cholinergic transmission correlated with resistance of behavior to hyperthermia. Activation of cholinergic transmission by moderate heat stress can be the reason of movement speed increase in such adaptive behavior as noxious heat escape. Inhibition of ACh release is one of reasons for behavior failure caused by extreme high temperature since partial inhibition of ACh-esterase by aldicarb protected C. elegans and C. briggsae behavior against hyperthermia. Antagonist of mAChRs atropine almost completely prevented the rise in behavior thermotolerance caused by aldicarb. Pilocarpine, agonist of mAChRs, protected nematodes behavior against hyperthermia similarly with aldicarb. Therefore it is evident that it is the deficiency of mAChRs activity that is the reason for nematodes' behavior failure by hyperthermia. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Cholinergic imaging in dementia spectrum disorders

    Energy Technology Data Exchange (ETDEWEB)

    Roy, Roman; Niccolini, Flavia; Pagano, Gennaro; Politis, Marios [Institute of Psychiatry, Psychology and Neuroscience, King' s College London, Neurodegeneration Imaging Group, Department of Basic and Clinical Neuroscience, London (United Kingdom)


    The multifaceted nature of the pathology of dementia spectrum disorders has complicated their management and the development of effective treatments. This is despite the fact that they are far from uncommon, with Alzheimer's disease (AD) alone affecting 35 million people worldwide. The cholinergic system has been found to be crucially involved in cognitive function, with cholinergic dysfunction playing a pivotal role in the pathophysiology of dementia. The use of molecular imaging such as SPECT and PET for tagging targets within the cholinergic system has shown promise for elucidating key aspects of underlying pathology in dementia spectrum disorders, including AD or parkinsonian dementias. SPECT and PET studies using selective radioligands for cholinergic markers, such as [{sup 11}C]MP4A and [{sup 11}C]PMP PET for acetylcholinesterase (AChE), [{sup 123}I]5IA SPECT for the α{sub 4}β{sub 2} nicotinic acetylcholine receptor and [{sup 123}I]IBVM SPECT for the vesicular acetylcholine transporter, have been developed in an attempt to clarify those aspects of the diseases that remain unclear. This has led to a variety of findings, such as cortical AChE being significantly reduced in Parkinson's disease (PD), PD with dementia (PDD) and AD, as well as correlating with certain aspects of cognitive function such as attention and working memory. Thalamic AChE is significantly reduced in progressive supranuclear palsy (PSP) and multiple system atrophy, whilst it is not affected in PD. Some of these findings have brought about suggestions for the improvement of clinical practice, such as the use of a thalamic/cortical AChE ratio to differentiate between PD and PSP, two diseases that could overlap in terms of initial clinical presentation. Here, we review the findings from molecular imaging studies that have investigated the role of the cholinergic system in dementia spectrum disorders. (orig.)

  9. The role of cholinergic networks of the anterior basal and inferior frontal lobes in the predatory behaviour of Sepia officinalis. (United States)

    Halm, M P; Chichery, M P; Chichery, R


    The predatory behaviour of the cuttlefish has been the subject of a few detailed studies and can be divided into several stages: prey detection, orientation, positioning, prey-seizing, prey-manipulation and ingestion. Nevertheless, the data about its control by the CNS remain fragmentary. By injecting a cholinergic agonist (nicotine) and antagonists (alpha-bungarotoxin, mecamylamine), the implication of cholinergic networks of the anterior basal and inferior frontal lobes in the control of predatory behaviour are demonstrated. Through these cholinergic networks, the anterior basal lobe takes an important part in the orientation and positioning. The inferior frontal lobe seems to play a role in the control of brachial manipulative and buccal mass activities. The implication of cholinergic networks of the anterior basal and inferior frontal lobes in the predatory behaviour and the pharmacology of nicotinic receptors are discussed.

  10. Outcomes of different protocols of pelvic floor physical therapy and anti-cholinergics in women with wet over-active bladder: A 4-year follow-up. (United States)

    Azuri, Joseph; Kafri, Rachel; Ziv-Baran, Tomer; Stav, Kobi


    We investigated the 4-year outcomes of three protocols of pelvic floor physical therapy and anticholinergic drug in women with wet over-active bladder (OAB). One hundred and sixty-four women were randomly allocated to one of four interventions: drug therapy (DT), bladder training (BT), pelvic floor muscle training (PFMT), or combined pelvic floor rehabilitation (CPFR) that includes BT, PFMT, and behavioral advice. The active treatment in each group lasted 3 months. Of the 132 women who completed a 1-year follow-up, 120 women (90%) responded to our questionnaires and therefore were included in this study. Outcome measures were the number of voids per day, number of urgency urinary incontinence (UUI) episodes per week, completely dry rate and Incontinence Quality of Life questionnaire (I-QOL) at 4 years. After 4 years of follow-up, the outcome measures improved significantly and equally in all four groups. The median number of UUI episodes/week dropped by 3, 1, 2, and 2 in the DT, BT, PFMT, and CPFR groups, respectively (P = ns). The dry rates were 25%, 31%, 44%, 34% in the DT, BT, PFMT, and CPFR groups, respectively (P = ns). I-QOL scores improved significantly in all four groups. Women who suffer from wet-OAB may experience the same degree of long-term improvement following various pelvic floor physical therapy protocols as they would from drug therapy. Neurourol. Urodynam. 36:755-758, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  11. Targeting the Cholinergic System to Develop a Novel Therapy for Huntington's Disease. (United States)

    D'Souza, Gary X; Waldvogel, Henry J


    In this review, we outline the role of the cholinergic system in Huntington's disease, and briefly describe the dysfunction of cholinergic transmission, cholinergic neurons, cholinergic receptors and cholinergic survival factors observed in post-mortem human brains and animal models of Huntington's disease. We postulate how the dysfunctional cholinergic system can be targeted to develop novel therapies for Huntington's disease, and discuss the beneficial effects of cholinergic therapies in pre-clinical and clinical studies.

  12. Time perspective and physical activity among central Appalachian adolescents. (United States)

    Gulley, Tauna


    Time perspective is a cultural behavioral concept that reflects individuals' orientations or attitudes toward the past, present, or future. Individuals' time perspectives influence their choices regarding daily activities. Time perspective is an important consideration when teaching adolescents about the importance of being physically active. However, little is known about the relationship between time perspective and physical activity among adolescents. The purpose of this study was to determine the time perspective of central Appalachian adolescents and explore the relationship between time perspective and physical activity. This study was guided by The theory of planned behavior (TPB). One hundred and ninety-three students completed surveys to examine time perspective and physical activity behaviors. Data were collected in one school. Results of this study can inform school nurses and high school guidance counselors about the importance of promoting a future-oriented time perspective to improve physical activity and educational outcomes.

  13. Cholinergic symptoms and QTc prolongation following donepezil overdose. (United States)

    Pourmand, A; Shay, C; Redha, W; Aalam, A; Mazer-Amirshahi, M


    Donepezil is the most commonly prescribed acetylcholinesterase inhibitor for the treatment of Alzheimer's disease, an ailment that affects millions of older adult patients. By inhibiting the breakdown of acetylcholine in the central nervous system, donepezil has been shown to slow cognitive decline and improve patients' functional status. While donepezil is well-tolerated and generally considered safe at therapeutic doses, taking more than the prescribed dose could result in adverse cholinergic effects that range from mild gastrointestinal distress to serious cardiac dysrhythmias. We present a case of an 84-year-old man who developed gastrointestinal and cardiac disturbances after ingesting seven-times his daily dose of donepezil. As no specific antidote is available for donepezil overdose, this case highlights the importance of supportive care with particular attention to the management of cardiac dysrhythmias in patients displaying signs of toxicity. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Depletion of biogenic amines and enhancement of cholinergic activity in the olfactory bulb and central olfactory connections with chronic methedrine intoxication

    Directory of Open Access Journals (Sweden)

    O. Duarte-Escalante


    Full Text Available Em seqüência a estudos anteriores os autores visam, neste relato, a apresentar as alterações histoquímicas que ocorrem no sistema olfatório de gatos nos quais se desenvolveu nítida estereotipia de fungação (sniffing após administração prolongada de metedrina. Foram intoxicados 12 gatos mediante injeções diárias, durante 10 dias, de doses progressivas de metedrina. Os tecidos a examinar (bulbos olfatórios e suas conexões centrais foram preparados histoquimicamente para demonstrar a fluorescência das aminas biogênicas e reações colinérgicas. Mediante algumas modificações à metodologia recomendada por outros pesquisadores, os autores puderam demonstrar a presença de monoaminas e de acetilcolina no bulbo olfatório e de grupos de fibras adrenérgicas curtas e multi-ramificadas que parecem ser conectadas com os neurônios fluorescentes do bulbo olfatório, a partir de onde estabelecem conexões, pelo tracto olfatório medial, com os neurônios do septum e, pelo tracto olfatório lateral, com os neurônios do complexo amigdalóide.

  15. Cholinergic anti-inflammatory pathway in the non-obese diabetic mouse model

    NARCIS (Netherlands)

    Koopman, F. A.; Vosters, J. L.; Roescher, N.; Broekstra, N.; Tak, P. P.; Vervoordeldonk, M. J.


    Activation of the cholinergic anti-inflammatory pathway (CAP) has been shown to reduce inflammation in animal models, while abrogation of the pathway increases inflammation. We investigated whether modulation of CAP influences inflammation in the non-obese diabetic (NOD) mouse model for Sjögren's

  16. Chick eye extract promotes expression of a cholinergic enzyme in sympathetic ganglia in culture. (United States)

    Iacovitti, L; Teitelman, G; Joh, T H; Reis, D J


    Previous studies have demonstrated that, in rat, individual sympathetic neurons can express both adrenergic and cholinergic biosynthetic enzymes in culture. Moreover, the levels of these enzymes can be regulated by factors present in their environment. In the present study, we sought to determine whether cultures of chick sympathetic neurons express both adrenergic and cholinergic enzymes, whether both enzymes are expressed in the same neurons, and whether the levels of these enzymes can be influenced by environmental factors. In our system, we tested one such factor found in embryonic eye extract (EEE) which has been shown to specifically increase the activity of the cholinergic enzyme choline acetyltransferase (ChAT) in cultures of chick parasympathetic neurons Varon et al., Brain Res., 173 (1979) 29-45; Nishi and Berg. J. Neurosci., 1 (1981) 505-513). At various times in vitro, cultures were analyzed using biochemical, immunocytochemical and autoradiographic techniques. We found that only those cultures of sympathetic neurons supplemented with EEE developed detectable levels of ChAT enzyme activity at 2 days, which increased significantly by 14 days in vitro. Supplementation with EEE did not affect the level of tyrosine hydroxylase (TH) activity. Furthermore, irrespective of nutrient medium, all neurons in all cultures contained TH immunoreactivity and possessed a high-affinity amine uptake system as demonstrated by autoradiography. These studies suggest that neurons of chick sympathetic ganglia can be influenced by factors present in EEE to express a cholinergic enzyme and that this enzyme is coexpressed by cells also exhibiting an adrenergic phenotype.

  17. [Cholinergic syndrome with unconsciousness in amanita poisoning]. (United States)

    Hohn, H; Schoenemann, J


    A 41-year-old patient was found in his flat in a state of coma. After emergency treatment his vital signs were stable and he was transferred to an acute hospital with possible cannabis intoxication. The patient, a hobby gardener, was previously well and had an adversion to the use of any chemical substances. The main symptom showed a cholinergic syndrome with deep coma. We assumed plant ingestion because of the clinical picture and history. The laboratory results were within normal limits apart from a slight rise of the serum creatinine kinase level. The electrocardiogram showed a bradycardia. A drug-screening could not be performed. The differential diagnosis of plant alkaloids or mushroom toxins were considered due to possible plant ingestion and a cholinergic syndrome. Later the toadstool (Amanita muscaria) was found. After treatment oft the cholinergic syndrome with high doses of atropine primary poison elimination was performed. 24 hours later the patient awoke from his coma. Visual hallucinations persisted for a few days. No organic damage due to the intoxication was found. Toxic mushroom ingestion can produce a variety of clinical pictures. Most commonly an anticholinergic syndrome is found, but this was not the case in this patient. The effect of the poison depends on the amount and the preparation, so that no reliable outcome prediction can be made. The drug "poisonous mushroom" is legal and hallucinogenic substances are trendy. As a result clinical signs like those described here will have to be expected in the future.

  18. Space-Based Detection of Sinkhole Activity in Central Florida (United States)

    Oliver-Cabrera, T.; Kruse, S.; Wdowinski, S.


    Central Florida's thick carbonate deposits and hydrological conditions have made the area prone to sinkhole development. Sinkhole collapse is a major geologic hazard in central Florida threatening human life and causing substantial damage to property. According to the Florida Senate report in 2010, between 2006-2010 total insurance claims due to sinkhole activity were around $200 million per year. Detecting sinkhole deformation before a collapse is a very difficult task, due to small or sometimes unnoticeable surface changes. Most techniques used to monitor sinkholes provide very localized information and cannot be implemented to study broad areas. This is the case of central Florida, where the active zone spans over hundreds of square-kilometers. In this study we use Interferometric Synthetic Aperture Radar (InSAR) observations acquired over several locations in central Florida to detect possible pre-collapse deformation. The study areas were selected because they have shown suspicious sinkhole behavior. One of the sites collapsed on March 2013 destroying a property and killing a man. To generate the InSAR results we use six datasets acquired by the TerraSAR-X and Cosmo-SkyMed satellites with various acquisition modes reflecting pixel resolutions between 25cm and 2m. Preliminary InSAR results show good coherence over constructed areas and low coherence in vegetated zones, justifying our analysis that focuses on the man-made structures. After full datasets will be acquired, a Persistent Scatterer Interferometry (PSI) time series analysis will be performed for detecting localized deformation at spatial scale of 1-5 meters. The project results will be verified using Ground Penetrating Radar.

  19. Determining Central Black Hole Masses in Distant Active Galaxies

    DEFF Research Database (Denmark)

    Vestergaard, Marianne


    An empirical relationship, of particular interest for studies of high redshift active galactic nuclei (AGNs) and quasars, between the masses of their central black-holes and rest-frame ultraviolet (UV) parameters measured in single-epoch AGN spectra is presented. This relationship is calibrated...... black-hole demographics at high redshift as well as to statistically study the fundamental properties of AGNs. The broad line region size - luminosity relationship is key to the calibrations presented here. The fact that its intrinsic scatter is also the main source of uncertainty in the calibrations...

  20. Synoptic atmospheric circulation patterns controlling avalanche activity in central Svalbard (United States)

    Hancock, Holt; Prokop, Alexander; Eckerstorfer, Markus; Hendrikx, Jordy


    Central Svalbard's avalanche activity is primarily controlled by the local and synoptic scale meteorological conditions characterizing the region's winter storms. Previous work has described Svalbard's direct-action snow climate as High-Arctic maritime based on the unique meteorological conditions and resulting snowpack stratigraphy observed in the region. To gain a better understanding of the broad-scale spatial controls on regional avalanche activity in Svalbard, this work investigates synoptic atmospheric circulation patterns associated with observed avalanche cycles during the 2007/2008 to 2015/2016 winter seasons. We use avalanche observations systematically recorded as part of the Cryoslope Svalbard project from 2007-2010 in combination with additional observations from notable avalanche events from 2010-2016 to develop a regional avalanche cycle history. We then compare the timing of these avalanche cycles to an existing daily calendar of synoptic types and NCEP/NCAR Reanalysis datasets to characterize the synoptic atmospheric circulation patterns influencing this avalanche activity. Our results indicate regional avalanche cycles are driven by cyclonic activity in the seas surrounding Svalbard under synoptic circulation patterns associated with warm air advection and moisture transport from lower latitudes to Svalbard. The character and spatial distribution of observed avalanche activity can be differentiated by atmospheric circulation type: mid-winter slushflow and wet slab avalanche cycles, for example, are typically associated with meridional southerly flow over the North Atlantic bringing warm air and heavy precipitation to Svalbard. Such analyses can provide a foundation upon which to improve the understanding of central Svalbard's snow climate to facilitate regional avalanche forecasting efforts.

  1. From Structure to Activity: Using Centrality Measures to Predict Neuronal Activity. (United States)

    Fletcher, Jack McKay; Wennekers, Thomas


    It is clear that the topological structure of a neural network somehow determines the activity of the neurons within it. In the present work, we ask to what extent it is possible to examine the structural features of a network and learn something about its activity? Specifically, we consider how the centrality (the importance of a node in a network) of a neuron correlates with its firing rate. To investigate, we apply an array of centrality measures, including In-Degree, Closeness, Betweenness, Eigenvector, Katz, PageRank, Hyperlink-Induced Topic Search (HITS) and NeuronRank to Leaky-Integrate and Fire neural networks with different connectivity schemes. We find that Katz centrality is the best predictor of firing rate given the network structure, with almost perfect correlation in all cases studied, which include purely excitatory and excitatory-inhibitory networks, with either homogeneous connections or a small-world structure. We identify the properties of a network which will cause this correlation to hold. We argue that the reason Katz centrality correlates so highly with neuronal activity compared to other centrality measures is because it nicely captures disinhibition in neural networks. In addition, we argue that these theoretical findings are applicable to neuroscientists who apply centrality measures to functional brain networks, as well as offer a neurophysiological justification to high level cognitive models which use certain centrality measures.

  2. Does cholesterol act as a protector of cholinergic projections in Alzheimer's disease?

    Directory of Open Access Journals (Sweden)

    Bohr Iwo J


    Full Text Available Abstract The relationship between Alzheimer's disease (AD and progressive degeneration of the forebrain cholinergic system is very well established, whereas mechanisms linking this disease with cholesterol, apolipoprotein E (apoE phenotype, and amyloid precursor protein (APP metabolism have not been fully elucidated even though there is a plethora of publications separately on each of these issues. The intention of this hypothesis is to unify knowledge coming from all of these areas. It is based on an assumption that the process of APP hypermetabolism is a neuroprotective response for age-related cholinergic deterioration. In some individuals this initially positive process becomes highly overregulated by genetic or/and epigenetic risk factors and after many years of accumulations lead eventually to AD. I hypothesise that neuroprotective role of APP-hypermetabolism might be related to enrichment of neuronal membranes (lipid rafts in particular in cholesterol in order to compensate for decrease in presynaptic cholinergic transmission and/or AD-related decrease in cholesterol levels. The above is consistent with findings indicating that activity of both muscarinic and nicotinic cholinergic receptors is correlated in a positive manner with cholesterol plasmalemmal content. Briefly – APP metabolism together with transport of cholesterol in apoE containing lipoproteins seem to play a key role in mobilising cholesterol into neuronal membranes.

  3. Involvement of the basolateral amygdala in muscarinic cholinergic modulation of extinction memory consolidation (United States)

    Boccia, Mariano M.; Blake, Mariano G.; Baratti, Carlos M.; McGaugh, James L.


    Previous studies have reported that drugs affecting neuromodulatory systems within the basolateral amygdala (BLA), including drugs affecting muscarinic cholinergic receptors, modulate the consolidation of many kinds of training, including contextual fear conditioning (CFC). The present experiments investigated the involvement of muscarinic cholinergic influences within the BLA in modulating the consolidation of CFC extinction memory. Male Sprague Dawley rats implanted with unilateral cannula aimed at the BLA were trained on a CFC task, using footshock stimulation, and 24 and 48 h later were given extinction training by replacing them in the apparatus without footshock. Following each extinction session they received intra-BLA infusions of the cholinergic agonist oxotremorine (10 ng). Immediate post-extinction BLA infusions significantly enhanced extinction but infusions administered 180 min after extinction training did not influence extinction. Thus the oxotremorine effects were time-dependent and not attributable to non-specific effects on retention performance. These findings provide evidence that, as previously found with original CFC learning, cholinergic activation within the BLA modulates the consolidation of CFC extinction. PMID:18706510

  4. Effects of L-DOPA/benserazide co-treatment on colonic excitatory cholinergic motility and enteric inflammation following dopaminergic nigrostriatal neurodegeneration. (United States)

    Pellegrini, C; Antonioli, L; Colucci, R; Tirotta, E; Gentile, D; Ippolito, C; Segnani, C; Levandis, G; Cerri, S; Blandini, F; Barocelli, E; Ballabeni, V; Bernardini, N; Blandizzi, C; Fornai, M


    The mainstay therapy for Parkinson's disease (PD) relies on L-3,4-dihydroxyphenylalanine (L-DOPA) plus a DOPA-decarboxylase inhibitor. However, their effects on colonic dysmotility and inflammation observed in PD are undetermined. This study examined the effects of L-DOPA plus benserazide (BE) on colonic motility and inflammation in rats with central nigrostriatal dopaminergic denervation. Neurodegeneration was induced by 6-hydroxydopamine (6-OHDA) injection into the medial forebrain bundle (MFB). 6-OHDA animals were treated orally with L-DOPA/BE for 28 days, starting 28 days after 6-OHDA injection. At the end of treatment, in vivo colonic transit was evaluated by a radiologic assay. Electrically stimulated (ES) cholinergic contractions were recorded in vitro from colonic preparations, while acetylcholine release was measured in the incubation medium. Choline acetyltransferase (ChAT) and glial fibrillary acidic protein (GFAP) expression as well as eosinophil and mast cell density were examined in the colonic wall by immunohistochemistry. Colonic TNF and IL-1β levels were also assayed. 6-OHDA animals displayed: 1) decrease in in vivo colonic transit; 2) impairment of ES-stimulated cholinergic contractions; 3) decreased acetylcholine release from myenteric nerves; 4) decrease in ChAT and increase in GFAP myenteric immunopositivity; 5) increase in eosinophil and mast cell density; 6) increase in TNF and IL-1β levels. Treatment with L-DOPA/BE elicited an improvement of in vivo and in vitro colonic motor activity, a normalization of acetylcholine release, ChAT immunopositivity, as well as pro-inflammatory cytokine patterns, ganglionic GFAP levels, eosinophil and mast cell density. Under dopaminergic nigrostriatal denervation, treatment with L-DOPA/BE ameliorated colonic motility through a normalization of myenteric cholinergic neurotransmission, along with an improvement of colonic inflammation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Whole-Brain Monosynaptic Afferent Inputs to Basal Forebrain Cholinergic System

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    Rongfeng Hu


    Full Text Available The basal forebrain cholinergic system (BFCS robustly modulates many important behaviors, such as arousal, attention, learning and memory, through heavy projections to cortex and hippocampus. However, the presynaptic partners governing BFCS activity still remain poorly understood. Here, we utilized a recently developed rabies virus-based cell-type-specific retrograde tracing system to map the whole-brain afferent inputs of the BFCS. We found that the BFCS receives inputs from multiple cortical areas, such as orbital frontal cortex, motor cortex, and insular cortex, and that the BFCS also receives dense inputs from several subcortical nuclei related to motivation and stress, including lateral septum (LS, central amygdala (CeA, paraventricular nucleus of hypothalamus (PVH, dorsal raphe (DRN and parabrachial nucleus (PBN. Interestingly, we found that the BFCS receives inputs from the olfactory areas and the entorhinal-hippocampal system. These results greatly expand our knowledge about the connectivity of the mouse BFCS and provided important preliminary indications for future exploration of circuit function.

  6. Involvement of Cholinergic and Opioid System in γ-Terpinene-Mediated Antinociception

    Directory of Open Access Journals (Sweden)

    Flávia Franceli de Brito Passos


    Full Text Available The literature shows that the monoterpenes are great candidates for the development of new drugs for the treatment of various pathological processes, including painful conditions. The gamma terpinene (γ-TPN is a monoterpene present in plant species that have multiple pharmacological properties and has structural similarity to antinociceptive monoterpenes, such as limonene and alpha-phellandrene. The γ-TPN molecular mass was evaluated by mass spectrometry and showed a pseudomolecular ion with m/z 137.0 Da. The animals did not present any signs of acute toxicity at 2 g/kg, p.o. γ-TPN (1.562 to 50 mg/kg, p.o. showed an antinociceptive effect in the formalin, capsaicin, and glutamate tests. γ-TPN has antinociceptive action when administered by others routes in glutamate test. To eliminate a possible sedative effect of γ-TPN, the open field and rota-rod test were conducted and the γ-TPN did not show muscle relaxant activity or central depressant effect. To investigate the mechanisms of action, the animals were pretreated with naloxone, glibenclamide, atropine, mecamylamine, or L-arginine in the glutamate test. γ-TPN antinociception was inhibited in the presence of naloxone, glibenclamide, atropine, and mecamylamine. The results suggest that the γ-TPN (p.o. produced antinociceptive effect in models of chemical nociception through the cholinergic and opioid systems involvement.

  7. Cholinergic influences on cortical development and adult neurogenesis

    NARCIS (Netherlands)

    Bruel-Jungerman, E.; Lucassen, P.J.; Francis, F.


    In this review, we focus on immature neurons and their regulation by the cholinergic system, both during cortical development as well as during adult neurogenesis. We discuss various studies that indicate roles for acetylcholine in precursor development and neuronal differentiation. Cholinergic

  8. Cortical cholinergic decline parallels the progression of Borna virus encephalitis

    NARCIS (Netherlands)

    Gies, U; Gorcs, TJ; Mulder, J; Planz, O; Stitz, L; Bilzer, T; Luiten, PGM; Harkany, T; Görcs, Tamás J.


    Borna disease virus (BDV)-induced meningoencephalitis is associated with the dysfunction of the cholinergic system. Temporal development of this cholinergic decline during pre-encephalitic and encephalitic stages of BDV infection remains however elusive. Changes in choline acetyltransferase (ChAT)

  9. Mesopontine organization of cholinergic and catecholaminergic cell groups in the normal and narcoleptic dog. (United States)

    Tafti, M; Nishino, S; Liao, W; Dement, W C; Mignot, E


    Canine narcolepsy is a unique experimental model of a human sleep disorder characterized by excessive daytime sleepiness and cataplexy. There is a consensus recognition of an imbalance between cholinergic and catecholaminergic systems in narcolepsy although the underlying mechanisms remain poorly understood. Possible substrates could be an abnormal organization, numbers and/or ratio of cholinergic to catecholaminergic cells in the brain of narcoleptic dogs. Therefore, we sought to characterize the corresponding neuronal populations in normal and narcoleptic dogs (Doberman Pinscher) by using choline acetyltransferase (ChAT), nicotinamide adenosine dinucleotide phosphate (NADPH)-diaphorase, tyrosine hydroxylase (TH), and dopamine beta-hydroxylase (DBH). Cholinergic cell groups were found in an area extending from the central to the gigantocellular tegmental field and the periventricular gray corresponding to the pedunculopontine tegmental nucleus (PPT), the laterodorsal tegmental nucleus (LDT), and the parabrachial nucleus. An almost perfect co-localization of ChAT and NADPH-diaphorase was also observed. Catecholaminergic cell groups detected included the ventral tegmental area, the substantia nigra, and the locus coeruleus nucleus (LC). The anatomical distribution of catecholaminergic neurons was unusual in the dog in two important aspects: i) TH- and/or DBH-immunoreactive neurons of the LC were found almost exclusively in the reticular formation and not within the periventricular gray, ii) very few, if any TH-positive neurons were found in the central gray and dorsal raphe. Quantitative analysis did not reveal any significant differences in the organization and the number of cells identified in the LDT, PPT, and LC of normal and narcoleptic dogs. Moreover, the cholinergic to catecholaminergic ratio was found identical in the two groups. In conclusion, the present results do not support the hypothesis that the neurochemical imbalance in narcolepsy could result from

  10. Late Pleistocene dune activity in the central Great Plains, USA (United States)

    Mason, J. A.; Swinehart, J. B.; Hanson, P. R.; Loope, D. B.; Goble, R. J.; Miao, X.; Schmeisser, R. L.


    Stabilized dunes of the central Great Plains, especially the megabarchans and large barchanoid ridges of the Nebraska Sand Hills, provide dramatic evidence of late Quaternary environmental change. Episodic Holocene dune activity in this region is now well-documented, but Late Pleistocene dune mobility has remained poorly documented, despite early interpretations of the Sand Hills dunes as Pleistocene relicts. New optically stimulated luminescence (OSL) ages from drill cores and outcrops provide evidence of Late Pleistocene dune activity at sites distributed across the central Great Plains. In addition, Late Pleistocene eolian sands deposited at 20-25 ka are interbedded with loess south of the Sand Hills. Several of the large dunes sampled in the Sand Hills clearly contain a substantial core of Late Pleistocene sand; thus, they had developed by the Late Pleistocene and were fully mobile at that time, although substantial sand deposition and extensive longitudinal dune construction occurred during the Holocene. Many of the Late Pleistocene OSL ages fall between 17 and 14 ka, but it is likely that these ages represent only the later part of a longer period of dune construction and migration. At several sites, significant Late Pleistocene or Holocene large-dune migration also probably occurred after the time represented by the Pleistocene OSL ages. Sedimentary structures in Late Pleistocene eolian sand and the forms of large dunes potentially constructed in the Late Pleistocene both indicate sand transport dominated by northerly to westerly winds, consistent with Late Pleistocene loess transport directions. Numerical modeling of the climate of the Last Glacial Maximum has often yielded mean monthly surface winds southwest of the Laurentide Ice Sheet that are consistent with this geologic evidence, despite strengthened anticyclonic circulation over the ice sheet. Mobility of large dunes during the Late Pleistocene on the central Great Plains may have been the result of

  11. Late Pleistocene dune activity in the central Great Plains, USA (United States)

    Mason, J.A.; Swinehart, J.B.; Hanson, P.R.; Loope, D.B.; Goble, R.J.; Miao, X.; Schmeisser, R.L.


    Stabilized dunes of the central Great Plains, especially the megabarchans and large barchanoid ridges of the Nebraska Sand Hills, provide dramatic evidence of late Quaternary environmental change. Episodic Holocene dune activity in this region is now well-documented, but Late Pleistocene dune mobility has remained poorly documented, despite early interpretations of the Sand Hills dunes as Pleistocene relicts. New optically stimulated luminescence (OSL) ages from drill cores and outcrops provide evidence of Late Pleistocene dune activity at sites distributed across the central Great Plains. In addition, Late Pleistocene eolian sands deposited at 20-25 ka are interbedded with loess south of the Sand Hills. Several of the large dunes sampled in the Sand Hills clearly contain a substantial core of Late Pleistocene sand; thus, they had developed by the Late Pleistocene and were fully mobile at that time, although substantial sand deposition and extensive longitudinal dune construction occurred during the Holocene. Many of the Late Pleistocene OSL ages fall between 17 and 14 ka, but it is likely that these ages represent only the later part of a longer period of dune construction and migration. At several sites, significant Late Pleistocene or Holocene large-dune migration also probably occurred after the time represented by the Pleistocene OSL ages. Sedimentary structures in Late Pleistocene eolian sand and the forms of large dunes potentially constructed in the Late Pleistocene both indicate sand transport dominated by northerly to westerly winds, consistent with Late Pleistocene loess transport directions. Numerical modeling of the climate of the Last Glacial Maximum has often yielded mean monthly surface winds southwest of the Laurentide Ice Sheet that are consistent with this geologic evidence, despite strengthened anticyclonic circulation over the ice sheet. Mobility of large dunes during the Late Pleistocene on the central Great Plains may have been the result of

  12. Comparative analyses of the cholinergic locus of ChAT and VAChT and its expression in the silkworm Bombyx mori. (United States)

    Banzai, Kota; Adachi, Takeshi; Izumi, Susumu


    The cholinergic locus, which encodes choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT), is specifically expressed in cholinergic neurons, maintaining the cholinergic phenotype. The organization of the locus is conserved in Bilateria. Here we examined the structure of cholinergic locus and cDNA coding for ChAT and VAChT in the silkworm, Bombyx mori. The B. mori ChAT (BmChAT) cDNA encodes a deduced polypeptide including a putative choline/carnitine O-acyltransferase domain and a conserved His residue required for catalysis. The B. mori VAChT (BmVAChT) cDNA encodes a polypeptide including a putative major facilitator superfamily domain and 10 putative transmembrane domains. BmChAT and BmVAChT cDNAs share the 5'-region corresponding to the first and second exon of cholinergic locus. Polymerase chain reaction analyses revealed that BmChAT and BmVAChT mRNAs were specifically expressed in the brain and segmental ganglia. The expression of BmChAT was detected 3 days after oviposition. The expression level was almost constant during the larval stage, decreased in the early pupal stage, and increased toward eclosion. The average ratios of BmChAT mRNA to BmVAChT mRNA in brain-subesophageal ganglion complexes were 0.54±0.10 in the larvae and 1.92±0.11 in adults. In addition, we examined promoter activity of the cholinergic locus and localization of cholinergic neurons, using a baculovirus-mediated gene transfer system. The promoter sequence, located 2kb upstream from the start of transcription, was essential for cholinergic neuron-specific gene õexpression. Cholinergic neurons were found in several regions of the brain and segmental ganglia in the larvae and pharate adults. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Cholinergic vasodilator mechanism in human fingers

    Energy Technology Data Exchange (ETDEWEB)

    Coffman, J.D.; Cohen, R.A.


    The effect of a cholinergic agonist and antagonist on finger blood flow (FBF) was studied in 10 normal subjects. Total finger blood flow was measured by venous occlusion, air plethysmography, and capillary blood flow (FCF) by the disappearance rate of a radio-isotope from a fingertip injection. Methacholine in doses of 10-80 was given by constant infusion via a brachial artery catheter. Average FBF and vascular resistance were not significantly affected. However, the half time (t/sub 1/2/) of the disappearance rate decreased from 50.8 +/- 13.4 to 11.1 +/- 1.5 min; a decrease occurred in all subjects. In seven subjects, atropine (0.2 mg) had no affect alone but inhibited the effect of methacholine on FCF and prevented the redness and sweating of the forearm and hand that occurs with this agent. This study demonstrates a muscarinic cholinergic vasodilator mechanism in the fingertip that uniquely increase capillary blood flow.

  14. Forebrain Cholinergic Dysfunction and Systemic and Brain Inflammation in Murine Sepsis Survivors

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    Nahla Zaghloul


    Full Text Available Sepsis, a complex disorder characterized by immune, metabolic, and neurological dysregulation, is the number one killer in the intensive care unit. Mortality remains alarmingly high even in among sepsis survivors discharged from the hospital. There is no clear strategy for managing this lethal chronic sepsis illness, which is associated with severe functional disabilities and cognitive deterioration. Providing insight into the underlying pathophysiology is desperately needed to direct new therapeutic approaches. Previous studies have shown that brain cholinergic signaling importantly regulates cognition and inflammation. Here, we studied the relationship between peripheral immunometabolic alterations and brain cholinergic and inflammatory states in mouse survivors of cecal ligation and puncture (CLP-induced sepsis. Within 6 days, CLP resulted in 50% mortality vs. 100% survival in sham-operated controls. As compared to sham controls, sepsis survivors had significantly lower body weight, higher serum TNF, interleukin (IL-1β, IL-6, CXCL1, IL-10, and HMGB1 levels, a lower TNF response to LPS challenge, and lower serum insulin, leptin, and plasminogen activator inhibitor-1 levels on day 14. In the basal forebrain of mouse sepsis survivors, the number of cholinergic [choline acetyltransferase (ChAT-positive] neurons was significantly reduced. In the hippocampus and the cortex of mouse sepsis survivors, the activity of acetylcholinesterase (AChE, the enzyme that degrades acetylcholine, as well as the expression of its encoding gene were significantly increased. In addition, the expression of the gene encoding the M1 muscarinic acetylcholine receptor was decreased in the hippocampus. In parallel with these forebrain cholinergic alterations, microglial activation (in the cortex and increased Il1b and Il6 gene expression (in the cortex, and Il1b gene expression (in the hippocampus were observed in mouse sepsis survivors. Furthermore, microglial

  15. The detailed nature of active central cluster galaxies (United States)

    Loubser, S. I.; Soechting, I. K.


    We present detailed integral field unit observations of the central few kiloparsecs of the ionized nebulae surrounding four active central cluster galaxies (CCGs) in cooling flow clusters (Abell 0496, 0780, 1644 and 2052). Our sample consists of CCGs with Hα filaments, and have existing data from the X-ray regime available. Here, we present the detailed optical emission-line (and simultaneous absorption line) data over a broad wavelength range to probe the dominant ionization processes, excitation sources, morphology and kinematics of the hot gas (as well as the morphology and kinematics of the stars). This, combined with the other multiwavelength data, will form a complete view of the different phases (hot and cold gas and stars) and how they interact in the processes of star formation and feedback detected in central galaxies in cooling flow clusters, as well as the influence of the host cluster. We derive the optical dust extinction maps of the four nebulae. We also derive a range of different kinematic properties, given the small sample size. For Abell 0496 and 0780, we find that the stars and gas are kinematically decoupled, and in the case of Abell 1644 we find that these components are aligned. For Abell 2052, we find that the gaseous components show rotation even though no rotation is apparent in the stellar components. To the degree that our spatial resolution reveals, it appears that all the optical forbidden and hydrogen recombination lines originate in the same gas for all the galaxies. Based on optical diagnostic ratios ([O III] λ5007/Hβ against [N II] λ6584/Hα, [S II] λλ6717, 6731/Hα and [O I] λ6300/Hα), all galaxies show extended low-ionization nuclear emission-line region emission, but that at least one has significant Seyfert emission areas, and at least one other has significant H II-like emission line ratios for many pixels. We also show that the hardness of the ionizing continuum do not decrease with galactocentric distance within our

  16. Central nervous system activity of Illicium verum fruit extracts. (United States)

    Chouksey, Divya; Upmanyu, Neeraj; Pawar, R S


    To research the acute toxicity of Illicium verum (I. verum) fruit extracts and its action on central nervous system. The TLC and HPTLC techniques were used as fingerprints to determine the chemical components present in I. verum. Male albino rats and mice were utilized for study. The powdered material was successively extracted with n-hexane, ethyl acetate and methanol using a Soxhlet extractor. Acute toxicity studies were performed as per OECD guidelines. The CNS activity was evaluated on parameters of general behavior, sleeping pattern, locomotor activity, anxiety and myocoordination activity. The animals were trained for seven days prior to experiments and the divided into five groups with six animals in each. The drug was administered by intraperitoneal route according to body weight. The dosing was done as prescribed in each protocol. Toxicity studies reported 2 000 mg/kg as toxicological dose and 1/10 of the same dose was taken as therapeutic dose Intraperitoneal injection of all extracts at dose of 200 mg prolonged phenobarbitone induced sleeping time, produced alteration in general behavior pattern, reduced locomotor activity and produced anxiolytic effects but the extracts do not significantly alter muscles coordination activity. The three extracts of I. verum at the dose of 200 mg, methanol extract was found to produce more prominent effects, then hexane and ethylacetate extracts. The observation suggested that the extracts of I. verum possess potent CNS depressant action and anxiolytic effect without interfering with motor coordination. Copyright © 2013 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

  17. Decrease of a Current Mediated by Kv1.3 Channels Causes Striatal Cholinergic Interneuron Hyperexcitability in Experimental Parkinsonism

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    Cecilia Tubert


    Full Text Available The mechanism underlying a hypercholinergic state in Parkinson’s disease (PD remains uncertain. Here, we show that disruption of the Kv1 channel-mediated function causes hyperexcitability of striatal cholinergic interneurons in a mouse model of PD. Specifically, our data reveal that Kv1 channels containing Kv1.3 subunits contribute significantly to the orphan potassium current known as IsAHP in striatal cholinergic interneurons. Typically, this Kv1 current provides negative feedback to depolarization that limits burst firing and slows the tonic activity of cholinergic interneurons. However, such inhibitory control of cholinergic interneuron excitability by Kv1.3-mediated current is markedly diminished in the parkinsonian striatum, suggesting that targeting Kv1.3 subunits and their regulatory pathways may have therapeutic potential in PD therapy. These studies reveal unexpected roles of Kv1.3 subunit-containing channels in the regulation of firing patterns of striatal cholinergic interneurons, which were thought to be largely dependent on KCa channels.

  18. Active tectonics of the Qom region, Central Iran (United States)

    Hollingsworth, J.; Fattahi, M.; Jackson, J. A.; Talebian, M.; Nazari, H.; Bahroudi, A.


    balanced cross section indicates ~18% shortening (1.5 km) in a period bracketed by the Upper Red Fmtn (5.3 Ma), yielding shortening rates of 0.1-0.3 mm/yr. The right-lateral Kashan fault lies SE of the Qom region, and appears to be kinematically linked to the thrust faults around Qom, which probably represent thrust terminations. Historical earthquakes have occurred on the Kashan fault, and clear evidence for recent movement is seen in the Quaternary geomorphology. Reconstruction of the geology across the Kashan fault indicates ~45 km of total right-lateral motion, which suggests it has played a significant role in the accommodation of regional shortening. Late Cenozoic estimates of N-S shortening in the Qom region are 0.03-0.5 mm/yr. The difference in GPS velocities north and south of Qom indicates 1.1±1.9 mm/yr shortening across this region. This study suggests that Central Iran plays an important role in accommodating Arabia-Eurasia shortening over Quaternary to geological timescales. Efforts should be made to better constrain the seismic hazard posed by active faults to large populations in the Central Iran region.

  19. Muscarinic cholinergic receptors and the canine model of narcolepsy. (United States)

    Kilduff, T S; Bowersox, S S; Kaitin, K I; Baker, T L; Ciaranello, R D; Dement, W C


    The role of the muscarinic cholinergic receptor in narcolepsy was examined using radioligand binding to various brain regions of normal and genetically narcoleptic Doberman pinschers. In this multi-litter study, a previous report of a proliferation of muscarinic cholinergic receptors in the brainstem was confirmed, and the concentration of the M2 receptor subtype, in particular, was elevated. This up-regulation of brainstem cholinergic receptors suggests a problem with release of acetylcholine, which, together with previous reports of an impairment of dopamine release, may be indicative of a fundamental membrane problem in narcolepsy.

  20. Pure Cold-Induced Cholinergic Urticaria in a Pediatric Patient

    Directory of Open Access Journals (Sweden)

    Tina Abraham


    Full Text Available Cold urticaria and cholinergic urticaria are two distinct entities. The presentation of exclusive cold-induced cholinergic urticaria is very rare. The patient described herein had experienced urticaria in the exclusive setting of exercising in a cold environment. Urticarial testing including laboratory and in-office testing was all negative. The patient has prevented urticaria symptoms with oral antihistamine therapy. Pure cold-induced cholinergic urticaria is rarely described in literature. This form of urticaria has yet to be described in a pediatric patient.

  1. Basic and modern concepts on cholinergic receptor: A review

    Directory of Open Access Journals (Sweden)

    Prashant Tiwari


    Full Text Available Cholinergic system is an important system and a branch of the autonomic nervous system which plays an important role in memory, digestion, control of heart beat, blood pressure, movement and many other functions. This article serves as both structural and functional sources of information regarding cholinergic receptors and provides a detailed understanding of the determinants governing specificity of muscarinic and nicotinic receptor to researchers. The study helps to give overall information about the fundamentals of the cholinergic system, its receptors and ongoing research in this field.

  2. Cholinergic interactions between donepezil and prucalopride in human colon: potential to treat severe intestinal dysmotility. (United States)

    Broad, J; Kung, V W S; Boundouki, G; Aziz, Q; De Maeyer, J H; Knowles, C H; Sanger, G J


    Cholinesterase inhibitors such as neostigmine are used for acute colonic pseudo-obstruction, but cardio-bronchial side-effects limit use. To minimize side-effects, lower doses could be combined with a 5-HT4 receptor agonist, which also facilitates intestinal cholinergic activity. However, safety concerns, especially in the elderly, require drugs with good selectivity of action. These include the AChE inhibitor donepezil (used for Alzheimer's disease, with reduced cardio-bronchial liability) and prucalopride, the first selective, clinically available 5-HT4 receptor agonist. This study examined their individual and potential synergistic activities in human colon. Neuronally mediated muscle contractions and relaxations of human colon were evoked by electrical field stimulation (EFS) and defined phenotypically as cholinergic, nitrergic or tachykinergic using pharmacological tools; the effects of drugs were determined as changes in 'area under the curve'. Prucalopride increased cholinergically mediated contractions (EC50 855 nM; 33% maximum increase), consistent with its ability to stimulate intestinal motility; donepezil (477%) and neostigmine (2326%) had greater efficacy. Concentrations of donepezil (30-100 nM) found in venous plasma after therapeutic doses had minimal ability to enhance cholinergic activity. However, donepezil (30 nM) together with prucalopride (3, 10 μM) markedly increased EFS-evoked contractions compared with prucalopride alone (P = 0.04). For example, the increases observed with donepezil and prucalopride 10 μM together or alone were, respectively, 105 ± 35%, 4 ± 6% and 35 ± 21% (n = 3-7, each concentration). Potential synergy between prucalopride and donepezil activity calls for exploration of this combination as a safer, more effective treatment of colonic pseudo-obstruction. © 2013 The British Pharmacological Society.

  3. Effects of acute exposure to chlorpyrifos on cholinergic and non-cholinergic targets in normal and high-fat fed male C57BL/6J mice. (United States)

    Kondakala, Sandeep; Lee, Jung Hwa; Ross, Matthew K; Howell, George E


    The prevalence of obesity is increasing at an alarming rate in the United States with 36.5% of adults being classified as obese. Compared to normal individuals, obese individuals have noted pathophysiological alterations which may alter the toxicokinetics of xenobiotics and therefore alter their toxicities. However, the effects of obesity on the toxicity of many widely utilized pesticides has not been established. Therefore, the present study was designed to determine if the obese phenotype altered the toxicity of the most widely used organophosphate (OP) insecticide, chlorpyrifos (CPS). Male C57BL/6J mice were fed normal or high-fat diet for 4weeks and administered a single dose of vehicle or CPS (2.0mg/kg; oral gavage) to assess cholinergic (acetylcholinesterase activities) and non-cholinergic (carboxylesterase and endocannabinoid hydrolysis) endpoints. Exposure to CPS significantly decreased red blood cell acetylcholinesterase (AChE) activity, but not brain AChE activity, in both diet groups. Further, CPS exposure decreased hepatic carboxylesterase activity and hepatic hydrolysis of a major endocannabinoid, anandamide, in a diet-dependent manner with high-fat diet fed animals being more sensitive to CPS-mediated inhibition. These in vivo studies were corroborated by in vitro studies using rat primary hepatocytes, which demonstrated that fatty acid amide hydrolase and CES activities were more sensitive to CPS-mediated inhibition than 2-arachidonoylglycerol hydrolase activity. These data demonstrate hepatic CES and FAAH activities in high-fat diet fed mice were more potently inhibited than those in normal diet fed mice following CPS exposure, which suggests that the obese phenotype may exacerbate some of the non-cholinergic effects of CPS exposure. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Biospeleological activities in Central Europe – a status report

    Directory of Open Access Journals (Sweden)

    Dieter Weber


    Full Text Available Catalogues of cave fauna from Belgium, Switzerland, Austria, Germany (Swabian Alb, Franconian Alb, Westfalia, Hesse, Harz, Rhenish Palatinate and Saarland, and Luxembourg are available. Several activities deal with public relations, education, and training: the cave animal of the year, a camp for young cavers, the day nature, and the biospeleological workgroup. The German Barcoding of Life is a project which aims to obtain CO1 barcodes from every species in Germany with a sub-project on cave fauna. Special projects deal with Bythiospeum, niphargids, diplurans, sphaerocerids, and the biodiversity and ecology of cave invertebrates in the Central European Uplands. Zusammenfassung Es gibt Höhlenfaunenkataloge von Belgien, der Schweiz, Österreich, Deutschland (Schwäbische Alb, Fränkische Alb, Westfalen, Hessen, Harz und Rheinland-Pfalz/Saarland und Luxemburg. Verschiedene Aktivitäten befassen sich mit Öffentlichkeitsarbeit und Schulungen; Das Höhlentier des Jahres, ein Trainingslager für junge Höhlenforscher, der Tag der Natur und eine biospeläologische Arbeitsgruppe. Das Projekt „German Barcoding of Life“ versucht CO1-Barcodes aller deutschen Arten zu erstellen. Es hat ein Unterprojekt zur Höhlenfauna. Tiergruppenspezifische Projekte behandeln Bythiospeum, Niphargen, Dipluren, Sphaeroceriden und Biodiversität und Ökologie von Höhlenevertebraten der zentraleuropäischen Mittelgebirge.

  5. Functional Bowel Disorders Are Associated with a Central Immune Activation

    Directory of Open Access Journals (Sweden)

    Per G. Farup


    Full Text Available Background. Subjects with depression and unexplained neurological symptoms have a high prevalence of gastrointestinal comorbidity probably related to the brain-gut communication. This study explored associations between functional gastrointestinal disorders (FGID and inflammatory markers in subjects with these disorders. Methods. The FGID, including irritable bowel syndrome (IBS, were classified according to the Rome III criteria, and degree of symptoms was assessed with IBS symptom severity score (IBS-SSS. A range of interleukins (IL, chemokines and growth factors, tryptophan, and kynurenine were analysed in serum and the cerebrospinal fluid (CSF, and short-chain fatty acids (SCFA were analysed in the faeces. The results are reported as partial correlation (pc and p values. Results. Sixty-six subjects were included. IBS was associated with high levels of tryptophan (p=0.048 and kynurenine (p=0.019 and low level of IL-10 (p=0.047 in the CSF. IBS-SSS was associated with high tumor necrosis factor and low IL-10 in the CSF; pc=0.341 and p=0.009 and pc=−0.299 and p=0.023, respectively. Propionic minus butyric acid in faeces was negatively associated with IL-10 in the CSF (pc=−0.416, p=0.005. Conclusions. FGID were associated with a proinflammatory immune activation in the central nervous system and a disturbed tryptophan metabolism that could have been mediated by the faecal microbiota.

  6. Vagal-immune interactions involved in cholinergic anti-inflammatory pathway. (United States)

    Zila, I; Mokra, D; Kopincova, J; Kolomaznik, M; Javorka, M; Calkovska, A


    Inflammation and other immune responses are involved in the variety of diseases and disorders. The acute response to endotoxemia includes activation of innate immune mechanisms as well as changes in autonomic nervous activity. The autonomic nervous system and the inflammatory response are intimately linked and sympathetic and vagal nerves are thought to have anti-inflammation functions. The basic functional circuit between vagus nerve and inflammatory response was identified and the neuroimmunomodulation loop was called cholinergic anti-inflammatory pathway. Unique function of vagus nerve in the anti-inflammatory reflex arc was found in many experimental and pre-clinical studies. They brought evidence on the cholinergic signaling interacting with systemic and local inflammation, particularly suppressing immune cells function. Pharmacological/electrical modulation of vagal activity suppressed TNF-alpha and other proinflammatory cytokines production and had beneficial therapeutic effects. Many questions related to mapping, linking and targeting of vagal-immune interactions have been elucidated and brought understanding of its basic physiology and provided the initial support for development of Tracey´s inflammatory reflex. This review summarizes and critically assesses the current knowledge defining cholinergic anti-inflammatory pathway with main focus on studies employing an experimental approach and emphasizes the potential of modulation of vagally-mediated anti-inflammatory pathway in the treatment strategies.

  7. Right Cervical Vagotomy Aggravates Viral Myocarditis in Mice Via the Cholinergic Anti-inflammatory Pathway. (United States)

    Li-Sha, Ge; Xing-Xing, Chen; Lian-Pin, Wu; De-Pu, Zhou; Xiao-Wei, Li; Jia-Feng, Lin; Yue-Chun, Li


    The autonomic nervous system dysfunction with increased sympathetic activity and withdrawal of vagal activity may play an important role in the pathogenesis of viral myocarditis. The vagus nerve can modulate the immune response and control inflammation through a 'cholinergic anti-inflammatory pathway' dependent on the α7-nicotinic acetylcholine receptor (α7nAChR). Although the role of β-adrenergic stimulation on viral myocarditis has been investigated in our pervious studies, the direct effect of vagal tone in this setting has not been yet studied. Therefore, in the present study, we investigated the effects of cervical vagotomy in a murine model of viral myocarditis. In a coxsackievirus B3 murine myocarditis model (Balb/c), effects of right cervical vagotomy and nAChR agonist nicotine on echocardiography, myocardial histopathology, viral RNA, and proinflammatory cytokine levels were studied. We found that right cervical vagotomy inhibited the cholinergic anti-inflammatory pathway, aggravated myocardial lesions, up-regulated the expression of TNF-α, IL-1β, and IL-6, and worsened the impaired left ventricular function in murine viral myocarditis, and these changes were reversed by co-treatment with nicotine by activating the cholinergic anti-inflammatory pathway. These results indicate that vagal nerve plays an important role in mediating the anti-inflammatory effect in viral myocarditis, and that cholinergic stimulation with nicotine also plays its peripheral anti-inflammatory role relying on α7nAChR, without requirement for the integrity of vagal nerve in the model. The findings suggest that vagus nerve stimulation mediated inhibition of the inflammatory processes likely provide important benefits in myocarditis treatment.

  8. Cholinergic Changes in Aging and Alzheimer Disease: An [18F]-F-A-85380 Exploratory PET Study. (United States)

    Lagarde, Julien; Sarazin, Marie; Chauviré, Valérie; Stankoff, Bruno; Kas, Aurélie; Lacomblez, Lucette; Peyronneau, Marie-Anne; Bottlaender, Michel


    The central cholinergic system undergoes changes during the physiological process of aging and the pathologic process of Alzheimer disease (AD). We aimed to analyze the impairment of cholinergic pathways by positron emission tomography using the [F]-F-A-85380 (FA85) tracer, which has a high affinity for nicotinic acetylcholine receptors (nAChRs). Aging was assessed by comparing young (n=10) and elderly (n=4) healthy subjects, and the pathologic process of AD was assessed by comparing elderly controls and age-matched AD patients (n=8). We measured an index of the nAChR density in the cortex and the hippocampus and the total number of FA85-binding sites by taking into account the volume changes. In AD, the nAChR density was preserved in both the cortex and hippocampus. The total estimated number of FA85-binding sites was decreased in the hippocampus despite the lack of a significant loss of volume, whereas the difference in the cortex did not withstand the adjustment for multiple comparisons despite a significant loss of volume. In contrast, in aging, the estimated number of FA85-binding sites was decreased in both the cortex and hippocampus with significant hippocampal atrophy. These findings suggest a preferential impairment of cholinergic pathways in the cortex during aging, whereas in AD, this damage predominated in the hippocampus with a potential compensatory cholinergic effect in the cortex.

  9. Demodex canis regulates cholinergic system mediated immunosuppressive pathways in canine demodicosis. (United States)

    Kumari, P; Nigam, R; Singh, A; Nakade, U P; Sharma, A; Garg, S K; Singh, S K


    Demodex canis infestation in dogs remains one of the main challenges in veterinary dermatology. The exact pathogenesis of canine demodicosis is unknown but an aberration in immune status is considered very significant. No studies have underpinned the nexus between induction of demodicosis and neural immunosuppressive pathways so far. We have evaluated the involvement of cholinergic pathways in association with cytokines regulation as an insight into the immuno-pathogenesis of canine demodicosis in the present study. Remarkable elevations in circulatory immunosuppressive cytokine interleukin-10 and cholinesterase activity were observed in dogs with demodicosis. Simultaneously, remarkable reduction in circulatory pro-inflammatory cytokine tumour necrosis factor-alpha level was observed in dogs with demodicosis. Findings of the present study evidently suggest that Demodex mites might be affecting the cholinergic pathways to induce immunosuppression in their host and then proliferate incessantly in skin microenvironment to cause demodicosis.

  10. Functional role of acetylcholine and the expression of cholinergic receptors and components in osteoblasts. (United States)

    Sato, Tsuyoshi; Abe, Takahiro; Chida, Dai; Nakamoto, Norimichi; Hori, Naoko; Kokabu, Shoichiro; Sakata, Yasuaki; Tomaru, Yasuhisa; Iwata, Takanori; Usui, Michihiko; Aiko, Katsuya; Yoda, Tetsuya


    Recent studies have indicated that acetylcholine (ACh) plays a vital role in various tissues, while the role of ACh in bone metabolism remains unclear. Here we demonstrated that ACh induced cell proliferation and reduced alkaline phosphatase (ALP) activity via nicotinic (nAChRs) and muscarinic acetylcholine receptors (mAChRs) in osteoblasts. We detected mRNA expression of several nAChRs and mAChRs. Furthermore, we showed that cholinergic components were up-regulated and subunits/subtypes of acetylcholine receptors altered during osteoblast differentiation. To our knowledge, this is the first report demonstrating that osteoblasts express specific acetylcholine receptors and cholinergic components and that ACh plays a possible role in regulating the proliferation and differentiation of osteoblasts. Crown Copyright 2010. Published by Elsevier B.V. All rights reserved.

  11. Memory-Relevant Mushroom Body Output Synapses Are Cholinergic. (United States)

    Barnstedt, Oliver; Owald, David; Felsenberg, Johannes; Brain, Ruth; Moszynski, John-Paul; Talbot, Clifford B; Perrat, Paola N; Waddell, Scott


    Memories are stored in the fan-out fan-in neural architectures of the mammalian cerebellum and hippocampus and the insect mushroom bodies. However, whereas key plasticity occurs at glutamatergic synapses in mammals, the neurochemistry of the memory-storing mushroom body Kenyon cell output synapses is unknown. Here we demonstrate a role for acetylcholine (ACh) in Drosophila. Kenyon cells express the ACh-processing proteins ChAT and VAChT, and reducing their expression impairs learned olfactory-driven behavior. Local ACh application, or direct Kenyon cell activation, evokes activity in mushroom body output neurons (MBONs). MBON activation depends on VAChT expression in Kenyon cells and is blocked by ACh receptor antagonism. Furthermore, reducing nicotinic ACh receptor subunit expression in MBONs compromises odor-evoked activation and redirects odor-driven behavior. Lastly, peptidergic corelease enhances ACh-evoked responses in MBONs, suggesting an interaction between the fast- and slow-acting transmitters. Therefore, olfactory memories in Drosophila are likely stored as plasticity of cholinergic synapses. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  12. Role of brainstem TRH/TRH-R1 receptors in the vagal gastric cholinergic response to various stimuli including sham-feeding. (United States)

    Taché, Y; Yang, H; Miampamba, M; Martinez, V; Yuan, P Q


    Pavlov's pioneering work established that sham-feeding induced by sight or smell of food or feeding in dogs with permanent esophagostomy stimulates gastric acid secretion through vagal pathways. Brain circuitries and transmitters involved in the central vagal regulation of gastric function have recently been unraveled. Neurons in the dorsal vagal complex including the dorsal motor nucleus of the vagus (DMN) express thyrotropin-releasing hormone (TRH) receptor and are innervated by TRH fibers originating from TRH synthesizing neurons in the raphe pallidus, raphe obscurus and the parapyramidal regions. TRH injected into the DMN or cisterna magna increases the firing of DMN neurons and gastric vagal efferent discharge, activates cholinergic neurons in gastric submucosal and myenteric plexuses, and induces a vagal-dependent, atropine-sensitive stimulation of gastric secretory (acid, pepsin) and motor functions. TRH antibody or TRH-R1 receptor oligodeoxynucleotide antisense pretreatment in the cisterna magna or DMN abolished vagal-dependent gastric secretory and motor responses to sham-feeding, 2-deoxy-D-glucose, cold exposure and chemical activation of cell bodies in medullary raphe nuclei. TRH excitatory action in the DMN is potentiated by co-released prepro-TRH-(160-169) flanking peptide, Ps4 and 5-HT, and inhibited by a number of peptides involved in the stress/immune response and inhibition of food-intake. These neuroanatomical, electrophysiological and neuropharmacological data are consistent with a physiological role of brainstem TRH in the central vagal stimulation of gastric myenteric cholinergic neurons in response to several vagal dependent stimuli including sham-feeding.

  13. Unraveling the mechanism of neuroprotection of curcumin in arsenic induced cholinergic dysfunctions in rats

    Energy Technology Data Exchange (ETDEWEB)

    Srivastava, Pranay [CSIR-Indian Institute of Toxicology Research, Post Box 80, MG Marg, Lucknow 226 001 (India); Yadav, Rajesh S. [CSIR-Indian Institute of Toxicology Research, Post Box 80, MG Marg, Lucknow 226 001 (India); Department of Crimnology and Forensic Science, Harisingh Gour University, Sagar 470 003 (India); Chandravanshi, Lalit P.; Shukla, Rajendra K.; Dhuriya, Yogesh K.; Chauhan, Lalit K.S. [CSIR-Indian Institute of Toxicology Research, Post Box 80, MG Marg, Lucknow 226 001 (India); Dwivedi, Hari N. [Babu Banarasi Das University, BBD City, Faizabad Road, Lucknow 227 015 (India); Pant, Aditiya B. [CSIR-Indian Institute of Toxicology Research, Post Box 80, MG Marg, Lucknow 226 001 (India); Khanna, Vinay K., E-mail: [CSIR-Indian Institute of Toxicology Research, Post Box 80, MG Marg, Lucknow 226 001 (India)


    Earlier, we found that arsenic induced cholinergic deficits in rat brain could be protected by curcumin. In continuation to this, the present study is focused to unravel the molecular mechanisms associated with the protective efficacy of curcumin in arsenic induced cholinergic deficits. Exposure to arsenic (20 mg/kg body weight, p.o) for 28 days in rats resulted to decrease the expression of CHRM2 receptor gene associated with mitochondrial dysfunctions as evident by decrease in the mitochondrial membrane potential, activity of mitochondrial complexes and enhanced apoptosis both in the frontal cortex and hippocampus in comparison to controls. The ultrastructural images of arsenic exposed rats, assessed by transmission electron microscope, exhibited loss of myelin sheath and distorted cristae in the mitochondria both in the frontal cortex and hippocampus as compared to controls. Simultaneous treatment with arsenic (20 mg/kg body weight, p.o) and curcumin (100 mg/kg body weight, p.o) for 28 days in rats was found to protect arsenic induced changes in the mitochondrial membrane potential and activity of mitochondrial complexes both in frontal cortex and hippocampus. Alterations in the expression of pro- and anti-apoptotic proteins and ultrastructural damage in the frontal cortex and hippocampus following arsenic exposure were also protected in rats simultaneously treated with arsenic and curcumin. The data of the present study reveal that curcumin could protect arsenic induced cholinergic deficits by modulating the expression of pro- and anti-apoptotic proteins in the brain. More interestingly, arsenic induced functional and ultrastructural changes in the brain mitochondria were also protected by curcumin. - Highlights: • Neuroprotective mechanism of curcumin in arsenic induced cholinergic deficits studied • Curcumin protected arsenic induced enhanced expression of stress markers in rat brain • Arsenic compromised mitochondrial electron transport chain protected

  14. Protective role of the cholinergic anti-inflammatory pathway in a mouse model of viral myocarditis.

    Directory of Open Access Journals (Sweden)

    Zheng Cheng

    Full Text Available Activation of the cholinergic anti-inflammatory pathway, which relies on the α7nAchR (alpha 7 nicotinic acetylcholine receptor, has been shown to decrease proinflammatory cytokines. This relieves inflammatory responses and improves the prognosis of patients with experimental sepsis, endotoxemia, ischemia/reperfusion injury, hemorrhagic shock, pancreatitis, arthritis and other inflammatory syndromes. However, whether the cholinergic anti-inflammatory pathway has an effect on acute viral myocarditis has not been investigated. Here, we studied the effects of the cholinergic anti-inflammatory pathway on acute viral myocarditis.In a coxsackievirus B3 murine myocarditis model (Balb/c, nicotine and methyllycaconitine were used to stimulate and block the cholinergic anti-inflammatory pathway, respectively. Relevant signal pathways were studied to compare their effects on myocarditis, survival rate, histopathological changes, ultrastructural changes, and cytokine levels. Nicotine treatments significantly improved survival rate, attenuated myocardial lesions, and downregulated the expression of TNF-α and IL-6. Methyllycaconitine decreased survival rate, aggravated myocardial lesions, and upregulated the expression of TNF-α and IL-6. In addition, levels of the signaling protein phosphorylated STAT3 were higher in the nicotine group and lower in the methyllycaconitine group compared with the untreated myocarditis group.These results show that nicotine protects mice from CVB3-induced viral myocarditis and that methyllycaconitine aggravates viral myocarditis in mice. Because nicotine is a α7nAchR agonist and methyllycaconitine is a α7nAchR antagonist, we conclude that α7nAchR activation increases the phosphorylation of STAT3, reduces the expression of TNF-α and IL-6, and, ultimately, alleviates viral myocarditis. We also conclude that blocking α7nAchR reduces the phosphorylation of STAT3, increases the expression of TNF-α and IL-6, aggravating viral

  15. Antidiarrhoeal Activity of Hydroethanolic Leaf Extract of Bryophyllum ...

    African Journals Online (AJOL)

    Conclusion: The results showed that the hydroethanolic leaf extract of Bryophyllum pinnatum possesses antidiarrhoeal activity possibly mediated by interaction with â adrenoceptor, muscarinic cholinergic receptor and nitric oxide pathway. Keywords: Bryophyllum pinnatum; diarrhoea; muscarinic cholinergic; nitrergic ...

  16. Statistical evaluation of the simulated convective activity over Central Greece (United States)

    Kartsios, Stergios; Kotsopoulos, Stylianos; Karacostas, Theodore S.; Tegoulias, Ioannis; Pytharoulis, Ioannis; Bampzelis, Dimitrios


    In the framework of the project DAPHNE (, the non-hydrostatic Weather Research and Forecasting model with the Advanced Research dynamic solver (WRF-ARW, version 3.5.1) is used to produce very high spatiotemporal resolution simulations of the convective activity over Thessaly plain and hence, enhancing our knowledge on the impact of high resolution elevation and land use data in the moist convection. The expecting results act as a precursor for the potential applicability of a planned precipitation enhancement program. The three model domains, covering Europe, the Mediterranean Sea and northern Africa (d01), the wider area of Greece (d02) and Thessaly region-central Greece (d03), are used at horizontal grid-spacings of 15km, 5km and 1km respectively. ECMWF operational analyses at 6-hourly intervals (0.25ox0.25o lat.-long.) are imported as initial and boundary conditions of the coarse domain, while in the vertical, 39 sigma levels (up to 50 hPa) are used, with increased resolution in the boundary layer. Microphysical processes are represented by WSM6 scheme, sub-grid scale convection by Kain-Fritsch scheme, longwave and shortwave radiation by RRTMG scheme, surface layer by Monin-Obukhov (MM5), boundary layer by Yonsei University and soil physics by NOAH Unified model. Six representative days with different upper-air synoptic circulation types are selected, while high resolution (3'') elevation data from the Shuttle Radar Topography Mission (SRTM - version 4) are inserted in the innermost domain (d03), along with the Corine Land Cover 2000 raster data (3''x3''). The aforementioned data sets are used in different configurations, in order to evaluate the impact of each one on the simulated convective activity in the vicinity of Thessaly region, using a grid of available meteorological stations in the area. For each selected day, four (4) sensitivity simulations are performed, setting a total number of 24 runs. Finally, the best configuration provides

  17. The effect of LRRK2 mutations on the cholinergic system in manifest and premanifest stages of Parkinson's disease: a cross-sectional PET study. (United States)

    Liu, Shu-Ying; Wile, Daryl J; Fu, Jessie Fanglu; Valerio, Jason; Shahinfard, Elham; McCormick, Siobhan; Mabrouk, Rostom; Vafai, Nasim; McKenzie, Jess; Neilson, Nicole; Perez-Soriano, Alexandra; Arena, Julieta E; Cherkasova, Mariya; Chan, Piu; Zhang, Jing; Zabetian, Cyrus P; Aasly, Jan O; Wszolek, Zbigniew K; McKeown, Martin J; Adam, Michael J; Ruth, Thomas J; Schulzer, Michael; Sossi, Vesna; Stoessl, A Jon


    Markers of neuroinflammation are increased in some patients with LRRK2 Parkinson's disease compared with individuals with idiopathic Parkinson's disease, suggesting possible differences in disease pathogenesis. Previous PET studies have suggested amplified dopamine turnover and preserved serotonergic innervation in LRRK2 mutation carriers. We postulated that patients with LRRK2 mutations might show abnormalities of central cholinergic activity, even before the diagnosis of Parkinson's disease. Between June, 2009, and December, 2015, we recruited participants from four movement disorder clinics in Canada, Norway, and the USA. Patients with Parkinson's disease were diagnosed by movement disorder neurologists on the basis of the UK Parkinson's Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. We used the PET tracer N- 11 C-methyl-piperidin-4-yl propionate to scan for acetylcholinesterase activity. The primary outcome measure was rate of acetylcholinesterase hydrolysis, calculated using the striatal input method. We compared acetylcholinesterase hydrolysis rates between groups using ANCOVA, with adjustment for age based on the results of linear regression analysis. We recruited 14 patients with LRRK2 Parkinson's disease, 16 LRRK2 mutation carriers without Parkinson's disease, eight patients with idiopathic Parkinson's disease, and 11 healthy controls. We noted significant between-group differences in rates of acetylcholinesterase hydrolysis in cortical regions (average cortex p=0·009, default mode network-related regions p=0·006, limbic network-related regions p=0·020) and the thalamus (p=0·008). LRRK2 mutation carriers without Parkinson's disease had increased acetylcholinesterase hydrolysis rates compared with healthy controls in the cortex (average cortex, p=0·046). Patients with LRRK2 Parkinson's disease had significantly higher acetylcholinesterase activity in some cortical regions (average cortex p=0

  18. Both central command and exercise pressor reflex activate cardiac sympathetic nerve activity in decerebrate cats. (United States)

    Tsuchimochi, Hirotsugu; Hayes, Shawn G; McCord, Jennifer L; Kaufman, Marc P


    Both static and dynamic exercise are known to increase cardiac pump function as well as arterial blood pressure. Feedforward control by central command and feedback control by the exercise pressor reflex are thought to be the neural mechanisms causing these effects during exercise. It remains unknown as to how each mechanism activates cardiac sympathetic nerve activity (CSNA) during exercise, especially at its onset. Thus we examined the response of CSNA to stimulation of the mesencephalic locomotor region (MLR, i.e., central command) and to static muscle contraction of the triceps surae muscles or stretch of the calcaneal tendon in decerebrate cats. We found that MLR stimulation immediately increased CSNA, which was followed by a gradual increase in heart rate, mean arterial pressure, and ventral root activity in a stimulus intensity-dependent manner. The latency of the increase in CSNA from the onset of MLR stimulation ranged from 67 to 387 ms. Both static contraction and tendon stretch also rapidly increased CSNA. Their latency from the development of tension in response to ventral root stimulation ranged from 78 to 670 ms. These findings suggest that both central command and the muscle mechanoreflex play a role in controlling cardiac sympathetic outflow at the onset of exercise.

  19. Traced on the Timeline: Discovery of Acetylcholine and the Components of the Human Cholinergic System in a Primitive Unicellular Eukaryote Acanthamoeba spp. (United States)

    Baig, Abdul Mannan; Rana, Zohaib; Tariq, Sumayya; Lalani, Salima; Ahmad, H R


    Acetylcholine (ACh) is the neurotransmitter of cholinergic signal transduction that affects the target cells via muscarinic (mAChR) and nicotinic (nAChR) cholinergic receptors embedded in the cell membrane. Of the cholinergic receptors that bind to ACh, the mAChRs execute several cognitive and metabolic functions in the human central nervous system (CNS). Very little is known about the origins and autocrine/paracrine roles of the ACh in primitive life forms. With the recent report of the evidence of an ACh binding mAChR1 like receptor in Acanthamoeba spp., it was tempting to investigate the origin and functional roles of cholinergic G-Protein coupled receptors (GPCRs) in the biology of eukaryotes. We inferred the presence of ACh, its synthetic, degradation system, and a signal transduction pathway in an approximately ∼2.0 billion year old primitive eukaryotic cell Acanthamoeba castellanii. Bioinformatics analysis, ligand binding prediction, and docking methods were used to establish the origins of enzymes involved in the synthesis and degradation of ACh. Notably, we provide evidence of the presence of ACh in A. castellanii by colorimetric analysis, which to date is the only report of its presence in this primitive unicellular eukaryote. We show the evidence for the presence of homology of evolutionary conserved key enzymes of the cholinergic system like choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) in A. castellanii spp., which were found to be near identical to their human counterparts. Tracing the origin, functions of ACh, and primeval mAChRs in primitive eukaryotic cells has the potential of uncovering covert cholinergic pathways that can be extended to humans in order to understand the states of cholinergic deficiency in neurodegenerative diseases (ND).

  20. Discharge profiles across the sleep-waking cycle of identified cholinergic, GABAergic, and glutamatergic neurons in the pontomesencephalic tegmentum of the rat. (United States)

    Boucetta, Soufiane; Cissé, Youssouf; Mainville, Lynda; Morales, Marisela; Jones, Barbara E


    Distributed within the laterodorsal tegmental and pedunculopontine tegmental nuclei (LDT and PPT), cholinergic neurons in the pontomesencephalic tegmentum have long been thought to play a critical role in stimulating cortical activation during waking (W) and paradoxical sleep (PS, also called REM sleep), yet also in promoting PS with muscle atonia. However, the discharge profile and thus precise roles of the cholinergic neurons have remained uncertain because they lie intermingled with GABAergic and glutamatergic neurons, which might also assume these roles. By applying juxtacellular recording and labeling in naturally sleeping-waking, head-fixed rats, we investigated the discharge profiles of histochemically identified cholinergic, GABAergic, and glutamatergic neurons in the LDT, SubLDT, and adjoining medial part of the PPT (MPPT) in relation to sleep-wake states, cortical activity, and muscle tone. We found that all cholinergic neurons were maximally active during W and PS in positive correlation with fast (γ) cortical activity, as "W/PS-max active neurons." Like cholinergic neurons, many GABAergic and glutamatergic neurons were also "W/PS-max active." Other GABAergic and glutamatergic neurons were "PS-max active," being minimally active during W and maximally active during PS in negative correlation with muscle tone. Conversely, some glutamatergic neurons were "W-max active," being maximally active during W and minimally active during PS in positive correlation with muscle tone. Through different discharge profiles, the cholinergic, GABAergic, and glutamatergic neurons of the LDT, SubLDT, and MPPT thus appear to play distinct roles in promoting W and PS with cortical activation, PS with muscle atonia, or W with muscle tone.

  1. Evidence for the tonic inhibition of spinal pain by nicotinic cholinergic transmission through primary afferents

    Directory of Open Access Journals (Sweden)

    Inoue Makoto


    Full Text Available Abstract Background We have proposed that nerve injury-specific loss of spinal tonic cholinergic inhibition may play a role in the analgesic effects of nicotinic acetylcholine receptor (nAChR agonists on neuropathic pain. However, the tonic cholinergic inhibition of pain remains to be well characterized. Results Here, we show that choline acetyltransferase (ChAT signals were localized not only in outer dorsal horn fibers (lamina I–III and motor neurons in the spinal cord, but also in the vast majority of neurons in the dorsal root ganglion (DRG. When mice were treated with an antisense oligodeoxynucleotide (AS-ODN against ChAT, which decreased ChAT signals in the dorsal horn and DRG, but not in motor neurons, they showed a significant decrease in nociceptive thresholds in paw pressure and thermal paw withdrawal tests. Furthermore, in a novel electrical stimulation-induced paw withdrawal (EPW test, the thresholds for stimulation through C-, Aδ- and Aβ-fibers were all decreased by AS-ODN-pretreatments. The administration of nicotine (10 nmol i.t. induced a recovery of the nociceptive thresholds, decreased by the AS-ODN, in the mechanical, thermal and EPW tests. However, nicotine had no effects in control mice or treated with a mismatch scramble (MS-ODN in all of these nociception tests. Conclusion These findings suggest that primary afferent cholinergic neurons produce tonic inhibition of spinal pain through nAChR activation, and that intrathecal administration of nicotine rescues the loss of tonic cholinergic inhibition.

  2. Urtica dioica leaves modulates muscarinic cholinergic system in the hippocampus of streptozotocin-induced diabetic mice. (United States)

    Patel, Sita Sharan; Parashar, Arun; Udayabanu, Malairaman


    Diabetes mellitus is a chronic metabolic disorder and has been associated with cognitive dysfunction. In our earlier study, chronic Urtica dioica (UD) treatment significantly ameliorated diabetes induced associative and spatial memory deficit in mice. The present study was designed to explore the effect of UD leaves extract on muscarinic cholinergic system, which has long been known to be involved in cognition. Streptozotocin (STZ) (50 mg/kg, i.p., consecutively for 5 days) was used to induce diabetes followed by treatment with UD extract (50 mg/kg, oral) or rosiglitazone (5 mg/kg, oral) for 8 weeks. STZ-induced diabetic mice showed significant reduction in hippocampal muscarinic acetylcholine receptor-1 and choline acetyltransferase expressions. Chronic diabetes significantly up-regulated the protein expression of acetylcholinesterase associated with oxidative stress in hippocampus. Besides, STZ-induced diabetic mice showed hypolocomotion with up-regulation of muscarinic acetylcholine receptor-4 expression in striatum. Chronic UD treatment significantly attenuated the cholinergic dysfunction and oxidative stress in the hippocampus of diabetic mice. UD had no effect on locomotor activity and muscarinic acetylcholine receptor-4 expression in striatum. In conclusion, UD leaves extract has potential to reverse diabetes mediated alteration in muscarinic cholinergic system in hippocampus and thereby improve memory functions.

  3. Nerve growth factor scales endocannabinoid signaling by regulating monoacylglycerol lipase turnover in developing cholinergic neurons. (United States)

    Keimpema, Erik; Tortoriello, Giuseppe; Alpár, Alán; Capsoni, Simona; Arisi, Ivan; Calvigioni, Daniela; Hu, Sherry Shu-Jung; Cattaneo, Antonino; Doherty, Patrick; Mackie, Kenneth; Harkany, Tibor


    Endocannabinoid, particularly 2-arachidonoyl glycerol (2-AG), signaling has recently emerged as a molecular determinant of neuronal migration and synapse formation during cortical development. However, the cell type specificity and molecular regulation of spatially and temporally confined morphogenic 2-AG signals remain unexplored. Here, we demonstrate that genetic and pharmacological manipulation of CB(1) cannabinoid receptors permanently alters cholinergic projection neuron identity and hippocampal innervation. We show that nerve growth factor (NGF), implicated in the morphogenesis and survival of cholinergic projection neurons, dose-dependently and coordinately regulates the molecular machinery for 2-AG signaling via tropomyosine kinase A receptors in vitro. In doing so, NGF limits the sorting of monoacylglycerol lipase (MGL), rate limiting 2-AG bioavailability, to proximal neurites, allowing cell-autonomous 2-AG signaling at CB(1) cannabinoid receptors to persist at atypical locations to induce superfluous neurite extension. We find that NGF controls MGL degradation in vitro and in vivo and identify the E3 ubiquitin ligase activity of breast cancer type 1 susceptibility protein (BRCA1) as a candidate facilitating MGL's elimination from motile neurite segments, including growth cones. BRCA1 inactivation by cisplatin or genetically can rescue and reposition MGL, arresting NGF-induced growth responses. These data indicate that NGF can orchestrate endocannabinoid signaling to promote cholinergic differentiation and implicate BRCA1 in determining neuronal morphology.

  4. [Effects of RNA on blood circulation and its adrenergic and cholinergic regulation]. (United States)

    Neshcheret, O P; Tkachuk, Z Iu; Moĭbenko, O O


    Experimental investigations of the impacts of microRNA agent nucleks on heart function, coronary and systemic circulation as well as on adrenergic and cholinergic mechanisms of cardiohaemodynamics regulation were performed on anaesthetized dogs. Bolus injection (0.1-100.0 mg) or prolonged infusion (2.5 mg/min) of nucleks into perfusion coronary artery blood stream induced coronary dilatation. Under the intracoronary infusion of nucleks we observed more pronounced coronary vasodilatation and left ventricle pressure elevation in response to adrenergic heart receptors stimulation by norepinephrine (0.05-5.0 mkg, intracoronary). Besides that the drug infusion into coronary blood stream promoted the acceleration of recovery processes of the studied cardiohaemnodynamic parameters after norepinephrine injection. After intracoronary infusion of nucleks the sensitivity of cholinergic receptors to the stimulation by acetylcholine (0.001-1.0 mkg, intracoronary) increased significantly. After NO-synthase blockade (L-NAME, infusion 2.0 mg/min, intracoronary) nucleks did not cause any effect on coronary vessels tone and heart activity both it did not change their adrenergic and cholinergic reactivity.

  5. Functional Consequences of Repeated Organophosphate Exposure: Potential Non-Cholinergic Mechanisms (United States)

    Terry, A.V.


    The class of chemicals known as the “organophosphates” (OPs) comprises many of the most common agricultural and commercial pesticides that are used worldwide as well as the highly toxic chemical warfare agents. The mechanism of the acute toxicity of OPs in both target and non-target organisms is primarily attributed to inhibitory actions on various forms of cholinesterase leading to excessive peripheral and central cholinergic activity. However, there is now substantial evidence that this canonical (cholinesterase-based) mechanism cannot alone account for the wide-variety of adverse consequences of OP exposure that have been described, especially those associated with repeated exposures to levels that produce no overt signs of acute toxicity. This type of exposure has been associated with prolonged impairments in attention, memory, and other domains of cognition, as well as chronic illnesses where these symptoms are manifested (e.g., Gulf War Illness, Alzheimer’s disease). Due to their highly reactive nature, it is not surprising that OPs might alter the function of a number of enzymes and proteins (in addition to cholinesterase). However, the wide variety of long-term neuropsychiatric symptoms that have been associated with OPs suggests that some basic or fundamental neuronal process was adversely affected during the exposure period. The purpose of this review is to discuss several non-cholinesterase targets of OPs that might affect such fundamental processes and includes cytoskeletal and motor proteins involved in axonal transport, neurotrophins and their receptors, and mitochondria (especially their morphology and movement in axons). Potential therapeutic implications of these OP interactions are also discussed. PMID:22465060

  6. Fishing activities on the Central Oyster Grounds 2006-2011

    NARCIS (Netherlands)

    Oostenbrugge, van J.A.E.; Bartelings, H.; Hamon, K.G.


    The Central Oyster Grounds are generally awarded for their ecological values. The area is especially important for benthos because of their species diversity and density, the total biomass, distribution of species, and the balanced composition of the benthic community' (Ministry of Economic affairs,

  7. Peripheral blood lymphocytes muscarinic cholinergic receptor subtypes in Alzheimer's disease: a marker of cholinergic dysfunction? (United States)

    Tayebati, S K; Amenta, F; Amici, S; El-Assouad, D; Gallai, V; Ricci, A; Parnetti, L


    Muscarinic M2-M5 muscarinic cholinergic receptors were investigated in peripheral blood lymphocytes of patients with mild cognitive impairment of the Alzheimer's type (MCIAT), probable Alzheimer's disease (AD) and probable vascular dementia (VaD). [3H]-N-methyl scopolamine (NMS) in the presence of muscarinic antagonists and Mamba venom to occlude different receptor subtypes was used as radioligand. Analysis of [3H]-NMS binding curves without receptor subtype assessment resulted in a slight decrease of receptor density in AD patients. Evaluation of receptor subtypes in MCIAT and AD patients revealed a decrease of M3 receptor by more than 50%, an increase of M4 receptor expression by about 20% and no changes of M2 or M5 receptors. The expression of M2-M5 receptors was unaltered in VaD patients. Strong positive and negative correlations respectively were found between the density of lymphocyte M3 and M4 receptors and MMSE score in both MCIAT (0.78 for M3 receptor and 0.80 for M4 receptor) and AD (0.82 for M3 receptor and 0.83 for M4 receptor) patients. These findings suggest that changes in the expression of peripheral blood lymphocyte M3 and M4 receptors in AD are related to the degree of cognitive impairment. Assessment of lymphocyte muscarinic receptor subtypes may contribute to characterization of cholinergic impairment in AD.

  8. Cholinergic modulation of cognitive processing: insights drawn from computational models

    Directory of Open Access Journals (Sweden)

    Ehren L Newman


    Full Text Available Acetylcholine plays an important role in cognitive function, as shown by pharmacological manipulations that impact working memory, attention, episodic memory and spatial memory function. Acetylcholine also shows striking modulatory influences on the cellular physiology of hippocampal and cortical neurons. Modeling of neural circuits provides a framework for understanding how the cognitive functions may arise from the influence of acetylcholine on neural and network dynamics. We review the influences of cholinergic manipulations on behavioral performance in working memory, attention, episodic memory and spatial memory tasks, the physiological effects of acetylcholine on neural and circuit dynamics, and the computational models that provide insight into the functional relationships between the physiology and behavior. Specifically, we discuss the important role of acetylcholine in governing mechanisms of active maintenance in working memory tasks and in regulating network dynamics important for effective processing of stimuli in attention and episodic memory tasks. We also propose that theta rhythm play a crucial role as an intermediary between the physiological influences of acetylcholine and behavior in episodic and spatial memory tasks. We conclude with a synthesis of the existing modeling work and highlight future directions that are likely to be rewarding given the existing state of the literature for both empiricists and modelers.

  9. Endogenous cholinergic neurotransmission contributes to behavioral sensitization to morphine.

    Directory of Open Access Journals (Sweden)

    Dusica Bajic

    Full Text Available Neuroplasticity in the mesolimbic dopaminergic system is critical for behavioral adaptations associated with opioid reward and addiction. These processes may be influenced by cholinergic transmission arising from the laterodorsal tegmental nucleus (LDTg, a main source of acetylcholine to mesolimbic dopaminergic neurons. To examine this possibility we asked if chronic systemic morphine administration affects expression of genes in ventral and ventrolateral periaqueductal gray at the level of the LDTg using rtPCR. Specifically, we examined gene expression changes in the area of interest using Neurotransmitters and Receptors PCR array between chronic morphine and saline control groups. Analysis suggested that chronic morphine administration led to changes in expression of genes associated, in part, with cholinergic neurotransmission. Furthermore, using a quantitative immunofluorescent technique, we found that chronic morphine treatment produced a significant increase in immunolabeling of the cholinergic marker (vesicular acetylcholine transporter in neurons of the LDTg. Finally, systemic administration of the nonselective and noncompetitive neuronal nicotinic antagonist mecamylamine (0.5 or 2 mg/kg dose-dependently blocked the expression, and to a lesser extent the development, of locomotor sensitization. The same treatment had no effect on acute morphine antinociception, antinociceptive tolerance or dependence to chronic morphine. Taken together, the results suggest that endogenous nicotinic cholinergic neurotransmission selectively contributes to behavioral sensitization to morphine and this process may, in part, involve cholinergic neurons within the LDTg.

  10. Selenium induces cholinergic motor neuron degeneration in Caenorhabditis elegans. (United States)

    Estevez, Annette O; Mueller, Catherine L; Morgan, Kathleen L; Szewczyk, Nathaniel J; Teece, Luke; Miranda-Vizuete, Antonio; Estevez, Miguel


    Selenium is an essential micronutrient required for cellular antioxidant systems, yet at higher doses it induces oxidative stress. Additionally, in vertebrates environmental exposures to toxic levels of selenium can cause paralysis and death. Here we show that selenium-induced oxidative stress leads to decreased cholinergic signaling and degeneration of cholinergic neurons required for movement and egg-laying in Caenorhabditis elegans. Exposure to high levels of selenium leads to proteolysis of a soluble muscle protein through mechanisms suppressible by two pharmacological agents, levamisole and aldicarb which enhance cholinergic signaling in muscle. In addition, animals with reduction-of-function mutations in genes encoding post-synaptic levamisole-sensitive acetylcholine receptor subunits or the vesicular acetylcholine transporter developed impaired forward movement faster during selenium-exposure than normal animals, again confirming that selenium reduces cholinergic signaling. Finally, the antioxidant reduced glutathione, inhibits selenium-induced reductions in egg-laying through a cellular protective mechanism dependent on the C. elegans glutaredoxin, GLRX-21. These studies provide evidence that the environmental toxicant selenium induces neurodegeneration of cholinergic neurons through depletion of glutathione, a mechanism linked to the neuropathology of Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. Copyright © 2012 Elsevier Inc. All rights reserved.

  11. The satiety signaling neuropeptide perisulfakinin inhibits the activity of central neurons promoting general activity

    Directory of Open Access Journals (Sweden)

    Dieter Wicher


    Full Text Available The metabolic state is one of the determinants of the general activity level. Satiety is related to resting or sleep whereas hunger correlates to wakefulness and activity. The counterpart to the mammalian satiety signal cholecystokinin (CCK in insects are the sulfakinins. The aim of this study was to resolve the mechanism by which the antifeedant activity of perisulfakinin (PSK in Periplaneta americana is mediated. We identified the sources of PSK which is used both as hormone and as paracrine messenger. PSK is found in the neurohemal organ of the brain and in nerve endings throughout the central nervous system. To correlate the distributions of PSK and its receptor (PSKR, we cloned the gene coding for PSKR and provide evidence for its expression within the nervous system. It occurs only in a few neurons, among them are the dorsal unpaired median (DUM neurons which release octopamine thereby regulating the general level of activity. Application of PSK to DUM neurons attenuated the spiking frequency (EC50=11pM due to reduction of a pacemaker Ca2+ current through cAMP-inhibited pTRPγ channels. PSK increased the intracellular cAMP level while decreasing the intracellular Ca2+ concentration in DUM neurons. Thus, the satiety signal conferred by PSK acts antagonistically to the hunger signal, provided by the adipokinetic hormone (AKH: PSK depresses the electrical activity of DUM neurons by inhibiting the pTRPγ channel that is activated by AKH under conditions of food shortage.

  12. Phosphoric acid activation of phosphorites of Central Kyzylkum


    Atanazar Seitnazarov; Shavkat Namazov; Boris Beglov


    The article presents a method of receiving the concentrated single phosphate fertilizers with the content of absorbable P2O5. The experiment made assumed processing of ordinary phosphate flour, washed concentrate, dust fraction, mineralized mass and thermoconcentrate of Central Kyzylkum’s phosphorites by incomplete norm of wet-process phosphoric acid. This process lasts 30 minutes at 75oC; the weight ratio of P2O5 in acid to P2O5 in raw material makes 1 : 0,3 and 1 : 0,5.

  13. Increased Airway Reactivity and Hyperinsulinemia in Obese Mice Are Linked by ERK Signaling in Brain Stem Cholinergic Neurons

    Directory of Open Access Journals (Sweden)

    Luiz O.S. Leiria


    Full Text Available Obesity is a major risk factor for asthma, which is characterized by airway hyperreactivity (AHR. In obesity-associated asthma, AHR may be regulated by non-TH2 mechanisms. We hypothesized that airway reactivity is regulated by insulin in the CNS, and that the high levels of insulin associated with obesity contribute to AHR. We found that intracerebroventricular (ICV-injected insulin increases airway reactivity in wild-type, but not in vesicle acetylcholine transporter knockdown (VAChT KDHOM−/−, mice. Either neutralization of central insulin or inhibition of extracellular signal-regulated kinases (ERK normalized airway reactivity in hyperinsulinemic obese mice. These effects were mediated by insulin in cholinergic nerves located at the dorsal motor nucleus of the vagus (DMV and nucleus ambiguus (NA, which convey parasympathetic outflow to the lungs. We propose that increased insulin-induced activation of ERK in parasympathetic pre-ganglionic nerves contributes to AHR in obese mice, suggesting a drug-treatable link between obesity and asthma.

  14. Cholinergic neurotransmission in human corpus cavernosum. II. Acetylcholine synthesis

    Energy Technology Data Exchange (ETDEWEB)

    Blanco, R.; De Tejada, S.; Goldstein, I.; Krane, R.J.; Wotiz, H.H.; Cohen, R.A. (Boston Univ. Medical Center, MA (USA))


    Physiological and histochemical evidence indicates that cholinergic nerves may participate in mediating penile erection. Acetylcholine synthesis and release was studied in isolated human corporal tissue. Human corpus cavernosum incubated with ({sup 3}H)choline accumulated ({sup 3}H)choline and synthesized ({sup 3}H)acethylcholine in an concentration-dependent manner. ({sup 3}H)Acetylcholine accumulation by the tissue was inhibited by hemicholinium-3, a specific antagonist of the high-affinity choline transport in cholinergic nerves. Transmural electrical field stimulation caused release of ({sup 3}H)acetylcholine which was significantly diminished by inhibiting neurotransmission with calcium-free physiological salt solution or tetrodotoxin. These observations provide biochemical and physiological evidence for the existence of cholinergic innervation in human corpus cavernosum.

  15. Transient hepatocellular injury during attacks of cholinergic urticaria. (United States)

    Niv, Y; Elkan, I; Fraser, G M


    Cholinergic urticaria presents as wheals and erythroderma that develop in response to a variety of factors which stimulate muscarinic receptors, including exercise, heat, cold, sweat and emotional stress. We describe a 25-year-old man with ulcerative colitis who developed cholinergic urticaria diagnosed by a metacholine test. He had had seven previous attacks over 8 years, and the finding of elevated liver enzymes required admission to four different hospitals. The clinical picture was identical: urticaria, hepatosplenomegaly, lymphadenopathy and elevation of liver enzymes. The causative agent was never identified and recovery was complete, with or without antibiotic therapy. To the best of our knowledge, this is the first description of liver involvement in cholinergic urticaria noted in the English-language medical literature.

  16. Time Perspective and Physical Activity among Central Appalachian Adolescents (United States)

    Gulley, Tauna


    Time perspective is a cultural behavioral concept that reflects individuals' orientations or attitudes toward the past, present, or future. Individuals' time perspectives influence their choices regarding daily activities. Time perspective is an important consideration when teaching adolescents about the importance of being physically active.…

  17. [Pharmacovigilance in Portugal: Activity of the Central Pharmacovigilance Unit]. (United States)

    Batel-Marques, Francisco; Mendes, Diogo; Alves, Carlos; Penedones, Ana; Dias, Patricia; Martins, Angelina; Santiago, Luiz Miguel; Fontes-Ribeiro, Carlos; Caramona, Margarida; Macedo, Tice


    The aim of this study was to characterize the spontaneous reports of adverse events that were received by the Central Portugal Regional Pharmacovigilance Unit. Spontaneous reports received between 01/2001 and 12/2013 were considered. The annual reporting ratios were estimated. The cases were characterized according to their seriousness, previous description, causality assessment, origin and professional group of the reporter, type of adverse event and pharmacotherapeutic groups of the suspected drugs most frequently reported. The Pharmacovigilance Unit received 2408 reports that contained 5749 adverse events. In 2013, the reporting rate was estimated at 171 reports per million inhabitants. Fifty-five percent of the reports were assessed as serious. Ninety percent of the cases were assessed as being at least possibly related with the suspected drug. The suspected drugs most frequently reported were anti-infectives for systemic use (n = 809, 33%). The most frequently reported adverse events were "Skin and subcutaneous tissue disorders" (n = 1139, 20%). There were 154 (6.4%) reports resulting in life-threatening situations and/or death, and 88 (3.6%) containing at least one adverse event assessed as serious, unknown and certain or probable. The present results are in line with those found in other studies, namely the seriousness and type of the adverse events and the pharmacotherapeutic groups of the most frequently reported suspected drugs. In the last years, the Central Portugal Regional Pharmacovigilance Unit has registered a growth in the reporting rate in general, as well as an increase in the reporting of unknown and serious adverse drug reactions.

  18. Central venous catheter associated thrombosis of major veins: thrombolytic treatment with recombinant tissue plasminogen activator

    NARCIS (Netherlands)

    Rodenhuis, S.; van't Hek, L. G.; Vlasveld, L. T.; Kröger, R.; Dubbelman, R.; van Tol, R. G.


    Major thromboses can occur in the venous system in association with central venous catheters. This usually necessitates removal of the catheter. The effectiveness of low dose recombinant tissue type plasminogen activator (rt-PA) in combination with heparin was assessed in patients with central

  19. 77 FR 13618 - Agency Information Collection Activities: Dominican Republic-Central America-United States Free... (United States)


    ... SECURITY U.S. Customs and Border Protection Agency Information Collection Activities: Dominican Republic- Central America-United States Free Trade Agreement (CAFTA-DR) AGENCY: U.S. Customs and Border Protection...-Central America-United States Free Trade Agreement (CAFTA-DR). This is a proposed extension of an...

  20. Widespread expression of BDNF but not NT3 by target areas of basal forebrain cholinergic neurons

    Energy Technology Data Exchange (ETDEWEB)

    Phillips, H.S.; Hains, J.M.; Laramee, G.R.; Rosenthal, A.; Winslow, J.W. (Genentech, San Francisco, CA (USA))


    Brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) are homologs of the well-known neurotrophic factor nerve growth factor. The three members of this family display distinct patterns of target specificity. To examine the distribution in brain of messenger RNA for these molecules, in situ hybridization was performed. Cells hybridizing intensely to antisense BDNF probe were located throughout the major targets of the rat basal forebrain cholinergic system, that is, the hippocampus, amygdala, and neocortex. Strongly hybridizing cells were also observed in structures associated with the olfactory system. The distribution of NT3 mRNA in forebrain was much more limited. Within the hippocampus, labeled cells were restricted to CA2, the most medial portion of CA1, and the dentate gyrus. In human hippocampus, cells expressing BDNF and mRNA are distributed in a fashion similar to that observed in the rat. These findings point to both basal forebrain cholinergic cells and olfactory pathways as potential central targets for BDNF.

  1. Stress, chemical defense agents, and cholinergic receptors. Midterm report, 1 November 1987-31 July 1989

    Energy Technology Data Exchange (ETDEWEB)

    Lane, J.D.


    This project is assessing the affects of exposure to a chemical defense agent on anxiety and stress, by using rat models of anxiety (conditioned emotional response (CER); conditioned suppression) and unconditioned non-specific stres (exposure to footshock). The specific experiments determined the plasticity of muscarinic cholinergic binding sites in the central nervous system. The neuroanatomical locus and neuropharmacological profile of changes in binding sites were assessed in brain areas enriched in cholinergic markers. Acetylcholine turnover was measured to determine if the receptor response is compensatory or independent. The effects of acute exposure to doses of a chemical defense agent (soman--XGD) on lethality and behaviors were examined. The experiments involved training and conditioning adult rats to CER using standard operant/respondent techniques. The binding of radiolabelled ligand was studied in vitro using brain membranes and tissue sections (autoradiography). The major findings are that CER produces increases in acetylcholine turnover in brain areas involved in anxiety, and that primarily post-synaptic M1 receptors compensatorly decrease in response. These neurochemical phenomena are directly correlated with several behaviors, including onset and extinction of CER and non-specific stress. Followup experiments have been designed to test the interaction of CER, XGD and neurochemistry.

  2. Un dia en la vida: The Everyday Activities of Young Children from Central American Immigrant Families (United States)

    Denmark, Nicole; Jones Harden, Brenda


    The aim of this article was to explore the everyday activities of young children from low-income Central American (CA) immigrant families. From the perspective that everyday activities propel children's development of culturally and contextually valued behaviours and skills, 48 mothers were interviewed regarding the activities that are available…


    Recent evidence suggests that septohippocampal cholinergic activity is suppressed in rats exposed to low levels of lead (Pb). As a result, noradrenergic activity may be elevated due to compensatory sympathetic sprouting. Therefore, the goals of this study were to (a) determine...

  4. Role of central alpha-1 adrenoceptors in canine narcolepsy. (United States)

    Mignot, E; Guilleminault, C; Bowersox, S; Rappaport, A; Dement, W C


    The role of central alpha-1 adrenergic receptors in cataplexy was investigated in genetically narcoleptic Doberman pinschers. Treatment of narcoleptic dogs with 25-600 micrograms/kg prazosin, a selective alpha-1 adrenergic receptor blocker, exacerbated cataplexy, whereas treatment with the alpha-1 agonist, methoxamine, ameliorated it. Subsequent studies showed that the beneficial effects of classical treatments of human narcolepsy (amphetamines and tricyclic antidepressants) are antagonized by prazosin, suggesting that these drugs are active through an indirect alpha-1 stimulation (via an increase of norepinephrine in the synaptic cleft). Other studies confirmed that the observed effects were not due to peripheral alpha-1 cardiovascular involvement. Atropine, a central anticholinergic agent, but not methylatropine, a peripheral one, completely suppressed the prazosin effect, which suggests that adrenergic and cholinergic systems act sequentially and not independently to generate cataplexy. Little is known about the physiological role of central alpha-1 adrenoceptors. This series of experiments implicates these receptors in narcolepsy-cataplexy.

  5. The cholinergic system, sigma-1 receptors and cognition

    NARCIS (Netherlands)

    van Waarde, Aren; Ramakrishnan, Nisha K.; Rybczynska, Anna A.; Elsinga, Philip H.; Ishiwata, Kiichi; Nijholt, Ingrid M.; Luiten, Paul G. M.; Dierckx, Rudi A.


    This article provides an overview of present knowledge regarding the relationship between the cholinergic system and sigma-1 receptors, and discusses potential applications of sigma-1 receptor agonists in the treatment of memory deficits and cognitive disorders. Sigma-1 receptors, initially

  6. Cypermethrin Poisoning and Anti-cholinergic Medication- A Case ...

    African Journals Online (AJOL)

    A 30 years old male was brought to emergency department of Manipal Teaching Hospital, Pokhara, Nepal with alleged history of consumption of pyrethroid compound 'cypermethrin'. It was found to be newer insecticide poisoning reported in Nepal. We reported this case to show effectiveness of anti-cholinergic like ...

  7. Cholinergic Nociceptive Mechanisms in Rat Meninges and Trigeminal Ganglia: Potential Implications for Migraine Pain

    Directory of Open Access Journals (Sweden)

    Rashid Giniatullin


    Full Text Available BackgroundParasympathetic innervation of meninges and ability of carbachol, acetylcholine (ACh receptor (AChR agonist, to induce headaches suggests contribution of cholinergic mechanisms to primary headaches. However, neurochemical mechanisms of cholinergic regulation of peripheral nociception in meninges, origin place for headache, are almost unknown.MethodsUsing electrophysiology, calcium imaging, immunohistochemistry, and staining of meningeal mast cells, we studied effects of cholinergic agents on peripheral nociception in rat hemiskulls and isolated trigeminal neurons.ResultsBoth ACh and carbachol significantly increased nociceptive firing in peripheral terminals of meningeal trigeminal nerves recorded by local suction electrode. Strong nociceptive firing was also induced by nicotine, implying essential role of nicotinic AChRs in control of excitability of trigeminal nerve endings. Nociceptive firing induced by carbachol was reduced by muscarinic antagonist atropine, whereas the action of nicotine was prevented by the nicotinic blocker d-tubocurarine but was insensitive to the TRPA1 antagonist HC-300033. Carbachol but not nicotine induced massive degranulation of meningeal mast cells known to release multiple pro-nociceptive mediators. Enzymes terminating ACh action, acetylcholinesterase (AChE and butyrylcholinesterase, were revealed in perivascular meningeal nerves. The inhibitor of AChE neostigmine did not change the firing per se but induced nociceptive activity, sensitive to d-tubocurarine, after pretreatment of meninges with the migraine mediator CGRP. This observation suggested the pro-nociceptive action of endogenous ACh in meninges. Both nicotine and carbachol induced intracellular Ca2+ transients in trigeminal neurons partially overlapping with expression of capsaicin-sensitive TRPV1 receptors.ConclusionTrigeminal nerve terminals in meninges, as well as dural mast cells and trigeminal ganglion neurons express a repertoire of pro

  8. Higher Physical Activity Is Associated With Lower Aortic Stiffness but Not With Central Blood Pressure

    DEFF Research Database (Denmark)

    Laursen, Anne Sofie Dam; Hansen, Anne-Louise Smidt; Wiinberg, Niels


    sedentary behavior with 1 hour light or moderate-to-vigorous physical activity on central hemodynamics was examined. Median physical activity energy expenditure was 28.0 kJ/kg/d (IQR: 19.8; 38.7). A 10 kJ/kg/d higher energy expenditure was associated with 0.75% lower aortic pulse wave velocity (CI: -1.......47; -0.03). Associations with central systolic blood pressure and central pulse pressure were not statistically significant. We observed no difference in central hemodynamics when substituting 1 hour sedentary behavior with 1 hour light or moderate-to-vigorous physical activity. In this relatively...

  9. Role of nitric oxide in non-adrenergic, non-cholinergic inhibitory junction potentials in canine ileocolonic sphincter.


    Ward, S. M.; McKeen, E. S.; Sanders, K. M.


    1. Electrical field stimulation causes neurally-mediated relaxation of the ileocolonic sphincter that is due to activation of non-adrenergic and non-cholinergic (NANC) nerves. Recent studies have suggested that nitric oxide (NO) is the neurotransmitter that mediates relaxation. 2. Using intracellular recording techniques, we have tested whether NANC inhibitory junction potentials ( in the canine ileocolonic sphincter are also mediated by NO. 3. Electrical field stimulation elicited exc...

  10. Antiinflammatory activity of melatonin in central nervous system. (United States)

    Esposito, Emanuela; Cuzzocrea, Salvatore


    Melatonin is mainly produced in the mammalian pineal gland during the dark phase. Its secretion from the pineal gland has been classically associated with circadian and circanual rhythm regulation. However, melatonin production is not confined exclusively to the pineal gland, but other tissues including retina, Harderian glands, gut, ovary, testes, bone marrow and lens also produce it. Several studies have shown that melatonin reduces chronic and acute inflammation. The immunomodulatory properties of melatonin are well known; it acts on the immune system by regulating cytokine production of immunocompetent cells. Experimental and clinical data showing that melatonin reduces adhesion molecules and pro-inflammatory cytokines and modifies serum inflammatory parameters. As a consequence, melatonin improves the clinical course of illnesses which have an inflammatory etiology. Moreover, experimental evidence supports its actions as a direct and indirect antioxidant, scavenging free radicals, stimulating antioxidant enzymes, enhancing the activities of other antioxidants or protecting other antioxidant enzymes from oxidative damage. Several encouraging clinical studies suggest that melatonin is a neuroprotective molecule in neurodegenerative disorders where brain oxidative damage has been implicated as a common link. In this review, the authors examine the effect of melatonin on several neurological diseases with inflammatory components, including dementia, Alzheimer disease, Parkinson disease, multiple sclerosis, stroke, and brain ischemia/reperfusion but also in traumatic CNS injuries (traumatic brain and spinal cord injury).

  11. Kisspeptin Regulation of Neuronal Activity throughout the Central Nervous System

    Directory of Open Access Journals (Sweden)

    Xinhuai Liu


    Full Text Available Kisspeptin signaling at the gonadotropin-releasing hormone (GnRH neuron is now relatively well characterized and established as being critical for the neural control of fertility. However, kisspeptin fibers and the kisspeptin receptor (KISS1R are detected throughout the brain suggesting that kisspeptin is involved in regulating the activity of multiple neuronal circuits. We provide here a review of kisspeptin actions on neuronal populations throughout the brain including the magnocellular oxytocin and vasopressin neurons, and cells within the arcuate nucleus, hippocampus, and amygdala. The actions of kisspeptin in these brain regions are compared to its effects upon GnRH neurons. Two major themes arise from this analysis. First, it is apparent that kisspeptin signaling through KISS1R at the GnRH neuron is a unique, extremely potent form or neurotransmission whereas kisspeptin actions through KISS1R in other brain regions exhibit neuromodulatory actions typical of other neuropeptides. Second, it is becoming increasingly likely that kisspeptin acts as a neuromodulator not only through KISS1R but also through other RFamide receptors such as the neuropeptide FF receptors (NPFFRs. We suggest likely locations of kisspeptin signaling through NPFFRs but note that only limited tools are presently available for examining kisspeptin cross-signaling within the RFamide family of neuropeptides.

  12. "Central command" and insular activation during attempted foot lifting in paraplegic humans

    DEFF Research Database (Denmark)

    Lonsdale, Markus Nowak; Holm, Søren; Biering-Sørensen, Fin


    The relationship between cardiovascular regulation and brain activation was investigated during attempted foot lifting in paraplegic subjects and during rhythmic handgrip exercise at one-third of maximum voluntary contraction force. Brain areas of interest were the primary sensory-motor area and ...... showing responses common to handgrip and attempted foot lifting revealed activation in the right central insula (P command feed-forward hypothesis....... and the insula, a hypothesized center for a central nervous feed-forward mechanism involved in cardiovascular control ("central command"). This mechanism is complementary to the usual known feedback pathways such as skeletal muscle afferent signals. Regional cerebral blood flow (rCBF) was measured in eight...... activation tasks, heart rate and mean arterial pressure increased. PET activation responses (P

  13. Early (pre–8 Ma) fault activity and temporal strain accumulation in the central Indian Ocean

    Digital Repository Service at National Institute of Oceanography (India)

    Krishna, K.S.; Bull, J.M.; Scrutton, R.A.

    -reflection profiles within the central Indian Ocean demonstrate that compressional activity started much earlier than previously thought, at around 15.4-13.9 Ma. From reconstructions of fault activity histories, it is shown that 12% of the total reverse fault...

  14. Decentralization and centralization: governing the activation of social assistance recipients in Europe

    NARCIS (Netherlands)

    Minas, R.; Wright, S.; van Berkel, H.H.A.


    Purpose – The purpose of this article is to examine the governance of activation in relation to the decentralization and centralization of activation for social assistance recipients in Sweden, The Netherlands and the UK. Design/methodology/approach – This paper outlines broad trends in the

  15. Cholinergic mechanisms in canine narcolepsy--I. Modulation of cataplexy via local drug administration into the pontine reticular formation. (United States)

    Reid, M S; Tafti, M; Geary, J N; Nishino, S; Siegel, J M; Dement, W C; Mignot, E


    Cataplexy in the narcoleptic canine has been shown to increase after systemic administration of cholinergic agonists. Furthermore, the number of cholinergic receptors in the pontine reticular formation of narcoleptic canines is significantly elevated. In the present study we have investigated the effects of cholinergic drugs administered directly into the pontine reticular formation on cataplexy, as defined by brief episodes of hypotonia induced by emotions, in narcoleptic canines. Carbachol and atropine were perfused through microdialysis probes implanted bilaterally in the pontine reticular formation of freely moving, narcoleptic and control Doberman pinschers. Cataplexy was quantified using the Food-Elicited Cataplexy Test, and analysed using recordings of electroencephalogram, electrooculogram and electromyogram. Cataplexy was characterized by a desynchronized electroencephalogram and a drop in electromyogram and electrooculogram activity. In narcoleptic canines, both unilateral and bilateral carbachol (10(-5) to 10(-3) M) produced a dose-dependent increase in cataplexy, which resulted in complete muscle tone suppression at the highest concentration. In control canines, neither bilateral nor unilateral carbachol (10(-5) to 10(-3) M) produced cataplexy, although bilateral carbachol, did produce muscle atonia at the highest dose (10(-3)). The increase in cataplexy after bilateral carbachol (10(-4) M) was rapidly reversed when the perfusion medium was switched to one containing atropine (10(-4) M). Bilateral atropine (10(-3) to 10(-2) M) alone did not produce any significant effects on cataplexy in narcoleptic canines; however, bilateral atropine (10(-2) M) did reduce the increase in cataplexy produced by systemic administration of physostigmine (0.05 mg/kg, i.v.). These findings demonstrate that cataplexy in narcoleptic canines can be stimulated by applying cholinergic agonists directly into the pontine reticular formation. The ability of atropine to inhibit

  16. Earthquake Probability Assessment for the Active Faults in Central Taiwan: A Case Study

    Directory of Open Access Journals (Sweden)

    Yi-Rui Lee


    Full Text Available Frequent high seismic activities occur in Taiwan due to fast plate motions. According to the historical records the most destructive earthquakes in Taiwan were caused mainly by inland active faults. The Central Geological Survey (CGS of Taiwan has published active fault maps in Taiwan since 1998. There are 33 active faults noted in the 2012 active fault map. After the Chi-Chi earthquake, CGS launched a series of projects to investigate the details to better understand each active fault in Taiwan. This article collected this data to develop active fault parameters and referred to certain experiences from Japan and the United States to establish a methodology for earthquake probability assessment via active faults. We consider the active faults in Central Taiwan as a good example to present the earthquake probability assessment process and results. The appropriate “probability model” was used to estimate the conditional probability where M ≥ 6.5 and M ≥ 7.0 earthquakes. Our result shows that the highest earthquake probability for M ≥ 6.5 earthquake occurring in 30, 50, and 100 years in Central Taiwan is the Tachia-Changhua fault system. Conversely, the lowest earthquake probability is the Chelungpu fault. The goal of our research is to calculate the earthquake probability of the 33 active faults in Taiwan. The active fault parameters are important information that can be applied in the following seismic hazard analysis and seismic simulation.

  17. Neuroprotective effects of sulforaphane on cholinergic neurons in mice with Alzheimer's disease-like lesions. (United States)

    Zhang, Rui; Zhang, Jingzhu; Fang, Lingduo; Li, Xi; Zhao, Yue; Shi, Wanying; An, Li


    Alzheimer's disease (AD) is a common neurodegenerative disease in elderly individuals, and effective therapies are unavailable. This study was designed to investigate the neuroprotective effects of sulforaphane (an activator of NF-E2-related factor 2) on mice with AD-like lesions induced by combined administration of aluminum and D-galactose. Step-down-type passive avoidance tests showed sulforaphane ameliorated cognitive impairment in AD-like mice. Immunohistochemistry results indicated sulforaphane attenuated cholinergic neuron loss in the medial septal and hippocampal CA1 regions in AD-like mice. However, spectrophotometry revealed no significant difference in acetylcholine level or the activity of choline acetyltransferase or acetylcholinesterase in the cerebral cortex among groups of control and AD-like mice with and without sulforaphane treatment. Sulforaphane significantly increased the numbers of 5-bromo-2'-deoxyuridine-positive neurons in the subventricular and subgranular zones in AD-like mice which were significantly augmented compared with controls. Atomic absorption spectrometry revealed significantly lower aluminum levels in the brains of sulforaphane-treated AD-like mice than in those that did not receive sulforaphane treatment. In conclusion, sulforaphane ameliorates neurobehavioral deficits by reducing cholinergic neuron loss in the brains of AD-like mice, and the mechanism may be associated with neurogenesis and aluminum load reduction. These findings suggest that phytochemical sulforaphane has potential application in AD therapeutics.

  18. Cholinergic Potentiation of Restoration of Visual Function after Optic Nerve Damage in Rats

    Directory of Open Access Journals (Sweden)

    Mira Chamoun


    Full Text Available Enhancing cortical plasticity and brain connectivity may improve residual vision following a visual impairment. Since acetylcholine plays an important role in attention and neuronal plasticity, we explored whether potentiation of the cholinergic transmission has an effect on the visual function restoration. To this end, we evaluated for 4 weeks the effect of the acetylcholinesterase inhibitor donepezil on brightness discrimination, visually evoked potentials, and visual cortex reactivity after a bilateral and partial optic nerve crush in adult rats. Donepezil administration enhanced brightness discrimination capacity after optic nerve crush compared to nontreated animals. The visually evoked activation of the primary visual cortex was not restored, as measured by evoked potentials, but the cortical neuronal activity measured by thallium autometallography was not significantly affected four weeks after the optic nerve crush. Altogether, the results suggest a role of the cholinergic system in postlesion cortical plasticity. This finding agrees with the view that restoration of visual function may involve mechanisms beyond the area of primary damage and opens a new perspective for improving visual rehabilitation in humans.

  19. Spinal cholinergic involvement after treatment with aspirin and paracetamol in rats

    DEFF Research Database (Denmark)

    Abelson, Klas S P; Kommalage, Mahinda; Höglund, A Urban


    Aspirin and paracetamol have been shown to suppress non-inflammatory pain conditions like thermal, visceral and mechanical pain in mice and rats. The non-inflammatory antinociception appears to be mediated by central receptor mechanisms, such as the cholinergic system. In this study, we tested...... the hypothesis that the non-inflammatory antinociception of aspirin and paracetamol could be mediated by an increase of intraspinal acetylcholine release. Microdialysis probes were placed intraspinally in anesthetized rats for acetylcholine sampling. Subcutaneously administered aspirin 100 and 300 mg....../kg increased, while paracetamol 300 mg/kg decreased intraspinal acetylcholine release. Intraspinal drug administration did not affect acetylcholine release. Our results suggest that an increased intraspinal acetylcholine release could be involved in part of the non-inflammatory pain suppression by aspirin...

  20. Cholinergic PET imaging in infections and inflammation using 11C-donepezil and 18F-FEOBV

    DEFF Research Database (Denmark)

    Jørgensen, Nis Pedersen; Alstrup, Aage Kristian Olsen; Mortensen, Frank Viborg


    Introduction Immune cells utilize acetylcholine as a paracrine-signaling molecule. Many white blood cells express components of the cholinergic signaling pathway, and these are up-regulated when immune cells are activated. However, in vivo molecular imaging of cholinergic signaling in the context...... with Staphylococcus aureus, and PET scanned at 24, 72, 120, and 144 h post-inoculation. Four pigs with post-operative abscesses were also imaged. Finally, we present initial data from human patients with infections, inflammation, and renal and lung cancer. Results In mice, the FDG uptake in abscesses peaked at 24 h...... and remained stable. The 11C-donepezil and 18F-FEOBV uptake displayed progressive increase, and at 120–144 h was nearly at the FDG level. Moderate 11C-donepezil and slightly lower 18F-FEOBV uptake were seen in pig abscesses. PCR analyses suggested that the 11C-donepezil signal in inflammatory cells is derived...

  1. Increasing brain angiotensin converting enzyme 2 activity decreases anxiety-like behavior in male mice by activating central Mas receptors. (United States)

    Wang, Lei; de Kloet, Annette D; Pati, Dipanwita; Hiller, Helmut; Smith, Justin A; Pioquinto, David J; Ludin, Jacob A; Oh, S Paul; Katovich, Michael J; Frazier, Charles J; Raizada, Mohan K; Krause, Eric G


    Over-activation of the brain renin-angiotensin system (RAS) has been implicated in the etiology of anxiety disorders. Angiotensin converting enzyme 2 (ACE2) inhibits RAS activity by converting angiotensin-II, the effector peptide of RAS, to angiotensin-(1-7), which activates the Mas receptor (MasR). Whether increasing brain ACE2 activity reduces anxiety by stimulating central MasR is unknown. To test the hypothesis that increasing brain ACE2 activity reduces anxiety-like behavior via central MasR stimulation, we generated male mice overexpressing ACE2 (ACE2 KI mice) and wild type littermate controls (WT). ACE2 KI mice explored the open arms of the elevated plus maze (EPM) significantly more than WT, suggesting increasing ACE2 activity is anxiolytic. Central delivery of diminazene aceturate, an ACE2 activator, to C57BL/6 mice also reduced anxiety-like behavior in the EPM, but centrally administering ACE2 KI mice A-779, a MasR antagonist, abolished their anxiolytic phenotype, suggesting that ACE2 reduces anxiety-like behavior by activating central MasR. To identify the brain circuits mediating these effects, we measured Fos, a marker of neuronal activation, subsequent to EPM exposure and found that ACE2 KI mice had decreased Fos in the bed nucleus of stria terminalis but had increased Fos in the basolateral amygdala (BLA). Within the BLA, we determined that ∼62% of GABAergic neurons contained MasR mRNA and expression of MasR mRNA was upregulated by ACE2 overexpression, suggesting that ACE2 may influence GABA neurotransmission within the BLA via MasR activation. Indeed, ACE2 overexpression was associated with increased frequency of spontaneous inhibitory postsynaptic currents (indicative of presynaptic release of GABA) onto BLA pyramidal neurons and central infusion of A-779 eliminated this effect. Collectively, these results suggest that ACE2 may reduce anxiety-like behavior by activating central MasR that facilitate GABA release onto pyramidal neurons within the

  2. GABAergic actions on cholinergic laterodorsal tegmental neurons

    DEFF Research Database (Denmark)

    Kohlmeier, K A; Kristiansen, Uffe


    (IRK) mediated this effect. Further, outward currents were never additive with those induced by application of carbachol, suggesting that they were mediated by activation of GABA(B) receptors linked to the same G(IRK) activated in these cells by muscarinic receptor stimulation. Activation of GABA(B) receptors...

  3. Cholinergic modulation of the hippocampal region and memory function. (United States)

    Haam, Juhee; Yakel, Jerrel L


    Acetylcholine (ACh) plays an important role in memory function and has been implicated in aging-related dementia, in which the impairment of hippocampus-dependent learning strongly manifests. Cholinergic neurons densely innervate the hippocampus, mediating the formation of episodic as well as semantic memory. Here, we will review recent findings on acetylcholine's modulation of memory function, with a particular focus on hippocampus-dependent learning, and the circuits involved. In addition, we will discuss the complexity of ACh actions in memory function to better understand the physiological role of ACh in memory. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms. © 2017 International Society for Neurochemistry.

  4. Direct muscarinic cholinergic inhibition of hepatic glucose production in humans.


    Boyle, P. J.; Liggett, S B; Shah, S D; Cryer, P E


    To explore the potential role of the parasympathetic nervous system in human glucoregulatory physiology, responses to the muscarinic cholinergic agonist bethanechol (5.0 mg s.c.) and antagonist atropine (1.0 mg i.v.) were measured in normal humans. There were no changes in the plasma glucose concentration or rates of glucose production or utilization following atropine administration. After bethanechol administration there were no changes in the plasma glucose concentration or fluxes despite ...

  5. Genetically-induced cholinergic hyper-innervation enhances taste learning

    Directory of Open Access Journals (Sweden)

    Selin eNeseliler


    Full Text Available Acute inhibition of acetylcholine (ACh has been shown to impair many forms of simple learning, and notably conditioned taste aversion (CTA. The most adhered-to theory that has emerged as a result of this work—that ACh increases a taste’s perceived novelty, and thereby its associability—would be further strengthened by evidence showing that enhanced cholinergic function improves learning above normal levels. Experimental testing of this corollary hypothesis has been limited, however, by side-effects of pharmacological ACh agonism and by the absence of a model that achieves long-term increases in cholinergic signaling. Here, we present this further test of the ACh hypothesis, making use of mice lacking the p75 pan-neurotrophin receptor gene, which show a resultant over-abundance of cholinergic neurons in subregions of the basal forebrain (BF. We first demonstrate that the p75-/- abnormality directly affects portions of the CTA circuit, locating mouse gustatory cortex (GC using a functional assay and then using immunohistochemisty to demonstrate cholinergic hyperinnervation of GC in the mutant mice—hyperinnervation that is unaccompanied by changes in cell numbers or compensatory changes in muscarinic receptor densities. We then demonstrate that both p75-/- and wild-type mice learn robust CTAs, which extinguish more slowly in the mutants. Further testing to distinguish effects on learning from alterations in memory retention demonstrate that p75-/- mice do in fact learn stronger CTAs than wild-type mice. These data provide novel evidence for the hypothesis linking ACh and taste learning.

  6. Modulatory compartments in cortex and local regulation of cholinergic tone. (United States)

    Coppola, Jennifer J; Ward, Nicholas J; Jadi, Monika P; Disney, Anita A


    Neuromodulatory signaling is generally considered broad in its impact across cortex. However, variations in the characteristics of cortical circuits may introduce regionally-specific responses to diffuse modulatory signals. Features such as patterns of axonal innervation, tissue tortuosity and molecular diffusion, effectiveness of degradation pathways, subcellular receptor localization, and patterns of receptor expression can lead to local modification of modulatory inputs. We propose that modulatory compartments exist in cortex and can be defined by variation in structural features of local circuits. Further, we argue that these compartments are responsible for local regulation of neuromodulatory tone. For the cholinergic system, these modulatory compartments are regions of cortical tissue within which signaling conditions for acetylcholine are relatively uniform, but between which signaling can vary profoundly. In the visual system, evidence for the existence of compartments indicates that cholinergic modulation likely differs across the visual pathway. We argue that the existence of these compartments calls for thinking about cholinergic modulation in terms of finer-grained control of local cortical circuits than is implied by the traditional view of this system as a diffuse modulator. Further, an understanding of modulatory compartments provides an opportunity to better understand and perhaps correct signal modifications that lead to pathological states. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Dysfunctional penile cholinergic nerves in diabetic impotent men

    Energy Technology Data Exchange (ETDEWEB)

    Blanco, R.; Saenz de Tejada, I.; Goldstein, I.; Krane, R.J.; Wotiz, H.H.; Cohen, R.A. (Boston Univ. School of Medicine, MA (USA))


    Impotence in the diabetic man may be secondary to a neuropathic condition of the autonomic penile nerves. The relationship between autonomic neuropathy and impotence in diabetes was studied in human corporeal tissue obtained during implantation of a penile prosthesis in 19 impotent diabetic and 15 nondiabetic patients. The functional status of penile cholinergic nerves was assessed by determining their ability to accumulate tritiated choline (34), and synthesize (34) and release (19) tritiated-acetylcholine after incubation of corporeal tissue with tritiated-choline (34). Tritiated-choline accumulation, and tritiated-acetylcholine synthesis and release were significantly reduced in the corporeal tissue from diabetic patients compared to that from nondiabetic patients (p less than 0.05). The impairment in acetylcholine synthesis worsened with the duration of diabetes (p less than 0.025). No differences in the parameters measured were found between insulin-dependent (11) and noninsulin-dependent (8) diabetic patients. The ability of the cholinergic nerves to synthesize acetylcholine could not be predicted clinically with sensory vibration perception threshold testing. It is concluded that there is a functional penile neuropathic condition of the cholinergic nerves in the corpus cavernosum of diabetic impotent patients that may be responsible for the erectile dysfunction.

  8. On the Formation and Amplification of Magnetic Fields in the Central Part of Active Galaxies (United States)

    Andreasyan, R. R.


    We suggest a mechanism of formation and amplification of magnetic fields in the central fast rotating region of active galaxies, when exists an outflow or inflow of ionized matter from or on the central part. Because of the large differences between the time of scattering of electrons and protons of expanding or collapsing matter with the particles of rotating medium, in every point of rotating medium the rotation velocity of scattered electrons and protons will be different and correspond to the rotation velocity of their last scattering point. In the result of this difference are forming circular electric currents in the central part of Active galaxies, and forms dipolar magnetic fields. If the process of outflow or inflow continues sufficiently long time the equipartition of magnetic and rotational energy of the central part of the galaxy will be reached. Observed large amount of fast rotating matter in the central region and the existence of outflow or inflow of plasma in active galaxies provide a good condition for the working of suggested mechanism.

  9. Enhanced mu opioid receptor-dependent opioidergic modulation of striatal cholinergic transmission in DYT1 dystonia. (United States)

    Ponterio, Giulia; Tassone, Annalisa; Sciamanna, Giuseppe; Vanni, Valentina; Meringolo, Maria; Santoro, Massimo; Mercuri, Nicola Biagio; Bonsi, Paola; Pisani, Antonio


    Mu opioid receptor activation modulates acetylcholine release in the dorsal striatum, an area deeply involved in motor function, habit formation, and reinforcement learning as well as in the pathophysiology of different movement disorders, such as dystonia. Although the role of opioids in drug reward and addiction is well established, their involvement in motor dysfunction remains largely unexplored. We used a multidisciplinary approach to investigate the responses to mu activation in 2 mouse models of DYT1 dystonia (Tor1a+/Δgag mice, Tor1a+/- torsinA null mice, and their respective wild-types). We performed electrophysiological recordings to characterize the pharmacological effects of receptor activation in cholinergic interneurons as well as the underlying ionic currents. In addition, an analysis of the receptor expression was performed both at the protein and mRNA level. In mutant mice, selective mu receptor activation caused a stronger G-protein-dependent, dose-dependent inhibition of firing activity in cholinergic interneurons when compared with controls. In Tor1a+/- mice, our electrophysiological analysis showed an abnormal involvement of calcium-activated potassium channels. Moreover, in both models we found increased levels of mu receptor protein. In addition, both total mRNA and the mu opioid receptor splice variant 1S (MOR-1S) splice variant of the mu receptor gene transcript, specifically enriched in striatum, were selectively upregulated. Mice with the DYT1 dystonia mutation exhibit an enhanced response to mu receptor activation, dependent on selective receptor gene upregulation. Our data suggest a novel role for striatal opioid signaling in motor control, and more important, identify mu opioid receptors as potential targets for pharmacological intervention in dystonia. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

  10. Quantitative Imaging of Cholinergic Interneurons Reveals a Distinctive Spatial Organization and a Functional Gradient across the Mouse Striatum. (United States)

    Matamales, Miriam; Götz, Jürgen; Bertran-Gonzalez, Jesus


    Information processing in the striatum requires the postsynaptic integration of glutamatergic and dopaminergic signals, which are then relayed to the output nuclei of the basal ganglia to influence behavior. Although cellularly homogeneous in appearance, the striatum contains several rare interneuron populations which tightly modulate striatal function. Of these, cholinergic interneurons (CINs) have been recently shown to play a critical role in the control of reward-related learning; however how the striatal cholinergic network is functionally organized at the mesoscopic level and the way this organization influences striatal function remains poorly understood. Here, we systematically mapped and digitally reconstructed the entire ensemble of CINs in the mouse striatum and quantitatively assessed differences in densities, spatial arrangement and neuropil content across striatal functional territories. This approach demonstrated that the rostral portion of the striatum contained a higher concentration of CINs than the caudal striatum and that the cholinergic content in the core of the ventral striatum was significantly lower than in the rest of the regions. Additionally, statistical comparison of spatial point patterns in the striatal cholinergic ensemble revealed that only a minor portion of CINs (17%) aggregated into cluster and that they were predominantly organized in a random fashion. Furthermore, we used a fluorescence reporter to estimate the activity of over two thousand CINs in naïve mice and found that there was a decreasing gradient of CIN overall function along the dorsomedial-to-ventrolateral axis, which appeared to be independent of their propensity to aggregate within the striatum. Altogether this work suggests that the regulation of striatal function by acetylcholine across the striatum is highly heterogeneous, and that signals originating in external afferent systems may be principally determining the function of CINs in the striatum.

  11. Quantitative Imaging of Cholinergic Interneurons Reveals a Distinctive Spatial Organization and a Functional Gradient across the Mouse Striatum.

    Directory of Open Access Journals (Sweden)

    Miriam Matamales

    Full Text Available Information processing in the striatum requires the postsynaptic integration of glutamatergic and dopaminergic signals, which are then relayed to the output nuclei of the basal ganglia to influence behavior. Although cellularly homogeneous in appearance, the striatum contains several rare interneuron populations which tightly modulate striatal function. Of these, cholinergic interneurons (CINs have been recently shown to play a critical role in the control of reward-related learning; however how the striatal cholinergic network is functionally organized at the mesoscopic level and the way this organization influences striatal function remains poorly understood. Here, we systematically mapped and digitally reconstructed the entire ensemble of CINs in the mouse striatum and quantitatively assessed differences in densities, spatial arrangement and neuropil content across striatal functional territories. This approach demonstrated that the rostral portion of the striatum contained a higher concentration of CINs than the caudal striatum and that the cholinergic content in the core of the ventral striatum was significantly lower than in the rest of the regions. Additionally, statistical comparison of spatial point patterns in the striatal cholinergic ensemble revealed that only a minor portion of CINs (17% aggregated into cluster and that they were predominantly organized in a random fashion. Furthermore, we used a fluorescence reporter to estimate the activity of over two thousand CINs in naïve mice and found that there was a decreasing gradient of CIN overall function along the dorsomedial-to-ventrolateral axis, which appeared to be independent of their propensity to aggregate within the striatum. Altogether this work suggests that the regulation of striatal function by acetylcholine across the striatum is highly heterogeneous, and that signals originating in external afferent systems may be principally determining the function of CINs in the

  12. Effects of Aged Garlic Extract on Cholinergic, Glutamatergic and GABAergic Systems with Regard to Cognitive Impairment in Aβ-Induced Rats

    Directory of Open Access Journals (Sweden)

    Piyaporn Thorajak


    Full Text Available Alzheimer’s disease (AD has been linked to the degeneration of central cholinergic and glutamatergic transmission, which correlates with progressive memory loss and the accumulation of amyloid-β (Aβ. It has been claimed that aged garlic extract (AGE has a beneficial effect in preventing neurodegeneration in AD. Therefore, the objective of this study was to investigate the effects of AGE on Aβ-induced cognitive dysfunction with a biochemical basis in the cholinergic, glutamatergic, and GABAergic systems in rats. Adult male Wistar rats were orally administered three doses of AGE (125, 250, and 500 mg/kg daily for 65 days. At day 56, they were injected with 1 μL of aggregated Aβ (1–42 into each lateral ventricle, bilaterally. After six days of Aβ injection, the rats’ working and reference memory was tested using a radial arm maze. The rats were then euthanized to investigate any changes to the cholinergic neurons, vesicular glutamate transporter 1 and 2 proteins (VGLUT1 and VGLUT2, and glutamate decarboxylase (GAD in the hippocampus. The results showed that AGE significantly improved the working memory and tended to improve the reference memory in cognitively-impaired rats. In addition, AGE significantly ameliorated the loss of cholinergic neurons and increased the VGLUT1 and GAD levels in the hippocampus of rat brains with Aβ-induced toxicity. In contrast, the VGLUT2 protein levels did not change in any of the treated groups. We concluded that AGE was able to attenuate the impairment of working memory via the modification of cholinergic neurons, VGLUT1, and GAD in the hippocampus of Aβ-induced rats.

  13. Intrinsic Cholinergic Mechanisms Regulating Cerebral Blood Flow as a Target for Organophosphate Action. (United States)


    will facilitate the vasodilation associated with cortical arousal or hypercapnia, an effect blocked by atropine (see Scremin 1982, for review ) and that...stimulation of the fastiglal nucleus (FN) on ICBF (mean S.E.M.) int d ralyzed tanesthetized pral rat. n_ -31- Pons - Vestibular comp. R 189 +- 15 346...sources for the cholinergic link in this pathway are local cholinergic neurons of the cortex, or nerve terminals of afferent cholinergic fibers arising

  14. Age-dependent changes of calcium related activity in the central auditory pathway. (United States)

    Gröschel, Moritz; Hubert, Nikolai; Müller, Susanne; Ernst, Arne; Basta, Dietmar


    Age-related hearing loss (ARHL) represents one of the most common chronic health problems that faces an aging population. In the peripheral auditory system, aging is accompanied by functional loss or degeneration of sensory as well as non-sensory tissue. It has been recently described that besides the degeneration of cochlear structures, the central auditory system is also involved in ARHL. Although mechanisms of central presbycusis are not well understood, previous animal studies have reported some signs of central neurodegeneration in the lower auditory pathway. Moreover, changes in neurophysiology are indicated by alterations in synaptic transmission. In particular, neurotransmission and spontaneous neuronal activity appear to be affected in aging animals. Therefore, it was the aim of the present study to determine the neuronal activity within the central auditory pathway in aging mice over their whole lifespan compared to a control group (young adult animals, ~3months of age) using the non-invasive manganese-enhanced MRI technique. MRI signal strength showed a comparable pattern in most investigated auditory brain areas. An increase in activity was particularly pronounced in the middle-aged groups (13 or 18 months), with the largest effect in the dorsal and ventral cochlear nucleus. In higher auditory structures, namely the inferior colliculus, medial geniculate body and auditory cortex, the enhancement was much less expressed; while a decrease was detected in the superior olivary complex. Interestingly, calcium-dependent activity reduced to control levels in the oldest animals (22 months) in the cochlear nucleus and was significantly reduced in higher auditory structures. A similar finding was also found in the hippocampus. The observed changes might be related to central neuroplasticity (including hyperactivity) as well as neurodegenerative mechanisms and represent central nervous correlates of the age-related decline in auditory processing and perception

  15. Intrinsic membrane plasticity via increased persistent sodium conductance of cholinergic neurons in the rat laterodorsal tegmental nucleus contributes to cocaine-induced addictive behavior. (United States)

    Kamii, Hironori; Kurosawa, Ryo; Taoka, Naofumi; Shinohara, Fumiya; Minami, Masabumi; Kaneda, Katsuyuki


    The laterodorsal tegmental nucleus (LDT) is a brainstem nucleus implicated in reward processing and is one of the main sources of cholinergic afferents to the ventral tegmental area (VTA). Neuroplasticity in this structure may affect the excitability of VTA dopamine neurons and mesocorticolimbic circuitry. Here, we provide evidence that cocaine-induced intrinsic membrane plasticity in LDT cholinergic neurons is involved in addictive behaviors. After repeated experimenter-delivered cocaine exposure, ex vivo whole-cell recordings obtained from LDT cholinergic neurons revealed an induction of intrinsic membrane plasticity in regular- but not burst-type neurons, resulting in increased firing activity. Pharmacological examinations showed that increased riluzole-sensitive persistent sodium currents, but not changes in Ca(2+) -activated BK, SK or voltage-dependent A-type potassium conductance, mediated this plasticity. In addition, bilateral microinjection of riluzole into the LDT immediately before the test session in a cocaine-induced conditioned place preference (CPP) paradigm inhibited the expression of cocaine-induced CPP. These findings suggest that intrinsic membrane plasticity in LDT cholinergic neurons is causally involved in the development of cocaine-induced addictive behaviors. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  16. 76 FR 75893 - Agency Information Collection Activities: Dominican Republic-Central America-United States Free... (United States)


    ... SECURITY U.S. Customs and Border Protection Agency Information Collection Activities: Dominican Republic- Central America-United States Free Trade Agreement (CAFTA-DR) AGENCY: U.S. Customs and Border Protection... paperwork and respondent burden, CBP invites the general public and other Federal agencies to comment on an...

  17. Chronic dietary ginseng extract administration ameliorates antioxidant and cholinergic systems in the brains of aged mice

    Directory of Open Access Journals (Sweden)

    Mi Ra Lee


    Conclusion: The results suggest that supplementation with the tested ginseng extracts may suppress the cognitive decline associated with aging, via regulation of the cholinergic and antioxidant defense systems.

  18. Planning dance activities for pre-school children in the Central Slovenia region


    Peklaj, Anita


    The aim of the present thesis is to analyse the planning of dance activities of pre-school children in the Central Slovenia region. Our interest was focused on the standpoint of pre-school teachers to the integration of the art of dance in kindergartens, on the frequency of the planning of dance activities, on the kind of the most frequently planned dance activities and on the question if pre-school teachers connect dance activities with other fields from the Curriculum for kindergartens. We ...

  19. Cholinergic enhancement reduces orientation-specific surround suppression but not visual crowding

    Directory of Open Access Journals (Sweden)

    Anna A. Kosovicheva


    Full Text Available Acetylcholine (ACh reduces the spatial spread of excitatory fMRI responses in early visual cortex and the receptive field sizes of V1 neurons. We investigated the perceptual consequences of these physiological effects of ACh with surround suppression and crowding, two tasks that involve spatial interactions between visual field locations. Surround suppression refers to the reduction in perceived stimulus contrast by a high-contrast surround stimulus. For grating stimuli, surround suppression is selective for the relative orientations of the center and surround, suggesting that it results from inhibitory interactions in early visual cortex. Crowding refers to impaired identification of a peripheral stimulus in the presence of flankers and is thought to result from excessive integration of visual features. We increased synaptic ACh levels by administering the cholinesterase inhibitor donepezil to healthy human subjects in a placebo-controlled, double-blind design. In Exp. 1, we measured surround suppression of a central grating using a contrast discrimination task with three conditions: 1 surround grating with the same orientation as the center (parallel, 2 surround orthogonal to the center, or 3 no surround. Contrast discrimination thresholds were higher in the parallel than in the orthogonal condition, demonstrating orientation-specific surround suppression (OSSS. Cholinergic enhancement reduced thresholds only in the parallel condition, thereby reducing OSSS. In Exp. 2, subjects performed a crowding task in which they reported the identity of a peripheral letter flanked by letters on either side. We measured the critical spacing between the target and flanking letters that allowed reliable identification. Cholinergic enhancement had no effect on critical spacing. Our findings suggest that ACh reduces spatial interactions in tasks involving segmentation of visual field locations but that these effects may be limited to early visual cortical

  20. Geological factors associated with megabenthic activity in the Central Indian Ocean Basin

    Digital Repository Service at National Institute of Oceanography (India)

    Sharma, R.; Rao, A.

    39, No. 3/4, pp. 7(15-713, 1992. 0198~)149/92 $5.(X) + 0.0t~ Printed in Great Britain. © 1992 Pergamon Press p\\[c NOTE Geological factors associated with megabenthic activity in the Central Indian Basin RAHUL SHARMA* and ARADHANA S. RAO... with respect to various geological features, particularly the substrates, in the Central Indian Basin (CIB), as observed from seabed photographs taken during manganese nodule surveys. DATA ACQUISITION AND INTERPRETATION The data were collected in the CIB...

  1. The Effects of L-glucose on memory in mice are modulated by peripherally acting cholinergic drugs. (United States)

    Lawson, Catherine J; Homewood, Judi; Taylor, Alan J


    D-Glucose improves memory in animals and humans and in subjects with memory pathologies. To date, the accepted conclusion drawn from animal research is that D-glucose improves memory via alterations in central cholinergic systems. However, recent evidence suggests that a sugar which does not cross the blood-brain barrier also facilitates memory (Talley, Arankowsky-Sandoval, McCarty, & Gold, 1999). The present study examined the effects of peripherally administered L-glucose, a stereoisomer of D-glucose, in male mice. Intraperitoneal administration of L-glucose (300 mg/kg) before testing enhanced place learning in the Morris water maze. Mice injected with L-glucose had significantly shorter escape latencies than mice injected with saline (1 ml/kg). Effects were observed on both reference memory and working memory tasks. L-Glucose did not facilitate performance on either task when it was simultaneously administered with cholinergic antagonists that are excluded from the central nervous system. Thus, simultaneous administration of either methyl-scopolamine (0.3 mg/kg), a peripherally acting muscarinic receptor blocker, or hexamethonium (1 mg/kg), a peripherally acting nicotinic receptor blocker, reversed the effect of L-glucose on memory. These findings suggest that the memory effects of l-glucose may be mediated by facilitated acetylcholine synthesis and/or release in the peripheral nervous system. Copyright 2002 Elsevier Science.

  2. A GPR54-Activating Mutation in a Patient with Central Precocious Puberty (United States)

    Teles, Milena Gurgel; Bianco, Suzy D.C.; Brito, Vinicius Nahime; Trarbach, Ericka B.; Kuohung, Wendy; Xu, Shuyun; Seminara, Stephanie B.; Mendonca, Berenice B.; Kaiser, Ursula B.; Latronico, Ana Claudia


    SUMMARY Gonadotropin-dependent, or central, precocious puberty is caused by early maturation of the hypothalamic–pituitary–gonadal axis. In girls, this condition is most often idiopathic. Recently, a G protein–coupled receptor, GPR54, and its ligand, kisspeptin, were described as an excitatory neuroregulator system for the secretion of gonadotropin-releasing hormone (GnRH). In this study, we have identified an autosomal dominant GPR54 mutation — the substitution of proline for arginine at codon 386 (Arg386Pro) — in an adopted girl with idiopathic central precocious puberty (whose biologic family was not available for genetic studies). In vitro studies have shown that this mutation leads to prolonged activation of intracellular signaling pathways in response to kisspeptin. The Arg386Pro mutant appears to be associated with central precocious puberty. PMID:18272894

  3. Comparative study in mice of tetrazepam and other centrally active skeletal muscle relaxants. (United States)

    Simiand, J; Keane, P E; Biziere, K; Soubrie, P


    Tetrazepam is a 1,4 benzodiazepine (BZD) clinically used in France and Germany as a muscle relaxant. The activity of tetrazepam was compared to that of diazepam, baclofen, mephenesin and chlormezanone in mice, in pharmacological models which are predictive of muscle relaxant and sedative properties. Tetrazepam was active in all the 6 tests of muscle relaxation (traction, chimney, inclined screen, grip force, horizontal grid and morphine-induced Straub tail). The overall muscle relaxant potency of tetrazepam was inferior to that of diazepam, but was clearly superior to that of chlormezanone and mephenesin. Baclofen was less active than tetrazepam in 3 tests (traction, horizontal grid, and grip strength), but more active in the other 3 tests. The administration of the benzodiazepine receptor antagonist Ro 15-1788 blocked the effects of tetrazepam and diazepam in 2 representative tests, morphine-induced Straub tail and the rotarod test, but did not modify the activities of the other centrally acting muscle relaxants in these same models. The selectivity ratio (ED50 rotarod or ED50 locomotor activity/ED50 in each muscle relaxant test) for tetrazepam was superior to that of diazepam and all the other muscle relaxant drugs examined. It is concluded that tetrazepam exerts its muscle relaxant activity by stimulating central BZD receptors, and presents the advantage of a wide dissociation between muscle relaxant and sedative potencies.

  4. Cholinergic PET imaging in infections and inflammation using {sup 11}C-donepezil and {sup 18}F-FEOBV

    Energy Technology Data Exchange (ETDEWEB)

    Joergensen, Nis Pedersen; Hoegsberg Schleimann, Mariane [Aarhus University Hospital, Department of Infectious Diseases, Aarhus (Denmark); Alstrup, Aage K.O.; Knudsen, Karoline; Jakobsen, Steen; Bender, Dirk; Gormsen, Lars C.; Borghammer, Per [Aarhus University Hospital, Department of Nuclear Medicine and PET Centre, Aarhus C (Denmark); Mortensen, Frank V. [Aarhus University Hospital, Department of Gastroenterology, Aarhus (Denmark); Madsen, Line Bille [Aarhus University Hospital, Department of Histopathology, Aarhus (Denmark); Breining, Peter [Aarhus University Hospital, Department of Endocrinology and Metabolism, Aarhus (Denmark); Petersen, Mikkel Steen [Aarhus University Hospital, Department of Clinical Immunology, Aarhus (Denmark); Dagnaes-Hansen, Frederik [Aarhus University, Department of Biomedicine, Aarhus (Denmark)


    Immune cells utilize acetylcholine as a paracrine-signaling molecule. Many white blood cells express components of the cholinergic signaling pathway, and these are up-regulated when immune cells are activated. However, in vivo molecular imaging of cholinergic signaling in the context of inflammation has not previously been investigated. We performed positron emission tomography (PET) using the glucose analogue 18F-FDG, and 11C-donepezil and 18F-FEOBV, markers of acetylcholinesterase and the vesicular acetylcholine transporter, respectively. Mice were inoculated subcutaneously with Staphylococcus aureus, and PET scanned at 24, 72, 120, and 144 h post-inoculation. Four pigs with post-operative abscesses were also imaged. Finally, we present initial data from human patients with infections, inflammation, and renal and lung cancer. In mice, the FDG uptake in abscesses peaked at 24 h and remained stable. The 11C-donepezil and 18F-FEOBV uptake displayed progressive increase, and at 120-144 h was nearly at the FDG level. Moderate 11C-donepezil and slightly lower 18F-FEOBV uptake were seen in pig abscesses. PCR analyses suggested that the 11C-donepezil signal in inflammatory cells is derived from both acetylcholinesterase and sigma-1 receptors. In humans, very high 11C-donepezil uptake was seen in a lobar pneumonia and in peri-tumoral inflammation surrounding a non-small cell lung carcinoma, markedly superseding the 18F-FDG uptake in the inflammation. In a renal clear cell carcinoma no 11C-donepezil uptake was seen. The time course of cholinergic tracer accumulation in murine abscesses was considerably different from 18F-FDG, demonstrating in the 11C-donepezil and 18F-FEOBV image distinct aspects of immune modulation. Preliminary data in humans strongly suggest that 11C-donepezil can exhibit more intense accumulation than 18F-FDG at sites of chronic inflammation. Cholinergic PET imaging may therefore have potential applications for basic research into cholinergic

  5. Cholinergic PET imaging in infections and inflammation using (11)C-donepezil and (18)F-FEOBV. (United States)

    Jørgensen, Nis Pedersen; Alstrup, Aage K O; Mortensen, Frank V; Knudsen, Karoline; Jakobsen, Steen; Madsen, Line Bille; Bender, Dirk; Breining, Peter; Petersen, Mikkel Steen; Schleimann, Mariane Høgsberg; Dagnæs-Hansen, Frederik; Gormsen, Lars C; Borghammer, Per


    Immune cells utilize acetylcholine as a paracrine-signaling molecule. Many white blood cells express components of the cholinergic signaling pathway, and these are up-regulated when immune cells are activated. However, in vivo molecular imaging of cholinergic signaling in the context of inflammation has not previously been investigated. We performed positron emission tomography (PET) using the glucose analogue 18F-FDG, and 11C-donepezil and 18F-FEOBV, markers of acetylcholinesterase and the vesicular acetylcholine transporter, respectively. Mice were inoculated subcutaneously with Staphylococcus aureus, and PET scanned at 24, 72, 120, and 144 h post-inoculation. Four pigs with post-operative abscesses were also imaged. Finally, we present initial data from human patients with infections, inflammation, and renal and lung cancer. In mice, the FDG uptake in abscesses peaked at 24 h and remained stable. The 11C-donepezil and 18F-FEOBV uptake displayed progressive increase, and at 120-144 h was nearly at the FDG level. Moderate 11C-donepezil and slightly lower 18F-FEOBV uptake were seen in pig abscesses. PCR analyses suggested that the 11C-donepezil signal in inflammatory cells is derived from both acetylcholinesterase and sigma-1 receptors. In humans, very high 11C-donepezil uptake was seen in a lobar pneumonia and in peri-tumoral inflammation surrounding a non-small cell lung carcinoma, markedly superseding the 18F-FDG uptake in the inflammation. In a renal clear cell carcinoma no 11C-donepezil uptake was seen. The time course of cholinergic tracer accumulation in murine abscesses was considerably different from 18F-FDG, demonstrating in the 11C-donepezil and 18F-FEOBV image distinct aspects of immune modulation. Preliminary data in humans strongly suggest that 11C-donepezil can exhibit more intense accumulation than 18F-FDG at sites of chronic inflammation. Cholinergic PET imaging may therefore have potential applications for basic research into cholinergic

  6. Partial expression of catecholaminergic traits in cholinergic chick ciliary ganglia: studies in vivo and in vitro. (United States)

    Iacovitti, L; Joh, T H; Albert, V R; Park, D H; Reis, D J; Teitelman, G


    We have previously demonstrated that at embryonic Day (E) 8, some cells of the chick ciliary ganglion (CG) contain the catecholaminergic (CA) enzyme tyrosine hydroxylase (TH), but not phenylethanolamine-N-methyltransferase (PNMT); and that in culture essentially all cells express both enzymes. In the present study, we sought to determine, first, whether the expression of adrenergic traits in the CG in vivo is transient or permanent in the CG. To do so, CGs were removed from E5 to postnatal Day 5, fixed, and processed for the immunocytochemical localization of the CA enzymes: TH, L-amino acid decarboxylase (AADC), and PNMT. At all stages examined, some CG neurons expressed TH immunoreactivity (TH-IR) and all contained AADC-IR. However, none stained with PNMT antibodies, indicating that these cells stably express some, but not all, of the CA enzymes. Second, we examined whether CG neurons in culture expressed other CA markers. CG neurons did not contain detectable levels of TH enzyme activity nor did they transport and store exogenously supplied monoamines. These results indicate that some but not all traits necessary for adrenergic function are present in CG neurons in vitro. Third, we sought to establish whether CA expression in CG neurons is affected by modification in culture conditions. Cultures of CG neurons continued to express TH-IR even when grown in the presence of either 50% HCM or 20 mM KCl for 5 days. Finally, the expression of the cholinergic enzyme, choline acetyltransferase (CAT) was assessed in CG cultures by biochemical assay. CAT activity increased five-fold between 5 and 17 days in vitro, irrespective of the presence of TH-IR in 100% of the CG neurons of sister cultures. These data suggest that at least a subpopulation of CG neurons express both TH and CAT in culture. We conclude that the postmitotic neurons of the CG are able to express some but not all of the traits characteristic of a CA phenotype while maintaining cholinergic expression. These

  7. Reducing cholinergic constriction: the major reversible mechanism in COPD

    Directory of Open Access Journals (Sweden)

    V. Brusasco


    Full Text Available The airway narrowing in chronic obstructive pulmonary disease (COPD has often been misunderstood as being irreversible. However, a large proportion of patients with COPD do respond to bronchodilator agents with significant changes in lung function. Unlike in asthma, abnormalities in airway smooth muscle structure or function are not believed to play a key role in COPD airway narrowing. Although there are only limited data suggesting that cholinergic tone may be increased in COPD, the well-documented efficacy of antimuscarinic agents in increasing airway calibre suggests that cholinergic tone represents the major reversible component of airflow obstruction in these patients. Airway wall thickening and loss of airway-to-parenchyma interdependence are nonreversible components of airflow obstruction in COPD that may amplify the effect of changes in airway smooth muscle tone. Thus, keeping airway smooth muscle tone to a minimum might offer patients long-lasting airway patency and protection against breathlessness, which is the major complaint of patients with COPD. Receptor antagonism by anticholinergic agents can achieve effective relaxation of airway smooth muscle in COPD. According to a classical view of cholinergic receptor function and distribution, the ideal anticholinergic bronchodilator would be one that blocks both M1 and M3 receptors, which mediate airway smooth muscle contraction, but not the M2 receptor, stimulation of which reduces acetylcholine release from vagus nerve endings and prevents the airway smooth muscle from contracting by excessive increments. Agents with such pharmacodynamic selectivity are not available, but effective and prolonged inhibition of airway smooth muscle tone has been obtained with tiotropium, which binds to all three major muscarinic receptor subtypes, but for much longer to M3 than to M2 receptors. Recent data show that long-term treatment with tiotropium for 1 yr helps sustain 24-h airway patency. This

  8. Immunocytochemical localization of cholinergic amacrine cells in the bat retina. (United States)

    Park, Eun-Bee; Gu, Ya-Nan; Jeon, Chang-Jin


    The purpose of this study was to localize the cholinergic amacrine cells, one of the key elements of a functional retina, in the retina of a microbat, Rhinolophus ferrumequinum. The presence and localization of choline acetyltransferase-immunoreactive (ChAT-IR) cells in the microbat retina were investigated using immunocytochemistry, confocal microscopy, and quantitative analysis. These ChAT-IR cells were present in the ganglion cell layer (GCL) and inner part of the inner nuclear layer (INL), as previously reported in various animals. However, the bat retina also contained some ChAT-IR cells in the outer part of the INL. The dendrites of these cells extended into the outer plexiform layer, and those of the cells in the inner INL extended within the outer part of the inner plexiform layer (IPL). The dendrites of the ChAT-IR cells in the GCL extended into the middle of the IPL and some fibers ramified up to the outer IPL. The average densities of ChAT-IR cells in the GCL, inner INL, and outer INL were 259±31cells/mm 2 , 469±48cells/mm 2 , and 59±8cells/mm 2 , respectively. The average total density of the ChAT-IR cells was 788±58cells/mm 2 (mean±S.D.; n=3; 2799±182 cells/retina). We also found that the cholinergic amacrine cells in the bat retina contained calbindin, one of the calcium-binding proteins, but not calretinin or parvalbumin. As the cholinergic amacrine cells play key roles in the direction selectivity and optokinetic eye reflex in the other mammalian retinas, the present study might provide better information of the cytoarchitecture of bat retina and the basic sources for further physiological studies. Copyright © 2017 Elsevier GmbH. All rights reserved.

  9. Central command does not decrease cardiac parasympathetic efferent nerve activity during spontaneous fictive motor activity in decerebrate cats. (United States)

    Kadowaki, Akito; Matsukawa, Kanji; Wakasugi, Rie; Nakamoto, Tomoko; Liang, Nan


    To examine whether withdrawal of cardiac vagal efferent nerve activity (CVNA) predominantly controls the tachycardia at the start of exercise, the responses of CVNA and cardiac sympathetic efferent nerve activity (CSNA) were directly assessed during fictive motor activity that occurred spontaneously in unanesthetized, decerebrate cats. CSNA abruptly increased by 71 ± 12% at the onset of the motor activity, preceding the tachycardia response. The increase in CSNA lasted for 4-5 s and returned to the baseline, even though the motor activity was not ended. The increase of 6 ± 1 beats/min in heart rate appeared with the same time course of the increase in CSNA. In contrast, CVNA never decreased but increased throughout the motor activity, in parallel with a rise in mean arterial blood pressure (MAP). The peak increase in CVNA was 37 ± 9% at 5 s after the motor onset. The rise in MAP gradually developed to 21 ± 2 mmHg and was sustained throughout the spontaneous motor activity. Partial sinoaortic denervation (SAD) blunted the baroreflex sensitivity of the MAP-CSNA and MAP-CVNA relationship to 22-33% of the control. Although partial SAD blunted the initial increase in CSNA to 53% of the control, the increase in CSNA was sustained throughout the motor activity. In contrast, partial SAD almost abolished the increase in CVNA during the motor activity, despite the augmented elevation of 31 ± 1 mmHg in MAP. Because afferent inputs from both muscle receptors and arterial baroreceptors were absent or greatly attenuated in the partial SAD condition, only central command was operating during spontaneous fictive motor activity in decerebrate cats. Therefore, it is likely that central command causes activation of cardiac sympathetic outflow but does not produce withdrawal of cardiac parasympathetic outflow during spontaneous motor activity.

  10. Central as well as peripheral attentional bottlenecks in dual-task performance activate lateral prefrontal cortices

    Directory of Open Access Journals (Sweden)

    Andre J Szameitat


    Full Text Available Human information processing suffers from severe limitations in parallel processing. In particular, when required to respond to two stimuli in rapid succession, processing bottlenecks may appear at central and peripheral stages of task processing. Importantly, it has been suggested that executive functions are needed to resolve the interference arising at such bottlenecks. The aims of the present study were to test whether central attentional limitations (i.e., bottleneck at the decisional response selection stage as well as peripheral limitations (i.e., bottleneck at response initiation both demand executive functions located in the lateral prefrontal cortex. For this, we re-analysed two previous studies, in which a total of 33 participants performed a dual-task according to the paradigm of the psychological refractory period (PRP during fMRI. In one study (N=17, the PRP task consisted of two two-choice response tasks known to suffer from a central bottleneck (CB group. In the other study (N=16, the PRP task consisted of two simple-response tasks known to suffer from a peripheral bottleneck (PB group. Both groups showed considerable dual-task costs in form of slowing of the second response in the dual-task (PRP effect. Imaging results are based on the subtraction of both single-tasks from the dual-task within each group. In the CB group, the bilateral middle frontal gyri and inferior frontal gyri were activated. Higher activation in these areas was associated with lower dual-task costs. In the PB group, the right middle frontal and inferior frontal gyrus were activated. Here, higher activation was associated with higher dual-task costs. In conclusion we suggest that central and peripheral bottlenecks both demand executive functions located in lateral prefrontal cortices. Differences between the CB and PB groups with respect to the exact prefrontal areas activated and the correlational patterns suggest that the executive functions resolving

  11. Water vapour loss threshold and induction of cholinergic urticaria. (United States)

    Tupker, R A; Doeglas, H M


    A patient is described with cholinergic urticaria (CU) in whom the symptoms could be provoked by gustatory stimuli. The aim of this study was to investigate whether there is a threshold of sweating (monitored by skin water vapour loss (SVL) measurements) at which CU can be provoked. Provocations with lemon and sal-ammoniac liquorice induced transient sweating differing both in degree and duration. Only 'doubly salted' liquorice, which caused the most intense sweat response, resulted in urticarial lesions. This findings suggest a threshold dependency for the induction of CU. SVL measurement may be a useful method for the evaluation of sweating tests in CU patients.

  12. Cholinergic System Under Aluminium Toxicity in Rat Brain


    Yellamma, K.; Saraswathamma, S.; Kumari, B. Nirmala


    The present investigation envisages the toxic effects of aluminium on the cholinergic system of male albino rat brain. Aluminium toxicity (LD50/24 h) evaluated as per Probit method was found to be 700 mg/kg body weight. One-fifth of lethal dose was taken as the sublethal dose. For acute dose studies, rats were given a single lethal dose of aluminium acetate orally for one day only and for chronic dose studies, the rats were administered with sublethal dose of aluminium acetate once in a day f...

  13. Cholinergic and anticholinesterase activities of total protein extract ...

    African Journals Online (AJOL)

    Traditional herbal medicines such as Morinda morindoïdes are used for treatment of intestinal disorders including constipation in Ivory Coast. The aim of present study was to investigate the effect of total protein of Morinda morindoïdes extract (PT-Mm) on rabbit duodenum contractility and the involved possible ...

  14. Cholinergic neurotransmission seems not to be involved in depression but possibly in personality.


    Fritze, J; Lanczik, M; Sofic, E.; M. Struck; Riederer, P


    Concordant with the adrenergic-cholinergic imbalance hypothesis of affective psychosis, there is a cholinergic supersensitivity in depression. Thus, the anticholinergic properties of some antidepressants might contribute to their efficacy. However, in the present double-blind studies (n = 20) with mianserin and viloxazine, respectively, which lack anticholinergic properties, adjunctive treatment with the anticholinergic biperiden versus placebo did not enhance the antidepressive efficacy. The...

  15. Central Hemodynamics and Oxygen Transport in Various Activation of Patients Operated On Under Extracorporeal Circulation

    Directory of Open Access Journals (Sweden)

    Ye. V. Dzybinskaya


    Full Text Available Objective: to study central hemodynamics, the determinants of myocardial oxygen balance, and the parameters of oxygen transport in various activation of patients after surgery under extracorporeal circulation. Subjects and methods. Thirty-four patients aged 57.8±2.5 years who had coronary heart disease were divided into 2 groups: 1 those with late activation (artificial ventilation time 157±9 min and 2 those with immediate activation (artificial ventilation time 33±6 min. Group 2 patients were, if required, given fentanyl, midazolam, or myorelaxants. Results. During activation, there were no intergroup differences in the mean levels of the major parameters of cardiac pump function, in the determinants of coronary blood flow (coronary perfusion gradients and myocardial oxygen demand (the product of heart rate by systolic blood pressure, and in the parameters of oxygen transport, including arterial lactatemia. After tracheal extubation, the left ventricular pump coefficient was increased considerably (up to 3.8±0.2 and 4.4±0.2 gm/mm Hg/m2 in Groups 1 and 2, respectively; p<0.05 with minimum inotropic support (dopamine and/or dobutamine being used at 2.7±0.3 and 2.4±0.3 mg/kg/min, respectively. In both groups, there were no close correlations between the indices of oxygen delivery and consumption at all stages of the study, which was indicative of no transport-dependent oxygen uptake. Conclusion. When the early activation protocol was followed up, the maximum acceleration of early activation, including that using specific antagonists of anesthetics, has no negative impact on central hemodynamics, the determinants of myocardial oxygen balance and transport in patients operated on under extracorporeal circulation. Key words: early activation, surgery under extracorporeal circulation, tracheal extubation in the operating-room, central hemodynamics, oxygen transport.

  16. A cholinergic feedback circuit to regulate striatal population uncertainty and optimize reinforcement learning. (United States)

    Franklin, Nicholas T; Frank, Michael J


    Convergent evidence suggests that the basal ganglia support reinforcement learning by adjusting action values according to reward prediction errors. However, adaptive behavior in stochastic environments requires the consideration of uncertainty to dynamically adjust the learning rate. We consider how cholinergic tonically active interneurons (TANs) may endow the striatum with such a mechanism in computational models spanning three Marr's levels of analysis. In the neural model, TANs modulate the excitability of spiny neurons, their population response to reinforcement, and hence the effective learning rate. Long TAN pauses facilitated robustness to spurious outcomes by increasing divergence in synaptic weights between neurons coding for alternative action values, whereas short TAN pauses facilitated stochastic behavior but increased responsiveness to change-points in outcome contingencies. A feedback control system allowed TAN pauses to be dynamically modulated by uncertainty across the spiny neuron population, allowing the system to self-tune and optimize performance across stochastic environments.

  17. Central European MetEor NeTwork: Current status and future activities (United States)

    Srba, J.; Koukal, J.; Ferus, M.; Lenža, L.; Gorková, S.; Civiš, S.; Simon, J.; Csorgei, T.; Jedlièka, M.; Korec, M.; Kaniansky, S.; Polák, J.; Spurný, M.; Brázdil, T.; Mäsiar, J.; Zima, M.; Delinèák, P.; Popek, M.; Bahýl, V.; Piffl, R.; Èechmánek, M.


    The Central European video Meteor Network (CEMeNt) established in 2010 is a platform for cross-border cooperation in the field of video meteor observations between Czech Republic and Slovakia. During five years of operation the CEMeNt network went through an extensive development. In total, 37 video systems were working on 20 permanent stations located in Czech Republic and Slovakia during 2015. In this paper we summarize CEMeNt current status and introduce some future activities.

  18. Pauses in Striatal Cholinergic Interneurons: What is Revealed by Their Common Themes and Variations?

    Directory of Open Access Journals (Sweden)

    Yan-Feng Zhang


    Full Text Available Striatal cholinergic interneurons, the so-called tonically active neurons (TANs, pause their firing in response to sensory cues and rewards during classical conditioning and instrumental tasks. The respective pause responses observed can demonstrate many commonalities, such as constant latency and duration, synchronous occurrence in a population of cells, and coincidence with phasic activities of midbrain dopamine neurons (DANs that signal reward predictions and errors. Pauses can however also show divergent properties. Pause latencies and durations can differ in a given TAN between appetitive vs. aversive outcomes in classical conditioning, initial excitation can be present or absent, and a second pause can variably follow a rebound. Despite more than 20 years of study, the functions of these pause responses are still elusive. Our understanding of pause function is hindered by an incomplete understanding of how pauses are generated. In this mini-review article, we compare pause types, as well as current key hypotheses for inputs underlying pauses that include dopamine-induced inhibition through D2-receptors, a GABA input from ventral tegmental area, and a prolonged afterhyperpolarization induced by excitatory input from the cortex or from the thalamus. We review how each of these mechanisms alone explains some but not all aspects of pause responses. These mechanisms might need to operate in specific but variable sets of sequences to generate a full range of pause responses. Alternatively, these mechanisms might operate in conjunction with an underlying control mechanism within cholinergic interneurons which could potentially provide a framework to generate the common themes and variations seen amongst pause responses.

  19. Restraint stress increases serotonin release in the central nucleus of the amygdala via activation of corticotropin-releasing factor receptors. (United States)

    Mo, Bing; Feng, Na; Renner, Kenneth; Forster, Gina


    Decreases in serotonergic activity in the central nucleus of the amygdala reduce responses to stressors, suggesting an important role for serotonin in this region of the amygdala in stress reactivity. However, it is not known whether exposure to stressors actually increases serotonin release in the central nucleus of the amygdala. The current experiment tested the hypothesis that restraint stress increases extracellular serotonin within the central nucleus of the amygdala and adjacent medial amygdala using in vivo microdialysis in awake male rats during the dark phase of the light-dark cycle. Serotonin release in the central nucleus increased immediately in response to restraint stress. In contrast, there was no change in serotonin release within the adjacent medial amygdala during or following restraint. Since corticotropin-releasing factor is an important mediator of both responses to stressors and serotonergic activity, subsequent experiments tested the hypothesis that central nucleus serotonergic response to restraint stress is mediated by central corticotropin-releasing factor receptors. Administration of the corticotropin-releasing factor type 1 and 2 receptor antagonist d-Phe-CRF (icv, 10 microg/5 microl) prior to restraint stress suppressed restraint-induced serotonin release in the central nucleus. The results suggest that restraint stress rapidly and selectively increases serotonin release in the central nucleus of the amygdala by the activation of central corticotropin-releasing factor receptors. Furthermore, the results imply that corticotropin-releasing factor mediated serotonergic activity in central nucleus of the amygdala may be an important component of a stress response.

  20. [Central nervous system infections in HIV patients in the era of high activity antiretroviral treatment]. (United States)

    Rivas González, P; Fernández Guerrero, M L


    Although the incidence of most central nervous system infections in HIV+ patients has decreased after the introduction of the modern antiretroviral treatments, they are still a major cause of morbidity and mortality. New technologies in molecular biology and neuroradiology establish the diagnosis in many cases and have decreased the need for cerebral biopsy. Prognosis has improved substantially after the introduction of high activity antiretroviral treatment; more active treatments are needed, however, for infections as PML or citomegalovirus encephalitis because of their still unacceptably high mortality.

  1. The effect of intravitreal cholinergic drugs on motor control. (United States)

    Willis, Gregory L; Freelance, Christopher B


    The retina bears embryological, neurochemical and functional similarities to the circadian and dopamine systems of the brain. Recent studies have shown that the intravitreal injection of minute quantities of L-dopa and of the melatonin receptor antagonist ML-23 have anti-Parkinsonian potential. Furthermore, it has been suggested that light therapy may be potentially useful in treating some aspects of Parkinson's disease (PD) and it is hypothesized that this treatment works via the circadian system. Given that little is known about the mechanism by which such treatments work the present study was designed to examine the role of the acetyl cholinergic system of the retina in gross bodily movement. While IVIT atropine was shown to improve movement in intact rats Cogentin treated rats showed impairment of motor function compared to control rats or to rats treated with any other cholinergic drug. Furthermore, a link between the phase of the light/dark cycle and the efficacy of these drugs in altering movement was demonstrated. These results show that anticholinergic systems in the retina can exert control over movement which has been solely attributed to the function of deep brain structures. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Bovine pancreatic polypeptide as an antagonist of muscarinic cholinergic receptors

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    Pan, G.Z.; Lu, L.; Qian, J.; Xue, B.G.


    In dispersed acini from rat pancreas, it was found that bovine pancreatic polypeptide (BPP) and its C-fragment hexapeptide amide (PP-6), at concentrations of 0.1 and 30, respectively, could significantly inhibit amylase secretion stimulated by carbachol, and this inhibition by BPP was dose dependent. /sup 45/Ca outflux induced by carbachol was also inhibited by BPP or PP-6, but they had no effect on cholecystokinin octapeptide- (CCK-8) or A23187-stimulated /sup 45/Ca outflux. BPP was also capable of displacing the specific binding of (/sup 3/H)-quinuclidinyl benzilate to its receptors, and it possessed a higher affinity (K/sub i/35nM) than carbachol (K/sub i/ 1.8 in binding with M-receptors. It is concluded from this study that BPP acts as an antagonist of muscarinic cholinergic receptors in rat pancreatic acini. In addition, BPP inhibited the potentiation of amylase secretion caused by the combination of carbachol plus secretin or vasoactive intestinal peptide. This may be a possible explanation of the inhibitory effect of BPP on secretin-induced pancreatic enzyme secretion shown in vivo, since pancreatic enzyme secretion stimulated by secretin under experimental conditions may be the result of potentiation of enzyme release produced by the peptide in combination with a cholinergic stimulant.

  3. Central activation, metabolites, and calcium handling during fatigue with repeated maximal isometric contractions in human muscle. (United States)

    Cairns, Simeon P; Inman, Luke A G; MacManus, Caroline P; van de Port, Ingrid G L; Ruell, Patricia A; Thom, Jeanette M; Thompson, Martin W


    To determine the roles of calcium (Ca 2+ ) handling by sarcoplasmic reticulum (SR) and central activation impairment (i.e., central fatigue) during fatigue with repeated maximal voluntary isometric contractions (MVC) in human muscles. Contractile performance was assessed during 3 min of repeated MVCs (7-s contraction, 3-s rest, n = 17). In ten participants, in vitro SR Ca 2+ -handling, metabolites, and fibre-type composition were quantified in biopsy samples from quadriceps muscle, along with plasma venous [K + ]. In 11 participants, central fatigue was compared using tetanic stimulation superimposed on MVC in quadriceps and adductor pollicis muscles. The decline of peak MVC force with fatigue was similar for both muscles. Fatigue resistance correlated directly with % type I fibre area in quadriceps (r = 0.77, P = 0.009). The maximal rate of ryanodine-induced Ca 2+ -release and Ca 2+ -uptake fell by 31 ± 26 and 28 ± 13%, respectively. The tetanic force depression was correlated with the combined reduction of ATP and PCr, and increase of lactate (r = 0.77, P = 0.009). Plasma venous [K + ] increased from 4.0 ± 0.3 to 5.4 ± 0.8 mM over 1-3-min exercise. Central fatigue occurred during the early contractions in the quadriceps in 7 out of 17 participants (central activation ratio fell from 0.98 ± 0.05 to 0.86 ± 0.11 at 1 min), but dwindled at exercise cessation. Central fatigue was seldom apparent in adductor pollicis. Fatigue with repeated MVC in human limb muscles mainly involves peripheral aspects which include impaired SR Ca 2+ -handling and we speculate that anaerobic metabolite changes are involved. A faster early force loss in quadriceps muscle with some participants is attributed to central fatigue.

  4. Variations in Tectonic Activities of the Central and Southwestern Foothills, Taiwan, Inferred from River Hack Profiles

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    Yen-Chieh Chen


    Full Text Available A longitudinal profile of a river under static equilibrium shows no degradation or aggradation and can be ideally described as a straight line on a semi-logarithmic graph. This type of profile is called a “Hack profile”. If a river runs across uprising active structure systems, its Hack profile becomes convex. Accumulated tectonic strain varies positively with the intensity of the upwarping in Hack-profile convexity. In this paper, we compare curvature changes in Hack profiles of a series of rivers running through faults in the central and southwestern Foothills of Taiwan. Longitudinal profiles of these rivers were derived from two versions of topographic maps (1904 and 1985 and recent DTM data (2000. Prior to comparisons, we calibrated the 1904 topographic map, named “Taiwan Bautu”, by “offsetting” horizontal coordinates north and westward approximately 440 m and then “linear transforming” the elevation values. The Tungtzchiau fault of the central Foothills has remained inactive since 1935. Here relatively high uplift activity near the Wu River is indicated by significantly convex Hack profiles. This strain accumulation can be attributed to a lack of small magnitude earthquakes along the fault over the past 70 years. In the southwestern Foothills, relatively high uplift activity of similar intensity to the central Foothills is indicted near the Neocho River. Significant profiles with concave segments below the ideal graded profiles, at the lower reaches of rivers where continuous small magnitude strain release events have occurred, can only be found along the Sandieh, Neocho and Bazhang rivers in the southwestern Foothills. All these findings indicate that fault systems in the central Foothills tend to be locked and these faults could yield large earthquakes similar to the Chi-Chi event.

  5. Active tectonics and Quaternary landscape evolution across the western Panama block, Costa Rica, Central America (United States)

    Marshall, Jeffrey Scott

    Three aspects of active tectonism are examined across central Costa Rica: (1) fault kinematics; (2) volcanic arc retreat; and (3) spatially variable coastal uplift. Diffuse faulting along the Central Costa Rica Deformed Belt (CCRDB) defines the western margin of the Panama block and aligns with the rough-smooth boundary (RSB) on the subducting Cocos plate. Sub-horizontal subduction of rough, hotspot thickened crust (Cocos Ridge and seamounts) shifts active shortening into the volcanic arc along the CCRDB. Mesoscale faults express variable kinematics across three domains: transtension in the forearc, transcurrent motion across the volcanic arc, and transpression in the back arc. Fault kinematics agree with seismicity and GPS data, and isotopic ages confirm that faulting postdates the late Neogene onset of shallow subduction. Stratigraphic correlation augmented by 40Ar/39Ar dating constrain the timing of Quaternary arc migration from the Neogene Aguacate range to the modern Cordillera Central. The Valle Central basin, between the cordilleras, filled with thick sequences of lavas, pyroclastic flows, and lahars. Middle Pleistocene drainage capture across the Aguacate arc linked the Valle Central with the Pacific slope and ash flows descended onto the coastal Orotina debris fan. Arc retreat reflects slab shallowing and enhanced tectonic erosion as rough crust entered the subduction zone. Differing subduction parameters across the RSB (crustal age, slab dip, roughness) produce marked contrasts in coastal tectonism. Varying uplift rates across coastal faults reflect sub-horizontal subduction of seamount roughness. Three groups (I--III) of fluvial terraces are correlated along the coast by isotopic ages and geomorphic characteristics. Base level fluctuations and terrace genesis reflect interaction between eustatic sea level and spatially variable rock uplift. Low uplift rates (north of RSB), yield one surface per terrace group, whereas moderate rates (south of RSB

  6. [Interaction of the cholinergic and adrenergic systems during generation of 2 forms of sleep in Rana temporaria frogs and Emys orbicularis turtles]. (United States)

    Karmanova, I G; Belich, A I; Voronov, I B; Shilling, N V


    Universal role of cholinergic mechanisms has been revealed in triggering of activation during two forms of sleep in cold-blooded animals--the primary sleep (fish, amphibians) and intermediate sleep (reptiles). The intensity of activation phenomenon in the brain during these forms of the sleep is controlled by functional interaction between cholinergic and adrenergic systems of the brain. It is suggested that the vegetative nervous system is the most ancient regulatory system of the cycle awakefulness-sleep in vertebrates. The observed activation phenomenon, developing during sleep in the cold-blooded animals, with respect to its biological role plays presumably the same function as paradoxical stage during slow--wave sleep in warm-blooded animals.

  7. Cholinergic Transactivation of the EGFR in HaCaT Keratinocytes Stimulates a Flotillin-1 Dependent MAPK-Mediated Transcriptional Response

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    Sina Kühne


    Full Text Available Acetylcholine and its receptors regulate numerous cellular processes in keratinocytes and other non-neuronal cells. Muscarinic acetylcholine receptors are capable of transactivating the epidermal growth factor receptor (EGFR and, downstream thereof, the mitogen-activated protein kinase (MAPK cascade, which in turn regulates transcription of genes involved in cell proliferation and migration. We here show that cholinergic stimulation of human HaCaT keratinocytes results in increased transcription of matrix metalloproteinase MMP-3 as well as several ligands of the epidermal growth factor family. Since both metalloproteinases and the said ligands are involved in the transactivation of the EGFR, this transcriptional upregulation may provide a positive feed-forward loop for EGFR/MAPK activation. We here also show that the cholinergic EGFR and MAPK activation and the upregulation of MMP-3 and EGF-like ligands are dependent on the expression of flotillin-1 which we have previously shown to be a regulator of MAPK signaling.

  8. Fatigue versus activity-dependent fatigability in patients with central or peripheral motor impairments. (United States)

    Dobkin, Bruce H


    In the rehabilitation literature, fatigue is a common symptom of patients with any neurological impairment when defined as a subjective lack of physical and mental energy that interferes with usual activities. Some complaints may, however, arise from fatigability , an objective decline in strength as routine use of muscle groups proceeds. By this refined definition of fatigue, exercise or sustained use reduces the ability of muscles to produce force or power, regardless of whether the task can be sustained. Fatigability may be masked clinically because (1) the degree of weakening is not profound, (2) activity-induced weakness rapidly lessens with cessation of exertion, and (3) clinicians rarely test for changes in strength after repetitive movements to objectively entertain the diagnosis. The repetitive movements that induce fatigability during daily activities are an iterative physiological process that depends on changing states induced by activation of spared central and peripheral neurons and axons and compromised muscle. Fatigability may be especially difficult to localize in patients undergoing neurorehabilitation, in part because no finite boundary exists between the central and peripheral components of motor reserve and endurance. At the bedside, however, manual muscle testing before and after repetitive movements could at least put some focus on the presence of fatigability in any patient with motor impairments and related disabilities. Reliable measures of fatigability beyond a careful clinical examination, such as physiological changes monitored by cerebral functional neuroimaging techniques and more standardized central and peripheral electrical and magnetic stimulation paradigms, may help determine the mechanisms of activity-dependent weakening and lead to specific therapies. Testable interventions to increase motor reserve include muscle strengthening and endurance exercises, varying the biomechanical requirements of repetitive muscle contractions

  9. Tetrodotoxin-resistant non-cholinergic neurogenic contraction evoked by capsaicinoids and piperine on the guinea-pig trachea. (United States)

    Szolcsányi, J


    Contraction of the isolated tracheal strip to capsaicin was prevented by chronic denervation of the tissue. Tetrodotoxin, hyoscine and hexamethonium caused no inhibition of the response, suggesting that tetrodotoxin-resistant terminal portions of non-cholinergic nerves were activated in this way. There was a strong correlation between the pain-producing and tracheoconstrictor effects of piperine, pungent and non-pungent capsaicin congeners. Common site of action was evidenced by crossed tachyphylaxis. It is concluded that the capsaicin-sensitive sensory nerve endings have a dual sensory-efferent function. Excitation-secretion coupling in this system could operate without an axon reflex.

  10. Application of geodetic leveling data on recent fault activity in Central Alborz, Iran (United States)

    Saberi, Ehsan; Yassaghi, Ali; Djamour, Yahya


    In this paper, geodetic leveling data in three lines across the Central Alborz range have been utilized to analyse recent activities of the range major faults. These data gathered by National Cartographic Center of Iran in three times during the past 22-32 yr. Mathematical modeling is applied to remove systematic errors from the raw leveling data. The vertical movement (uplift or subsidence) rate is estimated from height differences of benchmarks during geodetic leveling data times. The results show that the average uplift in Central Alborz during data times varies from 17.0 ± 0.9 to 18.1 ± 0.9 mm in the hangingwall of the major North Tehran and Mosha faults, respectively. The lower values of the uplift across the faults are taken as an account for the faults locking during the data times and their possible seismic potential. Evaluation of the uplift rate for the major faults under study in Central Alborz indicates the reduction of vertical uplift from west to east along the main proven faults like the Mosha Fault. The rate of uplift in the hangingwall of the Mosha Fault decreases from 0.921 ± 0.283 (mm yr-1) (20.3 ± 0.905 mm 22 yr-1) in west to the rate of 0.508 ± 0.228 (mm yr-1) (11.7 ± 1.031 (mm 23 yr-1)) in east. The unusual subsidence anomalous in some benchmarks is considered as the effect of geological features such as Karst phenomena. Moreover, comparison on the rate of vertical movement across the Central Alborz shows the greater uplift in the southern flank (10.4 ± 0.9 mm) with respect to its northern flank (6.3 ± 0.9 mm) during the data times. This interpretation is in agreement with Global Positioning System studies that indicates a progress of young deformation in Central Alborz toward the range southern hillside.

  11. Involvement of cholinergic nicotinic receptors in the menthol-induced gastric relaxation. (United States)

    Amato, Antonella; Serio, Rosa; Mulè, Flavia


    We have previously demonstrated that menthol reduces murine gastric tone in part through a neural mechanism, involving adrenergic pathways and reduction of ongoing release of acetylcholine from enteric nerves. In the present study we aimed to verify whether the gastric relaxation to menthol may be triggered by interaction with neural receptors or ionic channels proteins, such as transient receptor potential (TRP)-melastatin8 (TRPM8), TRP-ankyrin 1 (TRPA1), 5-hydroxytriptamine 3 (5-HT3) receptor or cholinergic nicotinic receptors. Spontaneous mechanical activity was detected in vitro as changes in intraluminal pressure from isolated mouse stomach. Menthol (0.3-30 mM) induced gastric relaxation which was not affected by 5-benzyloxytryptamine, a TRPM8 receptor antagonist, HC030031, a TRPA1 channel blocker. In addition, allylisothiocyanate, a TRPA1 agonist, but not (2S,5R)-2-Isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexanecarboximide, a selective TRPM8 agonist, induced gastric relaxation. Genic expression of TRPA1, but not of TRPM8, was revealed in mouse stomach. Indeed, menthol-induced gastric relaxation was significantly reduced by hexamethonium, cholinergic nicotinic receptor antagonist. Menthol, at concentrations that failed to affect gastric tone, reduced the contraction induced by dimethylphenylpiperazinium, nicotinic receptor agonist. The joint application of hexamethonium and atropine, muscarinc receptor antagonist, or hexamethonium and phentholamine, α-adrenergic receptor antagonist, did not produce any additive reduction of the relaxant response to menthol. Lastly, ondansetron, a 5-HT3 receptor antagonist, was ineffective. In conclusion, our study suggests that nicotinic receptors, but not TRP and 5-HT3 receptors, are molecular targets for menthol inducing murine gastric relaxation, ultimately due to the reduction of acetylcholine release from enteric nerves. Copyright © 2014 Elsevier B.V. All rights reserved.

  12. VTA GABA neurons modulate specific learning behaviours through the control of dopamine and cholinergic systems

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    Meaghan C Creed


    Full Text Available The mesolimbic reward system is primarily comprised of the ventral tegmental area (VTA and the nucleus accumbens (NAc as well as their afferent and efferent connections. This circuitry is essential for learning about stimuli associated with motivationally-relevant outcomes. Moreover, addictive drugs affect and remodel this system, which may underlie their addictive properties. In addition to DA neurons, the VTA also contains approximately 30% ɣ-aminobutyric acid (GABA neurons. The task of signalling both rewarding and aversive events from the VTA to the NAc has mostly been ascribed to DA neurons and the role of GABA neurons has been largely neglected until recently. GABA neurons provide local inhibition of DA neurons and also long-range inhibition of projection regions, including the NAc. Here we review studies using a combination of in vivo and ex vivo electrophysiology, pharmacogenetic and optogenetic manipulations that have characterized the functional neuroanatomy of inhibitory circuits in the mesolimbic system, and describe how GABA neurons of the VTA regulate reward and aversion-related learning. We also discuss pharmacogenetic manipulation of this system with benzodiazepines (BDZs, a class of addictive drugs, which act directly on GABAA receptors located on GABA neurons of the VTA. The results gathered with each of these approaches suggest that VTA GABA neurons bi-directionally modulate activity of local DA neurons, underlying reward or aversion at the behavioural level. Conversely, long-range GABA projections from the VTA to the NAc selectively target cholinergic interneurons (CINs to pause their firing and temporarily reduce cholinergic tone in the NAc, which modulates associative learning. Further characterization of inhibitory circuit function within and beyond the VTA is needed in order to fully understand the function of the mesolimbic system under normal and pathological conditions.

  13. Characterization of cholinergic muscarinic receptor-stimulated phosphoinositide metabolism in brain from immature rats

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    Balduini, W.; Murphy, S.D.; Costa, L.G. (Univ. of Washington, Seattle (USA))


    Hydrolysis of phosphoinositides elicited by stimulation of cholinergic muscarinic receptors has been studied in brain from neonatal (7-day-old) rats in order to determine: (1) whether the neonatal rat could provide a good model system to study this signal-transduction pathway; and (2) whether potential differences with adult nerve tissue would explain the differential, age-related effects of cholinergic agonists. Accumulation of (3H) inositol phosphates in (3H)inositol prelabeled slices from neonatal and adult rats was measured as an index of phosphoinositide metabolism. Full (acetylcholine, methacholine, carbachol) and partial (oxotremorine, bethanechol) agonists had qualitatively similar, albeit quantitatively different, effects in neonatal and adult rats. Atropine and pirenzepine effectively blocked the carbachol-induced response with inhibition constants of 1.2 and 20.7 nM, respectively. In all brain areas, response to all agonists was higher in neonatal than adult rats, and in hippocampus and cerebral cortex the response was higher than in cerebellum or brainstem. The relative intrinsic activity of partial agonists was higher in the latter two areas (0.6-0.7) than in the former two (0.3-0.4). Carbachol-stimulated phosphoinositide metabolism in brain areas correlated well with the binding of (3H)QNB (r2 = 0.627) and, particularly, with (3H)pirenzepine (r2 = 0.911). In cerebral cortex the effect of carbachol was additive to that of norepinephrine and glutamate. The presence of calcium (250-500 microM) was necessary for maximal response to carbachol to be elicited; the EC50 value for Ca2+ was 65.4 microM. Addition of EDTA completely abolished the response. Removal of sodium ions from the incubation medium reduced the response to carbachol by 50%.

  14. Vagus nerve stimulation attenuates cerebral ischemia and reperfusion injury via endogenous cholinergic pathway in rat.

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    Ying Jiang

    Full Text Available Inflammation and apoptosis play critical roles in the acute progression of ischemic injury pathology. Emerging evidence indicates that vagus nerve stimulation (VNS following focal cerebral ischemia and reperfusion (I/R may be neuroprotective by limiting infarct size. However, the underlying molecular mechanisms remain unclear. In this study, we investigated whether the protective effects of VNS in acute cerebral I/R injury were associated with anti-inflammatory and anti-apoptotic processes. Male Sprague-Dawley (SD rats underwent VNS at 30 min after focal cerebral I/R surgery. Twenty-four h after reperfusion, neurological deficit scores, infarct volume, and neuronal apoptosis were evaluated. In addition, the levels of pro-inflammatory cytokines were detected using enzyme-linked immune sorbent assay (ELISA, and immunofluorescence staining for the endogenous "cholinergic anti-inflammatory pathway" was also performed. The protein expression of a7 nicotinic acetylcholine receptor (a7nAchR, phosphorylated Akt (p-Akt, and cleaved caspase 3 in ischemic penumbra were determined with Western blot analysis. I/R rats treated with VNS (I/R+VNS had significantly better neurological deficit scores, reduced cerebral infarct volume, and decreased number of TdT mediated dUTP nick end labeling (TUNEL positive cells. Furthermore, in the ischemic penumbra of the I/R+VNS group, the levels of pro-inflammatory cytokines and cleaved caspase 3 protein were significantly decreased, and the levels of a7nAchR and phosphorylated Akt were significantly increased relative to the I/R alone group. These results indicate that VNS is neuroprotective in acute cerebral I/R injury by suppressing inflammation and apoptosis via activation of cholinergic and a7nAchR/Akt pathways.

  15. The cholinergic basal forebrain system during development and its influence on cognitive processes: important questions and potential answers. (United States)

    Berger-Sweeney, Joanne


    This review seeks to address, though perhaps not answer fully, four important questions about the cholinergic basal forebrain (BF) system in developing mammals. First, what role does the cholinergic basal forebrain system play in the development of cognitive functions? Second, does the cholinergic BF system play a fundamentally similar role in development vs. adulthood? Third, does sexual dimorphism of the developing cholinergic BF system influence cognition differently in the two sexes? Finally, what role does the developing cholinergic BF system play in developmental disorders such as Down syndrome and Rett syndrome? Examples from the literature, primarily studies in mice and rats, are given in an attempt to answer these important questions.

  16. Inhibitory role of the spinal cholinergic system in the control of urethral continence reflex during sneezing in rats. (United States)

    Yoshikawa, Satoru; Kitta, Takeya; Miyazato, Minoru; Sumino, Yasuhiro; Yoshimura, Naoki


    The urethral continence reflex during stress conditions such as sneezing or coughing is an important mechanism preventing stress urinary incontinence (SUI). Although the spinal noradrenergic and serotonergic pathways are known to modulate this reflex activity, the role of spinal cholinergic pathways in the control of urethral continence reflex has not been elucidated. We therefore investigated the effect of intrathecal administration of an acetylcholine esterase (AChE) inhibitor, which increases ACh in synaptic terminals, and anti-cholinergic agents on the sneeze-induced urethral reflex in rats. Female SD rats were anesthetized with urethane. Urethral function was evaluated during sneezing induced by insertion of the rat whisker into the nostril. Effects of an AChE inhibitor, neostigmine, and muscarinic or nicotinic receptor antagonists administered at the level of L6-S1 spinal cord were examined. Neostigmine dose-dependently and significantly decreased the amplitude of urethral responses during sneezing (A-URS) with an approximately 70% reduction at 3 nmol, without changing urethral baseline pressure. The neostigmine-induced decrease in A-URS was significantly reversed by pretreatment with atropine (nonselective muscarinic receptor antagonist), methoctramine (M2 receptor antagonist) or 4-DAMP (M3 receptor antagonist), but not with pirenzepine (M1 receptor antagonist), tropicamide (M4 receptor antagonist), or mecamylamine (nicotinic receptor antagonist). These results indicate that an increase in endogenous ACh in the lumbosacral spinal cord inhibits the sneeze-induced urethral continence reflex via activation of M2 and/or M3-muscarinic receptors, implying the inhibitory role of spinal cholinergic pathways in the control of urethral continence reflex under stress conditions such as sneezing. © 2013 Wiley Periodicals, Inc.

  17. Acute administration of fenproporex increased acetylcholinesterase activity in brain of young rats

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    Full Text Available Fenproporex is the second most commonly amphetamine-based anorectic consumed worldwide; this drug is rapidly converted into amphetamine, in vivo, and acts by increasing dopamine levels in the synaptic cleft. Considering that fenproporex effects on the central nervous system are still poorly known and that acetylcholinesterase is a regulatory enzyme which is involved in cholinergic synapses and may indirectly modulate the release of dopamine, the present study investigated the effects of acute administration of fenproporex on acetylcholinesterase activity in brain of young rats. Young male Wistar rats received a single injection of fenproporex (6.25, 12.5 or 25mg/kg i.p. or vehicle (2% Tween 80. Two hours after the injection, the rats were killed by decapitation and the brain was removed for evaluation of acetylcholinesterase activity. Results showed that fenproporex administration increased acetylcholinesterase activity in the hippocampus and posterior cortex, whereas in the prefrontal cortex, striatum and cerebellum the enzyme activity was not altered. In conclusion, in the present study we demonstrated that acute administration of fenproporex exerts an effect in the cholinergic system causing an increase in the activity of acetylcholinesterase in a dose-dependent manner in the hippocampus and posterior cortex. Thus, we suggest that the imbalance in cholinergic homeostasis could be considered as an important pathophysiological mechanism underlying the brain damage observed in patients who use amphetamines such as fenproporex.

  18. Effect of voluntary running on adult hippocampal neurogenesis in cholinergic lesioned mice

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    Dawe Gavin S


    Full Text Available Abstract Background Cholinergic neuronal dysfunction of the basal forebrain is observed in patients with Alzheimer's disease and dementia, and has been linked to decreased neurogenesis in the hippocampus, a region involved in learning and memory. Running is a robust inducer of adult hippocampal neurogenesis. This study aims to address the effect of running on hippocampal neurogenesis in lesioned mice, where septohippocampal cholinergic neurones have been selectively eliminated in the medial septum and diagonal band of Broca of the basal forebrain by infusion of mu-p75-saporin immunotoxin. Results Running increased the number of newborn cells in the dentate gyrus of the hippocampus in cholinergic denervated mice compared to non-lesioned mice 24 hours after injection of bromodeoxyuridine (BrdU. Although similar levels of surviving cells were present in cholinergic depleted animals and their respective controls four weeks after injection of BrdU, the majority of progenitors that proliferate in response to the initial period of running were not able to survive beyond one month without cholinergic input. Despite this, the running-induced increase in the number of surviving neurones was not affected by cholinergic depletion. Conclusion The lesion paradigm used here models aspects of the cholinergic deficits associated with Alzheimer's Disease and aging. We showed that running still increased the number of newborn cells in the adult hippocampal dentate gyrus in this model of neurodegenerative disease.

  19. Screening of the topical anti-inflammatory activity of some Central American plants. (United States)

    Sosa, S; Balick, M J; Arvigo, R; Esposito, R G; Pizza, C; Altinier, G; Tubaro, Aurelia


    Hexane, chloroform and methanol extracts of seven herbal drugs used in the folk medicine of Central America against skin disorders (Aristolochia trilobata leaves and bark, Bursera simaruba bark, Hamelia patens leaves, Piper amalago leaves, and Syngonium podophyllum leaves and bark) were evaluated for their topical anti-inflammatory activity against the Croton oil-induced ear oedema in mice. Most of the extracts induced a dose-dependent oedema reduction. The chloroform extract of almost all the drugs exhibited interesting activities with ID(50) values ranging between 108 and 498 micro g/cm(2), comparable to that of indomethacin (93 micro g/cm(2)). Therefore, the tested plants are promising sources of principles with high anti-inflammatory activity.

  20. Screening of anti-bacterial activity of medicinal plants from Belize (Central America). (United States)

    Camporese, A; Balick, M J; Arvigo, R; Esposito, R G; Morsellino, N; De Simone, F; Tubaro, A


    Twenty-one extracts from seven herbal drugs, Aristolochia trilobata (Aristolochiaceae) leaves and bark, Bursera simaruba (Burseraceae) bark, Guazuma ulmifolia (Sterculiaceae) bark, Hamelia patens (Rubiaceae) leaves and Syngonium podophyllum (Araceae) leaves and bark, used in traditional medicine of Belize (Central America) as deep and superficial wound healers, were evaluated for their anti-bacterial properties. Activity was tested against standard strains of Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 25923 and Enterococcus faecalis ATCC 29212. Almost all the extracts were able to inhibit the growth of one or more of the bacterial strains, except that of Enterococcus faecalis. For the first time an anti-microbial activity is reported for Aristolochia trilobata as well as for Syngonium podophyllum. The hexane extracts of Aristolochia trilobata leaves and bark were the most active extracts against Staphylococcus aureus (MIC=0.31 and 0.625mg/ml, respectively).

  1. Acute and prolonged complement activation in the central nervous system during herpes simplex encephalitis. (United States)

    Eriksson, Charlotta E; Studahl, Marie; Bergström, Tomas


    Herpes simplex encephalitis (HSE) is characterized by a pronounced inflammatory activity in the central nervous system (CNS). Here, we investigated the acute and prolonged complement system activity in HSE patients, by using enzyme-linked immunosorbent assays (ELISAs) for numerous complement components (C). We found increased cerebrospinal fluid concentrations of C3a, C3b, C5 and C5a in HSE patients compared with healthy controls. C3a and C5a concentrations remained increased also compared with patient controls. Our results conclude that the complement system is activated in CNS during HSE in the acute phase, and interestingly also in later stages supporting previous reports of prolonged inflammation. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Hippocampal long term memory: effect of the cholinergic system on local protein synthesis. (United States)

    Lana, Daniele; Cerbai, Francesca; Di Russo, Jacopo; Boscaro, Francesca; Giannetti, Ambra; Petkova-Kirova, Polina; Pugliese, Anna Maria; Giovannini, Maria Grazia


    The present study was aimed at establishing a link between the cholinergic system and the pathway of mTOR and its downstream effector p70S6K, likely actors in long term memory encoding. We performed in vivo behavioral experiments using the step down inhibitory avoidance test (IA) in adult Wistar rats to evaluate memory formation under different conditions, and immunohistochemistry on hippocampal slices to evaluate the level and the time-course of mTOR and p70S6K activation. We also examined the effect of RAPA, inhibitor of mTORC1 formation, and of the acetylcholine (ACh) muscarinic receptor antagonist scopolamine (SCOP) or ACh nicotinic receptor antagonist mecamylamine (MECA) on short and long term memory formation and on the functionality of the mTOR pathway. Acquisition test was performed 30 min after i.c.v. injection of RAPA, a time sufficient for the drug to diffuse to CA1 pyramidal neurons, as demonstrated by MALDI-TOF-TOF imaging. Recall test was performed 1 h, 4 h or 24 h after acquisition. To confirm our results we performed in vitro experiments on live hippocampal slices: we evaluated whether stimulation of the cholinergic system with the cholinergic receptor agonist carbachol (CCh) activated the mTOR pathway and whether the administration of the above-mentioned antagonists together with CCh could revert this activation. We found that (1) mTOR and p70S6K activation in the hippocampus were involved in long term memory formation; (2) RAPA administration caused inhibition of mTOR activation at 1 h and 4 h and of p70S6K activation at 4 h, and long term memory impairment at 24 h after acquisition; (3) scopolamine treatment caused short but not long term memory impairment with an early increase of mTOR/p70S6K activation at 1 h followed by stabilization at longer times; (4) mecamylamine plus scopolamine treatment caused short term memory impairment at 1 h and 4 h and reduced the scopolamine-induced increase of mTOR/p70S6K activation at 1 h and 4 h; (5

  3. Structural basis for cholinergic regulation of neural circuits in the mouse olfactory bulb. (United States)

    Hamamoto, Masakazu; Kiyokage, Emi; Sohn, Jaerin; Hioki, Hiroyuki; Harada, Tamotsu; Toida, Kazunori


    Odor information is regulated by olfactory inputs, bulbar interneurons, and centrifugal inputs in the olfactory bulb (OB). Cholinergic neurons projecting from the nucleus of the horizontal limb of the diagonal band of Broca and the magnocellular preoptic nucleus are one of the primary centrifugal inputs to the OB. In this study, we focused on cholinergic regulation of the OB and analyzed neural morphology with a particular emphasis on the projection pathways of cholinergic neurons. Single-cell imaging of a specific neuron within dense fibers is critical to evaluate the structure and function of the neural circuits. We labeled cholinergic neurons by infection with virus vector and then reconstructed them three-dimensionally. We also examined the ultramicrostructure of synapses by electron microscopy tomography. To further clarify the function of cholinergic neurons, we performed confocal laser scanning microscopy to investigate whether other neurotransmitters are present within cholinergic axons in the OB. Our results showed the first visualization of complete cholinergic neurons, including axons projecting to the OB, and also revealed frequent axonal branching within the OB where it innervated multiple glomeruli in different areas. Furthermore, electron tomography demonstrated that cholinergic axons formed asymmetrical synapses with a morphological variety of thicknesses of the postsynaptic density. Although we have not yet detected the presence of other neurotransmitters, the range of synaptic morphology suggests multiple modes of transmission. The present study elucidates the ways that cholinergic neurons could contribute to the elaborate mechanisms involved in olfactory processing in the OB. J. Comp. Neurol. 525:574-591, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  4. Obesity and Metabolic Syndrome Affect the Cholinergic Transmission a nd Cognitive Functions. (United States)

    Martinelli, Ilenia; Tomassoni, Daniele; Moruzzi, Michele; Traini, Enea; Amenta, Francesco; Tayebati, Seyed Khosrow


    Worldwide, at least 2.8 million people die each year as a result of being overweight or obese. Obesity leads to metabolic syndrome, a pathological condition characterized by adverse metabolic effects on blood pressure, cholesterol, triglycerides and insulin resistance. Population- based investigations have suggested that obesity and metabolic syndrome may be associated with poorer cognitive performance. A structured search of bibliographic source (PubMed) was undertaken. The following terms "inflammation and obesity and brain", "cholinergic system and obesity", "cholinergic system and metabolic syndrome", "Cognitive impairment and obesity" and "metabolic syndrome and brain" were used as search strings. Over 200 papers, mainly published in the past 10 years were analysed. The major results regarded keyword "metabolic syndrome and brain" followed by, "Cognitive impairment and obesity", "inflammation and obesity and brain", "cholinergic system and obesity" and "cholinergic system and metabolic syndrome". Most papers were pre-clinical but, in general, they were inhomogeneous. Therefore, the results were cited according their contribution to clarify the molecular involvement of obesity and/or metabolic syndrome in cholinergic impairment. This review focuses on the correlation between brain cholinergic system alterations and high-fat diet, describing the involvement of cholinergic system in inflammatory processes related to metabolic syndrome and obesity, which may lead to cognitive decline. Metabolic syndrome has been suggested as a risk factor for cerebrovascular diseases and has been associated with cognitive impairment in different functional brain domains. Preclinical and clinical studies have identified the cholinergic system as a specific target of metabolic syndrome and obesity. The modifications of cholinergic neurotransmission and its involvement in neuro-inflammation may be related to cognitive impairment that affects obese patients. Copyright© Bentham

  5. Time spent in sedentary activities in a pediatric population in Pretoria Central, South Africa. (United States)

    Goon, Daniel T; Nsibambi, Constance A; Chebet, Milton


    Scant information exist on screen time behavior of South Africa children and whether they do not meet the recommendation of American Association of Pediatrics (AAP) concerning screen time activity for children is only speculative. Therefore, the purpose of this study was to examine the time spent in sedentary activities, especially screen time of South African children with regard to gender. This cross-sectional study involved a random sample of 1136 school children (548 boys; 588 girls) aged 9-13 years attending public schools in Central Pretoria, South Africa. Questionnaire was used to collect data on the participants' sedentary behaviors. The prevalence estimates for sedentary time activity was based on the guidelines (i.e., spent more than two hours per day (exceeding the AAP recommendation for sedentary activity) watching TV (3.0%), worked or played on the computer (25.4%), read (1.0%), played music (27.9%), played board games (14.7%), washing clothes (8.0%), floor sweeping (10.5%), art work (18.2%), and spent time on other unspecified activities (28.6%). Boys spent more time (2 hours, 3-4 hours) watching TV (38.3%; P=0.001), playing computer (31.8 %; P=0.024) and board games (17.4%; P=0.012) than girls. The corresponding figures for girls were 35.7%, 19.2% and 12.5% for TV, computer and board games, respectively. However, the proportion of those who spent more time playing music was higher among girls (32.7%) than boys (22.4%) (P=0.002). Overall, the time spent exceeding AAP recommendation (≥ 2 hours) was not statistically (P=0.427) different between boys and girls. The time spent in sedentary activities, particularly in screen time activity among urban primary school children in Pretoria Central is excessively higher than the recommendation (i.e., ≥2 hours per day) set for children. Also, gender differences exist in the sedentary activities of the children, with boys having higher screen time and other sedentary activities than girls. Children's screen

  6. Active fragmentation of Adria, the north African promontory, central Mediterranean orogen (United States)

    Oldow, J. S.; Ferranti, L.; Lewis, D. S.; Campbell, J. K.; D'Argenio, B.; Catalano, R.; Pappone, G.; Carmignani, L.; Conti, P.; Aiken, C. L. V.


    Global Positioning System (GPS) velocities indicate that Adria no longer behaves as a rigid tectonic indenter into southern Europe and is divided into northwestern and southeastern velocity domains. Differential motions are recognized in a velocity field determined from the Peri-Tyrrhenian Geodetic Array (PTGA) and International GPS Service (IGS) sites in the circum-Tyrrhenian region of the central Mediterranean and published GPS velocities from the eastern Adriatic coast. In a fixed Eurasian reference frame, PTGA and IGS site velocities in Sicily and southern Italy are as much as 10 mm/yr in a northward direction, similar to GPS velocities along the eastern coast of the Adriatic Sea. In contrast, velocities in northern Italy are small or statistically insignificant and similar to velocities in Sardinia and Corsica outboard of western Adria. The tectonic boundary dividing Adria is seismically active and passes around the southern and eastern margins of the Tyrrhenian Basin, crosses central Italy, extends into the Adriatic Sea, and follows the western margin of the Dinaride tectonic belt north to the Gulf of Venice. The eastern margin of Adria is approximately located and follows the axis of the central Dinaric Alps southeast to the Hellenic arc. Southeastern Adria has a velocity related to northward motion of Africa, whereas northwestern Adria has negligible differential motion in the Eurasian frame and now is part of the Alpine collage of southern Europe.

  7. The Antiosteoporotic Activity of Central-Icaritin (CIT) on Bone Metabolism of Ovariectomized Rats


    Jun Jiang; Jie Li; Xiaobin Jia


    Central-icaritin (CIT) is a flavonoid aglycone first discovered in our laboratory, which is an isomeric aglycone of icaritin (IT). We wanted to know whether CIT also had anti-osteoporosis activity. In this study, CIT was investigated in an ovariectomized rat (OVX) model. Fifty-six 6-month old female Sprague-Dawley rats were randomly assigned to sham operated group (Sham) and six OVX subgroups (n = 8 each). The OVX rats were then subdivided into six groups treated with vehicle (OVX), icaritin ...

  8. Relation between the intrinsic and observed central engine activity time: implications for ultra-long GRBs


    Gao, He; Mészáros, Peter


    The GRB central engine intrinsic activity time $T_{\\rm ce}$ is usually described through either the $\\gamma$-ray duration $T_{90}$ or through a generalized burst duration $t_{\\rm burst}$ which includes both the $\\gamma$-ray emission and (when present) an extended flaring X-ray plateau. Here, we define a more specific operational description of $T_{\\rm ce}$, and within the framework of the internal-external shock model, we develop a numerical code to study the relationship between $T_{90}$ and...

  9. Use of Inertial Central to Analyse Skill of Inter-Limb Coordination in Sport Activities

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    Caritu Yanis


    Full Text Available Kinematical movement analysis is regularly conducted through 3D video device, studying great number of parameters. The aim of this study is to focus on movement variability, following dynamical system perspectives, that is suitable through the use of inertial central to collect data in ecological context. This study gives two examples of sport activity (breaststroke swimming and rock climbing for which the motor skill was analysed through a macroscopic parameter, notably upper-lower limb coordination. The results showed higher intraindividual movement variability in experts while beginners used basic modes of coordination.

  10. The involvement of cholinergic neurons in the spreading of tau pathology

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    Diana eSimon


    Full Text Available Long time ago, it was described the selective loss of cholinergic neurons during the development of Alzheimer disease. Recently, it has been suggested that tau protein may play a role in that loss of cholinergic neurons through a mechanism involving the interaction of extracellular tau with M1/M3 muscarinic receptors present in the cholinergic neurons. This interaction between tau and muscarinic receptors may be a way, although not the only one, to explain the spreading of tau pathology occurring in Alzheimer disease.

  11. The relationship between precipitation anomalies and satellite-derived vegetation activity in Central Asia (United States)

    Gessner, Ursula; Naeimi, Vahid; Klein, Igor; Kuenzer, Claudia; Klein, Doris; Dech, Stefan


    In Central Asia, water is a particularly scarce and valuable good. In many ecosystems of this region, the vegetation development during the growing season is dependent on water provided by rainfall. With climate change, alterations of the seasonal distribution of precipitation patterns and a higher frequency of extreme events are expected. Vegetation dynamics are likely to respond to these changes and thus ecosystem services will be affected. However, there is still a lack in understanding the response of vegetation to precipitation anomalies, especially for dryland regions such as Central Asia. This study aims to contribute to an improved understanding of vegetation sensitivity to precipitation anomalies and corresponding temporal reaction patterns at regional scale. The presented analyses are based on time-series of Normalized Difference Vegetation Index (NDVI) and gridded precipitation datasets (GPCC Full Data Reanalysis) for the years 1982-2006. Time-series correlation analyses show that vegetation development is sensitive to precipitation anomalies for nearly 80% of the Central Asian land surface. Results indicate a particularly strong sensitivity of vegetation in areas with 100-400 mm of annual rainfall. Temporal rainfall-NDVI response patterns show a temporal lag between precipitation anomalies and vegetation activity of 1-3 months. The reaction of vegetation was found to be strongest for precipitation anomalies integrated over periods of 2-4 months. The observed delayed response of vegetation to precipitation anomalies reveals potential for drought prediction in Central Asia. The spatial patterns of vegetation reactions are discussed with focus on the role of precipitation amount and seasonality, land use and land cover.

  12. Inflammatory cytokines in general and central obesity and modulating effects of physical activity.

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    Frank M Schmidt

    Full Text Available Chronic systemic inflammation in obesity originates from local immune responses in visceral adipose tissue. However, assessment of a broad range of inflammation-mediating cytokines and their relationship to physical activity and adipometrics has scarcely been reported to date.To characterize the profile of a broad range of pro- and anti-inflammatory cytokines and the impact of physical activity and energy expenditure in individuals with general obesity, central obesity, and non-obese subjects.A cross-sectional study comprising 117 obese patients (body mass index (BMI ≥ 30 and 83 non-obese community-based volunteers.Serum levels of interleukin (IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF, interferon (IFN-γ and tumor necrosis factor (TNF-α were measured. Physical activity and energy expenditure (MET were assessed with actigraphy. Adipometrics comprised BMI, weight, abdominal-, waist- and hip-circumference, waist to hip ratio (WHR, and waist-to-height-ratio (WHtR.General obesity was associated with significantly elevated levels of IL-5, IL-10, IL-12, IL-13, IFN-γ and TNF-α, central obesity with significantly elevated IL-5, IL-10, IL-12, IL-13 and IFN-γ-levels. In participants with general obesity, levels of IL-4, IL-10 and IL-13 were significantly elevated in participants with low physical activity, even when controlled for BMI which was negatively associated with physical acitivity. Cytokines significantly correlated with adipometrics, particularly in obese participants.Results confirm up-regulation of certain pro- and anti-inflammatory cytokines in obesity. In obese subjects, physical activity may lower levels and thus reduce pro-inflammatory effects of cytokines that may link obesity, insulin resistance and diabetes.

  13. Dual nitrergic/cholinergic control of short-term plasticity of corticostriatal inputs to striatal projection neurons

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    Craig Peter Blomeley


    Full Text Available The ability of nitric oxide and acetylcholine to modulate the short-term plasticity of corticostriatal inputs was investigated using current-clamp recordings in BAC mouse brain slices. Glutamatergic responses were evoked by stimulation of corpus callosum in D1 and D2 dopamine receptor-expressing medium spiny neurons (D1-MSNs and D2-MSN, respectively. Paired-pulse stimulation (50 ms intervals evoked depressing or facilitating responses in subgroups of both D1-MSNs and D2 MSNs. In both neuronal types, glutamatergic responses of cells that displayed paired-pulse depression were not significantly affected by the nitric oxide donor S-nitroso-N-acetylpenicillamine (SNAP; 100 µM. Conversely, in D1-MSNs and D2-MSNs that displayed paired-pulse facilitation, SNAP did not affect the first evoked response, but significantly reduced the amplitude of the second evoked EPSP, converting paired-pulse facilitation into paired-pulse depression. SNAP also strongly excited cholinergic interneurons and increased their cortical glutamatergic responses acting through a presynaptic mechanism. The effects of SNAP on glutamatergic response of D1-MSNs and D2-MSN were mediated by acetylcholine. The broad-spectrum muscarinic receptor antagonist atropine (25 µM did not affect paired-pulse ratios and did not prevent the effects of SNAP. Conversely, the broad-spectrum nicotinic receptor antagonist tubocurarine (10 µM fully mimicked and occluded the effects of SNAP. We concluded that phasic acetylcholine release mediates feedforward facilitation in MSNs through activation of nicotinic receptors on glutamatergic terminals and that nitric oxide, while increasing cholinergic interneurons’ firing, functionally impairs their ability to modulate glutamatergic inputs of MSNs. These results show that nitrergic and cholinergic transmission control the short-term plasticity of glutamatergic inputs in the striatum and reveal a novel cellular mechanism underlying paired

  14. Morphometric analysis of relative tectonic activity in the Baturagung Mountain, Central Java, Indonesia (United States)

    Mulyasari, Rahmi; Brahmantyo, Budi; Supartoyo


    Special Region of Yogyakarta and Klaten district, Central Java is one of areas in Indonesia that is prone to earthquake caused by subduction in Indian Ocean and active fault in land. The earthquake sources from active fault probable from Opak and other faults located in Baturagung Mountain. Active faults controlling landform development in tectonically active regions, and it has significantly affected fluvial systems and mountain - front landscapes in the Baturagung Mountain. To assess tectonic activities in the area used quantitative analysis (morphometric). Morphometric analysis consists of 5 parameters geomorphic indices: drainage basin asymmetry (AF), hypsometric curve and integral (Hc and Hi), stream length gradient (SL) index, basin shape index (Bs), and mountain-front sinuosity (Smf). These indices were combined to yield the relative tectonic activity index (RTAI) using geographic information systems (GIS). The result found that RTAI in the study area are divided into three classes: Class 2 (high 0.6% of the watershed area (1.32 km2)); Class 3 (moderate 58.9% (122.1 km2)); and Class 4 (low 40.4% (83.75 km2)). All of morphometric analysis generally indicates this area more influenced by tectonics than erosion. The results are consistent with geomorphological observations.

  15. Cholinergic and non-cholinergic projections from the pedunculopontine and laterodorsal tegmental nuclei to the medial geniculate body in guinea pigs

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    Susan D Motts


    Full Text Available The midbrain tegmentum is the source of cholinergic innervation of the thalamus and has been associated with arousal and control of the sleep/wake cycle. In general, the innervation arises bilaterally from the pedunculopontine tegmental nucleus (PPT and the laterodorsal tegmental nucleus (LDT. While this pattern has been observed for many thalamic nuclei, a projection from the LDT to the medial geniculate body (MG has been questioned in some species. We combined retrograde tracing with immunohistochemistry for choline acetyltransferase (ChAT to identify cholinergic projections from the brainstem to the MG in guinea pigs. Double-labeled cells (retrograde and immunoreactive for ChAT were found in both the PPT (74% and the LDT (26%. In both nuclei, double-labeled cells were more numerous on the ipsilateral side. About half of the retrogradely labeled cells were immunonegative, suggesting they are non-cholinergic. The distribution of these immunonegative cells was similar to that of the immunopositive ones: more were in the PPT than the LDT and more were on the ipsilateral than the contralateral side. The results indicate that both the PPT and the LDT project to the MG, and suggest that both cholinergic and non-cholinergic cells contribute substantially to these projections.

  16. Changes in the cholinergic system of rat sciatic nerve and skeletal muscle following suspension induced disuse (United States)

    Gupta, R. C.; Misulis, K. E.; Dettbarn, W. D.


    Muscle disused induced changes in the cholinergic system of sciatic nerve, slow twitch soleus (SOL) and fast twitch extensor digitorum longus (EDL) muscle were studied in rats. Rats with hindlimbs suspended for 2 to 3 weeks showed marked elevation in the activity of choline acetyltransferase (ChAT) in sciatic nerve (38%), in SOL (108%) and in EDL (67%). Acetylcholinesterase (AChE) activity in SOL increased by 163% without changing the molecular forms pattern of 4S, 10S, 12S, and 16S. No significant changes in activity and molecular forms pattern of AChE were seen in EDL or in AChE activity of sciatic nerve. Nicotinic receptor binding of 3H-acetylcholine was increased in both muscles. When measured after 3 weeks of hindlimb suspension the normal distribution of type 1 fibers in SOL was reduced and a corresponding increase in type IIa and IIb fibers is seen. In EDL no significant change in fiber proportion is observed. Muscle activity, such as loadbearing, appears to have a greater controlling influence on the characteristics of the slow twitch SOL muscle than upon the fast twitch EDL muscle.

  17. Active sleep unmasks apnea and delayed arousal in infant rat pups lacking central serotonin. (United States)

    Young, Jacob O; Geurts, Aron; Hodges, Matthew R; Cummings, Kevin J


    Sudden infant death syndrome (SIDS), occurring during sleep periods, is highly associated with abnormalities within serotonin (5-HT) neurons, including reduced 5-HT. There is evidence that future SIDS cases experience more apnea and have abnormal arousal from sleep. In rodents, a loss of 5-HT neurons is associated with apnea in early life and, in adulthood, delayed arousal. As the activity of 5-HT neurons changes with vigilance state, we hypothesized that the degree of apnea and delayed arousal displayed by rat pups specifically lacking central 5-HT varies with state. Two-week-old tryptophan hydroxylase 2-deficient (TPH2-/-) and wild-type (WT) rat pups were placed in plethysmographic chambers supplied with room air. At the onset of active (AS) or quiet (QS) sleep, separate groups of rats were exposed to hypercapnia (5% CO2) or mild hypoxia (~17% O2) or maintained in room air. Upon arousal, rats received room air. Apnea indexes and latencies to spontaneous arousal from AS and QS were determined for pups exposed only to room air. Arousal latencies were also calculated for TPH2-/- and WT pups exposed to hypoxia or hypercapnia. Compared with WT, TPH2-/- pups hypoventilated in all states but were profoundly more apneic solely in AS. TPH2-/- pups had delayed arousal in response to increasing CO2, and AS selectively delayed the arousal of TPH2-/- pups, irrespective of the gas they breathed. Thus infants who are deficient in CNS 5-HT may be at increased risk for SIDS in AS because of increased apnea and delayed arousal compared with QS.NEW & NOTEWORTHY Sudden infant death syndrome (SIDS) occurs during sleep and is associated with central serotonin (5-HT) deficiency. We report that rat pups deficient in central 5-HT (TPH2-/-) are profoundly more apneic in active sleep (AS) but not quiet sleep (QS). Unlike control pups, the arousal of TPH2-/- pups in air, CO2, and hypoxia was delayed in AS compared with QS. Thus for infants deficient in central 5-HT, the risk of SIDS may be

  18. Diurnal activity of the American Mink (Neovison vison in Central Spain

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    Pablo García


    Full Text Available Abstract The American mink (Neovison vison is an invasive species in Spain and its population ecology is poorly understood. Diurnal activity was studied in a population of central Spain by means of direct observations. This activity peaked in summer and winter, mink being more active just after daybreak (06:00-08:00 and before dawn (16:00-18:00. Foraging (50% of observations; N = 146 and travelling (38.2%, were the main activities recorded during daylight. Mink were recorded as either in water or on land. In the latter, their distance from the water edge never exceeded 5.5 m. This pattern of daylight activity could be a mechanism for reducing potential interactions with nocturnal mammals sharing the same habitats. The success of culling campaigns could be increased by extending trapping sessions to daylight hours. Riassunto Attività diurna del visone americano (Neovison visonM nella Spagna centrale. L’ecologia dell’alloctono visone americano in Spagna è tuttora poco nota. Tramite osservazione diretta, è stata indagata l’incidenza della attività diurna in una popolazione della Spagna centrale. Tale attività è risultata più frequente in estate ed inverno, quando i visoni sono attivi nelle prime ore del giorno (06:00-08:00 e prima del tramonto (16:00-18:00. Le attività registrate più frequentemente sono state il foraggiamento (50% delle osservazioni, N = 146 e gli spostamenti (travelling, 38,2%. I visoni sono stati osservati indistintamente sia in acqua che a terra; in quest’ultimo caso la distanza dalla riva non è mai stata superiore a 5,5 m. Si ipotizza che l’attività diurna potrebbe essere un meccanismo per ridurre le interazioni con mammiferi prevalentemente notturni legati ai medesimi ambienti. In base ai risultati ottenuti, si suggerisce che il successo delle operazioni di controllo della specie potrebbe essere incrementato estendendo il

  19. Daily pattern of flight activity of Aedes albifasciatus in Central Argentina

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    Francisco F. Ludueña Almeida


    Full Text Available Aedes albifasciatus is an important common mosquito in Central Argentina. Its a confirmed vector of the Western Equine Encephalitis and is responsible for loss of milk production in dairy cattle during peak populations. This paper reports the flight activity pattern of Ae. albifasciatus for different seasons, in the southern coast of the Mar Chiquita Lake (Central Argentina. Data were collected by sampling two sites between 1992 and 1993 with CDC traps and human-bait captures. Adult mosquito population density, estimated by CDC trapping and human-bait, were highly correlated. However, when compared to other species, the proportion of Ae. albifasciatus was higher in human-bait collections. Adult female populations were active only when temperature were higher than 6§C. Two daily biting peaks were observed (dusk and dawn during the spring, summer and autumn, and only one peak during winter (around 15:00 pm. Adult abundance was significantly correlated (R²= 0.71; p<0.01 with temperature and illumination.

  20. Diet, activity and reproduction of bat species (Mammalia, Chiroptera in Central Amazonia, Brazil

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    Enrico Bernard


    Full Text Available The diet, activity and reproductive patterns of several species of bats were investigated in primary forests of Central Amazon. Between August 1996 and August 1997, using mist nets set both at canopy and understorey levels, 936 bats, belonging to 51 species, 31 genera and 6 families were captured. Fecal samples from 35 species were examined, with four food categories and 25 food items identified. Time of captures indicate a wide variation, but the major part of the species presented a peak of activity around the first hour after sunset. Three reproductive peaks were observed: October-November; January-February; and July-August, but reproductive patterns varied among the families. The structure of the bat fauna in Manaus is similar to other sites in the Amazon and Central America, the main common points being: a a high diversity of bat species, usually more than 40 species representing 6-8 families; b 3-4 very common and geographically widespread species; c most species are represented by a few captures; d frugivorous species dominate the fauna and insectivorous species are less often captured; and e most species cluster in 2-3 guilds, dominated by small (< 12 g species.

  1. Central Dog-ma Disease Detectives: A Molecular Biology Inquiry Activity for Undergraduates (United States)

    Quan, T. K.; Yuh, P.; Black, F.


    The Minority Access to Research Careers (MARC) and Minority Biomedical Research Support (MBRS) are programs at the University of California at Santa Cruz designed to support minority undergraduate students majoring in the sciences. Each summer MARC/MBRS sponsors a Summer Institute that involves week long "rotations" with different faculty mentors. In 2008, the Center for Adaptive Optics (CfAO) Professional Development Program (PDP) was responsible for overseeing one week of the Summer Institute, and designed it to be a Biomedical Short Course. As part of this short course, we designed a four-hour activity in which students collected their own data and explored relationships between the basic biomolecules DNA, RNA, and protein. The goal was to have the students use experimental data to support their explanation of the "Central Dogma" of molecular biology. Here we describe details of our activity and provide a post-teaching reflection on its success.

  2. Axial seamount: An active ridge axis volcano on the Central Juan De Fuca Ridge (United States)

    Johnson, H. Paul; Embley, Robert W.


    Axial Seamount (some of the manuscripts in this special section refer to the edifice with the more precise name of "Axial Volcano"), a large ridge axis volcano, is located on the central segment of the Juan de Fuca Ridge approximately 250 nautical miles west of the Washington/Oregon/British Columbia coast. Currently both volcanically and hydrothermally active, Axial lies directly at the intersection of the Cobb-Eickelberg Seamount Chain and the Juan de Fuca Ridge (Figure 1). The volcanic activity associated with the seamount formation strongly interacts with, and is affected by, the normal seafloor spreading processes at the intersection. Because of this unique geologic setting, its proximity to west coast ports and oceanographie institutions, and its shallow depth, Axial has become the focus of a large number of scientific investigations over the past decade.

  3. Kinin B1 Receptor Promotes Neurogenic Hypertension Through Activation of Centrally Mediated Mechanisms. (United States)

    Sriramula, Srinivas; Lazartigues, Eric


    Hypertension is associated with increased activity of the kallikrein-kinin system. Kinin B1 receptor (B1R) activation leads to vasoconstriction and inflammation. Despite evidence supporting a role for the B1R in blood pressure regulation, the mechanisms by which B1R could alter autonomic function and participate in the pathogenesis of hypertension remain unidentified. We sought to explore whether B1R-mediated inflammation contributes to hypertension and investigate the molecular mechanisms involved. In this study, we tested the hypothesis that activation of B1R in the brain is involved in the pathogenesis of hypertension, using the deoxycorticosterone acetate-salt model of neurogenic hypertension in wild-type and B1R knockout mice. Deoxycorticosterone acetate-salt treatment in wild-type mice led to significant increases in B1R mRNA and protein levels and bradykinin levels, enhanced gene expression of carboxypeptidase N supporting an increase in the B1R ligand, associated with enhanced blood pressure, inflammation, sympathoexcitation, autonomic dysfunction, and impaired baroreflex sensitivity, whereas these changes were blunted or prevented in B1R knockout mice. B1R stimulation was further shown to involve activation of the ASK1-JNK-ERK1/2 and NF-κB pathways in the brain. To dismiss potential developmental alterations in knockout mice, we further used B1R blockade selectively in the brain of wild-type mice. Supporting the central origin of this mechanism, intracerebroventricular infusion of a specific B1R antagonist, attenuated the deoxycorticosterone acetate-salt-induced increase in blood pressure in wild-type mice. Our data provide the first evidence of a central role for B1R-mediated inflammatory pathways in the pathogenesis of deoxycorticosterone acetate-salt hypertension and offer novel insights into possible B1R-targeted therapies for the treatment of neurogenic hypertension. © 2017 American Heart Association, Inc.

  4. Implementation of Central Library’s Special Activities in Croatian Public Libraries

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    Andreja Videc


    Full Text Available The paper presents the public library system in Croatia in which central libraries and their special activities play an important role. It also presents the importance of special activities for the development of Croatian public libraries. On the basis of a selected literature review, reports on performing special activities and an analysis of statistical indicators of library services in three counties (Bjelovarsko-Bilogorska, Primorsko-goranska and Zadarska we research the impact of special activities on the development of public libraries in the county. The data analysis showed that library services have been improved in recent years, especially in the field of spatial conditions and in the expansion of library network. Comparison of some general public library performance indicators between Slovenia and Croatia in the year 2013 shows a markedly better situation in Slovenia. The study is limited to the statistics report for the year 2013. The study represents the first analysis of Croatian public libraries’ special activities and presents a comparison of Croatian and Slovenian public library system organisation.

  5. Acupuncture for ischemic stroke: cerebellar activation may be a central mechanism following Deqi

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    Miao-keng Li


    Full Text Available The needling sensation of Deqi during acupuncture is a key factor of influencing acupuncture outcome. Recent studies have mainly focused on the brain function effects of Deqi in a physiological state. Functional magnetic resonance imaging (fMRI on the effects of acupuncture at Waiguan (SJ5 in pathological and physiological states is controversial. In this study, 12 patients with ischemic stroke received acupuncture at Waiguan (SJ5 and simultaneously underwent fMRI scanning of the brain, with imaging data of the activated areas obtained. Based on the patient′s sensation, imaging data were allocated to either the Deqi group or non-Deqi group. In the Deqi group, the activated/deactivated areas were the left superior temporal gyrus (BA39/right anterior lobe of the cerebellum and left thalamus. In the non-Deqi group, the activated areas included the medial frontal gyrus of the right frontal lobe (BA11, right limbic lobe (BA30, 35, and left frontal lobe (BA47, while the only deactivated area was the right parietal lobe (BA40. Compared with the non-Deqi group, the Deqi group exhibited marked activation of the right anterior lobe of the cerebellum and right limbic lobe (BA30. These findings confirm that the clinical effect of Deqi during acupuncture is based on brain functional changes. Cerebellar activation may be one of the central mechanisms of acupuncture in the treatment of ischemic stroke.

  6. L- and T-type voltage-gated Ca2+ channels in human granulosa cells: functional characterization and cholinergic regulation. (United States)

    Platano, Daniela; Magli, M Cristina; Ferraretti, Anna Pia; Gianaroli, Luca; Aicardi, Giorgio


    Using the whole-cell configuration of the patch-clamp technique, we have characterized two types of ionic currents through voltage-dependent Ca2+ channels in human granulosa cells. One is long-lasting, activates at approximately -20 mV, reaches the peak at approximately +20 mV, has an inactivation time constant of 132.5 +/- 5.6 msec at 20 mV, and is sensitive to dihydropyridines. The other is transient, activates at approximately -40 mV, peaks at approximately -10 mV, has an inactivation time constant of 38.8 +/- 1.8 msec at -10 mV, displays a voltage-dependent inactivation, and is sensitive to 100 microm Ni2+, but not to dihydropyridines. Biophysical and pharmacological properties of these currents indicate that they are gated through L- and T-type calcium channels, respectively. The cholinergic receptor agonist carbachol (50 microm) reduces the amplitude of the currents through both L-type (-34.7 +/- 6.4%; n = 10) and T-type (-52.6 +/- 7.4%; n = 8) channels, suggesting a possible role of these channels in the cholinergic regulation of human ovarian functions.

  7. Neuroprotective Effects of Sulforaphane on Cholinergic Neurons in Mice with Alzheimer’s Disease-Like Lesions (United States)

    Zhang, Rui; Zhang, Jingzhu; Fang, Lingduo; Li, Xi; Zhao, Yue; Shi, Wanying; An, Li


    Alzheimer’s disease (AD) is a common neurodegenerative disease in elderly individuals, and effective therapies are unavailable. This study was designed to investigate the neuroprotective effects of sulforaphane (an activator of NF-E2-related factor 2) on mice with AD-like lesions induced by combined administration of aluminum and d-galactose. Step-down-type passive avoidance tests showed sulforaphane ameliorated cognitive impairment in AD-like mice. Immunohistochemistry results indicated sulforaphane attenuated cholinergic neuron loss in the medial septal and hippocampal CA1 regions in AD-like mice. However, spectrophotometry revealed no significant difference in acetylcholine level or the activity of choline acetyltransferase or acetylcholinesterase in the cerebral cortex among groups of control and AD-like mice with and without sulforaphane treatment. Sulforaphane significantly increased the numbers of 5-bromo-2'-deoxyuridine-positive neurons in the subventricular and subgranular zones in AD-like mice which were significantly augmented compared with controls. Atomic absorption spectrometry revealed significantly lower aluminum levels in the brains of sulforaphane-treated AD-like mice than in those that did not receive sulforaphane treatment. In conclusion, sulforaphane ameliorates neurobehavioral deficits by reducing cholinergic neuron loss in the brains of AD-like mice, and the mechanism may be associated with neurogenesis and aluminum load reduction. These findings suggest that phytochemical sulforaphane has potential application in AD therapeutics. PMID:25196440

  8. Regulation of Prostate Development and Benign Prostatic Hyperplasia by Autocrine Cholinergic Signaling via Maintaining the Epithelial Progenitor Cells in Proliferating Status

    Directory of Open Access Journals (Sweden)

    Naitao Wang


    Full Text Available Regulation of prostate epithelial progenitor cells is important in prostate development and prostate diseases. Our previous study demonstrated a function of autocrine cholinergic signaling (ACS in promoting prostate cancer growth and castration resistance. However, whether or not such ACS also plays a role in prostate development is unknown. Here, we report that ACS promoted the proliferation and inhibited the differentiation of prostate epithelial progenitor cells in organotypic cultures. These results were confirmed by ex vivo lineage tracing assays and in vivo renal capsule recombination assays. Moreover, we found that M3 cholinergic receptor (CHRM3 was upregulated in a large subset of benign prostatic hyperplasia (BPH tissues compared with normal tissues. Activation of CHRM3 also promoted the proliferation of BPH cells. Together, our findings identify a role of ACS in maintaining prostate epithelial progenitor cells in the proliferating state, and blockade of ACS may have clinical implications for the management of BPH.

  9. Effects of proton irradiation of the lumbar intumescence on intra-axonal transport of acetylcholine and cholinergic enzymes in rat sciatic nerve

    Energy Technology Data Exchange (ETDEWEB)

    Boeoej, S.; Dahlstroem, A.; Larsson, P.A.; Rosander, K.; Rosengren, B. (Goeteborg Univ. (Sweden). Institutionen foer Neurobiologi)


    The content and intra-axonal transport of acetylcholine (ACh) and the cholinergic enzymes cholineacetyl-transferase (CAT) and ACh-esterase (AChE) in sciatic nerve were investigated in rats following single dose proton irradiation of the lumbar intumescence of the spinal cord with 60 Gy or 200 Gy. One, 7 or 30 days after irradiation nerve-crush operations were performed 12 hours before killing and the levels of ACh and enzyme activities in nerve segments relative to the crushes were estimated by biologic (ACh) to chemical (enzyme) methods. The results indicate that alterations in intra-neuronal dynamics of ACh and related enzymes are not a major cause for the development of neurologic symptoms of the motor system after irradiation, and that descending myelinated axons are of minor importance for the regulation of cholinergic substances in rat motor nerves.

  10. The association of cholinergic and cold-induced urticaria: diagnosis and management (United States)

    Torabi, Bahar; Ben-Shoshan, Moshe


    Physical urticaria is often challenging to diagnose and manage. We present a case of both cholinergic and cold-induced urticaria and discuss the diagnosis and management strategies of these two important conditions. PMID:25694628

  11. Outcome of Patients with Cholinergic Insecticide Poisoning Treated with Gastric Lavage: A Prospective Observational Cohort Study

    Directory of Open Access Journals (Sweden)

    Mekkattukunnel Andrews


    Conclusion: Number or timing of GL does not show any association with mortality while multiple GL had protective effect against development of late RF and IMS. Hence, GL might be beneficial in cholinergic insecticide poisoning.

  12. Growth Factor Dependent Cholinergic Function and Survival in Primary Mouse Spinal Cord Cultures

    National Research Council Canada - National Science Library

    Sheridan, Robert E; Adler, Michael


    .... However, while the mature spinal cord contains an appreciable number of cholinergic% motoneurons, cultures of embryonic spinal cord have a paucity of these neurons and release little or no acetylcholine upon stimulation...

  13. A cholinergic contribution to the circulatory responses evoked at the onset of handgrip exercise in humans

    DEFF Research Database (Denmark)

    Vianna, Lauro C; Fadel, Paul J; Secher, Niels H


    A cholinergic (muscarinic) contribution to the initial circulatory response to exercise in humans remains controversial. Herein, we posit that this may be due to exercise mode with a cholinergic contribution being important during isometric handgrip exercise, where the hyperemic response of the m......A cholinergic (muscarinic) contribution to the initial circulatory response to exercise in humans remains controversial. Herein, we posit that this may be due to exercise mode with a cholinergic contribution being important during isometric handgrip exercise, where the hyperemic response...... of the muscle is relatively small compared with the onset of leg cycling, where a marked increase in muscle blood flow rapidly occurs as a consequence of multiple redundant mechanisms. We recorded blood pressure (BP; brachial artery), stroke volume (pulse contour analysis), cardiac output, and systemic vascular...

  14. Volatile budget for an unusual Central Oregon Cascades cinder cone and implications for future activity (United States)

    Walsh, L. K.; Wallace, P. J.; Cashman, K. V.


    Sand Mountain is one of many hundred mafic vents in the Central Oregon Cascades, and is the largest in a chain consisting of twenty-three mafic cones 30km NNW of the Three Sisters Volcanoes. Sand Mountain represents the maximum probable tephra hazard for mafic activity in Central Oregon because of its unusually large tephra deposit (≥0.9km3), most likely due to interaction with groundwater. To date, no focused analyses have been performed on the volatiles of Sand Mountain. Here we analyze melt inclusions, tephra and lava flows to constrain the volatile budget associated with Sand Mountain with specific focus on the potential impact of future activity on human and livestock populations in Central Oregon. Preliminary analyses of sulfur, chlorine and fluorine in glass show original dissolved volatile contents of 2014 ppm S, 954 ppm Cl and 646 ppm F; these measured abundances translate to a total species budget of 5.54 Mt SO2, 1.35 Mt HCl, and 0.94 Mt HF for the erupted magma (estimated at 0.5 km3 DRE). Comparison of volatile abundances in melt inclusions and matrix glass shows that during eruption, the Sand Mountain magma released 99% of its sulfur, 44% of its chlorine and 35% of its fluorine, equivalent to 5.48 Mt SO2, 0.59 Mt HCl and 0.33 Mt HF. The 1783-1784 AD Laki eruption in Iceland, which had a devastating impact on both proximal and distal populations, showed similar percentages of volatile release, although the total volatile budget was much higher because of the large volume of erupted magma. However, an interesting difference between the Sand Mountain eruption and the Laki eruption is the mechanism of degassing: at Laki, about half of the gas loss occurred during lava flow emplacement; in contrast, at Sand Mountain, the volatile release appears to have been focused in the explosive phase of the eruption, suggesting efficient transfer of gas species with the eruptive plume, which traveled east toward central Oregon. We will test this interpretation by

  15. Cholinergic axon length reduced by 300 meters in the brain of an Alzheimer mouse model

    DEFF Research Database (Denmark)

    Nikolajsen, Gitte; Jensen, Morten Skovgaard; West, Mark J.


    Modern stereological techniques have been used to show that the total length of the cholinergic fibers in the cerebral cortex of the APPswe/PS1deltaE9 mouse is reduced by almost 300 meters at 18 months of age and has a nonlinear relationship to the amount of transgenetically-induced amyloidosis. ....... These data provide rigorous quantitative morphological evidence that Alzheimer's-like amyloidosis affects the axons of the cholinergic enervation of the cerebral cortex....

  16. Activation of Microglial Cells: the Bridge between the Immune System and Pain in Central Nervous System

    Directory of Open Access Journals (Sweden)

    Ali Dabbagh


    Full Text Available Background: Pain is one of the main protests of inflammatory diseases, hence, understanding the mechanisms which involved in the induction and persistence of pain is essential. Microglia is a contributing factor in the onset and maintenance of inflammation. Increased microglial   activation increases the level of central pro-inflammatory cytokines and the development of central sensitization following inflammation. The aim of this study was evaluate the relation of spinal microglia activity with pain related behaviors during Complete Freund’s adjuvant (CFA-induced inflammation.Materials and Methods: Inflammation caused by subcutaneous injection of Complete Freund’s adjuvant (CFA in a single dose to the animals right hind paw. The edema and hyperalgesia caused by inflammation, respectively are measured by Plethysmometer and Radiant Heat, on days 0,7,14 and 21. Spinal Iba-1 protein expression was detected by Western blotting. Minocycline hydrochloride (Sigma, U.S.A was administered i.p. at a dose of 40mg/kg daily.Results: Our study findings indicated that CFA injection to right hindpaw of rats increased paw volume and hyperalgesia significantly during different stages of study, while Minocycline treatment significantly reduced paw volume and hyperalgesia. CFA injection into the right hindpaw of the rat increases the expression of molecules Ionized calcium binding adaptor molecule -1 (Iba-1 on different days of study, while Minocycline administration reduced spinal Iba-1 expression significantly compared to the CFA group.Conclusion: The results of this study indicated the significant roles of microglia activation in deterioration of pain related behaviors during different stages of CFA-induced inflammation. The steady injection of Minocycline (as a microglia inhibitor could reduce the inflammatory symptoms.

  17. Impact of irrigations on simulated convective activity over Central Greece: A high resolution study (United States)

    Kotsopoulos, S.; Tegoulias, I.; Pytharoulis, I.; Kartsios, S.; Bampzelis, D.; Karacostas, T.


    The aim of this research is to investigate the impact of irrigations in the characteristics of convective activity simulated by the non-hydrostatic Weather Research and Forecasting model with the Advanced Research dynamic solver (WRF-ARW, version 3.5.1), under different upper air synoptic conditions in central Greece. To this end, 42 cases equally distributed under the six most frequent upper air synoptic conditions, which are associated with convective activity in the region of interest, were utilized considering two different soil moisture scenarios. In the first scenario, the model was initialized with the surface soil moisture of the ECMWF analysis data that usually does not take into account the modification of soil moisture due to agricultural activity in the area of interest. In the second scenario, the soil moisture in the upper soil layers of the study area was modified to the field capacity for the irrigated cropland. Three model domains, covering Europe, the Mediterranean Sea and northern Africa (d01), the wider area of Greece (d02) and central Greece - Thessaly region (d03) are used at horizontal grid-spacings of 15km, 5km and 1km respectively. The model numerical results indicate a strong dependence of convective spatiotemporal characteristics from the soil moisture difference between the two scenarios. Acknowledgements: This research is co-financed by the European Union (European Regional Development Fund) and Greek national funds, through the action "COOPERATION 2011: Partnerships of Production and Research Institutions in Focused Research and Technology Sectors" (contract number 11SYN_8_1088 - DAPHNE) in the framework of the operational programme "Competitiveness and Entrepreneurship" and Regions in Transition (OPC II, NSRF 2007-2013).

  18. Acute central ghrelin and GH secretagogues induce feeding and activate brain appetite centers. (United States)

    Lawrence, Catherine B; Snape, Amelie C; Baudoin, Florence M-H; Luckman, Simon M


    Ghrelin was recently identified as the endogenous ligand for the GH secretagogue (GHS) receptor. Like the synthetic GHSs [e.g. GH-releasing peptide-6 (GHRP-6)], ghrelin stimulates feeding and increases body weight in rats. The aim of this study was to identify brain regions that are activated by GHSs and determine whether the responses observed were secondary to food intake. In addition, possible mediators of GHS actions were examined. Intracerebroventricular (icv) injection of ghrelin or GHRP-6 into rats significantly stimulated food intake and transiently reduced core body temperature. The effect of both ghrelin and GHRP-6 on food intake was blocked by preadministration of a Y1 NPY receptor antagonist (BIBO3304). Using c-Fos immunohistochemistry, we demonstrated that icv ghrelin or GHRP-6 activated several hypothalamic brain regions, including the arcuate nucleus, paraventricular nucleus, dorsomedial nucleus, lateral hypothalamus, and two regions of the brainstem, the nucleus of the tractus solitarius and the area postrema. The cell activation induced by GHRP-6 was independent of food intake, as the same pattern and extent of c-Fos expression were observed in animals that were denied access to food following treatment. Finally, double immunohistochemistry indicated that orexin-containing, but not melanin-concentrating hormone-containing, neurons in the lateral hypothalamus were activated significantly by central administration of GHRP-6.

  19. Immune activation in the central nervous system throughout the course of HIV infection. (United States)

    Spudich, Serena S


    Robust and dynamic innate and adaptive responses characterize the acute central nervous system (CNS) response to HIV and other viral infections. In a state of chronic infection or viral latency, persistent immune activation associates with abnormality in the CNS. Understanding this process is critical, as immune-mediated abnormality in nonrenewable CNS cells may result in long-term neurologic sequelae for HIV-infected individuals. In humans, immune activation is reduced by suppressive combination antiretroviral therapy, but persists at abnormally elevated levels on treatment. CNS immune activation is initiated in acute infection and progressively increases until combination antiretroviral therapy is started. Newly identified characteristics of the CNS immune surveillance network include features of homeostasis and function of brain microglial cells, lymphatic drainage from CNS to cervical lymph nodes, and cells in cerebrospinal fluid associated with neurocognitive impairment. More research is required to determine whether early intervention to reduce infection limits the immunopathology established by sustained immune responses that ultimately fail to resolve infection, and to unravel mechanisms of persistent immune activation during treated HIV so that strategies can be developed to therapeutically protect the brain.

  20. Hydrochemical evaluation of the influences of mining activities on river water chemistry in central northern Mongolia. (United States)

    Batsaikhan, Bayartungalag; Kwon, Jang-Soon; Kim, Kyoung-Ho; Lee, Young-Joon; Lee, Jeong-Ho; Badarch, Mendbayar; Yun, Seong-Taek


    Although metallic mineral resources are most important in the economy of Mongolia, mining activities with improper management may result in the pollution of stream waters, posing a threat to aquatic ecosystems and humans. In this study, aiming to evaluate potential impacts of metallic mining activities on the quality of a transboundary river (Selenge) in central northern Mongolia, we performed hydrochemical investigations of rivers (Tuul, Khangal, Orkhon, Haraa, and Selenge). Hydrochemical analysis of river waters indicates that, while major dissolved ions originate from natural weathering (especially, dissolution of carbonate minerals) within watersheds, they are also influenced by mining activities. The water quality problem arising from very high turbidity is one of the major environmental concerns and is caused by suspended particles (mainly, sediment and soil particles) from diverse erosion processes, including erosion of river banks along the meandering river system, erosion of soils owing to overgrazing by livestock, and erosion by human activities, such as mining and agriculture. In particular, after passing through the Zaamar gold mining area, due to the disturbance of sediments and soils by placer gold mining, the Tuul River water becomes very turbid (up to 742 Nephelometric Turbidity Unit (NTU)). The Zaamar area is also the contamination source of the Tuul and Orkhon rivers by Al, Fe, and Mn, especially during the mining season. The hydrochemistry of the Khangal River is influenced by heavy metal (especially, Mn, Al, Cd, and As)-loaded mine drainage that originates from a huge tailing dam of the Erdenet porphyry Cu-Mo mine, as evidenced by δ34S values of dissolved sulfate (0.2 to 3.8 ‰). These two contaminated rivers (Tuul and Khangal) merge into the Orkhon River that flows to the Selenge River near the boundary between Mongolia and Russia and then eventually flows into Lake Baikal. Because water quality problems due to mining can be critical, mining

  1. Cholinergic receptor alterations in the cerebral cortex of spinal cord injured rat

    Directory of Open Access Journals (Sweden)

    R. Chinthu


    Full Text Available Many areas of the cerebral cortex process sensory information or coordinate motor output necessary for control of movement. Disturbances in cortical cholinergic system can affect locomotor coordination. Spinal cord injury causes severe motor impairment and disturbances in cholinergic signalling can aggravate the situation. Considering the impact of cortical cholinergic firing in locomotion, we focussed the study in understanding the cholinergic alterations in cerebral cortex during spinal cord injury. The gene expression of key enzymes in cholinergic pathway - acetylcholine esterase and choline acetyl transferase showed significant upregulation in the cerebral cortex of spinal cord injured group compared to control with the fold increase in expression of acetylcholine esterase prominently higher than cholineacetyl transferase. The decreased muscarinic receptor density and reduced immunostaining of muscarinic receptor subtypes along with down regulated gene expression of muscarinic M1 and M3 receptor subtypes accounts for dysfunction of metabotropic acetylcholine receptors in spinal cord injury group. Ionotropic acetylcholine receptor alterations were evident from the decreased gene expression of alpha 7 nicotinic receptors and reduced immunostaining of alpha 7 nicotinic receptors in confocal imaging. Our data pin points the disturbances in cortical cholinergic function due to spinal cord injury; which can augment the locomotor deficits. This can be taken into account while devising a proper therapeutic approach to manage spinal cord injury.

  2. Normal Weight with Central Obesity, Physical Activity, and Functional Decline: Data from the Osteoarthritis Initiative. (United States)

    Batsis, John A; Zbehlik, Alicia J; Scherer, Emily A; Barre, Laura K; Bartels, Stephen J


    To identify the risks of the combination of normal body mass index (BMI) and central obesity (normal weight and central obesity (NWCO)) on physical activity and function. Longitudinal Osteoarthritis Initiative Study. Community based. Adults aged 60 and older at risk of osteoarthritis (N = 2,210; mean age 68, range 67.1-69.0) were grouped according to BMI (normal 18.5-24.9 kg/m(2) , overweight 25.0-29.9 kg/m(2) , obese ≥30.0 kg/m(2) ). High waist circumference (WC) was defined as greater than 88 cm for women and greater than 102 cm for men. Subjects were subcategorized according to WC (five categories). Subjects with normal BMI and a large WC were considered to have NWCO (n = 280, 12.7%). Six-year changes in the Physical Component Summary of the Medical Outcomes Study 12-item Short Form Survey (PCS), Physical Activity Scale for the Elderly (PASE), and Late-Life Function and Disability Index (LL-FDI) were examined. The association between BMI and WC over 6 years was assessed (reference normal BMI, normal WC). Stratified analyses were performed according to age (60-69; ≥70). Physical component scores, PASE, and LL-FDI declined with time. Mean PASE scores at 6 years differed between the NWCO group and the group with normal BMI and WC (117.7 vs 141.5), but rate of change from baseline to 6 years was not significantly different (P = .35). In adjusted models, those with NWCO had greater decline in PCS over time, particularly those aged 70 and older than those with normal BMI and WC (time interaction β = -0.37, 95% confidence interval = -0.68 to -0.06). Normal weight and central obesity in older adults at risk of osteoarthritis may be a risk factor for declining function and physical activity, particularly in those aged 70 and older, suggesting the value of targeting those with NWCO who would otherwise be labeled as low risk. © 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society.

  3. Different correlation patterns of cholinergic and GABAergic interneurons with striatal projection neurons

    Directory of Open Access Journals (Sweden)

    Avital eAdler


    Full Text Available The striatum is populated by a single projection neuron group, the medium spiny neurons (MSNs, and several groups of interneurons. Two of the electrophysiologically well-characterized striatal interneuron groups are the tonically active neurons (TANs, which are presumably cholinergic interneurons, and the fast spiking interneurons (FSIs, presumably parvalbumin (PV expressing GABAergic interneurons. To better understand striatal processing it is thus crucial to define the functional relationship between MSNs and these interneurons in the awake and behaving animal. We used multiple electrodes and standard physiological methods to simultaneously record MSN spiking activity and the activity of TANs or FSIs from monkeys engaged in a classical conditioning paradigm. All three cell populations were highly responsive to the behavioral task. However, they displayed different average response profiles and a different degree of response synchronization (signal correlation. TANs displayed the most transient and synchronized response, MSNs the most diverse and sustained response and FSIs were in between on both parameters. We did not find evidence for direct monosynaptic connectivity between the MSNs and either the TANs or the FSIs. However, while the cross correlation histograms of TAN to MSN pairs were flat, those of FSI to MSN displayed positive asymmetrical broad peaks. The FSI-MSN correlogram profile implies that the spikes of MSNs follow those of FSIs and both are driven by a common, most likely cortical, input. Thus, the two populations of striatal interneurons are probably driven by different afferents and play complementary functional roles in the physiology of the striatal microcircuit.

  4. Rosmarinus officinalis polyphenols produce anti-depressant like effect through monoaminergic and cholinergic functions modulation. (United States)

    Sasaki, Kazunori; El Omri, Abdelfatteh; Kondo, Shinji; Han, Junkyu; Isoda, Hiroko


    Rosmarinus officinalis (R. officinalis), a culinary aromatic and medicinal plant, is very rich in polyphenols and flavonoids with high antioxidant properties. This plant was reported to exert multiple benefits for neuronal system and alleviate mood disorder. In our previous study, we demonstrated that R. officinalis and its active compounds, luteolin (Lut), carnosic acid (CA), and rosmarinic acid (RA), exhibited neurotrophic effects and improved cholinergic functions in PC12 cells in correlation with mitogen-activated protein kinase (MAPK), ERK1/2 signaling pathway. The current study was conducted to evaluate and understand the anti-depressant effect of R. officinalis using tail suspension test (TST) in ICR mice and PC12 cells as in vitro neuronal model. Proteomics analysis of PC12 cells treated with R. officinalis polyphenols (ROP) Lut, CA, and RA revealed a significant upregulation of tyrosine hydroxylase (TH) and pyruvate carboxylase (PC) two major genes involved in dopaminergic, serotonergic and GABAergic pathway regulations. Moreover, ROP were demonstrated to protect neuronal cells against corticosterone-induced toxicity. These results were concordant with decreasing immobility time in TST and regulation of several neurotransmitters (dopamine, norepinephrine, serotonin and acetylcholine) and gene expression in mice brain like TH, PC and MAPK phosphatase (MKP-1). To the best of our knowledge this is the first evidence to contribute to the understanding of molecular mechanism behind the anti-depressant effect of R. officinalis and its major active compounds. Copyright © 2012 Elsevier B.V. All rights reserved.

  5. Ionospheric transients observed at mid-latitudes prior to earthquake activity in Central Italy

    Directory of Open Access Journals (Sweden)

    P. Nenovski


    Full Text Available Ionograms from Rome (41.8N, 12.5E and Sofia (42.4N, 23.2E ionospheric stations during earthquake (EQ activity with magnitude (M between 5 and 6 in Central Italy are analyzed. It is found that several ionospheric disturbances occur in the intermediate E-F region before the EQ shock. In fact, besides sporadic E (Es layer development (of type h of short duration (transients, fmin increase, trace gaps near the critical frequencies, and E region trace disappearance are also observed within one to three hours before the EQ shock. Before the EQ shocks we find that the F2 region parameters are practically undisturbed. The only exception is the so-called fork trace that appears mostly near the critical frequency of the F2 region. Acoustic gravity waves (AGW are suggested as one of the possible sources of transients observed in the ionosphere before the EQ shock.

  6. Developing Social Media Practices in SMEs - The Role of Distributed and Centralized Leadership Activities

    DEFF Research Database (Denmark)

    Simmelsgaard, Sonni Hansen; Lutz, Salla; Brink, Tove

    for business purposes. This study aims to contribute to the scarce existing literature on leadership activities in relation to a company’s social media practices by conducting a qualitative analysis that is based on three theoretical propositions. Managerially the paper wishes to emphasize the importance...... of leadership’s awareness on the increasing relevance of adopting social media practices. Furthermore, the need for specific sense making of both social media practices in SME organisations and the integration of distributed and central leadership is highlighted as important for progress. Our research has......Social media practices are implemented in a growing number of B2B-companies. However, it seems that SMEs adoption of these practices is lagging behind compared with larger firms. In this context the support from the leadership is essential in order to enhance a firm’s use of social media...

  7. Central nervous system activity of the ethanol leaf extract of Sida acuta in rats. (United States)

    Ibironke, G F; Umukoro, A S; Ajonijebu, D C


    The study investigated the pharmacological effects of ethanol extract of Sida acuta leaves on central nervous system activities in mice. Adult male mice (18 - 25g) were used for the study. The extract was administered orally in male mice and evaluated in the following tests: forced swimming, tail suspension, formalin-induced paw licking, acetic acid--induced mouse writhing and apomorphine-induced stereotypy. The results revealed a reduction in the frequency of abdominal constrictions induced by acetic acid, decreased licking times in both phases of the formalin test, reduction in immobility times in forced swimming and tail suspension tests. However, the extract produced no effect on apomorphine-induced stereotyped behaviour. These results suggest that the ethanol extract of Sida acuta contains psychoactive substances with analgesic and antidepressant-like properties which may be beneficial in the management of pain.

  8. Effects of the total alkaloidal extract of Murraya koenigii leaf on oxidative stress and cholinergic transmission in aged mice. (United States)

    Mani, Vasudevan; Ramasamy, Kalavathy; Ahmad, Aliya; Wahab, Siti Norshazwani; Jaafar, Siti Murnirah; Kek, Teh Lay; Salleh, Mohd Zaki; Majeed, Abu Bakar Abdul


    Alzheimer's disease (AD) is characterized by signs of major oxidative stress and the loss of cholinergic cells. The present study was designed to investigate the role of the total alkaloidal extract from Murraya koenigii (MKA) leaves on age related oxidative stress and the cholinergic pathway in aged mice. Ascorbic acid (100 mg/kg, p.o.) was used as a standard drug. The MKA improved the level of protective antioxidants such as glutathione peroxidase (GPx), reduced glutathione (GSH), glutathione reductase (GRD), superoxide dismutase (SOD) and catalase (CAT) in brain homogenate at higher doses (20 and 40 mg/kg, p.o.). Moreover, a dose dependent decline was noted in lipid peroxidation (LPO) and the nitric oxide assay (NO) at all doses of MKA (10, 20 and 40 mg/kg, p.o.). Interestingly, significant progress was noted with the supplementation of MKA by an improvement of the acetylcholine (ACh) levels and a reduction in the acetylcholinesterase (AChE) activity in aged mouse brain. In addition, a significant elevation of serum albumin (ALBU), alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST) and total protein as well as a decline in creatinine, total cholesterol, urea nitrogen and glucose levels with MKA also ameliorated the hepatic and renal functions in normal ageing process. The results showed the possible utility of Murraya koenigii leaves in neuroprotection against neurodegenerative disorders such as Alzheimer's disease. Copyright © 2012 John Wiley & Sons, Ltd.

  9. Activated central galanin type 1 receptor alleviated insulin resistance in diabetic rat muscle. (United States)

    Bu, Le; Chang, Xusheng; Cheng, Xiaoyun; Yao, Qian; Su, Bin; Sheng, Chunjun; Qu, Shen


    Evidence indicates that central galanin is involved in regulation of insulin resistance in animals. This study investigates whether type 1 galanin receptor (GAL1) in the brain mediates the ameliorative effect of galanin on insulin resistance in skeletal muscles of type 2 diabetic rats. Rats were intracerebroventricularly (i.c.v.) injected with galanin(1-13)-bradykinin(2-9) amide (M617), a GAL1 agonist, and/or Akti-1/2, an Akt inhibitor, via caudal veins once per day for 10 days. Insulin resistance in muscle tissues was evaluated by glucose tolerance and 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) tests, peroxisome proliferator-activated receptor-γ (PPARγ), glucose transporter 4 (GLUT4) mRNA expression levels, Akt phosphorylation, and GLUT4 and vesicle-associated membrane protein 2 (VAMP2) concentration at plasma membranes in muscle cells. The results show that i.c.v. treatment with M617 increased glucose tolerance, 2-NBDG uptake, PPARγ levels, Akt phosphorylation, GLUT4 protein, and GLUT4 mRNA expression levels as well as GLUT4 and VAMP2 concentration at plasma membranes. All increases may be blocked by pretreatment with Akti-1/2. These results suggest that activated central GAL1 may trigger the Akt signaling pathway to alleviate insulin resistance in muscle cells. Therefore, the impact of galanin on insulin resistance is mediated mainly by GAL1 in the brain, and the GAL1 agonist may be taken as a potential antidiabetic agent for treatment of type 2 diabetes mellitus. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  10. The Central Italy Electromagnetic Network and the 2009 L'Aquila Earthquake: Observed Electric Activity

    Directory of Open Access Journals (Sweden)

    Cristiano Fidani


    Full Text Available A network of low frequency electromagnetic detectors has been operating in Central Italy for more than three years, consisting of identical instruments that continuously record the electrical components of the electromagnetic field, ranging from a few Hz to tens of kHz. These signals are analyzed in real time and their power spectrum contents and time/frequency data are available online. To date, specific interest has been devoted to searching for any possible electromagnetic features which correlate with seismic activity in the same region. In this study, spectral analysis has evidenced very distinct power spectrum signatures that increased in intensity when strong seismic activity occurred near the stations of the 2009 L'Aquila earthquake. These signatures have revealed horizontally oriented electric fields, between 20 Hz to 400 Hz, lasting from several minutes to up to two hours. Their power intensities have been found to be about 1 μV/m. Moreover, a large number of man-made signals and meteorologic electric perturbations were recorded. Anthropogenic signatures have come from power line disturbances at 50 Hz and higher harmonics up to several kHz, while radio transmissions have influenced the higher kHz spectrum. Reception from low frequency transmitters is also provided in relation to seismic activity. Meteorologic signatures cover the lower frequency band through phenomena such as spherics, Schumann resonances and rain electrical perturbations. All of these phenomena are useful teaching tools for introducing students to this invisible electromagnetic world.

  11. [Central Pattern Generators: Mechanisms of the Activity and Their Role in the Control of "Automatic" Movements]. (United States)

    Arshavsky, I; Deliagina, T G; Orlovsky, G N


    Central pattern generators (CPGs) are a set of interconnected neurons capable of generating a basic pattern of motor output underlying "automatic" movements (breathing, locomotion, chewing, swallowing, and so on) in the absence of afferent signals from the executive motor apparatus. They can be divided into the constitutive CPGs active throughout the entire lifetime (respiratory CPGs) and conditional CPGs controlling episodic movements (locomotion, chewing, swallowing, and others). Since a motor output of CPGs is determined by their internal organization, the activities of the conditional CPGs are initiated by simple commands coming from higher centers. We describe the structural and functional organization of the locomotor CPGs in the marine mollusk Clione limacina, lamprey, frog embryo, and laboratory mammals (cat, mouse, and rat), CPGs controlling the respiratory and swallowing movements in mammals, and CPGs controlling discharges of the electric organ in the gymnotiform fish. It is shown that in all these cases, the generation of rhythmic motor output is based both on the endogenous (pacemaker) activity of specific groups of interneurons and on interneural interactions. These two interrelated mechanisms complement each other, ensuring the high reliability of CPG functionality. We discuss how the experience obtained in studying CPGs can be used to understand mechanisms of more complex functions of the brain, including its cognitive functions.

  12. Effects of seasonal variation on the central nervous system activity of Ocimum gratissimum L. essential oil. (United States)

    Freire, Cristiana M Murbach; Marques, Márcia Ortiz M; Costa, Mirtes


    Ocimum gratissimum L. (Lamiaceae) and other species of the same genus are used as medicines to treat central nervous system (CNS) diseases, commonly encountered in warm regions of the world. The chemical composition of Ocimum gratissimum essential oil varies according to their chemotypes: timol, eugenol or geraniol. In this study, the essential oil type eugenol was extracted by hydrodistillation in each of the four seasons of the year. Activity upon CNS was evaluated in the open-field and rota-rod tests; sleeping time induced by sodium pentobarbital (PBS, 40 mg/kg, intra-peritoneally, i.p.) and anticonvulsant activity against seizures induced by both pentylenetetrazole (PTZ; 85 mg/kg, s.c.) and maximal electroshock (MES, 50 mA, 0.11 s) were determined. Essential oils obtained in each season were effective in increasing the sleeping duration and a preparation obtained in Spring was able to protect animals against tonic seizures induced by electroshock. In each season, eugenol and 1,8-cineole were the most abundant compounds, and in Spring the essential oil presented the greatest relative percentage of sesquiterpenes, suggesting that these compounds could explain the differences observed in the biological activity in essential oils obtained in different seasons of the year.

  13. Amylin Acts in the Central Nervous System to Increase Sympathetic Nerve Activity (United States)

    Fernandes-Santos, Caroline; Zhang, Zhongming; Morgan, Donald A.; Guo, Deng-Fu; Russo, Andrew F.


    The pancreatic hormone amylin acts in the central nervous system (CNS) to decrease food intake and body weight. We hypothesized that amylin action in the CNS promotes energy expenditure by increasing the activity of the sympathetic nervous system. In mice, ip administration of amylin significantly increased c-Fos immunoreactivity in hypothalamic and brainstem nuclei. In addition, mice treated with intracerebroventricular (icv) amylin (0.1 and 0.2 nmol) exhibited a dose-related decrease in food intake and body weight, measured 4 and 24 hours after treatment. The icv injection of amylin also increased body temperature in mice. Using direct multifiber sympathetic nerve recording, we found that icv amylin elicited a significant and dose-dependent increase in sympathetic nerve activity (SNA) subserving thermogenic brown adipose tissue (BAT). Of note, icv injection of amylin also evoked a significant and dose-related increase in lumbar and renal SNA. Importantly, icv pretreatment with the amylin receptor antagonist AC187 (20 nmol) abolished the BAT SNA response induced by icv amylin, indicating that the sympathetic effects of amylin are receptor-mediated. Conversely, icv amylin-induced BAT SNA response was enhanced in mice overexpressing the amylin receptor subunit, RAMP1 (receptor-activity modifying protein 1), in the CNS. Our data demonstrate that CNS action of amylin regulates sympathetic nerve outflow to peripheral tissues involved in energy balance and cardiovascular function. PMID:23645151

  14. Cholinergic transmission during nicotine withdrawal is influenced by age and pre-exposure to nicotine: implications for teenage smoking. (United States)

    Carcoba, Luis M; Orfila, James E; Natividad, Luis A; Torres, Oscar V; Pipkin, Joseph A; Ferree, Patrick L; Castañeda, Eddie; Moss, Donald E; O'Dell, Laura E


    Adolescence is a unique period of development characterized by enhanced tobacco use and long-term vulnerability to neurochemical changes produced by adolescent nicotine exposure. In order to understand the underlying mechanisms that contribute to developmental differences in tobacco use, this study compared changes in cholinergic transmission during nicotine exposure and withdrawal in naïve adult rats compared to (1) adolescent rats and (2) adult rats that were pre-exposed to nicotine during adolescence. The first study compared extracellular levels of acetylcholine (ACh) in the nucleus accumbens (NAc) during nicotine exposure and precipitated withdrawal using microdialysis procedures. Adolescent (postnatal day, PND, 28-42) and adult rats (PND60-74) were prepared with osmotic pumps that delivered nicotine for 14 days (adolescents 4.7 mg/kg/day; adults 3.2 mg/kg/day; expressed as base). Another group of adults was exposed to nicotine during adolescence and then again in adulthood (pre-exposed adults) using similar methods. Control rats received a sham surgery. Following 13 days of nicotine exposure, the rats were implanted with microdialysis probes in the NAc. The following day, dialysis samples were collected during baseline and following systemic administration of the nicotinic receptor antagonist mecamylamine (1.5 and 3.0 mg/kg, i.p.) to precipitate withdrawal. A second study compared various metabolic differences in cholinergic transmission using the same treatment procedures as the first study. Following 14 days of nicotine exposure, the NAc was dissected and acetylcholinesterase (AChE) activity was compared across groups. In order to examine potential group differences in nicotine metabolism, blood plasma levels of cotinine (a nicotine metabolite) were also compared following 14 days of nicotine exposure. The results from the first study revealed that nicotine exposure increased baseline ACh levels to a greater extent in adolescent versus adult rats. During

  15. [Effect of salidroside on rat bone marrow mesenchymal stem cells differentiation into cholinergic nerve cells]. (United States)

    Zhang, Ming; Zhao, Hongbin; Li, Zhiyun; Yang, Yinshu; Wen, Yimin; Dong, Juzi; Zhang, Quanwei; Ge, Baofeng


    To investigate the effect of salidroside on rat bone marrow mesenchymal stem cells (BMSCs) differentiation into the cholinergic nerve cells, so as to provide the theory basis of the combination of salidroside and stem cells for clinical therapy of nervous system diseases. BMSCs were isolated from 2 Wistar rats (aged 4-6 weeks,weighing 120 g), which were identified by CD34, CD45, CD90, and CD106 with flow cytometry. According to inducing method, BMSCs at passage 2 were divided into 3 groups: In groups A and B, BMSCs were induced by salidroside (20 microg/mL) and retinoic acid (5 micromol/mL) respectively for 1, 3, 6, and 9 days, in group C, BMSCs were cultured with serum-free DMEM/F12 medium as control. MTT assay was used to detect the cellular proliferation activity. The immunofluorescence chemical technology was used to detect the expressions of nerve growth factor (NGF) and relevant marker molecule of nerve cells, including neuron-specific enolase (NSE), microtubule-associated protein 2 (MAP2), beta-Tubulin III, glial fibrillary acidic protein (GFAP), and the marker of cholinergic neuron, such as Acetylcholine (Ach) and NGF. RT-PCR was used to detect mRNA expressions of NSE, beta-Tubulin III, GFAP,brain derived neurotrophic factor (BDNF),and gamma-aminobutyric acid (GABA). ELISA was used to detect the levels of BDNF and NGF, and the expression level of NGF protein was analyzed by Western blot. The results of the flow cytometry showed that the cultured cells were CD90 and CD106 positive, and CD34 and CD45 negative,which indicated that the cells were BMSCs. The cellular proliferation activity in groups A and B were significantly higher than that in group C at 6 days and 9 days (P 0.05). The expression level of NGF protein in groups A and B were significantly higher than that in group C (P nerve cells in vitro.

  16. Acute cholinergic syndrome in a patient with mild Alzheimer's type dementia who had applied a large number of rivastigmine transdermal patches on her body. (United States)

    Suzuki, Yoshiki; Kamijo, Yoshito; Yoshizawa, Tomohiro; Fujita, Yuji; Usui, Kiyotaka; Kishino, Tohru


    A 91-year-old woman was transferred to our Emergency Medical Center and Poison Center with somnolence, hypertension (186/61 mm Hg), and repeated vomiting. Three hours later, 10 transdermal patches, each containing 18 mg of rivastigmine (9.5 mg/24 h), were found on her lower back and both thighs, when miosis, facial and trunk sweating, enhanced bowel sound, hypertension, and sinus tachycardia were noted. She was diagnosed with acute cholinergic syndrome due to rivastigmine poisoning. Her hypertension and sinus tachycardia peaked 8 and 5 h after all the patches were removed, respectively. Her symptoms subsided spontaneously after 17 h. In the present case, our patient was presented with acute cholinergic syndrome due to carbamate intoxication after massive transdermal exposure to rivastigmine. Toxicological analysis revealed a remarkably high estimated serum rivastigmine concentration (150.6 ng/ml) and notably low serum butyrylcholinesterase activity (35 IU/l) on admission, with a markedly prolonged calculated elimination half-life of 6.5 h. Emergency physicians should consider acetylcholinesterase inhibitor exposure (e.g., rivastigmine) when patients are present with acute cholinergic syndrome.

  17. Long-term effects of immunotoxic cholinergic lesions in the septum on acquisition of the cone-field task and noncognitive measures in rats. (United States)

    van der Staay, F Josef; Bouger, Pascale; Lehmann, Olivia; Lazarus, Christine; Cosquer, Brigitte; Koenig, Julie; Stump, Veronika; Cassel, Jean-Christophe


    In rats, nonspecific mechanical or neurotoxic lesions of the septum impair spatial memory in, e.g., Morris water- and radial-maze tasks. Unfortunately, the lack of specificity of such lesions limits inferences about the role of the cholinergic hippocampal projections in spatial cognition. We therefore tested the effects of septal lesions produced by 192 IgG-saporin in rats, which is highly selective for basal forebrain cholinergic neurons, on home cage activity, noncognitive tests (modified Irwin test, open field and forced swimming tests, and various sensorimotor tasks), and the cone-field spatial learning task. The immunotoxic lesion reduced acetylcholine (ACh) levels in the septum (-61%) and hippocampus (>-75%). Rats with lesions showed mild home-cage hyperactivity at 4 weeks postlesion, but no noncognitive deficits at 13 weeks postsurgery. In the cone-field task, rats with septal lesions made more working- and reference-memory errors than the controls, but acquisition curves were parallel in both groups. The speed of visiting cones was faster in the rats with lesions, indicative of disturbed attention or increased motivation. These data support the growing evidence that involvement of the septohippocampal cholinergic system in spatial learning and memory may have been overestimated in studies that used lesions with poor selectivity. (c) 2006 Wiley-Liss, Inc.

  18. Ligands for SPECT and PET imaging of muscarinic-cholinergic receptors of the heart and brain

    Energy Technology Data Exchange (ETDEWEB)

    Knapp, F.F. Jr.; McPherson, D.W.; Luo, H. [and others


    Interest in the potential use of cerebral SPECT and PET imaging for determination of the density and activity of muscarinic-cholinergic receptors (mAChR) has been stimulated by the changes in these receptors which occur in many neurological diseases. In addition, the important involvement of mAChR in modulating negative inotropic cardiac activity suggests that such receptor ligands may have important applications in evaluation of changes which may occur in cardiac disease. In this paper, the properties of several key muscarinic receptor ligands being developed or which have been used for clinical SPECT and PET are discussed. In addition, the ORNL development of the new iodinated IQNP ligand based on QNB and the results of in vivo biodistribution studies in rats, in vitro competitive binding studies and ex vivo autoradiographic experiments are described. The use of radioiodinated IQNP may offer several advantages in comparison to IQNB because of its easy and high yield preparation and high brain uptake and the potential usefulness of the {open_quotes}partial{close_quotes} subtype selective IONP isomers. We also describe the development of new IQNP-type analogues which offer the opportunity for radiolabeling with positron-emitting radioisotopes (carbon-11, fluorine-18 and bromine-76) for potential use with PET.

  19. Functional selectivity of central Gα-subunit proteins in mediating the cardiovascular and renal excretory responses evoked by central α(2) -adrenoceptor activation in vivo. (United States)

    Wainford, R D; Kapusta, D R


    Activation of brain α(2) -adrenoceptors in conscious rodents decreases heart rate (HR) and mean arterial blood pressure (MAP) and increases urine output and urinary sodium excretion. In vitro, α(2) -adrenoceptor stimulation activates Gα(i(1-3)) , Gα(o) and Gα(s) -subunit protein-gated signal transduction pathways. Here we have investigated whether these same Gα-subunit protein-gated pathways mediate the cardiovascular and renal excretory responses to central α(2) -adrenoceptor activation in conscious Sprague-Dawley rats. Rats were pre-treated by intracerebroventricular injection (i.c.v.) with an oligodeoxynucleotide (ODN) targeted to a Gα(i1) , Gα(i2) , Gα(i3) , Gα(o) , Gα(s) or a scrambled (SCR) ODN sequence (25 µg, 24 h). On the day of study, the α(2) -adrenoceptor agonist guanabenz (50 µg) or saline vehicle, was injected i.c.v. into ODN-pre-treated conscious rats. MAP and HR were recorded, and urine was collected for 150 min. In vehicle- and SCR ODN-pre-treated rats, i.c.v. guanabenz decreased MAP and HR, and produced marked diuretic and natriuretic responses. Selective ODN-mediated down-regulation of brain Gα(i2) -subunit proteins abolished the central guanabenz-induced hypotension and natriuresis. In contrast, following selective Gα(s) down-regulation, the characteristic hypotensive response to i.c.v. guanabenz was converted to an immediate increase in MAP. The bradycardic and diuretic responses to i.c.v. guanabenz were not blocked by pre-treatment with any ODN. There was functional selectivity of Gα(i2) and Gα(s) subunit protein-gated signal transduction pathways in mediating the hypotensive and natriuretic, but not bradycardic or diuretic, responses evoked by central α(2) -adrenoceptor activation in vivo. Published 2011. This article is a U.S. Government work and is in the public domain in the USA.

  20. Replicated Risk Nicotinic Cholinergic Receptor Genes for Nicotine Dependence. (United States)

    Zuo, Lingjun; Garcia-Milian, Rolando; Guo, Xiaoyun; Zhong, Chunlong; Tan, Yunlong; Wang, Zhiren; Wang, Jijun; Wang, Xiaoping; Kang, Longli; Lu, Lu; Chen, Xiangning; Li, Chiang-Shan R; Luo, Xingguang


    It has been hypothesized that the nicotinic acetylcholine receptors (nAChRs) play important roles in nicotine dependence (ND) and influence the number of cigarettes smoked per day (CPD) in smokers. We compiled the associations between nicotinic cholinergic receptor genes (CHRNs) and ND/CPD that were replicated across different studies, reviewed the expression of these risk genes in human/mouse brains, and verified their expression using independent samples of both human and mouse brains. The potential functions of the replicated risk variants were examined using cis-eQTL analysis or predicted using a series of bioinformatics analyses. We found replicated and significant associations for ND/CPD at 19 SNPs in six genes in three genomic regions (CHRNB3-A6, CHRNA5-A3-B4 and CHRNA4). These six risk genes are expressed in at least 18 distinct areas of the human/mouse brain, with verification in our independent human and mouse brain samples. The risk variants might influence the transcription, expression and splicing of the risk genes, alter RNA secondary or protein structure. We conclude that the replicated associations between CHRNB3-A6, CHRNA5-A3-B4,CHRNA4 and ND/CPD are very robust. More research is needed to examine how these genetic variants contribute to the risk for ND/CPD.

  1. Cholinergic chemosensory cells in the trachea regulate breathing. (United States)

    Krasteva, Gabriela; Canning, Brendan J; Hartmann, Petra; Veres, Tibor Z; Papadakis, Tamara; Mühlfeld, Christian; Schliecker, Kirstin; Tallini, Yvonne N; Braun, Armin; Hackstein, Holger; Baal, Nelli; Weihe, Eberhard; Schütz, Burkhard; Kotlikoff, Michael; Ibanez-Tallon, Ines; Kummer, Wolfgang


    In the epithelium of the lower airways, a cell type of unknown function has been termed "brush cell" because of a distinctive ultrastructural feature, an apical tuft of microvilli. Morphologically similar cells in the nose have been identified as solitary chemosensory cells responding to taste stimuli and triggering trigeminal reflexes. Here we show that brush cells of the mouse trachea express the receptors (Tas2R105, Tas2R108), the downstream signaling molecules (α-gustducin, phospholipase C(β2)) of bitter taste transduction, the synthesis and packaging machinery for acetylcholine, and are addressed by vagal sensory nerve fibers carrying nicotinic acetylcholine receptors. Tracheal application of an nAChR agonist caused a reduction in breathing frequency. Similarly, cycloheximide, a Tas2R108 agonist, evoked a drop in respiratory rate, being sensitive to nicotinic receptor blockade and epithelium removal. This identifies brush cells as cholinergic sensors of the chemical composition of the lower airway luminal microenvironment that are directly linked to the regulation of respiration.

  2. Effects of the cholinergic agonist nicotine on reorienting of visual spatial attention and top-down attentional control. (United States)

    Thiel, C M; Fink, G R


    The cholinergic agonist nicotine facilitates detection of invalidly cued trials in location-cueing paradigms and reduces the associated neural activity in human inferior parietal cortex. By using functional magnetic resonance imaging we test the hypothesis that the nicotinic modulation of attentional reorienting may result from reduced use of top-down information derived from prior cues. In a within subjects design non-smoking volunteers were given either placebo or nicotine (Nicorette 2 mg gum) prior to performing a cued target discrimination task. Attention was either validly (80%) or invalidly (20%) cued to the right or left visual hemifield. The difference in reaction times to invalidly and validly cued targets is termed the 'validity effect' and indicates the costs for attentional reorienting. Nicotine reduced the validity effect and reorienting-related neural activity in right inferior parietal cortex. Further regions consistently modulated in their activity by nicotine were the right middle temporal gyrus, left middle frontal gyrus, left parahippocampal gyrus and right cerebellum. The effects of nicotine upon top-down modulation were investigated by comparing occipital activity when attending to the right vs. left visual hemifield under placebo and nicotine. If nicotine reduced the use of top-down information attentional modulation in occipital cortex should be smaller under nicotine as compared with placebo. Even though an attention-related modulation of neural activity was observed in the fusiform and middle occipital gyrus we found no evidence for differences in attentional modulation under placebo and nicotine. Our data support a role of nicotinic cholinergic receptors in facilitating several subcomponents of attentional reorienting via modulation of right inferior parietal, temporal and frontal brain activity. In contrast, the findings in the occipital cortex do not support the hypothesis that the effects of nicotine on attentional reorienting are due

  3. Sedentary Behavior and Light Physical Activity Are Associated with Brachial and Central Blood Pressure in Hypertensive Patients

    DEFF Research Database (Denmark)

    Gerage, A. M.; Benedetti, T. R. B.; Farah, B. Q.


    their physical activity assessed over a 7 day period using an accelerometer and the time spent in sedentary activities, light physical activities, moderate physical activities and moderate-to-vigorous physical activities was obtained. The primary outcomes were brachial and central blood pressure. Arterial...... stiffness parameters (augmentation index and pulse wave velocity) and cardiac autonomic modulation (sympathetic and parasympathetic modulation in the heart) were also obtained as secondary outcomes. Results Sedentary activities and light physical activities were positively and inversely associated......-to-vigorous physical activities. Arterial stiffness parameters and cardiac autonomic modulation were not associated with the time spent in sedentary activities and in light physical activities (P > 0.05). Conclusion Lower time spent in sedentary activities and higher time spent in light physical activities...

  4. Centrally administered resistin enhances sympathetic nerve activity to the hindlimb but attenuates the activity to brown adipose tissue. (United States)

    Kosari, S; Rathner, J A; Chen, F; Kosari, S; Badoer, E


    Resistin, an adipokine, is believed to act in the brain to influence energy homeostasis. Plasma resistin levels are elevated in obesity and are associated with metabolic and cardiovascular disease. Increased muscle sympathetic nerve activity (SNA) is a characteristic of obesity, a risk factor for diabetes and cardiovascular disease. We hypothesized that resistin affects SNA, which contributes to metabolic and cardiovascular dysfunction. Here we investigated the effects of centrally administered resistin on SNA to muscle (lumbar) and brown adipose tissue (BAT), outputs that influence cardiovascular and energy homeostasis. Overnight-fasted rats were anesthetized, and resistin (7 μg) was administered into the lateral cerebral ventricle (intracerebroventricular). The lumbar sympathetic nerve trunk or sympathetic nerves supplying BAT were dissected free, and nerve activity was recorded. Arterial blood pressure, heart rate, body core temperature, and BAT temperature were also recorded. Responses to resistin or vehicle were monitored for 4 h after intracerebroventricular administration. Acutely administered resistin increased lumbar SNA but decreased BAT SNA. Mean arterial pressure and heart rate, however, were not significantly affected by resistin. BAT temperature was significantly reduced by resistin, and there was a concomitant fall in body temperature. The findings indicate that resistin has differential effects on SNA to tissues involved in metabolic and cardiovascular regulation. The decreased BAT SNA and the increased lumbar SNA elicited by resistin suggest that it may contribute to the increased muscle SNA and reduced energy expenditure observed in obesity and diabetes.

  5. Central and direct regulation of testicular activity by gonadotropin-inhibitory hormone and its receptor

    Directory of Open Access Journals (Sweden)

    Takayoshi eUbuka


    Full Text Available Gonadotropin-inhibitory hormone (GnIH was first identified in Japanese quail to be an inhibitor of gonadotropin synthesis and release. GnIH peptides have since been identified in all vertebrates, and all share an LPXRFamide (X = L or Q motif at their C-termini. The receptor for GnIH is the G protein-coupled receptor 147 (GPR147, which inhibits cAMP signaling. Cell bodies of GnIH neurons are located in the paraventricular nucleus (PVN in birds and the dorsomedial hypothalamic area (DMH in most mammals. GnIH neurons in the PVN or DMH project to the median eminence to control anterior pituitary function via GPR147 expressed in gonadotropes. Further, GnIH inhibits gonadotropin-releasing hormone (GnRH -induced gonadotropin subunit gene transcription by inhibiting the adenylate cyclase/cAMP/PKA -dependent ERK pathway in an immortalized mouse gonadotrope cell line (LT2 cells. GnIH neurons also project to GnRH neurons that express GPR147 in the preoptic area (POA in birds and mammals. Accordingly, GnIH can inhibit gonadotropin synthesis and release by decreasing the activity of GnRH neurons as well as by directly inhibiting pituitary gonadotrope activity. GnIH and GPR147 can thus centrally suppress testosterone secretion and spermatogenesis by acting in the hypothalamic-pituitary-gonadal axis. GnIH and GPR147 are also expressed in the testis of birds and mammals, possibly acting in an autocrine/paracrine manner to suppress testosterone secretion and spermatogenesis. GnIH expression is also regulated by melatonin, stress and social environment in birds and mammals. Accordingly, the GnIH-GPR147 system may play a role in transducing physical and social environmental information to regulate optimal testicular activity in birds and mammals. This review discusses central and direct inhibitory effects of GnIH and GPR147 on testosterone secretion and spermatogenesis in birds and mammals.

  6. Neuroprotective Activity of Thioctic Acid in Central Nervous System Lesions Consequent to Peripheral Nerve Injury

    Directory of Open Access Journals (Sweden)

    Daniele Tomassoni


    Full Text Available Peripheral neuropathies are heterogeneous disorders presenting often with hyperalgesia and allodynia. This study has assessed if chronic constriction injury (CCI of sciatic nerve is accompanied by increased oxidative stress and central nervous system (CNS changes and if these changes are sensitive to treatment with thioctic acid. Thioctic acid is a naturally occurring antioxidant existing in two optical isomers (+- and (−-thioctic acid and in the racemic form. It has been proposed for treating disorders associated with increased oxidative stress. Sciatic nerve CCI was made in spontaneously hypertensive rats (SHRs and in normotensive reference cohorts. Rats were untreated or treated intraperitoneally for 14 days with (+/−-, (+-, or (−-thioctic acid. Oxidative stress, astrogliosis, myelin sheets status, and neuronal injury in motor and sensory cerebrocortical areas were assessed. Increase of oxidative stress markers, astrogliosis, and neuronal damage accompanied by a decreased expression of neurofilament were observed in SHR. This phenomenon was more pronounced after CCI. Thioctic acid countered astrogliosis and neuronal damage, (+-thioctic acid being more active than (+/−- or (−-enantiomers. These findings suggest a neuroprotective activity of thioctic acid on CNS lesions consequent to CCI and that the compound may represent a therapeutic option for entrapment neuropathies.

  7. Pharmacological Mechanisms of Cortical Enhancement Induced by the Repetitive Pairing of Visual/Cholinergic Stimulation.

    Directory of Open Access Journals (Sweden)

    Jun-Il Kang

    Full Text Available Repetitive visual training paired with electrical activation of cholinergic projections to the primary visual cortex (V1 induces long-term enhancement of cortical processing in response to the visual training stimulus. To better determine the receptor subtypes mediating this effect the selective pharmacological blockade of V1 nicotinic (nAChR, M1 and M2 muscarinic (mAChR or GABAergic A (GABAAR receptors was performed during the training session and visual evoked potentials (VEPs were recorded before and after training. The training session consisted of the exposure of awake, adult rats to an orientation-specific 0.12 CPD grating paired with an electrical stimulation of the basal forebrain for a duration of 1 week for 10 minutes per day. Pharmacological agents were infused intracortically during this period. The post-training VEP amplitude was significantly increased compared to the pre-training values for the trained spatial frequency and to adjacent spatial frequencies up to 0.3 CPD, suggesting a long-term increase of V1 sensitivity. This increase was totally blocked by the nAChR antagonist as well as by an M2 mAChR subtype and GABAAR antagonist. Moreover, administration of the M2 mAChR antagonist also significantly decreased the amplitude of the control VEPs, suggesting a suppressive effect on cortical responsiveness. However, the M1 mAChR antagonist blocked the increase of the VEP amplitude only for the high spatial frequency (0.3 CPD, suggesting that M1 role was limited to the spread of the enhancement effect to a higher spatial frequency. More generally, all the drugs used did block the VEP increase at 0.3 CPD. Further, use of each of the aforementioned receptor antagonists blocked training-induced changes in gamma and beta band oscillations. These findings demonstrate that visual training coupled with cholinergic stimulation improved perceptual sensitivity by enhancing cortical responsiveness in V1. This enhancement is mainly mediated by n

  8. The Areas of Activation of Islamic Fundamental Movements in the post-soviet Central Asian states

    Directory of Open Access Journals (Sweden)

    Rinat Ahmatgalievich Nabiev


    Full Text Available This article deals with the problem of radical Islam in the Fergana valley. Main characteristics of the region and the factors that contribute to the spread of extremist religious movements have been identified and described by the authors. The region that already has a high potential for confliction because of unresolved inter-state, inter-ethnic issues is a storm center of radical religious movements’ development. The revival of Islam has predetermined its further politicization, and then because of objective and subjective reasons its radicalization. The processes of re-islamization typical for Central Asian countries in the late twentieth century, accompanied by attempts of the leaders to get the support of the population. Radical Islam, in turn, became widespread in the territory of neighboring countries, in particular the Russian Federation. Thus, it should be noted that improper treatment of the foundations of traditional Islam, the spread of radical ideas represent a threat to stability and security not only at national but also at regional and global levels. Causes of the radical extremist movements, as well as increasing number of followers of these organizations in the Fergana Valley are important part of the article. The authors of the paper have assessed the activities of Islamic movements in the three countries of the Central Asian region, as well as a comparative analysis of the situation in Uzbekistan, Kyrgyzstan and Tajikistan have been provided. The article presents the differences in the approaches and methods of struggling of the governments of Uzbekistan, Tajikistan and Kyrgyzstan against nonconformist religious movements. The main conclusion of the article is the recognition of the diversity within the accepted approaches of neighboring states to solve the problem of radical Islamist movements. The article notes the high probability of downfall of the “fragile stability” that occurred in the Ferghana Valley.

  9. The nuclear activity and central structure of the elliptical galaxy NGC 5322 (United States)

    Dullo, Bililign T.; Knapen, Johan H.; Williams, David R. A.; Beswick, Robert J.; Bendo, George; Baldi, Ranieri D.; Argo, Megan; McHardy, Ian M.; Muxlow, Tom; Westcott, J.


    We have analysed a new high-resolution e-MERLIN 1.5 GHz radio continuum map together with HST and SDSS imaging of NGC 5322, an elliptical galaxy hosting radio jets, aiming to understand the galaxy's central structure and its connection to the nuclear activity. We decomposed the composite HST + SDSS surface brightness profile of the galaxy into an inner stellar disc, a spheroid, and an outer stellar halo. Past works showed that this embedded disc counter-rotates rapidly with respect to the spheroid. The HST images reveal an edge-on nuclear dust disc across the centre, aligned along the major-axis of the galaxy and nearly perpendicular to the radio jets. After careful masking of this dust disc, we find a central stellar mass deficit Mdef in the spheroid, scoured by SMBH binaries with final mass MBH such that Mdef/MBH ˜ 1.3 - 3.4. We propose a three-phase formation scenario for NGC 5322 where a few (2 - 7) `dry' major mergers involving SMBHs built the spheroid with a depleted core. The cannibalism of a gas-rich satellite subsequently creates the faint counter-rotating disc and funnels gaseous material directly onto the AGN, powering the radio core with a brightness temperature of TB, core ˜ 4.5 × 107 K and the low-power radio jets (Pjets ˜ 7.04 × 1020 W Hz-1) which extend ˜1.6 kpc. The outer halo can later grow via minor mergers and the accretion of tidal debris. The low-luminosity AGN/jet-driven feedback may have quenched the late-time nuclear star formation promptly, which could otherwise have replenished the depleted core.

  10. Activation of central nesfatin-1/NucB2 after intraperitoneally administered cisplatin in rats. (United States)

    Akiyama, Yasuki; Yoshimura, Mitsuhiro; Nishimura, Kazuaki; Nishimura, Haruki; Sonoda, Satomi; Ueno, Hiromichi; Mitojima, Yasuhito; Saito, Reiko; Maruyama, Takashi; Nonaka, Yuki; Hashimoto, Hirofumi; Uezono, Yasuhito; Hirata, Keiji; Ueta, Yoichi


    Cisplatin, known as an anticancer drug, has been widely used; however, diverse disadvantageous side effects, including appetite loss, afflict patients. Nesfatin-1/NucB2, discovered as an anorexic neuropeptide, is broadly expressed in the central nervous system (CNS) and peripheral organ. In the present study, we examined the effects of intraperitoneally (i.p.) administered cisplatin on central nesfatin-1/NucB2. Saline, as control, or cisplatin (6 mg/kg dissolved in saline) was i.p. administered in adult male Wistar rats (180-220 g). Cumulative food intake was remarkably suppressed for at least 24 h and body weight was significantly smaller at 24 h after i.p. administration of cisplatin compared to control group. At 90 min after i.p. administration, they were perfused, followed by carrying out double-immunohistochemistry for Fos and nesfatin-1/NucB2. The percentage of nesfatin-1/NucB2 immunoreactive neurons expressing Fos was marked increased in the hypothalamus and brainstem after i.p. administration of cisplatin. Intracerebroventricularlly administered nesfatin-1/NucB2-antisense resulted in a significant attenuation of decreased food intake for 2 h after i.p. administration of cisplatin compared to nesfatin-1/NucB2-missense treated group. These results suggest that i.p. administration of cisplatin activated, at least in part, nesfatin-1/NucB2 neuron in the CNS and may exert anorexigenic effects in rats. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Formation and Dynamics of Waves in a Cortical Model of Cholinergic Modulation.

    Directory of Open Access Journals (Sweden)

    James P Roach


    Full Text Available Acetylcholine (ACh is a regulator of neural excitability and one of the neurochemical substrates of sleep. Amongst the cellular effects induced by cholinergic modulation are a reduction in spike-frequency adaptation (SFA and a shift in the phase response curve (PRC. We demonstrate in a biophysical model how changes in neural excitability and network structure interact to create three distinct functional regimes: localized asynchronous, traveling asynchronous, and traveling synchronous. Our results qualitatively match those observed experimentally. Cortical activity during slow wave sleep (SWS differs from that during REM sleep or waking states. During SWS there are traveling patterns of activity in the cortex; in other states stationary patterns occur. Our model is a network composed of Hodgkin-Huxley type neurons with a M-current regulated by ACh. Regulation of ACh level can account for dynamical changes between functional regimes. Reduction of the magnitude of this current recreates the reduction in SFA the shift from a type 2 to a type 1 PRC observed in the presence of ACh. When SFA is minimal (in waking or REM sleep state, high ACh patterns of activity are localized and easily pinned by network inhomogeneities. When SFA is present (decreasing ACh, traveling waves of activity naturally arise. A further decrease in ACh leads to a high degree of synchrony within traveling waves. We also show that the level of ACh determines how sensitive network activity is to synaptic heterogeneity. These regimes may have a profound functional significance as stationary patterns may play a role in the proper encoding of external input as memory and traveling waves could lead to synaptic regularization, giving unique insights into the role and significance of ACh in determining patterns of cortical activity and functional differences arising from the patterns.

  12. Active faults paragenesis and the state of crustal stresses in the Late Cenozoic in Central Mongolia

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    V. A. Sankov


    Full Text Available Active faults of the Hangay-Hentiy tectonic saddle region in Central Mongolia are studied by space images interpretation, relief analysis, structural methods and tectonic stress reconstruction. The study results show that faults activation during the Late Cenozoic stage was selective, and a cluster pattern of active faults is typical for the study region. Morphological and genetic types and the kinematics of faults in the Hangay-Hentiy saddle region are related the direction of the ancient inherited structural heterogeneities. Latitudinal and WNW trending faults are left lateral strike-slips with reverse or thrust component (Dzhargalantgol and North Burd faults. NW trending faults are reverse faults or thrusts with left lateral horizontal component. NNW trending faults have right lateral horizontal component. The horizontal component of the displacements, as a rule, exceeds the vertical one. Brittle deformations in fault zones do not conform with the Pliocene and, for the most part, Pleistocene topography. With some caution it may be concluded that the last phase of revitalization of strike slip and reverse movements along the faults commenced in the Late Pleistocene. NE trending disjunctives are normal faults distributed mainly within the Hangay uplift. Their features are more early activation within the Late Cenozoic and the lack of relation to large linear structures of the previous tectonic stages. According to the stress tensor reconstructions of the last phase of deformation in zones of active faults of the Hangay-Hentiy saddle using data on tectonic fractures and fault displacements, it is revealed that conditions of compression and strike-slip with NNE direction of the axis of maximum compression were dominant. Stress tensors of extensional type with NNW direction of minimum compression are reconstructed for the Orkhon graben. It is concluded that the activation of faults in Central Mongolia in the Pleistocene-Holocene, as well as

  13. Active faults paragenesis and the state of crustal stresses in the Late Cenozoic in Central Mongolia

    Directory of Open Access Journals (Sweden)

    V. A. Sankov


    Full Text Available Active faults of the Hangay-Hentiy tectonic saddle region in Central Mongolia are studied by space images interpretation, relief analysis, structural methods and tectonic stress reconstruction. The study results show that faults activation during the Late Cenozoic stage was selective, and a cluster pattern of active faults is typical for the study region. Morphological and genetic types and the kinematics of faults in the Hangay-Hentiy saddle region are related the direction of the ancient inherited structural heterogeneities. Latitudinal and WNW trending faults are left lateral strike-slips with reverse or thrust component (Dzhargalantgol and North Burd faults. NW trending faults are reverse faults or thrusts with left lateral horizontal component. NNW trending faults have right lateral horizontal component. The horizontal component of the displacements, as a rule, exceeds the vertical one. Brittle deformations in fault zones do not conform with the Pliocene and, for the most part, Pleistocene topography. With some caution it may be concluded that the last phase of revitalization of strike slip and reverse movements along the faults commenced in the Late Pleistocene. NE trending disjunctives are normal faults distributed mainly within the Hangay uplift. Their features are more early activation within the Late Cenozoic and the lack of relation to large linear structures of the previous tectonic stages. According to the stress tensor reconstructions of the last phase of deformation in zones of active faults of the Hangay-Hentiy saddle using data on tectonic fractures and fault displacements, it is revealed that conditions of compression and strike-slip with NNE direction of the axis of maximum compression were dominant. Stress tensors of extensional type with NNW direction of minimum compression are reconstructed for the Orkhon graben. It is concluded that the activation of faults in Central Mongolia in the Pleistocene-Holocene, as well as

  14. Trends in biological activity research of wild-growing aromatic plants from Central Balkans

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    Džamić, A.M.


    Full Text Available Flowering plants consists of more than 300.000 species around the world, out of which a small percentage has been sufficiently investigated from phytochemical and biological activity aspects. Plant diversity of the Balkans is very rich, but still poorly investigated. The aim of this paper is survey of current status and trends in research of wild-growing aromatic plants from Central Balkans. Many aromatic plants are investigated from morphological, physiological, ecological, systematic and phytochemical aspects. However, traditionally used medicinal and aromatic plants can also be considered from applicative aspects, concerning their health effects, and from wide range of usage in cosmetics, and as food, agrochemical and pharmaceutical products. In order to achieve all planned objectives, following methodology has been applied: field research, taxonomic authentication and, comparative biologically assayed phytochemical investigations. The total herbal extracts, postdistillation waste (deodorized extracts, essential oils and individual compounds of some autochthonous plants have been considered as potential source of antibacterial, antifungal, anti-biofilm, antioxidant and cytotoxic agents. In this manuscript, composition of essential oils and extracts were evaluated in a number of species, from the Apiaceae, Lamiaceae, Rosaceae and Asteraceae families. Extracts which were rich in phenols mostly of flavonoids, often showed high antioxidant potential. Also, phenolic compounds identified in essential oils and extracts were mostly responsible for expected antimicrobial activity. Current worldwide demand is to reduce or, if possible, eliminate chemically synthesized food additives. Plant-produced compounds are becoming of interest as a source of more effective and safe substances than synthetically produced antimicrobial agents (as inhibitors, growth reducers or even inactivators that control growth of microorganisms. Many different pathogens have

  15. Morphotectonic records of neotectonic activity in the vicinity of North Almora Thrust Zone, Central Kumaun Himalaya (United States)

    Kothyari, Girish Ch; Kandregula, Raj Sunil; Luirei, Khayingshing


    The landform development and valley floor morphology of active regions is significantly controlled by tectonic processes. In the present study the upper catchments of Kosi and Gagas river valleys have been investigated with special emphasis on aggradational landforms to explain the spatial and temporal variability of aggradation/incision in response to tectonic activity during the late Quaternary and Holocene in Central Kumaun Himalaya. Major tectonic elements such as the North Almora thrust (NAT), Rasiyari fault (RF), and Gagas fault (GF) are considered to be controlling the development of landforms in the region. The valleys have preserved debris flow terraces, bedrock strath terraces, and fluviolacustrine terraces that provide signatures of tectonic activity. Morphostratigraphy of the terraces reveals that the oldest landforms are preserved in the hanging wall block of the NAT, RF, and along the GF. Reconstructions based on morphostratigraphy through the application of optical chronology suggests multiple phases of fluvial aggradation in the upper catchment of the Kosi and Gagas rivers that were initiated around 34 ka. The youngest phase of aggradation is dated to be around early to mid-Holocene (7-1 ka). Based on terrace morphology, four major phases of enhanced uplift have been estimated during 34, 15.8, 7, and 3 ka. The older uplift event dated to be around 34 ka is represented uplift along GF, which accommodated onset of valley-fill aggradation in Gagas valley. The 15.8 ka event represents uplift along RF, which led to the generation of debris flow from adjacent hillslopes. The 7 ka event represents uplift of a hanging wall block of the NAT and deposition of debris flow terraces. However, the youngest 3 ka event represents enhanced uplift, which is responsible for the incision of the older valley fill sediments and bedrock. Following this, a phase of accelerated incision/erosion owing to an increase in uplift rate occurred, as evident from the strath

  16. Groundwater fluoride enrichment in an active rift setting: Central Kenya Rift case study

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    Olaka, Lydia A., E-mail: [Department of Geology, University of Nairobi, P.O Box 30197, Nairobi (Kenya); Wilke, Franziska D.H. [Geoforschungs Zentrum, Telegrafenberg, 14473 Potsdam (Germany); Olago, Daniel O.; Odada, Eric O. [Department of Geology, University of Nairobi, P.O Box 30197, Nairobi (Kenya); Mulch, Andreas [Senckenberg Biodiversity and Climate Research Centre, Senckenberganlage 25, 60325 Frankfurt (Germany); Institut für Geowissenschaften, Goethe Universität Frankfurt, Altenhöferallee 1, 60438 Frankfurt (Germany); Musolff, Andreas [UFZ-Helmholtz-Centre for Environmental Research, Department of Hydrogeology, Permoserstr. 15, 04318 Leipzig (Germany)


    Groundwater is used extensively in the Central Kenya Rift for domestic and agricultural demands. In these active rift settings groundwater can exhibit high fluoride levels. In order to address water security and reduce human exposure to high fluoride in drinking water, knowledge of the source and geochemical processes of enrichment are required. A study was therefore carried out within the Naivasha catchment (Kenya) to understand the genesis, enrichment and seasonal variations of fluoride in the groundwater. Rocks, rain, surface and groundwater sources were sampled for hydrogeochemical and isotopic investigations, the data was statistically and geospatially analyzed. Water sources have variable fluoride concentrations between 0.02–75 mg/L. 73% exceed the health limit (1.5 mg/L) in both dry and wet seasons. F{sup −} concentrations in rivers are lower (0.2–9.2 mg/L) than groundwater (0.09 to 43.6 mg/L) while saline lake waters have the highest concentrations (0.27–75 mg/L). The higher values are confined to elevations below 2000 masl. Oxygen (δ{sup 18}O) and hydrogen (δD) isotopic values range from − 6.2 to + 5.8‰ and − 31.3 to + 33.3‰, respectively, they are also highly variable in the rift floor where they attain maximum values. Fluoride base levels in the precursor vitreous volcanic rocks are higher (between 3750–6000 ppm) in minerals such as cordierite and muscovite while secondary minerals like illite and kaolinite have lower remnant fluoride (< 1000 ppm). Thus, geochemical F{sup −} enrichment in regional groundwater is mainly due to a) rock alteration, i.e. through long residence times and natural discharge and/or enhanced leakages of deep seated geothermal water reservoirs, b) secondary concentration fortification of natural reservoirs through evaporation, through reduced recharge and/or enhanced abstraction and c) through additional enrichment of fluoride after volcanic emissions. The findings are useful to help improve water management

  17. Is modulation of nicotinic acetylcholine receptors by melatonin relevant for therapy with cholinergic drugs? (United States)

    Markus, Regina P; Silva, Claudia L M; Franco, Daiane Gil; Barbosa, Eduardo Mortani; Ferreira, Zulma S


    Melatonin, the darkness hormone, synchronizes several physiological functions to light/dark cycle. Besides the awake/sleep cycle that is intuitively linked to day/night, daily variations in memory acquisition and innate or acquired immune responses are some of the major activities linked to melatonin rhythm. The daily variation of these complex processes is due to changes in specific mechanisms. In the last years we focused on the influence of melatonin on the expression and function of nicotinic acetylcholine receptors (nAChRs). Melatonin, either "in vivo" or "in vitro", increases, in a selective manner, the efficiency of alpha-bungarotoxin (alpha-BTX)-sensitive nAChRs. Melatonin's effect on receptors located in rat sympathetic nerve terminals, cerebellum, skeletal muscle and chick retina, was tested. We observed that melatonin is essential for the development of alpha-BTX-sensitive nAChRs, and important for receptor maintenance in aging models. Taking into account that both melatonin and alpha-7 nAChRs (one of the subtypes sensitive to alpha-BTX) are involved in the development of Alzheimer's disease, here we discuss the possibility of a therapeutic strategy focused on both melatonin replacement and its potential association with cholinergic drugs. Copyright 2010 Elsevier Inc. All rights reserved.

  18. Alterations of Ca2+ responsive proteins within cholinergic neurons in aging and AD (United States)

    Riascos, David; Nicholas, Alexander; Samaeekia, Ravand; Yukhnanov, Rustam; Mesulam, M.-Marsel; Bigio, Eileen H.; Weintraub, Sandra; Guo, Ling; Geula, Changiz


    The molecular basis of selective neuronal vulnerability in Alzheimer ’s disease (AD) remains poorly understood. Using basal forebrain cholinergic neurons (BFCN) as a model and immunohistochemistry, we have demonstrated significant age-related loss of the calcium binding protein calbindin-D28K (CB) from BFCN, which was associated with tangle formation and degeneration in AD. Here we determined alterations in RNA and protein for CB and other Ca2+ responsive proteins Ca2+/calmodulin-dependent protein kinase I (CaMKI), growth-associated protein-43 (GAP43), calpain in the basal forebrain. We observed progressive downregulation of CB and CaMKI RNA in laser-captured BFCN in the normal-aged-AD continuum. We also detected progressive loss of CB, CaMKI-Delta, and GAP43 proteins in BF homogenates in aging and AD. Activated μ-calpain, a calcium-sensitive protease that degrades CaMKI and GAP-43, was significantly increased in the normal aged BF and was 10-times higher in AD BF. Overactivation of μ-calpain was confirmed using proteolytic fragments of its substrate spectrin. Substantial age and AD related alterations in Ca2+-sensing proteins most likely contribute to selective vulnerability of BFCN to degeneration in AD. PMID:24461366

  19. Effects of furosemide on cochlear neural activity, central hyperactivity and behavioural tinnitus after cochlear trauma in guinea pig. (United States)

    Mulders, Wilhelmina H A M; Barry, Kristin M; Robertson, Donald


    Cochlear trauma causes increased spontaneous activity (hyperactivity) to develop in central auditory structures, and this has been suggested as a neural substrate for tinnitus. Using a guinea pig model we have previously demonstrated that for some time after cochlear trauma, central hyperactivity is dependent on peripheral afferent drive and only later becomes generated intrinsically within central structures. Furosemide, a loop diuretic, reduces spontaneous firing of auditory afferents. We investigated in our guinea pig model the efficacy of furosemide in reducing 1) spontaneous firing of auditory afferents, using the spectrum of neural noise (SNN) from round window recording, 2) hyperactivity in inferior colliculus, using extracellular single neuron recordings and 3) tinnitus at early time-points after cochlear trauma. Tinnitus was assessed using gap prepulse inhibition of acoustic startle (GPIAS). Intraperitoneal furosemide, but not saline, caused a marked decrease in both SNN and central hyperactivity. Intracochlear perfusion with furosemide similarly reversed central hyperactivity. In animals in which GPIAS measurements suggested the presence of tinnitus (reduced GPIAS), this could be reversed with an intraperitoneal injection with furosemide but not saline. The results are consistent with furosemide reducing central hyperactivity and behavioural signs of tinnitus by acting peripherally to decrease spontaneous firing of auditory afferents. The data support the notion that hyperactivity may be involved in the generation of tinnitus and further suggest that there may be a therapeutic window after cochlear trauma using drug treatments that target peripheral spontaneous activity.

  20. Impact of Location of the Central Activities on Development of Open Public Space in the City Centers of Small Cities

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    Volgemut, Mateja


    Full Text Available Urban areas of the central activities with mixed land use are crucial for the development of city center, even in small cities. In the last decades or two the attention is drawn on the retail and service activities that are usually located outside of cities near main roads. Municipalities had already detected this problem, but they are not implementing any of the measures (Rebernik, 2010. The purpose of this paper is to demonstrate that the central activities in small cities in Slovenia are located in freestanding buildings, which is most appropriate in terms of forming the open public space in the city center. In this research we compared ten central activities (Vrišer, 1988, 1990, Kokole, 1971 in 34 small cities. We selected only those small cities (Prosen et al, 2008 which have among other activities a county court. The results showed the differences and commonalities of the central activities in selected small cities according to the indicators. Litija, Domžale and Sevnica are small cities, where activities that could articulate open public space are located in the larger building complexes. The phenomenon is similar to a modern machine, where action in it and indirectly the insight into the functioning of the society is invisible to the observer (Kos, 2008. We found out that in these tree cities the central activities are not forming the open public spaces in front of the public buildings (Vertelj Nared, 2014. The result is problematic image of the city and changed forces of the city life.

  1. Vegetation dynamics and responses to climate change and human activities in Central Asia. (United States)

    Jiang, Liangliang; Guli Jiapaer; Bao, Anming; Guo, Hao; Ndayisaba, Felix


    Knowledge of the current changes and dynamics of different types of vegetation in relation to climatic changes and anthropogenic activities is critical for developing adaptation strategies to address the challenges posed by climate change and human activities for ecosystems. Based on a regression analysis and the Hurst exponent index method, this research investigated the spatial and temporal characteristics and relationships between vegetation greenness and climatic factors in Central Asia using the Normalized Difference Vegetation Index (NDVI) and gridded high-resolution station (land) data for the period 1984-2013. Further analysis distinguished between the effects of climatic change and those of human activities on vegetation dynamics by means of a residual analysis trend method. The results show that vegetation pixels significantly decreased for shrubs and sparse vegetation compared with those for the other vegetation types and that the degradation of sparse vegetation was more serious in the Karakum and Kyzylkum Deserts, the Ustyurt Plateau and the wetland delta of the Large Aral Sea than in other regions. The Hurst exponent results indicated that forests are more sustainable than grasslands, shrubs and sparse vegetation. Precipitation is the main factor affecting vegetation growth in the Kazakhskiy Melkosopochnik. Moreover, temperature is a controlling factor that influences the seasonal variation of vegetation greenness in the mountains and the Aral Sea basin. Drought is the main factor affecting vegetation degradation as a result of both increased temperature and decreased precipitation in the Kyzylkum Desert and the northern Ustyurt Plateau. The residual analysis highlighted that sparse vegetation and the degradation of some shrubs in the southern part of the Karakum Desert, the southern Ustyurt Plateau and the wetland delta of the Large Aral Sea were mainly triggered by human activities: the excessive exploitation of water resources in the upstream areas

  2. Differential responses in central dopaminergic activity induced by apomorphine in IPL nude rat. (United States)

    Estrella, Cecilia Ruth; Bregonzio, Claudia; Cabrera, Ricardo Jorge


    The IPL nude rat, derived by spontaneous mutation from the Sprague-Dawley strain, presents alterations in the prolactin synthesis and secretion due to an increased dopaminergic inhibition. However, there are no reports concerned to central dopamine activity. The corpus striatum is a brain area involved in the development of stereotyped behavior after the activation of mesolimbic and/or nigro-striatal dopamine pathways. In order to identify possible mesolimbic and/or nigro-striatal dysfunctions in the IPL nude rat, we study the spontaneous oral behaviors and the effects of apomorphine-induced dopaminergic activation on stereotyped behavior and neurochemical changes. Males from both strains were injected with saline or apomorphine (2 and 5 mg/kgs.c.) and evaluated during 30 min in a stereotypes oral tests. The corpus striatum and nucleus accumbens were used to measure dopamine (DA), 3,4-dihydroxyphenylalanine (DOPA) and 3,4-dihydroxyphenylacetic acid (DOPAC) by HPLC. The concentrations were expressed as synthesis rate (DA/DOPA) and turnover rate (DOPAC/DA). We observed that the spontaneous gnaw movements were significantly different between the untreated IPL nude and Sprague-Dawley (SD) rats. Apomophine injection decreased the amount of stereotyped gnawing in IPL nude rats at the two doses used, but it induced an increase in SD rats. Apomorphine also caused an enhancement in the number of biting and sniffing without modifying the licking behavior. In addition, modifications of the dopaminergic activity were also observed. Synthesis rate in the striatum of IPL nude rats was higher than in SD rats after the injection of saline. Apomorphine caused a reduction of the synthesis rate in both strains. Turnover rate was significantly lower in the striatum of IPL nude rats than in the SD rats injected with saline. Apomorphine caused an increase in the turnover rate in both strains. Contrary to observed in the striatum, the 2 mg/kg dose of apomorphine caused a significant

  3. Chronic Cerebral Ischaemia Forms New Cholinergic Mechanisms of Learning and Memory

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    E. I. Zakharova


    Full Text Available The purpose of this research was a comparative analysis of cholinergic synaptic organization following learning and memory in normal and chronic cerebral ischaemic rats in the Morris water maze model. Choline acetyltransferase and protein content were determined in subpopulations of presynapses of “light” and “heavy” synaptosomal fractions of the cortex and the hippocampus, and the cholinergic projective and intrinsic systems of the brain structures were taken into consideration. We found a strong involvement of cholinergic systems, both projective and intrinsic, in all forms of cognition. Each form of cognition had an individual cholinergic molecular profile and the cholinergic synaptic compositions in the ischaemic rat brains differed significantly from normal ones. Our data demonstrated that under ischaemic conditions, instead of damaged connections new key synaptic relationships, which were stable against pathological influences and able to restore damaged cognitive functions, arose. The plasticity of neurochemical links in the individual organization of certain types of cognition gave a new input into brain pathology and can be used in the future for alternative corrections of vascular and other degenerative dementias.

  4. Cholinergic synaptic signaling mechanisms underlying behavioral teratogenicity: effects of nicotine, chlorpyrifos, and heroin converge on protein kinase C translocation in the intermedial part of the hyperstriatum ventrale and on imprinting behavior in an avian model. (United States)

    Izrael, Michal; Van der Zee, Eddy A; Slotkin, Theodore A; Yanai, Joseph


    A wide variety of otherwise unrelated neuroteratogens elicit a common set of behavioral defects centering around cholinergic contributions to cognitive function. We utilized the developing chick to overcome confounds related to maternal effects and compared the actions of nicotine, chlorpyrifos, and heroin on cholinergic signaling in the intermedial part of the hyperstriatum ventrale (IMHV), which controls imprinting behavior. Chicken eggs were injected with nicotine (10 mg/kg of egg), chlorpyrifos (10 mg/kg of egg), or heroin (20 mg/kg of egg; all doses below the threshold for dysmorphology) on incubation days (ID) 0 and 5, and then tests were conducted posthatching. All three compounds elicited significant deficits in imprinting behavior. We also found defects in cholinergic synaptic signaling specifically involving the muscarinic receptor-mediated membrane translocation of protein kinase C (PKC)-gamma and in the basal levels of both PKCgamma and PKCbetaII, the two isoforms known to be relevant to behavioral performance. In contrast, there were no alterations in the response of PKCalpha, an isoform that does not contribute to the behavior, nor were cytosolic levels of any of the isoforms affected. Taken together with similar results obtained in rodents, our findings suggest that disparate neuroteratogens all involve signaling defects centering on the ability of cholinergic receptors to elicit PKCgamma translocation/activation and that this effect is direct, i.e., not mediated by maternal confounds. The chick thus provides a suitable model for the rapid screening of neuroteratogens and elucidation of the mechanisms underlying behavioral anomalies.

  5. Expression of non-neuronal cholinergic system in maxilla of rat in vivo. (United States)

    Guo, Jie; Wang, Lue; Xu, Haihua; Che, Xiaoxia


    Acetylcholine (ACh) is known to be a key neurotransmitter in the central and peripheral nervous systems, which is also produced in a variety of non-neuronal tissues and cell. The existence of ACh in maxilla in vivo and potential regulation role for osteogenesis need further study. Components of the cholinergic system (ACh, esterase, choline acetyltransferase, high-affinity choline uptake, n- and mAChRs) were determined in maxilla of rat in vivo, by means of Real-Time PCR and immunohistochemistry. Results showed RNA for CarAT, carnitine/acylcarnitine translocase member 20 (Slc25a20), VAChT, OCTN2, OCT1, OCT3, organic cation transporter member 4 (Slc22a4), AChE, BChE, nAChR subunits α1, α2, α3, α5, α7, α10, β1, β2, β4, γ and mAChR subunits M1, M2, M3, M4, M5 were detected in rat's maxilla. RNA of VAChT, AChE, nAChR subunits α2, β1, β4 and mAChR subunits M4 had abundant expression (2(-ΔCt) > 0.03). Immunohistochemical staining was conducted for ACh, VAChT, nAChRα7 and AChE. ACh was expressed in mesenchymal cells, chondroblast, bone and cartilage matrix and bone marrow cells, The VAChT expression was very extensively while ACh receptor α7 was strongly expressed in newly formed bone matrix of endochondral and bone marrow ossification, AchE was found only in mesenchymal stem cells, cartilage and bone marrow cells. ACh might exert its effect on the endochondral and bone marrow ossification, and bone matrix mineralization in maxilla.

  6. Cholinergic urticaria patients of different age groups have distinct features. (United States)

    Asady, A; Ruft, J; Ellrich, A; Hawro, T; Maurer, M; Altrichter, S


    Cholinergic urticaria (CholU) is a common skin disease characterized by the development of pinpoint-sized weals and severe itch upon physical exercise. Little is known about the epidemiology of CholU. CholU can occur at any age and has the highest prevalence among young adults. As of now, it is unclear whether patients of different age show differences in the clinical manifestation of CholU, duration of disease, comorbidities or response to treatment. Here, we analysed the demographic data and clinical characteristics including disease duration and comorbidities of 200 patients with CholU, 12-76 years of age. We identified two distinct types of CholU, one with early onset (EO, 71%) and one with late onset (LO, 29%). Patients with EO and LO CholU markedly differ in key characteristics: patients with EO, who had a disease onset before the age of 36, showed no gender preponderance and had a significantly higher rate of concomitant atopic dermatitis (16.9% vs 5.2%; P = .028) and higher IgE levels (295.5 vs 267.1 IU/mL; P = .020) as compared to patients with LO, who were mainly female (69%), had a shorter duration of disease (33.3 vs 63.7 months; P = .005), a higher rate of concomitant other forms of urticaria (48.3% vs 33.1%; P = .044) and a higher rate of psychiatric comorbidities (12.1% vs 1.4%; P = .001). There are two subtypes of CholU patients with different gender ratios, disease duration and comorbidities. These findings suggest that two distinct underlying pathogenetic pathways are relevant in these two subgroups of patients with CholU. © 2017 John Wiley & Sons Ltd.

  7. A cholinergic chloride conductance in neurones of Helix aspersa. (United States)

    Finkel, A S


    Inhibitory Cl- -mediated currents through cholinergic channels on the soma of identified neurones from the right parietal ganglion of Helix aspersa were studied under voltage clamp. Voltage-jump relaxation analysis showed that these currents decreased with hyperpolarization. In 3 microM-acetylcholine (ACh), the normalized fraction of channels in the open configuration (rho) decreased e-fold with each 191 mV of membrane hyperpolarization. The steady-state membrane conductance, G(infinity), decreased e-fold with each 128 mV of membrane hyperpolarization. The difference in the voltage sensitivities of rho and G(infinity) arose because of the voltage sensitivity of the instantaneous membrane conductance, G(0). G(0) rectified in the direction predicted by the Goldman-Hodgkin-Katz conductance model. The degree of rectification decreased when the internal Cl- concentration was raised. The relaxing currents were composed of two exponential components. At membrane potential (Vm) = -160 mV, 12 degrees C, the time constants of the two components were 4.1 ms and 21 ms in 3 microM-ACh, and 3.6 ms and 18 ms in 100 microM-tetramethylammonium (TMA). Fluctuation analysis in neurones loaded with Cl- yielded spectra which were composed of two Lorentzian components. In 3 microM-ACh the mean single-channel conductance (gamma) appeared to rise from a low value observed in cells with normal intracellular Cl- to 2.7 pS in cells whose internal Cl- concentration was raised four-fold. The voltage sensitivity of rho was attributed to the conformational change step of a gating mechanism having three kinetically distinguishable states. PMID:6317849

  8. Effect of honey bee venom on differentiation of cholinergic neurons. (United States)

    Kouchesfahani, Homa Mohseni; Nabiuni, Mohammad; Parivar, Kazem; Ebrahimi, Somayeh


    Mouse P19 embryonic carcinoma (EC) cells are pluripotent and can differentiate into a population consisting largely of neurons and glia cells using a concentration of 5x10(-7)M of retinoic acid (RA). Thus, P19 EC cells are a good model system to study events occurring during the critical phases of neuronal differentiation, in vitro. Honey bee venom (BV) consists of mellitin, phospholipase A2, apamin and several other bioactive substances. Previous studies have shown that mellitin and phospholipase A2 - two major components of BV - play an important role in the differentiation of neurons. The purpose of this study was to examine effects of BV and RA on the differentiation of cholinergic neuron in P19 cell line. Preliminary results obtained from morphological examination showed that six days after treatment with 5x10(-7)M RA, P19 cells produced processes, and gradually obtained neuronal phenotype at approximately day-10. All cells then died at day-11. P19 cells treated with 1.3μg/ml BV produced processes on day-6 and neurons appeared in the next four days. They then proceeded to total size until day-10 and produced elongated processes; however, all cells died on day-11. Using BV and RA together had the same effect but more pronounced differentiating results. It can be concluded that applying BV with RA has an additive effect on cell differentiation and proliferation. The presence of acetylcholinesterase (AChE), frequently used as a marker for neuronal differentiation, was also determined and found using DTNB.

  9. The Mechanism of Interaction of Oximes with the Muscarinic Cholinergic Complex in the Central Nervous System. (United States)


    lead to the improved design of mixtures of oxin-s oid muiscarinic antagonists for pharmaceutical protection against ,rgan’ :2hspl:at" poisoning...sites was observed with clomiphene (40), for wh i thte data were interinr d in t-,,rw )o it jv ccm , r’ ti- - vity. Dunlap and Brown (37) have shown that

  10. Neutron activation analysis of the central nervous system tissues in neurological diseases

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    Yasui, Masayuki; Ota, Kiichiro [Wakayama Medical Coll. (Japan); Sasajima, Kazuhisa


    As the diseases due to excessive metals in living bodies and the metals of their causes, Minamata disease due to Hg, itai-itai disease due to Cd, dialysis brain disease due to Al, hemochromatosis due to Fe, Wilson disease due to Cu and so on have been known. Also as the neural diseases, in which the possibility that metals take part in them is presumed, there are amyotrophic lateral sclerosis, Alzheimer disease, Parkinson disease, Parkinsonism dementia and so on. In order to know the causes of the diseases due to excessive metals in living bodies and neurological diseases, the authors have measured Cu, Ca, Al, Mn, Zn and Fe in central nervous system tissues by activation analysis nondestructive method. The cases investigated were 4 cases of hepatocerebral diseases, 6 cases of ALS, 4 cases of Parkinson disease, 4 cases of Parkinsonism dementia, 4 cases of multiple sclerosis and 5 cases without CNS disease for the control. The method of measurement is described. The results for respective diseases are reported. Cu and Fe are in the relation of mirror images, and Cu formed Cu-superoxide dismutase (SOD) similarly to Zn and Mn as SOD carrier metals, and protects living bodies and CNS from oxidative stress. (K.I.).

  11. Immune System Activation and Depression: Roles of Serotonin in the Central Nervous System and Periphery. (United States)

    Robson, Matthew J; Quinlan, Meagan A; Blakely, Randy D


    Serotonin (5-hydroxytryptamine, 5-HT) has long been recognized as a key contributor to the regulation of mood and anxiety and is strongly associated with the etiology of major depressive disorder (MDD). Although more known for its roles within the central nervous system (CNS), 5-HT is recognized to modulate several key aspects of immune system function that may contribute to the development of MDD. Copious amounts of research have outlined a connection between alterations in immune system function, inflammation status, and MDD. Supporting this connection, peripheral immune activation results in changes in the function and/or expression of many components of 5-HT signaling that are associated with depressive-like phenotypes. How 5-HT is utilized by the immune system to effect CNS function and ultimately behaviors related to depression is still not well understood. This Review summarizes the evidence that immune system alterations related to depression affect CNS 5-HT signaling that can alter MDD-relevant behaviors and that 5-HT regulates immune system signaling within the CNS and periphery. We suggest that targeting the interrelationships between immune and 5-HT signaling may provide more effective treatments for subsets of those suffering from inflammation-associated MDD.

  12. Dengue Virus Type 2: Protein Binding and Active Replication in Human Central Nervous System Cells

    Directory of Open Access Journals (Sweden)

    Ma Isabel Salazar


    Full Text Available An increased number of dengue cases with neurological complications have been reported in recent years. The lack of reliable animal models for dengue has hindered studies on dengue virus (DENV pathogenesis and cellular tropism in vivo. We further investigate the tropism of DENV for the human central nervous system (CNS, characterizing DENV interactions with cell surface proteins in human CNS cells by virus overlay protein binding assays (VOPBA and coimmunoprecipitations. In VOPBA, three membrane proteins (60, 70, and 130 kDa from the gray matter bound the entire virus particle, whereas only a 70 kDa protein bound in white matter. The coimmunoprecipitation assays revealed three proteins from gray matter consistently binding virus particles, one clearly distinguishable protein (~32 kDa and two less apparent proteins (100 and 130 kDa. Monoclonal anti-NS3 targeted the virus protein in primary cell cultures of human CNS treated with DENV-2, which also stained positive for NeuH, a neuron-specific marker. Thus, our results indicate (1 that DENV-2 exhibited a direct tropism for human neurons and (2 that human neurons sustain an active DENV replication as was demonstrated by the presence of the NS3 viral antigen in primary cultures of these cells treated with DENV-2.

  13. Eluvial gold placer formation on actively rising mountain ranges, Central Otago, New Zealand (United States)

    Craw, D.; Youngson, J. H.


    Eluvial gold deposits in Central Otago, New Zealand, have formed and are still forming on the flanks of actively rising antiformal mountain ranges. These gold deposits are derived mainly by erosion and concentration of fine-grained ( soil and sequences (up to 60 m thick) of poorly sorted immature schist gravels. The gravel sequences consist mainly of matrix-supported mass flow deposits and channellised proximal fan deposits, intercalated on a 1-10 m scale. Gold is concentrated in coarse lag gravels (up to 40 cm clasts) at channel bases. Topographic slopes on the rising ranges show an evolutionary trend in space and time, from gentle weakly dissected surfaces, through slightly degraded but convex slopes, to deeply incised convex streams. Eluvial gold occurs sporadically on the gentle slopes, but the most efficient concentration processes occurred where steeper convex slopes yielded an apron of fan sediments. Gold concentration at these sites resulted from selective and localized removal ("winnowing") of most schist debris, leaving coarse lag gravels and gold. The combination of authigenic grain size increase and residual concentration ensures that the eluvial deposits retain coarse-grained gold, and that only fine-grained gold is released to the alluvial systems downstream.

  14. Revealing Physical Activity of GRB Central Engine with Macronova/Kilonova Data

    Energy Technology Data Exchange (ETDEWEB)

    Shen, Zhao-Qiang; Jin, Zhi-Ping; Liang, Yun-Feng; Li, Xiang; Fan, Yi-Zhong; Wei, Da-Ming, E-mail:, E-mail: [Key Laboratory of dark Matter and Space Astronomy, Purple Mountain Observatory, Chinese Academy of Science, Nanjing 210008 (China)


    The modeling of Li-Paczyński macronova/kilonova signals gives a reasonable estimate on the neutron-rich material ejected during the neutron star mergers. Usually the accretion disk is more massive than the macronova ejecta, with which the efficiencies of converting the disk mass into prompt emission of three merger-driven GRBs can hence be directly constrained. Supposing the macronovae/kilonovae associated with GRB 050709, GRB 060614, and GRB 130603B arose from radioactive decay of the r -process material, the upper limit on energy conversion efficiencies are found to be as low as ∼10{sup −6}–10{sup −4}. Moreover, for all three events, neutrino annihilation is likely powerful enough to account for the brief gamma-ray flashes. Neutrino annihilation can also explain the “extended” emission lasting ∼100 s in GRB 050709, but does not work for the one in GRB 060614. These progresses demonstrate that the macronova can serve as a novel probe of the central engine activity.

  15. Production from Activated Sludge Process of Sago Industry Wastewater Using Central Composite Design

    Directory of Open Access Journals (Sweden)

    B. Subha


    Full Text Available Sago industries effluent containing large amounts of organic content produced excess sludge which is a serious problem in wastewater treatment. In this study ozonation has been employed for the reduction of excess sludge production in activated sludge process. Central composite design is used to study the effect of ozone treatment for the reduction of excess sludge production in sago effluent and to optimise the variables such as pH, ozonation time, and retention time. ANOVA showed that the coefficient determination value (R2 of VSS and COD reduction were 0.9689 and 0.8838, respectively. VSS reduction (81% was achieved at acidic pH 6.9, 12 minutes ozonation, and retention time of 10 days. COD reduction (87% was achieved at acidic pH 6.7, 8 minutes of ozonation time, and retention time of 6 days. Low ozonation time and high retention time influence maximum sludge reduction, whereas low ozonation time with low retention time was effective for COD reduction.

  16. Soil-gas radon monitoring in an active granite quarry from central Portugal (United States)

    Pereira, A. J. S. C.; Barbosa, S. M.; Neves, L. J. P. F.; Aumento, F.


    Seven soil-gas radon monitoring stations were placed along the active front of a granite quarry in Canas de senhorim, Central Portugal, recording continuously for 81 days. Important differences in the radon concentration were found between stations, with average values comprised between 102 and 2982 Bq m-3, which can be explained by the local presence of uranium anomalies in the regional late-orogenic Hercynian granite, usually associated with faults. One of the boreholes exhibits large radon anomalies lasting for several days, and two, contrary to the others, show a clear daily periodic behaviour, with minima around 19:00 LT and maxima around 07:00 LT. The different patterns observed in stations placed at such a short distance (<100 m) has no clear explanation and deserves further investigation. Data analysis shows no evidence of soil-gas radon concentration changes during explosions carried out at the quarry. This is likely to result from the absence of a progressive stress field affecting the rock, as typically occurs before an earthquake.

  17. Soil-gas radon monitoring in an active granite quarry from central Portugal

    Directory of Open Access Journals (Sweden)

    A. J. S. C. Pereira


    Full Text Available Seven soil-gas radon monitoring stations were placed along the active front of a granite quarry in Canas de senhorim, Central Portugal, recording continuously for 81 days. Important differences in the radon concentration were found between stations, with average values comprised between 102 and 2982 Bq m−3, which can be explained by the local presence of uranium anomalies in the regional late-orogenic Hercynian granite, usually associated with faults. One of the boreholes exhibits large radon anomalies lasting for several days, and two, contrary to the others, show a clear daily periodic behaviour, with minima around 19:00 LT and maxima around 07:00 LT. The different patterns observed in stations placed at such a short distance (<100 m has no clear explanation and deserves further investigation. Data analysis shows no evidence of soil-gas radon concentration changes during explosions carried out at the quarry. This is likely to result from the absence of a progressive stress field affecting the rock, as typically occurs before an earthquake.

  18. Human-biting activities of Anopheles species in south-central Ethiopia. (United States)

    Kenea, Oljira; Balkew, Meshesha; Tekie, Habte; Gebre-Michael, Teshome; Deressa, Wakgari; Loha, Eskindir; Lindtjørn, Bernt; Overgaard, Hans J


    Indoor residual spraying (IRS) and long-lasting insecticidal nets (LLINs) are the key malaria vector control interventions in Ethiopia. The success of these interventions rely on their efficacy to repel or kill indoor feeding and resting mosquitoes. This study was undertaken to monitor human-biting patterns of Anopheles species in south-central Ethiopia. Human-biting patterns of anophelines were monitored for 40 nights in three houses using human landing catches (HLC) both indoors and outdoors between July and November 2014, in Edo Kontola village, south-central Ethiopia. This time coincides with the major malaria transmission season in Ethiopia, which is usually between September and November. Adult mosquitoes were collected from 19:00 to 06:00 h and identified to species. Comparisons of HLC data were done using incidence rate ratio (IRR) calculated by negative binomial regression. The nocturnal biting activities of each Anopheles species was expressed as mean number of mosquitoes landing per person per hour. To assess malaria infections in Anopheles mosquitoes the presence of Plasmodium falciparum and P. vivax circumsporozoite proteins (CSP) were determined by enzyme-linked immunosorbent assay (ELISA). Altogether 3,408 adult female anophelines were collected, 2,610 (76.6 %) outdoors and 798 (23.4 %) indoors. Anopheles zeimanni was the predominant species (66.5 %) followed by An. arabiensis (24.8 %), An. pharoensis (6.8 %) and An. funestus (s.l.) (1.8 %). The overall mean anopheline density was 3.3 times higher outdoors than indoors (65.3 vs 19.9/person/night, IRR: 3.3, 95 % CI: 1.1-5.1, P = 0.001). The mean density of An. zeimanni, An. pharoensis and An. funestus (s.l.) collected outdoors was significantly higher than indoors for each species (P < 0.05). However, the mean An. arabiensis density outdoors was similar to that indoors (11.8 vs 9.4/person/night, IRR: 1.3, 95 % CI: 0.8-1.9, P = 0.335). The mean hourly human-biting density of An

  19. Anti-inflammatory, anti-cholinergic and cytotoxic effects of Sida rhombifolia. (United States)

    Mah, Siau Hui; Teh, Soek Sin; Ee, Gwendoline Cheng Lian


    Sida (Malvaceae) has been used as a traditional remedy for the treatment of diarrhoea, malarial, gastrointestinal dysentery, fevers, asthma and inflammation. This study evaluates the anti-inflammatory, cytotoxic and anti-cholinergic activities of Sida rhombifolia Linn. whole plant for the first time. S. rhombifolia whole plant was extracted by n-hexane, ethyl acetate and methanol using Soxhlet apparatus. The plant extracts were evaluated for their antioxidant (DPPH, FIC and FRAP), anti-inflammatory (NO and protein denaturation inhibitions), cytotoxic (MTT) and anti-cholinesterase (AChE) properties in a range of concentrations to obtain IC50 values. GC-MS analysis was carried out on the n-hexane extract. The ethyl acetate extract exhibited the most significant antioxidant activities by scavenging DPPH radicals and ferrous ions with EC50 of 380.5 and 263.4 μg/mL, respectively. In contrast, the n-hexane extract showed the strongest anti-inflammatory activity with IC50 of 52.16 and 146.03 μg/mL for NO and protein denaturation inhibition assays, respectively. The same extract also revealed the strongest effects in anti-cholinesterase and cytotoxic tests at the concentration of 100 μg/mL, AChE enzyme inhibition was 58.55% and human cancer cells, SNU-1 and Hep G2 inhibition was 68.52% and 47.82%, respectively. The phytochemicals present in the n-hexane extract are palmitic acid, linoleic acid and γ-sitosterol. The present study revealed that the n-hexane extract possessed relatively high pharmacological activities in anti-inflammation, cytotoxicity and anti-cholinesterase assays. Thus, further work on the detail mechanism of the bioactive phytochemicals which contribute to the biological properties are strongly recommended.

  20. Cholinergic degeneration is associated with increased plaque deposition and cognitive impairment in APPswe/PS1dE9 mice

    DEFF Research Database (Denmark)

    Laursen, Bettina; Mørk, Arne; Plath, Niels


    APP/PS1 mice in a behavioural paradigm addressing working memory. Conversely, the performance of Wt mice was unaffected by SAP treatment. Choline acetyltransferase activity was reduced in the hippocampus and frontal cortex following SAP treatment. The selective effect of a mild SAP lesion in APP/PS1...... mice was not due to a more extensive cholinergic degeneration since the reduction in choline acetyltransferase activity was similar following SAP treatment in APP/PS1 mice and Wt. Interestingly, plaque load was significantly increased in SAP treated APP/PS1 mice relative to sham lesioned APP/PS1 mice...

  1. Muscle sympathetic nerve responses to passive and active one-legged cycling: insights into the contributions of central command. (United States)

    Doherty, Connor J; Incognito, Anthony V; Notay, Karambir; Burns, Matthew J; Slysz, Joshua T; Seed, Jeremy D; Nardone, Massimo; Burr, Jamie F; Millar, Philip J


    The contribution of central command to the peripheral vasoconstrictor response during exercise has been investigated using primarily handgrip exercise. The purpose of the present study was to compare muscle sympathetic nerve activity (MSNA) responses during passive (involuntary) and active (voluntary) zero-load cycling to gain insights into the effects of central command on sympathetic outflow during dynamic exercise. Hemodynamic measurements and contralateral leg MSNA (microneurography) data were collected in 18 young healthy participants at rest and during 2 min of passive and active zero-load one-legged cycling. Arterial baroreflex control of MSNA burst occurrence and burst area were calculated separately in the time domain. Blood pressure and stroke volume increased during exercise ( P cycling ( P > 0.05). In contrast, heart rate, cardiac output, and total vascular conductance were greater during the first and second minute of active cycling ( P cycling ( P 0.05). Reductions in total MSNA were attenuated during the first ( P cycling, in concert with increased MSNA burst amplitude ( P = 0.02 and P = 0.005, respectively). The sensitivity of arterial baroreflex control of MSNA burst occurrence was lower during active than passive cycling ( P = 0.01), while control of MSNA burst strength was unchanged ( P > 0.05). These results suggest that central feedforward mechanisms are involved primarily in modulating the strength, but not the occurrence, of a sympathetic burst during low-intensity dynamic leg exercise. NEW & NOTEWORTHY Muscle sympathetic nerve activity burst frequency decreased equally during passive and active cycling, but reductions in total muscle sympathetic nerve activity were attenuated during active cycling. These results suggest that central command primarily regulates the strength, not the occurrence, of a muscle sympathetic burst during low-intensity dynamic leg exercise.

  2. Geomorphic evidence of active faults growth in the Norcia seismic area (central Apennines, Italy) (United States)

    Materazzi, Marco; Aringoli, Domenico; Farabollini, Piero; Giacopetti, Marco; Pambianchi, Gilberto; Tondi, Emanuele; Troiani, Francesco


    Fault-growth by segment linkage is one of the fundamental processes controlling the evolution, in both time and the space, of fault systems. In fact, step-like trajectories shown by length-displacement diagrams for individual fault arrays suggest that the development of evolved structures result by the linkage of single fault segments. The type of interaction between faults and the rate at which faults reactivate not only control the long term tectonic evolution of an area, but also influence the seismic hazard, as earthquake recurrence intervals tend to decrease as fault slip rate increase. The use of Geomorphological investigations represents an important tool to constrain the latest history of active faults. In this case, attention has to be given to recognize morphostructural, historical, environmental features at the surface, since they record the long-term seismic behavior due to the fault growth processes (Tondi and Cello, 2003). The aim of this work is to investigate the long term morphotectonic evolution of a well know seismic area in the central Apennines: the Norcia intramontane basin (Aringoli et al., 2005). The activity of the Norcia seismic area is characterized by moderate events and by strong earthquakes with maximum intensities of X-XI degrees MCS and equivalent magnitudes around 6.5±7.0 (CPTI, 2004). Based on the morphostructural features as well as on the historical seismicity of the area, we may divide the Norcia seismic area into three minor basins roughly NW-SE oriented: the Preci sub-basin in the north; the S. Scolastica and the Castel S. Maria sub-basins in the south. The wider basin (S. Scolastica) is separated from the other two by ridges transversally oriented with respect the basins themselves; they are the geomorphological response to the tectonic deformation which characterizes the whole area. Other geomorphological evidences of tectonic activity are represented by deformation of old summit erosional surfaces, hydrographic network

  3. Effect of neurturin deficiency on cholinergic and catecholaminergic innervation of the murine eye. (United States)

    Hoover, Jeffrey L; Bond, Cherie E; Hoover, Donald B; Defoe, Dennis M


    Neurturin (NRTN) is a neurotrophic factor required for the development of many parasympathetic neurons and normal cholinergic innervation of the heart, lacrimal glands and numerous other tissues. Previous studies with transgenic mouse models showed that NRTN is also essential for normal development and function of the retina (J. Neurosci. 28:4123-4135, 2008). NRTN knockout (KO) mice exhibit a marked thinning of the outer plexiform layer (OPL) of the retina, with reduced abundance of horizontal cell dendrites and axons, and aberrant projections of horizontal cells and bipolar cells into the outer nuclear layer. The effects of NRTN deletion on specific neurotransmitter systems in the retina and on cholinergic innervation of the iris are unknown. To begin addressing this deficiency, we used immunohistochemical methods to study cholinergic and noradrenergic innervation of the iris and the presence and localization of cholinergic and dopaminergic neurons and nerve fibers in eyes from adult male wild-type (WT) and NRTN KO mice (age 4-6 months). Mice were euthanized, and eyes were removed and fixed in cold neutral buffered formalin or 4% paraformaldehyde. Formalin-fixed eyes were embedded in paraffin, and 5 μm cross-sections were collected. Representative sections were stained with hematoxylin and eosin or processed for fluorescence immunohistochemistry after treatment for antigen retrieval. Whole mount preparations were dissected from paraformaldehyde fixed eyes and used for immunohistochemistry. Cholinergic and catecholaminergic nerve fibers were labeled with primary antibodies to the vesicular acetylcholine transporter (VAChT) and tyrosine hydroxylase (TH), respectively. Cholinergic and dopaminergic cell bodies were labeled with antibodies to choline acetyltransferase (ChAT) and TH, respectively. Cholinergic innervation of the mouse iris was restricted to the sphincter region, and noradrenergic fibers occurred throughout the iris and in the ciliary processes. This

  4. Cholinergic Neurons - Keeping Check on Amyloid beta in the Cerebral Cortex

    Directory of Open Access Journals (Sweden)

    Saak V. Ovsepian


    Full Text Available The physiological relevance of the uptake of ligands with no apparent trophic functions via the p75 neurotrophin receptor (p75NTR remains unclear. Herein, we propose a homeostatic role for this in clearance of amyloid β (Aβ in the brain. We hypothesize that uptake of Aβ in conjunction with p75NTR followed by its degradation in lysosomes endows cholinergic basalo-cortical projections enriched in this receptor a facility for maintaining physiological levels of Aβ in target areas. Thus, in addition to the diffuse modulator influence and channeling of extra-thalamic signals, cholinergic innervations could supply the cerebral cortex with an elaborate system for Aβ drainage. Interpreting the emerging relationship of new molecular data with established role of cholinergic modulator system in regulating cortical network dynamics should provide new insights into the brain physiology and mechanisms of neuro-degenerative diseases.

  5. Localization of pre- and postsynaptic cholinergic markers in rodent forebrain : A brief history and comparison of rat and mouse

    NARCIS (Netherlands)

    Van der Zee, E. A.; Keijser, J.N.


    Rat and mouse models are widely used for studies in cognition and pathophysiology, among others. Here, we sought to determine to what extent these two model species differ for cholinergic and cholinoceptive features. For this purpose, we focused on cholinergic innervation patterns based on choline

  6. The significance of hypersensitivity to autologous sweat and serum in cholinergic urticaria: cholinergic urticaria may have different subtypes. (United States)

    Kim, Jung Eun; Jung, Kwan Ho; Cho, Hyun Hee; Kang, Hoon; Park, Young Min; Park, Hyun Jeong; Lee, Jun Young


    The pathogenesis of cholinergic urticaria (ChU) has been unclear except for the involvement of acetylcholine. Attempts to classify ChU according to etiology have rarely been performed. To evaluate the significance of responsiveness to autologous sweat and serum in ChU in relation to their clinical characteristics. This study involved 18 patients diagnosed with ChU between January 2010 and April 2011 in the Catholic Medical Center-St. Paul's Hospital. History taking included symptom duration, association with atopy, decreased sweat secretions, seasonal variation, and response to treatment. Intradermal autologous serum skin test (ASST) and autologous sweat skin test (ASwST) and basophil histamine release test with sweat were done. Sweat hypersensitivity was proven by a positive ASwST and basophil histamine release test in only 37.5% of patients with ChU, and in none of the healthy controls. The weal size of ASwST correlated with percentage basophil histamine release. A positive response to autologous serum was displayed by 38.9% of patients, whereas 10% of healthy controls showed a positive ASST response. Intriguingly, patients with a positive ASwST had a negative ASST, and vice versa. Despite this, there was no difference in the clinical characteristics between positive ASST and positive ASwST groups. The frequency of hypersensitivity to autologous sweat and serum was significantly higher in patients with ChU, compared with healthy controls. This suggests that autoimmunity to an unknown serum factor as well as sweat hypersensitivity may be involved in the pathogenesis of ChU. © 2014 The International Society of Dermatology.

  7. Patient with Macular Disease, Good Visual Acuity, and Central Visual Field Disruption and Significant Difficulties with Activities of Daily Living (United States)

    Fletcher, Donald C.; Schuchard, Ronald A.; Walker, Joseph P.; Raskauskas, Paul A.


    It is generally appreciated that patients with macular disease frequently experience reduced visual acuity. It is not as widely appreciated that they often have significant central visual field disruption, which, by itself, can cause significant problems with activities of daily living, such as reading and driving, even when they maintain good…

  8. Variations on a theme: species differences in synaptic connectivity do not predict central pattern generator activity. (United States)

    Gunaratne, Charuni A; Sakurai, Akira; Katz, Paul S


    A fundamental question in comparative neuroethology is the extent to which synaptic wiring determines behavior vs. the extent to which it is constrained by phylogeny. We investigated this by examining the connectivity and activity of homologous neurons in different species. Melibe leonina and Dendronotus iris (Mollusca, Gastropoda, Nudibranchia) have homologous neurons and exhibit homologous swimming behaviors consisting of alternating left-right (LR) whole body flexions. Yet, a homologous interneuron (Si1) differs between the two species in its participation in the swim motor pattern (SMP) and synaptic connectivity. In this study we examined Si1 homologs in two additional nudibranchs: Flabellina iodinea , which evolved LR swimming independently of Melibe and Dendronotus , and Tritonia diomedea , which swims with dorsal-ventral (DV) body flexions. In Flabellina , the contralateral Si1s exhibit alternating rhythmic bursting activity during the SMP and are members of the swim central pattern generator (CPG), as in Melibe The Si1 homologs in Tritonia do not burst rhythmically during the DV SMP but are inhibited and receive bilaterally synchronous synaptic input. In both Flabellina and Tritonia , the Si1 homologs exhibit reciprocal inhibition, as in Melibe However, in Flabellina the inhibition is polysynaptic, whereas in Tritonia it is monosynaptic, as in Melibe In all species, the contralateral Si1s are electrically coupled. These results suggest that Flabellina and Melibe convergently evolved a swim CPG that contains Si1; however, they differ in monosynaptic connections. Connectivity is more similar between Tritonia and Melibe , which exhibit different swimming behaviors. Thus connectivity between homologous neurons varies independently of both behavior and phylogeny. NEW & NOTEWORTHY This research shows that the synaptic connectivity between homologous neurons exhibits species-specific variations on a basic theme. The neurons vary in the extent of electrical

  9. Measurement of radium isotope activities in reservoir and spring water in the Cameroon Central Region

    Directory of Open Access Journals (Sweden)

    Rose Lydie Marie


    Full Text Available Purpose: To determine the activities of 226Ra and 228Ra in the reservoir and spring water samples respectively during the dry and the rainy seasons; and to calculate the annual intake Ii (Bq/y for each type of water samples. Methods: Using both well calibrated Canberra NaI(Tl and HPGe detector systems, it was possible to determine the average specific activity of those radium’s isotopes in water samples which were collected in 2010, from Reservoirs and springs in Cameroon central region including Ngoaekelle, Minboman, Etoudi and Njoungolo. Results: The average specific activity values obtained for 226Ra and 228Ra in reservoir water samples were 8.76 ± 3.50 BqL-1 and 0.64 ± 0.28 BqL-1 during the dry season and, 8.24 ±3.48 BqL-1 and 0.58 ± 0.24 BqL-1 during the rainy season respectively. For spring water, the average values were 3.50 ± 0.63 BqL-1 and below 0.0002 BqL-1 (detection limit of 228Ra in water during the dry season; 3.20 ± 0.60 BqL-1 and below 0.0002 BqL-1 (detection limit of 228Ra in water during the rainy season respectively. Assuming that the volume of drinking water for adult is 2.5 litres per day, the average annual intakes of 226Ra and 228Ra through ingestion in these water samples were 7702 Bq/y and 575 Bq/y for reservoir water; 2993 Bq/y and < 0.25 for spring water respectively. Conclusion: The results have indicated that the annual intake by the population of sampling region as a result of 226Ra in these drinking waters is 7.7 × 103Bq/y more than the maximum limit fixed by ICRP which is 7 × 103 Bq/y. There is a need for regular monitoring the radiological water quality aspect in this region.

  10. Participation of the cholinergic system in the ethanol-induced suppression of paradoxical sleep in rats

    Directory of Open Access Journals (Sweden)

    L.A. Papale


    Full Text Available Sleep disturbance is among the many consequences of ethanol abuse in both humans and rodents. Ethanol consumption can reduce REM or paradoxical sleep (PS in humans and rats, respectively. The first aim of this study was to develop an animal model of ethanol-induced PS suppression. This model administered intragastrically (by gavage to male Wistar rats (3 months old, 200-250 g 0.5 to 3.5 g/kg ethanol. The 3.5 g/kg dose of ethanol suppressed the PS stage compared with the vehicle group (distilled water during the first 2-h interval (0-2 h; 1.3 vs 10.2; P < 0.001. The second aim of this study was to investigate the mechanisms by which ethanol suppresses PS. We examined the effects of cholinergic drug pretreatment. The cholinergic system was chosen because of the involvement of cholinergic neurotransmitters in regulating the sleep-wake cycle. A second set of animals was pretreated with 2.5, 5.0, and 10 mg/kg pilocarpine (cholinergic agonist or atropine (cholinergic antagonist. These drugs were administered 1 h prior to ethanol (3.5 g/kg or vehicle. Treatment with atropine prior to vehicle or ethanol produced a statistically significant decrease in PS, whereas pilocarpine had no effect on minutes of PS. Although the mechanism by which ethanol induces PS suppression is not fully understood, these data suggest that the cholinergic system is not the only system involved in this interaction.

  11. Muscarinic signaling influences the patterning and phenotype of cholinergic amacrine cells in the developing chick retina

    Directory of Open Access Journals (Sweden)

    Fischer Andy J


    Full Text Available Abstract Background Many studies in the vertebrate retina have characterized the differentiation of amacrine cells as a homogenous class of neurons, but little is known about the genes and factors that regulate the development of distinct types of amacrine cells. Accordingly, the purpose of this study was to characterize the development of the cholinergic amacrine cells and identify factors that influence their development. Cholinergic amacrine cells in the embryonic chick retina were identified by using antibodies to choline acetyltransferase (ChAT. Results We found that as ChAT-immunoreactive cells differentiate they expressed the homeodomain transcription factors Pax6 and Islet1, and the cell-cycle inhibitor p27kip1. As differentiation proceeds, type-II cholinergic cells, displaced to the ganglion cell layer, transiently expressed high levels of cellular retinoic acid binding protein (CRABP and neurofilament, while type-I cells in the inner nuclear layer did not. Although there is a 1:1 ratio of type-I to type-II cells in vivo, in dissociated cell cultures the type-I cells (ChAT-positive and CRABP-negative out-numbered the type-II cells (ChAT and CRABP-positive cells by 2:1. The relative abundance of type-I to type-II cells was not influenced by Sonic Hedgehog (Shh, but was affected by compounds that act at muscarinic acetylcholine receptors. In addition, the abundance and mosaic patterning of type-II cholinergic amacrine cells is disrupted by interfering with muscarinic signaling. Conclusion We conclude that: (1 during development type-I and type-II cholinergic amacrine cells are not homotypic, (2 the phenotypic differences between these subtypes of cells is controlled by the local microenvironment, and (3 appropriate levels of muscarinic signaling between the cholinergic amacrine cells are required for proper mosaic patterning.

  12. Cholinergic intrapancreatic neurons induce Ca²+ signaling and early-response gene expression in pancreatic acinar cells. (United States)

    Turner, D J; cowles, R A; Segura, B J; Romanchuk, G; Barnhart, D C; Mulholland, M W


    Pancreatic exocrine function has been demonstrated to be under neuronal regulation. The pathways responsible for this effect, and the long-term consequences of such interactions, are incompletely described. The effects of neuronal depolarization on pancreatic acinar cells were studied to determine whether calcium signaling and c-fos expression were activated. In pancreatic lobules, which contain both neurons and acinar cells, agonists that selectively stimulated neurons increased intracellular calcium in acinar cells. Depolarization also led to the expression of c-fos protein in 24% +/- 4% of the acinar cells. In AR42J pancreatic acinar cells, cholinergic stimulation demonstrated an average increase of 398 +/- 19 nmol/L in intracellular calcium levels, and induced c-fos expression that was time and dose dependent. The data indicate that intrapancreatic neurons induce Ca²+ signaling and early-response gene expression in pancreatic acinar cells.

  13. Antidepressant-like properties of sildenafil in a genetic rat model of depression: Role of cholinergic cGMP-interactions

    DEFF Research Database (Denmark)

    Liebenberg, Nico; Brink, Christiaan; Brand, Linda


    any antidepressant-like effect when administered alone. In the current study, we investigated these findings in a genetic animal model of depression, the Flinders Sensitive Line (FSL) rats. In addition, we evaluated the dose-dependency and onset of action for sildenafil + atropine, as well....... Conclusions: Using a genetic animal model of depression, we have confirmed the antidepressant-like property of sildenafil following “unmasking” by concomitant block of muscarinic receptors. These findings hint at a novel interaction between the cGMP and cholinergic systems in depression, and suggest...... was scored during five minutes swim in the FST. In addition, locomotor activity was evaluated in the Open Field Test 2 hours prior to the FST. Results: Fluoxetine and imipramine separately decreased immobility in FSL rats, comparable to that of FRL control rats, after 14 but not after 7 days. Likewise, when...

  14. Tephra layers from Holocene lake sediments of the Sulmona Basin, central Italy: implications for volcanic activity in Peninsular Italy and tephrostratigraphy in the central Mediterranean area (United States)

    Giaccio, B.; Messina, P.; Sposato, A.; Voltaggio, M.; Zanchetta, G.; Galadini, F.; Gori, S.; Santacroce, R.


    We present a new tephrostratigraphic record from the Holocene lake sediments of the Sulmona basin, central Italy. The Holocene succession is represented by whitish calcareous mud that is divided into two units, SUL2 (ca 32 m thick) and SUL1 (ca 8 m thick), for a total thickness of ca 40 m. These units correspond to the youngest two out of six sedimentary cycles recognised in the Sulmona basin that are related to the lake sedimentation since the Middle Pleistocene. Height concordant U series age determinations and additional chronological data constrain the whole Holocene succession to between ca 8000 and 1000 yrs BP. This includes a sedimentary hiatus that separates the SUL2 and SUL1 units, which is roughly dated between Somma-Vesuvius Holocene volcanic activity, and one to the Ischia Island eruption of the Cannavale tephra (2920 ± 450 cal yrs BP). The 27 ash layers compatible with Mt. Somma-Vesuvius activity are clustered in three different time intervals: from ca 2000 to >1000; from 3600 to 3100; and from 7600 to 4700 yrs BP. The first, youngest cluster, comprises six layers and correlates with the intense explosive activity of Mt. Somma-Vesuvius that occurred after the prominent AD 79 Pompeii eruption, but only the near-Plinian event of AD 472 has been tentatively recognised. The intermediate cluster (3600-3100 yrs BP) starts with tephra that chemically and chronologically matches the products from the "Pomici di Avellino" eruption (ca 3800 ± 200 yrs BP). This is followed by eight further layers, where the glasses exhibit chemical features that are similar in composition to the products from the so-called "Protohistoric" or AP eruptions; however, only the distal equivalents of three AP events (AP3, AP4 and AP6) are tentatively designated. Finally, the early cluster (7600-4700 yrs BP) comprises 12 layers that contain evidence of a surprising, previously unrecognised, activity of the Mt. Somma-Vesuvius volcano during its supposed period of quiescence, between

  15. Cholinergic manipulation of digestive function in ruminants and other domestic livestock: a review. (United States)

    Croom, W J; Froetschel, M A; Hagler, W M


    Exocrine secretions in the digestive tract of domestic livestock are controlled by a combination of neural and endocrine inputs. The parasympathetic domain of the autonomic nervous system is responsible for efferent signals that regulate most exocrine secretory processes. Exocrine tissues possess cholinergic muscarinic receptor subtypes that are different from those found in brain, heart and muscle tissues. Cholinergic stimulation of specific muscarinic receptor subtypes has enhanced secretions of the salivary glands and pancreas. These changes in output of exocrine glands can alter digestive function that may benefit production of cattle and swine.

  16. Cholecystokinin activation of central satiety centers changes seasonally in a mammalian hibernator. (United States)

    Otis, Jessica P; Raybould, Helen E; Carey, Hannah V


    Hibernators that rely on lipids during winter exhibit profound changes in food intake over the annual cycle. The mechanisms that regulate appetite changes in seasonal hibernators remain unclear, but likely consist of complex interactions between gut hormones, adipokines, and central processing centers. We hypothesized that seasonal changes in the sensitivity of neurons in the nucleus tractus solitarius (NTS) to the gut hormone cholecystokinin (CCK) may contribute to appetite regulation in ground squirrels. Spring (SPR), late summer (SUM), and winter euthermic hibernating (HIB) 13-lined ground squirrels (Ictidomys tridecemlineatus) were treated with intraperitoneal CCK (100 μg/kg) or vehicle (CON) for 3h and Fos expression in the NTS was quantified. In CON squirrels, numbers of Fos-positive neurons in HIB were low compared to SPR and SUM. CCK treatment increased Fos-positive neurons in the NTS at the levels of the area postrema (AP) and pre AP during all seasons and at the level of the rostral AP in HIB squirrels. The highest absolute levels of Fos-positive neurons were found in SPR CCK squirrels, but the highest relative increase from CON was found in HIB CCK squirrels. Fold-changes in Fos-positive neurons in SUM were intermediate between SPR and HIB. Thus, CCK sensitivity falls from SPR to SUM suggesting that seasonal changes in sensitivity of NTS neurons to vagally-derived CCK may influence appetite in the active phase of the annual cycle in hibernating squirrels. Enhanced sensitivity to CCK signaling in NTS neurons of hibernators indicates that changes in gut-brain signaling may contribute to seasonal changes in food intake during the annual cycle. Copyright © 2011 Elsevier Inc. All rights reserved.

  17. Water Infused Surface Protection as an Active Mechanism for Fibrin Sheath Prevention in Central Venous Catheters. (United States)

    Sutherland, David W; Zhang, Xin; Charest, Joseph L


    Protein adhesion in central venous catheters (CVCs) leads to fibrin sheath formation, the precursor to thrombotic and biofilm-related CVC failures. Advances in material properties and surface coatings do not completely prevent fibrin sheath formation and post-formation treatment options are limited and expensive. We propose water infused surface protection (WISP), an active method for prevention of fibrin sheath formation on CVCs, which creates a blood-free boundary layer on the inner surface of the CVC, limiting blood contact with the CVC lumen wall. A hollow fiber membrane (HFM) in a benchtop device served as a CVC testing model to demonstrate the WISP concept. Porcine blood was pumped through the HFM while phosphate buffered saline (PBS) was infused through the HFM wall, creating the WISP boundary layer. Protein adherences on model CVC surfaces were measured and imaged. Analytical and finite volume lubrication models were used to justify the assumption of a blood-free boundary layer. We found a 92.2% reduction in average adherent protein density when WISP is used, compared with our model CVC without WISP flow. Lubrication models matched our experimental pressure drop measurements suggesting that a blood-free boundary layer was created. The WISP technique also provides a novel strategy for drug administration for biofilm treatment. Reduction in adherent protein indicates a restriction on long-term fibrin sheath and biofilm formation making WISP a promising technology which improves a wide range of vascular access treatments. © 2017 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

  18. Pre-collisional accretionary growth of the southern Laurasian active margin, Central Pontides, Turkey (United States)

    Aygül, Mesut; Okay, Aral I.; Oberhänsli, Roland; Sudo, Masafumi


    Cretaceous subduction-accretionary complexes crop out over wide areas in the central part of the Pontides, northern Turkey. To the north, the wedge consists of a low-grade metaflysch sequence with blocks of marble, Na-amphibole-bearing metabasite (PT = 7-12 kbar; 400 ± 70 °C) and serpentinite. 40Ar/39Ar phengite ages from the phyllites of the metaflysch are ca. 100 Ma. The metaflysch sequence is underlain by oceanic crust-derived HP/LT metabasites and micaschists along a major detachment fault. The metabasites are epidote-blueschists consisting of glaucophane, epidote, titanite, and phengite locally with garnet. Fresh lawsonite-blueschists are exposed as blocks along the detachment fault. Peak metamorphic conditions of a garnet-blueschist are constrained to 17 ± 1 kbar and 500 ± 40 °C and of a lawsonite-blueschist to 14 ± 2 kbar and 370-440 °C. 40Ar/39Ar phengite dating on the micaschists constrains the HP/LT metamorphism as 101-92 Ma, younging southward. Middle Jurassic (ca. 160 Ma) accretionary complexes consisting of blueschist to lower greenschist facies metabasites, marble and volcanogenic metasediment intercalations are exposed at the southern part of the Cretaceous wedge. In the studied area, the North Anatolian Fault forms the contact between Cretaceous and Middle Jurassic HP/LT metamorphic rocks. Wide distribution of Cretaceous subduction-accretionary complexes implies accretionary tectonic continental growth along the Laurasian active margin. High amount of clastic sediment flux into the trench has a major effect on enlarging the wedge during the Albian. Tectonic thickening of the oceanic HP/LT metamorphic sequence, however, was possibly achieved by propagation of the décollement along the retreating slab which can create the space necessary for progressive deep level basal underplating and extension of the wedge for subsequent syn-subduction exhumation.

  19. Paradoxical (REM) sleep genesis: the switch from an aminergic-cholinergic to a GABAergic-glutamatergic hypothesis. (United States)

    Luppi, Pierre-Hervé; Gervasoni, Damien; Verret, Laure; Goutagny, Romain; Peyron, Christelle; Salvert, Denise; Leger, Lucienne; Fort, Patrice


    In the middle of the last century, Michel Jouvet discovered paradoxical sleep (PS), a sleep phase paradoxically characterized by cortical activation and rapid eye movements and a muscle atonia. Soon after, he showed that it was still present in "pontine cats" in which all structures rostral to the brainstem have been removed. Later on, it was demonstrated that the pontine peri-locus coeruleus alpha (peri-LCalpha in cats, corresponding to the sublaterodorsal nucleus, SLD, in rats) is responsible for PS onset. It was then proposed that the onset and maintenance of PS is due to a reciprocal inhibitory interaction between neurons presumably cholinergic specifically active during PS localized in this region and monoaminergic neurons. In the last decade, we have tested this hypothesis with our model of head-restrained rats and functional neuroanatomical studies. Our results confirmed that the SLD in rats contains the neurons responsible for the onset and maintenance of PS. They further indicate that (1) these neurons are non-cholinergic possibly glutamatergic neurons, (2) they directly project to the glycinergic premotoneurons localized in the medullary ventral gigantocellular reticular nucleus (GiV), (3) the main neurotransmitter responsible for their inhibition during waking (W) and slow wave sleep (SWS) is GABA rather than monoamines, (4) they are constantly and tonically excited by glutamate and (5) the GABAergic neurons responsible for their tonic inhibition during W and SWS are localized in the deep mesencephalic reticular nucleus (DPMe). We also showed that the tonic inhibition of locus coeruleus (LC) noradrenergic and dorsal raphe (DRN) serotonergic neurons during sleep is due to a tonic GABAergic inhibition by neurons localized in the dorsal paragigantocellular reticular nucleus (DPGi) and the ventrolateral periaqueductal gray (vlPAG). We propose that these GABAergic neurons also inhibit the GABAergic neurons of the DPMe at the onset and during PS and are

  20. Chemosynthetic activity prevails in deep-sea sediments of the Central Indian Basin

    Digital Repository Service at National Institute of Oceanography (India)

    Das, A.; Sujith, P.P.; Mourya, B.S.; Biche, S.U.; LokaBharathi, P.A.

    It is hypothesized that in the deep-sea, under psychrophilic, barophilic and oligotrophic conditions, microbial community of Central Indian Basin (CIB) sediments could be chemosynthetic. In the dark, at near ambient temperature, 4 + or –2 degrees C...

  1. Age-related changes in nicotine response of cholinergic and non-cholinergic laterodorsal tegmental neurons: implications for the heightened adolescent susceptibility to nicotine addiction

    DEFF Research Database (Denmark)

    Christensen, Mark Holm; Ishibashi, Masaru; Nielsen, Michael Linnemann


    The younger an individual starts smoking, the greater the likelihood that addiction to nicotine will develop, suggesting that neurobiological responses vary across age to the addictive component of cigarettes. Cholinergic neurons of the laterodorsal tegmental nucleus (LDT) are importantly involved...... in the development of addiction, however, the effects of nicotine on LDT neuronal excitability across ontogeny are unknown. Nicotinic effects on LDT cells across different age groups were examined using calcium imaging and whole-cell patch clamping. Within the youngest age group (P7–P15), nicotine induced larger...... intracellular calcium transients and inward currents. Nicotine induced a greater number of excitatory synaptic currents in the youngest animals, whereas larger amplitude inhibitory synaptic events were induced in cells from the oldest animals (P15–P34). Nicotine increased neuronal firing of cholinergic cells...

  2. Norepinephrine release from Locus Ceruleus:a central regulator for the CNS spatio-temporal activation pattern?

    Directory of Open Access Journals (Sweden)

    Marco Atzori


    Full Text Available Norepinephrine (NE is synthesized in the Locus Coeruleus (LC of the brainstem, from where it is released by axonal varicosities throughout the brain via volume transmission. A wealth of data from clinics and from animal models indicates that this catecholamine coordinates the activity of the central nervous system and of the whole organism by modulating cell function in a vast number of brain areas in a coordinated manner. The ubiquity of NE receptors, the daunting number of cerebral areas regulated by the catecholamine, as well as the variety of cellular effects and of their timescales have contributed so far to defeat the attempts to integrate central adrenergic function into a unitary and coherent framework.Since three main families of NE receptors are represented – in decreasing order of affinity for the catecholamine – by: 2 adrenoceptors (2Rs, high affinity, 1 adrenoceptors (1Rs, intermediate affinity, and  adrenoceptors (Rs, low affinity, on a pharmacological basis, and on the ground of recent studies on cellular and systemic central noradrenergic effects, we propose that an increase in LC tonic activity promotes the emergence of four global states covering the whole spectrum of brain activation: 1 sleep: virtual absence of NE, 2 quiet wake: activation of 2Rs, 3 active wake/physiological stress: activation of 2- and 1Rs, 4 distress: activation of 2-, 1-, and Rs.We postulate that excess intensity and/or duration of states 3 and 4 may lead to maladaptive plasticity, causing – in turn – a variety of neuropsychiatric illnesses including depression, schizophrenic psychoses, anxiety disorders, and attention deficit. The interplay between tonic and phasic LC activity identified in the LC in relationship with behavioral response is of critical importance in defining the short- and long-term biological mechanisms associated with the basic states postulated for the central nervous system. While the model

  3. Central Administration of Ghrelin and Agouti-Related Protein (83–132) Increases Food Intake and Decreases Spontaneous Locomotor Activity in Rats

    National Research Council Canada - National Science Library

    Tang-Christensen, Mads; Vrang, Niels; Ortmann, Sylvia; Bidlingmaier, Martin; Horvath, Tamas L; Tschöp, Matthias


    .... ghrelin stimulates food intake and promotes adiposity after peripheral or central administration, likely by activating hypothalamic neurons expressing the orexigenic neuropeptides neuropeptide Y (NPY...

  4. Contradicting Estimates of Location, Geometry, and Rupture History of Highly Active Faults in Central Japan (United States)

    Okumura, K.


    Accurate location and geometry of seismic sources are critical to estimate strong ground motion. Complete and precise rupture history is also critical to estimate the probability of the future events. In order to better forecast future earthquakes and to reduce seismic hazards, we should consider over all options and choose the most likely parameter. Multiple options for logic trees are acceptable only after thorough examination of contradicting estimates and should not be a result from easy compromise or epoche. In the process of preparation and revisions of Japanese probabilistic and deterministic earthquake hazard maps by Headquarters for Earthquake Research Promotion since 1996, many decisions were made to select plausible parameters, but many contradicting estimates have been left without thorough examinations. There are several highly-active faults in central Japan such as Itoigawa-Shizuoka Tectonic Line active fault system (ISTL), West Nagano Basin fault system (WNBF), Inadani fault system (INFS), and Atera fault system (ATFS). The highest slip rate and the shortest recurrence interval are respectively ~1 cm/yr and 500 to 800 years, and estimated maximum magnitude is 7.5 to 8.5. Those faults are very hazardous because almost entire population and industries are located above the fault within tectonic depressions. As to the fault location, most uncertainties arises from interpretation of geomorphic features. Geomorphological interpretation without geological and structural insight often leads to wrong mapping. Though non-existent longer fault may be a safer estimate, incorrectness harm reliability of the forecast. Also this does not greatly affect strong motion estimates, but misleading to surface displacement issues. Fault geometry, on the other hand, is very important to estimate intensity distribution. For the middle portion of the ISTL, fast-moving left-lateral strike-slip up to 1 cm/yr is obvious. Recent seismicity possibly induced by 2011 Tohoku

  5. Using Analogy Role-Play Activity in an Undergraduate Biology Classroom to Show Central Dogma Revision (United States)

    Takemura, Masaharu; Kurabayashi, Mario


    For the study of biology in an undergraduate classroom, a classroom exercise was developed: an analogy role-play to learn mechanisms of gene transcription and protein translation (central dogma). To develop the central dogma role-play exercise, we made DNA and mRNA using paper sheets, tRNA using a wire dress hanger, and amino acids using Lego®…

  6. Sleep disturbances and severe stress as glial activators: key targets for treating central sensitization in chronic pain patients? (United States)

    Nijs, Jo; Loggia, Marco L; Polli, Andrea; Moens, Maarten; Huysmans, Eva; Goudman, Lisa; Meeus, Mira; Vanderweeën, Luc; Ickmans, Kelly; Clauw, Daniel


    The mechanism of sensitization of the central nervous system partly explains the chronic pain experience in many patients, but the etiological mechanisms of this central nervous system dysfunction are poorly understood. Recently, an increasing number of studies suggest that aberrant glial activation takes part in the establishment and/or maintenance of central sensitization. Areas covered: This review focused on preclinical work and mostly on the neurobiochemistry studied in animals, with limited human studies available. Glial overactivation results in a low-grade neuroinflammatory state, characterized by high levels of BDNF, IL-1β, TNF-α, which in turn increases the excitability of the central nervous system neurons through mechanisms like long-term potentiation and increased synaptic efficiency. Aberrant glial activity in chronic pain might have been triggered by severe stress exposure, and/or sleeping disturbances, each of which are established initiating factors for chronic pain development. Expert opinion: Potential treatment avenues include several pharmacological options for diminishing glial activity, as well as conservative interventions like sleep management, stress management and exercise therapy. Pharmacological options include propentofylline, minocycline, β -adrenergic receptor antagonists, and cannabidiol. Before translating these findings from basic science to clinical settings, more human studies exploring the outlined mechanisms in chronic pain patients are needed.

  7. Active fault characterization throughout the Caribbean and Central America for seismic hazard modeling (United States)

    Styron, Richard; Pagani, Marco; Garcia, Julio


    The region encompassing Central America and the Caribbean is tectonically complex, defined by the Caribbean plate's interactions with the North American, South American and Cocos plates. Though active deformation over much of the region has received at least cursory investigation the past 50 years, the area is chronically understudied and lacks a modern, synoptic characterization. Regardless, the level of risk in the region - as dramatically demonstrated by the 2010 Haiti earthquake - remains high because of high-vulnerability buildings and dense urban areas home to over 100 million people, who are concentrated near plate boundaries and other major structures. As part of a broader program to study seismic hazard worldwide, the Global Earthquake Model Foundation is currently working to quantify seismic hazard in the region. To this end, we are compiling a database of active faults throughout the region that will be integrated into similar models as recently done in South America. Our initial compilation hosts about 180 fault traces in the region. The faults show a wide range of characteristics, reflecting the diverse styles of plate boundary and plate-margin deformation observed. Regional deformation ranges from highly localized faulting along well-defined strike-slip faults to broad zones of distributed normal or thrust faulting, and from readily-observable yet slowly-slipping structures to inferred faults with geodetically-measured slip rates >10 mm/yr but essentially no geomorphic expression. Furthermore, primary structures such as the Motagua-Polochic Fault Zone (the strike-slip plate boundary between the North American and Caribbean plates in Guatemala) display strong along-strike slip rate gradients, and many other structures are undersea for most or all of their length. A thorough assessment of seismic hazard in the region will require the integration of a range of datasets and techniques and a comprehensive characterization of epistemic uncertainties driving

  8. Modulation of c-Jun NH2-Terminal (JNK) by Cholinergic Autoantibodies from Patients with Sjögren’s Syndrome


    Borda, Enri Santiago; Passafaro, Daniela; Reina, Silvia; Sterin Borda, Leonor


    Background: We wanted to determine (via an immunopharmacological approach) whether the c-Jun NH2 terminal kinase (JNK) cascade is phosphorylated in the submandibular gland by carbachol and cholinergic autoantibodies (IgG) present in the sera of patients with primary Sjögren’s syndrome (pSS) by interaction and activation of salivary gland muscarinic acetylcholine receptors (mAChRs). Methods: The JNK, PGE2 and NOS assays were measured in rat sub- mandibular gland with pSS IgG and carbachol alon...

  9. More signs of neurotoxicity of surfactants and flame retardants - Neonatal PFOS and PBDE 99 cause transcriptional alterations in cholinergic genes in the mouse CNS. (United States)

    Hallgren, Stefan; Fredriksson, Anders; Viberg, Henrik


    Maternally and lactionally transferred persistent organic pollutants may interfere with CNS development. Here, 10-day-old male mice were exposed to single oral doses of PFOS (perflourooctanosulphonate) or PBDE 99 (2,2',4,4',5-penta-bromodiphenyl ether), and examined for changes in cholinergic gene transcription in the CNS 24h and 7 weeks later. 24h after exposure qPCR analyses revealed decreased transcription of nAChR-β2 and AChE in cortex, and increased mAChR-5 in hippocampus of PFOS treated mice. Neonatal PFOS treatment altered spontaneous behaviour at 2 months of age but did not affect gene transcription in adults. At 2 months of age neonatally PBDE 99 treated mice had altered spontaneous behaviour, and cortical transcription of AChE, nAChR-α4, nAChR-β2 and mAChR-5 were elevated. Our results indicate that PFOS and PBDE 99 affects the developing central cholinergic system by altering gene transcription in cortex and hippocampus, which may in part account for mechanisms causing changes in spontaneous behaviour. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Neuroanatomical and neuropharmacological approaches to postictal antinociception-related prosencephalic neurons: the role of muscarinic and nicotinic cholinergic receptors (United States)

    de Freitas, Renato Leonardo; Bolognesi, Luana Iacovelo; Twardowschy, André; Corrêa, Fernando Morgan Aguiar; Sibson, Nicola R; Coimbra, Norberto Cysne


    Several studies have suggested the involvement of the hippocampus in the elaboration of epilepsy. There is evidence that suggests the hippocampus plays an important role in the affective and motivational components of nociceptive perception. However, the exact nature of this involvement remains unclear. Therefore, the aim of this study was to determine the role of muscarinic and nicotinic cholinergic receptors in the dorsal hippocampus (dH) in the organization of postictal analgesia. In a neuroanatomical study, afferent connections were found from the somatosensory cortex, the medial septal area, the lateral septal area, the diagonal band of Broca, and the dentate gyrus to the dH; all these areas have been suggested to modulate convulsive activity. Outputs to the dH were also identified from the linear raphe nucleus, the median raphe nucleus (MdRN), the dorsal raphe nucleus, and the locus coeruleus. All these structures comprise the endogenous pain modulatory system and may be involved either in postictal pronociception or antinociception that is commonly reported by epileptic patients. dH-pretreatment with cobalt chloride (1.0 mmol/L CoCl2/0.2 μL) to transiently inhibit local synapses decreased postictal analgesia 10 min after the end of seizures. Pretreatment of the dH with either atropine or mecamylamine (1.0 μg/0.2 μL) attenuated the postictal antinociception 30 min after seizures, while the higher dose (5.0 μg/0.2 μL) decreased postictal analgesia immediately after the end of seizures. These findings suggest that the dH exerts a critical role in the organization of postictal analgesia and that muscarinic and nicotinic cholinergic receptor-mediated mechanisms in the dH are involved in the elaboration of antinociceptive processes induced by generalized tonic-clonic seizures. PMID:23785660

  11. Environmental changes in the central Po Plain (northern Italy) due to fluvial modifications and anthropogenic activities (United States)

    Marchetti, Mauro


    The fluvial environment of the central Po Plain, the largest plain in Italy, is discussed in this paper. Bounded by the mountain chains of the Alps and the Apennines, this plain is a link between the Mediterranean environment and the cultural and continental influences of both western and eastern Europe. In the past decades, economic development has been responsible for many changes in the fluvial environment of the area. This paper discusses the changes in fluvial dynamics that started from Late Pleistocene and Early Holocene due to distinct climatic changes. The discussion is based on geomorphological, pedological, and archaeological evidences and radiocarbon dating. In the northern foothills, Late Pleistocene palaeochannels indicate several cases of underfit streams among the northern tributaries of the River Po. On the other hand, on the southern side of the Po Plain, no geomorphological evidence of similar discharge reduction has been found. Here, stratigraphic sections, together with archaeological remains buried under the fluvial deposits, show a reduction in the size of fluvial sediments after the 10th millennium BC. During the Holocene, fluvial sedimentation became finer, and was characterised by minor fluctuations in the rate of deposition, probably related to short and less intense climatic fluctuations. Given the high rate of population growth and the development of human activities since the Neolithic Age, human influence on fluvial dynamics, especially since the Roman Age, prevailed over other factors (i.e., climate, tectonics, vegetation, etc.). During the Holocene, the most important changes in the Po Plain were not modifications in water discharge but in sediment. From the 1st to 3rd Century AD, land grants to war veterans caused almost complete deforestation, generalised soil erosion, and maximum progradation of the River Po delta. At present, land abandonment in the mountainous region has led to reafforestation. Artificial channel control in the

  12. Soil-gas radon concentration monitoring in an active granite quarry from Central Portugal (United States)

    Neves, Luís.; Barbosa, Susana; Pereira, Alcides; Aumento, Fabrizio


    This study was carried out in an active quarry located nearby the town of Nelas (Central Portugal), with the primary objective of assessing the effect of regular explosions on soil-gas radon concentrations. Here, a late-orogenic Hercynian porphyritic biotite granite occurs and is exploited for the production of high quality aggregates for different building purposes. This granite is part of the Beiras batholiths, being a geochemically moderately evolved rock, slightly peraluminous, and widely known by the frequent occurrence of associated uranium mineralizations. In fact, more than 4000t of U3O8 was produced from 60 mines of the Beiras region in the last century, over a wide area of more than 10.000 km2, and thousands of anomalies related with the local accumulation of uranium in fault filling materials, metasedimentary enclaves and doleritic veins were recognized during prospecting works. The heterogeneity of uranium distribution in this rock is reflected at the test site; indeed, a gamma ray survey shows that some of the faults that occur in the quarry are slightly mineralized. A total of 7 radon monitoring stations were implemented in the quarry, at a typical depth comprised between 1 and 2 meters, in holes drilled for the purpose. Aware RM-70 pancake GM detectors were used, sensitive to alpha, beta and gamma/X-rays above 10 keV, connected to palmtop computers for data registration (1 minute interval) and power supplied by batteries. Monitoring was carried out during 6 months, in Spring/Summer conditions and the exact time of each explosion was registered manually. Several problems of data loss and power supply affected the stations during the experiment, leading to discontinuities in the records. Still the available data showed important differences in the soil-gas radon concentrations between stations, which can be explained by the heterogeneity of uranium distribution in the rock and increased local permeability. Furthermore, all stations showed a clear daily

  13. Interaction between active tectonics, erosion and diapirism, a case study from Habble-Rud in Southern Central Alborz (Northern Iran) (United States)

    Jaberi, Maryam; Ghassemi, Mohammad R.; Shayan, Siavosh; Yamani, Mojtaba; Zamanzadeh, Seyed Mohammad


    The Alborz mountain chain is a region of active deformation within the Arabia-Eurasia continental collision zone. The southern part of central Alborz Mountains, in the north of Iran, represents complex tectonics because it is located at the border of two developing continental sedimentary basins between southern central Alborz and Central Iran. An arid and semi-arid climate, a large extent of Quaternary sediments, rugged topography, salt domes and faults with historical seismicity influence the Habble-Rud River catchment. In the present research, a number of tectonic geomorphologic indices were extracted from satellite imagery and 10 m DEM (digital elevation model) data in order to identify relative tectonic activity within the basin. The indices include: stream length-gradient index (Sl), drainage basin asymmetry (Af), index of mountain front sinuosity (Smf), hypsometric integral (Hi), index of drainage basin shape (Bs), ratio of valley-floor width to valley height (Vf), and fault density (Fd). Due to the presence of heterogeneous indices for all sections of the catchment causing large extension of Habble-Rud (3260 km2), all of the variables such as extremely erodible formations, faults and folds and salt tectonics on the Southern part; were put into a matrix table. As a new approach, the variables were put into the SAW (simple additive model) model as one of MADM (multi-attribute decision-making models) techniques. The study area was divided into four regions according to the values of SAW. These classes include very high (%11), high (48.3%), moderate (34.7%), and low activity (3.4%). The result of the model suggests that the study area is located on a changing tectonic trend in central Alborz from NW-SE to NE-SW. The regions with high relative tectonic activity in HR catchment correspond to the active Garmsar and Sorkhe-Kalout faults and diapirs.

  14. Hippocampal cholinergic interneurons visualized with the choline acetyltransferase promoter: anatomical distribution, intrinsic membrane properties, neurochemical characteristics, and capacity for cholinergic modulation

    Directory of Open Access Journals (Sweden)

    Feng eYi


    Full Text Available Release of acetylcholine (ACh in the hippocampus (HC occurs during exploration, arousal, and learning. Although the medial septum-diagonal band of Broca (MS-DBB is the major extrinsic source of cholinergic input to the HC, cholinergic neurons intrinsic to the HC also exist but remain poorly understood. Here, ChAT-tauGFP and ChAT-CRE/Rosa26YFP (ChAT-Rosa mice were examined in HC. The HC of ChAT-tauGFP mice was densely innervated with GFP-positive axons, often accompanied by large GFP-positive structures, some of which were Neurotrace/DAPI-negative and likely represent large axon terminals. In the HC of ChAT-Rosa mice, ChAT-YFP cells were Neurotrace-positive and more abundant in CA3 and dentate gyrus than CA1 with partial overlapping with calretinin/VIP. Moreover, an anti-ChAT antibody consistently showed ChAT immunoreactivity in ChAT-YFP cells from MS-DBB but rarely from HC. Furthermore, ChAT-YFP cells from CA1 stratum radiatum/stratum lacunosum moleculare (SR/SLM exhibited a stuttering firing phenotype but a delayed firing phenotype in stratum pyramidale (SP of CA3. Input resistance and capacitance were also different between CA1 SR/LM and CA3 SP ChAT-YFP cells. Bath application of ACh increased firing frequency in all ChAT-YFP cells; however, cholinergic modulation was larger in CA1 SR/SLM than CA3 SP ChAT-YFP cells. Finally, CA3 SP ChAT-YFP cells exhibited a wider AP half-width and weaker cholinergic modulation than YFP-negative CA3 pyramidal cells. Consistent with CRE expression in a subpopulation of principal cells, optogenetic stimulation evoked glutamatergic postsynaptic currents in CA1 SR/SLM interneurons. In conclusion, the presence of fluorescently labeled hippocampal cells common to both ChAT-Rosa and ChAT-tauGFP mice are in good agreement with previous reports on the existence of cholinergic interneurons, but both transgenic mouse lines exhibited unexpected anatomical features that departed considerably from earlier observations.

  15. Sex-specific peculiarities of cholinergic regulation of the cardiovascular system in normal and hypertensive rats. (United States)

    Semyachkina-Glushkovskaya, O V; Anishchenko, T G; Berdnikova, V A; Najdyonova, O S


    Cardiovascular sensitivity to atropine and acetylcholine is reduced in renal hypertension. Hypertension in females is more benign and the hypotensive effects of acetylcholine in them are less attenuated than in males. Cardiovascular sensitivity to cholinergic effects in females is higher in health and hypertension, which improves their resistance to cardiovascular pathology.

  16. Extensive Lesions of Cholinergic Basal Forebrain Neurons Do Not Impair Spatial Working Memory (United States)

    Vuckovich, Joseph A.; Semel, Mara E.; Baxter, Mark G.


    A recent study suggests that lesions to all major areas of the cholinergic basal forebrain in the rat (medial septum, horizontal limb of the diagonal band of Broca, and nucleus basalis magnocellularis) impair a spatial working memory task. However, this experiment used a surgical technique that may have damaged cerebellar Purkinje cells. The…

  17. Cholinergic Septo-Hippocampal Innervation Is Required for Trace Eyeblink Classical Conditioning (United States)

    Fontan-Lozano, Angela; Troncoso, Julieta; Munera, Alejandro; Carrion, Angel Manuel; Delgado-Garcia, Jose Maria


    We studied the effects of a selective lesion in rats, with 192-IgG-saporin, of the cholinergic neurons located in the medial septum/diagonal band (MSDB) complex on the acquisition of classical and instrumental conditioning paradigms. The MSDB lesion induced a marked deficit in the acquisition, but not in the retrieval, of eyeblink classical…


    NARCIS (Netherlands)


    Striatal cholinergic interneurons have been shown to receive input from striatal gamma-aminobutyric acid (GABA)-containing cell elements. GABA is known to act on two different types of receptors, the GABA(A) and the GABA(B) receptor. Using in vivo microdialysis, we have studied the effect of

  19. Cholinergic Modulation during Acquisition of Olfactory Fear Conditioning Alters Learning and Stimulus Generalization in Mice (United States)

    Pavesi, Eloisa; Gooch, Allison; Lee, Elizabeth; Fletcher, Max L.


    We investigated the role of cholinergic neurotransmission in olfactory fear learning. Mice receiving pairings of odor and foot shock displayed fear to the trained odor the following day. Pretraining injections of the nicotinic antagonist mecamylamine had no effect on subsequent freezing, while the muscarinic antagonist scopolamine significantly…


    NARCIS (Netherlands)


    The effects of early postnatal (PD 8) intracerebroventricular injection of ethylcholine mustard aziridinium ion (AF64A) on development of open-field and cognitive behaviors and cholinergic markers in several brain areas were examined in the rat. The cholinotoxin was bilaterally administered in a

  1. Red Dermographism in Autism Spectrum Disorders: A Clinical Sign of Cholinergic Dysfunction? (United States)

    Lemonnier, E.; Grandgeorge, M.; Jacobzone-Leveque, C.; Bessaguet, C.; Peudenier, S.; Misery, L.


    The authors hypothesised that red dermographism--a skin reaction involving the cholinergic system--is more frequent in children with autism spectrum disorders (ASDs) than in children exhibiting typical development. We used a dermatological examination to study red dermographism in this transverse study, which compared forty six children with ASDs…

  2. People with Down's syndrome can be distinguished on the basis of cholinergic dysfunction. (United States)

    Sacks, B; Smith, S


    The mydriatic response to eyedrops of the anticholinergic agent tropicamide at very low concentration (0.01%) has been studied in people with Down's syndrome. By comparison with healthy subjects people with Down's syndrome had responses approximately three times greater, suggesting a peripheral imbalance between cholinergic and adrenergic autonomic influences. PMID:2531786

  3. The effect of the augmentation of cholinergic neurotransmission by nicotine on EEG indices of visuospatial attention

    NARCIS (Netherlands)

    Logemann, H.N.A.; Bocker, K.B.E.; Deschamps, P.K.H.; Kemner, C.; Kenemans, J.L.


    The cholinergic system has been implicated in visuospatial attention but the exact role remains unclear. In visuospatial attention, bias refers to neuronal signals that modulate the sensitivity of sensory cortex, while disengagement refers to the decoupling of attention making reorienting possible.

  4. Dynamic Insights on Surgical Activity in a New Modern Warfare: The French Role 2 in Bangui, Central African Republic. (United States)

    Barbier, Olivier; Pasquier, Pierre; Racle, Maelle; Baudoin, Yoann; Malgras, Brice


    In December 2013, France deployed more than 2,000 soldiers in Central African Republic with two main missions, to restore security and to improve the humanitarian situation. The objectives of this article were to analyze the surgical activity of forward surgical teams in Central African Republic over 2 years and to discuss features of training for deployed surgeons. From December 5, 2013, to September 30, 2015, we retrospectively reviewed the electronic surgical database. Surgical activity was described as patient status, type of lesion, surgical procedures performed, and anatomic regions involved. During this study period, 431 surgical procedures were performed on 401 patients; 66% of the patients were civilians, 26% French soldiers, and 11% foreign soldiers. Surgical procedures were divided into 34% orthopedic activity and 66% general surgery activity. Orthopedic activity was mainly performed during the first months of the operation Sangaris, whereas general surgery occurred after summer 2014 with a return to peacetime. Our study demonstrated original and dynamic insights into the nature of surgical activity throughout the operation with mainly orthopedic surgery during the initial deployment for management of combat casualties and general surgery later, dedicated to elective surgery for local citizens. These data should enhance staffing, training, and deployment of future surgical teams in combat settings with continuous training programs to maintain specific competences, especially in cases of low surgical activity, such as virtual learning or e-learning that could be developed in the future. Reprint & Copyright © 2017 Association of Military Surgeons of the U.S.

  5. Modulation of specific sensory cortical areas by segregated basal forebrain cholinergic neurons demonstrated by neuronal tracing and optogenetic stimulation in mice

    Directory of Open Access Journals (Sweden)

    Irene eChaves-Coira


    Full Text Available Neocortical cholinergic activity plays a fundamental role in sensory processing and cognitive functions. Previous results have suggested a refined anatomical and functional topographical organization of basal forebrain (BF projections that may control cortical sensory processing in a specific manner. We have used retrograde anatomical procedures to demonstrate the existence of specific neuronal groups in the BF involved in the control of specific sensory cortices. Fluoro-gold and Fast Blue fluorescent retrograde tracers were deposited into the primary somatosensory (S1 and primary auditory (A1 cortices in mice. Our results revealed that the BF is a heterogeneous area in which neurons projecting to different cortical areas are segregated into different neuronal groups. Most of the neurons located in the horizontal limb of the diagonal band of Broca (HDB projected to the S1 cortex, indicating that this area is specialized in the sensory processing of tactile stimuli. However, the nucleus basalis magnocellularis (B nucleus shows a similar number of cells projecting to the S1 as to the A1 cortices. In addition, we analyzed the cholinergic effects on the S1 and A1 cortical sensory responses by optogenetic stimulation of the BF neurons in urethane-anesthetized transgenic mice. We used transgenic mice expressing the light-activated cation channel, channelrhodopsin-2, tagged with a fluorescent protein (ChR2-YFP under the control of the choline-acetyl transferase promoter (ChAT. Cortical evoked potentials were induced by whisker deflections or by auditory clicks. According to the anatomical results, optogenetic HDB stimulation induced more extensive facilitation of tactile evoked potentials in S1 than auditory evoked potentials in A1, while optogenetic stimulation of the B nucleus facilitated either tactile or auditory evoked potentials equally. Consequently, our results suggest that cholinergic projections to the cortex are organized into segregated

  6. Modulation of Specific Sensory Cortical Areas by Segregated Basal Forebrain Cholinergic Neurons Demonstrated by Neuronal Tracing and Optogenetic Stimulation in Mice. (United States)

    Chaves-Coira, Irene; Barros-Zulaica, Natali; Rodrigo-Angulo, Margarita; Núñez, Ángel


    Neocortical cholinergic activity plays a fundamental role in sensory processing and cognitive functions. Previous results have suggested a refined anatomical and functional topographical organization of basal forebrain (BF) projections that may control cortical sensory processing in a specific manner. We have used retrograde anatomical procedures to demonstrate the existence of specific neuronal groups in the BF involved in the control of specific sensory cortices. Fluoro-Gold (FlGo) and Fast Blue (FB) fluorescent retrograde tracers were deposited into the primary somatosensory (S1) and primary auditory (A1) cortices in mice. Our results revealed that the BF is a heterogeneous area in which neurons projecting to different cortical areas are segregated into different neuronal groups. Most of the neurons located in the horizontal limb of the diagonal band of Broca (HDB) projected to the S1 cortex, indicating that this area is specialized in the sensory processing of tactile stimuli. However, the nucleus basalis magnocellularis (B) nucleus shows a similar number of cells projecting to the S1 as to the A1 cortices. In addition, we analyzed the cholinergic effects on the S1 and A1 cortical sensory responses by optogenetic stimulation of the BF neurons in urethane-anesthetized transgenic mice. We used transgenic mice expressing the light-activated cation channel, channelrhodopsin-2, tagged with a fluorescent protein (ChR2-YFP) under the control of the choline-acetyl transferase promoter (ChAT). Cortical evoked potentials were induced by whisker deflections or by auditory clicks. According to the anatomical results, optogenetic HDB stimulation induced more extensive facilitation of tactile evoked potentials in S1 than auditory evoked potentials in A1, while optogenetic stimulation of the B nucleus facilitated either tactile or auditory evoked potentials equally. Consequently, our results suggest that cholinergic projections to the cortex are organized into segregated

  7. Effects of 12-Week Bacopa monnieri Consumption on Attention, Cognitive Processing, Working Memory, and Functions of Both Cholinergic and Monoaminergic Systems in Healthy Elderly Volunteers

    Directory of Open Access Journals (Sweden)

    Tatimah Peth-Nui


    Full Text Available At present, the scientific evidence concerning the effect of Bacopa monnieri on brain activity together with working memory is less available. Therefore, we aimed to determine the effect of B. monnieri on attention, cognitive processing, working memory, and cholinergic and monoaminergic functions in healthy elderly. A randomized double-blind placebo-controlled design was utilized. Sixty healthy elderly subjects (mean age 62.62 years; SD 6.46, consisting of 23 males and 37 females, received either a standardized extract of B. monnieri (300 and 600 mg or placebo once daily for 12 weeks. The cholinergic and monoaminergic systems functions were determined using AChE and MAO activities. Working memory was assessed using percent accuracy and reaction time of various memory tests as indices, whereas attention and cognitive processing were assessed using latencies and amplitude of N100 and P300 components of event-related potential. All assessments were performed before treatment, every four weeks throughout study period, and at four weeks after the cessation of intervention. B. monnieri-treated group showed improved working memory together with a decrease in both N100 and P300 latencies. The suppression of plasma AChE activity was also observed. These results suggest that B. monnieri can improve attention, cognitive processing, and working memory partly via the suppression of AChE activity.

  8. Low Plasma Cholinesterase Activities are Associated with Deficits in Spatial Orientation, Reduced Ability to Perform Basic Activities of Daily Living, and Low Body Mass Index in Patients with Progressed Alzheimer's Disease. (United States)

    Dingova, Dominika; Fazekas, Tomas; Okuliarova, Petra; Strbova, Jaroslava; Kucera, Matej; Hrabovska, Anna


    Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder characterized by a central cholinergic deficit. Non-neuronal cholinergic changes are, however, described as well. Here we focused on possible changes in the activity of the plasma cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), in hospitalized AD patients. We analyzed plasma AChE and BChE activities with regards to age, gender, body mass index (BMI), cognitive functions, and ability to perform activities of daily living in AD patients in comparison to healthy subjects. We observed lower AChE activity and trend toward lower BChE activity in AD patients, which both correlated with low BMI. AD patients unable to perform basic activities of daily living (feeding, bathing, dressing, and grooming) showed reduced plasma AChE activities, while worse spatial orientation was linked to lower BChE activities. Three out of four AD patients with the lowest BChE activities died within one year. In conclusion, progressed AD was accompanied by lower plasma AChE activity and trend toward lower BChE activity, which correlated with BMI and deficits in different components of the AD.

  9. Unraveling the central processing of pain by studying brain activity and behaviour in rats

    NARCIS (Netherlands)

    Schaap, M.W.H.|info:eu-repo/dai/nl/314411488


    Pain is described as a subjective unpleasant sensory and emotional experience, which is generated in the brain. In both humans and animals, pain is frequently undertreated. The primary barrier to an effective pain treatment is the incomplete knowledge about underlying central mechanisms. In animals,

  10. Earthworm activity and soil structural changes under conservation agriculture in central Mexico

    NARCIS (Netherlands)

    Castellanos Navarrete, A.; Rodriguez-Aragonés, C.; Goede, de R.G.M.; Kooistra, M.J.; Sayre, K.D.; Brussaard, L.; Pulleman, M.M.


    Crop residue mulching combined with zero tillage and crop rotation, known as conservation agriculture (CA), is being promoted as an alternative system to revert soil degradation in maize-based farming in the central highlands of Mexico. The goal of this paper was to determine the effects of CA vs.

  11. Burrow architecture and turbative activity of the thalassinid shrimp Callianassa subterranea from the central North Sea

    NARCIS (Netherlands)

    Stamhuis, EJ; Schreurs, CE; Videler, JJ


    The architecture and development of the burrows of the endobenthic shrimp Callianassa subterranea from the central North Sea were studied in sediment-filled containers and thin cuvettes in the laboratory. Three-dimensional burrows of 81 shrimps were used to describe the 3-dimensional burrow

  12. Measurement of acetylcholinesterase (AChE) activity in living brain by positron emission tomography (PET)

    Energy Technology Data Exchange (ETDEWEB)

    Irie, Toshiaki [National Inst. of Radiological Sciences, Chiba (Japan)


    Central cholinergic neuronal system has been known to be related to learning and memory, and its deficit is found in the brain of Alzheimer's disease (AD) and other degenerative disorders. Postmortem studies have shown that acetylcholinesterase (AChE), one of biochemical markers of central cholinergic nerve system, is consistently reduced in the cerebral cortex of patients with Alzheimer's disease (AD). Non-invasive mapping and/or measuring AChE activity in the living brain by positron emission tomography (PET) would be a useful tool for assessment of cholinergic dysfunction in AD and other disorders, and provide a direct method for validation of therapeutic efficacy of drugs, AChE inhibitors. We have challenged to measure AChE activity using tracers of substrate type, radiolabelled acetylcholine analogs, which are lipophilic enough to go across blood brain barrier and are metabolically trapped by AChE in the brain. The analogs designed, N-methylpiperidyl esters, were evaluated in terms of their metabolic rate and specificity against AChE. Studies examining the response to AChE activity showed metabolic accumulation of some analogs responded well to changes in cortical AChE activity in an animal model of AD. The study was further applied to living human by PET using [{sup 11}C]N-methylpiperidyl-4-acetate (MP4A), which was chosen on the basis of its reactivity and specificity suitable for the human cortical AChE. Regional cerebral metabolic rate of MP4A reflecting AChE activity was quantitatively determined using three compartment model analysis of dynamic PET data and the arterial input function obtained by TLC-radioluminography or plasma samples. The kinetic analyses showed that AChE activities estimated were well agree with those of postmortem examination in cerebral cortices and thalamus in healthy subjects, and that there was significant reduction of cortical AChE activity in patients with AD. The results suggest feasibility of the present method for

  13. Central command does not suppress baroreflex control of cardiac sympathetic nerve activity at the onset of spontaneous motor activity in the decerebrate cat. (United States)

    Matsukawa, Kanji; Ishii, Kei; Asahara, Ryota; Idesako, Mitsuhiro


    Our laboratory has reported that central command blunts the sensitivity of the aortic baroreceptor-heart rate (HR) reflex at the onset of voluntary static exercise in animals. We have examined whether baroreflex control of cardiac sympathetic nerve activity (CSNA) and/or cardiovagal baroreflex sensitivity are altered at the onset of spontaneously occurring motor behavior, which was monitored with tibial nerve activity in paralyzed, decerebrate cats. CSNA exhibited a peak increase (126 ± 17%) immediately after exercise onset, followed by increases in HR and mean arterial pressure (MAP). With development of the pressor response, CSNA and HR decreased near baseline, although spontaneous motor activity was not terminated. Atropine methyl nitrate (0.1-0.2 mg/kg iv) with little central influence delayed the initial increase in HR but did not alter the response magnitudes of HR and CSNA, while atropine augmented the pressor response. The baroreflex-induced decreases in CSNA and HR elicited by brief occlusion of the abdominal aorta were challenged at the onset of spontaneous motor activity. Spontaneous motor activity blunted the baroreflex reduction in HR by aortic occlusion but did not alter the baroreflex inhibition of CSNA. Similarly, atropine abolished the baroreflex reduction in HR but did not influence the baroreflex inhibition of CSNA. Thus it is likely that central command increases CSNA and decreases cardiac vagal outflow at the onset of spontaneous motor activity while preserving baroreflex control of CSNA. Accordingly, central command must attenuate cardiovagal baroreflex sensitivity against an excess rise in MAP as estimated from the effect of muscarinic blockade. Copyright © 2016 the American Physiological Society.

  14. Activation of RAGE/STAT3 pathway by methylglyoxal contributes to spinal central sensitization and persistent pain induced by bortezomib. (United States)

    Wei, Jia-You; Liu, Cui-Cui; Ouyang, Han-Dong; Ma, Chao; Xie, Man-Xiu; Liu, Meng; Lei, Wan-Long; Ding, Huan-Huan; Wu, Shao-Ling; Xin, Wen-Jun


    Bortezomib is a first-line chemotherapeutic drug widely used for multiple myeloma and other nonsolid malignancies. Although bortezomib-induced persistent pain is easily diagnosed in clinic, the pathogenic mechanism remains unclear. Here, we studied this issue with use of a rat model of systemic intraperitoneal administration of bortezomib for consecutive 5days. Consisted with our previous study, we found that bortezomib treatment markedly induced mechanical allodynia in rats. Furthermore, we first found that bortezomib treatment significantly induced the upregulation of methylglyoxal in spinal dorsal horn of rats. Spinal local application of methylglyoxal also induced mechanical allodynia and central sensitization in normal rats. Moreover, administration of bortezomib upregulated the expression of receptors for advanced glycation end products (RAGE) and phosphorylated STAT3 (p-STAT3) in dorsal horn. Importantly, intrathecal injection of metformin, a known scavenger of methylglyoxal, significantly attenuated the upregulation of methylglyoxal and RAGE in dorsal horn, central sensitization and mechanical allodynia induced by bortezomib treatment, and blockage of RAGE also prevented the upregulation of p-STAT3, central sensitization and mechanical allodynia induced by bortezomib treatment. In addition, inhibition of STAT3 activity by S3I-201 attenuated bortezomib-induced mechanical allodynia and central sensitization. Local knockdown of STAT3 also ameliorated the mechanical allodynia induced by bortezomib administration. Our results suggest that accumulation of methylglyoxal may activate the RAGE/STAT3 signaling pathway in dorsal horn, and contributes to the spinal central sensitization and persistent pain induced by bortezomib treatment. Copyright © 2017 Elsevier Inc. All rights reserved.


    Directory of Open Access Journals (Sweden)

    Chennakesavan eKarthick


    Full Text Available Although several drugs revealed moderate amelioration of symptoms, none of them have sufficient potency to prevent or reverse the progression towards Alzheimer’s disease (AD pathology. Resveratrol (RSV, a polyphenolic compound has shown an outstanding therapeutic effect on a broad spectrum of diseases like age-associated neurodegeneration, inflammation etc. The present study was thus conducted to assess the therapeutic efficacy of RSV in ameliorating the deleterious effects of Ibotenic acid (IBO in male Wistar rats. Stereotactic intrahippocampal administration of IBO (5µg/µl lesioned rats impairs cholinergic transmission, learning and memory performance that is rather related to AD and thus chosen as a suitable model to understand the drug efficacy in preventing AD pathophysiology. Since IBO is an agonist of glutamate, it is expected to exhibit an excitotoxic effect by altering glutamatergic receptors like NMDA receptor. The current study displayed significant alterations in the mRNA expression of NR2A and NR2B subunits of NMDA receptors, and further it is surprising to note that cholinergic receptors decreased in expression particularly α7-nAChR with increased m1AChR. RSV administration (20mg/kg body weight, i.p significantly reduced these changes in IBO induced rats. Glutamatergic and cholinergic receptor alterations were associated with significant changes in the behavioral parameters of rats induced by IBO. While RSV improved spatial learning performance, attenuated immobility and improvised open field activity in IBO induced rats. NR2B activation in the present study might mediate cell death through oxidative stress that form the basis of abnormal behavioral pattern in IBO induced rats. Interestingly, RSV that could efficiently encounter oxidative stress have significantly decreased stress markers viz., nitrite, PCO, and MDA levels by enhancing antioxidant status. Histopathological analysis displayed significant reduction in the

  16. Attenuation of cadmium-induced decline in spatial, habituation and recognition memory by long-term administration of almond and walnut supplementation: Role of cholinergic function. (United States)

    Batool, Zehra; Agha, Faiza; Ahmad, Saara; Liaquat, Laraib; Tabassum, Saiqa; Khaliq, Saima; Anis, Lubna; Sajid, Irfan; Emad, Shaista; Perveen, Tahira; Haider, Saida


    Excessive exposure of cadmium which is regarded as a neurotoxin can stimulate aging process by inducing abnormality in neuronal function. It has been reported that supplementation of almond and walnut attenuate age-related memory loss. Present study was designed to investigate the weekly administration of cadmium for one month on learning and memory function with relation to cholinergic activity. Cadmium was administered at the dose of 50 mg/kg/week. Whereas, almond and walnut was supplemented at the dose of 400 mg/kg/day along with cadmium administration to separate set of rats. At the end of experiment, memory function was assessed by Morris water maze, open field test and novel object recognition test. Results of the present study showed that cadmium administration significantly reduced memory retention. Reduced acetylcholine levels and elevated acetyl cholinesterase activity were also observed in frontal cortex and hippocampus of cadmium treated rats. Malondialdehyde levels were also significantly increased following the administration of cadmium. Daily supplementation of almond and walnut for 28 days significantly attenuated cadmium-induced memory impairment in rats. Results of the present study are discussed in term of cholinergic activity in cadmium-induced memory loss and its attenuation by nuts supplementation in rats.

  17. Bi-annual report 1994-1995. Research and operational activities of Central Laboratory for Radiological Protection

    Energy Technology Data Exchange (ETDEWEB)



    BI-annual report of Central Laboratory for Radiological Protection, Warsaw, shows its activities in 1994-1995. The general information and organization of CLOR have been performed in the opening part of the report. The second part contains extended abstracts of scientific activities especially in: environmental radioactivity monitoring, supervision and control of the users of radioactive sources, dosimetry problems, calibration and standardization of dosimetric equipment, radiobiology and radiological hazard assessment. The report also includes the full list of publications of CLOR scientific staff issued in the period of 1994-1995.

  18. Cholinergic modulation of dopamine pathways through nicotinic acetylcholine receptors.

    NARCIS (Netherlands)

    de Kloet, S.F.; Mansvelder, H.D.; de Vries, T.J.


    Nicotine addiction is highly prevalent in current society and is often comorbid with other diseases. In the central nervous system, nicotine acts as an agonist for nicotinic acetylcholine receptors (nAChRs) and its effects depend on location and receptor composition. Although nicotinic receptors are


    Directory of Open Access Journals (Sweden)

    Ruxandra Irina POPESCU


    Full Text Available After a prolonged and complex process of reconstruction, extension and modernization, Central University Library "Carol I" in Bucharest has re-opened to public access in November 2001, bringing a new concept on what library services should mean. Under these auspicious circumstances, the library's offer has widened, the quality of services offered has improved, gradually displaying an interest in developing a closer relationship with its customers. The necessity of being more oriented to the marketing tools and techniques has become more apparent. Therefore, the top managers of the Central University Library have included in their three general development strategies produced so far, specific objectives, such as: an increase of the volume of paid serviced provided, promoting the services and work elaborated by its specialists through leaflets, presentations, albums, folders with press extracts. Beyond these actions with positive effects, the efforts of Central University Library for strengthening its position on the market of the providers of information services are diminished by the various malfunctions that characterize the marketing activity of this institution. Therefore, this work intends to contribute to the improvement of the marketing activity of the library by coming up with some solutions that could remove or at least diminish these weak points.

  20. rhoCentralRfFoam: An OpenFOAM solver for high speed chemically active flows - Simulation of planar detonations - (United States)

    Gutiérrez Marcantoni, L. F.; Tamagno, J.; Elaskar, S.


    A new solver developed within the framework of OpenFOAM 2.3.0, called rhoCentralRfFoam which can be interpreted like an evolution of rhoCentralFoam, is presented. Its use, performing numerical simulations on initiation and propagation of planar detonation waves in combustible mixtures H2-Air and H2-O2-Ar, is described. Unsteady one dimensional (1D) Euler equations coupled with sources to take into account chemical activity, are numerically solved using the Kurganov, Noelle and Petrova second order scheme in a domain discretized with finite volumes. The computational code can work with any number of species and its corresponding reactions, but here it was tested with 13 chemically active species (one species inert), and 33 elementary reactions. A gaseous igniter which acts like a shock-tube driver, and powerful enough to generate a strong shock capable of triggering exothermic chemical reactions in fuel mixtures, is used to start planar detonations. The following main aspects of planar detonations are here, treated: induction time of combustible mixtures cited above and required mesh resolutions; convergence of overdriven detonations to Chapman-Jouguet states; detonation structure (ZND model); and the use of reflected shocks to determine induction times experimentally. The rhoCentralRfFoam code was verified comparing numerical results and it was validated, through analytical results and experimental data.

  1. Age-related changes in nicotine response of cholinergic and non-cholinergic laterodorsal tegmental neurons: implications for the heightened adolescent susceptibility to nicotine addiction (United States)

    Christensen, Mark H.; Ishibashi, Masaru; Nielsen, Michael L.; Leonard, Christopher S.; Kohlmeier, Kristi A.


    The younger an individual starts smoking, the greater the likelihood that addiction to nicotine will develop, suggesting that neurobiological responses vary across age to the addictive component of cigarettes. Cholinergic neurons of the laterodorsal tegmental nucleus (LDT) are importantly involved in the development of addiction, however, the effects of nicotine on LDT neuronal excitability across ontogeny are unknown. Nicotinic effects on several parameters affecting LDT cells across different age groups were examined using calcium imaging and whole-cell patch clamping. Within the youngest age group (P7-P15), nicotine was found to induce larger intracellular calcium transients and inward currents. Nicotine induced a greater number of excitatory synaptic currents in the youngest animals, whereas larger amplitude inhibitory synaptic events were induced in cells from the oldest animals (P15-P34). Nicotine increased neuronal firing of cholinergic cells to a greater degree in younger animals, possibly linked to development associated differences found in nicotinic effects on action potential shape and afterhyperpolarization. We conclude that in addition to age-associated alterations of several properties expected to affect resting cell excitability, parameters affecting cell excitability are altered by nicotine differentially across ontogeny. Taken together, our data suggest that nicotine induces a larger excitatory response in cholinergic LDT neurons from the youngest animals, which could result in a greater excitatory output from these cells to target regions involved in development of addiction. Such output would be expected to be promotive of addiction; therefore, ontogenetic differences in nicotine-mediated increases in the excitability of the LDT could contribute to the differential susceptibility to nicotine addiction seen across age. PMID:24863041

  2. Central nervous system complications and neuroradiological findings in children with chronic active Epstein-Barr virus infection. (United States)

    Ishikawa, Nobutsune; Kawaguchi, Hiroshi; Nakamura, Kazuhiro; Kobayashi, Masao


    Although many neurological complications have been described in acute Epstein-Barr virus infection, few reports have discussed the central nervous system complications in chronic active Epstein-Barr virus (CAEBV) infection. We retrospectively surveyed the medical records of 14 patients with CAEBV infection in our institute. Neuroradiological studies were performed in 10 of these patients. Five had no neurological symptoms, whereas two presented with posterior reversible encephalopathy syndrome, one presented with basal ganglia calcification, and one presented with falx cerebri hemorrhage. Although both of the posterior reversible encephalopathy syndrome cases developed epilepsy several years after recovering from prolonged neurological deterioration, the others had no neurological sequelae. This study revealed that various central nervous system complications may occur during the clinical course in pediatric CAEBV patients. © 2012 The Authors. Pediatrics International © 2012 Japan Pediatric Society.

  3. Characterizing the subsurface geology in and around the U.S. Army Camp Stanley Storage Activity, south-central Texas (United States)

    Blome, Charles D.; Clark, Allan K.


    Several U.S. Geological Survey projects, supported by the National Cooperative Geologic Mapping Program, have used multi-disciplinary approaches over a 14-year period to reveal the surface and subsurface geologic frameworks of the Edwards and Trinity aquifers of central Texas and the Arbuckle-Simpson aquifer of south-central Oklahoma. Some of the project achievements include advancements in hydrostratigraphic mapping, three-dimensional subsurface framework modeling, and airborne geophysical surveys as well as new methodologies that link geologic and groundwater flow models. One area where some of these milestones were achieved was in and around the U.S. Army Camp Stanley Storage Activity, located in north­western Bexar County, Texas, about 19 miles north­west of downtown San Antonio.

  4. Hook-up of GluA2, GRIP and liprin-α for cholinergic muscarinic receptor-dependent LTD in the hippocampus

    Directory of Open Access Journals (Sweden)

    Wu Long-Jun


    Full Text Available Abstract The molecular mechanism underlying muscarinic acetylcholine receptor-dependent LTD (mAChR-LTD in the hippocampus is less studied. In a recent study, a novel mechanism is described. The induction of mAChR-LTD required the activation of protein tyrosine phosphatase (PTP, and the expression was mediated by AMPA receptor endocytosis via interactions between GluA2, GRIP and liprin-α. The hook-up of these proteins may result in the recruitment of leukocyte common antigen-related receptor (LAR, a PTP that is known to be involved in AMPA receptor trafficking. Interestingly, the similar molecular interaction cannot be applied to mGluR-LTD, despite the fact that the same G-protein involved in LTD is activated by both mAChR and mGluR. This discovery provides key molecular insights for cholinergic dependent cognitive function, and mAChR-LTD can serve as a useful cellular model for studying the roles of cholinergic mechanism in learning and memory.

  5. Iodo-QNB cortical binding and brain perfusion: effects of a cholinergic basal forebrain lesion in the rat

    Energy Technology Data Exchange (ETDEWEB)

    Sorger, Dietlind E-mail:; Kaempfer, Ingrid; Schliebs, Reinhard; Rossner, Steffen; Dannenberg, Claudia; Knapp, Wolfram H


    This study deals with the question of whether in vivo application of [{sup 125}I]iodo-quinuclidinylbenzilate (QNB) is able to demonstrate changes in cortical muscarinic receptor density induced by a cholinergic immunolesion of the rat basal forebrain cholinergic system, and whether the potential effects on IQNB distribution in vivo are also associated with effects on regional cerebral perfusion. Immunolesioned and control animals were injected with (R,S) [{sup 125}I]iodo-QNB and with [{sup 99m}Tc]-d,l-hexamethylpropyleneamine oxime (HMPAO). The cerebral distribution of both tracers was imaged using double tracer autoradiography. Impaired cholinergic transmission was paralleled by a 10-15% increase of [{sup 125}I]iodo-QNB binding in the regions of cortex and hippocampus. The local cerebral blood flow remained unchanged after cholinergic lesion.

  6. Nicotine Increases Codeine Analgesia Through the Induction of Brain CYP2D and Central Activation of Codeine to Morphine. (United States)

    McMillan, Douglas M; Tyndale, Rachel F


    CYP2D metabolically activates codeine to morphine, which is required for codeine analgesia. Permeability across the blood-brain barrier, and active efflux, suggests that initial morphine in the brain after codeine is due to brain CYP2D metabolism. Human CYP2D is higher in the brains, but not in the livers, of smokers and 7-day nicotine treatment induces rat brain, but not hepatic, CYP2D. The role of nicotine-induced rat brain CYP2D in the central metabolic activation of peripherally administered codeine and resulting analgesia was investigated. Rats received 7-day nicotine (1 mg/kg subcutaneously) and/or a single propranolol (CYP2D mechanism-based inhibitor; 20 μg intracerebroventricularly) pretreatment, and then were tested for analgesia and drug levels following codeine (20 mg/kg intraperitoneally) or morphine (3.5 mg/kg intraperitoneally), matched for peak analgesia. Nicotine increased codeine analgesia (1.59X AUC(0-30 min) vs vehicle; p0.1). Nicotine increased, while propranolol decreased, brain, but not plasma, morphine levels, and analgesia correlated with brain (p0.4), morphine levels after codeine. Pretreatments did not alter baseline or morphine analgesia. Here we show that brain CYP2D alters drug response despite the presence of substantial first-pass metabolism of codeine and further that nicotine induction of brain CYP2D increases codeine response in vivo. Thus variation in brain CYP2D activity, due to genetics or environment, may contribute to individual differences in response to centrally acting substrates. Exposure to nicotine may increase central drug metabolism, not detected peripherally, contributing to altered drug efficacy, onset time, and/or abuse liability.


    Energy Technology Data Exchange (ETDEWEB)

    Zhang Binbin; Burrows, David N.; Meszaros, Peter; Falcone, Abraham D. [Department of Astronomy and Astrophysics, Pennsylvania State University, University Park, PA 16802 (United States); Zhang Bing [Department of Physics, University of Nevada, Las Vegas, NV 89154 (United States); Wang Xiangyu [Department of Astronomy, Nanjing University, Nanjing 210093 (China); Stratta, Giulia; D' Elia, Valerio [ASI-Science Data Center, Via Galileo Galilei, I-00044 Frascati (Italy); Frederiks, Dmitry; Golenetskii, Sergey [Ioffe Physico-Technical Institute, Laboratory for Experimental Astrophysics, 26 Polytekhnicheskaya, St Petersburg 194021 (Russian Federation); Cummings, Jay R.; Barthelmy, Scott D.; Gehrels, Neil [NASA Goddard Space Flight Center, Greenbelt, MD 20771 (United States); Norris, Jay P., E-mail: [Physics Department, Boise State University, 1910 University Drive, Boise, ID 83725 (United States)


    The double burst, GRB 110709B, triggered the Swift/Burst Alert Telescope (BAT) twice at 21:32:39 UT and 21:43:45 UT, respectively, on 2011 July 9. This is the first time we observed a gamma-ray burst (GRB) with two BAT triggers. In this paper, we present simultaneous Swift and Konus-WIND observations of this unusual GRB and its afterglow. If the two events originated from the same physical progenitor, their different time-dependent spectral evolution suggests they must belong to different episodes of the central engine, which may be a magnetar-to-BH accretion system.

  8. Analysis of preference and frequency of physical activity in girls aged 7-14 from canton Central Bosnia

    Directory of Open Access Journals (Sweden)

    Karakaš Sead


    Full Text Available School and extracurricular sections are aim to quality development of morphological, motor skills and functional abilities of children. In order to preserve the health, well­being of the individual, but also the entire population increasingly points to the importance and necessity of active lifestyle with regular physical activity throughout the life span, both in times of childhood and adolescence and in the adult age. The purpose of the research is to analyze the preferences and frequency of physical exercise in girls aged 7-14 years with the Central Bosnia Canton. The sample was composed of 291 child, female, ages 7-14 years, various primary schools in Central Bosnia Canton. The respondents are members of the entertainment football school. The survey was conducted in 2014 in Travnik. Were determined by morphological measurements (height and weight, early in the morning, on the basis of which calculated the body mass index. After measuring the girls met the anonymous questionnaire consisted of eight questions from the questionnaire 'Fels physical activity questionnaire for children' (FPAQ. On the basis of the questionnaire were calculated indices in the field of sports (IS, leisure time (ISVs, housework (ICP and the total score of physical activity (UTA. According to the level of physical activity according to the Likert scale, the largest proportion of girls who are mainly engaged in physical activity 167 (57.39%, while the total sample there is no proportion of girls who are in no way involved in physical activity. Today's daily habits are changing due to new forms of entertainment (TV, Internet, video games, etc. which consequently leads to a growing number of children and adolescents with overweight and obesity. Therefore, there is a concern that new habits and a sedentary lifestyle have contributed to this phenomenon in recent years.

  9. The Central Hinge Link Truncation of the Antimicrobial Peptide Fowlicidin-3 Enhances Its Cell Selectivity without Antibacterial Activity Loss. (United States)

    Qu, Pei; Gao, Wei; Chen, Huixian; Li, Dan; Yang, Na; Zhu, Jian; Feng, Xingjun; Liu, Chunlong; Li, Zhongqiu


    Antimicrobial peptides (AMPs) have been paid considerable attention because of their broad-spectrum antimicrobial activity and a reduced possibility of the development of bacterial drug resistance. Fowlicidin-3 (Fow-3) is an identified type of chicken cathelicidin AMP that has exhibited considerable antimicrobial activity and cytotoxicity. To reduce cell toxicity and improve cell selectivity, several truncated peptides of fowlicidin-3, Fow-3(1-15), Fow-3(1-19), Fow-3(1-15-20-27), and Fow-3(20-27), were synthesized. Our results indicated that neither the N- nor C-terminal segment alone [Fow-3(1-15), Fow-3(1-19), Fow-3(20-27)] was sufficient to confer antibacterial activity. However, Fow-3(1-19) with the inclusion of the central hinge link (-AGIN-) retained substantial cell toxicity, which other analogs lost. Fow-3(1-15-20-27) displayed potent antimicrobial activity for a wide range of Gram-negative and Gram-positive bacteria and no obvious hemolytic activity or cytotoxicity. The central link region was shown to be critically important in the function of cell toxicity but was not relevant to antibacterial activity. Fow-3(1-15-20-27) maintained antibacterial activity in the presence of physiological concentrations of salts. The results from fluorescence spectroscopy, scanning electron microcopy, and transmission electron microcopy showed that Fow-3(1-15-20-27) as well as fowlicidin-3 killed bacterial cells by increasing membrane permeability and damaging the membrane envelope integrity. Fow-3(1-15-20-27) could be a promising antimicrobial agent for clinical application. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  10. Cholinergic neuronal lesions in the medial septum and vertical limb of the diagonal bands of Broca induce contextual fear memory generalization and impair acquisition of fear extinction. (United States)

    Knox, Dayan; Keller, Samantha M


    Previous research has shown that the ventral medial prefrontal cortex (vmPFC) and hippocampus (Hipp) are critical for extinction memory. Basal forebrain (BF) cholinergic input to the vmPFC and Hipp is critical for neural function in these substrates, which suggests BF cholinergic neurons may be critical for extinction memory. In order to test this hypothesis, we applied cholinergic lesions to different regions of the BF and observed the effects these lesions had on extinction memory. Complete BF cholinergic lesions induced contextual fear memory generalization, and this generalized fear was resistant to extinction. Animals with complete BF cholinergic lesions could not acquire cued fear extinction. Restricted cholinergic lesions in the medial septum and vertical diagonal bands of Broca (MS/vDBB) mimicked the effects that BF cholinergic lesions had on contextual fear memory generalization and acquisition of fear extinction. Cholinergic lesions in the horizontal diagonal band of Broca and nucleus basalis (hDBB/NBM) induced a small deficit in extinction of generalized contextual fear memory with no accompanying deficits in cued fear extinction. The results of this study reveal that MS/vDBB cholinergic neurons are critical for inhibition and extinction of generalized contextual fear memory, and via this process, may be critical for acquisition of cued fear extinction. Further studies delineating neural circuits and mechanisms through which MS/vDBB cholinergic neurons facilitate these emotional memory processes are needed. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

  11. Cholinergic neurodegeneration in an Alzheimer mouse model overexpressing amyloid-precursor protein with the Swedish-Dutch-Iowa mutations. (United States)

    Foidl, Bettina Maria; Do-Dinh, Patricia; Hutter-Schmid, Bianca; Bliem, Harald R; Humpel, Christian


    Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is mainly characterized by beta-amyloid (Aβ) plaque deposition, Tau pathology and dysfunction of the cholinergic system causing memory impairment. The aim of the present study was to examine (1) anxiety and cognition, (2) Aβ plaque deposition and (3) degeneration of cholinergic neurons in the nucleus basalis of Meynert (nbM) and cortical cholinergic innervation in an Alzheimer mouse model (APP_SweDI; overexpressing amyloid precursor protein (APP) with the Swedish K670N/M671L, Dutch E693Q, and Iowa D694N mutations). Our results show that 12-month-old APP_SweDI mice were more anxious and had more memory impairment. A large number of Aβ plaques were already visible at the age of 6 months and increased with age. A significant decrease in cholinergic neurons was seen in the transgenic mouse model in comparison to the wild-type mice, identified by immunohistochemistry against choline acetyltransferase (ChAT) and p75 neurotrophin receptor as well as by in situ hybridization. Moreover, a significant decrease in cortical cholinergic fiber density was found in the transgenic mice as compared to the wild-type. In the cerebral cortex of APP_SweDI mice, swollen cholinergic varicosities were seen in the vicinity of Aβ plaques. In conclusion, the present study shows that in an AD mouse model (APP_SweDI mice) a high Aβ plaque load in the cortex causes damage to cholinergic axons in the cortex, followed by subsequent retrograde-induced cell death of cholinergic neurons and some forms of compensatory processes. This degeneration was accompanied by enhanced anxiety and impaired cognition. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Activation of mTor Signaling by Gene Transduction to Induce Axon Regeneration in the Central Nervous System Following Neural Injury (United States)


    AWARD NUMBER: W81XWH-12-1-0051 TITLE: Activation of mTor Signaling by Gene Transduction to Induce Axon Regeneration in the Central Nervous System ...Central Nervous System Following Neural Injury 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-12-1-0051 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Robert...mature mammalian central nervous system (CNS), unlike the peripheral nervous system (PNS), is incapable of axon regeneration. There are currently two



    Liu, Jing Z.; Lewandowski, Beth; Karakasis, Chris; Yao, Bing; Siemionow, Vlodek; Sahgal, Vinod; Yue, Guang H.


    Accumulating evidence suggests that the overall level of cortical activation controlling a voluntary motor task that leads to significant muscle fatigue does not decrease as much as the activation level of the motoneuron pool projecting to the muscle. One possible explanation for this “muscle fatigue>cortical fatigue” phenomenon is that the brain is an organ with built-in redundancies: it has multiple motor centers and parallel pathways, and the center of activation may shift from one locatio...

  14. The Central Metabolism Regulator EIIAGlc Switches Salmonella from Growth Arrest to Acute Virulence through Activation of Virulence Factor Secretion

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    Alain Mazé


    Full Text Available The ability of Salmonella to cause disease depends on metabolic activities and virulence factors. Here, we show that a key metabolic protein, EIIAGlc, is absolutely essential for acute infection, but not for Salmonella survival, in a mouse typhoid fever model. Surprisingly, phosphorylation-dependent EIIAGlc functions, including carbohydrate transport and activation of adenylate cyclase for global regulation, do not explain this virulence phenotype. Instead, biochemical studies, in vitro secretion and translocation assays, and in vivo genetic epistasis experiments suggest that EIIAGlc binds to the type three secretion system 2 (TTSS-2 involved in systemic virulence, stabilizes its cytoplasmic part including the crucial TTSS-2 ATPase, and activates virulence factor secretion. This unexpected role of EIIAGlc reveals a striking direct link between central Salmonella metabolism and a crucial virulence mechanism.

  15. Endogenous GLP-1 mediates postprandial reductions in activation in central reward and satiety areas in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Ten Kulve, Jennifer S; Veltman, Dick J; van Bloemendaal, Liselotte


    -lowering agents. We assessed CNS activation, defined as blood oxygen level dependent (BOLD) signal, in response to food pictures in obese patients with type 2 diabetes (n = 20) and healthy lean individuals (n = 20) using functional magnetic resonance imaging (fMRI). fMRI was performed in the fasted state......Aims/hypothesis The central nervous system (CNS) is a major player in the regulation of food intake. The gut hormone glucagon-like peptide-1 (GLP-1) has been proposed to have an important role in this regulation by relaying information about nutritional status to the CNS. We hypothesised...... was determined by block randomisation. The primary outcome was the difference in BOLD signal, i.e. in CNS activation, in predefined regions in the CNS in response to viewing food pictures. Results All patients were included in the analyses. Patients with type 2 diabetes showed increased CNS activation in CNS...

  16. White Matter Damage in the Cholinergic System Contributes to Cognitive Impairment in Subcortical Vascular Cognitive Impairment, No Dementia. (United States)

    Liu, Qing; Zhu, Zude; Teipel, Stefan J; Yang, Jianwei; Xing, Yi; Tang, Yi; Jia, Jianping


    Cholinergic deficiency has been implicated in the pathogenesis of vascular cognitive impairment (VCI), but the extent of involvement and underlying mechanism remain unclear. In this study, targeting the early stage of VCI, we determined regional atrophy within the basal forebrain and deficiency in cholinergic pathways in 25 patients with vascular cognitive impairment no dementia (VCIND) compared to 24 healthy elderly subjects. By applying stereotaxic cytoarchitectonic maps of the nucleus basalis of Meynert (NbM), no significant atrophy was identified in VCIND. Using probabilistic tractography analysis, our study tracked the two major white matter tracks which map to cholinergic pathways. We identified significantly lower fractional anisotropy (FA) in VCIND. Mediation analysis demonstrated that FA in the tracked pathways could fully account for the executive dysfunction, and partly mediate the memory and global cognition impairment. Our study suggests that the fibers mapped to the cholinergic pathways, but not the NbM, are significantly impaired in VCIND. MRI-based in vivo tracking of cholinergic pathways together with NbM measurement may become a valuable in vivo marker for evaluating the cholinergic system in cognitive disorders.

  17. Mouse brain distribution of a carbon-11 labeled vesamicol derivative: presynaptic marker of cholinergic neurons. (United States)

    Kilbourn, M R; Jung, Y W; Haka, M S; Gildersleeve, D L; Kuhl, D E; Wieland, D M


    The regional mouse brain distribution of a new carbon-11 labeled derivative of vesamicol, [11C]-5-(N-methylamino)benzovesamicol [( 11C]MABV) is reported. Radiotracer concentrations in vivo are in the rank order of striatum greater than cortex greater than hippocampus greater than hypothalamus greater than cerebellum, consistent with reported distributions of other presynaptic cholinergic neuronal markers. In time course studies, striatum/cerebellum and cortex/cerebellum ratios for (-)-[11C]MABV continue to increase to values of 13 and 5, respectively, 75 min after i.v. injection of [11C]MABV. The specific binding in striatum and cortex is lowered by pretreatment with (+/-)-vesamicol, and shows stereoselectivity with lower uptake and lower ratios for the (+)-enantiomer. (-)-enantiomer. (-)-[11C]MABV is proposed as a positron-emitting radioligand for the in vivo study of presynaptic cholinergic neurons.

  18. Antibacterial Activity, Antioxidant Effect and Chemical Composition of Propolis from the Región del Maule, Central Chile. (United States)

    Nina, Nélida; Quispe, Cristina; Jiménez-Aspee, Felipe; Theoduloz, Cristina; Feresín, Gabriela Egly; Lima, Beatriz; Leiva, Elba; Schmeda-Hirschmann, Guillermo


    Propolis is commercialized in Chile as an antimicrobial agent. It is obtained mainly from central and southern Chile, but is used for the same purposes regardless of its origin. To compare the antimicrobial effect, the total phenolic (TP), the total flavonoid (TF) content and the phenolic composition, 19 samples were collected in the main production centers in the Región del Maule, Chile. Samples were extracted with MeOH and assessed for antimicrobial activity against Gram (+) and Gram (-) bacteria. TP and TF content, antioxidant activity by the DPPH, FRAP and TEAC methods were also determined. Sample composition was assessed by HPLD-DAD-ESI-MS/MS. Differential compounds in the samples were isolated and characterized. The antimicrobial effect of the samples showed MICs ranging from 31.5 to > 1000 µg/mL. Propolis from the central valley was more effective as antibacterial than those from the coastal area or Andean slopes. The samples considered of interest (MIC ≤ 62.5 µg/mL) showed effect on Escherichia coli, Pseudomonas sp., Yersinia enterocolitica and Salmonella enteritidis. Two new diarylheptanoids, a diterpene, the flavonoids pinocembrin and chrysin were isolated and elucidated by spectroscopic and spectrometric means. Some 29 compounds were dereplicated by HPLC-MS and tentatively identified, including nine flavones/flavonol derivatives, one flavanone, eight dihydroflavonols and nine phenyl-propanoids. Propolis from the Región del Maule showed large variation in antimicrobial effect, antioxidant activity and composition. So far the presence of diarylheptanoids in samples from the coastal area of central Chile can be considered as a marker of a new type of propolis.

  19. Antibacterial Activity, Antioxidant Effect and Chemical Composition of Propolis from the Región del Maule, Central Chile

    Directory of Open Access Journals (Sweden)

    Nélida Nina


    Full Text Available Propolis is commercialized in Chile as an antimicrobial agent. It is obtained mainly from central and southern Chile, but is used for the same purposes regardless of its origin. To compare the antimicrobial effect, the total phenolic (TP, the total flavonoid (TF content and the phenolic composition, 19 samples were collected in the main production centers in the Región del Maule, Chile. Samples were extracted with MeOH and assessed for antimicrobial activity against Gram (+ and Gram (− bacteria. TP and TF content, antioxidant activity by the DPPH, FRAP and TEAC methods were also determined. Sample composition was assessed by HPLD-DAD-ESI-MS/MS. Differential compounds in the samples were isolated and characterized. The antimicrobial effect of the samples showed MICs ranging from 31.5 to > 1000 µg/mL. Propolis from the central valley was more effective as antibacterial than those from the coastal area or Andean slopes. The samples considered of interest (MIC ≤ 62.5 µg/mL showed effect on Escherichia coli, Pseudomonas sp., Yersinia enterocolitica and Salmonella enteritidis. Two new diarylheptanoids, a diterpene, the flavonoids pinocembrin and chrysin were isolated and elucidated by spectroscopic and spectrometric means. Some 29 compounds were dereplicated by HPLC-MS and tentatively identified, including nine flavones/flavonol derivatives, one flavanone, eight dihydroflavonols and nine phenyl-propanoids. Propolis from the Región del Maule showed large variation in antimicrobial effect, antioxidant activity and composition. So far the presence of diarylheptanoids in samples from the coastal area of central Chile can be considered as a marker of a new type of propolis.

  20. Phosphorus Availability and Release Pattern from Activated Dolomite Phosphate Rock in Central Florida. (United States)

    Mao, Xiaoyun; Lu, Qin; Mo, Wei; Xin, Xiaoping; Chen, Xian; He, Zhenli


    In this study, novel technology was developed to convert dolomite phosphate rock (DPR) into slow release P fertilizers. The DPR was powdered to <100 mesh and activated with organic molecules under optimal reaction conditions. As compared to original DPR, available P, estimated by water-soluble P released from the three DPRs activated with three types of organic molecules, increased by 6.86, 3.32, and 7.46 times, respectively. Phosphorus supply from the activated DPRs was greater than that of superphosphates (SP). Use of activated DPRs resulted in a significant increase in plant biomass of maize (Zea mays) and millet (Pennisetum glaucum) (succeeding crop), as compared to original DPR, and displayed better effectiveness than monoammonium phosphate or SP. The XRD and FTIR analyses showed that activation did not change the crystal structure of DPR, but the interactions between organic molecules and the P-bearing minerals stimulated P release from DPR.

  1. Active and latent tuberculosis in prisoners in the Central-West Region of Brazil

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    Anderson Oliveira Estevan


    Full Text Available Introduction Jailed populations exhibit high rates of tuberculosis (TB infection and active disease. Methods A cross-sectional study was performed to estimate the prevalence of latent and active TB and to identify factors associated with latent infection in inmates. Results The prevalence of latent TB was 49%, and the prevalence of active TB was 0.4%. The presence of a Bacille Calmette-Guérin (BCG scar (prevalence ratio (PR=1.65; 95% confidence interval (CI: 1.09-2.50; p=0.0162 and the World Health Organization (WHO score for active TB in prisons (PR=1.07; 95% CI: 1.01-1.14; p=0.0181 were correlated with infection. Conclusions The identification of associated factors and the prevalence of latent and active TB allows the development of plans to control this disease in jails.