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Sample records for central serotonergic neurons

  1. Subset specification of central serotonergic neurons

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    Marten P Smidt

    2013-10-01

    Full Text Available The last decade the serotonin (5-hydroxytryptamine; 5-HT system has received enormous attention due to its role in regulation of behavior, exemplified by the discovery that increased 5-HT tone in the central nervous system is able to alleviate affective disorders. Here, we review the developmental processes, with a special emphasis on subset specification, leading to the formation of the 5-HT system in the brain. Molecular classification of 5-HT neuronal groups leads to the definition of two independent rostral groups positioned in rhombomere 1 and 2/3 and a caudal group in rhombomere 5-8. In addition, more disperse refinement of these subsets is present as shown by the selective expression of the 5-HT1A autoreceptor, indicating functional diversity between 5-HT subsets. The functional significance of the molecular coding differences is not well known and the molecular basis of described specific connectivity patterns remain to be elucidated. Recent developments in genetic lineage tracing models will provide these data and form a major step-up towards the full understanding of the importance of developmental programming and function of 5-HT neuronal subsets.

  2. Abnormal anxiety- and depression-like behaviors in mice lacking both central serotonergic neurons and pancreatic islet cells.

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    Jia, Yun-Fang; Song, Ning-Ning; Mao, Rong-Rong; Li, Jin-Nan; Zhang, Qiong; Huang, Ying; Zhang, Lei; Han, Hui-Li; Ding, Yu-Qiang; Xu, Lin

    2014-01-01

    Dysfunction of central serotonin (5-HT) system has been proposed to be one of the underlying mechanisms for anxiety and depression, and the association of diabetes mellitus and psychiatric disorders has been noticed by the high prevalence of anxiety/depression in patients with diabetes mellitus. This promoted us to examine these behaviors in central 5-HT-deficient mice and those also suffering with diabetes mellitus. Mice lacking either 5-HT or central serotonergic neurons were generated by conditional deletion of Tph2 or Lmx1b respectively. Simultaneous depletion of both central serotonergic neurons and pancreatic islet cells was achieved by administration of diphtheria toxin (DT) in Pet1-Cre;Rosa26-DT receptor (DTR) mice. The central 5-HT-deficient mice showed reduced anxiety-like behaviors as they spent more time in and entered more often into the light box in the light/dark box test compared with controls; similar results were observed in the elevated plus maze test. However, they displayed no differences in the immobility time of the forced swimming and tail suspension tests suggesting normal depression-like behaviors in central 5-HT-deficient mice. As expected, DT-treated Pet1-Cre;Rosa26-DTR mice lacking both central serotonergic neurons and pancreatic islet endocrine cells exhibited several classic diabetic symptoms. Interestingly, they displayed increased anxiety-like behaviors but reduced immobility time in the forced swimming and tail suspension tests. Furthermore, the hippocampal neurogenesis was dramatically enhanced in these mice. These results suggest that the deficiency of central 5-HT may not be sufficient to induce anxiety/depression-like behaviors in mice, and the enhanced hippocampal neurogenesis may contribute to the altered depression-like behaviors in the 5-HT-deficient mice with diabetes. Our current investigation provides understanding the relationship between diabetes mellitus and psychiatric disorders.

  3. Abnormal anxiety- and depression-like behaviors in mice lacking both central serotonergic neurons and pancreatic islet cells

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    Yun-Fang eJia

    2014-09-01

    Full Text Available Dysfunction of central serotonin (5-HT system has been proposed to be one of the underlying mechanisms for anxiety and depression, and the association of diabetes mellitus and psychiatric disorders has been noticed by the high prevalence of anxiety/depression in patients with diabetes mellitus. This promoted us to examine these behaviors in central 5-HT-deficient mice and those also suffering with diabetes mellitus. Mice lacking either 5-HT or central serotonergic neurons were generated by conditional deletion of Tph2 or Lmx1b respectively. Simultaneous depletion of both central serotonergic neurons and pancreatic islet cells was achieved by administration of diphtheria toxin (DT in Pet1-Cre;Rosa26-DT receptor (DTR mice. The central 5-HT-deficient mice showed reduced anxiety-like behaviors as they spent more time in and entered more often into the light box in the light/dark box test compared with controls; similar results were observed in the elevated plus maze test. However, they displayed no differences in the immobility time of the forced swimming and tail suspension tests suggesting normal depression-like behaviors in central 5-HT-deficient mice. As expected, DT-treated Pet1-Cre;Rosa26-DTR mice lacking both central serotonergic neurons and pancreatic islet endocrine cells exhibited several classic diabetic symptoms. Interestingly, they displayed increased anxiety-like behaviors but reduced immobility time in the forced swimming and tail suspension tests. Furthermore, the hippocampal neurogenesis was dramatically enhanced in these mice. These results suggest that the deficiency of central 5-HT may not be sufficient to induce anxiety/depression-like behaviors in mice, and the enhanced hippocampal neurogenesis may contribute to the altered depression-like behaviors in the 5-HT-deficient mice with diabetes. Our current investigation provides a novel insight into understanding the relationship between diabetes mellitus and psychiatric disorders.

  4. Selective serotonergic excitation of callosal projection neurons

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    Daniel eAvesar

    2012-03-01

    Full Text Available Serotonin (5-HT acting as a neurotransmitter in the cerebral cortex is critical for cognitive function, yet how 5-HT regulates information processing in cortical circuits is not well understood. We tested the serotonergic responsiveness of layer 5 pyramidal neurons (L5PNs of the mouse medial prefrontal cortex (mPFC, and found 3 distinct response types: long-lasting 5-HT1A (1A receptor-dependent inhibitory responses (84% of L5PNs, 5-HT2A (2A receptor-dependent excitatory responses (9%, and biphasic responses in which 2A-dependent excitation followed brief inhibition (5%. Relative to 5-HT-inhibited neurons, those excited by 5-HT had physiological properties characteristic of callosal/commissural (COM neurons that project to the contralateral cortex. We tested whether serotonergic responses in cortical pyramidal neurons are correlated with their axonal projection pattern using retrograde fluorescent labeling of COM and corticopontine-projecting (CPn neurons. 5-HT generated excitatory or biphasic responses in all 5-HT-responsive layer 5 COM neurons. Conversely, CPn neurons were universally inhibited by 5-HT. Serotonergic excitation of COM neurons was blocked by the 2A antagonist MDL 11939, while serotonergic inhibition of CPn neurons was blocked by the 1A antagonist WAY 100635, confirming a role for these two receptor subtypes in regulating pyramidal neuron activity. Selective serotonergic excitation of COM neurons was not layer-specific, as COM neurons in layer 2/3 were also selectively excited by 5-HT relative to their non-labeled pyramidal neuron neighbors. Because neocortical 2A receptors are implicated in the etiology and pathophysiology of schizophrenia, we propose that COM neurons may represent a novel cellular target for intervention in psychiatric disease.

  5. Central serotonergic neurons activate and recruit thermogenic brown and beige fat and regulate glucose and lipid homeostasis

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    McGlashon, Jacob M; Gorecki, Michelle C; Kozlowski, Amanda E;

    2015-01-01

    diphtheria toxin receptor (DTR) was selectively expressed in central 5-HT neurons. Treatment with diphtheria toxin (DT) eliminated 5-HT neurons and caused loss of thermoregulation, brown adipose tissue (BAT) steatosis, and a >50% decrease in uncoupling protein 1 (Ucp1) expression in BAT and inguinal white...... glucose and lipid homeostasis, in part through recruitment and metabolic activation of brown and beige adipocytes....

  6. Tetracycline inducible gene manipulation in serotonergic neurons.

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    Tillmann Weber

    Full Text Available The serotonergic (5-HT neuronal system has important and diverse physiological functions throughout development and adulthood. Its dysregulation during development or later in adulthood has been implicated in many neuropsychiatric disorders. Transgenic animal models designed to study the contribution of serotonergic susceptibility genes to a pathological phenotype should ideally allow to study candidate gene overexpression or gene knockout selectively in serotonergic neurons at any desired time during life. For this purpose, conditional expression systems such as the tet-system are preferable. Here, we generated a transactivator (tTA mouse line (TPH2-tTA that allows temporal and spatial control of tetracycline (Ptet controlled transgene expression as well as gene deletion in 5-HT neurons. The tTA cDNA was inserted into a 196 kb PAC containing a genomic mouse Tph2 fragment (177 kb by homologous recombination in E. coli. For functional analysis of Ptet-controlled transgene expression, TPH2-tTA mice were crossed to a Ptet-regulated lacZ reporter line (Ptet-nLacZ. In adult double-transgenic TPH2-tTA/Ptet-nLacZ mice, TPH2-tTA founder line L62-20 showed strong serotonergic β-galactosidase expression which could be completely suppressed with doxycycline (Dox. Furthermore, Ptet-regulated gene expression could be reversibly activated or inactivated when Dox was either withdrawn or added to the system. For functional analysis of Ptet-controlled, Cre-mediated gene deletion, TPH2-tTA mice (L62-20 were crossed to double transgenic Ptet-Cre/R26R reporter mice to generate TPH2-tTA/Ptet-Cre/R26R mice. Without Dox, 5-HT specific recombination started at E12.5. With permanent Dox administration, Ptet-controlled Cre-mediated recombination was absent. Dox withdrawal either postnatally or during adulthood induced efficient recombination in serotonergic neurons of all raphe nuclei, respectively. In the enteric nervous system, recombination could not be detected. We

  7. Activity of Raphé Serotonergic Neurons Controls Emotional Behaviors

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    Anne Teissier

    2015-12-01

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

  8. Effect of sex steroid hormones on the number of serotonergic neurons in rat dorsal raphe nucleus.

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    Kunimura, Yuyu; Iwata, Kinuyo; Iijima, Norio; Kobayashi, Makito; Ozawa, Hitoshi

    2015-05-01

    Disorders caused by the malfunction of the serotonergic system in the central nervous system show sex-specific prevalence. Many studies have reported a relationship between sex steroid hormones and the brain serotonergic system; however, the interaction between sex steroid hormones and the number of brain neurons expressing serotonin has not yet been elucidated. In the present study, we determined whether sex steroid hormones altered the number of serotonergic neurons in the dorsal raphe nucleus (DR) of adult rat brains. Animals were divided into five groups: ovariectomized (OVX), OVX+low estradiol (E2), OVX+high E2, castrated males, and intact males. Antibodies against 5-hydroxytryptamine (5-HT, serotonin) and tryptophan hydroxylase (Tph), an enzyme for 5-HT synthesis, were used as markers of 5-HT neurons, and the number of 5-HT-immunoreactive (ir) or Tph-ir cells was counted. We detected no significant differences in the number of 5-HT-ir or Tph-ir cells in the DR among the five groups. By contrast, the intensity of 5-HT-ir showed significant sex differences in specific subregions of the DR independent of sex steroid levels, suggesting that the manipulation of sex steroid hormones after maturation does not affect the number and intensive immunostaining of serotonergic neurons in rat brain. Our results suggest that, the sexual dimorphism observed in the serotonergic system is due to factors such as 5-HT synthesis, transportation, and degradation but not to the number of serotonergic neurons.

  9. A Single Pair of Serotonergic Neurons Counteracts Serotonergic Inhibition of Ethanol Attraction in Drosophila.

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    Xu, Li; He, Jianzheng; Kaiser, Andrea; Gräber, Nikolas; Schläger, Laura; Ritze, Yvonne; Scholz, Henrike

    2016-01-01

    Attraction to ethanol is common in both flies and humans, but the neuromodulatory mechanisms underlying this innate attraction are not well understood. Here, we dissect the function of the key regulator of serotonin signaling-the serotonin transporter-in innate olfactory attraction to ethanol in Drosophila melanogaster. We generated a mutated version of the serotonin transporter that prolongs serotonin signaling in the synaptic cleft and is targeted via the Gal4 system to different sets of serotonergic neurons. We identified four serotonergic neurons that inhibit the olfactory attraction to ethanol and two additional neurons that counteract this inhibition by strengthening olfactory information. Our results reveal that compensation can occur on the circuit level and that serotonin has a bidirectional function in modulating the innate attraction to ethanol. Given the evolutionarily conserved nature of the serotonin transporter and serotonin, the bidirectional serotonergic mechanisms delineate a basic principle for how random behavior is switched into targeted approach behavior.

  10. Inducible gene manipulations in brain serotonergic neurons of transgenic rats.

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    Tillmann Weber

    Full Text Available The serotonergic (5-HT system has been implicated in various physiological processes and neuropsychiatric disorders, but in many aspects its role in normal and pathologic brain function is still unclear. One reason for this might be the lack of appropriate animal models which can address the complexity of physiological and pathophysiological 5-HT functioning. In this respect, rats offer many advantages over mice as they have been the animal of choice for sophisticated neurophysiological and behavioral studies. However, only recently technologies for the targeted and tissue specific modification of rat genes - a prerequisite for a detailed study of the 5-HT system - have been successfully developed. Here, we describe a rat transgenic system for inducible gene manipulations in 5-HT neurons. We generated a Cre driver line consisting of a tamoxifen-inducible CreERT2 recombinase under the control of mouse Tph2 regulatory sequences. Tissue-specific serotonergic Cre recombinase expression was detected in four transgenic TPH2-CreERT2 rat founder lines. For functional analysis of Cre-mediated recombination, we used a rat Cre reporter line (CAG-loxP.EGFP, in which EGFP is expressed after Cre-mediated removal of a loxP-flanked lacZ STOP cassette. We show an in-depth characterisation of this rat Cre reporter line and demonstrate its applicability for monitoring Cre-mediated recombination in all major neuronal subpopulations of the rat brain. Upon tamoxifen induction, double transgenic TPH2-CreERT2/CAG-loxP.EGFP rats show selective and efficient EGFP expression in 5-HT neurons. Without tamoxifen administration, EGFP is only expressed in few 5-HT neurons which confirms minimal background recombination. This 5-HT neuron specific CreERT2 line allows Cre-mediated, inducible gene deletion or gene overexpression in transgenic rats which provides new opportunities to decipher the complex functions of the mammalian serotonergic system.

  11. The serotonergic central nervous system of the Drosophila larva: anatomy and behavioral function.

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    Annina Huser

    Full Text Available The Drosophila larva has turned into a particularly simple model system for studying the neuronal basis of innate behaviors and higher brain functions. Neuronal networks involved in olfaction, gustation, vision and learning and memory have been described during the last decade, often up to the single-cell level. Thus, most of these sensory networks are substantially defined, from the sensory level up to third-order neurons. This is especially true for the olfactory system of the larva. Given the wealth of genetic tools in Drosophila it is now possible to address the question how modulatory systems interfere with sensory systems and affect learning and memory. Here we focus on the serotonergic system that was shown to be involved in mammalian and insect sensory perception as well as learning and memory. Larval studies suggested that the serotonergic system is involved in the modulation of olfaction, feeding, vision and heart rate regulation. In a dual anatomical and behavioral approach we describe the basic anatomy of the larval serotonergic system, down to the single-cell level. In parallel, by expressing apoptosis-inducing genes during embryonic and larval development, we ablate most of the serotonergic neurons within the larval central nervous system. When testing these animals for naïve odor, sugar, salt and light perception, no profound phenotype was detectable; even appetitive and aversive learning was normal. Our results provide the first comprehensive description of the neuronal network of the larval serotonergic system. Moreover, they suggest that serotonin per se is not necessary for any of the behaviors tested. However, our data do not exclude that this system may modulate or fine-tune a wide set of behaviors, similar to its reported function in other insect species or in mammals. Based on our observations and the availability of a wide variety of genetic tools, this issue can now be addressed.

  12. The serotonergic central nervous system of the Drosophila larva: anatomy and behavioral function.

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    Huser, Annina; Rohwedder, Astrid; Apostolopoulou, Anthi A; Widmann, Annekathrin; Pfitzenmaier, Johanna E; Maiolo, Elena M; Selcho, Mareike; Pauls, Dennis; von Essen, Alina; Gupta, Tripti; Sprecher, Simon G; Birman, Serge; Riemensperger, Thomas; Stocker, Reinhard F; Thum, Andreas S

    2012-01-01

    The Drosophila larva has turned into a particularly simple model system for studying the neuronal basis of innate behaviors and higher brain functions. Neuronal networks involved in olfaction, gustation, vision and learning and memory have been described during the last decade, often up to the single-cell level. Thus, most of these sensory networks are substantially defined, from the sensory level up to third-order neurons. This is especially true for the olfactory system of the larva. Given the wealth of genetic tools in Drosophila it is now possible to address the question how modulatory systems interfere with sensory systems and affect learning and memory. Here we focus on the serotonergic system that was shown to be involved in mammalian and insect sensory perception as well as learning and memory. Larval studies suggested that the serotonergic system is involved in the modulation of olfaction, feeding, vision and heart rate regulation. In a dual anatomical and behavioral approach we describe the basic anatomy of the larval serotonergic system, down to the single-cell level. In parallel, by expressing apoptosis-inducing genes during embryonic and larval development, we ablate most of the serotonergic neurons within the larval central nervous system. When testing these animals for naïve odor, sugar, salt and light perception, no profound phenotype was detectable; even appetitive and aversive learning was normal. Our results provide the first comprehensive description of the neuronal network of the larval serotonergic system. Moreover, they suggest that serotonin per se is not necessary for any of the behaviors tested. However, our data do not exclude that this system may modulate or fine-tune a wide set of behaviors, similar to its reported function in other insect species or in mammals. Based on our observations and the availability of a wide variety of genetic tools, this issue can now be addressed.

  13. Central serotonergic and noradrenergic receptors in functional dyspepsia

    Institute of Scientific and Technical Information of China (English)

    S O'Mahony; TG Dinan; PW Keeling; ASB Chua

    2006-01-01

    Functional dyspepsia is a symptom complex characterised by upper abdominal discomfort or pain, early satiety,motor abnormalities, abdominal bloating and nausea in the absence of organic disease. The central nervous system plays an important role in the conducting and processing of visceral signals. Alterations in brain processing of pain, perception and affective responses may be key factors in the pathogenesis of functional dyspepsia. Central serotonergic and noradrenergic receptor systems are involved in the processing of motor,sensory and secretory activities of the gastrointestinal tract. Visceral hypersensitivity is currently regarded as the mechanism responsible for both motor alterations and abdominal pain in functional dyspepsia. Some studies suggest that there are alterations in central serotonergic and noradrenergic systems which may partially explain some of the symptoms of functional dyspepsia. Alterations in the autonomic nervous system may be implicated in the motor abnormalities and increases in visceral sensitivity in these patients.Noradrenaline is the main neurotransmitter in the sympathetic nervous system and again alterations in the functioning of this system may lead to changes in motor function. Functional dyspepsia causes considerable burden on the patient and society. The pathophysiology of functional dyspepsia is not fully understood but alterations in central processing by the serotonergic and noradrenergic systems may provide plausible explanations for at least some of the symptoms and offer possible treatment targets for the future.

  14. Serotonergic neurons of the Drosophila air-puff-stimulated flight circuit

    Indian Academy of Sciences (India)

    Sufia Sadaf; Gaiti Hasan

    2014-09-01

    Monoaminergic modulation of insect flight is well documented. Recently, we demonstrated that synaptic activity is required in serotonergic neurons for Drosophila flight. This requirement is during early pupal development, when the flight circuit is formed, as well as in adults. Using a Ca2+-activity-based GFP reporter, here we show that serotonergic neurons in both prothoracic and mesothoracic segments are activated upon air-puff-stimulated flight. Moreover ectopic activation of the entire serotonergic system by TrpA1, a heat activated cation channel, induces flight, even in the absence of an air-puff stimulus.

  15. Serotonergic neurons in the caudal raphe nuclei discharge in association with activity of masticatory muscles

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    Ribeiro-do-Valle L.E.

    1997-01-01

    Full Text Available There is a dense serotonergic projection from nucleus raphe pallidus and nucleus raphe obscurus to the trigeminal motor nucleus and serotonin exerts a strong facilitatory action on the trigeminal motoneurons. Some serotonergic neurons in these caudal raphe nuclei increase their discharge during feeding. The objective of the present study was to investigate the possibility that the activity of these serotonergic neurons is related to activity of masticatory muscles. Cats were implanted with microelectrodes and gross electrodes. Caudal raphe single neuron activity, electrocorticographic activity, and splenius, digastric and masseter electromyographic activities were recorded during active behaviors (feeding and grooming, during quiet waking and during sleep. Seven presumed serotonergic neurons were identified. These neurons showed a long duration action potential (>2.0 ms, and discharged slowly (2-7 Hz and very regularly (interspike interval coefficient of variation <0.3 during quiet waking. The activity of these neurons decreased remarkably during fast wave sleep (78-100%. Six of these neurons showed tonic changes in their activity positively related to digastric and/or masseter muscle activity but not to splenius muscle activity during waking. These data are consistent with the hypothesis that serotonergic neurons in the caudal raphe nuclei play an important role in the control of jaw movements

  16. Role of cholecystokinin and central serotonergic receptors in functional dyspepsia

    Institute of Scientific and Technical Information of China (English)

    Andrew Seng Boon Chua; PWN Keeling; TG Dinan

    2006-01-01

    Symptoms of functional dyspepsia are characterized by upper abdominal discomfort or pain, early satiety, postprandial fullness, bloating, nausea and vomiting. It is a chronic disorder, with symptoms more than 3 mo per year, and no evidence of organic diseases. Dysfunctional motility, altered visceral sensation, and psychosocial factors have all been identified as major pathophysiological mechanisms. It is believed that these pathophysiological mechanisms interact to produce the observed symptoms.Dyspepsia has been categorized into three subgroups based on dominant symptoms. Dysmotility-like dyspepsia describes a subgroup of patients whose symptom complex is usually related to a gastric sensorimotor dysfunction. The brain-gut peptide cholecystokinin (CCK)and serotonin (5-HT) share certain physiological effects.Both have been shown to decrease gastric emptying and affect satiety. Furthermore the CCK induced anorexia depended on serotonergic functions probably acting via central pathways. We believe that abnormalities of central serotonergic receptors functioning together with a hyper responsiveness to CCK or their interactions may be responsible for the genesis of symptoms in functional dyspepsia (FD).

  17. Central terminal sensitization of TRPV1 by descending serotonergic facilitation modulates chronic pain.

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    Kim, Yu Shin; Chu, Yuxia; Han, Liang; Li, Man; Li, Zhe; Lavinka, Pamela Colleen; Sun, Shuohao; Tang, Zongxiang; Park, Kyoungsook; Caterina, Michael J; Ren, Ke; Dubner, Ronald; Wei, Feng; Dong, Xinzhong

    2014-02-19

    The peripheral terminals of primary nociceptive neurons play an essential role in pain detection mediated by membrane receptors like TRPV1, a molecular sensor of heat and capsaicin. However, the contribution of central terminal TRPV1 in the dorsal horn to chronic pain has not been investigated directly. Combining primary sensory neuron-specific GCaMP3 imaging with a trigeminal neuropathic pain model, we detected robust neuronal hyperactivity in injured and uninjured nerves in the skin, soma in trigeminal ganglion, and central terminals in the spinal trigeminal nucleus. Extensive TRPV1 hyperactivity was observed in central terminals innervating all dorsal horn laminae. The central terminal TRPV1 sensitization was maintained by descending serotonergic (5-HT) input from the brainstem. Central blockade of TRPV1 or 5-HT/5-HT3A receptors attenuated central terminal sensitization, excitatory primary afferent inputs, and mechanical hyperalgesia in the territories of injured and uninjured nerves. Our results reveal central mechanisms facilitating central terminal sensitization underlying chronic pain.

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

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

    2009-07-01

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

  19. Modulation of firing and synaptic transmission of serotonergic neurons by intrinsic G protein-coupled receptors and ion channels

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    Takashi eMaejima

    2013-05-01

    Full Text Available Serotonergic neurons project to virtually all regions of the CNS and are consequently involved in many critical physiological functions such as mood, sexual behavior, feeding, sleep/wake cycle, memory, cognition, blood pressure regulation, breathing and reproductive success. Therefore serotonin release and serotonergic neuronal activity have to be precisely controlled and modulated by interacting brain circuits to adapt to specific emotional and environmental states. We will review the current knowledge about G protein-coupled receptors and ion channels involved in the regulation of serotonergic system, how their regulation is modulating the intrinsic activity of serotonergic neurons and its transmitter release and will discuss the latest methods for controlling the modulation of serotonin release and intracellular signaling in serotonergic neurons in vitro and in vivo.

  20. Impairment of the serotonergic neurons underlying reinforcement elicits extinction of the repeatedly reactivated context memory

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    Balaban, Pavel M.; Vinarskaya, Alia Kh.; Zuzina, Alena B.; Ierusalimsky, Victor N.; Malyshev, Aleksey Yu.

    2016-01-01

    We analyzed changes in the activity of individually identifiable neurons involved in the networks underlying feeding and withdrawal behaviors in snails before, during, and after aversive learning in vitro. Responses to food in the “reinforcing” serotonergic neurons involved in withdrawal changed significantly after training, implying that these serotonergic cells participate in the reactivation of memory and are involved in the reconsolidation process. In behavioral experiments it was shown that impairment of the functioning of the serotonergic system with the selective neurotoxin 5,7-DiHT did not change the memory, when tested once, but resulted in a complete extinction of the contextual memory after repeated reactivation of memory. Conversely, the cued memory to a specific type of food was significantly reduced but still present. Thus, we conclude that it is only for the context memory, that participation of the “reinforcing” serotonergic neurons in memory retrieval may be the gate condition for the choice between extinction/reconsolidation. PMID:27841309

  1. Interactions of histaminergic and serotonergic neurons in the hypothalamic regulation of prolactin and ACTH secretion.

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    Jørgensen, H; Knigge, U; Kjaer, A; Warberg, J

    1996-11-01

    Serotonergic and histaminergic neuronal systems are both involved in mediation of the stress-induced release of the pituitary hormones prolactin (PRL) and ACTH. We investigated the possibility of an interaction between serotonin (5-HT) and histamine (HA) in regulation of PRL and ACTH secretion in conscious male rats. Animals were pretreated systemically with antagonists to 5-HT1, 5-HT2 or 5-HT3 receptors prior to intracerebroventricular (icv) administration of HA. The 5-HT1 + 2 receptor antagonist methysergide prevented and the 5-HT2 receptor antagonist LY 53857 attenuated the HA-induced PRL release while the 5-HT3 receptor antagonist ondansetron had no effect on this response. None of the three 5-HT receptor antagonists affected the ACTH response to HA. Specific blockade of HA synthesis by alpha-fluoromethylhistidine or blockade of postsynaptic HA receptors by icv infusion of the H1 receptor antagonist mepyramine or the H2 receptor antagonist cimetidine inhibited the PRL response to 5-HT or to the 5-HT precursor 5-hydroxytryptophan (5- HTP) given in combination with the 5-HT reuptake inhibitor fluoxetine (Flx). Blockade of the histaminergic system had no effect on the ACTH response to serotonergic stimulation. The H3 receptors are inhibitory HA receptors. Systemic pretreatment with the H3 receptor agonist R(alpha)methylhistamine, or the H3 receptor antagonist thioperamide had no effect on the hormone response to activation of the serotonergic system by 5-HTP plus Flx. We conclude that the serotonergic and histaminergic neuronal systems interact in their stimulation of PRL secretion, but not in their stimulation of ACTH secretion. This interaction involves serotonergic 5-HT1 and 5-HT2 receptors and histaminergic H1 and H2 receptors. Furthermore, the previously observed inhibitory effect of the H3 receptor agonist R(alpha)methylhistamine on stress-induced PRL and ACTH release seems not to be exerted by activation of presynaptic H3 receptors located on serotonergic

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

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    Lise Gutknecht

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

  3. Chronic alcoholics without Wernicke-Korsakoff syndrome or cirrhosis do not lose serotonergic neurons in the dorsal raphe nucleus.

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    Baker, K G; Halliday, G M; Kril, J J; Harper, C G

    1996-02-01

    Despite the considerable evidence that alcoholics have perturbation of serotonergic function, there is little pathological evidence for alcohol directly affecting the nervous system. The present study aims to assess neuronal loss that occurs as a consequence of alcohol neurotoxicity in the serotonergic dorsal raphe nucleus (DRN). To that end, the brains of eight alcoholics and eight age-matched control cases were carefully screened to eliminate serious liver disease, the sequela of thiamine deficiency, Wernicke-Korsakoff syndrome (WKS), and other pathological abnormalities. Brains were formalin-fixed for 2 weeks, cut, and then immunohistochemically stained using a monoclonal PH8 antibody specific for the rate-limiting enzyme of serotonin synthesis, tryptophan hydroxylase. The morphology of the serotonin-synthesizing neurons and their average size was similar in all cases. However, there was a reduction in the staining intensity of the reaction product in the DRN serotonergic neurons of most alcoholics. Neuronal counts on spaced serial sections revealed that there were an estimated average total of 106,100 +/- 19,500 serotonergic neurons in the DRN of alcoholics and 108,300 +/- 11,800 in the DRN of controls, indicating that in most alcoholics there is no reduction in the number of these neurons. Therefore, the effect of chronic alcohol consumption on the serotonergic system, in the absence of WKS or liver disease, seems to be functional rather than neuropathological.

  4. The evolution of the serotonergic nervous system

    DEFF Research Database (Denmark)

    Hay-Schmidt, Anders

    2000-01-01

    Anatomy, serotonergic nervous system, neurons, invertebrates, phylogeny, development, apical ganglion......Anatomy, serotonergic nervous system, neurons, invertebrates, phylogeny, development, apical ganglion...

  5. Serotonergic neurons mediate dyskinesia side effects in Parkinson's patients with neural transplants.

    Science.gov (United States)

    Politis, Marios; Wu, Kit; Loane, Clare; Quinn, Niall P; Brooks, David J; Rehncrona, Stig; Bjorklund, Anders; Lindvall, Olle; Piccini, Paola

    2010-06-30

    Troublesome involuntary movements in the absence of dopaminergic medication, so-called off-medication dyskinesias, are a serious adverse effect of fetal neural grafts that hinders the development of cell-based therapies for Parkinson's disease. The mechanisms underlying these dyskinesias are not well understood, and it is not known whether they are the same as in the dyskinesias induced by l-dopa treatment. Using in vivo brain imaging, we show excessive serotonergic innervation in the grafted striatum of two patients with Parkinson's disease, who had exhibited major motor recovery after transplantation with dopamine-rich fetal mesencephalic tissue but had later developed off-medication dyskinesias. The dyskinesias were markedly attenuated by systemic administration of a serotonin [5-hydroxytryptamine (5-HT)] receptor (5-HT(1A)) agonist, which dampens transmitter release from serotonergic neurons, indicating that the dyskinesias were caused by the serotonergic hyperinnervation. Our observations suggest strategies for avoiding and treating graft-induced dyskinesias that result from cell therapies for Parkinson's disease with fetal tissue or stem cells.

  6. Imbalanced Dopaminergic Transmission Mediated by Serotonergic Neurons in L-DOPA-Induced Dyskinesia

    Directory of Open Access Journals (Sweden)

    Sylvia Navailles

    2012-01-01

    Full Text Available L-DOPA-induced dyskinesias (LIDs are one of the main motor side effects of L-DOPA therapy in Parkinson's disease. The review will consider the biochemical evidence indicating that the serotonergic neurons are involved in the dopaminergic effects of L-DOPA in the brain. The consequences are an ectopic and aberrant release of dopamine that follows the serotonergic innervation of the brain. After mid- to long-term treatment with L-DOPA, the pattern of L-DOPA-induced dopamine release is modified. In several brain regions, its effect is dramatically reduced while, in the striatum, its effect is quite preserved. LIDs could appear when the dopaminergic effects of L-DOPA fall in brain areas such as the cortex, enhancing the subcortical impact of dopamine and promoting aberrant motor responses. The consideration of the serotonergic system in the core mechanism of action of L-DOPA opens an important reserve of possible strategies to limit LIDs.

  7. Involvement of central serotonergic systems in dextromethorphan-induced behavioural syndrome in rats.

    Science.gov (United States)

    Gaikwad, R V; Gaonkar, R K; Jadhav, S A; Thorat, V M; Jadhav, J H; Balsara, J J

    2005-07-01

    Dextromethorphan, a noncompetitive blocker of the N-methyl-D-aspartate (NMDA) type of glutamate receptor, at 45, 60 and 75 mg/kg, ip doses induced a behavioural syndrome characterised by reciprocal forepaw treading, lateral head-weaving, hind-limb abduction and flat body posture. Such type of behavioural syndrome is induced by 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPAT) by directly stimulating the central postsynaptic 5-hydroxytryptamine (5-HT, serotonin) receptors of the 5-HT1A type. Pretreatment with buspirone (5, 10 mg/kg, ip) and l-propranolol (10, 20 mg/kg, ip) antagonised the behavioural syndrome induced by 8-OH-DPAT and dextromethorphan. Pretreatment with p-chlorophenylalanine (100 mg/kg/day x 4 days) antagonised the behavioural syndrome induced by dextromethorphan and dexfenfluramine but had no significant effect on 8-OH-DPAT induced behavioural syndrome. This indicates that dextromethorphan induces the behavioural syndrome by releasing 5-HT from serotonergic neurons with resultant activation of the postsynaptic 5-HT1A receptors by the released 5-HT. Pretreatment with fluoxetine (10 mg/kg, ip) significantly potentiated the behavioural syndrome induced by dextromethorphan and 5-hydroxytryptophan but significantly antagonised dexfenfluramine induced behavioural syndrome. This indicates that dextromethorphan releases 5-HT by a mechanism which differs from that of dexfenfluramine. Dextromethorphan may be releasing 5-HT by blocking the NMDA receptors and thereby counteracting the inhibitory influence of l-glutamate on 5-HT release.

  8. Serotonergic innervation and serotonin receptor expression of NPY-producing neurons in the rat lateral and basolateral amygdaloid nuclei.

    Science.gov (United States)

    Bonn, M; Schmitt, A; Lesch, K-P; Van Bockstaele, E J; Asan, E

    2013-03-01

    Pharmacobehavioral studies in experimental animals, and imaging studies in humans, indicate that serotonergic transmission in the amygdala plays a key role in emotional processing, especially for anxiety-related stimuli. The lateral and basolateral amygdaloid nuclei receive a dense serotonergic innervation in all species studied to date. We investigated interrelations between serotonergic afferents and neuropeptide Y (NPY)-producing neurons, which are a subpopulation of inhibitory interneurons in the rat lateral and basolateral nuclei with particularly strong anxiolytic properties. Dual light microscopic immunolabeling showed numerous appositions of serotonergic afferents on NPY-immunoreactive somata. Using electron microscopy, direct membrane appositions and synaptic contacts between serotonin-containing axon terminals and NPY-immunoreactive cellular profiles were unequivocally established. Double in situ hybridization documented that more than 50 %, and about 30-40 % of NPY mRNA-producing neurons, co-expressed inhibitory 5-HT1A and excitatory 5-HT2C mRNA receptor subtype mRNA, respectively, in both nuclei with no gender differences. Triple in situ hybridization showed that individual NPY mRNA-producing interneurons co-express both 5-HT1A and 5-HT2C mRNAs. Co-expression of NPY and 5-HT3 mRNA was not observed. The results demonstrate that serotonergic afferents provide substantial innervation of NPY-producing neurons in the rat lateral and basolateral amygdaloid nuclei. Studies of serotonin receptor subtype co-expression indicate a differential impact of the serotonergic innervation on this small, but important, population of anxiolytic interneurons, and provide the basis for future studies of the circuitry underlying serotonergic modulation of emotional stimulus processing in the amygdala.

  9. Orexin receptor activation generates gamma band input to cholinergic and serotonergic arousal system neurons and drives an intrinsic Ca2+-dependent resonance in LDT and PPT cholinergic neurons.

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    Masaru eIshibashi

    2015-06-01

    Full Text Available A hallmark of the waking state is a shift in EEG power to higher frequencies with epochs of synchronized intracortical gamma activity (30-60 Hz - a process associated with high-level cognitive functions. The ascending arousal system, including cholinergic laterodorsal (LDT and pedunculopontine (PPT tegmental neurons and serotonergic dorsal raphe (DR neurons, promotes this state. Recently, this system has been proposed as a gamma wave generator, in part, because some neurons produce high-threshold, Ca2+-dependent oscillations at gamma frequencies. However, it is not known whether arousal-related inputs to these neurons generate such oscillations, or whether such oscillations are ever transmitted to neuronal targets. Since key arousal input arises from hypothalamic orexin (hypocretin neurons, we investigated whether the unusually noisy, depolarizing orexin current could provide significant gamma input to cholinergic and serotonergic neurons, and whether such input could drive Ca2+-dependent oscillations. Whole-cell recordings in brain slices were obtained from mice expressing Cre-induced fluorescence in cholinergic LDT and PPT, and serotonergic DR neurons. After first quantifying reporter expression accuracy in cholinergic and serotonergic neurons, we found that the orexin current produced significant high frequency, including gamma, input to both cholinergic and serotonergic neurons. Then, by using a dynamic clamp, we found that adding a noisy orexin conductance to cholinergic neurons induced a Ca2+-dependent resonance that peaked in the theta and alpha frequency range (4 - 14 Hz and extended up to 100 Hz. We propose that this orexin current noise and the Ca2+ dependent resonance work synergistically to boost the encoding of high-frequency synaptic inputs into action potentials and to help ensure cholinergic neurons fire during EEG activation. This activity could reinforce thalamocortical states supporting arousal, REM sleep and intracortical

  10. Reciprocal connections between CART-immunoreactive, hypothalamic paraventricular neurons and serotonergic dorsal raphe cells in the rat: Light microscopic study.

    Science.gov (United States)

    Lee, Ji S; Lee, Hyun S

    2014-04-29

    Based on the overlapping physiological roles of cocaine- and amphetamine-regulated transcript (CART) peptides and serotonin, the present study examined the anatomical connection between the hypothalamic paraventricular nucleus (PVN) and the dorsal raphe (DR). The first series of experiments were performed to investigate descending projections from the CART-immunoreactive (CART-ir) PVN to serotonergic DR cells. CART-ir varicosities made contact with serotonergic DR neurons. An anterograde tracing study revealed that varicosities originating from the PVN formed close appositions to serotonergic neuronal profiles along the entire rostro-caudal extent of the DR. A retrograde study demonstrated that CART neurons projecting to the DR were mainly localized in the caudal parvicellular PVN, comprising approximately 3.0%±0.4% (n=8) of total CART cells. A second series of experiments was performed to investigate ascending projections from the DR to CART-ir PVN cells. Serotonin transporter-ir boutons made contact with CART-ir PVN neurons. Anterograde tracing revealed that varicosities originating from the DR formed close appositions to CART-ir PVN cells. Retrograde examination demonstrated that serotonergic neurons projecting to the parvicellular PVN were located along the entire rostro-caudal extent of the DR. The present observation provided an anatomical basis for accumulating evidence in the literature that suggests a functional interaction between the CART and serotonin systems during the regulation of energy balance, emotional behavior, and arousal.

  11. Nicotine increases GABAergic input on rat dorsal raphe serotonergic neurons through alpha7 nicotinic acetylcholine receptor.

    Science.gov (United States)

    Hernández-Vázquez, F; Chavarría, K; Garduño, J; Hernández-López, S; Mihailescu, S P

    2014-12-15

    The dorsal raphe nucleus (DRN) contains large populations of serotonergic (5-HT) neurons. This nucleus receives GABAergic inhibitory afferents from many brain areas and from DRN interneurons. Both GABAergic and 5-HT DRN neurons express functional nicotinic acetylcholine receptors (nAChRs). Previous studies have demonstrated that nicotine increases 5-HT release and 5-HT DRN neuron discharge rate by stimulating postsynaptic nAChRs and by increasing glutamate and norepinephrine release inside DRN. However, the influence of nicotine on the GABAergic input to 5-HT DRN neurons was poorly investigated. Therefore, the aim of this work was to determine the effect of nicotine on GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) of 5-HT DRN neurons and the subtype of nAChR(s) involved in this response. Experiments were performed in coronal slices obtained from young Wistar rats. GABAergic sIPSCs were recorded from post hoc-identified 5-HT DRN neurons with the whole cell voltage patch-clamp technique. Administration of nicotine (1 μM) increased sIPSC frequency in 72% of identified 5-HT DRN neurons. This effect was not reproduced by the α4β2 nAChR agonist RJR-2403 and was not influenced by TTX (1 μM). It was mimicked by the selective agonist for α7 nAChR, PNU-282987, and exacerbated by the positive allosteric modulator of the same receptor, PNU-120596. The nicotine-induced increase in sIPSC frequency was independent on voltage-gated calcium channels and dependent on Ca(2+)-induced Ca(2+) release (CICR). These results demonstrate that nicotine increases the GABAergic input to most 5-HT DRN neurons, by activating α7 nAChRs and producing CICR in DRN GABAergic terminals.

  12. Central serotonergic hypofunction in autism: results of the 5-hydroxy-tryptophan challenge test.

    Science.gov (United States)

    Croonenberghs, Jan; Wauters, Annick; Deboutte, Dirk; Verkerk, Robert; Scharpe, Simon; Maes, Michael

    2007-08-01

    Some studies have suggested that disorders in the central serotonergic function may play a role in the pathophysiology of autistic disorder. In order to assess the central serotonergic turnover in autism, this study examines the cortisol and prolactin responses to administration of L-5-hydroxy-tryptophan (5-HTP), the direct precursor of 5-HT in 18 male, post-pubertal, Caucasian autistic patients (age 13-19 y.; I.Q.>55) and 22 matched healthy volunteers. Serum cortisol and prolactin were determined 45 and 30 minutes before administration of 5-HTP (4 mg/kg in non enteric-coated tablets) or an identical placebo in a single blind order and, thereafter, every 30 minutes over a 3-hour period. The 5-HTP-induced increases in serum cortisol were significantly lower in autistic patients than in controls, whereas there were no significant differences in 5-HTP-induced prolactin responses between both study groups. In baseline conditions, no significant differences were found in serum cortisol and prolactin between autistic and normal children. The results suggest that autism is accompanied by a central serotonergic hypoactivity and that the latter could play a role in the pathophysiology of autism.

  13. Divergent in vivo activity of non‐serotonergic and serotonergic VGluT3–neurones in the median raphe region

    Science.gov (United States)

    Domonkos, Andor; Nikitidou Ledri, Litsa; Laszlovszky, Tamás; Cserép, Csaba; Borhegyi, Zsolt; Papp, Edit; Nyiri, Gábor; Freund, Tamás F.

    2016-01-01

    Key points The median raphe is a key subcortical modulatory centre involved in several brain functions, such as regulation of the sleep–wake cycle, emotions and memory storage.A large proportion of median raphe neurones are glutamatergic and implement a radically different mode of communication compared to serotonergic cells, although their in vivo activity is unknown.We provide the first description of the in vivo, brain state‐dependent firing properties of median raphe glutamatergic neurones identified by immunopositivity for the vesicular glutamate transporter type 3 (VGluT3) and serotonin (5‐HT). Glutamatergic populations (VGluT3+/5‐HT– and VGluT3+/5‐HT+) were compared with the purely serotonergic (VGluT3–/5‐HT+ and VGluT3–/5‐HT–) neurones.VGluT3+/5‐HT+ neurones fired similar to VGluT3–/5‐HT+ cells, whereas they significantly diverged from the VGluT3+/5‐HT– population. Activity of the latter subgroup resembled the spiking of VGluT3–/5‐HT– cells, except for their diverging response to sensory stimulation.The VGluT3+ population of the median raphe may broadcast rapidly varying signals on top of a state‐dependent, tonic modulation. Abstract Subcortical modulation is crucial for information processing in the cerebral cortex. Besides the canonical neuromodulators, glutamate has recently been identified as a key cotransmitter of numerous monoaminergic projections. In the median raphe, a pure glutamatergic neurone population projecting to limbic areas was also discovered with a possibly novel, yet undetermined function. In the present study, we report the first functional description of the vesicular glutamate transporter type 3 (VGluT3)‐expressing median raphe neurones. Because there is no appropriate genetic marker for the separation of serotonergic (5‐HT+) and non‐serotonergic (5‐HT–) VGluT3+ neurones, we utilized immunohistochemistry after recording and juxtacellular labelling in anaesthetized rats. VGluT3+/5

  14. Functional and Developmental Identification of a Molecular Subtype of Brain Serotonergic Neuron Specialized to Regulate Breathing Dynamics

    Directory of Open Access Journals (Sweden)

    Rachael D. Brust

    2014-12-01

    Full Text Available Serotonergic neurons modulate behavioral and physiological responses from aggression and anxiety to breathing and thermoregulation. Disorders involving serotonin (5HT dysregulation are commensurately heterogeneous and numerous. We hypothesized that this breadth in functionality derives in part from a developmentally determined substructure of distinct subtypes of 5HT neurons each specialized to modulate specific behaviors. By manipulating developmentally defined subgroups one by one chemogenetically, we find that the Egr2-Pet1 subgroup is specialized to drive increased ventilation in response to carbon dioxide elevation and acidosis. Furthermore, this subtype exhibits intrinsic chemosensitivity and modality-specific projections—increasing firing during hypercapnic acidosis and selectively projecting to respiratory chemosensory but not motor centers, respectively. These findings show that serotonergic regulation of the respiratory chemoreflex is mediated by a specialized molecular subtype of 5HT neuron harboring unique physiological, biophysical, and hodological properties specified developmentally and demonstrate that the serotonergic system contains specialized modules contributing to its collective functional breadth.

  15. Inhibiton of neurons in the amygdala by dorsal raphe stimulation: mediation through a direct serotonergic pathway.

    Science.gov (United States)

    Wang, R Y; Aghajanian, G K

    1977-01-14

    This study presents data showing that the dorsal raphe nucleus (DRN) has a marked inhibitory influence upon neurons in the amygdala and that this inhibitory effect is mediated by a direct DRN-amygdala serotonergic pathway. The evidence may be briefly summarized as follows:(1) on the same amygdaloid cells, both iontophoresis of serotonin (5-HT) and electrical stimulation of the DRN markedly inhibited spontaneous single unit activities; (2) the latency of DRN-induced inhibition was relatively short and is compatible with the conduction velocities (which were determined by antidromic activation of the 5-HT pathway) of unmyelinated 5-HT fibers; (3) destruction of 5-HT projections by 5,7-dihydroxytryptamine (5,7-DHT) or pharmacological depletion of 5-HT by parachlorophenylalanine (PCPA) prevented the inhibitory responsed to DRN stimulation in the great majority of cells studied; (4) in PCPA-pretreated animals, injection of 5-hydroxytryptophan (5-HTP) reversed the PCPA effect, restoring the responses of amygdaloid cells to DRN stimulation. In the amygdala, the presumptive 5-HT antagonists which we tested did not block the inhibitory effects of 5-HT except that intravenously administered LSD blocked the inhibitory responses produced by submaximal DRN stimulation. The implications of these results for the possible functions of 5-HT in the amygdala is discussed.

  16. GDNF family ligands display distinct action profiles on cultured GABAergic and serotonergic neurons of rat ventral mesencephalon

    DEFF Research Database (Denmark)

    Ducray, Angélique; Krebs, Sandra H:; Schaller, Benoft;

    2006-01-01

    of the GFLs affected soma size of GABA-ir neurons. In contrast, only NRTN treatment significantly increased 5-HT-ir cells densities at 10 ng/ml (1.3-fold), while an augmentation was seen for GDNF and PSPN at 100 ng/ml (2.4-fold and 1.7-fold, respectively). ARTN had no effect on 5-HT-ir cell densities....... Morphological analysis of 5-HT-ir neurons revealed a significant increase of soma size, number of primary neurites/neuron and neurite length/neuron after GDNF exposure, while PSPN only affected soma size, and NRTN and ARTN failed to exert any effect. In conclusion, we identified GFLs as effective neurotrophic...... factors for VM GABAergic and serotonergic neurons, demonstrating characteristic individual action profiles emphasizing their important and distinct roles during brain development....

  17. Comparative morphology of serotonergic-like immunoreactive elements in the central nervous system of kinorhynchs (Kinorhyncha, Cyclorhagida).

    Science.gov (United States)

    Herranz, María; Pardos, Fernando; Boyle, Michael J

    2013-03-01

    Cycloneuralian taxa exhibit similar organ system architectures, providing informative characters of metazoan evolution, yet very few modern comparative descriptions of cellular and molecular homologies within and among those taxa are available. We immunolabeled and characterized elements of the serotonergic nervous system in the kinorhynchs Echinoderes spinifurca, Antygomonas paulae, and Zelinkaderes brightae using confocal laser scanning microscopy. Fluorescent markers targeting DNA were combined with observations of auto-fluorescent structures to guide interpretations of the internal and external anatomy in each species. Results show a common pattern of the central nervous system with a circumenteric brain divided into ring-shaped anterior and posterior neuronal somata and a central neuropil connected to a multi-stringed, longitudinal ventral nerve cord. Structural similarities and differences in the nervous systems of these species were observed and described, stressing the incomplete ring nature of the anterior region of the kinorhynch brain, the functional relationship between the brain and the movable introvert, and the number and arrangement of nerve strings and somata of the ventral nerve cord. The ventral cord ends in two ventrolateral cell bodies in E. spinifurca, and forms a terminal loop associated with a midterminal spine in A. paulae and Z. brightae. The possible functional and phylogenetic significance of these features and arrangements are discussed.

  18. Early-life Social Isolation Impairs the Gonadotropin-Inhibitory Hormone Neuronal Activity and Serotonergic System in Male Rats

    Directory of Open Access Journals (Sweden)

    Tomoko eSoga

    2015-11-01

    Full Text Available Social isolation in early life deregulates the serotonergic system of the brain, compromising reproductive function. Gonadotropin-inhibitory hormone (GnIH neurons in the dorsomedial hypothalamic nucleus are critical to the inhibitory regulation of gonadotropin-releasing hormone neuronal activity in the brain and release of luteinising hormone by the pituitary gland. Although GnIH responds to stress, the role of GnIH in social isolation-induced deregulation of the serotonin system and reproductive function remains unclear. We investigated the effect of social isolation in early life on the serotonergic–GnIH neuronal system using enhanced green fluorescent protein (EGFP-tagged GnIH-transgenic rats. Socially isolated rats were observed for anxious and depressive behaviours. Using immunohistochemistry, we examined c-Fos protein expression in EGFP–GnIH neurons in 9-week-old adult male rats after 6 weeks post-weaning isolation or group -housing. We also inspected serotonergic fibre juxtapositions in EGFP–GnIH neurons in control and socially isolated male rats. Socially isolated rats exhibited anxious and depressive behaviours. The total number of EGFP–GnIH neurons was the same in control and socially isolated rats, but c-Fos expression in GnIH neurons was significantly reduced in socially isolated rats. Serotonin fibre juxtapositions on EGFP–GnIH neurons was also lower in socially isolated rats. In addition, levels of tryptophan hydroxylase mRNA expression in the dorsal raphe nucleus were significantly attenuated in these rats. These results suggest that social isolation in early life results in lower serotonin levels, which reduce GnIH neuronal activity and may lead to reproductive failure.

  19. Quantitative analysis of serotonin secreted by human embryonic stem cells-derived serotonergic neurons via pH-mediated online stacking-CE-ESI-MRM.

    Science.gov (United States)

    Zhong, Xuefei; Hao, Ling; Lu, Jianfeng; Ye, Hui; Zhang, Su-Chun; Li, Lingjun

    2016-04-01

    A CE-ESI-MRM-based assay was developed for targeted analysis of serotonin released by human embryonic stem cells-derived serotonergic neurons in a chemically defined environment. A discontinuous electrolyte system was optimized for pH-mediated online stacking of serotonin. Combining with a liquid-liquid extraction procedure, LOD of serotonin in the Krebs'-Ringer's solution by CE-ESI-MS/MS on a 3D ion trap MS was0.15 ng/mL. The quantitative results confirmed the serotonergic identity of the in vitro developed neurons and the capacity of these neurons to release serotonin in response to stimulus.

  20. Pharmacological and kinetic characterization of two functional classes of serotonergic modulation in Aplysia sensory neurons.

    Science.gov (United States)

    Stark, L L; Mercer, A R; Emptage, N J; Carew, T J

    1996-02-01

    1. Modulation of mechanoafferent sensory neurons (SNs) by the neutrotransmitter serotonin (5HT) plays a significant role in behavioral sensitization of several withdrawal reflexes in Aplysia. The modulatory effects of 5HT on these SNs include increased excitability, increased input resistance, action potential broadening, and increased synaptic transmission. Based on a previously described dissociation of some of these modulatory effects, revealed with the 5HT-receptor antagonist, cyproheptadine, we investigated whether a similar dissociation could be found by systematically varying the concentration of the endogenous agonist, 5HT. 2. We first applied a range of 5HT concentrations to isolated pleural/pedal ganglia (containing tail SNs and tail motor neurons, respectively), and measured the magnitude of 5HT-induced modulation of spike broadening and increased excitability. The resulting dose-response curve showed that both forms of modulation increase monotonically as a function of 5HT concentration, but that excitability has a lower threshold for modulation by 5HT than does spike duration. 3. We further characterized the modulatory effects of 5HT on Aplysia SNs by comparing the time course of onset of modulation by 5HT and the time course of recovery after washout. Independent of 5HT concentration, modulation of excitability increases rapidly in the presence of 5HT and recovers rapidly (broadening, which resembles the kinetics of increased excitability and increased input resistance. Higher concentrations of 5HT (2.5 and 5 microM) induce a more slowly developing and prolonged-recovery form of spike broadening (> 9 min). At these higher concentrations, the recovery profile for prolonged spike broadening is significantly different from those observed for both increased excitability and increased input resistance. 4. We next compared the relationship between spike broadening and short-term synaptic facilitation. We found that significant facilitation of synaptic

  1. Serotonergic systems associated with arousal and vigilance behaviors following administration of anxiogenic drugs

    DEFF Research Database (Denmark)

    Abrams, J K; Johnson, P L; Hay-Schmidt, Anders;

    2005-01-01

    drugs on topographically organized subpopulations of serotonergic neurons using double immunohistochemical staining for c-Fos and tryptophan hydroxylase combined with topographical analysis of the rat dorsal raphe nucleus (DR). Anxiogenic drugs with diverse pharmacological properties including...... and vigilance behaviors consistent with an increase in anxiety state. In addition, these anxiogenic drugs, excluding yohimbine, had convergent actions on an anatomically-defined subset of serotonergic neurons within the middle and caudal, dorsal subdivision of the DR. High resolution topographical analysis...... drugs have selective actions on a subpopulation of serotonergic neurons projecting to a distributed central autonomic and emotional motor control system regulating anxiety states and anxiety-related physiological and behavioral responses....

  2. Chronic alcoholism in the absence of Wernicke-Korsakoff syndrome and cirrhosis does not result in the loss of serotonergic neurons from the median raphe nucleus.

    Science.gov (United States)

    Baker, K G; Halliday, G M; Kril, J J; Harper, C G

    1996-09-01

    Previous studies have identified alcohol, thiamine deficiency and liver disease as contributing to the neuropathology of alcohol-related brain damage. In order to examine the effects of alcohol toxicity and thiamine deficiency on serotonergic neurons in the median raphe nucleus (MnR), alcoholic and previously published Wernicke-Korsakoff syndrome (WKS) cases without liver disease, were compared with age-matched non-alcoholic controls. While there was no difference between the estimated number of serotonergic neurons in either controls or alcoholics without WKS (means of 63,010 +/- 8,900 and 59,560 +/- 8,010 respectively), a substantial loss of serotonergic neurons was previously found in WKS cases (mean of 19,050 +/- 13,140). Further analysis revealed a significant difference in the maximum daily alcohol consumption between these groups. However, analysis of covariance showed that the number or serotonergic neurons in the MnR did not correlate with the amount of alcohol consumed. Therefore, our results suggest that cell loss in the MnR can be attributed to thiamine deficiency rather than alcohol per se.

  3. Transcription factors lhx1/5-1 and pitx are required for the maintenance and regeneration of serotonergic neurons in planarians.

    Science.gov (United States)

    Currie, Ko W; Pearson, Bret J

    2013-09-01

    In contrast to most adult organisms, freshwater planarians can regenerate any injured body part, including their entire nervous system. This allows for the analysis of genes required for both the maintenance and regeneration of specific neural subtypes. In addition, the loss of specific neural subtypes may uncover previously unknown behavioral roles for that neural population in the context of the adult animal. Here we show that two homeodomain transcription factor homologs, Smed-lhx1/5-1 and Smed-pitx, are required for the maintenance and regeneration of serotonergic neurons in planarians. When either lhx1/5-1 or pitx was knocked down by RNA interference, the expression of multiple canonical markers for serotonergic neurons was lost. Surprisingly, the loss of serotonergic function uncovered a role for these neurons in the coordination of motile cilia on the ventral epidermis of planarians that are required for their nonmuscular gliding locomotion. Finally, we show that in addition to its requirement in serotonergic neurons, Smed-pitx is required for proper midline patterning during regeneration, when it is required for the expression of the midline-organizing molecules Smed-slit in the anterior and Smed-wnt1 in the posterior.

  4. Non-Serotonergic Neurotoxicity by MDMA (Ecstasy) in Neurons Derived from Mouse P19 Embryonal Carcinoma Cells.

    Science.gov (United States)

    Popova, Dina; Forsblad, Andréas; Hashemian, Sanaz; Jacobsson, Stig O P

    2016-01-01

    3,4-methylenedioxymethamphetamine (MDMA; ecstasy) is a commonly abused recreational drug that causes neurotoxic effects in both humans and animals. The mechanism behind MDMA-induced neurotoxicity is suggested to be species-dependent and needs to be further investigated on the cellular level. In this study, the effects of MDMA in neuronally differentiated P19 mouse embryonal carcinoma cells have been examined. MDMA produces a concentration-, time- and temperature-dependent toxicity in differentiated P19 neurons, as measured by intracellular MTT reduction and extracellular LDH activity assays. The P19-derived neurons express both the serotonin reuptake transporter (SERT), that is functionally active, and the serotonin metabolizing enzyme monoamine oxidase A (MAO-A). The involvement of these proteins in the MDMA-induced toxicity was investigated by a pharmacological approach. The MAO inhibitors clorgyline and deprenyl, and the SERT inhibitor fluoxetine, per se or in combination, were not able to mimic the toxic effects of MDMA in the P19-derived neurons or block the MDMA-induced cell toxicity. Oxidative stress has been implicated in MDMA-induced neurotoxicity, but pre-treatment with the antioxidants α-tocopherol or N-acetylcysteine did not reveal any protective effects in the P19 neurons. Involvement of mitochondria in the MDMA-induced cytotoxicity was also examined, but MDMA did not alter the mitochondrial membrane potential (ΔΨm) in the P19 neurons. We conclude that MDMA produce a concentration-, time- and temperature-dependent neurotoxicity and our results suggest that the mechanism behind MDMA-induced toxicity in mouse-derived neurons do not involve the serotonergic system, oxidative stress or mitochondrial dysfunction.

  5. The LIM and POU homeobox genes ttx-3 and unc-86 act as terminal selectors in distinct cholinergic and serotonergic neuron types.

    Science.gov (United States)

    Zhang, Feifan; Bhattacharya, Abhishek; Nelson, Jessica C; Abe, Namiko; Gordon, Patricia; Lloret-Fernandez, Carla; Maicas, Miren; Flames, Nuria; Mann, Richard S; Colón-Ramos, Daniel A; Hobert, Oliver

    2014-01-01

    Transcription factors that drive neuron type-specific terminal differentiation programs in the developing nervous system are often expressed in several distinct neuronal cell types, but to what extent they have similar or distinct activities in individual neuronal cell types is generally not well explored. We investigate this problem using, as a starting point, the C. elegans LIM homeodomain transcription factor ttx-3, which acts as a terminal selector to drive the terminal differentiation program of the cholinergic AIY interneuron class. Using a panel of different terminal differentiation markers, including neurotransmitter synthesizing enzymes, neurotransmitter receptors and neuropeptides, we show that ttx-3 also controls the terminal differentiation program of two additional, distinct neuron types, namely the cholinergic AIA interneurons and the serotonergic NSM neurons. We show that the type of differentiation program that is controlled by ttx-3 in different neuron types is specified by a distinct set of collaborating transcription factors. One of the collaborating transcription factors is the POU homeobox gene unc-86, which collaborates with ttx-3 to determine the identity of the serotonergic NSM neurons. unc-86 in turn operates independently of ttx-3 in the anterior ganglion where it collaborates with the ARID-type transcription factor cfi-1 to determine the cholinergic identity of the IL2 sensory and URA motor neurons. In conclusion, transcription factors operate as terminal selectors in distinct combinations in different neuron types, defining neuron type-specific identity features.

  6. Injections of urocortin 1 into the basolateral amygdala induce anxiety-like behavior and c-Fos expression in brainstem serotonergic neurons.

    Science.gov (United States)

    Spiga, F; Lightman, S L; Shekhar, A; Lowry, C A

    2006-01-01

    The amygdala plays a key role in emotional processing and anxiety-related physiological and behavioral responses. Previous studies have shown that injections of the anxiety-related neuropeptide corticotropin-releasing factor or the related neuropeptide urocortin 1 into the region of the basolateral amygdaloid nucleus induce anxiety-like behavior in several behavioral paradigms. Brainstem serotonergic systems in the dorsal raphe nucleus and median raphe nucleus may be part of a distributed neural system that, together with the basolateral amygdala, regulates acute and chronic anxiety states. We therefore investigated the effect of an acute bilateral injection of urocortin 1 into the basolateral amygdala on behavior in the social interaction test and on c-Fos expression within serotonergic neurons in the dorsal raphe nucleus and median raphe nucleus. Male rats were implanted with bilateral cannulae directed at the region of the basolateral amygdala; 72 h after surgery, rats were injected with urocortin 1 (50 fmol/100 nl) or vehicle (100 nl of 1% bovine serum albumin in distilled water). Thirty minutes after injection, a subgroup of rats from each experimental group was exposed to the social interaction test; remaining animals were left in the home cage. Two hours after injection rats were perfused with paraformaldehyde and brains were removed and processed for immunohistochemistry. Acute injection of urocortin 1 had anxiogenic effects in the social interaction test, reducing total interaction time without affecting locomotor activity or exploratory behavior. These behavioral effects were associated with increases in c-Fos expression within brainstem serotonergic neurons. In home cage rats and rats exposed to the social interaction test, urocortin 1 treatment increased the number of c-Fos-immunoreactive serotonergic neurons within subdivisions of both the dorsal raphe nucleus and median raphe nucleus. These results are consistent with the hypothesis that the

  7. Lmx1b controls peptide phenotypes in serotonergic and dopaminergic neurons

    Institute of Scientific and Technical Information of China (English)

    Rui Yan; Tianwen Huang; Zhiqin Xie; Guannan Xia; Hui Qian; Xiaolin Zhao; Leping Cheng

    2013-01-01

    Serotonin (5-HT) neurons synthesize a variety of peptides.How these peptides are controlled during development remains unclear.It has been reported that the co-localization of peptides and 5-HT varies by species.In contrast to the situations in the rostral 5-HT neurons of human and rat brains,several peptides do not coexist with 5-HT in the rostral 5-HT neurons of mouse brain.In this study,we found that the peptide substance P and peptide genes,including those encoding peptides thyrotropin-releasing hormone,enkephalin,and calcitonin gene-related peptide,were expressed in the caudal 5-HT neurons of mouse brain; these findings are in line with observations in rat and monkey 5-HT neurons.We also revealed that these peptides/peptide genes partially overlapped with the transcription factor Lmx1b that specifies the 5-HT cell fate.Furthermore,we found that the peptide cholecystokinin was expressed in developing dopaminergic neurons and greatly overlapped with Lmx1b that specifies the dopaminergic cell fate.By examining the phenotype of Lmx1b deletion mice,we found that Lmx1b was required for the expression of above peptides expressed in 5-HT or dopaminergic neurons.Together,our results indicate that Lmx1b,a key transcription factor for the specification of 5-HT and dopaminergic transmitter phenotypes during embryogenesis,determines some peptide phenotypes in these neurons as well.

  8. Somatic influences on subjective well-being and affective disorders: the convergence of thermosensory and central serotonergic systems

    Directory of Open Access Journals (Sweden)

    Charles L Raison

    2015-01-01

    Full Text Available Current theories suggest that the brain is the sole source of mental illness. However, affective disorders, and major depressive disorder (MDD in particular, may be better conceptualized as brain-body disorders that involve peripheral systems as well. This perspective emphasizes the embodied, multifaceted physiology of well-being, and suggests that afferent signals from the body may contribute to cognitive and emotional states. In this review, we focus on evidence from preclinical and clinical studies suggesting that afferent thermosensory signals contribute to well-being and depression. Although thermoregulatory systems have traditionally been conceptualized as serving primarily homeostatic functions, increasing evidence suggests neural pathways responsible for regulating body temperature may be linked more closely with emotional states than previously recognized, an affective warmth hypothesis. Human studies indicate that increasing physical warmth activates brain circuits associated with cognitive and affective functions, promotes interpersonal warmth and prosocial behaviour, and has antidepressant effects. Consistent with these effects, preclinical studies in rodents demonstrate that physical warmth activates brain serotonergic neurons implicated in antidepressant-like effects. Together, these studies suggest that 1 thermosensory pathways interact with brain systems that control affective function, 2 these pathways are dysregulated in affective disorders, and 3 activating warm thermosensory pathways promotes a sense of well-being and has therapeutic potential in the treatment of affective disorders.

  9. Somatic influences on subjective well-being and affective disorders: the convergence of thermosensory and central serotonergic systems.

    Science.gov (United States)

    Raison, Charles L; Hale, Matthew W; Williams, Lawrence E; Wager, Tor D; Lowry, Christopher A

    2014-01-01

    Current theories suggest that the brain is the sole source of mental illness. However, affective disorders, and major depressive disorder (MDD) in particular, may be better conceptualized as brain-body disorders that involve peripheral systems as well. This perspective emphasizes the embodied, multifaceted physiology of well-being, and suggests that afferent signals from the body may contribute to cognitive and emotional states. In this review, we focus on evidence from preclinical and clinical studies suggesting that afferent thermosensory signals contribute to well-being and depression. Although thermoregulatory systems have traditionally been conceptualized as serving primarily homeostatic functions, increasing evidence suggests neural pathways responsible for regulating body temperature may be linked more closely with emotional states than previously recognized, an affective warmth hypothesis. Human studies indicate that increasing physical warmth activates brain circuits associated with cognitive and affective functions, promotes interpersonal warmth and prosocial behavior, and has antidepressant effects. Consistent with these effects, preclinical studies in rodents demonstrate that physical warmth activates brain serotonergic neurons implicated in antidepressant-like effects. Together, these studies suggest that (1) thermosensory pathways interact with brain systems that control affective function, (2) these pathways are dysregulated in affective disorders, and (3) activating warm thermosensory pathways promotes a sense of well-being and has therapeutic potential in the treatment of affective disorders.

  10. Prior cold water swim stress alters immobility in the forced swim test and associated activation of serotonergic neurons in the rat dorsal raphe nucleus.

    Science.gov (United States)

    Drugan, R C; Hibl, P T; Kelly, K J; Dady, K F; Hale, M W; Lowry, C A

    2013-12-01

    Prior adverse experience alters behavioral responses to subsequent stressors. For example, exposure to a brief swim increases immobility in a subsequent swim test 24h later. In order to determine if qualitative differences (e.g. 19°C versus 25°C) in an initial stressor (15-min swim) impact behavioral, physiological, and associated neural responses in a 5-min, 25°C swim test 24h later, rats were surgically implanted with biotelemetry devices 1 week prior to experimentation then randomly assigned to one of six conditions (Day 1 (15 min)/Day 2 (5 min)): (1) home cage (HC)/HC, (2) HC/25°C swim, (3) 19°C swim/HC, (4) 19°C swim/25°C swim, (5) 25°C swim/HC, (6) 25°C swim/25°C swim. Core body temperature (Tb) was measured on Days 1 and 2 using biotelemetry; behavior was measured on Day 2. Rats were transcardially perfused with fixative 2h following the onset of the swim on Day 2 for analysis of c-Fos expression in midbrain serotonergic neurons. Cold water (19°C) swim on Day 1 reduced Tb, compared to both 25°C swim and HC groups on Day 1, and, relative to rats exposed to HC conditions on Day 1, reduced the hypothermic response to the 25°C swim on Day 2. The 19°C swim on Day 1, relative to HC exposure on Day 1, increased immobility during the 5-min swim on Day 2. Also, 19°C swim, relative to HC conditions, on Day 1 reduced swim (25°C)-induced increases in c-Fos expression in serotonergic neurons within the dorsal and interfascicular parts of the dorsal raphe nucleus. These results suggest that exposure to a 5-min 19°C cold water swim, but not exposure to a 5-min 25°C swim alters physiological, behavioral and serotonergic responses to a subsequent stressor.

  11. The Deakin/Graeff hypothesis: focus on serotonergic inhibition of panic

    Science.gov (United States)

    Paul, Evan D.; Johnson, Philip L.; Shekhar, Anantha; Lowry, Christopher A.

    2014-01-01

    The Deakin/Graeff hypothesis proposes that different subpopulations of serotonergic neurons through topographically organized projections to forebrain and brainstem structures modulate the response to acute and chronic stressors, and that dysfunction of these neurons increases vulnerability to affective and anxiety disorders, including Panic Disorder. We outline evidence supporting the existence of a serotonergic system originally discussed by Deakin/Graeff that is implicated in the inhibition of panic-like behavioral and physiological responses. Evidence supporting this panic inhibition system comes from the following observations: 1) serotonergic neurons located in the ‘ventrolateral dorsal raphe nucleus (DRVL) as well as the ventrolateral periaqueductal gray (VLPAG) inhibit dorsal periaqueductal gray-elicited panic-like responses; 2) chronic, but not acute, antidepressant treatment potentiates serotonin’s panicolytic effect; 3) contextual fear activates a central nucleus of the amygdala-DRVL/VLPAG circuit implicated in mediating freezing and inhibiting panic-like escape behaviors; 4) DRVL/VLPAG serotonergic neurons are central chemoreceptors and modulate the behavioral and cardiorespiratory response to panicogenic agents such as sodium lactate and CO2. Implications of the panic inhibition system are discussed. PMID:24661986

  12. The cholinergic agonist carbachol increases the frequency of spontaneous GABAergic synaptic currents in dorsal raphe serotonergic neurons in the mouse.

    Science.gov (United States)

    Yang, C; Brown, R E

    2014-01-31

    Dorsal raphe nucleus (DRN) serotonin (5-HT) neurons play an important role in feeding, mood control and stress responses. One important feature of their activity across the sleep-wake cycle is their reduced firing during rapid-eye-movement (REM) sleep which stands in stark contrast to the wake/REM-on discharge pattern of brainstem cholinergic neurons. A prominent model of REM sleep control posits a reciprocal interaction between these cell groups. 5-HT inhibits cholinergic neurons, and activation of nicotinic receptors can excite DRN 5-HT neurons but the cholinergic effect on inhibitory inputs is incompletely understood. Here, in vitro, in DRN brain slices prepared from GAD67-GFP knock-in mice, a brief (3 min) bath application of carbachol (50 μM) increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in GFP-negative, putative 5-HT neurons but did not affect miniature (tetrodotoxin-insensitive) IPSCs. Carbachol had no direct postsynaptic effect. Thus, carbachol likely increases the activity of local GABAergic neurons which synapse on 5-HT neurons. Removal of dorsal regions of the slice including the ventrolateral periaqueductal gray (vlPAG) region where GABAergic neurons projecting to the DRN have been identified, abolished the effect of carbachol on sIPSCs whereas the removal of ventral regions containing the oral region of the pontine reticular nucleus (PnO) did not. In addition, carbachol directly excited GFP-positive, GABAergic vlPAG neurons. Antagonism of both muscarinic and nicotinic receptors completely abolished the effects of carbachol. We suggest cholinergic neurons inhibit DRN 5-HT neurons when acetylcholine levels are lower i.e. during quiet wakefulness and the beginning of REM sleep periods, in part via excitation of muscarinic and nicotinic receptors located on local vlPAG and DRN GABAergic neurons. Higher firing rates or burst firing of cholinergic neurons associated with attentive wakefulness or phasic REM sleep periods

  13. Serotonergic chemosensory neurons modify the C. elegans immune response by regulating G-protein signaling in epithelial cells.

    Directory of Open Access Journals (Sweden)

    Alexandra Anderson

    Full Text Available The nervous and immune systems influence each other, allowing animals to rapidly protect themselves from changes in their internal and external environment. However, the complex nature of these systems in mammals makes it difficult to determine how neuronal signaling influences the immune response. Here we show that serotonin, synthesized in Caenorhabditis elegans chemosensory neurons, modulates the immune response. Serotonin released from these cells acts, directly or indirectly, to regulate G-protein signaling in epithelial cells. Signaling in these cells is required for the immune response to infection by the natural pathogen Microbacterium nematophilum. Here we show that serotonin signaling suppresses the innate immune response and limits the rate of pathogen clearance. We show that C. elegans uses classical neurotransmitters to alter the immune response. Serotonin released from sensory neurons may function to modify the immune system in response to changes in the animal's external environment such as the availability, or quality, of food.

  14. Non-Serotonergic Neurotoxicity by MDMA (Ecstasy) in Neurons Derived from Mouse P19 Embryonal Carcinoma Cells

    OpenAIRE

    Popova, Dina; Forsblad, Andréas; Hashemian, Sanaz; Jacobsson, Stig O. P.

    2016-01-01

    3,4-methylenedioxymethamphetamine (MDMA; ecstasy) is a commonly abused recreational drug that causes neurotoxic effects in both humans and animals. The mechanism behind MDMA-induced neurotoxicity is suggested to be species-dependent and needs to be further investigated on the cellular level. In this study, the effects of MDMA in neuronally differentiated P19 mouse embryonal carcinoma cells have been examined. MDMA produces a concentration-, time- and temperature-dependent toxicity in differen...

  15. Short-term effects of melatonin and pinealectomy on serotonergic neuronal activity across the light-dark cycle.

    Science.gov (United States)

    Domínguez-López, Sergio; Mahar, Ian; Bambico, Francis Rodriguez; Labonté, Benoit; Ochoa-Sánchez, Rafael; Leyton, Marco; Gobbi, Gabriella

    2012-06-01

    Melatonin (MLT) and serotonin (5-HT) are two biosynthetically related compounds implicated in several common physiological functions and the etiology of mood disorders. How they interact, though, is not yet fully understood. In this study, single-unit extracellular recordings were used to monitor dorsal raphe nucleus (DR) 5-HT neuronal activity in anesthetized rats, under basal conditions (CTRL), in response to MLT administration, and after pinealectomy (PX) across the light-dark cycle. Under basal conditions, the number of spontaneously active 5-HT neurons and their firing rate were both significantly lower in the dark phase. In the light phase, administration of MLT at low doses (0.5-1 mg/kg, i.v.) decreased 5-HT firing activity. This inhibitory effect of MLT was completely blocked by the MT₁/MT₂ receptor antagonist luzindole, but not by the selective MT(2) receptor antagonist 4P-PDOT, the selective 5-HT(1A) receptor antagonist WAY100635, or by the α₂ adrenoceptor antagonist idazoxan. In the opposite experiment, PX increased 5-HT firing activity in the dark phase, and this was reversed by MLT administration (1 mg/kg, i.v.). Finally, in a forced swim test, MLT (1 mg/kg, i.p.) increased immobility time and decreased swimming behavior. Together, these results suggest that nocturnal MLT secretion imposes tonic inhibitory control over a sub-population of DR 5-HT neurons. This MLT-induced decrease in 5-HT neurotransmission may represent a biological mechanism underlying mood disorders characterized by increased MLT secretion, such as seasonal affective disorder.

  16. 96-well electroporation method for transfection of mammalian central neurons.

    Science.gov (United States)

    Buchser, William J; Pardinas, Jose R; Shi, Yan; Bixby, John L; Lemmon, Vance P

    2006-11-01

    Manipulating gene expression in primary neurons has been a goal for many scientists for over 20 years. Vertebrate central nervous system neurons are classically difficult to transfect. Most lipid reagents are inefficient and toxic to the cells, and time-consuming methods such as viral infections are often required to obtain better efficiencies. We have developed an efficient method for the transfection of cerebellar granule neurons and hippocampal neurons with standard plasmid vectors. Using 96-well electroporation plates, square-wave pulses can introduce 96 different plasmids into neurons in a single step. The procedure results in greater than 20% transfection efficiencies and requires only simple solutions of nominal cost. In addition to enabling the rapid optimization of experimental protocols with multiple parameters, this procedure enables the use of high content screening methods to characterize neuronal phenotypes.

  17. The Role of the Serotonergic System in Locomotor Recovery after Spinal Cord Injury

    Directory of Open Access Journals (Sweden)

    Mousumi eGhosh

    2015-02-01

    Full Text Available Serotonin (5-HT, a monoamine neurotransmitter synthesized in various populations of brainstem neurons, plays an important role in modulating the activity of spinal networks involved in vertebrate locomotion. Following spinal cord injury (SCI there is a disruption of descending serotonergic projections to spinal motor areas, which results in a subsequent depletion in 5-HT, the dysregulation of serotonin transporters as well as the elevated expression, super-sensitivity and/or constitutive auto-activation of specific serotonin receptors. These changes in the serotonergic system can produce varying degrees of locomotor dysfunction through to paralysis. To date, various approaches targeting the different components of the serotonergic system have been employed to restore limb coordination and improve locomotor function in experimental models of SCI. These strategies have included pharmacological modulation of serotonergic receptors, through the administration of specific 5-HT receptor agonists, or by elevating the serotonin precursor 5-hydroxytryptophan, which produces a global activation of all classes of 5-HT receptors. Stimulation of these receptors leads to the activation of the locomotor central pattern generator (CPG below the site of injury to facilitate or improve the quality and frequency of movements, particularly when used in concert with the activation of other monoaminergic systems or coupled with electrical stimulation. Another approach has been to employ cell therapeutics to replace the loss of descending serotonergic input to the CPG, either through transplanted fetal brainstem 5-HT neurons at the site of injury that can supply 5-HT to below the level of the lesion or by other cell types to provide a substrate at the lesion for encouraging serotonergic axon regrowth across the lesion to the caudal spinal cord for restoring locomotion.

  18. Locomotor-activated neurons of the cat. I. Serotonergic innervation and co-localization of 5-HT7, 5-HT2A, and 5-HT1A receptors in the thoraco-lumbar spinal cord.

    Science.gov (United States)

    Noga, Brian R; Johnson, Dawn M G; Riesgo, Mirta I; Pinzon, Alberto

    2009-09-01

    Monoamines are strong modulators and/or activators of spinal locomotor networks. Thus monoaminergic fibers likely contact neurons involved in generating locomotion. The aim of the present study was to investigate the serotonergic innervation of locomotor-activated neurons within the thoraco-lumbar spinal cord following induction of hindlimb locomotion. This was determined by immunohistochemical co-localization of serotonin (5-HT) fibers or 5-HT(7)/5-HT2A/5-HT1A receptors with cells expressing the activity-dependent marker c-fos. Experiments were performed on paralyzed, decerebrate cats in which locomotion was induced by electrical stimulation of the mesencephalic locomotor region. Abundant c-fos immunoreactive cells were observed in laminae VII and VIII throughout the thoraco-lumbar segments of locomotor animals. Control sections from the same segments showed significantly fewer labeled neurons, mostly within the dorsal horn. Multiple serotonergic boutons were found in close apposition to the majority (80-100%) of locomotor cells, which were most abundant in lumbar segments L3-7. 5-HT7 receptor immunoreactivity was observed on cells across the thoraco-lumbar segments (T7-L7), in a dorsoventral gradient. Most locomotor-activated cells co-localized with 5-HT7, 5-HT2A, and 5-HT1A receptors, with largest numbers in laminae VII and VIII. Co-localization of c-fos and 5-HT7 receptor was highest in the L5-L7 segments (>90%) and decreased rostrally (to approximately 50%) due to the absence of receptors on cells within the intermediolateral nucleus. In contrast, 60-80 and 35-80% of c-fos immunoreactive cells stained positive for 5-HT2A and 5-HT1A receptors, respectively, with no rostrocaudal gradient. These results indicate that serotonergic modulation of locomotion likely involves 5-HT(7)/5-HT2A/5-HT1A receptors located on the soma and proximal dendrites of serotonergic-innervated locomotor-activated neurons within laminae VII and VIII of thoraco-lumbar segments.

  19. Neuronal activation in the central nervous system of rats in the initial stage of chronic kidney disease-modulatory effects of losartan and moxonidine.

    Science.gov (United States)

    Palkovits, Miklós; Šebeková, Katarína; Klenovics, Kristina Simon; Kebis, Anton; Fazeli, Gholamreza; Bahner, Udo; Heidland, August

    2013-01-01

    The effect of mild chronic renal failure (CRF) induced by 4/6-nephrectomy (4/6NX) on central neuronal activations was investigated by c-Fos immunohistochemistry staining and compared to sham-operated rats. In the 4/6 NX rats also the effect of the angiotensin receptor blocker, losartan, and the central sympatholyticum moxonidine was studied for two months. In serial brain sections Fos-immunoreactive neurons were localized and classified semiquantitatively. In 37 brain areas/nuclei several neurons with different functional properties were strongly affected in 4/6NX. It elicited a moderate to high Fos-activity in areas responsible for the monoaminergic innervation of the cerebral cortex, the limbic system, the thalamus and hypothalamus (e.g. noradrenergic neurons of the locus coeruleus, serotonergic neurons in dorsal raphe, histaminergic neurons in the tuberomamillary nucleus). Other monoaminergic cell groups (A5 noradrenaline, C1 adrenaline, medullary raphe serotonin neurons) and neurons in the hypothalamic paraventricular nucleus (innervating the sympathetic preganglionic neurons and affecting the peripheral sympathetic outflow) did not show Fos-activity. Stress- and pain-sensitive cortical/subcortical areas, neurons in the limbic system, the hypothalamus and the circumventricular organs were also affected by 4/6NX. Administration of losartan and more strongly moxonidine modulated most effects and particularly inhibited Fos-activity in locus coeruleus neurons. In conclusion, 4/6NX elicits high activity in central sympathetic, stress- and pain-related brain areas as well as in the limbic system, which can be ameliorated by losartan and particularly by moxonidine. These changes indicate a high sensitivity of CNS in initial stages of CKD which could be causative in clinical disturbances.

  20. Neuronal activation in the central nervous system of rats in the initial stage of chronic kidney disease-modulatory effects of losartan and moxonidine.

    Directory of Open Access Journals (Sweden)

    Miklós Palkovits

    Full Text Available The effect of mild chronic renal failure (CRF induced by 4/6-nephrectomy (4/6NX on central neuronal activations was investigated by c-Fos immunohistochemistry staining and compared to sham-operated rats. In the 4/6 NX rats also the effect of the angiotensin receptor blocker, losartan, and the central sympatholyticum moxonidine was studied for two months. In serial brain sections Fos-immunoreactive neurons were localized and classified semiquantitatively. In 37 brain areas/nuclei several neurons with different functional properties were strongly affected in 4/6NX. It elicited a moderate to high Fos-activity in areas responsible for the monoaminergic innervation of the cerebral cortex, the limbic system, the thalamus and hypothalamus (e.g. noradrenergic neurons of the locus coeruleus, serotonergic neurons in dorsal raphe, histaminergic neurons in the tuberomamillary nucleus. Other monoaminergic cell groups (A5 noradrenaline, C1 adrenaline, medullary raphe serotonin neurons and neurons in the hypothalamic paraventricular nucleus (innervating the sympathetic preganglionic neurons and affecting the peripheral sympathetic outflow did not show Fos-activity. Stress- and pain-sensitive cortical/subcortical areas, neurons in the limbic system, the hypothalamus and the circumventricular organs were also affected by 4/6NX. Administration of losartan and more strongly moxonidine modulated most effects and particularly inhibited Fos-activity in locus coeruleus neurons. In conclusion, 4/6NX elicits high activity in central sympathetic, stress- and pain-related brain areas as well as in the limbic system, which can be ameliorated by losartan and particularly by moxonidine. These changes indicate a high sensitivity of CNS in initial stages of CKD which could be causative in clinical disturbances.

  1. Serotonergic gene variation: implications for personality traits and psychopathology.

    Science.gov (United States)

    Lesch, K P

    1999-06-01

    Serotonin 5-hydroxytryptamine (5-HT) is an important regulator of morphogenetic activities during early central nervous system development, including cell proliferation, migration, and differentiation as well as synapto-genesis. Serotonergic raphe neurons diffusely project to a variety of brain regions (e.g. cortex, amygdala, hippocampus) and play known roles in integrating emotion, cognition, motor function as well as in food intake, sleep, pain, and sexual activity. The diversity of physiologic functions is due to the fact that 5-HT acts as a master control neurotransmitter within a highly complex system of neural communication mediated by multiple pre- and postsynaptic 5-HT receptors, thus orchestrating the activity and interaction of several other neurotransmitter systems. Since proteins involved in the regulation of central serotonergic activity (e.g. enzymes, receptors, transporter) play pivotal role in brain 5-HT homeostasis, polymorphisms in the regulatory regions of their genes resulting in variation of expression and function are likely to influence complex traits, such as temperament/personality and psychopathology.

  2. PROTEIN KINASES AND CENTRAL SENSITIZATION OF SPINAL DORSAL HORN NEURONS:CENTRAL MECHANISMS OF PAIN

    Institute of Scientific and Technical Information of China (English)

    QING LIN

    2003-01-01

    @@ The enhanced responsiveness of spinal dorsal horn neurons, including spinothalamic tract (STT) cells, that follows peripheral tissue injury or inflammation is thought to underlie the development of secondary hyperalgesia and allodynia and is referred to as "central sensitization" because the increases in excitability do not appear to depend on continued activity of peripheral nociceptors.

  3. Localization of Biogenic Amines in the Foregut of Aplysia californica: Catecholaminergic and Serotonergic Innervation

    Science.gov (United States)

    Martínez-Rubio, Clarissa; Serrano, Geidy E.; Miller, Mark W.

    2009-01-01

    This study examined the catecholaminergic and serotonergic innervation of the foregut of Aplysia californica, a model system in which the control of feeding behaviors can be investigated at the cellular level. Similar numbers (15-25) of serotonin-like-immunoreactive (5HTli) and tyrosine hydroxylase-like-immunoreactive (THli) fibers were present in each (bilateral) esophageal nerve (En), the major source of pregastric neural innervation in this system. The majority of En 5HTli and THli fibers originated from the anterior branch (En2), which innervates the pharynx and the anterior esophagus. Fewer fibers were present in the posterior branch (En1), which innervates the majority of the esophagus and the crop. Backfills of the two En branches toward the central nervous system (CNS) labeled a single, centrifugally projecting serotonergic fiber, originating from the metacerebral cell (MCC). The MCC fiber projected only to En2. No central THli neurons were found to project to the En. Surveys of the pharynx and esophagus revealed major differences between their patterns of catecholaminergic (CA) and serotonergic innervation. Whereas THli fibers and cell bodies were distributed throughout the foregut, 5HTli fibers were present in restricted plexi, and no 5HTli somata were detected. Double-labeling experiments in the periphery revealed THli neurons projecting toward the buccal ganglion via En2. Other afferents received dense perisomatic serotonergic innervation. Finally, qualitative and quantitative differences were observed between the buccal motor programs (BMPs) produced by stimulation of the two En branches. These observations increase our understanding of aminergic contributions to the pregastric regulation of Aplysia feeding behaviors. PMID:19330814

  4. Causes and consequences of hyperexcitation in central clock neurons.

    Directory of Open Access Journals (Sweden)

    Casey O Diekman

    Full Text Available Hyperexcited states, including depolarization block and depolarized low amplitude membrane oscillations (DLAMOs, have been observed in neurons of the suprachiasmatic nuclei (SCN, the site of the central mammalian circadian (~24-hour clock. The causes and consequences of this hyperexcitation have not yet been determined. Here, we explore how individual ionic currents contribute to these hyperexcited states, and how hyperexcitation can then influence molecular circadian timekeeping within SCN neurons. We developed a mathematical model of the electrical activity of SCN neurons, and experimentally verified its prediction that DLAMOs depend on post-synaptic L-type calcium current. The model predicts that hyperexcited states cause high intracellular calcium concentrations, which could trigger transcription of clock genes. The model also predicts that circadian control of certain ionic currents can induce hyperexcited states. Putting it all together into an integrative model, we show how membrane potential and calcium concentration provide a fast feedback that can enhance rhythmicity of the intracellular circadian clock. This work puts forward a novel role for electrical activity in circadian timekeeping, and suggests that hyperexcited states provide a general mechanism for linking membrane electrical dynamics to transcription activation in the nucleus.

  5. Central vagal stimulation activates enteric cholinergic neurons in the stomach and VIP neurons in the duodenum in conscious rats.

    Science.gov (United States)

    Yuan, Pu-Qing; Kimura, Hiroshi; Million, Mulugeta; Bellier, Jean-Pierre; Wang, Lixin; Ohning, Gordon V; Taché, Yvette

    2005-04-01

    The influence of central vagal stimulation induced by 2h cold exposure or intracisternal injection of thyrotropin-releasing hormone (TRH) analog, RX-77368, on gastro-duodenal enteric cholinergic neuronal activity was assessed in conscious rats with Fos and peripheral choline acetyltransferase (pChAT) immunoreactivity (IR). pChAT-IR was detected in 68%, 70% and 73% of corpus, antrum and duodenum submucosal neurons, respectively, and in 65% of gastric and 46% of duodenal myenteric neurons. Cold and RX-77368 induced Fos-IR in over 90% of gastric submucosal and myenteric neurons, while in duodenum only 25-27% of submucosal and 50-51% myenteric duodenal neurons were Fos positive. In the stomach, cold induced Fos-IR in 93% of submucosal and 97% of myenteric pChAT-IR neurons, while in the duodenum only 7% submucosal and 5% myenteric pChAT-IR neurons were Fos positive. In the duodenum, cold induced Fos in 91% of submucosal and 99% of myenteric VIP-IR neurons. RX-77368 induces similar percentages of Fos/pChAT-IR and Fos/VIP-IR neurons. These results indicate that increased central vagal outflow activates cholinergic neurons in the stomach while in the duodenum, VIP neurons are preferentially stimulated.

  6. Sodium entry during action potentials of mammalian central neurons: incomplete inactivation and reduced metabolic efficiency in fast-spiking neurons

    OpenAIRE

    Carter, Brett C.; Bean, Bruce P.

    2009-01-01

    We measured the time course of sodium entry during action potentials of mouse central neurons at 37 °C to examine how efficiently sodium entry is coupled to depolarization. In cortical pyramidal neurons, sodium entry was nearly completely confined to the rising phase of the spike: only ~25% more sodium enters than the theoretical minimum necessary for spike depolarization. However, in fast-spiking GABAergic neurons (cerebellar Purkinje cells and cortical interneurons), twice as much sodium en...

  7. Central projections of auditory receptor neurons of crickets.

    Science.gov (United States)

    Imaizumi, Kazuo; Pollack, Gerald S

    2005-12-19

    We describe the central projections of physiologically characterized auditory receptor neurons of crickets as revealed by confocal microscopy. Receptors tuned to ultrasonic frequencies (similar to those produced by echolocating, insectivorous bats), to a mid-range of frequencies, and a subset of those tuned to low, cricket-like frequencies have similar projections, terminating medially within the auditory neuropile. Quantitative analysis shows that despite the general similarity of these projections they are tonotopic, with receptors tuned to lower frequencies terminating more medially. Another subset of cricket-song-tuned receptors projects more laterally and posteriorly than the other types. Double-fills of receptors and identified interneurons show that the three medially projecting receptor types are anatomically well positioned to provide monosynaptic input to interneurons that relay auditory information to the brain and to interneurons that modify this ascending information. The more laterally and posteriorly branching receptor type may not interact directly with this ascending pathway, but is well positioned to provide direct input to an interneuron that carries auditory information to more posterior ganglia. These results suggest that information about cricket song is segregated into functionally different pathways as early as the level of receptor neurons. Ultrasound-tuned and mid-frequency tuned receptors have approximately twice as many varicosities, which are sites of transmitter release, per receptor as either anatomical type of cricket-song-tuned receptor. This may compensate in part for the numerical under-representation of these receptor types.

  8. Programming and reprogramming neuronal subtypes in the central nervous system.

    Science.gov (United States)

    Rouaux, Caroline; Bhai, Salman; Arlotta, Paola

    2012-07-01

    Recent discoveries in nuclear reprogramming have challenged the dogma that the identity of terminally differentiated cells cannot be changed. The identification of molecular mechanisms that reprogram differentiated cells to a new identity carries profound implications for regenerative medicine across organ systems. The central nervous system (CNS) has historically been considered to be largely immutable. However, recent studies indicate that even the adult CNS is imparted with the potential to change under the appropriate stimuli. Here, we review current knowledge regarding the capability of distinct cells within the CNS to reprogram their identity and consider the role of developmental signals in directing these cell fate decisions. Finally, we discuss the progress and current challenges of using developmental signals to precisely direct the generation of individual neuronal subtypes in the postnatal CNS and in the dish.

  9. Acute responsivity of the serotonergic system to S-citalopram and positive emotionality – the moderating role of the 5-HTTLPR

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    Catrin eWielpuetz

    2013-08-01

    Full Text Available According to the idea that the central serotonergic system has a modulatory function on behavior and personality in general, we aimed to highlight its association to habitual positive emotionality. In a placebo-controlled double-blind and randomized cross-over neuroendocrine challenge design (n = 72 healthy males we investigated the association of the central serotonergic responsivity, 5-HTTLPR-genotype as well as their combined effects on positive emotionality. Regression analyses revealed an involvement of the serotonergic system in positive emotionality. There was, however, no direct association between positive emotionality and cortisol responses to S-citalopram; rather 5-HTTLPR-genotype showed an association (p < .05. That is, positive emotionality scores increased with the number of s-alleles carried by the individuals. Most notable was the moderating role of 5-HTTLPR-genotype (p < .05 on the association between acute serotonergic responsivity and positive emotionality. Indeed, this association was only found in ss-homozygotes, in which the acute responsivity of the serotonergic system additionally seems to contribute to the level of positive emotionality (r = .70, p < .05. The findings correspond to previous research demonstrating that the 5-HTTLPR is not only involved in the negative-emotional aspects of behavior and temperament, but is associated, moreover, with positive affectivity – supporting the assumption of its valence-neutrality. In addition, our data are in line with the idea of possible influences of the 5-HTTLPR-genotype on early neuronal development. They also indicate the need for further studies in order to clearly elucidate the role of the serotonergic system and its subcomponents in the regulation of positive emotionality.

  10. Identified central neurons convey a mitogenic signal from a peripheral target to the CNS.

    Science.gov (United States)

    Becker, T S; Bothe, G; Berliner, A J; Macagno, E R

    1996-08-01

    Regulation of central neurogenesis by a peripheral target has been previously demonstrated in the ventral nerve cord of the leech Hirudo medicinalis (Baptista, C. A., Gershon, T. R. and Macagno, E. R. (1990). Nature 346, 855-858) Specifically, innervation of the male genitalia by the fifth and sixth segmental ganglia (the sex ganglia) was shown to trigger the birth of several hundred central neurons (PIC neurons) in these ganglia. As reported here, removal of the target early during induction shows that PIC neurons can be independently induced in each side of a ganglion, indicating that the inductive signal is both highly localized and conveyed to each hemiganglion independently. Further, since recent observations (Becker, T., Berliner, A. J., Nitabach, M. N., Gan, W.-B. and Macagno, E. R. (1995). Development, 121, 359-369) had indicated that efferent projections are probably involved in this phenomenon, we individually ablated all possible candidates, which led to the identification of two central neurons that appear to play significant roles in conveying the inductive signal to the CNS. Ablation of a single ML neuron reduced cell proliferation in its own hemiganglion by nearly 50%, on the average. In contrast, proliferation on the opposite side of the ganglion increased by about 25%, suggesting the possibility of a compensatory response by the remaining contralateral ML neuron. Simultaneous ablation of both ML neurons in a sex ganglion caused similar reductions in cell proliferation in each hemiganglion. Deletion of a single AL neuron produced a weaker (7%) but nonetheless reproducible reduction. Ablation of the other nine central neurons that might have been involved in PIC neuron induction had no detectable effect. Both ML and AL neurons exhibit ipsilateral peripheral projections, and both arborize mostly in the hemiganglion where they reside. Thus, we conclude that peripheral regulation of central neurogenesis is mediated in the leech by inductive signals

  11. Folic acid supplementation rescues anomalies associated with knockdown of parkin in dopaminergic and serotonergic neurons in Drosophila model of Parkinson's disease.

    Science.gov (United States)

    Srivastav, Saurabh; Singh, Sandeep Kumar; Yadav, Amarish Kumar; Srikrishna, Saripella

    2015-05-08

    parkin loss associated early-onset of Parkinson's disease, involves mitochondrial dysfunction and oxidative stress as the plausible decisive molecular mechanisms in disease pathogenesis. Mitochondrial dysfunction involves several up/down regulation of gene products, one of which being p53 is found to be elevated. Elevated p53 is involved in mitochondrial mediated apoptosis of neuronal cells in Parkinson's patients who are folate deficient as well. The present study therefore attempts to examine the effect of Folic acid (FA) supplementation in alleviation of anomalies associated with parkin knockdown using RNAi approach, specific to Dopaminergic (DA) neurons in Drosophila model system. Here we show that FA supplementation provide protection against parkin RNAi associated discrepancies, thereby improves locomotor ability, reduces mortality and oxidative stress, and partially improves Zn levels. Further, metabolic active cell status and ATP levels were also found to be improved thereby indicating improved mitochondrial function. To corroborate FA supplementation in mitochondrial functioning further, status of p53 and spargel was checked by qRT-PCR. Here we show that folic acid supplementation enrich mitochondrial functioning as depicted from improved spargel level and lowered p53 level, which was originally vice versa in parkin knockdown flies cultured in standard media. Our data thus support the potential of folic acid in alleviating the behavioural defects, oxidative stress, augmentation of zinc and ATP levels in parkin knock down flies. Further, folic acid role in repressing mitochondrial dysfunction is encouraging to further explore its possible mechanistic role to be utilized as potential therapeutics for Parkinson's disease.

  12. Fibroblast growth factor deficiencies impact anxiety-like behavior and the serotonergic system.

    Science.gov (United States)

    Brooks, Leah R; Enix, Courtney L; Rich, Samuel C; Magno, Jinno A; Lowry, Christopher A; Tsai, Pei-San

    2014-05-01

    Serotonergic neurons in the dorsal raphe nucleus (DR) are organized in anatomically distinct subregions that form connections with specific brain structures to modulate diverse behaviors, including anxiety-like behavior. It is unclear if the functional heterogeneity of these neurons is coupled to their developmental heterogeneity, and if abnormal development of specific DR serotonergic subregions can permanently impact anxiety circuits and behavior. The goal of this study was to examine if deficiencies in different components of fibroblast growth factor (Fgf) signaling could preferentially impact the development of specific populations of DR serotonergic neurons to alter anxiety-like behavior in adulthood. Wild-type and heterozygous male mice globally hypomorphic for Fgf8, Fgfr1, or both (Fgfr1/Fgf8) were tested in an anxiety-related behavioral battery. Both Fgf8- and Fgfr1/Fgf8-deficient mice display increased anxiety-like behavior as measured in the elevated plus-maze and the open-field tests. Immunohistochemical staining of a serotonergic marker, tryptophan hydroxylase (Tph), revealed reductions in specific populations of serotonergic neurons in the ventral, interfascicular, and ventrolateral/ventrolateral periaqueductal gray subregions of the DR in all Fgf-deficient mice, suggesting a neuroanatomical basis for increased anxiety-like behavior. Overall, this study suggests Fgf signaling selectively modulates the development of different serotonergic neuron subpopulations. Further, it suggests anxiety-like behavior may stem from developmental disruption of these neurons, and individuals with inactivating mutations in Fgf signaling genes may be predisposed to anxiety disorders.

  13. Central brain neurons expressing doublesex regulate female receptivity in Drosophila.

    Science.gov (United States)

    Zhou, Chuan; Pan, Yufeng; Robinett, Carmen C; Meissner, Geoffrey W; Baker, Bruce S

    2014-07-02

    Drosophila melanogaster females respond to male courtship by either rejecting the male or allowing copulation. The neural mechanisms underlying these female behaviors likely involve the integration of sensory information in the brain. Because doublesex (dsx) controls other aspects of female differentiation, we asked whether dsx-expressing neurons mediate virgin female receptivity to courting males. Using intersectional techniques to manipulate the activities of defined subsets of dsx-expressing neurons, we found that activation of neurons in either the pCd or pC1 clusters promotes receptivity, while silencing these neurons makes females unreceptive. Furthermore, pCd and pC1 neurons physiologically respond to the male-specific pheromone cis-vaccenyl acetate (cVA), while pC1 neurons also respond to male courtship song. The pCd and pC1 neurons expressing dsx in females do not express transcripts from the fruitless (fru) P1 promoter. Thus, virgin female receptivity is controlled at least in part by neurons that are distinct from those governing male courtship.

  14. Neuronal expression of glucosylceramide synthase in central nervous system regulates body weight and energy homeostasis.

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    Viola Nordström

    Full Text Available Hypothalamic neurons are main regulators of energy homeostasis. Neuronal function essentially depends on plasma membrane-located gangliosides. The present work demonstrates that hypothalamic integration of metabolic signals requires neuronal expression of glucosylceramide synthase (GCS; UDP-glucose:ceramide glucosyltransferase. As a major mechanism of central nervous system (CNS metabolic control, we demonstrate that GCS-derived gangliosides interacting with leptin receptors (ObR in the neuronal membrane modulate leptin-stimulated formation of signaling metabolites in hypothalamic neurons. Furthermore, ganglioside-depleted hypothalamic neurons fail to adapt their activity (c-Fos in response to alterations in peripheral energy signals. Consequently, mice with inducible forebrain neuron-specific deletion of the UDP-glucose:ceramide glucosyltransferase gene (Ugcg display obesity, hypothermia, and lower sympathetic activity. Recombinant adeno-associated virus (rAAV-mediated Ugcg delivery to the arcuate nucleus (Arc significantly ameliorated obesity, specifying gangliosides as seminal components for hypothalamic regulation of body energy homeostasis.

  15. From behavioral context to receptors: serotonergic modulatory pathways in the IC.

    Science.gov (United States)

    Hurley, Laura M; Sullivan, Megan R

    2012-01-01

    In addition to ascending, descending, and lateral auditory projections, inputs extrinsic to the auditory system also influence neural processing in the inferior colliculus (IC). These types of inputs often have an important role in signaling salient factors such as behavioral context or internal state. One route for such extrinsic information is through centralized neuromodulatory networks like the serotonergic system. Serotonergic inputs to the IC originate from centralized raphe nuclei, release serotonin in the IC, and activate serotonin receptors expressed by auditory neurons. Different types of serotonin receptors act as parallel pathways regulating specific features of circuitry within the IC. This results from variation in subcellular localizations and effector pathways of different receptors, which consequently influence auditory responses in distinct ways. Serotonin receptors may regulate GABAergic inhibition, influence response gain, alter spike timing, or have effects that are dependent on the level of activity. Serotonin receptor types additionally interact in nonadditive ways to produce distinct combinatorial effects. This array of effects of serotonin is likely to depend on behavioral context, since the levels of serotonin in the IC transiently increase during behavioral events including stressful situations and social interaction. These studies support a broad model of serotonin receptors as a link between behavioral context and reconfiguration of circuitry in the IC, and the resulting possibility that plasticity at the level of specific receptor types could alter the relationship between context and circuit function.

  16. Identification of genes influencing dendrite morphogenesis in developing peripheral sensory and central motor neurons

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    Chwalla Barbara

    2008-07-01

    Full Text Available Abstract Background Developing neurons form dendritic trees with cell type-specific patterns of growth, branching and targeting. Dendrites of Drosophila peripheral sensory neurons have emerged as a premier genetic model, though the molecular mechanisms that underlie and regulate their morphogenesis remain incompletely understood. Still less is known about this process in central neurons and the extent to which central and peripheral dendrites share common organisational principles and molecular features. To address these issues, we have carried out two comparable gain-of-function screens for genes that influence dendrite morphologies in peripheral dendritic arborisation (da neurons and central RP2 motor neurons. Results We found 35 unique loci that influenced da neuron dendrites, including five previously shown as required for da dendrite patterning. Several phenotypes were class-specific and many resembled those of known mutants, suggesting that genes identified in this study may converge with and extend known molecular pathways for dendrite development in da neurons. The second screen used a novel technique for cell-autonomous gene misexpression in RP2 motor neurons. We found 51 unique loci affecting RP2 dendrite morphology, 84% expressed in the central nervous system. The phenotypic classes from both screens demonstrate that gene misexpression can affect specific aspects of dendritic development, such as growth, branching and targeting. We demonstrate that these processes are genetically separable. Targeting phenotypes were specific to the RP2 screen, and we propose that dendrites in the central nervous system are targeted to territories defined by Cartesian co-ordinates along the antero-posterior and the medio-lateral axes of the central neuropile. Comparisons between the screens suggest that the dendrites of peripheral da and central RP2 neurons are shaped by regulatory programs that only partially overlap. We focused on one common

  17. Distribution of SMI-32-immunoreactive neurons in the central auditory system of the rat.

    Science.gov (United States)

    Ouda, Ladislav; Druga, Rastislav; Syka, Josef

    2012-01-01

    SMI-32 antibody recognizes a non-phosphorylated epitope of neurofilament proteins, which are thought to be necessary for the maintenance of large neurons with highly myelinated processes. We investigated the distribution and quantity of SMI-32-immunoreactive(-ir) neurons in individual parts of the rat auditory system. SMI-32-ir neurons were present in all auditory structures; however, in most regions they constituted only a minority of all neurons (10-30%). In the cochlear nuclei, a higher occurrence of SMI-32-ir neurons was found in the ventral cochlear nucleus. Within the superior olivary complex, SMI-32-ir cells were particularly abundant in the medial nucleus of the trapezoid body (MNTB), the only auditory region where SMI-32-ir neurons constituted an absolute majority of all neurons. In the inferior colliculus, a region with the highest total number of neurons among the rat auditory subcortical structures, the percentage of SMI-32-ir cells was, in contrast to the MNTB, very low. In the medial geniculate body, SMI-32-ir neurons were prevalent in the ventral division. At the cortical level, SMI-32-ir neurons were found mainly in layers III, V and VI. Within the auditory cortex, it was possible to distinguish the Te1, Te2 and Te3 areas on the basis of the variable numerical density and volumes of SMI-32-ir neurons, especially when the pyramidal cells of layer V were taken into account. SMI-32-ir neurons apparently form a representative subpopulation of neurons in all parts of the rat central auditory system and may belong to both the inhibitory and excitatory systems, depending on the particular brain region.

  18. A modeling approach on why simple central pattern generators are built of irregular neurons.

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    Marcelo Bussotti Reyes

    Full Text Available The crustacean pyloric Central Pattern Generator (CPG is a nervous circuit that endogenously provides periodic motor patterns. Even after about 40 years of intensive studies, the rhythm genesis is still not rigorously understood in this CPG, mainly because it is made of neurons with irregular intrinsic activity. Using mathematical models we addressed the question of using a network of irregularly behaving elements to generate periodic oscillations, and we show some advantages of using non-periodic neurons with intrinsic behavior in the transition from bursting to tonic spiking (as found in biological pyloric CPGs as building components. We studied two- and three-neuron model CPGs built either with Hindmarsh-Rose or with conductance-based Hodgkin-Huxley-like model neurons. By changing a model's parameter we could span the neuron's intrinsic dynamical behavior from slow periodic bursting to fast tonic spiking, passing through a transition where irregular bursting was observed. Two-neuron CPG, half center oscillator (HCO, was obtained for each intrinsic behavior of the neurons by coupling them with mutual symmetric synaptic inhibition. Most of these HCOs presented regular antiphasic bursting activity and the changes of the bursting frequencies was studied as a function of the inhibitory synaptic strength. Among all HCOs, those made of intrinsic irregular neurons presented a wider burst frequency range while keeping a reliable regular oscillatory (bursting behavior. HCOs of periodic neurons tended to be either hard to change their behavior with synaptic strength variations (slow periodic burster neurons or unable to perform a physiologically meaningful rhythm (fast tonic spiking neurons. Moreover, 3-neuron CPGs with connectivity and output similar to those of the pyloric CPG presented the same results.

  19. A modeling approach on why simple central pattern generators are built of irregular neurons.

    Science.gov (United States)

    Reyes, Marcelo Bussotti; Carelli, Pedro Valadão; Sartorelli, José Carlos; Pinto, Reynaldo Daniel

    2015-01-01

    The crustacean pyloric Central Pattern Generator (CPG) is a nervous circuit that endogenously provides periodic motor patterns. Even after about 40 years of intensive studies, the rhythm genesis is still not rigorously understood in this CPG, mainly because it is made of neurons with irregular intrinsic activity. Using mathematical models we addressed the question of using a network of irregularly behaving elements to generate periodic oscillations, and we show some advantages of using non-periodic neurons with intrinsic behavior in the transition from bursting to tonic spiking (as found in biological pyloric CPGs) as building components. We studied two- and three-neuron model CPGs built either with Hindmarsh-Rose or with conductance-based Hodgkin-Huxley-like model neurons. By changing a model's parameter we could span the neuron's intrinsic dynamical behavior from slow periodic bursting to fast tonic spiking, passing through a transition where irregular bursting was observed. Two-neuron CPG, half center oscillator (HCO), was obtained for each intrinsic behavior of the neurons by coupling them with mutual symmetric synaptic inhibition. Most of these HCOs presented regular antiphasic bursting activity and the changes of the bursting frequencies was studied as a function of the inhibitory synaptic strength. Among all HCOs, those made of intrinsic irregular neurons presented a wider burst frequency range while keeping a reliable regular oscillatory (bursting) behavior. HCOs of periodic neurons tended to be either hard to change their behavior with synaptic strength variations (slow periodic burster neurons) or unable to perform a physiologically meaningful rhythm (fast tonic spiking neurons). Moreover, 3-neuron CPGs with connectivity and output similar to those of the pyloric CPG presented the same results.

  20. Neuronal chemokines : Versatile messengers in central nervous system cell interaction

    NARCIS (Netherlands)

    de Haas, A. H.; van Weering, H. R. J.; de Jong, E. K.; Boddeke, H. W. G. M.; Biber, K. P. H.

    2007-01-01

    Whereas chemokines are well known for their ability to induce cell migration, only recently it became evident that chemokines also control a variety of other cell functions and are versatile messengers in the interaction between a diversity of cell types. In the central nervous system (CNS), chemoki

  1. Central control of circadian phase in arousal-promoting neurons.

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    Carrie E Mahoney

    Full Text Available Cells of the dorsomedial/lateral hypothalamus (DMH/LH that produce hypocretin (HCRT promote arousal in part by activation of cells of the locus coeruleus (LC which express tyrosine hydroxylase (TH. The suprachiasmatic nucleus (SCN drives endogenous daily rhythms, including those of sleep and wakefulness. These circadian oscillations are generated by a transcriptional-translational feedback loop in which the Period (Per genes constitute critical components. This cell-autonomous molecular clock operates not only within the SCN but also in neurons of other brain regions. However, the phenotype of such neurons and the nature of the phase controlling signal from the pacemaker are largely unknown. We used dual fluorescent in situ hybridization to assess clock function in vasopressin, HCRT and TH cells of the SCN, DMH/LH and LC, respectively, of male Syrian hamsters. In the first experiment, we found that Per1 expression in HCRT and TH oscillated in animals held in constant darkness with a peak phase that lagged that in AVP cells of the SCN by several hours. In the second experiment, hamsters induced to split their locomotor rhythms by exposure to constant light had asymmetric Per1 expression within cells of the middle SCN at 6 h before activity onset (AO and in HCRT cells 9 h before and at AO. We did not observe evidence of lateralization of Per1 expression in the LC. We conclude that the SCN communicates circadian phase to HCRT cells via lateralized neural projections, and suggests that Per1 expression in the LC may be regulated by signals of a global or bilateral nature.

  2. Serotonergic neurotransmission in emotional processing

    DEFF Research Database (Denmark)

    Laursen, Helle Ruff; Henningsson, Susanne; Macoveanu, Julian;

    2016-01-01

    ,4-methylene-dioxymethamphetamine [MDMA]) induces alterations in serotonergic neurotransmission that are comparable to those observed in a depleted state. In this functional magnetic resonance imaging (fMRI) study, we investigated the responsiveness of the amygdala to emotional face stimuli in recreational...

  3. Peripheral nervous system genes expressed in central neurons induce growth on inhibitory substrates.

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    William J Buchser

    Full Text Available Trauma to the spinal cord and brain can result in irreparable loss of function. This failure of recovery is in part due to inhibition of axon regeneration by myelin and chondroitin sulfate proteoglycans (CSPGs. Peripheral nervous system (PNS neurons exhibit increased regenerative ability compared to central nervous system neurons, even in the presence of inhibitory environments. Previously, we identified over a thousand genes differentially expressed in PNS neurons relative to CNS neurons. These genes represent intrinsic differences that may account for the PNS's enhanced regenerative ability. Cerebellar neurons were transfected with cDNAs for each of these PNS genes to assess their ability to enhance neurite growth on inhibitory (CSPG or permissive (laminin substrates. Using high content analysis, we evaluated the phenotypic profile of each neuron to extract meaningful data for over 1100 genes. Several known growth associated proteins potentiated neurite growth on laminin. Most interestingly, novel genes were identified that promoted neurite growth on CSPGs (GPX3, EIF2B5, RBMX. Bioinformatic approaches also uncovered a number of novel gene families that altered neurite growth of CNS neurons.

  4. Peripheral nervous system genes expressed in central neurons induce growth on inhibitory substrates.

    Science.gov (United States)

    Buchser, William J; Smith, Robin P; Pardinas, Jose R; Haddox, Candace L; Hutson, Thomas; Moon, Lawrence; Hoffman, Stanley R; Bixby, John L; Lemmon, Vance P

    2012-01-01

    Trauma to the spinal cord and brain can result in irreparable loss of function. This failure of recovery is in part due to inhibition of axon regeneration by myelin and chondroitin sulfate proteoglycans (CSPGs). Peripheral nervous system (PNS) neurons exhibit increased regenerative ability compared to central nervous system neurons, even in the presence of inhibitory environments. Previously, we identified over a thousand genes differentially expressed in PNS neurons relative to CNS neurons. These genes represent intrinsic differences that may account for the PNS's enhanced regenerative ability. Cerebellar neurons were transfected with cDNAs for each of these PNS genes to assess their ability to enhance neurite growth on inhibitory (CSPG) or permissive (laminin) substrates. Using high content analysis, we evaluated the phenotypic profile of each neuron to extract meaningful data for over 1100 genes. Several known growth associated proteins potentiated neurite growth on laminin. Most interestingly, novel genes were identified that promoted neurite growth on CSPGs (GPX3, EIF2B5, RBMX). Bioinformatic approaches also uncovered a number of novel gene families that altered neurite growth of CNS neurons.

  5. A role of melanin-concentrating hormone producing neurons in the central regulation of paradoxical sleep

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    Salin Paul

    2003-09-01

    Full Text Available Abstract Background Peptidergic neurons containing the melanin-concentrating hormone (MCH and the hypocretins (or orexins are intermingled in the zona incerta, perifornical nucleus and lateral hypothalamic area. Both types of neurons have been implicated in the integrated regulation of energy homeostasis and body weight. Hypocretin neurons have also been involved in sleep-wake regulation and narcolepsy. We therefore sought to determine whether hypocretin and MCH neurons express Fos in association with enhanced paradoxical sleep (PS or REM sleep during the rebound following PS deprivation. Next, we compared the effect of MCH and NaCl intracerebroventricular (ICV administrations on sleep stage quantities to further determine whether MCH neurons play an active role in PS regulation. Results Here we show that the MCH but not the hypocretin neurons are strongly active during PS, evidenced through combined hypocretin, MCH, and Fos immunostainings in three groups of rats (PS Control, PS Deprived and PS Recovery rats. Further, we show that ICV administration of MCH induces a dose-dependant increase in PS (up to 200% and slow wave sleep (up to 70% quantities. Conclusion These results indicate that MCH is a powerful hypnogenic factor. MCH neurons might play a key role in the state of PS via their widespread projections in the central nervous system.

  6. Peripheral Nervous System Genes Expressed in Central Neurons Induce Growth on Inhibitory Substrates

    Science.gov (United States)

    Buchser, William J.; Smith, Robin P.; Pardinas, Jose R.; Haddox, Candace L.; Hutson, Thomas; Moon, Lawrence; Hoffman, Stanley R.; Bixby, John L.; Lemmon, Vance P.

    2012-01-01

    Trauma to the spinal cord and brain can result in irreparable loss of function. This failure of recovery is in part due to inhibition of axon regeneration by myelin and chondroitin sulfate proteoglycans (CSPGs). Peripheral nervous system (PNS) neurons exhibit increased regenerative ability compared to central nervous system neurons, even in the presence of inhibitory environments. Previously, we identified over a thousand genes differentially expressed in PNS neurons relative to CNS neurons. These genes represent intrinsic differences that may account for the PNS’s enhanced regenerative ability. Cerebellar neurons were transfected with cDNAs for each of these PNS genes to assess their ability to enhance neurite growth on inhibitory (CSPG) or permissive (laminin) substrates. Using high content analysis, we evaluated the phenotypic profile of each neuron to extract meaningful data for over 1100 genes. Several known growth associated proteins potentiated neurite growth on laminin. Most interestingly, novel genes were identified that promoted neurite growth on CSPGs (GPX3, EIF2B5, RBMX). Bioinformatic approaches also uncovered a number of novel gene families that altered neurite growth of CNS neurons. PMID:22701605

  7. Vasoactive intestinal polypeptide cerebrospinal fluid-contacting neurons of the monkey and cat spinal central canal.

    Science.gov (United States)

    LaMotte, C C

    1987-04-22

    Neurons immediately adjacent to the central canal were demonstrated in the cat and monkey to be immunoreactive for the peptide vasoactive intestinal polypeptide (VIP), by means of the peroxidase antiperoxidase method. Most of the cells were found in the thoracic and sacral segments, although a few were present at each level. The thoracic neurons were multipolar and either ependymal or subependymal; they usually had a large, thick dendrite that was oriented radially toward the center of the central canal; this dendrite penetrated through the ependymal layer and ended as a large, fringed podlike process (4-5-microns diameter) along the canal surface in contact with the cerebrospinal fluid (CSF). From the basal surface of the thoracic cell arose several small dendrites and a varicose axon. A few of the thoracic VIP neurons also contained two nuclei. In the sacral cord, the VIP neurons that lie along the central canal were of several types. They were round or multipolar and were either subependymal, within the ependyma, or supraependymal. Many had long dendrites and thin varicose axons stretching for long distances parallel to the cord surface. Other VIP neurons were smaller cells with short, highly branched, varicose processes. Most prominent in the sacral cord of the cat was a massive intricate network of intensely labelled processes extending in parallel along the canal surface. This network contained thick dendrites, highly varicose axons, and small neurons. Electron microscopy demonstrated VIP axons and varicosities containing small round clear vesicles and dense core vesicles. These processes were in desmosomal contact with ependymal cells and in direct contact with the CSF space. VIP processes were also found along the pial surface of the spinal cord at each level. In some cases single axons and bundles of axons arising from the area around the central canal could be traced to terminal fields along the ventral median fissure and the ventral and ventral lateral

  8. Activation of mesolimbic dopaminergic neurons following central administration of histamine is mediated by H1 receptors.

    Science.gov (United States)

    Fleckenstein, A E; Lookingland, K J; Moore, K E

    1993-01-01

    The effect of intracerebroventricular administration of histamine on the activity of mesolimbic and nigrostriatal dopaminergic (DA) neurons was determined in male rats. The activity of these neurons was estimated by measuring: (1) the accumulation of 3,4-dihydroxyphenylalanine (DOPA) after administration of a decarboxylase inhibitor, and (2) the concentration of 3,4-dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens and striatum, which contain the terminals of these neurons. Central administration of histamine increased both DOPA accumulation and DOPAC concentrations in the nucleus accumbens, but was without effect in the striatum. The increase in DOPAC concentrations in the nucleus accumbens occurred within 10 min and was sustained for at least 120 min. The H1 antagonist mepyramine blocked whereas the H2 antagonist zolantidine did not affect histamine-induced increases in DOPAC concentrations in the nucleus accumbens. Neither mepyramine nor zolantidine affected basal DOPAC concentrations in the nucleus accumbens. These results indicate that central administration of histamine stimulates mesolimbic DA neurons through an action at the H1 receptor, but has no effect upon the activity of nigrostriatal DA neurons.

  9. Serotonergic modulation of reward and punishment

    DEFF Research Database (Denmark)

    Macoveanu, Julian

    2014-01-01

    Until recently, the bulk of research on the human reward system was focused on studying the dopaminergic and opioid neurotransmitter systems. However, extending the initial data from animal studies on reward, recent pharmacological brain imaging studies on human participants bring a new line...... of evidence on the key role serotonin plays in reward processing. The reviewed research has revealed how central serotonin availability and receptor specific transmission modulates the neural response to both appetitive (rewarding) and aversive (punishing) stimuli in putative reward-related brain regions......-related processing and may also provide a neural correlated for the emotional blunting observed in the clinical treatment of psychiatric disorders with selective serotonin reuptake inhibitors. Given the unique profile of action of each serotonergic receptor subtype, future pharmacological studies may favor receptor...

  10. Pyrethroids differentially alter voltage-gated sodium channels from the honeybee central olfactory neurons.

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    Aklesso Kadala

    Full Text Available The sensitivity of neurons from the honey bee olfactory system to pyrethroid insecticides was studied using the patch-clamp technique on central 'antennal lobe neurons' (ALNs in cell culture. In these neurons, the voltage-dependent sodium currents are characterized by negative potential for activation, fast kinetics of activation and inactivation, and the presence of cumulative inactivation during train of depolarizations. Perfusion of pyrethroids on these ALN neurons submitted to repetitive stimulations induced (1 an acceleration of cumulative inactivation, and (2 a marked slowing of the tail current recorded upon repolarization. Cypermethrin and permethrin accelerated cumulative inactivation of the sodium current peak in a similar manner and tetramethrin was even more effective. The slow-down of channel deactivation was markedly dependent on the type of pyrethroid. With cypermethrin, a progressive increase of the tail current amplitude along with successive stimulations reveals a traditionally described use-dependent recruitment of modified sodium channels. However, an unexpected decrease in this tail current was revealed with tetramethrin. If one considers the calculated percentage of modified channels as an index of pyrethroids effects, ALNs are significantly more susceptible to tetramethrin than to permethrin or cypermethrin for a single depolarization, but this difference attenuates with repetitive activity. Further comparison with peripheral neurons from antennae suggest that these modifications are neuron type specific. Modeling the sodium channel as a multi-state channel with fast and slow inactivation allows to underline the effects of pyrethroids on a set of rate constants connecting open and inactivated conformations, and give some insights to their specificity. Altogether, our results revealed a differential sensitivity of central olfactory neurons to pyrethroids that emphasize the ability for these compounds to impair detection and

  11. A central neuropathic pain model by DSP-4 induced lesion of noradrenergic neurons: preliminary report.

    Science.gov (United States)

    Kudo, Takashi; Kushikata, Tetsuya; Kudo, Mihoko; Kudo, Tsuyoshi; Hirota, Kazuyoshi

    2010-09-06

    Neuropathic pain models are classified as central and peripheral pain models. Although various peripheral neuropathic pain models are established, central pain models are based only on spinal cord injury. DSP-4 is a competitive inhibitor of norepinephrine uptake that selectively degenerates the locus coeruleus (LC)-noradrenergic neurons projection to the cerebral cortex and hippocampus. In the present study, we have tested whether lesion of LC-noradrenergic neurons by ip DSP-4 (0, 10, 30, 50 mg/kg, n=7 each) could provide a new central neuropathic pain model in rats using a hot-plate and tail-flick tests. DSP-4 significantly reduced the hot-plate latency and norepinephrine contents especially in the coerulean regions. However, DSP-4 did not change tail-flick latency. There are significant correlations of the latency in the hot-plate test with norepinephrine contents in the cerebral cortex (r=0.432, p=0.022), the hippocampus (r=0.465, p=0.013) and the pons (r=0.400, p=0.035) but not with those in the hypothalamus and the spinal cord. As response to hot-plate and tail-flick implies supra-spinal process and spinal reflex, respectively, central neuropathic pain may be facilitated by DSP-4 depleting LC-noradrenergic neurons although the present data are preliminary.

  12. Fibroblast growth factor 8 deficiency compromises the functional response of the serotonergic system to stress.

    Directory of Open Access Journals (Sweden)

    Leah R Brooks

    Full Text Available Functionally heterogeneous populations of serotonergic neurons, located within the dorsal raphe nucleus (DR, play a role in stress-related behaviors and neuropsychiatric illnesses such as anxiety and depression. Abnormal development of these neurons may permanently alter their structure and connections, making the organism more susceptible to anxiety-related disorders. A factor that critically regulates the development of serotonergic neurons is fibroblast growth factor 8 (Fgf8. In this study, we used acute restraint stress followed by behavioral testing to examine whether Fgf8 signaling during development is important for establishing functional stress- and anxiety-related DR neurocircuits in adulthood. Wild-type and heterozygous male mice globally hypomorphic for Fgf8 were exposed to acute restraint stress and then tested for anxiety-like behavior on the elevated plus-maze. Further, we measured c-Fos immunostaining as a marker of serotonergic neuronal activation and tissue 5-hydroxyindoleacetic acid concentrations as a marker of serotonin functional output. Results showed that Fgf8 hypomorphs exhibited 1 an exaggerated response of DR anxiety-promoting circuits and 2 a blunted response of a DR panic-inhibiting circuit to stress, effects that together were associated with increased baseline anxiety-like behavior. Overall, our results provide a neural substrate upon which Fgf8 deficiency could affect stress response and support the hypothesis that developmental disruptions of serotonergic neurons affect their postnatal functional integrity.

  13. Emergent Central Pattern Generator Behavior in Gap-Junction-Coupled Hodgkin-Huxley Style Neuron Model

    Directory of Open Access Journals (Sweden)

    Kyle G. Horn

    2012-01-01

    Full Text Available Most models of central pattern generators (CPGs involve two distinct nuclei mutually inhibiting one another via synapses. Here, we present a single-nucleus model of biologically realistic Hodgkin-Huxley neurons with random gap junction coupling. Despite no explicit division of neurons into two groups, we observe a spontaneous division of neurons into two distinct firing groups. In addition, we also demonstrate this phenomenon in a simplified version of the model, highlighting the importance of afterhyperpolarization currents ( to CPGs utilizing gap junction coupling. The properties of these CPGs also appear sensitive to gap junction conductance, probability of gap junction coupling between cells, topology of gap junction coupling, and, to a lesser extent, input current into our simulated nucleus.

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

    Directory of Open Access Journals (Sweden)

    Dieter Wicher

    2007-12-01

    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.

  15. Effect of destruction of central noradrenergic and serotonergic nerve terminals by systemic neurotoxins on the long-term effects of antidepressants on. beta. -adrenoceptors and 5-HT/sub 2/ binding sites in the rat cerebral cortex

    Energy Technology Data Exchange (ETDEWEB)

    Hall, H.; Ross, S.B.; Saellemark, M. (Astra Pharmaceuticals AB, Soedertaelje (Sweden))

    1984-01-01

    The dependence of intact noradrenergic and serotonergic nerve terminals for the decrease in the number of ..beta..-adrenoceptors and 5-HT/sub 2/ binding sites in the cerebral cortex produced by long-term treatment of rats with antidepressant drugs was examined. Noradrenergic nerve terminals were destroyed with the selective noradrenaline neurotoxin DSP4, and serotonergic nerve terminals were destroyed with p-chloroamphetamine (PCA). It was found that lesioning of the noradrenergic nerve terminals abolished the decrease in ..beta..-adrenoceptors produced by desipramine, mianserin and zimeldine and partially antagonized that of the ..beta..-adrenoceptor agonist clenbuterol. PCA pretreatment did not antagonize the long-term effects on the ..beta..-adrenoceptor produced by these compounds. Lesioning of serotonergic nerve terminals affected the down-regulation of 5-HT/sub 2/ binding sites produced by long-term treatment with mianserin, desipramine and amiflamine. DSP4 pretreatment partially abolished the down-regulation of 5-HT/sub 2/ binding sites produced by long-term treatment with desipramine, while the effects of mianserin and amiflamine were inaffected by pretreatment with DSP4.

  16. Hypothalamic vasopressinergic projections innervate central amygdala GABAergic neurons: implications for anxiety and stress coping

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    Vito Salvador Hernandez

    2016-11-01

    Full Text Available The arginine-vasopressin (AVP-containing hypothalamic magnocellular neurosecretory neurons (VPMNNs are known for their role in hydro-electrolytic balance control via their projections to neurohypophysis. Recently, projections from these same neurons to hippocampus, habenula, and other brain regions, in which vasopressin infusion modulates contingent social and emotionally-affected behaviors, have been reported. Here, we present evidence that VPMNN collaterals also project to the amygdaloid complex, and establish synaptic connections with neurons in central amygdala (CeA. The density of AVP innervation in amygdala was substantially increased in adult rats that had experienced neonatal maternal separation (MS, consistent with our previous observations that MS enhances VPMNN number in the paraventricular (PVN and supraoptic (SON nuclei of the hypothalamus. In the CeA, V1a AVP receptor mRNA was only observed in GABAergic neurons, demonstrated by complete co-localization of V1a transcripts in neurons expressing Gad1 and Gad2 transcripts in CeA using the RNAscope method. V1b and V2 receptors mRNA were not detected, using the same method. Water-deprivation for 24 hrs, which increased the metabolic activity of VPMNNs, also increased anxiety-like behavior measured using the elevated plus maze test, and this effect was mimicked by bilateral microinfusion of VP into the CeA. Anxious behavior induced by either water deprivation or VP infusion was reversed by CeA infusion of V1a antagonist. VPMNNs are thus a newly discovered source of central amygdala inhibitory circuit modulation, through which both early-life and adult stress coping signals are conveyed from the hypothalamus to the amygdala.

  17. Co-localization of Gamma-Aminobutyric Acid and Glutamate in Neurons of the Spider Central Nervous System.

    Science.gov (United States)

    Fabian-Fine, Ruth; Meisner, Shannon; Torkkeli, Päivi H; Meinertzhagen, Ian A

    2015-12-01

    Spider sensory neurons with cell bodies close to various sensory organs are innervated by putative efferent axons from the central nervous system (CNS). Light and electronmicroscopic imaging of immunolabeled neurons has demonstrated that neurotransmitters present at peripheral synapses include γ-aminobutyric acid (GABA), glutamate and octopamine. Moreover, electrophysiological studies show that these neurotransmitters modulate the sensitivity of peripheral sensory neurons. Here, we undertook immunocytochemical investigations to characterize GABA and glutamate-immunoreactive neurons in three-dimensional reconstructions of the spider CNS. We document that both neurotransmitters are abundant in morphologically distinct neurons throughout the CNS. Labeling for the vesicular transporters, VGAT for GABA and VGLUT for glutamate, showed corresponding patterns, supporting the specificity of antibody binding. Whereas some neurons displayed strong immunolabeling, others were only weakly labeled. Double labeling showed that a subpopulation of weakly labeled neurons present in all ganglia expresses both GABA and glutamate. Double labeled, strongly and weakly labeled GABA and glutamate immunoreactive axons were also observed in the periphery along muscle fibers and peripheral sensory neurons. Electron microscopic investigations showed presynaptic profiles of various diameters with mixed vesicle populations innervating muscle tissue as well as sensory neurons. Our findings provide evidence that: (1) sensory neurons and muscle fibers are innervated by morphologically distinct, centrally located GABA- and glutamate immunoreactive neurons; (2) a subpopulation of these neurons may co-release both neurotransmitters; and (3) sensory neurons and muscles are innervated by all of these neurochemically and morphologically distinct types of neurons. The biochemical diversity of presynaptic innervation may contribute to how spiders filter natural stimuli and coordinate appropriate response

  18. Neuronal influence behind the central nervous system regulation of the immune cells

    Directory of Open Access Journals (Sweden)

    ANAHI eCHAVARRIA

    2013-09-01

    Full Text Available Central nervous system has a highly specialized microenvironment, and despite being initially considered an immune privileged site, this immune status is far from absolute because it varies with age and brain topography. The brain monitors immune responses by several means that act in parallel; one pathway involves afferent nerves (vagal nerve and the other resident cells (neurons and glia. These cell populations exert a strong role in the regulation of the immune system, favoring an immune-modulatory environment in the CNS. Neurons control glial cell and infiltrated T-cells by contact-dependent and -independent mechanisms. Contact-dependent mechanisms are provided by several membrane immune modulating molecules such as Sema-7A, CD95L, CD22, CD200, CD47, NCAM, ICAM-5 and cadherins; which can inhibit the expression of microglial inflammatory cytokines, induce apoptosis or inactivate infiltrated T-cells. On the other hand, soluble neuronal factors like Sema-3A, cytokines, neurotrophins, neuropeptides, and neurotransmitters attenuate microglial and/or T-cell activation. In this review, we focused on all known mechanism driven only by neurons in order to control the local immune cells.

  19. Neuronal classification and distribution in the central nervous system of the female mud crab, Scylla olivacea.

    Science.gov (United States)

    Kornthong, Napamanee; Tinikul, Yotsawan; Khornchatri, Kanjana; Saeton, Jirawat; Magerd, Sirilug; Suwansa-Ard, Saowaros; Kruangkum, Thanapong; Hanna, Peter J; Sobhon, Prasert

    2014-03-01

    The mud crab, Scylla olivacea, is one of the most economically valuable marine species in Southeast Asian countries. However, commercial cultivation is disadvantaged by reduced reproductive capacity in captivity. Therefore, an understanding of the general and detailed anatomy of central nervous system (CNS) is required before investigating the distribution and functions of neurotransmitters, neurohormones, and other biomolecules, involved with reproduction. We found that the anatomical structure of the brain is similar to other crabs. However, the ventral nerve cord (VNC) is unlike other caridian and dendrobrachiate decapods, as the subesophageal (SEG), thoracic and abdominal ganglia are fused, due to the reduction of abdominal segments and the tail. Neurons in clusters within the CNS varied in sizes, and we found that there were five distinct size classes (i.e., very small globuli, small, medium, large, and giant). Clusters in the brain and SEG contained mainly very small globuli and small-sized neurons, whereas, the VNC contained small-, medium-, large-, and giant-sized neurons. We postulate that the different sized neurons are involved in different functions.

  20. Central neuronal mechanisms of intestinal electrical stimulation: effects on duodenum distention-responsive (DD-R) neurons in the VMH of rats.

    Science.gov (United States)

    Zhang, Jing; Zhu, Hongbing; Chen, J D Z

    2009-06-19

    Intestinal electrical stimulation (IES) has been shown to produce inhibitory effects on gastric contractions, gastric emptying, food intake and body weight in rats and dogs, suggesting a therapeutic potential for obesity. The aims of this study were (1) to test the hypothesis that the neurons in the VMH are involved in the central mechanisms of IES treatment for obesity; (2) to compare the effects of IES at the duodenum and IES at the ileum on neuronal activities of the VMH; (3) to better understand if the neuronal activity modulated by IES was mediated via the vagal pathway. Extracellular potentials of neurons in the VMH were recorded in 18 anesthetized rats. IES at the duodenum or ileum was performed in duodenal-distention responsive (DD-R) neurons with 3 sets of parameters (IES-1 with trains of short-pulses: 4mA, 2s-on, 3s-off, 2ms, 20Hz; IES-2 with long-pulses: 6mA, 20cpm, 100ms; IES-3, same as IES-1 but 40Hz). IES-1 at the duodenum and the ileum activated 70.6% and 73.3% of the DD-R neurons, respectively. Similar percentages of the neurons were activated with IES-3 at the duodenum and the ileum (70.6% vs. 66.7%, P=0.91), respectively. IES-2 at these locations activated only 25% and 46.2% of the DD-R neurons, respectively (P>0.05). IES at the duodenum with parameter set, IES-1 or IES-3 was significantly more potent than the parameter set, IES-2 (neuronal activation: 70.6% vs. 25%, PDD, and IES with trains of short-pulses seems more effective than IES with long-pulses. The vagal pathway and extra-vagal pathways are involved in the modulatory effects of IES on the central neurons in the satiety center.

  1. Exercise-induced neuronal plasticity in central autonomic networks: role in cardiovascular control.

    Science.gov (United States)

    Michelini, Lisete C; Stern, Javier E

    2009-09-01

    It is now well established that brain plasticity is an inherent property not only of the developing but also of the adult brain. Numerous beneficial effects of exercise, including improved memory, cognitive function and neuroprotection, have been shown to involve an important neuroplastic component. However, whether major adaptive cardiovascular adjustments during exercise, needed to ensure proper blood perfusion of peripheral tissues, also require brain neuroplasticity, is presently unknown. This review will critically evaluate current knowledge on proposed mechanisms that are likely to underlie the continuous resetting of baroreflex control of heart rate during/after exercise and following exercise training. Accumulating evidence indicates that not only somatosensory afferents (conveyed by skeletal muscle receptors, baroreceptors and/or cardiopulmonary receptors) but also projections arising from central command neurons (in particular, peptidergic hypothalamic pre-autonomic neurons) converge into the nucleus tractus solitarii (NTS) in the dorsal brainstem, to co-ordinate complex cardiovascular adaptations during dynamic exercise. This review focuses in particular on a reciprocally interconnected network between the NTS and the hypothalamic paraventricular nucleus (PVN), which is proposed to act as a pivotal anatomical and functional substrate underlying integrative feedforward and feedback cardiovascular adjustments during exercise. Recent findings supporting neuroplastic adaptive changes within the NTS-PVN reciprocal network (e.g. remodelling of afferent inputs, structural and functional neuronal plasticity and changes in neurotransmitter content) will be discussed within the context of their role as important underlying cellular mechanisms supporting the tonic activation and improved efficacy of these central pathways in response to circulatory demand at rest and during exercise, both in sedentary and in trained individuals. We hope this review will stimulate

  2. Hypothalamic Vasopressinergic Projections Innervate Central Amygdala GABAergic Neurons: Implications for Anxiety and Stress Coping

    Science.gov (United States)

    Hernández, Vito S.; Hernández, Oscar R.; Perez de la Mora, Miguel; Gómora, María J.; Fuxe, Kjell; Eiden, Lee E.; Zhang, Limei

    2016-01-01

    The arginine-vasopressin (AVP)-containing hypothalamic magnocellular neurosecretory neurons (VPMNNs) are known for their role in hydro-electrolytic balance control via their projections to the neurohypophysis. Recently, projections from these same neurons to hippocampus, habenula and other brain regions in which vasopressin infusion modulates contingent social and emotionally-affected behaviors, have been reported. Here, we present evidence that VPMNN collaterals also project to the amygdaloid complex, and establish synaptic connections with neurons in central amygdala (CeA). The density of AVP innervation in amygdala was substantially increased in adult rats that had experienced neonatal maternal separation (MS), consistent with our previous observations that MS enhances VPMNN number in the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus. In the CeA, V1a AVP receptor mRNA was only observed in GABAergic neurons, demonstrated by complete co-localization of V1a transcripts in neurons expressing Gad1 and Gad2 transcripts in CeA using the RNAscope method. V1b and V2 receptor mRNAs were not detected, using the same method. Water-deprivation (WD) for 24 h, which increased the metabolic activity of VPMNNs, also increased anxiety-like behavior measured using the elevated plus maze (EPM) test, and this effect was mimicked by bilateral microinfusion of AVP into the CeA. Anxious behavior induced by either WD or AVP infusion was reversed by CeA infusion of V1a antagonist. VPMNNs are thus a newly discovered source of CeA inhibitory circuit modulation, through which both early-life and adult stress coping signals are conveyed from the hypothalamus to the amygdala. PMID:27932956

  3. Environment and the serotonergic system.

    Science.gov (United States)

    Oreland, L; Nordquist, N; Hallman, J; Harro, J; Nilsson, K W

    2010-06-01

    In summary, genetics, as well as foetal and early life environmental factors shape the size or capacity of our monoamine systems, of which the serotonergic one might play a leading role. Those constitutional properties then form the biological basis for personality traits, such as impulsiveness and "sensation seeking", which interact with psychosocial settings and life events to form a pattern of reactivity to a current life event or psychosocial situation, shown as a high or low order of magnitude of gene-environment interaction. In the present paper emphasis is put on the role of genotypes of the serotonin transporter, of monoamine oxidases A and B, and of platelet monoamine oxidase B activity, which all have been shown to be of importance for behaviour and with obvious effects of interactions with environment. Under unfortunate circumstances constitutional properties might be strong enough to result in vulnerability for suicide, even with a modest influence of environment.

  4. Modulation of anxiety circuits by serotonergic systems

    DEFF Research Database (Denmark)

    Lowry, Christopher A; Johnson, Philip L; Hay-Schmidt, Anders;

    2005-01-01

    of emotionally salient events, often when both rewarding and aversive outcomes are possible. In this review, we highlight recent advances in our understanding of the neural circuits regulating anxiety states and anxiety-related behavior with an emphasis on the role of brainstem serotonergic systems in modulating...... anxiety-related circuits. In particular, we explore the possibility that the regulation of anxiety states and anxiety-related behavior by serotonergic systems is dependent on a specific, topographically organized mesolimbocortical serotonergic system that originates in the mid-rostrocaudal and caudal...

  5. Neuroarchitecture and neuroanatomy of the Drosophila central complex: A GAL4-based dissection of protocerebral bridge neurons and circuits.

    Science.gov (United States)

    Wolff, Tanya; Iyer, Nirmala A; Rubin, Gerald M

    2015-05-01

    Insects exhibit an elaborate repertoire of behaviors in response to environmental stimuli. The central complex plays a key role in combining various modalities of sensory information with an insect's internal state and past experience to select appropriate responses. Progress has been made in understanding the broad spectrum of outputs from the central complex neuropils and circuits involved in numerous behaviors. Many resident neurons have also been identified. However, the specific roles of these intricate structures and the functional connections between them remain largely obscure. Significant gains rely on obtaining a comprehensive catalog of the neurons and associated GAL4 lines that arborize within these brain regions, and on mapping neuronal pathways connecting these structures. To this end, small populations of neurons in the Drosophila melanogaster central complex were stochastically labeled using the multicolor flip-out technique and a catalog was created of the neurons, their morphologies, trajectories, relative arrangements, and corresponding GAL4 lines. This report focuses on one structure of the central complex, the protocerebral bridge, and identifies just 17 morphologically distinct cell types that arborize in this structure. This work also provides new insights into the anatomical structure of the four components of the central complex and its accessory neuropils. Most strikingly, we found that the protocerebral bridge contains 18 glomeruli, not 16, as previously believed. Revised wiring diagrams that take into account this updated architectural design are presented. This updated map of the Drosophila central complex will facilitate a deeper behavioral and physiological dissection of this sophisticated set of structures.

  6. Multi-neuronal refractory period adapts centrally generated behaviour to reward.

    Directory of Open Access Journals (Sweden)

    Christopher A Harris

    Full Text Available Oscillating neuronal circuits, known as central pattern generators (CPGs, are responsible for generating rhythmic behaviours such as walking, breathing and chewing. The CPG model alone however does not account for the ability of animals to adapt their future behaviour to changes in the sensory environment that signal reward. Here, using multi-electrode array (MEA recording in an established experimental model of centrally generated rhythmic behaviour we show that the feeding CPG of Lymnaea stagnalis is itself associated with another, and hitherto unidentified, oscillating neuronal population. This extra-CPG oscillator is characterised by high population-wide activity alternating with population-wide quiescence. During the quiescent periods the CPG is refractory to activation by food-associated stimuli. Furthermore, the duration of the refractory period predicts the timing of the next activation of the CPG, which may be minutes into the future. Rewarding food stimuli and dopamine accelerate the frequency of the extra-CPG oscillator and reduce the duration of its quiescent periods. These findings indicate that dopamine adapts future feeding behaviour to the availability of food by significantly reducing the refractory period of the brain's feeding circuitry.

  7. Apoptosis of supraoptic AVP neurons is involved in the development of central diabetes insipidus after hypophysectomy in rats

    Directory of Open Access Journals (Sweden)

    Huang Lijin

    2008-06-01

    Full Text Available Abstract Background It has been reported that various types of axonal injury of hypothalamo-neurohypophyseal tract can result in degeneration of the magnocellular neurons (MCNs in hypothalamus and development of central diabetes insipidus (CDI. However, the mechanism of the degeneration and death of MCNs after hypophysectomy in vivo is still unclear. This present study was aimed to disclose it and to figure out the dynamic change of central diabetes insipidus after hypophysectomy. Results The analysis on the dynamic change of daily water consumption (DWC, daily urine volume(DUV, specific gravity of urine(USG and plasma vasopressin concentration showed that the change pattern of them was triphasic and neuron counting showed that the degeneration of vasopressin neurons began at 10 d, aggravated at 20 d and then stabilized at 30 d after hypophysectomy. There was marked upregulation of cleaved Caspase-3 expression of vasopressin neurons in hypophysectomy rats. A "ladder" pattern of migration of DNA internucleosomal fragments was detected and apoptotic ultrastructure was found in these neurons. There was time correlation among the occurrence of diabetes insipidus, the changes of plasma vasopressin concentration and the degeneration of vasopressin neurons after hypophysectomy. Conclusion This study firstly demonstrated that apoptosis was involved in degeneration of supraoptic vasopressin neurons after hypophysectomy in vivo and development of CDI. Our study on time course and correlations among water metabolism, degeneration and apoptosis of vasopressin neurons suggested that there should be an efficient therapeutic window in which irreversible CDI might be prevented by anti-apoptosis.

  8. Differentiation and molecular heterogeneity of inhibitory and excitatory neurons associated with midbrain dopaminergic nuclei.

    Science.gov (United States)

    Lahti, Laura; Haugas, Maarja; Tikker, Laura; Airavaara, Mikko; Voutilainen, Merja H; Anttila, Jenni; Kumar, Suman; Inkinen, Caisa; Salminen, Marjo; Partanen, Juha

    2016-02-01

    Local inhibitory GABAergic and excitatory glutamatergic neurons are important for midbrain dopaminergic and hindbrain serotonergic pathways controlling motivation, mood, and voluntary movements. Such neurons reside both within the dopaminergic nuclei, and in adjacent brain structures, including the rostromedial and laterodorsal tegmental nuclei. Compared with the monoaminergic neurons, the development, heterogeneity, and molecular characteristics of these regulatory neurons are poorly understood. We show here that different GABAergic and glutamatergic subgroups associated with the monoaminergic nuclei express specific transcription factors. These neurons share common origins in the ventrolateral rhombomere 1, where the postmitotic selector genes Tal1, Gata2 and Gata3 control the balance between the generation of inhibitory and excitatory neurons. In the absence of Tal1, or both Gata2 and Gata3, the GABAergic precursors adopt glutamatergic fates and populate the glutamatergic nuclei in excessive numbers. Together, our results uncover developmental regulatory mechanisms, molecular characteristics, and heterogeneity of central regulators of monoaminergic circuits.

  9. Serotonergic 5-HT7 receptors and cognition.

    Science.gov (United States)

    Gasbarri, Antonella; Pompili, Assunta

    2014-01-01

    The abundant distribution of serotonin (5-HT) in different areas of the central nervous system can explain the involvement of this neurotransmitter in the regulation of several functions, such as sleep, pain, feeding, and sexual and emotional behaviors. Moreover, the serotonergic system is also involved in other more complex roles, such as cognition, including learning and memory processes. Recent studies led to the discovery of various types and subtypes of receptors differentially associated to cognitive mechanisms. 5-HT7 is the most recently discovered receptor for 5-HT; therefore, it is also one of the least well characterized. Studies exist hypothesizing the role of 5-HT7 on the modulation of learning and memory processes and other cognitive functions. Moreover, much attention has been devoted to the possible role of 5-HT7 receptors in psychiatric disorders. Therefore, the aim of this review is to clarify the behavioral role of the recently discovered 5-HT7 type receptor and highlight its involvement in the cognitive functions, with particular attention to the modulation of learning and memory processes, thus providing a basis to obtain new therapeutic agents and strategies for the treatment of cognitive disorders.

  10. Volume Transmission in Central Dopamine and Noradrenaline Neurons and Its Astroglial Targets.

    Science.gov (United States)

    Fuxe, Kjell; Agnati, Luigi F; Marcoli, Manuela; Borroto-Escuela, Dasiel O

    2015-12-01

    Already in the 1960s the architecture and pharmacology of the brainstem dopamine (DA) and noradrenaline (NA) neurons with formation of vast numbers of DA and NA terminal plexa of the central nervous system (CNS) indicated that they may not only communicate via synaptic transmission. In the 1980s the theory of volume transmission (VT) was introduced as a major communication together with synaptic transmission in the CNS. VT is an extracellular and cerebrospinal fluid transmission of chemical signals like transmitters, modulators etc. moving along energy gradients making diffusion and flow of VT signals possible. VT interacts with synaptic transmission mainly through direct receptor-receptor interactions in synaptic and extrasynaptic heteroreceptor complexes and their signaling cascades. The DA and NA neurons are specialized for extrasynaptic VT at the soma-dendrtitic and terminal level. The catecholamines released target multiple DA and adrenergic subtypes on nerve cells, astroglia and microglia which are the major cell components of the trophic units building up the neural-glial networks of the CNS. DA and NA VT can modulate not only the strength of synaptic transmission but also the VT signaling of the astroglia and microglia of high relevance for neuron-glia interactions. The catecholamine VT targeting astroglia can modulate the fundamental functions of astroglia observed in neuroenergetics, in the Glymphatic system, in the central renin-angiotensin system and in the production of long-distance calcium waves. Also the astrocytic and microglial DA and adrenergic receptor subtypes mediating DA and NA VT can be significant drug targets in neurological and psychiatric disease.

  11. Is BDNF sufficient for information transfer between microglia and dorsal horn neurons during the onset of central sensitization?

    OpenAIRE

    2010-01-01

    Abstract Peripheral nerve injury activates spinal microglia. This leads to enduring changes in the properties of dorsal horn neurons that initiate central sensitization and the onset of neuropathic pain. Although a variety of neuropeptides, cytokines, chemokines and neurotransmitters have been implicated at various points in this process, it is possible that much of the information transfer between activated microglia and neurons, at least in this context, may be explicable in terms of the ac...

  12. Tetanus Toxin and Botulinum Toxin A Utilize Unique Mechanisms To Enter Neurons of the Central Nervous System

    OpenAIRE

    Blum, Faith C.; Chen CHEN; Kroken, Abby R.; Barbieri, Joseph T

    2012-01-01

    Botulinum neurotoxins (BoNTs) and tetanus neurotoxin (TeNT) are the most toxic proteins for humans. While BoNTs cause flaccid paralysis, TeNT causes spastic paralysis. Characterized BoNT serotypes enter neurons upon binding dual receptors, a ganglioside and a neuron-specific protein, either synaptic vesicle protein 2 (SV2) or synaptotagmin, while TeNT enters upon binding gangliosides as dual receptors. Recently, TeNT was reported to enter central nervous system (CNS) neurons upon synaptic ves...

  13. Development and distribution of PAG-immunoreactive neurons in the central pathway of trigeminal proprioception of the rat brainstem

    Institute of Scientific and Technical Information of China (English)

    PANG You-wang; LI Jin-lian

    2002-01-01

    Objective:To investigate the development and distribution of phosphate-activated glutaminase like immunoreactive (PAG-LI) neurons in the central pathway of trigeminal proprioception of the rat brainstem.Methods: The immunohistochemitry techniques were used. Results: (1) At embryonic day 17 (E17), PAGLI neurons were initially observed in the mesencephalic trigeminal nucleus (Vme). All PAG-LI neurons were large round neurons with moderate immunostaining. The immunoreactivity grew intense and attained adultlike pattern at P10. (2) Not until postnatal day 10 (P10) did a few PAG-LI neurons appear in the area ventral to the motor trigeminal nucleus (AVM) and area dorsal to the superior olivery nucleus (ADO), and not until P12 in the dorsomedial part of the subnucleus oralis of the spinal trigeminal nucleus (Vodm) and dorsomedial part of the principal sensory trigeminal nucleus (Vpdm). As development proceeded, more and more neurons in them were immunostained, and some PAG-LI neurons were detected in the lateral reticular formation adjacent to the Vodm(LRF)and the caudolateral part of the supratrigeminal nucleus (Vsup-CL) at P21.Conclusion: In the central pathway of trigeminal proprioception of the rat brainstem, PAG-LI neurons appeared during two stages: The first stage from E17 to P10, PAG-LI neurons appeared in the Vme and reached adult-like pattern; the second stage from P10 to P21, PAG-LI neurons appeared in the Vodm, LRF,Vpdm, Vsup-CL, ADO, AVM and gradually reached adult-like pattern. This might be relative to the establishment of jaw movement patterns.

  14. Role of nitric oxide in neuronal plasticity in the mammal central and peripheral nervous systems

    OpenAIRE

    2009-01-01

    La lesión de un nervio periférico induce la sobre-expresión de la enzima óxido nítrico sintasa (Nos) en el nervio afectado. Este tipo de lesión, así como ciertas enfermedades neurodegenerativas, cursan con una disminución de la densidad sínáptica central junto con la expresión de novo y/o sobre-expresión de NOS neuronal (nNOS) en las motoneuronas. Dado que el óxido nítrico (NO) participa en numerosos fenómenos de plasticidad sináptica, se podría sugerir un papel del NO en procesos de El princ...

  15. Individual differences in the sensitivity to serotonergic drugs: a pharmacobehavioural approach using rats selected on the basis of their response to novelty

    OpenAIRE

    Verheij, Michel M. M.; Veenvliet, Jesse V.; Groot Kormelink, Tom; Steenhof, Maaike; Cools, Alexander R.

    2009-01-01

    Rationale The mechanisms underlying individual differences in the response to serotonergic drugs are poorly understood. Rat studies may contribute to our knowledge of the neuronal substrates that underlie these individual differences. Objectives A pharmacobehavioural study was performed to assess individual differences in the sensitivity to serotonergic drugs in rats that were selected based on their response to a novel environment. Methods Low responders (LR) and high responders (HR) to nove...

  16. Localization of Motor Neurons and Central Pattern Generators for Motor Patterns Underlying Feeding Behavior in Drosophila Larvae.

    Directory of Open Access Journals (Sweden)

    Sebastian Hückesfeld

    Full Text Available Motor systems can be functionally organized into effector organs (muscles and glands, the motor neurons, central pattern generators (CPG and higher control centers of the brain. Using genetic and electrophysiological methods, we have begun to deconstruct the motor system driving Drosophila larval feeding behavior into its component parts. In this paper, we identify distinct clusters of motor neurons that execute head tilting, mouth hook movements, and pharyngeal pumping during larval feeding. This basic anatomical scaffold enabled the use of calcium-imaging to monitor the neural activity of motor neurons within the central nervous system (CNS that drive food intake. Simultaneous nerve- and muscle-recordings demonstrate that the motor neurons innervate the cibarial dilator musculature (CDM ipsi- and contra-laterally. By classical lesion experiments we localize a set of CPGs generating the neuronal pattern underlying feeding movements to the subesophageal zone (SEZ. Lesioning of higher brain centers decelerated all feeding-related motor patterns, whereas lesioning of ventral nerve cord (VNC only affected the motor rhythm underlying pharyngeal pumping. These findings provide a basis for progressing upstream of the motor neurons to identify higher regulatory components of the feeding motor system.

  17. A novel CaV2.2 channel inhibition by piracetam in peripheral and central neurons.

    Science.gov (United States)

    Bravo-Martínez, Jorge; Arenas, Isabel; Vivas, Oscar; Rebolledo-Antúnez, Santiago; Vázquez-García, Mario; Larrazolo, Arturo; García, David E

    2012-10-01

    No mechanistic actions for piracetam have been documented to support its nootropic effects. Voltage-gated calcium channels have been proposed as a promising pharmacological target of nootropic drugs. In this study, we investigated the effect of piracetam on Ca(V)2.2 channels in peripheral neurons, using patch-clamp recordings from cultured superior cervical ganglion neurons. In addition, we tested if Ca(V)2.2 channel inhibition could be related with the effects of piracetam on central neurons. We found that piracetam inhibited native Ca(V)2.2 channels in superior cervical ganglion neurons in a dose-dependent manner, with an IC(50) of 3.4 μmol/L and a Hill coefficient of 1.1. GDPβS dialysis did not prevent piracetam-induced inhibition of Ca(V)2.2 channels and G-protein-coupled receptor activation by noradrenaline did not occlude the piracetam effect. Piracetam altered the biophysical characteristics of Ca(V)2.2 channel such as facilitation ratio. In hippocampal slices, piracetam and ω-conotoxin GVIA diminished the frequency of excitatory postsynaptic potentials and action potentials. Our results provide evidence of piracetam's actions on Ca(V)2.2 channels in peripheral neurons, which might explain some of its nootropic effects in central neurons.

  18. The role of microtubule-associated protein 1B in axonal growth and neuronal migration in the central nervous system

    Institute of Scientific and Technical Information of China (English)

    Maoguang Yang; Xiaoyu Yang; Minfei Wu; Peng Xia; Chunxin Wang; Peng Yan; Qi Gao; Jian Liu; Haitao Wang; Xingwei Duan

    2012-01-01

    In this review, we discuss the role of microtubule-associated protein 1B (MAP1B) and its phosphorylation in axonal development and regeneration in the central nervous system. MAP1B exhibits similar functions during axonal development and regeneration. MAP1B and phosphorylated MAP1B in neurons and axons maintain a dynamic balance between cytoskeletal components, and regulate the stability and interaction of microtubules and actin to promote axonal growth, neural connectivity and regeneration in the central nervous system.

  19. Central action of FGF19 reduces hypothalamic AGRP/NPY neuron activity and improves glucose metabolism.

    Science.gov (United States)

    Marcelin, Geneviève; Jo, Young-Hwan; Li, Xiaosong; Schwartz, Gary J; Zhang, Ying; Dun, Nae J; Lyu, Rong-Ming; Blouet, Clémence; Chang, Jaw K; Chua, Streamson

    2014-02-01

    Tight control of glucose excursions has been a long-standing goal of treatment for patients with type 2 diabetes mellitus in order to ameliorate the morbidity and mortality associated with hyperglycemia. Fibroblast growth factor (FGF) 19 is a hormone-like enterokine released postprandially that emerged as a potential therapeutic agent for metabolic disorders, including diabetes and obesity. Remarkably, FGF19 treatment has hypoglycemic actions that remain potent in models of genetic and acquired insulin resistance. Here, we provided evidence that the central nervous system responds to FGF19 administered in the periphery. Then, in two mouse models of insulin resistance, leptin-deficiency and high-fat diet feeding, third intra-cerebro-ventricular infusions of FGF19 improved glycemic status, reduced insulin resistance and potentiated insulin signaling in the periphery. In addition, our study highlights a new mechanism of central FGF19 action, involving the suppression of AGRP/NPY neuronal activity. Overall, our work unveils novel regulatory pathways induced by FGF19 that will be useful in the design of novel strategies to control diabetes in obesity.

  20. Extending David Horrobin's membrane phospholipid theory of schizophrenia: overactivity of cytosolic phospholipase A(2) in the brain is caused by overdrive of coupled serotonergic 5HT(2A/2C) receptors in response to stress.

    Science.gov (United States)

    Eggers, Arnold E

    2012-12-01

    David Horrobin's membrane phospholipid theory of schizophrenia has held up well over time because his therapeutic prediction that dietary supplementation with eicosapentaenoic acid (EPA) would have a therapeutic effect has been partially verified and undergoes continued testing. In the final version of his theory, he hypothesized that there was hyperactivity of phosphoslipase A(2) (PLA(2)) or a related enzyme but did not explain how the hyperactivity came about. It is known that serotonergic 5HT(2A/2C) receptors are coupled to PLA(2), which hydrolyzes both arachidonic acid (AA) and EPA from diacylglycerides at the sn-2 position. In this paper, Horrobin's theory is combined with a previously published theory of chronic stress in which it was hypothesized that a disinhibited dorsal raphe nucleus, the principal nucleus of the serotonergic system, can organize the neuropathology of diseases such as migraine, hypertension, and the metabolic syndrome. The new or combined theory is that schizophrenia is a disease of chronic stress in which a disinhibited DRN causes widespread serotonergic overdrive in the cerebral cortex. This in turn causes overdrive of cPLA(2) and both central and peripheral depletion of AA and EPA. Because EPA is present in smaller amounts, it falls below threshold for maintaining an intracellular balance between AA-derived and EPA-derived second messenger cascades, which leads to abnormal patterns of neuronal firing. There are two causes of neuronal dysfunction: the disinhibited DRN and EPA depletion. Schizophrenia is statistically associated with metabolic syndrome, hypertension, and migraine because they form a cluster of diseases with similar pathophysiology. The theory provides an explanation for both the central and peripheral phospholipid abnormalities in schizophrenia. It also explains the role of stress in schizophrenia, elevated serum PLA(2) activity in schizophrenia, the relationship between untreated schizophrenia and metabolic syndrome

  1. Distribution of serotonergic and dopaminergic nerve fibers in the salivary gland complex of the cockroach Periplaneta americana

    Directory of Open Access Journals (Sweden)

    Kühnel Dana

    2002-06-01

    Full Text Available Abstract Background The cockroach salivary gland consists of secretory acini with peripheral ion-transporting cells and central protein-producing cells, an extensive duct system, and a pair of reservoirs. Salivation is controled by serotonergic and dopaminergic innervation. Serotonin stimulates the secretion of a protein-rich saliva, dopamine causes the production of a saliva without proteins. These findings suggest a model in which serotonin acts on the central cells and possibly other cell types, and dopamine acts selectively on the ion-transporting cells. To examine this model, we have analyzed the spatial relationship of dopaminergic and serotonergic nerve fibers to the various cell types. Results The acinar tissue is entangled in a meshwork of serotonergic and dopaminergic varicose fibers. Dopaminergic fibers reside only at the surface of the acini next to the peripheral cells. Serotonergic fibers invade the acini and form a dense network between central cells. Salivary duct segments close to the acini are locally associated with dopaminergic and serotonergic fibers, whereas duct segments further downstream have only dopaminergic fibers on their surface and within the epithelium. In addition, the reservoirs have both a dopaminergic and a serotonergic innervation. Conclusion Our results suggest that dopamine is released on the acinar surface, close to peripheral cells, and along the entire duct system. Serotonin is probably released close to peripheral and central cells, and at initial segments of the duct system. Moreover, the presence of serotonergic and dopaminergic fiber terminals on the reservoir indicates that the functions of this structure are also regulated by dopamine and serotonin.

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

    DEFF Research Database (Denmark)

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

    2008-01-01

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

  3. Mangiferin Upregulates Glyoxalase 1 Through Activation of Nrf2/ARE Signaling in Central Neurons Cultured with High Glucose.

    Science.gov (United States)

    Liu, Yao-Wu; Cheng, Ya-Qin; Liu, Xiao-Li; Hao, Yun-Chao; Li, Yu; Zhu, Xia; Zhang, Fan; Yin, Xiao-Xing

    2016-06-18

    Mangiferin, a natural C-glucoside xanthone, has anti-inflammatory, anti-oxidative, neuroprotective actions. Our previous study showed that mangiferin could attenuate diabetes-associated cognitive impairment of rats by enhancing the function of glyoxalase 1 (Glo-1) in brain. The aim of this study was to investigate whether Glo-1 upregulation by mangiferin in central neurons exposed to chronic high glucose may be related to activation of Nrf2/ARE pathway. Compared with normal glucose (25 mmol/L) culture, Glo-1 protein, mRNA, and activity levels were markedly decreased in primary hippocampal and cerebral cortical neurons cultured with high glucose (50 mmol/L) for 72 h, accompanied by the declined Nrf2 nuclear translocation and protein expression of Nrf2 in cell nucleus, as well as protein expression and mRNA level of γ-glutamylcysteine synthetase (γ-GCS) and superoxide dismutase activity, target genes of Nrf2/ARE signaling. Nonetheless, high glucose cotreating with mangiferin or sulforaphane, a typical inducer of Nrf2 activation, attenuated the above changes in both central neurons. In addition, mangiferin and sulforaphane significantly prevented the formation of advanced glycation end-products (AGEs) reflecting Glo-1 activity, while elevated the level of glutathione, a cofactor of Glo-1 activity and production of γ-GCS, in high glucose cultured central neurons. These findings demonstrated that Glo-1 was greatly downregulated in central neurons exposed to chronic high glucose, which is expected to lead the formation of AGEs and oxidative stress damages. We also proved that mangiferin enhanced the function of Glo-1 under high glucose condition by inducing activation of Nrf2/ARE signaling pathway.

  4. Central neuronal motor behaviour in skilled and less skilled novices - Approaching sports-specific movement techniques.

    Science.gov (United States)

    Vogt, Tobias; Kato, Kouki; Schneider, Stefan; Türk, Stefan; Kanosue, Kazuyuki

    2017-02-14

    Research on motor behavioural processes preceding voluntary movements often refers to analysing the readiness potential (RP). For this, decades of studies used laboratory setups with controlled sports-related actions. Further, recent applied approaches focus on athlete-non-athlete comparisons, omitting possible effects of training history on RP. However, RP preceding real sport-specific movements in accordance to skill acquisition remains to be elucidated. Therefore, after familiarization 16 right-handed males with no experience in archery volunteered to perform repeated sports-specific movements, i.e. 40 arrow-releasing shots at 60s rest on a 15m distant standard target. Continuous, synchronised EEG and right limb EMG recordings during arrow-releasing served to detect movement onsets for RP analyses over distinct cortical motor areas. Based on attained scores on target, archery novices were, a posteriori, subdivided into a skilled and less skilled group. EMG results for mean values revealed no significant changes (all p>0.05), whereas RP amplitudes and onsets differed between groups but not between motor areas. Arrow-releasing preceded larger RP amplitudes (p<0.05) and later RP onsets (p<0.05) in skilled compared to less skilled novices. We suggest this to reflect attentional orienting and greater effort that accompanies central neuronal preparatory states of a sports-specific movement.

  5. Activation of noradrenergic neurons projecting to the diencephalon following central administration of histamine is mediated by H1 receptors.

    Science.gov (United States)

    Fleckenstein, A E; Lookingland, K J; Moore, K E

    1994-02-28

    The effect of histamine on the activity of noradrenergic neurons terminating in discrete regions of the diencephalon was examined in male rats. Noradrenergic neuronal activity was estimated by measuring the concentration of norepinephrine and its metabolite 3-methoxy-4-hydroxyphenylethyleneglycol [MHPG] in the medial zona incerta [MZI] and in the dorsomedial [DMN], periventricular [PeVN] and medial preoptic hypothalamic nuclei [MPN]. The intracerebroventricular administration of histamine effected a time-related increase in MHPG concentrations in the MZI, DMN, PeVN and MPN; these effects were blocked by the H1 antagonist mepyramine but not the H2 antagonist zolantidine. Neither mepyramine nor zolantidine affected basal MHPG concentrations in any of the brain regions examined. These results indicate that central administration of histamine increases the activity of noradrenergic neurons projecting to the diencephalon via an action at H1 but not H2 receptors.

  6. Menin: a tumor suppressor that mediates postsynaptic receptor expression and synaptogenesis between central neurons of Lymnaea stagnalis.

    Directory of Open Access Journals (Sweden)

    Nichole Flynn

    Full Text Available Neurotrophic factors (NTFs support neuronal survival, differentiation, and even synaptic plasticity both during development and throughout the life of an organism. However, their precise roles in central synapse formation remain unknown. Previously, we demonstrated that excitatory synapse formation in Lymnaea stagnalis requires a source of extrinsic NTFs and receptor tyrosine kinase (RTK activation. Here we show that NTFs such as Lymnaea epidermal growth factor (L-EGF act through RTKs to trigger a specific subset of intracellular signalling events in the postsynaptic neuron, which lead to the activation of the tumor suppressor menin, encoded by Lymnaea MEN1 (L-MEN1 and the expression of excitatory nicotinic acetylcholine receptors (nAChRs. We provide direct evidence that the activation of the MAPK/ERK cascade is required for the expression of nAChRs, and subsequent synapse formation between pairs of neurons in vitro. Furthermore, we show that L-menin activation is sufficient for the expression of postsynaptic excitatory nAChRs and subsequent synapse formation in media devoid of NTFs. By extending our findings in situ, we reveal the necessity of EGFRs in mediating synapse formation between a single transplanted neuron and its intact presynaptic partner. Moreover, deficits in excitatory synapse formation following EGFR knock-down can be rescued by injecting synthetic L-MEN1 mRNA in the intact central nervous system. Taken together, this study provides the first direct evidence that NTFs functioning via RTKs activate the MEN1 gene, which appears sufficient to regulate synapse formation between central neurons. Our study also offers a novel developmental role for menin beyond tumour suppression in adult humans.

  7. Menin: A Tumor Suppressor That Mediates Postsynaptic Receptor Expression and Synaptogenesis between Central Neurons of Lymnaea stagnalis

    Science.gov (United States)

    Flynn, Nichole; Getz, Angela; Visser, Frank; Janes, Tara A.; Syed, Naweed I.

    2014-01-01

    Neurotrophic factors (NTFs) support neuronal survival, differentiation, and even synaptic plasticity both during development and throughout the life of an organism. However, their precise roles in central synapse formation remain unknown. Previously, we demonstrated that excitatory synapse formation in Lymnaea stagnalis requires a source of extrinsic NTFs and receptor tyrosine kinase (RTK) activation. Here we show that NTFs such as Lymnaea epidermal growth factor (L-EGF) act through RTKs to trigger a specific subset of intracellular signalling events in the postsynaptic neuron, which lead to the activation of the tumor suppressor menin, encoded by Lymnaea MEN1 (L-MEN1) and the expression of excitatory nicotinic acetylcholine receptors (nAChRs). We provide direct evidence that the activation of the MAPK/ERK cascade is required for the expression of nAChRs, and subsequent synapse formation between pairs of neurons in vitro. Furthermore, we show that L-menin activation is sufficient for the expression of postsynaptic excitatory nAChRs and subsequent synapse formation in media devoid of NTFs. By extending our findings in situ, we reveal the necessity of EGFRs in mediating synapse formation between a single transplanted neuron and its intact presynaptic partner. Moreover, deficits in excitatory synapse formation following EGFR knock-down can be rescued by injecting synthetic L-MEN1 mRNA in the intact central nervous system. Taken together, this study provides the first direct evidence that NTFs functioning via RTKs activate the MEN1 gene, which appears sufficient to regulate synapse formation between central neurons. Our study also offers a novel developmental role for menin beyond tumour suppression in adult humans. PMID:25347295

  8. Central sensitization of nociceptive neurons in rat medullary dorsal horn involves purinergic P2X7 receptors.

    Science.gov (United States)

    Itoh, K; Chiang, C-Y; Li, Z; Lee, J-C; Dostrovsky, J O; Sessle, B J

    2011-09-29

    Central sensitization is a crucial process underlying the increased neuronal excitability of nociceptive pathways following peripheral tissue injury and inflammation. Our previous findings have suggested that extracellular adenosine 5'-triphosphate (ATP) molecules acting at purinergic receptors located on presynaptic terminals (e.g., P2X2/3, P2X3 subunits) and glial cells are involved in the glutamatergic-dependent central sensitization induced in medullary dorsal horn (MDH) nociceptive neurons by application to the tooth pulp of the inflammatory irritant mustard oil (MO). Since growing evidence indicates that activation of P2X7 receptors located on glia is involved in chronic inflammatory and neuropathic pain, the aim of the present study was to test in vivo for P2X7 receptor involvement in this acute inflammatory pain model. Experiments were carried out in anesthetized Sprague-Dawley male rats. Single unit recordings were made in MDH functionally identified nociceptive neurons for which mechanoreceptive field, mechanical activation threshold and responses to noxious stimuli were tested. We found that continuous intrathecal (i.t.) superfusion over MDH of the potent P2X7 receptor antagonists brilliant blue G and periodated oxidized ATP could each significantly attenuate the MO-induced MDH central sensitization. MDH central sensitization could also be produced by i.t. superfusion of ATP and even more effectively by the P2X7 receptor agonist benzoylbenzoyl ATP. Superfusion of the microglial blocker minocycline abolished the MO-induced MDH central sensitization, consistent with reports that dorsal horn P2X7 receptors are mostly expressed on microglia. In control experiments, superfusion over MDH of vehicle did not produce any significant changes. These novel findings suggest that activation of P2X7 receptors in vivo may be involved in the development of central sensitization in an acute inflammatory pain model.

  9. Effects of penicillin on procaine-elicited bursts of potential in central neuron of snail, Achatina fulica.

    Science.gov (United States)

    Chen, Yi-Hung; Lu, Kuan-Ling; Hsiao, Ru-Wan; Lee, Ya-Ling; Tsai, Hong-Chieh; Lin, Chia Hsien; Tsai, Ming-Cheng

    2008-08-01

    Effects of penicillin on changes in procaine-elicited bursts of potential (BoP) were studied in a central neuron (RP4) of snail, Achatina fulica Ferussac. Procaine elicited BoP in the RP4 neuron while penicillin elicited depolarization of the neuron. Penicillin decreased the BoP elicited by procaine in a concentration-dependent manner. The effect of penicillin on the procaine-elicited BoP was not altered in the preparations treated with ascorbate or L-NAME (N-nitro-L-arginine methyl ester). However, the inhibitory effect of penicillin on the procaine-elicited BoP was enhanced with a decrease in extracellular sodium ion. Sodium ion was one of the important ions contributing to the action potential of the neuron. Two-electrode voltage-clamp studies revealed that penicillin decreased the fast sodium inward current of the neuron. It is concluded that penicillin inhibited the BoP elicited by procaine and sodium ion altered the effect of penicillin on procaine-elicited BoP.

  10. Reorganization of neuronal circuits of the central olfactory system during postprandial sleep.

    Science.gov (United States)

    Yamaguchi, Masahiro; Manabe, Hiroyuki; Murata, Koshi; Mori, Kensaku

    2013-01-01

    Plastic changes in neuronal circuits often occur in association with specific behavioral states. In this review, we focus on an emerging view that neuronal circuits in the olfactory system are reorganized along the wake-sleep cycle. Olfaction is crucial to sustaining the animals' life, and odor-guided behaviors have to be newly acquired or updated to successfully cope with a changing odor world. It is therefore likely that neuronal circuits in the olfactory system are highly plastic and undergo repeated reorganization in daily life. A remarkably plastic feature of the olfactory system is that newly generated neurons are continually integrated into neuronal circuits of the olfactory bulb (OB) throughout life. New neurons in the OB undergo an extensive selection process, during which many are eliminated by apoptosis for the fine tuning of neuronal circuits. The life and death decision of new neurons occurs extensively during a short time window of sleep after food consumption (postprandial sleep), a typical daily olfactory behavior. We review recent studies that explain how olfactory information is transferred between the OB and the olfactory cortex (OC) along the course of the wake-sleep cycle. Olfactory sensory input is effectively transferred from the OB to the OC during waking, while synchronized top-down inputs from the OC to the OB are promoted during the slow-wave sleep. We discuss possible neuronal circuit mechanisms for the selection of new neurons in the OB, which involves the encoding of olfactory sensory inputs and memory trace formation during waking and internally generated activities in the OC and OB during subsequent sleep. The plastic changes in the OB and OC are well coordinated along the course of olfactory behavior during wakefulness and postbehavioral rest and sleep. We therefore propose that the olfactory system provides an excellent model in which to understand behavioral state-dependent plastic mechanisms of the neuronal circuits in the brain.

  11. Reorganization of neuronal circuits of the central olfactory system during postprandial sleep

    Directory of Open Access Journals (Sweden)

    Masahiro eYamaguchi

    2013-08-01

    Full Text Available Plastic changes in neuronal circuits often occur in association with specific behavioral states. In this review, we focus on an emerging view that neuronal circuits in the olfactory system are reorganized along the wake-sleep cycle. Olfaction is crucial to sustaining the animals’ life, and odor-guided behaviors have to be newly acquired or updated to successfully cope with a changing odor world. It is therefore likely that neuronal circuits in the olfactory system are highly plastic and undergo repeated reorganization in daily life. A remarkably plastic feature of the olfactory system is that newly generated neurons are continually integrated into neuronal circuits of the olfactory bulb (OB throughout life. New neurons in the OB undergo an extensive selection process, during which many are eliminated by apoptosis for the fine tuning of neuronal circuits. The life and death decision of new neurons occurs extensively during a short time window of sleep after food consumption (postprandial sleep, a typical daily olfactory behavior. We review recent studies that explain how olfactory information is transferred between the OB and the olfactory cortex (OC along the course of the wake-sleep cycle. Olfactory sensory input is effectively transferred from the OB to the OC during waking, while synchronized top-down inputs from the OC to the OB are promoted during the slow-wave sleep. We discuss possible neuronal circuit mechanisms for the selection of new neurons in the OB, which involves the encoding of olfactory sensory inputs and memory trace formation during waking and internally generated activities in the OC and OB during subsequent sleep. The plastic changes in the OB and OC are well coordinated along the course of olfactory behavior during wakefulness and postbehavioral rest and sleep. We therefore propose that the olfactory system provides an excellent model in which to understand behavioral state-dependent plastic mechanisms of the neuronal

  12. Ablation of the central noradrenergic neurons for unraveling their roles in stress and anxiety.

    Science.gov (United States)

    Itoi, Keiichi

    2008-01-01

    Despite considerable evidence suggesting the relationship between the central noradrenergic (NA) system and fear/anxiety states, previous animal studies have not demonstrated sheer involvement of the locus coeruleus (LC) in mediating fear or anxiety. Following the negative results of 6-hydroexydopamine (6-OHDA)-induced LC ablation in fear-conditioning studies, most researchers dared not approach this problem using the ablation strategy. The results obtained by a limited number of endeavors, conducted later, were not consistent with the idea of LC being related to anxiety, either, with the exception of the study by Lapiz and colleagues. Since methodological problems were recognized in the neurotoxin-induced NA ablation, employed in previous studies, a novel mouse model was developed in which the LC-NA neurons were ablated selectively and thoroughly by the immunotoxin-mediated cellular targeting. The use of this model clearly demonstrated that the LC was part of the anxiety circuitry. The reason for the discrepancy between the latest study and previous ones is not clear, but it may be due either to the difference in the experimental paradigms or to the different methods for LC ablation. In any case, our findings have shed light on the LC as a locus pertaining to anxiety behavior, and may help link the apparently inconsistent results in previous studies. In addition, the novel method for the LC cell targeting, presented here may provide a potential means for studying the physiological roles of the LC including sleep/wakefulness, as well as its possible involvement in the pathogenesis of psychiatric disorders, including depression, anxiety disorders, and attention deficit/hyperactivity disorder.

  13. Molecular and celllar mechanisms underlying anti-neuronal antibody mediated disorders of the central nervous system

    NARCIS (Netherlands)

    van Coevorden - Hameete, Marleen; de Graaff, Esther; Titulaer, M.J; Hoogenraad, Casper; Sillevis Smitt, P.A.

    2014-01-01

    Over the last decade multiple autoantigens located on the plasma membrane of neurons have been identified. Neuronal surface antigens include molecules directly involved in neurotransmission and excitability. Binding of the antibody to the antigen may directly alter the target protein's function, res

  14. Estrogen receptor immunoreactivity is present in the majority of central histaminergic neurons: evidence for a new neuroendocrine pathway associated with luteinizing hormone-releasing hormone-synthesizing neurons in rats and humans.

    Science.gov (United States)

    Fekete, C S; Strutton, P H; Cagampang, F R; Hrabovszky, E; Kalló, I; Shughrue, P J; Dobó, E; Mihály, E; Baranyi, L; Okada, H; Panula, P; Merchenthaler, I; Coen, C W; Liposits, Z S

    1999-09-01

    The central regulation of the preovulatory LH surge requires a complex sequence of interactions between neuronal systems that impinge on LH-releasing hormone (LHRH)-synthesizing neurons. The reported absence of estrogen receptors (ERs) in LHRH neurons indicates that estrogen-receptive neurons that are afferent to LHRH neurons are involved in mediating the effects of this steroid. We now present evidence indicating that central histaminergic neurons, exclusively located in the tuberomammillary complex of the caudal diencephalon, serve as an important relay in this system. Evaluation of this system revealed that 76% of histamine-synthesising neurons display ERalpha-immunoreactivity in their nucleus; furthermore histaminergic axons exhibit axo-dendritic and axo-somatic appositions onto LHRH neurons in both the rodent and the human brain. Our in vivo studies show that the intracerebroventricular administration of the histamine-1 (H1) receptor antagonist, mepyramine, but not the H2 receptor antagonist, ranitidine, can block the LH surge in ovariectomized estrogen-treated rats. These data are consistent with the hypothesis that the positive feedback effect of estrogen in the induction of the LH surge involves estrogen-receptive histamine-containing neurons in the tuberomammillary nucleus that relay the steroid signal to LHRH neurons via H1 receptors.

  15. Propranolol modifies platelet serotonergic mechanisms in rats.

    Science.gov (United States)

    Zółtowski, R; Pawlak, R; Matys, T; Pietraszek, M; Buczko, W

    2002-06-01

    Though the mechanisms for the vascular actions of vasodilatory beta-blockers are mostly determined, some of their interactions with monoaminergic systems are not elucidated. Because there are evidences supporting a possible involvement of serotonin (5-HT) in the actions of beta-blockers, we studied the effect of propranolol on peripheral serotonergic mechanisms in normotensive and Goldblatt two-kidney - one clip (2K1C) hypertensive rats. In both groups of animals propranolol decreased systolic blood pressure, significantly increased whole blood serotonin concentration and at the same time it decreased platelet serotonin level. The uptake of the amine by platelets from hypertensive animals was lower than that of normotensive animals and it was decreased by propranolol only in the latter. In both groups propranolol inhibited potentiation of ADP-induced platelet aggregation by serotonin. In conclusion, this study provides evidence that propranolol modifies platelet serotonergic mechanisms in normotensive and renal hypertensive rats.

  16. Calcitonin gene-related peptide promotes cellular changes in trigeminal neurons and glia implicated in peripheral and central sensitization

    Directory of Open Access Journals (Sweden)

    Cady Ryan J

    2011-12-01

    Full Text Available Abstract Background Calcitonin gene-related peptide (CGRP, a neuropeptide released from trigeminal nerves, is implicated in the underlying pathology of temporomandibular joint disorder (TMD. Elevated levels of CGRP in the joint capsule correlate with inflammation and pain. CGRP mediates neurogenic inflammation in peripheral tissues by increasing blood flow, recruiting immune cells, and activating sensory neurons. The goal of this study was to investigate the capability of CGRP to promote peripheral and central sensitization in a model of TMD. Results Temporal changes in protein expression in trigeminal ganglia and spinal trigeminal nucleus were determined by immunohistochemistry following injection of CGRP in the temporomandibular joint (TMJ capsule of male Sprague-Dawley rats. CGRP stimulated expression of the active forms of the MAP kinases p38 and ERK, and PKA in trigeminal ganglia at 2 and 24 hours. CGRP also caused a sustained increase in the expression of c-Fos neurons in the spinal trigeminal nucleus. In contrast, levels of P2X3 in spinal neurons were only significantly elevated at 2 hours in response to CGRP. In addition, CGRP stimulated expression of GFAP in astrocytes and OX-42 in microglia at 2 and 24 hours post injection. Conclusions Our results demonstrate that an elevated level of CGRP in the joint, which is associated with TMD, stimulate neuronal and glial expression of proteins implicated in the development of peripheral and central sensitization. Based on our findings, we propose that inhibition of CGRP-mediated activation of trigeminal neurons and glial cells with selective non-peptide CGRP receptor antagonists would be beneficial in the treatment of TMD.

  17. Integration of stress and leptin signaling by CART producing neurons in the rodent midbrain centrally projecting Edinger-Westphal nucleus

    Directory of Open Access Journals (Sweden)

    Lu eXu

    2014-03-01

    Full Text Available Leptin targets the brain to regulate feeding, neuroendocrine function and metabolism. The leptin receptor is present in hypothalamic centers controlling energy metabolism as well as in the centrally projecting Edinger-Westphal nucleus (EWcp, a region implicated in the stress response and in various aspects of stress-related behaviors. We hypothesized that the stress response by cocaine- and amphetamine-regulated transcript (CART-producing EWcp-neurons would depend on the animal’s energy state. To test this hypothesis, we investigated the effects of changes in energy state (mimicked by low, normal and high leptin levels, which were achieved by 24h fasting, normal chow and leptin injection, respectively on the response of CART neurons in the EWcp of rats subjected or not to acute restraint stress. Our data show that leptin treatment alone significantly increases CART mRNA expression in the rat EWcp and that in leptin receptor deficient (db/db mice, the number of CART producing neurons in this nucleus is reduced. This suggests that leptin has a stimulatory effect on the production of CART in the EWcp under non-stressed condition. Under stressed condition, however, leptin blunts stress-induced activation of EWcp neurons and decreases their CART mRNA expression. Interestingly, fasting, does not influence the stress-induced activation of EWcp-neurons, and specifically EWcp-CART neurons are not activated. These results suggest that the stress response by the EWcp depends to some degree on the animal’s energy state, a mechanism that may contribute to a better understanding of the complex interplay between obesity and stress.

  18. Integration of stress and leptin signaling by CART producing neurons in the rodent midbrain centrally projecting Edinger-Westphal nucleus.

    Science.gov (United States)

    Xu, Lu; Janssen, Donny; van der Knaap, Noortje; Roubos, Eric W; Leshan, Rebecca L; Myers, Martin G; Gaszner, Balázs; Kozicz, Tamás

    2014-01-01

    Leptin targets the brain to regulate feeding, neuroendocrine function and metabolism. The leptin receptor is present in hypothalamic centers controlling energy metabolism as well as in the centrally projecting Edinger-Westphal nucleus (EWcp), a region implicated in the stress response and in various aspects of stress-related behaviors. We hypothesized that the stress response by cocaine- and amphetamine-regulated transcript (CART)-producing EWcp-neurons would depend on the animal's energy state. To test this hypothesis, we investigated the effects of changes in energy state (mimicked by low, normal and high leptin levels, which were achieved by 24 h fasting, normal chow and leptin injection, respectively) on the response of CART neurons in the EWcp of rats subjected or not to acute restraint stress. Our data show that leptin treatment alone significantly increases CART mRNA expression in the rat EWcp and that in leptin receptor deficient (db/db) mice, the number of CART producing neurons in this nucleus is reduced. This suggests that leptin has a stimulatory effect on the production of CART in the EWcp under non-stressed condition. Under stressed condition, however, leptin blunts stress-induced activation of EWcp neurons and decreases their CART mRNA expression. Interestingly, fasting, does not influence the stress-induced activation of EWcp-neurons, and specifically EWcp-CART neurons are not activated. These results suggest that the stress response by the EWcp depends to some degree on the animal's energy state, a mechanism that may contribute to a better understanding of the complex interplay between obesity and stress.

  19. The Effect of Desflurane on Neuronal Communication at a Central Synapse

    Science.gov (United States)

    Mapelli, Jonathan; Gandolfi, Daniela; Giuliani, Enrico; Prencipe, Francesco P.; Pellati, Federica; Barbieri, Alberto; D’Angelo, Egidio; Bigiani, Albertino

    2015-01-01

    Although general anesthetics are thought to modify critical neuronal functions, their impact on neuronal communication has been poorly examined. We have investigated the effect induced by desflurane, a clinically used general anesthetic, on information transfer at the synapse between mossy fibers and granule cells of cerebellum, where this analysis can be carried out extensively. Mutual information values were assessed by measuring the variability of postsynaptic output in relationship to the variability of a given set of presynaptic inputs. Desflurane synchronized granule cell firing and reduced mutual information in response to physiologically relevant mossy fibers patterns. The decrease in spike variability was due to an increased postsynaptic membrane excitability, which made granule cells more prone to elicit action potentials, and to a strengthened synaptic inhibition, which markedly hampered membrane depolarization. These concomitant actions on granule cells firing indicate that desflurane re-shapes the transfer of information between neurons by providing a less informative neurotransmission rather than completely silencing neuronal activity. PMID:25849222

  20. A Cell Line Producing Recombinant Nerve Growth Factor Evokes Growth Responses in Intrinsic and Grafted Central Cholinergic Neurons

    Science.gov (United States)

    Ernfors, Patrik; Ebendal, Ted; Olson, Lars; Mouton, Peter; Stromberg, Ingrid; Persson, Hakan

    1989-06-01

    The rat β nerve growth factor (NGF) gene was inserted into a mammalian expression vector and cotransfected with a plasmid conferring resistance to neomycin into mouse 3T3 fibroblasts. From this transfection a stable cell line was selected that contains several hundred copies of the rat NGF gene and produces excess levels of recombinant NGF. Such genetically modified cells were implanted into the rat brain as a probe for in vivo effects of NGF on central nervous system neurons. In a model of the cortical cholinergic deficits in Alzheimer disease, we demonstrate a marked increase in the survival of, and fiber outgrowth from, grafts of fetal basal forebrain cholinergic neurons, as well as stimulation of fiber formation by intact adult intrinsic cholinergic circuits in the cerebral cortex. Adult cholinergic interneurons in intact striatum also sprout vigorously toward implanted fibroblasts. Our results suggest that this model has implications for future treatment of neurodegenerative diseases.

  1. Premature ejaculation and serotonergic antidepressants-induced delayed ejaculation : the involvement of the serotonergic system

    NARCIS (Netherlands)

    Waldinger, MD; Berendsen, HHG; Blok, BFM; Olivier, B; Holstege, G

    1998-01-01

    Premature ejaculation has generally been considered a psychosexual disorder with psychogenic aetiology. Although still mainly treated by behavioural therapy, in recent years double-blind studies have indicated the beneficial effects of some of the serotonergic antidepressants (SSRIs) in delaying eja

  2. The effect of activation of central adrenergic receptors by clonidine on the excitability of the solitary tract neurons in cats.

    Science.gov (United States)

    Lipski, J; Solnicka, E

    1976-01-01

    The effect of i.v. administered clonidine (10-15 mug/kg) on the evoked potential recorded in the dosal part of medulla oblongata, during carotid sinus nerve stimulation, was studied in chloralose-urethane anaesthetized cats. Clonidine influenced the amplitude and configuration of the evoked potential and the changes were parallel to the blood pressure depressor response. However, the blood pressure drops, evoked by i.v. infusion of papaverine, did not influence the potential. It is concluded that the synaptic transmission from the carotid sinus nerve to the second order neurons in the solatary tract area can be modulated by the clonidine-induced activation of central adrenergic receptors.

  3. Different Serotonergic Expression in Nevomelanocytic Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Naimi-Akbar, Clara; Ritter, Markus; Demel, Sasika; El-Nour, Husameldin; Hedblad, Mari-Anne [Dermatology and Venereology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Solna (Sweden); Azmitia, Efrain C. [Department of Biology and Psychiatry, New York University, NY (United States); Nordlind, Klas, E-mail: klas.nordlind@karolinska.se [Dermatology and Venereology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Solna (Sweden)

    2010-06-07

    The neuromediator serotonin (5-hydroxytryptamine; 5-HT) has been proposed to play a role in tumor progression. Thus, the aim of the present investigation was to determine whether alterations in the serotonergic system occur in nevomelanocytic tumors. For this purpose, paraffin-embedded biopsies of superficial spreading malignant melanoma (SSM), dysplastic compound nevi (DN) and benign compound nevi (BCN) were characterized with regard to their expression of 5-HT, the 5-HT1A and 5-HT2A receptors, and the serotonin transporter protein (SERT), by immunohistochemical analysis. Melanocytes in the region surrounding the tumor were found to express both the 5-HT1A and 5-HT2A receptors. Tumor cells that immunostained positively for the different serotonergic markers were observed in the suprabasal epidermis of DN tissue and, to an even greater extent, in the case of SSM. Furthermore, some of these latter cells expressed both 5-HT1AR and 5-HT2AR. The level of expression of 5-HT1AR at the junctional area was lower for SSM than for DN or BCN. As the degree of atypia increased, the intensity of tumor cell staining in the dermis for 5-HT1AR and SERT declined. Vessel immunoreactivity for 5-HT2A was more intense in SSM than in BCN tissue. Round-to-dendritic cells that expressed both SERT and 5-HT1AR were seen to infiltrate into the dermal region of the tumor, this infiltration being more evident in the case of DN and SSM. These latter cells were also tryptase-positive, indicating that they are mast cells. Thus, alterations in serotonergic system may be involved in nevomelanocytic tumors and mast cells may play an important role in this connection.

  4. Different Serotonergic Expression in Nevomelanocytic Tumors

    Directory of Open Access Journals (Sweden)

    Clara Naimi-Akbar

    2010-06-01

    Full Text Available The neuromediator serotonin (5-hydroxytryptamine; 5-HT has been proposed to play a role in tumor progression. Thus, the aim of the present investigation was to determine whether alterations in the serotonergic system occur in nevomelanocytic tumors. For this purpose, paraffin-embedded biopsies of superficial spreading malignant melanoma (SSM, dysplastic compound nevi (DN and benign compound nevi (BCN were characterized with regard to their expression of 5-HT, the 5-HT1A and 5-HT2A receptors, and the serotonin transporter protein (SERT, by immunohistochemical analysis. Melanocytes in the region surrounding the tumor were found to express both the 5-HT1A and 5-HT2A receptors. Tumor cells that immunostained positively for the different serotonergic markers were observed in the suprabasal epidermis of DN tissue and, to an even greater extent, in the case of SSM. Furthermore, some of these latter cells expressed both 5-HT1AR and 5-HT2AR. The level of expression of 5-HT1AR at the junctional area was lower for SSM than for DN or BCN. As the degree of atypia increased, the intensity of tumor cell staining in the dermis for 5-HT1AR and SERT declined. Vessel immunoreactivity for 5-HT2A was more intense in SSM than in BCN tissue. Round-to-dendritic cells that expressed both SERT and 5-HT1AR were seen to infiltrate into the dermal region of the tumor, this infiltration being more evident in the case of DN and SSM. These latter cells were also tryptase-positive, indicating that they are mast cells. Thus, alterations in serotonergic system may be involved in nevomelanocytic tumors and mast cells may play an important role in this connection.

  5. The serotonergic system and cognitive function

    Directory of Open Access Journals (Sweden)

    Švob Štrac Dubravka

    2016-01-01

    Full Text Available Symptoms of cognitive dysfunction like memory loss, poor concentration, impaired learning and executive functions are characteristic features of both schizophrenia and Alzheimer’s disease (AD. The neurobiological mechanisms underlying cognition in healthy subjects and neuropsychiatric patients are not completely understood. Studies have focused on serotonin (5-hydroxytryptamine, 5-HT as one of the possible cognitionrelated biomarkers. The aim of this review is to provide a summary of the current literature on the role of the serotonergic (5-HTergic system in cognitive function, particularly in AD and schizophrenia.

  6. Serotonergic integration of circadian clock and ultradian sleep-wake cycles.

    Science.gov (United States)

    Miyamoto, Hiroyuki; Nakamaru-Ogiso, Eiko; Hamada, Kozo; Hensch, Takao K

    2012-10-17

    In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus generates a 24 h rhythm of sleep and arousal. While neuronal spiking activity in the SCN provides a functional circadian oscillator that propagates throughout the brain, the ultradian sleep-wake state is regulated by the basal forebrain/preoptic area (BF/POA). How this SCN circadian oscillation is integrated into the shorter sleep-wake cycles remains unclear. We examined the temporal patterns of neuronal activity in these key brain regions in freely behaving rats. Neuronal activity in various brain regions presented diurnal rhythmicity and/or sleep-wake state dependence. We identified a diurnal rhythm in the BF/POA that was selectively degraded when diurnal arousal patterns were disrupted by acute brain serotonin depletion despite robust circadian spiking activity in the SCN. Local blockade of serotonergic transmission in the BF/POA was sufficient to disrupt the diurnal sleep-wake rhythm of mice. These results suggest that the serotonergic system enables the BF/POA to couple the SCN circadian signal to ultradian sleep-wake cycles, thereby providing a potential link between circadian rhythms and psychiatric disorders.

  7. Descending serotonergic facilitation and the antinociceptive effects of pregabalin in a rat model of osteoarthritic pain

    Directory of Open Access Journals (Sweden)

    Dolphin Annette C

    2009-08-01

    descending serotonergic facilitation plays a role in mediating the brush and innocuous mechanical punctate evoked neuronal responses in MIA rats, suggesting an adaptive change in the excitatory serotonergic drive modulating low threshold evoked neuronal responses in MIA-induced OA pain. This alteration in excitatory serotonergic drive, alongside an increase in α2δ-1 mRNA levels, may underlie pregabalin's state dependent effects in this model of chronic pain.

  8. Gap Junction-Mediated Signaling from Motor Neurons Regulates Motor Generation in the Central Circuits of Larval Drosophila.

    Science.gov (United States)

    Matsunaga, Teruyuki; Kohsaka, Hiroshi; Nose, Akinao

    2017-02-22

    In this study, we used the peristaltic crawling of Drosophila larvae as a model to study how motor patterns are regulated by central circuits. We built an experimental system that allows simultaneous application of optogenetics and calcium imaging to the isolated ventral nerve cord (VNC). We then investigated the effects of manipulating local activity of motor neurons (MNs) on fictive locomotion observed as waves of MN activity propagating along neuromeres. Optical inhibition of MNs with halorhodopsin3 in a middle segment (A4, A5, or A6), but not other segments, dramatically decreased the frequency of the motor waves. Conversely, local activation of MNs with channelrhodopsin2 in a posterior segment (A6 or A7) increased the frequency of the motor waves. Since peripheral nerves mediating sensory feedback were severed in the VNC preparation, these results indicate that MNs send signals to the central circuits to regulate motor pattern generation. Our results also indicate segmental specificity in the roles of MNs in motor control. The effects of the local MN activity manipulation were lost in shaking-B(2) (shakB(2) ) or ogre(2) , gap-junction mutations in Drosophila, or upon acute application of the gap junction blocker carbenoxolone, implicating electrical synapses in the signaling from MNs. Cell-type-specific RNAi suggested shakB and ogre function in MNs and interneurons, respectively, during the signaling. Our results not only reveal an unexpected role for MNs in motor pattern regulation, but also introduce a powerful experimental system that enables examination of the input-output relationship among the component neurons in this system.SIGNIFICANCE STATEMENT Motor neurons are generally considered passive players in motor pattern generation, simply relaying information from upstream interneuronal circuits to the target muscles. This study shows instead that MNs play active roles in the control of motor generation by conveying information via gap junctions to the

  9. Neural activity, memory, and dementias: serotonergic markers.

    Science.gov (United States)

    Meneses, Alfredo

    2017-04-01

    Dysfunctional memory seems to be a key component of diverse dementias and other neuropsychiatric disorders; unfortunately, no effective treatment exists for this, probably because of the absence of neural biomarkers accompanying it. Diverse neurotransmission systems have been implicated in memory, including serotonin or 5-hydroxytryptamine (5-HT). There are multiple serotonergic pharmacological tools, well-characterized downstream signaling in mammals' species and neural markers providing new insights into memory functions and dysfunctions. Serotonin in mammal species has multiple neural markers, including receptors (5-HT1-7), serotonin transporter, and volume transmission, which are present in brain areas involved in memory. Memory, amnesia, and forgetting modify serotonergic markers; this influence is bidirectional. Evidence shows insights and therapeutic targets and diverse approaches support the translatability of using neural markers and cerebral functions and dysfunctions, including memory formation and amnesia. For instance, 5-HT2A/2B/2C, 5-HT4, and 5-HT6 receptors are involved in tau protein hyperphosphorylation in Alzheimer's disease. In addition, at least, 5-HT1A, 5-HT4, 5-HT6, and 5-HT7 receptors as well as serotonin transporter seem to be useful neural markers and therapeutic targets. Hence, available evidence supports the notion that several mechanisms cooperate to achieve synaptic plasticity or memory, including changes in the number of neurotransmitter receptors and transporters. Considering that memory is a key component of dementias, hence reversing or reducing memory deficits might positively affect them?

  10. The use of serotonergic drugs to treat obesity – is there any hope?

    Directory of Open Access Journals (Sweden)

    Nicholas T Bello

    2011-02-01

    Full Text Available Nicholas T Bello1, Nu-Chu Liang21Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA; 2Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USAAbstract: Surgical interventional strategies for the treatment of obesity are being implemented at an increasing rate. The safety and feasibility of these procedures are questionable for most overweight or obese individuals. The use of long-term pharmacotherapy options, on the other hand, can target a greater portion of the obese population and provide early intervention to help individuals maintain a healthy lifestyle to promote weight loss. Medications that act on the central serotonergic pathways have been a relative mainstay for the treatment of obesity for the last 35 years. The clinical efficacy of these drugs, however, has been encumbered by the potential for drug-associated complications. Two drugs that act, albeit by different mechanisms, on the central serotonergic system to reduce food intake and decrease body weight are sibutramine and lorcaserin. Sibutramine is a serotonin and norepinephrine reuptake inhibitor, whereas lorcaserin is a selective 5HT2C receptor agonist. The recent worldwide withdrawal of sibutramine and FDA rejection of lorcaserin has changed the landscape not only for serotonin-based therapeutics specifically, but for obesity pharmacotherapy in general. The purpose of this review is to focus on the importance of the serotonergic system in the control of feeding and its potential as a target for obesity pharmacotherapy. Advances in refining and screening more selective receptor agonists and a better understanding of the potential off-target effects of serotonergic drugs are needed to produce beneficial pharmacotherapy.Keywords: 5-hydroxytryptamine, serotonin 1B, fenfluramine, dexfenfluramine, satiety, dorsal raphe

  11. Serotonergic system and its role in epilepsy and neuropathic pain treatment: a review based on receptor ligands.

    Science.gov (United States)

    Panczyk, Katarzyna; Golda, Sylwia; Waszkielewicz, Anna; Zelaszczyk, Dorota; Gunia-Krzyzak, Agnieszka; Marona, Henryk

    2015-01-01

    The serotonergic system is involved in pathomechanisms of both epilepsy and neuropathic pain. So far, participation in the epileptogenesis and maintenance of epilepsy was proved for 5-HT1A, 5-HT2C, 5-HT3, 5-HT4 and 5-HT7 receptors as well as 5-HTT serotonin transporter. Depending on the receptor type or its localization, its stimulation may increase or decrease neuronal excitability. According to the available data, neuropathic pain mechanisms involve 5-HT1A/1B/1D, 5-HT2A/2B/2C, 5-HT3, 5-HT4, 5-HT6, 5-HT7 receptors and 5-HTT serotonin transporter. Changes in their expression modulate pain mainly by affecting the transmission through serotonergic descending pathways. Several compounds, whose mechanisms of action base on influence on the serotonergic system, are already in use. These are 5-HT3 agonists (triptans) in case of migraine, tricyclic antidepressants or monoamine reuptake inhibitors in neuropathic pain treatment. In addition, selective and non-selective ligands are tested for their anticonvulsant or analgesic properties. Some ED50 values have been already obtained in such animal models as maximal electroshock (MES)-induced seizures (epilepsy), spinal nerve ligation (SNL), chronic constriction injury (CCI) or formalin (neuropathic pain). This review shows that in case of drug discovery within the serotonergic system one must take into account special significance of factors such as: the species, the type of model, the route of administration, and the dose range.

  12. Mirror neurons are central for a second-person neuroscience: insights from developmental studies.

    Science.gov (United States)

    Simpson, Elizabeth Ann; Ferrari, Pier Francesco

    2013-08-01

    Based on mirror neurons' properties, viewers are emotionally engaged when observing others - even when not actively interacting; therefore, characterizing non-participatory action-viewing as isolated may be misleading. Instead, we propose a continuum of socio-emotional engagement. We also highlight recent developmental work that uses a second-person perspective, investigating behavioral, physiological, and neural activity during caregiver-infant interactions.

  13. MrgC agonism at central terminals of primary sensory neurons inhibits neuropathic pain.

    Science.gov (United States)

    He, Shao-Qiu; Li, Zhe; Chu, Yu-Xia; Han, Liang; Xu, Qian; Li, Man; Yang, Fei; Liu, Qin; Tang, Zongxiang; Wang, Yun; Hin, Niyada; Tsukamoto, Takashi; Slusher, Barbara; Tiwari, Vinod; Shechter, Ronen; Wei, Feng; Raja, Srinivasa N; Dong, Xinzhong; Guan, Yun

    2014-03-01

    Chronic neuropathic pain is often refractory to current pharmacotherapies. The rodent Mas-related G-protein-coupled receptor subtype C (MrgC) shares substantial homogeneity with its human homologue, MrgX1, and is located specifically in small-diameter dorsal root ganglion neurons. However, evidence regarding the role of MrgC in chronic pain conditions has been disparate and inconsistent. Accordingly, the therapeutic value of MrgX1 as a target for pain treatment in humans remains uncertain. Here, we found that intrathecal injection of BAM8-22 (a 15-amino acid peptide MrgC agonist) and JHU58 (a novel dipeptide MrgC agonist) inhibited both mechanical and heat hypersensitivity in rats after an L5 spinal nerve ligation (SNL). Intrathecal JHU58-induced pain inhibition was dose dependent in SNL rats. Importantly, drug efficacy was lost in Mrg-cluster gene knockout (Mrg KO) mice and was blocked by gene silencing with intrathecal MrgC siRNA and by a selective MrgC receptor antagonist in SNL rats, suggesting that the drug action is MrgC dependent. Further, in a mouse model of trigeminal neuropathic pain, microinjection of JHU58 into ipsilateral subnucleus caudalis inhibited mechanical hypersensitivity in wild-type but not Mrg KO mice. Finally, JHU58 attenuated the miniature excitatory postsynaptic currents frequency both in medullary dorsal horn neurons of mice after trigeminal nerve injury and in lumbar spinal dorsal horn neurons of mice after SNL. We provide multiple lines of evidence that MrgC agonism at spinal but not peripheral sites may constitute a novel pain inhibitory mechanism that involves inhibition of peripheral excitatory inputs onto postsynaptic dorsal horn neurons in different rodent models of neuropathic pain.

  14. Bone Injury and Repair Trigger Central and Peripheral NPY Neuronal Pathways

    Science.gov (United States)

    Alencastre, Inês S.; Neto, Estrela; Ribas, João; Ferreira, Sofia; Vasconcelos, Daniel M.; Sousa, Daniela M.; Summavielle, Teresa; Lamghari, Meriem

    2016-01-01

    Bone repair is a specialized type of wound repair controlled by complex multi-factorial events. The nervous system is recognized as one of the key regulators of bone mass, thereby suggesting a role for neuronal pathways in bone homeostasis. However, in the context of bone injury and repair, little is known on the interplay between the nervous system and bone. Here, we addressed the neuropeptide Y (NPY) neuronal arm during the initial stages of bone repair encompassing the inflammatory response and ossification phases in femoral-defect mouse model. Spatial and temporal analysis of transcriptional and protein levels of NPY and its receptors, Y1R and Y2R, reported to be involved in bone homeostasis, was performed in bone, dorsal root ganglia (DRG) and hypothalamus after femoral injury. The results showed that NPY system activity is increased in a time- and space-dependent manner during bone repair. Y1R expression was trigged in both bone and DRG throughout the inflammatory phase, while a Y2R response was restricted to the hypothalamus and at a later stage, during the ossification step. Our results provide new insights into the involvement of NPY neuronal pathways in bone repair. PMID:27802308

  15. The effect of 3,4-methylenedioxymethamphetamine ('Ecstasy') on serotonergic regulation of the mammalian circadian clock mechanism in rats: the role of dopamine and hyperthermia.

    Science.gov (United States)

    Dafters, Richard I; Biello, Stephany M

    2003-10-23

    The recreational drug 3,4-methylenedioxymethamphetamine (MDMA) is known to be a neurotoxin for serotonergic axons ascending from the raphe nucleus including those which terminate on neurons of the suprachiasmatic nuclei (SCN) of the hypothalamus, the putative mammalian circadian clock. Since dopamine release has been implicated in the serotonergic neurotoxicity, we examined the effects of the dopamine synthesis inhibitor alpha-methyl-p-tyrosine (AMPT) and the D2 receptor antagonist haloperidol (HAL) on the long-term effect of MDMA on serotonergic regulation of the SCN neuronal firing rhythm. Co-administration of AMPT or HAL with MDMA eliminated the acute hyperthermic response but had no effect on the MDMA-induced phase shift in the firing rhythm of SCN neurons to the selective 5-HT1A receptor agonist, 8-hydroxy-2-(dipropylamino)-tetralin. It is concluded that neither dopamine metabolism nor hyperthermia account for the altered serotonergic function in the SCN produced by MDMA. Toxic free radical production following MDMA metabolism may be responsible.

  16. Serotonergic contribution to boys' behavioral regulation.

    Directory of Open Access Journals (Sweden)

    Amélie Nantel-Vivier

    Full Text Available OBJECTIVES: Animal and human adult studies reveal a contribution of serotonin to behavior regulation. Whether these findings apply to children is unclear. The present study investigated serotonergic functioning in boys with a history of behavior regulation difficulties through a double-blind, acute tryptophan supplementation procedure. METHOD: Participants were 23 boys (age 10 years with a history of elevated physical aggression, recruited from a community sample. Eleven were given a chocolate milkshake supplemented with 500 mg tryptophan, and 12 received a chocolate milkshake without tryptophan. Boys engaged in a competitive reaction time game against a fictitious opponent, which assessed response to provocation, impulsivity, perspective taking, and sharing. Impulsivity was further assessed through a Go/No-Go paradigm. A computerized emotion recognition task and a staged instrumental help incident were also administered. RESULTS: Boys, regardless of group, responded similarly to high provocation by the fictitious opponent. However, boys in the tryptophan group adjusted their level of responding optimally as a function of the level of provocation, whereas boys in the control group significantly decreased their level of responding towards the end of the competition. Boys in the tryptophan group tended to show greater perspective taking, tended to better distinguish facial expressions of fear and happiness, and tended to provide greater instrumental help to the experimenter. CONCLUSIONS: The present study provides initial evidence for the feasibility of acute tryptophan supplementation in children and some effect of tryptophan supplementation on children's behaviors. Further studies are warranted to explore the potential impact of increased serotonergic functioning on boys' dominant and affiliative behaviors.

  17. SUMOylation of NaV1.2 channels mediates the early response to acute hypoxia in central neurons

    Science.gov (United States)

    Plant, Leigh D; Marks, Jeremy D; Goldstein, Steve AN

    2016-01-01

    The mechanism for the earliest response of central neurons to hypoxia—an increase in voltage-gated sodium current (INa)—has been unknown. Here, we show that hypoxia activates the Small Ubiquitin-like Modifier (SUMO) pathway in rat cerebellar granule neurons (CGN) and that SUMOylation of NaV1.2 channels increases INa. The time-course for SUMOylation of single NaV1.2 channels at the cell surface and changes in INa coincide, and both are prevented by mutation of NaV1.2-Lys38 or application of a deSUMOylating enzyme. Within 40 s, hypoxia-induced linkage of SUMO1 to the channels is complete, shifting the voltage-dependence of channel activation so that depolarizing steps evoke larger sodium currents. Given the recognized role of INa in hypoxic brain damage, the SUMO pathway and NaV1.2 are identified as potential targets for neuroprotective interventions. DOI: http://dx.doi.org/10.7554/eLife.20054.001 PMID:28029095

  18. Posttraumatic GABA(A)-mediated [Ca2+]i increase is essential for the induction of brain-derived neurotrophic factor-dependent survival of mature central neurons.

    Science.gov (United States)

    Shulga, Anastasia; Thomas-Crusells, Judith; Sigl, Thomas; Blaesse, Anne; Mestres, Pedro; Meyer, Michael; Yan, Qiao; Kaila, Kai; Saarma, Mart; Rivera, Claudio; Giehl, Klaus M

    2008-07-02

    A shift of GABA(A)-mediated responses from hyperpolarizing to depolarizing after neuronal injury leads to GABA(A)-mediated increase in [Ca2+](i). In addition, central neurons become dependent on BDNF for survival. Whether these two mechanisms are causally interrelated is an open question. Here, we show in lesioned CA3 hippocampal neurons in vitro and in axotomized corticospinal neurons in vivo that posttraumatic downregulation of the neuron-specific K-Cl cotransporter KCC2 leads to intracellular chloride accumulation by the Na-K-2Cl cotransporter NKCC1, resulting in GABA-induced [Ca2+](i) transients. This mechanism is required by a population of neurons to survive in a BDNF-dependent manner after injury, because blocking GABA(A)-depolarization with the NKCC1 inhibitor bumetanide prevents the loss of neurons on BDNF withdrawal. The resurgence of KCC2 expression during recovery coincides with loss of BDNF dependency for survival. This is likely mediated through BDNF itself, because injured neurons reverse their response to this neurotrophin by switching the BDNF-induced downregulation of KCC2 to upregulation.

  19. Low HDL cholesterol, aggression and altered central serotonergic activity.

    Science.gov (United States)

    Buydens-Branchey, L; Branchey, M; Hudson, J; Fergeson, P

    2000-03-01

    Many studies support a significant relation between low cholesterol levels and poor impulse, aggression and mood control. Evidence exists also for a causal link between low brain serotonin (5-HT) activity and these behaviors. Mechanisms linking cholesterol and hostile or self-destructive behavior are unknown, but it has been suggested that low cholesterol influences 5-HT function. This study was designed to explore the relationship between plasma cholesterol, measures of impulsivity and aggression, and indices of 5-HT function in personality disordered cocaine addicts. Thirty-eight hospitalized male patients (age 36.8+/-7.1) were assessed with the DSM-III-R, the Buss-Durkee Hostility Inventory (BDHI), the Barratt Impulsiveness Scale (BIS) and the Brown-Goodwin Assessment for Life History of Aggression. Fasting basal cholesterol (total, LDL and HDL) was determined 2 weeks after cocaine discontinuation. On the same day 5-HT function was assessed by neuroendocrine (cortisol and prolactin) and psychological (NIMH and 'high' self-rating scales) responses following meta-chlorophenylpiperazine (m-CPP) challenges. Reduced neuroendocrine responses, 'high' feelings and increased 'activation-euphoria' following m-CPP have been interpreted as indicating 5-HT alterations in a variety of psychiatric conditions. Significantly lower levels of HDL cholesterol were found in patients who had a history of aggression (P=0.005). Lower levels of HDL cholesterol were also found to be significantly associated with more intense 'high' and 'activation-euphoria' responses as well as with blunted cortisol responses to m-CPP (P=0.033, P=0.025 and P=0.018, respectively). This study gives further support to existing evidence indicating that in some individuals, the probability of exhibiting impulsive and violent behaviors may be increased when cholesterol is low. It also suggests that low cholesterol and alterations in 5-HT activity may be causally related.

  20. Influence of stimulus and oral adaptation temperature on gustatory responses in central taste-sensitive neurons.

    Science.gov (United States)

    Li, Jinrong; Lemon, Christian H

    2015-04-01

    The temperature of taste stimuli can modulate gustatory processing. Perceptual data indicate that the adapted temperature of oral epithelia also influences gustation, although little is known about the neural basis of this effect. Here, we electrophysiologically recorded orosensory responses (spikes) to 25°C (cool) and 35°C (warm) solutions of sucrose (0.1 and 0.3 M), NaCl (0.004, 0.1, and 0.3 M), and water from taste-sensitive neurons in the nucleus of the solitary tract in mice under varied thermal adaptation of oral epithelia. Conditions included presentation of taste stimuli isothermal to adaptation temperatures of 25°C (constant cooling) and 35°C (constant warming), delivery of 25°C stimuli following 35°C adaptation (relative cooling), and presentation of 35°C stimuli following 25°C adaptation (relative warming). Responses to sucrose in sucrose-oriented cells (n = 15) were enhanced under the constant and relative warming conditions compared with constant cooling, where contiguous cooling across adaptation and stimulus periods induced the lowest and longest latency responses to sucrose. Yet compared with constant warming, cooling sucrose following warm adaptation (relative cooling) only marginally reduced activity to 0.1 M sucrose and did not alter responses to 0.3 M sucrose. Thus, warmth adaptation counteracted the attenuation in sucrose activity associated with stimulus cooling. Analysis of sodium-oriented (n = 25) neurons revealed adaptation to cool water, and cooling taste solutions enhanced unit firing to 0.004 M (perithreshold) NaCl, whereas warmth adaptation and stimulus warming could facilitate activity to 0.3 M NaCl. The concentration dependence of this thermal effect may reflect a dual effect of temperature on the sodium reception mechanism that drives sodium-oriented cells.

  1. Molecular analysis of central feeding regulation by neuropeptide Y (NPY) neurons with NPY receptor small interfering RNAs (siRNAs).

    Science.gov (United States)

    Higuchi, Hiroshi

    2012-11-01

    Hypothalamic neuropeptides play important roles in central feeding behavior. Among them, neuropeptide Y (NPY) has the strongest orexigenic action. It is synthesized in NPY-expressing neurons in the arcuate nucleus (ARC), which projects to other nuclei, mainly to the paraventricular nucleus (PVN). PVN, which possesses NPY-Y1, -Y2 and -Y4, -Y5 receptors, is considered as feeding center for central feeding behavior. Herein I review recent results on feeding behavior obtained by gene knockdown technologies. The small interfering RNA (siRNA) plasmid-based vectors, which drive transcription of siRNA by U6 RNA polymerase III promoter to produce knockdown of the NPY and its receptor (Y1, Y2, Y4 and Y5) genes, were stereotaxically injected into mouse ARC and PVN. Feeding behaviors were measured for 6days after siRNA vector injection. NPY and its receptor mRNA levels were decreased, which were measured by RT-PCR and in situ hybridization, and simultaneous decrease in their proteins was also detected in separate nuclei by immunohistochemistry. In the NPY system, decrease in NPY, Y1 and Y5 expressions in specialized nuclei diminished central feeding behavior, whereas decrease in Y2 or Y4 expression in both ARC or PVN did not affect feeding behavior. Thus, specialized change in expressions of NPY and its receptors (especially Y1 and Y5) are important for regulation of endogenous feeding behavior in central regulation. Further analysis of NPY receptors may provide better understanding of feeding behavior and of potential therapeutic targets.

  2. [A pharmacological analysis of the central control of the preganglionic sympathetic neurons during stimulation of the afferent nerve fibers of the digestive tract].

    Science.gov (United States)

    Itina, L V; Posniak, V A

    1995-12-01

    In acute experiments on cats, effect of adrenergic brain neurons on impulse activity of preganglionic fibers of the left splanchnic nerve was studied. Afferent fibers of nerves innervating the stomach, duodenum, ileum and ileocecal angle were electrically stimulated. Phenoxybenzamine, obsidan, amizyl, iprazid, nuredal, dalargine, and morphine were used for pharmacological analysis. Nerves, stimulation at 20 Hz of different segments of the digestive tract was accompanied by different inhibition of preganglionic neurons. Sympathetic-stimulating effects were observed more frequently at 5 Hz stimulation. After vagotomy, alpha- and beta-adrenoreceptor block, central cholinoreceptor and monoamine oxidase (MAO) block, and after dalargine (0.1 and 0.01 mg/kg) nerves stimulation at 20 Hz was followed by sympathetic-stimulating effect. A weak regulatory effect of morphine (1 and 10 mg/kg) on ileal nerve stimulation effects was shown. It is suggested that excitation from afferent neurons of the vagus is transmitted to central cholinergic neurons which, in their turn, excite adrenergic neurons of the brain, and the latter inhibit impulsation of preganglionic fibers. MAO block increased the balance of excitatory effect of serotonin on spinal reflexes. Morphine and dalargine intracentrally may block adrenergic and cholinergic transmissions, as well as decrease the release of substance P from afferent neurons. Their regulatory action is revealed when different frequencies of stimulation are used.

  3. Cyclic-AMP regulation of calcium-dependent K channels in an insect central neurone.

    Science.gov (United States)

    David, J A; Pitman, R M

    1996-01-26

    In the cockroach fast coxal depressor motoneurone, either the muscarinic agonist McN-A-343 or dibutyryl cAMP (Db-cAMP) induced a reduction in voltage-dependent outward current. The response to McN is due to suppression of a calcium-dependent potassium current (IK,Ca) produced secondarily to a reduction in voltage-dependent calcium current (ICa). The response to Db-cAMP was investigated in order to establish whether cAMP might mediate the response to McN. ICa was suppressed by 3-isobutyl-1-methylxanthine (IBMX) but not by Db-cAMP. The effects of IBMX were therefore unlikely to be the result of phosphodiesterase inhibition. Since caffeine also suppressed ICa, the observed effect of IBMX is probably due to release of Ca2+ from intracellular stores. IK,Ca, evoked by injection of Ca2+, was reduced by Db-cAMP or forskolin but not by McN. These results indicate that the electrical response to McN in this neurone is not mediated by changes in cAMP.

  4. A transient outward current in a mammalian central neurone blocked by 4-aminopyridine

    OpenAIRE

    Gustafsson, B.; Galvan, Martin; Grafe, Peter; Wigström, H.

    1982-01-01

    It is becoming increasingly clear that nerve cells in the mammalian central nervous system (CNS) have a very complex electroresponsiveness. They exhibit not only time- and voltage-dependent Na+ and K+ conductances, analogous to those in the squid giant axon1, but also a variety of other conductances that have a significant role in the control of cell excitability. Of the outward currents, there are, in addition to the delayed rectifier, the Ca2+-activated K+ current2,3 which underlies the lon...

  5. The influence of aging on the number of neurons and levels of non-phosporylated neurofilament proteins in the central auditory system of rats

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    Jana eBurianová

    2015-03-01

    Full Text Available In the present study, an unbiased stereological method was used to determine the number of all neurons in Nissl stained sections of the inferior colliculus (IC, medial geniculate body (MGB and auditory cortex (AC in rats (strains Long Evans and Fischer 344 and their changes with aging. In addition, using the optical fractionator and western blot technique, we also evaluated the number of SMI-32-immunoreactive(-ir neurons and levels of non-phosphorylated neurofilament proteins in the IC, MGB, AC, and visual cortex (VC of young and old rats of the two strains. The SMI-32 positive neuronal population comprises about 10% of all neurons in the rat IC, MGB and AC and represents a prevalent population of large neurons with highly myelinated and projecting processes. In both Long Evans and Fischer 344 rats, the total number of neurons in the IC was roughly similar to that in the AC. With aging, we found a rather mild and statistically non-significant decline in the total number of neurons in all three analyzed auditory regions in both rat strains. In contrast to this, the absolute number of SMI-32-ir neurons in both Long Evans and Fischer 344 rats significantly decreased with aging in all the examined structures. The western blot technique also revealed a significant age-related decline in the levels of non-phosphorylated neurofilaments in the auditory brain structures, 30-35%. Our results demonstrate that presbycusis in rats is not likely to be primarily associated with changes in the total number of neurons. On the other hand, the pronounced age-related decline in the number of neurons containing non-phosphorylated neurofilaments as well as their protein levels in the central auditory system may contribute to age-related deterioration of hearing function.

  6. The rise and fall of mesodiencephalic dopaminergic neurons : Molecular programming by transcription factors Engrailed 1, Pitx3, and Nkx2.9 during the development of mesodiencephalic neurons

    NARCIS (Netherlands)

    Kouwenhoven, W.M.

    2016-01-01

    The mid- and hindbrain harbor two essential monoaminergic neuronal populations: the mesodiencephalic dopaminergic (mdDA) neurons in the midbrain and the serotonergic (5HT) neurons in the hindbrain. Both systems innervate multiple regions in the forebrain and are involved in the guidance of our mood,

  7. Central CRF neurons are not created equal: Phenotypic differences in CRF-containing neurons of the rat paraventricular hypothalamus and the bed nucleus of the stria terminalis.

    Directory of Open Access Journals (Sweden)

    Joanna eDabrowska

    2013-08-01

    Full Text Available Corticotrophin-releasing factor (CRF plays a key role in initiating many of the endocrine, autonomic, and behavioral responses to stress. CRF-containing neurons of the paraventricular nucleus of the hypothalamus (PVN are classically involved in regulating endocrine function through activation of the stress axis. However, CRF is also thought to play a critical role in mediating anxiety-like responses to environmental stressors, and dysfunction of the CRF system in extra-hypothalamic brain regions, like the bed nucleus of stria terminalis (BNST, has been linked to the etiology of many psychiatric disorders including anxiety and depression. Thus, although CRF neurons of the PVN and BNST share a common neuropeptide phenotype, they may represent two functionally diverse neuronal populations. Here, we employed dual-immunofluorescence, single-cell RT-PCR, and electrophysiological techniques to further examine this question and report that CRF neurons of the PVN and BNST are fundamentally different such that PVN CRF neurons are glutamatergic, whereas BNST CRF neurons are GABAergic. Moreover, these two neuronal populations can be further distinguished based on their electrophysiological properties, their co-expression of peptide neurotransmitters such as oxytocin and arginine-vasopressin, and their cognate receptors. Our results suggest that CRF neurons in the PVN and the BNST would not only differ in their response to local neurotransmitter release, but also in their action on downstream target structures.

  8. Reducing central serotonin in adulthood promotes hippocampal neurogenesis.

    Science.gov (United States)

    Song, Ning-Ning; Jia, Yun-Fang; Zhang, Lei; Zhang, Qiong; Huang, Ying; Liu, Xiao-Zhen; Hu, Ling; Lan, Wei; Chen, Ling; Lesch, Klaus-Peter; Chen, Xiaoyan; Xu, Lin; Ding, Yu-Qiang

    2016-02-03

    Chronic administration of selective serotonin reuptake inhibitors (SSRIs), which up-regulates central serotonin (5-HT) system function, enhances adult hippocampal neurogenesis. However, the relationship between central 5-HT system and adult neurogenesis has not fully been understood. Here, we report that lowering 5-HT level in adulthood is also able to enhance adult hippocampal neurogenesis. We used tamoxifen (TM)-induced Cre in Pet1-CreER(T2) mice to either deplete central serotonergic (5-HTergic) neurons or inactivate 5-HT synthesis in adulthood and explore the role of central 5-HT in adult hippocampal neurogenesis. A dramatic increase in hippocampal neurogenesis is present in these two central 5-HT-deficient mice and it is largely prevented by administration of agonist for 5-HTR2c receptor. In addition, the survival of new-born neurons in the hippocampus is enhanced. Furthermore, the adult 5-HT-deficient mice showed reduced depression-like behaviors but enhanced contextual fear memory. These findings demonstrate that lowering central 5-HT function in adulthood can also enhance adult hippocampal neurogenesis, thus revealing a new aspect of central 5-HT in regulating adult neurogenesis.

  9. Mapping of neurons in the central nervous system of the guinea pig by use of antisera specific to the molluscan neuropeptide FMRFamide

    DEFF Research Database (Denmark)

    Triepel, J; Grimmelikhuijzen, C J

    1984-01-01

    Immunoreactive neurons were mapped in the central nervous system of colchicine-treated and untreated guinea pigs with the use of two antisera to the molluscan neuropeptide FMRFamide. These antisera were especially selected for their incapability to react with peptides of the pancreatic polypeptide...

  10. Effects of in vitro lead exposure on voltage-sensitive calcium channels differ among cell types in central neurons of Lymnaea stagnalis.

    Science.gov (United States)

    Audesirk, G; Audesirk, T

    1989-01-01

    The effects of acute in vitro lead exposure on slowly inactivating voltage-sensitive calcium channels in central neurons of the freshwater pond snail Lymnaea stagnalis were studied under voltage clamp. Three physiologically distinct cell types were used: two subsets of the B cell cluster (Bpos and Bneg) and the pedal giant neuron (RPeD1). In Bpos neurons, 5 nM free Pb2+ irreversibly inhibited current flow through calcium channels by 38 +/- 10%. In Bneg neurons, 5 nM free Pb2+ slightly inhibited inward currents (12 +/- 6%) and may have shifted their voltage dependence to more depolarized voltages. The inhibition and voltage shift were irreversible. In RPeD1 neurons, Pb2+ caused a small, statistically insignificant inhibition of inward current (5 nM free Pb2+; 18 +/- 19%; 30 nM free Pb2+: 31 +/- 23%). The effects of Pb2+ were fully reversible. These data indicate that (1) voltage-sensitive calcium channels in Lymnaea neurons are inhibited by nanomolar concentrations of free Pb2+; (2) there are multiple types of calcium channels in Lymnaea neurons; and (3) the effects of in vitro lead exposure differ qualitatively among channel types.

  11. The habenulo-raphe serotonergic circuit encodes an aversive expectation value essential for adaptive active avoidance of danger.

    Science.gov (United States)

    Amo, Ryunosuke; Fredes, Felipe; Kinoshita, Masae; Aoki, Ryo; Aizawa, Hidenori; Agetsuma, Masakazu; Aoki, Tazu; Shiraki, Toshiyuki; Kakinuma, Hisaya; Matsuda, Masaru; Yamazaki, Masako; Takahoko, Mikako; Tsuboi, Takashi; Higashijima, Shin-ichi; Miyasaka, Nobuhiko; Koide, Tetsuya; Yabuki, Yoichi; Yoshihara, Yoshihiro; Fukai, Tomoki; Okamoto, Hitoshi

    2014-12-03

    Anticipation of danger at first elicits panic in animals, but later it helps them to avoid the real threat adaptively. In zebrafish, as fish experience more and more danger, neurons in the ventral habenula (vHb) showed tonic increase in the activity to the presented cue and activated serotonergic neurons in the median raphe (MR). This neuronal activity could represent the expectation of a dangerous outcome and be used for comparison with a real outcome when the fish is learning how to escape from a dangerous to a safer environment. Indeed, inhibiting synaptic transmission from vHb to MR impaired adaptive avoidance learning, while panic behavior induced by classical fear conditioning remained intact. Furthermore, artificially triggering this negative outcome expectation signal by optogenetic stimulation of vHb neurons evoked place avoidance behavior. Thus, vHb-MR circuit is essential for representing the level of expected danger and behavioral programming to adaptively avoid potential hazard.

  12. The serotonergic system and cognitive function

    Science.gov (United States)

    Pivac, Nela; Mück-Šeler, Dorotea

    2016-01-01

    Abstract Symptoms of cognitive dysfunction like memory loss, poor concentration, impaired learning and executive functions are characteristic features of both schizophrenia and Alzheimer’s disease (AD). The neurobiological mechanisms underlying cognition in healthy subjects and neuropsychiatric patients are not completely understood. Studies have focused on serotonin (5-hydroxytryptamine, 5-HT) as one of the possible cognitionrelated biomarkers. The aim of this review is to provide a summary of the current literature on the role of the serotonergic (5-HTergic) system in cognitive function, particularly in AD and schizophrenia. The role of the 5-HTergic system in cognition is modulated by the activity and function of 5-HT receptors (5-HTR) classified into seven groups, which differ in structure, action, and localization. Many 5-HTR are located in the regions linked to various cognitive processes. Preclinical studies using animal models of learning and memory, as well as clinical in vivo (neuroimaging) and in vitro (post-mortem) studies in humans have shown that alterations in 5-HTR activity influence cognitive performance. The current evidence implies that reduced 5-HT neurotransmission negatively influences cognitive functions and that normalization of 5-HT activity may have beneficial effects, suggesting that 5-HT and 5-HTR represent important pharmacological targets for cognition enhancement and restoration of impaired cognitive performance in neuropsychiatric disorders. PMID:28123820

  13. Effects of serotonergic system on the sleeping time and EEG in rats

    Directory of Open Access Journals (Sweden)

    Alaei H

    2001-08-01

    Full Text Available The phenomenon of sleep is an active nervous and biologic rhythm, which is under influence of neurotransmitters of central nervous system. In this study, the influence of serotonergic system on sleeping time have been assessed by agonist-antagonist drugs using two methods of induction and non-induction behavioral and electrophysiology. The method used for measurement of total sleeing time was Angle method. For assessment of drugs impact on brain waves, after opening two holes in frontal and temporal regions, two non-polarized silvery electrodes were fixed in above regions and was connected to physiograph and computer by linkers for waves analysis. Injection intra-ventriculary is done by stereotax apparatus. Results indicate that diazepam (2.5 mg/kg increases sleeping time in two stages of induction and non-induction (P<0.01. 5-HTP (15, 45 mg/kg increases dose-dependence sleeping time. p-CPA (150, 300 mg/kg shows biphasic influence on sleeping time. The 300 mg/kg dose of p-CPA reduces sleeping time while 150 mg/kg dose inverts sleeping time (P<0.05. Interferential affects of drugs with (5-HTP 45 mg/kg and p-CPA (300 mg/kg doses are similar to control groups. Injection of 5-HTP inverts p-CPA affect. Intra-ventriculary Injection of 5-HTP in 150 µg/kg and 300 µg/kg doses, decreases frequency of delta waves and significantly increases the frequencies of other waves but conversely, 500 µg/kg decreases it. Due to findings of this study, interferential affects of agonist-antagonist of 5-HTP, can not invert p-CPA affect. Supported by GABA affects, diazepam induces its inhibitory affect in per-synaptic and post-synaptic membrane through ascending reticular both systems and blocking stimulation of brain cortical and limbic system. Affects of two other drugs on sleeping time and brain waves are probably caused by increment of released serotonin in pre-synaptic neurons. Although their interferential affects with other neurotransmitter system should be

  14. Serotonergic blunting to meta-chlorophenylpiperazine (m-CPP) highly correlates with sustained childhood abuse in impulsive and autoaggressive female borderline patients

    NARCIS (Netherlands)

    Rinne, T; Westenberg, HGM; den Boer, JA

    2000-01-01

    Background: Disturbances of affect, impulse regulation and autoaggressive behavior which are all said to be related to an altered function of the central serotonergic (5-HT) system, are prominent features of borderline personality disorder (BPD). A high coincidence of childhood physical and sexual a

  15. Playing it safe but losing anyway-Serotonergic signaling of negative outcomes in dorsomedial prefrontal cortex in the context of risk-aversion

    DEFF Research Database (Denmark)

    Macoveanu, Julian; Rowe, James B; Hornboll, Bettina;

    2013-01-01

    the serotonergic tone, (ii) after acute tryptophan depletion (ATD) to reduce central serotonin levels, or (iii) without interventions. ATD and citalopram had opposite effects on outcome related activity in dorsomedial prefrontal cortex (dmPFC) and amygdala. Relative to the control condition, ATD increased...

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

    Directory of Open Access Journals (Sweden)

    Jae Hoon Jeong

    2015-06-01

    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.

  17. Dorsal border periaqueductal gray neurons project to the area directly adjacent to the central canal ependyma of the C4-T8 spinal cord in the cat.

    Science.gov (United States)

    Mouton, L J; Kerstens, L; Van der Want, J; Holstege, G

    1996-11-01

    In a previous study horseradish peroxidase (HRP) injections in the upper thoracic and cervical spinal cord revealed some faintly labeled small neurons at the dorsal border of the periaqueductal gray (PAG). The present light microscopic and electronmicroscopic tracing study describes the precise location of these dorsal border PAG-spinal neurons and their terminal organization. Wheat germ agglutinin-conjugated HRP (WGA-HRP) injections into cervical and upper thoracic spinal segments resulted in several hundreds of small retrogradely labeled neurons at the dorsal border of the ipsilateral caudal PAG. These neurons were not found after injections in more caudal segments. WGA-HRP injections in the dorsal border PAG region surprisingly resulted in anterogradely labeled fibers terminating in the area dorsally and laterally adjoining the central canal ependyma of the C4-T8 spinal cord. No anterogradely labeled fibers were found more caudal in the spinal cord. The labeled fibers found in the upper cervical cord were not located in the area immediately adjoining the ependymal layer of the central canal, but in the lateral part of laminae VI, VII and VIII and in area X bilaterally. Electronmicroscopic results of one case show that the dorsal border PAG-spinal neurons terminate in the neuropil of the subependymal area and in the vicinity of the basal membranes of capillaries located laterally to the central canal. The terminal profiles contain electron-lucent and densecored vesicles, suggesting a heterogeneity of possible transmitters. A striking observation was the lack of synaptic contacts, suggesting nonsynaptic release from the profiles. The function of the dorsal border PAG-spinal projection is unknown, but considering the termination pattern of the dorsal border PAG neurons on the capillaries the intriguing similarity between this projection system and the hypothalamohypophysial system is discussed.

  18. A pair of dopamine neurons target the D1-like dopamine receptor DopR in the central complex to promote ethanol-stimulated locomotion in Drosophila.

    Directory of Open Access Journals (Sweden)

    Eric C Kong

    Full Text Available Dopamine is a mediator of the stimulant properties of drugs of abuse, including ethanol, in mammals and in the fruit fly Drosophila. The neural substrates for the stimulant actions of ethanol in flies are not known. We show that a subset of dopamine neurons and their targets, through the action of the D1-like dopamine receptor DopR, promote locomotor activation in response to acute ethanol exposure. A bilateral pair of dopaminergic neurons in the fly brain mediates the enhanced locomotor activity induced by ethanol exposure, and promotes locomotion when directly activated. These neurons project to the central complex ellipsoid body, a structure implicated in regulating motor behaviors. Ellipsoid body neurons are required for ethanol-induced locomotor activity and they express DopR. Elimination of DopR blunts the locomotor activating effects of ethanol, and this behavior can be restored by selective expression of DopR in the ellipsoid body. These data tie the activity of defined dopamine neurons to D1-like DopR-expressing neurons to form a neural circuit that governs acute responding to ethanol.

  19. Evidence for Inhibitory Effects of Flupirtine, a Centrally Acting Analgesic, on Delayed Rectifier K+ Currents in Motor Neuron-Like Cells

    OpenAIRE

    Sheng-Nan Wu; Ming-Chun Hsu; Yu-Kai Liao; Fang-Tzu Wu; Yuh-Jyh Jong; Yi-Ching Lo

    2012-01-01

    Flupirtine (Flu), a triaminopyridine derivative, is a centrally acting, non-opiate analgesic agent. In this study, effects of Flu on K+ currents were explored in two types of motor neuron-like cells. Cell exposure to Flu decreased the amplitude of delayed rectifier K+ current (I K(DR)) with a concomitant raise in current inactivation in NSC-34 neuronal cells. The dissociation constant for Flu-mediated increase of I K(DR) inactivation rate was about 9.8  μ M. Neither linopirdine (10  μ M), NMD...

  20. Expression of Nav1.7 in DRG neurons extends from peripheral terminals in the skin to central preterminal branches and terminals in the dorsal horn

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    Black Joel A

    2012-11-01

    Full Text Available Abstract Background Sodium channel Nav1.7 has emerged as a target of considerable interest in pain research, since loss-of-function mutations in SCN9A, the gene that encodes Nav1.7, are associated with a syndrome of congenital insensitivity to pain, gain-of-function mutations are linked to the debiliting chronic pain conditions erythromelalgia and paroxysmal extreme pain disorder, and upregulated expression of Nav1.7 accompanies pain in diabetes and inflammation. Since Nav1.7 has been implicated as playing a critical role in pain pathways, we examined by immunocytochemical methods the expression and distribution of Nav1.7 in rat dorsal root ganglia neurons, from peripheral terminals in the skin to central terminals in the spinal cord dorsal horn. Results Nav1.7 is robustly expressed within the somata of peptidergic and non-peptidergic DRG neurons, and along the peripherally- and centrally-directed C-fibers of these cells. Nav1.7 is also expressed at nodes of Ranvier in a subpopulation of Aδ-fibers within sciatic nerve and dorsal root. The peripheral terminals of DRG neurons within skin, intraepidermal nerve fibers (IENF, exhibit robust Nav1.7 immunolabeling. The central projections of DRG neurons in the superficial lamina of spinal cord dorsal horn also display Nav1.7 immunoreactivity which extends to presynaptic terminals. Conclusions The expression of Nav1.7 in DRG neurons extends from peripheral terminals in the skin to preterminal central branches and terminals in the dorsal horn. These data support a major contribution for Nav1.7 in pain pathways, including action potential electrogenesis, conduction along axonal trunks and depolarization/invasion of presynaptic axons. The findings presented here may be important for pharmaceutical development, where target engagement in the right compartment is essential.

  1. A reassessment of the role of serotonergic system in the control of feeding behavior

    Directory of Open Access Journals (Sweden)

    Medeiros Magda A.

    2005-01-01

    Full Text Available The role of serotonergic system in the feeding behaviorwas appraised by electrolytic lesions in the dorsal raphe nucleus (DRN and administration of para-chlorophenylalanine (PCPA, 3 mg/5 mul, icv. Chronic evaluations were accomplished through 120 and 360 days in PCPA-injected and DRN-lesioned rats, respectively. Acute food intake was evaluated in fasted rats and submitted to injection of PCPA and hydroxytryptophan (LHTP, 30 mg/kg, ip. DRN-lesioned rats exhibited 22-80% increase in food intake up to sixth month, whereas the obesity was evident and sustained by whole period. In PCPA-injected rats was observed an initial increase in the food intake followed by hypophagy from 25th to 30th day and a transitory increase of body weight from 5th to 60th day. In the acute study, the LHTP reverted partially the PCPA-induced increase in food intake of fasted rats suggesting a sustained capacity of decarboxylation of precursor by serotonergic neurons. Slow restoration of the levels of food intake in DRN-lesioned rats reveals a neuroplasticity in the systems that regulate feeding behavior. A plateau on the body weight curve in lesioned rats possibly represents the establishment of a new and higher set point of energetic balance.

  2. Characterization of GABAergic neurons in rapid-eye-movement sleep controlling regions of the brainstem reticular formation in GAD67-green fluorescent protein knock-in mice.

    Science.gov (United States)

    Brown, Ritchie E; McKenna, James T; Winston, Stuart; Basheer, Radhika; Yanagawa, Yuchio; Thakkar, Mahesh M; McCarley, Robert W

    2008-01-01

    Recent experiments suggest that brainstem GABAergic neurons may control rapid-eye-movement (REM) sleep. However, understanding their pharmacology/physiology has been hindered by difficulty in identification. Here we report that mice expressing green fluorescent protein (GFP) under the control of the GAD67 promoter (GAD67-GFP knock-in mice) exhibit numerous GFP-positive neurons in the central gray and reticular formation, allowing on-line identification in vitro. Small (10-15 microm) or medium-sized (15-25 microm) GFP-positive perikarya surrounded larger serotonergic, noradrenergic, cholinergic and reticular neurons, and > 96% of neurons were double-labeled for GFP and GABA, confirming that GFP-positive neurons are GABAergic. Whole-cell recordings in brainstem regions important for promoting REM sleep [subcoeruleus (SubC) or pontine nucleus oralis (PnO) regions] revealed that GFP-positive neurons were spontaneously active at 3-12 Hz, fired tonically, and possessed a medium-sized depolarizing sag during hyperpolarizing steps. Many neurons also exhibited a small, low-threshold calcium spike. GFP-positive neurons were tested with pharmacological agents known to promote (carbachol) or inhibit (orexin A) REM sleep. SubC GFP-positive neurons were excited by the cholinergic agonist carbachol, whereas those in the PnO were either inhibited or excited. GFP-positive neurons in both areas were excited by orexins/hypocretins. These data are congruent with the hypothesis that carbachol-inhibited GABAergic PnO neurons project to, and inhibit, REM-on SubC reticular neurons during waking, whereas carbachol-excited SubC and PnO GABAergic neurons are involved in silencing locus coeruleus and dorsal raphe aminergic neurons during REM sleep. Orexinergic suppression of REM during waking is probably mediated in part via excitation of acetylcholine-inhibited GABAergic neurons.

  3. Serotonergic Psychedelics Temporarily Modify Information Transfer in Humans

    Science.gov (United States)

    Alonso, Joan Francesc; Romero, Sergio; Mañanas, Miquel Àngel

    2015-01-01

    Background: Psychedelics induce intense modifications in the sensorium, the sense of “self,” and the experience of reality. Despite advances in our understanding of the molecular and cellular level mechanisms of these drugs, knowledge of their actions on global brain dynamics is still incomplete. Recent imaging studies have found changes in functional coupling between frontal and parietal brain structures, suggesting a modification in information flow between brain regions during acute effects. Methods: Here we assessed the psychedelic-induced changes in directionality of information flow during the acute effects of a psychedelic in humans. We measured modifications in connectivity of brain oscillations using transfer entropy, a nonlinear measure of directed functional connectivity based on information theory. Ten healthy male volunteers with prior experience with psychedelics participated in 2 experimental sessions. They received a placebo or a dose of ayahuasca, a psychedelic preparation containing the serotonergic 5-HT2A agonist N,N-dimethyltryptamine. Results: The analysis showed significant changes in the coupling of brain oscillations between anterior and posterior recording sites. Transfer entropy analysis showed that frontal sources decreased their influence over central, parietal, and occipital sites. Conversely, sources in posterior locations increased their influence over signals measured at anterior locations. Exploratory correlations found that anterior-to-posterior transfer entropy decreases were correlated with the intensity of subjective effects, while the imbalance between anterior-to-posterior and posterior-to-anterior transfer entropy correlated with the degree of incapacitation experienced. Conclusions: These results suggest that psychedelics induce a temporary disruption of neural hierarchies by reducing top-down control and increasing bottom-up information transfer in the human brain. PMID:25820842

  4. Serotonergic mechanisms in the migraine brain - a systematic review

    DEFF Research Database (Denmark)

    Deen, Marie; Christensen, Casper Emil; Hougaard, Anders

    2017-01-01

    role of brain serotonergic mechanisms remains a matter of controversy. METHODS: We systematically searched PubMed for studies investigating the serotonergic system in the migraine brain by either molecular neuroimaging or electrophysiological methods. RESULTS: The literature search resulted in 59......BACKGROUND: Migraine is one of the most common and disabling of all medical conditions, affecting 16% of the general population, causing huge socioeconomic costs globally. Current available treatment options are inadequate. Serotonin is a key molecule in the neurobiology of migraine, but the exact...... papers, of which 13 were eligible for review. The reviewed papers collectively support the notion that migraine patients have alterations in serotonergic neurotransmission. Most likely, migraine patients have a low cerebral serotonin level between attacks, which elevates during a migraine attack...

  5. A large population of diverse neurons in the Drosophila central nervous system expresses short neuropeptide F, suggesting multiple distributed peptide functions

    Directory of Open Access Journals (Sweden)

    Wegener Christian

    2008-09-01

    Full Text Available Abstract Background Insect neuropeptides are distributed in stereotypic sets of neurons that commonly constitute a small fraction of the total number of neurons. However, some neuropeptide genes are expressed in larger numbers of neurons of diverse types suggesting that they are involved in a greater diversity of functions. One of these widely expressed genes, snpf, encodes the precursor of short neuropeptide F (sNPF. To unravel possible functional diversity we have mapped the distribution of transcript of the snpf gene and its peptide products in the central nervous system (CNS of Drosophila in relation to other neuronal markers. Results There are several hundreds of neurons in the larval CNS and several thousands in the adult Drosophila brain expressing snpf transcript and sNPF peptide. Most of these neurons are intrinsic interneurons of the mushroom bodies. Additionally, sNPF is expressed in numerous small interneurons of the CNS, olfactory receptor neurons (ORNs of the antennae, and in a small set of possibly neurosecretory cells innervating the corpora cardiaca and aorta. A sNPF-Gal4 line confirms most of the expression pattern. None of the sNPF immunoreactive neurons co-express a marker for the transcription factor DIMMED, suggesting that the majority are not neurosecretory cells or large interneurons involved in episodic bulk transmission. Instead a portion of the sNPF producing neurons co-express markers for classical neurotransmitters such as acetylcholine, GABA and glutamate, suggesting that sNPF is a co-transmitter or local neuromodulator in ORNs and many interneurons. Interestingly, sNPF is coexpressed both with presumed excitatory and inhibitory neurotransmitters. A few sNPF expressing neurons in the brain colocalize the peptide corazonin and a pair of dorsal neurons in the first abdominal neuromere coexpresses sNPF and insulin-like peptide 7 (ILP7. Conclusion It is likely that sNPF has multiple functions as neurohormone as well as

  6. Immunodetection of the serotonin transporter protein is a more valid marker for serotonergic fibers than serotonin

    DEFF Research Database (Denmark)

    Nielsen, Kirsten; Brask, Dorthe; Knudsen, Gitte M.

    2006-01-01

    Tracking serotonergic pathways in the brain through immunodetection of serotonin has widely been used for the anatomical characterization of the serotonergic system. Immunostaining for serotonin is also frequently applied for the visualization of individual serotonin containing fibers and quantif......Tracking serotonergic pathways in the brain through immunodetection of serotonin has widely been used for the anatomical characterization of the serotonergic system. Immunostaining for serotonin is also frequently applied for the visualization of individual serotonin containing fibers...

  7. Two distinct pools of large-conductance calcium-activated potassium channels in the somatic plasma membrane of central principal neurons

    Science.gov (United States)

    Kaufmann, W.A.; Kasugai, Y.; Ferraguti, F.; Storm, J.F.

    2010-01-01

    Although nerve cell membranes are often assumed to be uniform with respect to electrical properties, there is increasing evidence for compartmentalization into subdomains with heterogeneous impacts on the overall cell function. Such microdomains are characterized by specific sets of proteins determining their functional properties. Recently, clustering of large-conductance calcium-activated potassium (BKCa) channels was shown at sites of subsurface membrane cisterns in cerebellar Purkinje cells (PC), where they likely participate in building a subcellular signaling unit, the 'PLasmERosome'. By applying SDS-digested freeze-fracture replica labeling (SDS-FRL) and postembedding immunogold electron microscopy, we have now studied the spatial organization of somatic BKCa channels in neocortical layer 5 pyramidal neurons, principal neurons of the central and basolateral amygdaloid nuclei, hippocampal pyramidal neurons and dentate gyrus (DG) granule cells to establish whether there is a common organizational principle in the distribution of BKCa channels in central principal neurons. In all cell types analyzed, somatic BKCa channels were found to be non-homogenously distributed in the plasma membrane, forming two pools of channels with one pool consisting of clustered channels and the other of scattered channels in the extrasynaptic membrane. Quantitative analysis by means of SDS-FRL revealed that about two-thirds of BKCa channels belong to the scattered pool and about one-third to the clustered pool in principal cell somata. Overall densities of channels in both pools differed in the different cell types analyzed, although being considerably lower compared to cerebellar PC. Postembedding immunogold labeling revealed association of clustered channels with subsurface membrane cisterns and confirmed extrasynaptic localization of scattered channels. This study indicates a common organizational principle for somatic BKCa channels in central principal neurons with the

  8. Serotonergic modulation of receptor occupancy in rats treated with L-DOPA after unilateral 6-OHDA lesioning

    DEFF Research Database (Denmark)

    Nahimi, Adjmal; Høltzermann, Mette; Landau, Anne M.

    2012-01-01

    Recent studies suggest that l-3,4 dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID), a severe complication of conventional L-DOPA therapy of Parkinson's disease, may be caused by dopamine (DA) release originating in serotonergic neurons. To evaluate the in vivo effect of a 5-HT(1A) agonist...... [(±)-8-hydroxy-2-(dipropylamino) tetralin hydrobromide, 8-OHDPAT] on the L-DOPA-induced increase in extracellular DA and decrease in [(11) C]raclopride binding in an animal model of advanced Parkinson's disease and LID, we measured extracellular DA in response to L-DOPA or a combination of L...

  9. Co-culture of oligodendrocytes and neurons can be used to assess drugs for axon regeneration in the central nervous system

    Directory of Open Access Journals (Sweden)

    Lin Gang

    2015-01-01

    Full Text Available We present a novel in vitro model in which to investigate the efficacy of experimental drugs for the promotion of axon regeneration in the central nervous system. We co-cultured rat hippocampal neurons and cerebral cortical oligodendrocytes, and tested the co-culture system using a Nogo-66 receptor antagonist peptide (NEP1-40, which promotes axonal growth. Primary cultured oligodendrocytes suppressed axonal growth in the rat hippocampus, but NEP1-40 stimulated axonal growth in the co-culture system. Our results confirm the validity of the neuron-oligodendrocyte co-culture system as an assay for the evaluation of drugs for axon regeneration in the central nervous system.

  10. Co-culture of oligodendrocytes and neurons can be used to assess drugs for axon regeneration in the central nervous system.

    Science.gov (United States)

    Gang, Lin; Yao, Yu-Chen; Liu, Ying-Fu; Li, Yi-Peng; Yang, Kai; Lu, Lei; Cheng, Yuan-Chi; Chen, Xu-Yi; Tu, Yue

    2015-10-01

    We present a novel in vitro model in which to investigate the efficacy of experimental drugs for the promotion of axon regeneration in the central nervous system. We co-cultured rat hippocampal neurons and cerebral cortical oligodendrocytes, and tested the co-culture system using a Nogo-66 receptor antagonist peptide (NEP1-40), which promotes axonal growth. Primary cultured oligodendrocytes suppressed axonal growth in the rat hippocampus, but NEP1-40 stimulated axonal growth in the co-culture system. Our results confirm the validity of the neuron-oligodendrocyte co-culture system as an assay for the evaluation of drugs for axon regeneration in the central nervous system.

  11. Transient electromyographic findings in serotonergic toxicity due to combination of essitalopram and isoniazid

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    Çagdas Erdogan

    2013-01-01

    Full Text Available Here, we report a case of serotonergic toxicity due to combination of essitalopram and isoniazid, which was rarely reported before. Moreover, we observed transient neurogenic denervation potentials in needle electromyography, which disappeared with the treatment of serotonergic toxicity. As to our best knowledge, this is the first case, reporting transient electromyographic changes probably due to serotonergic toxicity.

  12. Serotonin Promotes Development and Regeneration of Spinal Motor Neurons in Zebrafish.

    Science.gov (United States)

    Barreiro-Iglesias, Antón; Mysiak, Karolina S; Scott, Angela L; Reimer, Michell M; Yang, Yujie; Becker, Catherina G; Becker, Thomas

    2015-11-01

    In contrast to mammals, zebrafish regenerate spinal motor neurons. During regeneration, developmental signals are re-deployed. Here, we show that, during development, diffuse serotonin promotes spinal motor neuron generation from pMN progenitor cells, leaving interneuron numbers unchanged. Pharmacological manipulations and receptor knockdown indicate that serotonin acts at least in part via 5-HT1A receptors. In adults, serotonin is supplied to the spinal cord mainly (90%) by descending axons from the brain. After a spinal lesion, serotonergic axons degenerate caudal to the lesion but sprout rostral to it. Toxin-mediated ablation of serotonergic axons also rostral to the lesion impaired regeneration of motor neurons only there. Conversely, intraperitoneal serotonin injections doubled numbers of new motor neurons and proliferating pMN-like progenitors caudal to the lesion. Regeneration of spinal-intrinsic serotonergic interneurons was unaltered by these manipulations. Hence, serotonin selectively promotes the development and adult regeneration of motor neurons in zebrafish.

  13. The potential role of serotonergic mechanisms in the spinal oxytocin-induced antinociception.

    Science.gov (United States)

    Godínez-Chaparro, Beatriz; Martínez-Lorenzana, Guadalupe; Rodríguez-Jiménez, Javier; Manzano-García, Alfredo; Rojas-Piloni, Gerardo; Condés-Lara, Miguel; González-Hernández, Abimael

    2016-12-01

    The role of oxytocin (OXT) in pain modulation has been suggested. Indeed, hypothalamic paraventricular nuclei (PVN) electrical stimuli reduce the nociceptive neuronal activity (i.e., neuronal discharge associated with activation of Aδ- and C-fibers) of the spinal dorsal horn wide dynamic range (WDR) cells and nociceptive behavior. Furthermore, raphe magnus nuclei lesion reduces the PVN-induced antinociception, suggesting a functional interaction between the OXT and the serotoninergic system. The present study investigated in Wistar rats the potential role of spinal serotonergic mechanisms in the OXT- and PVN-induced antinociception. In long-term secondary mechanical allodynia and hyperalgesia induced by formalin or extracellular unitary recordings of the WDR cells we evaluated the role of 5-hydroxytryptamine (5-HT) effect on the OXT-induced antinociception. All drugs were given intrathecally (i.t.). OXT (1×10(-5)-1×10(-4)nmol) or 5-HT (1×10(-3)-1×10(-1)nmol) prevented the formalin-induced sensitization, an effect mimicked by PVN stimulation. Moreover, administration of OXT (1×10(-5)nmol) plus 5-HT (1×10(-3)nmol) at ineffective doses, produced antinociception. This effect was antagonized by: (i) d(CH2)5[Tyr(Me)(2),Thr(4),Tyr-NH2(9)]OVT (oxytocin receptor antagonist; 2×10(-2)nmol); or (ii) methiothepin (a non-specific 5-HT1/2/5/6/7 receptor antagonist; 80nmol). Similar results were obtained with PVN stimulation plus 5-HT (5×10(-5)nmol). In WDR cell recordings, the PVN-induced antinociception was enhanced by i.t. 5-HT and partly blocked when the spinal cord was pre-treated with methiothepin (80nmol). Taken together, these results suggest that serotonergic mechanisms at the spinal cord level are partly involved in the OXT-induced antinociception.

  14. Serotonin modulates transmitter release at central Lymnaea synapses through a G-protein-coupled and cAMP-mediated pathway.

    Science.gov (United States)

    McCamphill, P K; Dunn, T W; Syed, N I

    2008-04-01

    Neuromodulation is central to all nervous system function, although the precise mechanisms by which neurotransmitters affect synaptic efficacy between central neurons remain to be fully elucidated. In this study, we examined the neuromodulatory action of serotonin [5-hydroxytryptamine (5-HT)] at central synapses between identified neurons from the pond snail Lymnaea stagnalis. Using whole-cell voltage-clamp and sharp electrode recording, we show that 5-HT strongly depresses synaptic strength between cultured, cholinergic neuron visceral dorsal 4 (VD4 - presynaptic) and its serotonergic target left pedal dorsal 1 (LPeD1 - postsynaptic). This inhibition was accompanied by a reduction in synaptic depression, but had no effect on postsynaptic input resistance, indicating a presynaptic origin. In addition, serotonin inhibited the presynaptic calcium current (I(Ca)) on a similar time course as the change in synaptic transmission. Introduction of a non-condensable GDP analog, GDP-beta-S, through the presynaptic pipette inhibited the serotonin-mediated effect on I(Ca.) Similar results were obtained with a membrane-impermeable inactive cAMP analog, 8OH-cAMP. Furthermore, stimulation of the serotonergic postsynaptic cell also inhibited presynaptic currents, indicating the presence of a negative feedback loop between LPeD1 and VD4. Taken together, this study provides direct evidence for a negative feedback mechanism, whereby the activity of a presynaptic respiratory central pattern-generating neuron is regulated by its postsynaptic target cell. We demonstrate that either serotonin or LPeD1 activity-induced depression of presynaptic transmitter release from VD4 involves voltage-gated calcium channels and is mediated through a G-protein-coupled and cAMP-mediated system.

  15. A gonadotropin-releasing hormone-like molecule modulates the activity of diverse central neurons in a gastropod mollusk, Aplysia californica

    Directory of Open Access Journals (Sweden)

    Biao eSun

    2011-09-01

    Full Text Available In vertebrates, gonadotropin-releasing hormone (GnRH is a crucial decapeptide that activates the hypothalamic-pituitary-gonadal (HPG axis to ensure successful reproduction. Recently, a GnRH-like molecule has been isolated from a gastropod mollusk, Aplysia californica. This GnRH (ap-GnRH is deduced to be an undecapeptide, and its function remains to be explored. Our previous study demonstrated that ap-GnRH did not stimulate a range of reproductive parameters. Instead, it affected acute behavioral and locomotive changes unrelated to reproduction. In this study, we used electrophysiology and retrograde tracing to further explore the central role of ap-GnRH. Sharp electrode intracellular recordings revealed that ap-GnRH had diverse effects on central neurons that ranged from excitatory, inhibitory, to the alteration of membrane potential. Unexpectedly, extracellular recordings revealed that ap-GnRH suppressed the onset of electrical afterdischarge (AD in bag cell neurons, suggesting an inhibitory effect on female reproduction. Lastly, using immunocytochemistry (ICC coupled with nickel-backfill, we demonstrated that some ap-GnRH neurons projected to efferent nerves known to innervate the foot and parapodia, suggesting ap-GnRH may directly modulate the motor output of these peripheral tissues. Overall, our results suggested that in A. californica, ap-GnRH more likely functioned as a central modulator of complex behavior and motor regulation rather than as a conventional reproductive stimulator.

  16. Single-cell Transcriptional Analysis Reveals Novel Neuronal Phenotypes and Interaction Networks involved In the Central Circadian Clock

    Directory of Open Access Journals (Sweden)

    James Park

    2016-10-01

    Full Text Available Single-cell heterogeneity confounds efforts to understand how a population of cells organizes into cellular networks that underlie tissue-level function. This complexity is prominent in the mammalian suprachiasmatic nucleus (SCN. Here, individual neurons exhibit a remarkable amount of asynchronous behavior and transcriptional heterogeneity. However, SCN neurons are able to generate precisely coordinated synaptic and molecular outputs that synchronize the body to a common circadian cycle by organizing into cellular networks. To understand this emergent cellular network property, it is important to reconcile single-neuron heterogeneity with network organization. In light of recent studies suggesting that transcriptionally heterogeneous cells organize into distinct cellular phenotypes, we characterized the transcriptional, spatial, and functional organization of 352 SCN neurons from mice experiencing phase-shifts in their circadian cycle. Using the community structure detection method and multivariate analytical techniques, we identified previously undescribed neuronal phenotypes that are likely to participate in regulatory networks with known SCN cell types. Based on the newly discovered neuronal phenotypes, we developed a data-driven neuronal network structure in which multiple cell types interact through known synaptic and paracrine signaling mechanisms. These results provide a basis from which to interpret the functional variability of SCN neurons and describe methodologies towards understanding how a population of heterogeneous single cells organizes into cellular networks that underlie tissue-level function.

  17. Starting of the steam generator of a fossil fuel power plant, using predictive control based in a neuronal model; Arranque del generador de vapor de una central termoelectrica, usando control predictivo basado en un modelo neuronal

    Energy Technology Data Exchange (ETDEWEB)

    Gallardo Dominguez, Tonatiuh

    2004-09-15

    In this thesis work it is presented the design and implementation of a simulator of total scope of a predictive controller based in the neuronal model of the temperature in two stages of the heating of the steam generator of a fossil fuel power plant. An implemented control scheme is detailed, as well as the methodology for the identification of a neuronal model utilized for the control. Finally the results of the implementation in the simulator located at the Instituto de Investigaciones Electricas (IIE) are shown to be satisfactory. This control structure is not applied directly in closed circuit, but provides the value of the control actions to a human operator. [Spanish] En este trabajo de tesis se presenta el diseno e implementacion, en un simulador de alcance total, de un controlador predictivo basado en un modelo neuronal para el control de la temperatura en dos etapas del calentamiento del generador de vapor de una central termoelectrica. Se detalla el esquema de control implementado, asi como la metodologia de identificacion de un modelo neuronal utilizado para la sintesis del control. Finalmente se muestran los resultados de la implementacion en el simulador que se encuentra en el Instituto de Investigaciones Electricas (IIE); dichos resultados fueron satisfactorios. Esta estructura de control no se aplica directamente en lazo cerrado, sino que provee el valor de las acciones de control a un operador humano.

  18. Human psychophysics and rodent spinal neurones exhibit peripheral and central mechanisms of inflammatory pain in the UVB and UVB heat rekindling models.

    Science.gov (United States)

    O'Neill, Jessica; Sikandar, Shafaq; McMahon, Stephen B; Dickenson, Anthony H

    2015-09-01

    Translational research is key to bridging the gaps between preclinical findings and the patients, and a translational model of inflammatory pain will ideally induce both peripheral and central sensitisation, more effectively mimicking clinical pathophysiology in some chronic inflammatory conditions. We conducted a parallel investigation of two models of inflammatory pain, using ultraviolet B (UVB) irradiation alone and UVB irradiation with heat rekindling. We used rodent electrophysiology and human quantitative sensory testing to characterise nociceptive processing in the peripheral and central nervous systems in both models. In both species, UVB irradiation produces peripheral sensitisation measured as augmented evoked activity of rat dorsal horn neurones and increased perceptual responses of human subjects to mechanical and thermal stimuli. In both species, UVB with heat rekindling produces central sensitisation. UVB irradiation alone and UVB with heat rekindling are translational models of inflammation that produce peripheral and central sensitisation, respectively. The predictive value of laboratory models for human pain processing is crucial for improving translational research. The discrepancy between peripheral and central mechanisms of pain is an important consideration for drug targets, and here we describe two models of inflammatory pain that involve ultraviolet B (UVB) irradiation, which can employ peripheral and central sensitisation to produce mechanical and thermal hyperalgesia in rats and humans. We use electrophysiology in rats to measure the mechanically- and thermally-evoked activity of rat spinal neurones and quantitative sensory testing to assess human psychophysical responses to mechanical and thermal stimulation in a model of UVB irradiation and in a model of UVB irradiation with heat rekindling. Our results demonstrate peripheral sensitisation in both species driven by UVB irradiation, with a clear mechanical and thermal hypersensitivity of

  19. Orientational Recognition and Low-Resistance Passing (LRP) Regulation of Segmental Re-innervation by Central Neurons in Leeches

    Institute of Scientific and Technical Information of China (English)

    张帆; 张人骥

    1994-01-01

    Re-innervation of sensory and motor neurons on a defined area of the body wall was studied in two species of leeches, Whitmania pigra and Hirudo medicinalis, as a model of segmental animals. Following isolation and rotation of a tube of body wall, the mechanical sensory and annular erection (AE) motor neurons re-innervated the body wall, at a rate of approximately 3. 8 -8. 4 μm/h. The patterns of re-innerva-tion by pairs of neurons on each side of a ganglion were bilaterally symmetric. The repairs are synchronous for the sensory and motor neurons which are of different functions but in a same ganglion. The gap junctions are widely spread in leech between neurons and glia cells, as well as among the neurons and glia cells themselves. Therefore, it is proposed that the nervous system repair is regulated by a low-resistance pathway. In the xenotransplantation experiments, neurons recognized target tissues before the immuno-recognition and rejection.

  20. Spindle-F Is the Central Mediator of Ik2 Kinase-Dependent Dendrite Pruning in Drosophila Sensory Neurons.

    Directory of Open Access Journals (Sweden)

    Tzu Lin

    2015-11-01

    Full Text Available During development, certain Drosophila sensory neurons undergo dendrite pruning that selectively eliminates their dendrites but leaves the axons intact. How these neurons regulate pruning activity in the dendrites remains unknown. Here, we identify a coiled-coil protein Spindle-F (Spn-F that is required for dendrite pruning in Drosophila sensory neurons. Spn-F acts downstream of IKK-related kinase Ik2 in the same pathway for dendrite pruning. Spn-F exhibits a punctate pattern in larval neurons, whereas these Spn-F puncta become redistributed in pupal neurons, a step that is essential for dendrite pruning. The redistribution of Spn-F from puncta in pupal neurons requires the phosphorylation of Spn-F by Ik2 kinase to decrease Spn-F self-association, and depends on the function of microtubule motor dynein complex. Spn-F is a key component to link Ik2 kinase to dynein motor complex, and the formation of Ik2/Spn-F/dynein complex is critical for Spn-F redistribution and for dendrite pruning. Our findings reveal a novel regulatory mechanism for dendrite pruning achieved by temporal activation of Ik2 kinase and dynein-mediated redistribution of Ik2/Spn-F complex in neurons.

  1. Serotonergic mediation of the antidepressant-like effect of the green leaves odor in mice.

    Science.gov (United States)

    Nakatomi, Yasuhito; Yokoyama, Chihiro; Kinoshita, Seijiro; Masaki, Daiki; Tsuchida, Hideto; Onoe, Hirotaka; Yoshimoto, Kanji; Fukui, Kenji

    2008-05-01

    The green odor (GO) that emanates from green leaves has been observed to have many physiological actions in mammals and may be associated with a healing effect in humans. This study examined the effect of GO (we used a mixture of cis-3-hexenol and trans-2-hexenal) on behavior in the forced swim test (FST) of depression in mice. Exposure of GO showed the antidepressant-like effect in the FST, i.e., a significant decrease in immobility time and increase in swimming time, but no change in climbing time. The behavioral responses of GO-exposed animals to FST were similar to those observed for animals given citalopram, which is a selective serotonin reuptake inhibitor. In contrast, desipramine, which is a selective noradrenaline reuptake inhibitor, decreased immobility time and increased climbing time without affecting swimming time. To examine the involvement of the serotonergic system in mediating the antidepressant-like action of GO, we performed further FST examinations in which GO-exposed mice were treated with p-chlorophenylalanine (PCPA). Prior PCPA administration induced depletion of central 5-HT in the brain and completely diminished the GO effect on the behavioral responses seen during the FST. No changes in locomotor activity after GO inhalation were observed. These results indicate that acute exposure to GO has an antidepressant-like effect that may involve the serotonergic system.

  2. Single-dose serotonergic stimulation shows widespread effects on functional brain connectivity.

    Science.gov (United States)

    Klaassens, Bernadet L; van Gorsel, Helene C; Khalili-Mahani, Najmeh; van der Grond, Jeroen; Wyman, Bradley T; Whitcher, Brandon; Rombouts, Serge A R B; van Gerven, Joop M A

    2015-11-15

    The serotonergic system is widely distributed throughout the central nervous system. It is well known as a mood regulating system, although it also contributes to many other functions. With resting state functional magnetic resonance imaging (RS-fMRI) it is possible to investigate whole brain functional connectivity. We used this non-invasive neuroimaging technique to measure acute pharmacological effects of the selective serotonin reuptake inhibitor sertraline (75 mg) in 12 healthy volunteers. In this randomized, double blind, placebo-controlled, crossover study, RS-fMRI scans were repeatedly acquired during both visits (at baseline and 3, 5, 7 and 9h after administering sertraline or placebo). Within-group comparisons of voxelwise functional connectivity with ten functional networks were examined (pSertraline induced widespread effects on functional connectivity with multiple networks; the default mode network, the executive control network, visual networks, the sensorimotor network and the auditory network. A common factor among these networks was the involvement of the precuneus and posterior cingulate cortex. Cognitive and subjective measures were taken as well, but yielded no significant treatment effects, emphasizing the sensitivity of RS-fMRI to pharmacological challenges. The results are consistent with the existence of an extensive serotonergic system relating to multiple brain functions with a possible key role for the precuneus and cingulate.

  3. Serotonergic function, substance craving, and psychopathology in detoxified alcohol-addicted males undergoing tryptophan depletion.

    Science.gov (United States)

    Wedekind, Dirk; Herchenhein, Thomas; Kirchhainer, Julia; Bandelow, Borwin; Falkai, Peter; Engel, Kirsten; Malchow, Berend; Havemann-Reinecke, Ursula

    2010-12-01

    Alcohol addiction is associated with alterations of central nervous dopaminergic and serotonergic functions. Acute tryptophan depletion has not yet been applied in detoxified alcohol-addicted patients in order to investigate its impact on psychopathology, psychoneuroendocrinology, and substance craving behaviour. 25 alcohol-addicted males randomly either received a tryptophan-free or tryptophan-containing amino acid drink and 7 days later the respective other drink. Anxiety, depression, and craving were assessed before and 5 h after the drink. Tryptophan, 5-HIAA, dopamine, norepinephrine, epinephrine, and HVA in serum were measured before and after both treatments. Nocturnal urinary cortisol measurements and genotyping for the HTTLPR polymorphism of the SLC6A4 gene were performed. Tryptophan depletion resulted in a significant reduction of total and free serum tryptophan while the tryptophan-rich drink increased serum levels. Both treatments caused a significant increase of serum serotonin levels, however, serum 5-HIAA was decreased after depletion but increased after sham depletion. Dopamine and norepinephrine were elevated after tryptophan depletion and sham. Depletion increased depression scores (MADRS), while the full amino acid drink improved state and trait anxiety ratings (STAI) and substance craving. Urinary cortisol excretion was not affected by both treatments. Patients with the ll genotype of the serotonin transporter gene displayed lower baseline tryptophan levels compared to patients with the heterozygous genotype. Results suggest an impaired serotonergic function in alcohol-addicted males.

  4. CPB-K mice a mouse model of schizophrenia? Differences in dopaminergic, serotonergic and behavioral markers compared to BALB/cJ mice.

    Science.gov (United States)

    Panther, P; Nullmeier, S; Dobrowolny, H; Schwegler, H; Wolf, R

    2012-04-21

    Schizophrenia is characterized by disturbances in social behavior, sensorimotor gating and cognitive function, that are discussed to be caused by a termination of different transmitter systems. Beside morphological alterations in cortical and subcortical areas reduced AMPA- NMDA-, 5-HT2-receptor densities and increased 5-HT1-receptor densities are found in the hippocampus.The two inbred mouse strains CPB-K and BALB/cJ are known to display considerable differences in cognitive function and prepulse inhibition, a stable marker of sensorimotor gating. Furthermore, CPB-K mice exhibit lower NMDA-, AMPA- and increased 5-HT-receptor densities in the hippocampus as compared to BALB/cJ mice. We investigated both mouse strains in social interaction test for differences in social behavior and with immuncytochemical approaches for alterations of dopaminergic and serotonergic parameters. Our results can be summarized as follows: compared to BALB/cJ, CPB-K mice showed:(1) significantly reduced traveling distance and number of contacts in social interaction test, (2) differences in the number of serotonin transporter-immunoreactive neurons and volume of raphe nuclei and a lower serotonergic fiber density in the ventral and dorsal hippocampal subfields CA1 and CA3, (3) no alterations of dopaminergic markers like neuron number, neuron density and volume in subregions of substantia nigra and ventral tegmental area, but a significantly higher dopaminergic fiber density in the dorsal hippocampus, the ventral hippocampus of CA1 and gyrus dentatus, (4) no significant differences in serotonergic and dopaminergic fiber densities in the amygdala.Based on our results and previous studies, CPB-K mice compared to BALB/cJ may serve as an important model to understand the interaction of the serotonergic and dopaminergic system and their impact on sensorimotor gating and cognitive function as related to neuropsychiatric disorders like schizophrenia.

  5. Separate urinary bladder and prostate neurons in the central nervous system of the rat: simultaneous labeling with two immunohistochemically distinguishable pseudorabies viruses

    Directory of Open Access Journals (Sweden)

    Nadelhaft Irving

    2002-07-01

    Full Text Available Abstract Background This work examines the central nervous system distribution of virus-labeled neurons from the rat urinary bladder and the prostate simultaneously within the same tissue sections. Two immunohistochemically distinct pseudorabies virus strains were simultaneously injected into male Sprague Dawley rats (~280 gm. One virus was injected into the bladder and the other into the prostate. After incubation intervals of 2.25, 2.5, 2.75, 3 and 4 days, sections from the spinal cord and brain were processed immunohistochemically to detect cells, within a single section, which were labeled separately by each virus or were labeled by both viruses. Results Each strain of virus labeled a separate population of neurons and some neurons were labeled by both strains. The majority of neurons labeled by virus from the urinary bladder were found in the L6-S1 spinal cord segments within the dorsal gray commissure, the intermediolateral area and the superficial dorsal horn. Neurons labeled by virus from the prostate were mainly found in the L1-L2 spinal cord segments in the dorsal gray commissure and the intermediolateral areas. Double-labeled interneurons in L1-L2 were mainly located in the intermediolateral area. In L6-S1 they were divided between the dorsal gray commissure and the intermediolateral area. Conclusions Spinal neurons innervating the bladder are clearly separate and different from those innervating the prostate. This difference also persists in the brain. In disagreement with previous reports, no direct anatomical evidence of parasympathetic innervation of the prostate was observed.

  6. Ribosomal DNA transcription in dorsal raphe nucleus neurons is increased in residual schizophrenia compared to depressed patients with affective disorders.

    Science.gov (United States)

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

    2015-12-15

    The central serotonergic system is implicated differentially in the pathogenesis of depression and schizophrenia. The dorsal raphe nucleus (DRN) is the main source of serotonergic innervation of forebrain limbic structures disturbed in both disorders. The study was carried out on paraffin-embedded brains from 27 depressed (15 major depressive disorder, MDD and 12 bipolar disorder, BD) and 17 schizophrenia (9 residual and 8 paranoid) patients and 28 matched controls without mental disorders. The transcriptional activity of ribosomal DNA (rDNA) in DRN neurons was evaluated by the AgNOR silver staining method. A significant effect of diagnosis on rDNA activity was found in the cumulative analysis of all DRN subnuclei. Further analysis revealed an increase in this activity in residual (but not paranoid) schizophrenia compared to depressed (both MDD and BD) patients. The effect was most probably neither confounded by suicide nor related to antidepressant and antipsychotic medication. Our findings suggest that increased activity of rDNA in DRN neurons is a distinct phenomenon in residual schizophrenia, related presumably to differentially disturbed inputs to the DRN and/or their local transformation compared with depressive episodes in patients with affective disorders.

  7. Single-neuron diversity generated by Protocadherin-β cluster in mouse central and peripheral nervous systems

    Directory of Open Access Journals (Sweden)

    Keizo eHirano

    2012-08-01

    Full Text Available The generation of complex neural circuits depends on the correct wiring of neurons with diverse individual characteristics. To understand the complexity of the nervous system, the molecular mechanisms for specifying the identity and diversity of individual neurons must be elucidated. The clustered protocadherins (Pcdh in mammals consist of approximately 50 Pcdh genes (Pcdh-α, Pcdh-β, and Pcdh-γ that encode cadherin-family cell surface adhesion proteins. Individual neurons express a random combination of Pcdh-α and Pcdh-γ, whereas the expression patterns for the Pcdh-β genes, 22 one-exon genes in mouse, are not fully understood. Here we show that the Pcdh-β genes are expressed in a 3’-polyadenylated form in mouse brain. In situ hybridization using a pan-Pcdh-β probe against a conserved Pcdh-β sequence showed widespread labeling in the brain, with prominent signals in the olfactory bulb, hippocampus, and cerebellum. In situ hybridization with specific probes for individual Pcdh-β genes showed their expression to be scattered in Purkinje cells from P10 to P150. The scattered expression patterns were confirmed by performing a newly developed single-cell 3’-RACE analysis of Purkinje cells, which clearly demonstrated that the Pcdh-β genes are expressed monoallelically and combinatorially in individual Purkinje cells. Scattered expression patterns of individual Pcdh-β genes were also observed in pyramidal neurons in the hippocampus and cerebral cortex, neurons in the trigeminal and dorsal root ganglion, GABAergic interneurons, and cholinergic neurons. Our results extend previous observations of diversity at the single-neuron level generated by Pcdh expression and suggest that the Pcdh-β cluster genes contribute to specifying the identity and diversity of individual neurons.

  8. Serotonergic modulation of spinal motor control

    DEFF Research Database (Denmark)

    Perrier, Jean-Francois Marie; Cotel, Florence

    2015-01-01

    Serotonin (5-HT) is a monoamine that powerfully modulates spinal motor control by acting on intrasynaptic and extrasynaptic receptors. Here we review the diversity of 5-HT actions on locomotor and motoneuronal activities. Two approaches have been used on in vitro spinal cord preparations: either...... and promotes the excitability of motoneurons, while stronger release inhibits rhythmic activity and motoneuron firing. This latter effect is responsible for central fatigue and secures rotation of motor units....

  9. Feeding motivation as a personality trait in Nile tilapia (Oreochromis niloticus): role of serotonergic neurotransmission

    DEFF Research Database (Denmark)

    Silva, P.I.M.; Martins, C.I.M.; Höglund, Erik;

    2014-01-01

    Consistent individual variation in behaviour and physiology (i.e. animal personality or coping style) has emerged as a central topic in many biological disciplines. Yet, underlying mechanisms of crucial personality traits like feeding behaviour in novel environments remain unclear. Comparative...... to determine to what degree brain 5-hydroxytryptamine (5-HT, serotonin) activity pertains to this aspect of animal personality, as a correlate to feed anticipatory behaviour and recovery of feed intake after transfer to a novel environment. Crucial to the definition of animal personality, a strong degree...... of individual consistency in different measures of feeding behaviour (feeding latency and feeding score), was demonstrated. Furthermore, low serotonergic activity in the hypothalamus was highly correlated with a personality characterized by high feeding motivation, with feeding motivation represented...

  10. Pharmacology of a Central Nervous System Delivered 2′-O-Methoxyethyl–Modified Survival of Motor Neuron Splicing Oligonucleotide in Mice and Nonhuman Primates

    OpenAIRE

    Rigo, Frank; Chun, Seung J.; Norris, Daniel A.; Hung, Gene; Lee, Sam; Matson, John; Fey, Robert A.; Gaus, Hans; Hua, Yimin; Grundy, John S.; Krainer, Adrian R; Henry, Scott P.; Bennett, C. Frank

    2014-01-01

    Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by the loss of survival of motor neuron (SMN) protein. Previously, we demonstrated that ISIS 396443, an antisense oligonucleotide (ASO) targeted to the SMN2 pre-mRNA, is a potent inducer of SMN2 exon 7 inclusion and SMN protein expression, and improves function and survival of mild and severe SMA mouse models. Here, we demonstrate that ISIS 396443 is the most potent ASO in central nervous system (CNS) tissues of adul...

  11. Further characterization of autoantibodies to GABAergic neurons in the central nervous system produced by a subset of children with autism

    Directory of Open Access Journals (Sweden)

    Wills Sharifia

    2011-04-01

    Full Text Available Abstract Background Autism is a neurodevelopmental disorder characterized by impairments in social interaction and deficits in verbal and nonverbal communication, together with the presence of repetitive behaviors or a limited repertoire of activities and interests. The causes of autism are currently unclear. In a previous study, we determined that 21% of children with autism have plasma autoantibodies that are immunoreactive with a population of neurons in the cerebellum that appear to be Golgi cells, which are GABAergic interneurons. Methods We have extended this analysis by examining plasma immunoreactivity in the remainder of the brain. To determine cell specificity, double-labeling studies that included one of the calcium-binding proteins that are commonly colocalized in GABAergic neurons (calbindin, parvalbumin or calretinin were also carried out to determine which GABAergic neurons are immunoreactive. Coronal sections through the rostrocaudal extent of the macaque monkey brain were reacted with plasma from each of seven individuals with autism who had previously demonstrated positive Golgi cell staining, as well as six negative controls. In addition, brain sections from adult male mice were similarly examined. Results In each case, specific staining was observed for neurons that had the morphological appearance of interneurons. By double-labeling sections with plasma and with antibodies directed against γ-aminobutyric acid (GABA, we determined that all autoantibody-positive neurons were GABAergic. However, not all GABAergic neurons were autoantibody-positive. Calbindin was colabeled in several of the autoantibody-labeled cells, while parvalbumin colabeling was less frequently observed. Autoantibody-positive cells rarely expressed calretinin. Sections from the mouse brain processed similarly to the primate sections also demonstrated immunoreactivity to interneurons distributed throughout the neocortex and many subcortical regions. Some

  12. The anatomy of the serotonergic nervous system of an entoproct creeping-type larva and its phylogenetic implications

    DEFF Research Database (Denmark)

    Wanninger, Andreas Wilhelm Georg; Fuchs, Judith; Haszprunar, Gerhard

    2007-01-01

    the anatomy of the serotonergic nervous system of the creeping-type larva of Loxosomella murmanica. The apical organ is very complex and comprises six to eight centrally positioned flask cells and eight bipolar peripheral cells. In addition, a prototroch nerve ring, an anterior nerve loop, a paired buccal...... molluscs and may be diagnostic for a mollusc-entoproct clade. In addition, the larva of Loxosomella expresses a mosaic of certain neural features that are also found in other larval or adult Spiralia, e.g., a prototroch nerve ring, an anterior nerve loop, and a buccal nervous system....

  13. Origins, actions and dynamic expression patterns of the neuropeptide VGF in rat peripheral and central sensory neurones following peripheral nerve injury

    Directory of Open Access Journals (Sweden)

    Costigan Michael

    2008-12-01

    Full Text Available Abstract Background The role of the neurotrophin regulated polypeptide, VGF, has been investigated in a rat spared injury model of neuropathic pain. This peptide has been shown to be associated with synaptic strengthening and learning in the hippocampus and while it is known that VGFmRNA is upregulated in dorsal root ganglia following peripheral nerve injury, the role of this VGF peptide in neuropathic pain has yet to be investigated. Results Prolonged upregulation of VGF mRNA and protein was observed in injured dorsal root ganglion neurons, central terminals and their target dorsal horn neurons. Intrathecal application of TLQP-62, the C-terminal active portion of VGF (5–50 nmol to naïve rats caused a long-lasting mechanical and cold behavioral allodynia. Direct actions of 50 nM TLQP-62 upon dorsal horn neuron excitability was demonstrated in whole cell patch recordings in spinal cord slices and in receptive field analysis in intact, anesthetized rats where significant actions of VGF were upon spontaneous activity and cold evoked responses. Conclusion VGF expression is therefore highly modulated in nociceptive pathways following peripheral nerve injury and can cause dorsal horn cell excitation and behavioral hypersensitivity in naïve animals. Together the results point to a novel and powerful role for VGF in neuropathic pain.

  14. Cough reflex is additively potentiated by inputs from the laryngeal and tracheobronchial [corrected] receptors and enhanced by stimulation of the central respiratory neurons.

    Science.gov (United States)

    Kondo, Tetsuri; Hayama, Naoki

    2009-09-01

    The cough is an essential airway defense reflex. In this study we investigated the coordination of inputs from the laryngeal and tracheobronchial receptors in the cough reflex. In 15 beagle dogs (7-9 kg) lightly anesthetized with intravenous profobol (20-30 mg/kg/h), the cough response was elicited with mechanical stimulation of either the vocal chord or tracheal bifurcation. Simultaneous stimulation of both sites increased all the parameters of cough strength, that is, mean pleural pressure (P (pl)), mean expiratory flow, number of cough bouts, and cough duration, in comparison with stimulation of the sites individually. The increases in mean P (pl) and cough duration reached statistical significance (13.3 vs. 18.4 cmH(2)O and 13.3 vs. 18.2 s, respectively). When the anesthetic level became deeper, the prolongation of cough duration almost disappeared, but the augmentation of mean P (pl) was much less affected. During stimulation of the central respiratory neurons by intravenous dimorphoramine or acute hyperoxic hypercapnia, the cough strength increased significantly. We concluded that inputs from the laryngeal and tracheobonchial cough receptors acted in concert and potentiated the cough reflex. Furthermore, stimulation of the central respiratory neurons may increase the intensity of a cough response.

  15. A tachykinin-like neuroendocrine signalling axis couples central serotonin action and nutrient sensing with peripheral lipid metabolism

    Science.gov (United States)

    Palamiuc, Lavinia; Noble, Tallie; Witham, Emily; Ratanpal, Harkaranveer; Vaughan, Megan; Srinivasan, Supriya

    2017-01-01

    Serotonin, a central neuromodulator with ancient ties to feeding and metabolism, is a major driver of body fat loss. However, mechanisms by which central serotonin action leads to fat loss remain unknown. Here, we report that the FLP-7 neuropeptide and its cognate receptor, NPR-22, function as the ligand-receptor pair that defines the neuroendocrine axis of serotonergic body fat loss in Caenorhabditis elegans. FLP-7 is secreted as a neuroendocrine peptide in proportion to fluctuations in neural serotonin circuit functions, and its release is regulated from secretory neurons via the nutrient sensor AMPK. FLP-7 acts via the NPR-22/Tachykinin2 receptor in the intestine and drives fat loss via the adipocyte triglyceride lipase ATGL-1. Importantly, this ligand-receptor pair does not alter other serotonin-dependent behaviours including food intake. For global modulators such as serotonin, the use of distinct neuroendocrine peptides for each output may be one means to achieve phenotypic selectivity. PMID:28128367

  16. The Drosophila neuropeptides PDF and sNPF have opposing electrophysiological and molecular effects on central neurons.

    Science.gov (United States)

    Vecsey, Christopher G; Pírez, Nicolás; Griffith, Leslie C

    2014-03-01

    Neuropeptides have widespread effects on behavior, but how these molecules alter the activity of their target cells is poorly understood. We employed a new model system in Drosophila melanogaster to assess the electrophysiological and molecular effects of neuropeptides, recording in situ from larval motor neurons, which transgenically express a receptor of choice. We focused on two neuropeptides, pigment-dispersing factor (PDF) and small neuropeptide F (sNPF), which play important roles in sleep/rhythms and feeding/metabolism. PDF treatment depolarized motor neurons expressing the PDF receptor (PDFR), increasing excitability. sNPF treatment had the opposite effect, hyperpolarizing neurons expressing the sNPF receptor (sNPFR). Live optical imaging using a genetically encoded fluorescence resonance energy transfer (FRET)-based sensor for cyclic AMP (cAMP) showed that PDF induced a large increase in cAMP, whereas sNPF caused a small but significant decrease in cAMP. Coexpression of pertussis toxin or RNAi interference to disrupt the G-protein Gαo blocked the electrophysiological responses to sNPF, showing that sNPFR acts via Gαo signaling. Using a fluorescent sensor for intracellular calcium, we observed that sNPF-induced hyperpolarization blocked spontaneous waves of activity propagating along the ventral nerve cord, demonstrating that the electrical effects of sNPF can cause profound changes in natural network activity in the brain. This new model system provides a platform for mechanistic analysis of how neuropeptides can affect target cells at the electrical and molecular level, allowing for predictions of how they regulate brain circuits that control behaviors such as sleep and feeding.

  17. Differential serotonergic mediation of aggression in roosters selected for resistance and susceptibility to Marek's disease

    Science.gov (United States)

    Serotonin (5-HT) is a primary regulating neurotransmitter involved in aggressive and impulsive behaviors in mammals. Previous studies have also demonstrated the function of serotonergic system in regulating aggression is affected by both genetic and environmental factors. The serotonergic system m...

  18. Long-term omega-3 supplementation modulates behavior, hippocampal fatty acid concentration, neuronal progenitor proliferation and central TNF-α expression in 7 month old unchallenged mice.

    Science.gov (United States)

    Grundy, Trent; Toben, Catherine; Jaehne, Emily J; Corrigan, Frances; Baune, Bernhard T

    2014-01-01

    Dietary polyunsaturated fatty acid (PUFA) manipulation is being investigated as a potential therapeutic supplement to reduce the risk of developing age-related cognitive decline (ARCD). Animal studies suggest that high omega (Ω)-3 and low Ω-6 dietary content reduces cognitive decline by decreasing central nervous system (CNS) inflammation and modifying neuroimmune activity. However, no previous studies have investigated the long term effects of Ω-3 and Ω-6 dietary levels in healthy aging mice leaving the important question about the preventive effects of Ω-3 and Ω-6 on behavior and underlying molecular pathways unaddressed. We aimed to investigate the efficacy of long-term Ω-3 and Ω-6 PUFA dietary supplementation in mature adult C57BL/6 mice. We measured the effect of low, medium, and high Ω-3:Ω-6 dietary ratio, given from the age of 3-7 months, on anxiety and cognition-like behavior, hippocampal tissue expression of TNF-α, markers of neuronal progenitor proliferation and gliogenesis and serum cytokine concentration. Our results show that a higher Ω-3:Ω-6 PUFA diet ratio increased hippocampal PUFA, increased anxiety, improved hippocampal dependent spatial memory and reduced hippocampal TNF-α levels compared to a low Ω-3:Ω-6 diet. Furthermore, serum TNF-α concentration was reduced in the higher Ω-3:Ω-6 PUFA ratio supplementation group while expression of the neuronal progenitor proliferation markers KI67 and doublecortin (DCX) was increased in the dentate gyrus as opposed to the low Ω-3:Ω-6 group. Conversely, Ω-3:Ω-6 dietary PUFA ratio had no significant effect on astrocyte or microglia number or cell death in the dentate gyrus. These results suggest that supplementation of PUFAs may delay aging effects on cognitive function in unchallenged mature adult C57BL/6 mice. This effect is possibly induced by increasing neuronal progenitor proliferation and reducing TNF-α.

  19. Long-term omega-3 supplementation modulates behavior, hippocampal fatty acid concentration, neuronal progenitor proliferation and central TNF-α expression in 7 month old unchallenged mice

    Directory of Open Access Journals (Sweden)

    Trent eGrundy

    2014-11-01

    Full Text Available Dietary polyunsaturated fatty acid (PUFA manipulation is being investigated as a potential therapeutic supplement to reduce the risk of developing age-related cognitive decline (ARCD. Animal studies suggest that high omega (Ω-3 and low Ω-6 dietary content reduces cognitive decline by decreasing central nervous system (CNS inflammation and modifying neuroimmune activity. However, no previous studies have investigated the long term effects of Ω-3 and Ω-6 dietary levels in healthy aging mice leaving the important question about the preventive effects of Ω-3 and Ω-6 on behavior and underlying molecular pathways unaddressed. We aimed to investigate the efficacy of long-term Ω-3 and Ω-6 PUFA dietary supplementation in mature adult C57BL/6 mice. We measured the effect of low, medium and high Ω-3:Ω-6 dietary ratio, given from the age of 3 to 7 months, on anxiety and cognition-like behavior, hippocampal tissue expression of TNF-α, markers of neuronal progenitor proliferation and gliogenesis and serum cytokine concentration. Our results show that a higher Ω-3:Ω-6 PUFA diet ratio increased hippocampal PUFA, increased anxiety, improved hippocampal dependent spatial memory and reduced hippocampal TNF-α levels compared to a low Ω-3:Ω-6 diet. Furthermore, serum TNF-α concentration was reduced in the higher Ω-3:Ω-6 PUFA ratio supplementation group while expression of the neuronal progenitor proliferation markers KI67 and doublecortin (DCX was increased in the dentate gyrus as opposed to the low Ω-3:Ω-6 group. Conversely, Ω-3:Ω-6 dietary PUFA ratio had no significant effect on astrocyte or microglia number or cell death in the dentate gyrus. These results suggest that supplementation of PUFAs may delay ageing effects on cognitive function in unchallenged mature adult C57BL/6 mice. This effect is possibly induced by increasing neuronal progenitor proliferation and reducing TNF-α.

  20. Integration of stress and leptin signaling by CART producing neurons in the rodent midbrain centrally projecting Edinger-Westphal nucleus

    NARCIS (Netherlands)

    Xu, L.; Janssen, D.; Knaap, N.J.F. van der; Roubos, E.W.; Leshan, R.L.; Myers, M.G.; Gaszner, B.; Kozicz, T.L.

    2014-01-01

    Leptin targets the brain to regulate feeding, neuroendocrine function and metabolism. The leptin receptor is present in hypothalamic centers controlling energy metabolism as well as in the centrally projecting Edinger-Westphal nucleus (EWcp), a region implicated in the stress response and in various

  1. Food-derived serotonergic modulators: effects on mood and cognition.

    Science.gov (United States)

    Hulsken, Sjoerd; Märtin, Antje; Mohajeri, M Hasan; Homberg, Judith Regina

    2013-12-01

    The most frequently described drugs in the treatment of mood disorders are selective serotonin reuptake and monoamine oxidase (MAO) inhibitors, enhancing serotonin levels in the brain. However, side-effects have been reported for these drugs. Because serotonin levels in the brain are dependent on the availability of the food-derived precursor tryptophan, foods such as chicken, soyabeans, cereals, tuna, nuts and bananas may serve as an alternative to improve mood and cognition. Here we discuss the effects of high- or low-tryptophan-containing food, as well as plant extracts with a modest monoamine reuptake and MAO-A inhibition functional profile, on mood and cognition in healthy and vulnerable human subjects and rodents. Together the studies suggest that there is an inverted U-shaped curve for plasma tryptophan levels, with low and too high tryptophan levels impairing cognition, and moderate to high tryptophan levels improving cognition. This relationship is found for both healthy and vulnerable subjects. Whereas this relationship may also exist for mood, the inverted U-shaped curve for plasma tryptophan levels and mood may be based on different tryptophan concentrations in healthy v. vulnerable individuals. Animal studies are emerging and allow further understanding of effects and the mode of action of food-derived serotonergic components on mood, cognition and mechanisms. Ultimately, insight into the concentrations of tryptophan and other serotonergic components in food having beneficial effects on mood and cognition in healthy, but particularly vulnerable, subjects may support well-being in our highly demanding society.

  2. The role of the serotonergic system in suicidal behavior

    Directory of Open Access Journals (Sweden)

    Sadkowski M

    2013-11-01

    Full Text Available Marta Sadkowski,1,* Brittany Dennis,2–4,* Robert C Clayden,2 Wala ElSheikh,5 Sumathy Rangarajan,5 Jane DeJesus,5 Zainab Samaan3–6 1Arts and Sciences Program, 2Faculty of Health Sciences, 3Department of Clinical Epidemiology and Biostatistics, 4Population Genomics Program, McMaster University, Hamilton, ON, Canada; 5Population Health Research Institute, Hamilton, ON, Canada; 6Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, ON, Canada *These authors contributed equally to this work Abstract: Serotonin is a widely investigated neurotransmitter in several psychopathologies, including suicidal behavior (SB; however, its role extends to several physiological functions involving the nervous system, as well as the gastrointestinal and cardiovascular systems. This review summarizes recent research into ten serotonergic genes related to SB. These genes – TPH1, TPH2, SLC6A4, SLC18A2, HTR1A, HTR1B, HTR2A, DDC, MAOA, and MAOB – encode proteins that are vital to serotonergic function: tryptophan hydroxylase; the serotonin transporter 5-HTT; the vesicular transporter VMAT2; the HTR1A, HTR1B, and HTR2A receptors; the L-amino acid decarboxylase; and the monoamine oxidases. This review employed a systematic search strategy and a narrative research methodology to disseminate the current literature investigating the link between SB and serotonin. Keywords: serotonin, suicide, genetic

  3. [Micro/nano-engineering to control growth of neuronal cells and tissue engineering applied to the central nervous system].

    Science.gov (United States)

    Béduer, Amélie; Vaysse, Laurence; Loubinoux, Isabelle; Vieu, Christophe

    2013-01-01

    Central nervous system pathologies are often characterized by the loss of cell populations. A promising therapy now being developed consists in using bioactive materials, associating grafted cells to biopolymers which provide a scaffold for the in vitro building of new tissues, to be implanted in vivo. In the present article, the state of the art of this field, at crossroads between microtechnology and neuroscience, is described in detail; thereafter our own approach and results about interactions between adult human neural stem cells and microstructured polymers are summarized and discussed. In a second part, some central nervous system repair strategies, based on cerebral tissue engineering, are presented. We will report the main results of our studies to work out and characterize in vivo a cerebral bioprosthesis.

  4. Pertussis toxin modulation of sodium channels in the central neurons of cyhalothrin-resistant and cyhalothrin-susceptible cotton bollworm, Helicoverpa armigera

    Institute of Scientific and Technical Information of China (English)

    QIANG ZHAO; DE-LING KONG; BING-JUN HE; YAN-QIANG LIU; XIAN-LIN FAN; AN-XI LIU

    2007-01-01

    Pertussis toxin (PTX) inhibits the activation of the α-subunit of the inhibitory heterotrimeric G-proteins (Gαi/o) and modulates voltage-gated sodium channels, which may be one of the primary targets of pyrethroids. To investigate the potential mechanisms of agricultural pests resistance to pyrethroid insecticides, we examined the modulations by PTX on sodium channels in the central neurons of the 3rd-4th instar larvae of cyhalothrin-resistant (Cy-R) and cyhalothrin-susceptible (Cy-S) Helicoverpa armigera by the whole-cell patch-clamp technique.The isolated neurons were cultured for 12-16 h in an improved L15 insect culture medium with or without PTX (400 ng/mL). The results showed that both the Cy-R and Cy-S sodium channels exhibited fast kinetics and tetrodotoxin (TTX) sensitivity. The Cy-R sodium channels exhibited not only altered gating properties, including a 8.88-mV right shift in voltage-dependent activation (V0.5act) and a 6.54-mV right shift in voltage-dependent inactivation (V0.5inact), but also a reduced peak in sodium channel density (Idensity) (55.2% of that in Cy-S neurons). Cy-R sodium channels also showed low excitability, as evidenced by right shift of activation potential (Vacti) by 5-10 mV and peak potential (Vpeak) by 20 mV. PTX exerted significant effects on Cy-S sodium channels,reducing sodium channel density by 70.04%, right shifting V0.5act by 14.41 mV and V0.5inact by 9.38 mV. It did not cause any significant changes of the parameters mentioned above in the Cy-R sodium channels. The activation time (Tpeak) from latency to peak at peak voltage and the fast inactivation time constant (τinact) in both Cy-S and Cy-R neurons were not affected. The results suggest that cotton bollworm resistant to pyrethroid insecticides involves not only mutations and allosteric alterations of voltage-gated sodium channels, but also might implicate perturbation of PTX-sensitive Gαi/o-coupled signaling transduction pathways.

  5. Effects of location and timing of co-activated neurons in the auditory midbrain on cortical activity: implications for a new central auditory prosthesis

    Science.gov (United States)

    Straka, Małgorzata M.; McMahon, Melissa; Markovitz, Craig D.; Lim, Hubert H.

    2014-08-01

    Objective. An increasing number of deaf individuals are being implanted with central auditory prostheses, but their performance has generally been poorer than for cochlear implant users. The goal of this study is to investigate stimulation strategies for improving hearing performance with a new auditory midbrain implant (AMI). Previous studies have shown that repeated electrical stimulation of a single site in each isofrequency lamina of the central nucleus of the inferior colliculus (ICC) causes strong suppressive effects in elicited responses within the primary auditory cortex (A1). Here we investigate if improved cortical activity can be achieved by co-activating neurons with different timing and locations across an ICC lamina and if this cortical activity varies across A1. Approach. We electrically stimulated two sites at different locations across an isofrequency ICC lamina using varying delays in ketamine-anesthetized guinea pigs. We recorded and analyzed spike activity and local field potentials across different layers and locations of A1. Results. Co-activating two sites within an isofrequency lamina with short inter-pulse intervals (hearing capabilities.

  6. Ontogeny of the serotonergic projection to rat neocortex: transient expression of a dense innervation to primary sensory areas

    Energy Technology Data Exchange (ETDEWEB)

    D' Amato, R.J.; Blue, M.E.; Largent, B.L.; Lynch, D.R.; Ledbetter, D.J.; Molliver, M.E.; Snyder, S.H.

    1987-06-01

    The development of serotonergic innervation to rat cerebral cortex was characterized by immunohistochemical localization of serotonin combined with autoradiographic imaging of serotonin-uptake sites. In neonatal rat, a transient, dense, serotonergic innervation appears in all primary sensory areas of cortex. In somatosensory cortex, dense patches of serotonergic innervation are aligned with specialized cellular aggregates called barrels. The dense patches are not apparent after 3 weeks of age, and the serotonergic innervation becomes more uniform in adult neocortex. This precocious neonatal serotonergic innervation may play a transient physiologic role in sensory areas of cortex or may exert a trophic influence on the development of cortical circuitry and thalamocortical connections.

  7. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner.

    Science.gov (United States)

    Clarke, G; Grenham, S; Scully, P; Fitzgerald, P; Moloney, R D; Shanahan, F; Dinan, T G; Cryan, J F

    2013-06-01

    Bacterial colonisation of the intestine has a major role in the post-natal development and maturation of the immune and endocrine systems. These processes are key factors underpinning central nervous system (CNS) signalling. Regulation of the microbiome-gut-brain axis is essential for maintaining homeostasis, including that of the CNS. However, there is a paucity of data pertaining to the influence of microbiome on the serotonergic system. Germ-free (GF) animals represent an effective preclinical tool to investigate such phenomena. Here we show that male GF animals have a significant elevation in the hippocampal concentration of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid, its main metabolite, compared with conventionally colonised control animals. Moreover, this alteration is sex specific in contrast with the immunological and neuroendocrine effects which are evident in both sexes. Concentrations of tryptophan, the precursor of serotonin, are increased in the plasma of male GF animals, suggesting a humoral route through which the microbiota can influence CNS serotonergic neurotransmission. Interestingly, colonisation of the GF animals post weaning is insufficient to reverse the CNS neurochemical consequences in adulthood of an absent microbiota in early life despite the peripheral availability of tryptophan being restored to baseline values. In addition, reduced anxiety in GF animals is also normalised following restoration of the intestinal microbiota. These results demonstrate that CNS neurotransmission can be profoundly disturbed by the absence of a normal gut microbiota and that this aberrant neurochemical, but not behavioural, profile is resistant to restoration of a normal gut flora in later life.

  8. Recent Advances in the Neuropsychopharmacology of Serotonergic Hallucinogens

    Science.gov (United States)

    Halberstadt, Adam L.

    2014-01-01

    Serotonergic hallucinogens, such as (+)-lysergic acid diethylamide, psilocybin, and mescaline, are somewhat enigmatic substances. Although these drugs are derived from multiple chemical families, they all produce remarkably similar effects in animals and humans, and they show cross-tolerance. This article reviews the evidence demonstrating the serotonin 5-HT2A receptor is the primary site of hallucinogen action. The 5-HT2A receptor is responsible for mediating the effects of hallucinogens in human subjects, as well as in animal behavioral paradigms such as drug discrimination, head twitch response, prepulse inhibition of startle, exploratory behavior, and interval timing. Many recent clinical trials have yielded important new findings regarding the psychopharmacology of these substances. Furthermore, the use of modern imaging and electrophysiological techniques is beginning to help unravel how hallucinogens work in the brain. Evidence is also emerging that hallucinogens may possess therapeutic efficacy. PMID:25036425

  9. Body sodium overload modulates the firing rate and fos immunoreactivity of serotonergic cells of dorsal raphe nucleus.

    Directory of Open Access Journals (Sweden)

    Andrea Godino

    Full Text Available In order to determine whether serotonergic (5HT dorsal raphe nucleus (DRN cells are involved in body sodium status regulation, the effect of a s.c. infusion of either 2 M or 0.15 M NaCl on 5HT DRN neuron firing was studied using single unit extracellular recordings. In separate groups of 2 M and 0.15 M NaCl-infused rats, water intake, oxytocin (OT plasma concentration, urine and plasma sodium and protein concentrations were also measured. Also, to determine the involvement of particular brain nuclei and neurochemical systems in body sodium overload (SO, animals from both groups were perfused for brain immunohistochemical detection of Fos, Fos-OT and Fos-5HT expression. SO produced a significant increase in serotonergic DRN neuron firing rate compared to baseline and 0.15 M NaCl-infused rats. As expected, 2 M NaCl s.c. infusion also induced a significant increase of water intake, diuresis and natriuresis, plasma sodium concentration and osmolality, even though plasma volume did not increase as indicated by changes in plasma protein concentration. The distribution of neurons along the forebrain and brainstem expressing Fos after SO showed the participation of the lamina terminalis, extended amygdala, supraoptic and paraventricular hypothalamic nuclei in the neural network that controls osmoregulatory responses. Both Fos-OT immunoreactive and plasma OT concentration increased after s.c. hypertonic sodium infusion. Finally, matching the "in vivo" electrophysiological study, SO doubled the number of Fos-5HT immunolabeled cells within the DRN. In summary, the results characterize the behavioral, renal and endocrine responses after body sodium overload without volume expansion and specify the cerebral nuclei that participate at different CNS levels in the control of these responses. The electrophysiological approach also allows us to determine in an "in vivo" model that DRN 5HT neurons increase their firing frequency during an increase in systemic

  10. The inhibition of neurons in the central nervous pathways for thermoregulatory cold defense induces a suspended animation state in the rat.

    Science.gov (United States)

    Cerri, Matteo; Mastrotto, Marco; Tupone, Domenico; Martelli, Davide; Luppi, Marco; Perez, Emanuele; Zamboni, Giovanni; Amici, Roberto

    2013-02-13

    The possibility of inducing a suspended animation state similar to natural torpor would be greatly beneficial in medical science, since it would avoid the adverse consequence of the powerful autonomic activation evoked by external cooling. Previous attempts to systemically inhibit metabolism were successful in mice, but practically ineffective in nonhibernators. Here we show that the selective pharmacological inhibition of key neurons in the central pathways for thermoregulatory cold defense is sufficient to induce a suspended animation state, resembling natural torpor, in a nonhibernator. In rats kept at an ambient temperature of 15°C and under continuous darkness, the prolonged inhibition (6 h) of the rostral ventromedial medulla, a key area of the central nervous pathways for thermoregulatory cold defense, by means of repeated microinjections (100 nl) of the GABA(A) agonist muscimol (1 mm), induced the following: (1) a massive cutaneous vasodilation; (2) drastic drops in deep brain temperature (reaching a nadir of 22.44 ± 0.74°C), heart rate (from 440 ± 13 to 207 ± 12 bpm), and electroencephalography (EEG) power; (3) a modest decrease in mean arterial pressure; and (4) a progressive shift of the EEG power spectrum toward slow frequencies. After the hypothermic bout, all animals showed a massive increase in NREM sleep Delta power, similarly to that occurring in natural torpor. No behavioral abnormalities were observed in the days following the treatment. Our results strengthen the potential role of the CNS in the induction of hibernation/torpor, since CNS-driven changes in organ physiology have been shown to be sufficient to induce and maintain a suspended animation state.

  11. Genetic polymorphisms in the serotonergic system are associated with circadian manifestations of bruxism.

    Science.gov (United States)

    Oporto, G H; Bornhardt, T; Iturriaga, V; Salazar, L A

    2016-11-01

    Bruxism (BRX) is a condition of great interest for researchers and clinicians in dental and medical areas. BRX has two circadian manifestations; it can occur during sleep (sleep bruxism, SB) or during wakefulness (awake bruxism, WB). However, it can be suffered together. Recent investigations suggest that central nervous system neurotransmitters and their genes could be involved in the genesis of BRX. Serotonin is responsible for the circadian rhythm, maintaining arousal, regulating stress response, muscle tone and breathing. Thus, serotonin could be associated with BRX pathogenesis. The aim of this work was to evaluate the frequency of genetic polymorphisms in the genes HTR1A (rs6295), HTR2A (rs1923884, rs4941573, rs6313, rs2770304), HTR2C (rs17260565) and SLC6A4 (rs63749047) in subjects undergoing BRX treatment. Patients included were classified according to their diagnosis in awake bruxism (61 patients), sleep bruxism (26 patients) and both (43 patients). The control group included 59 healthy patients with no signs of BRX. Data showed significant differences in allelic frequencies for the HTR2A rs2770304 polymorphism, where the C allele was associated with increased risk of SB (odds ratio = 2·13, 95% confidence interval: 1·08-4·21, P = 0·03). Our results suggest that polymorphisms in serotonergic pathways are involved in sleep bruxism. Further research is needed to clarify and increase the current understanding of BRX physiopathology.

  12. Serotonergic dysfunctions and abnormal iron metabolism: Relevant to mental fatigue of Parkinson disease.

    Science.gov (United States)

    Zuo, Li-Jun; Yu, Shu-Yang; Hu, Yang; Wang, Fang; Piao, Ying-Shan; Lian, Teng-Hong; Yu, Qiu-Jin; Wang, Rui-Dan; Li, Li-Xia; Guo, Peng; Du, Yang; Zhu, Rong-Yan; Jin, Zhao; Wang, Ya-Jie; Wang, Xiao-Min; Chan, Piu; Chen, Sheng-Di; Wang, Yong-Jun; Zhang, Wei

    2016-12-01

    Fatigue is a very common non-motor symptom in Parkinson disease (PD) patients. It included physical fatigue and mental fatigue. The potential mechanisms of mental fatigue involving serotonergic dysfunction and abnormal iron metabolism are still unknown. Therefore, we evaluated the fatigue symptoms, classified PD patients into fatigue group and non-fatigue group, and detected the levels of serotonin, iron and related proteins in CSF and serum. In CSF, 5-HT level is significantly decreased and the levels of iron and transferrin are dramatically increased in fatigue group. In fatigue group, mental fatigue score is negatively correlated with 5-HT level in CSF, and positively correlated with the scores of depression and excessive daytime sleepiness, and disease duration, also, mental fatigue is positively correlated with the levels of iron and transferrin in CSF. Transferrin level is negatively correlated with 5-HT level in CSF. In serum, the levels of 5-HT and transferrin are markedly decreased in fatigue group; mental fatigue score exhibits a negative correlation with 5-HT level. Thus serotonin dysfunction in both central and peripheral systems may be correlated with mental fatigue through abnormal iron metabolism. Depression, excessive daytime sleepiness and disease duration were the risk factors for mental fatigue of PD.

  13. Serotonergic modulation of resting state default mode network connectivity in healthy women.

    Science.gov (United States)

    Helmbold, K; Zvyagintsev, M; Dahmen, B; Biskup, C S; Bubenzer-Busch, S; Gaber, T J; Klasen, M; Eisert, A; Konrad, K; Habel, U; Herpertz-Dahlmann, B; Zepf, F D

    2016-04-01

    The default mode network (DMN) plays a central role in intrinsic thought processes. Altered DMN connectivity has been linked to diminished cerebral serotonin synthesis. Diminished brain serotonin synthesis is further associated with a lack of impulse control and various psychiatric disorders. Here, we investigated the serotonergic modulation of intrinsic functional connectivity (FC) within the DMN in healthy adult females, controlling for the menstrual cycle phase. Eighteen healthy women in the follicular phase (aged 20-31 years) participated in a double-blind controlled cross-over study of serotonin depletion. Acute tryptophan depletion (ATD) and a balanced amino acid load (BAL), used as the control condition, were applied on two separate days of assessment. Neural resting state data using functional magnetic resonance imaging (fMRI) and individual trait impulsivity scores were obtained. ATD compared with BAL significantly reduced FC with the DMN in the precuneus (associated with self-referential thinking) and enhanced FC with the DMN in the frontal cortex (associated with cognitive reasoning). Connectivity differences with the DMN between BAL and ATD in the precentral gyrus were significantly correlated with the magnitude of serotonin depletion. Right medial frontal gyrus and left superior frontal gyrus connectivity differences with the DMN were inversely correlated with trait impulsivity. These findings partially deviate from previous findings obtained in males and underline the importance of gender-specific studies and controlling for menstrual cycle to further elucidate the mechanism of ATD-induced changes within intrinsic thought processes.

  14. Association Between Genetic Polymorphisms in the Serotonergic System and Comorbid Personality Disorders Among Patients with First-Episode Depression

    DEFF Research Database (Denmark)

    Bukh, Jens D; Bock, Camilla; Kessing, Lars V

    2014-01-01

    the serotonin transporter, serotonin receptors 1A, 2A, 2C, and tryptophan hydroxylase 1 were genotyped. The authors found a significant effect of the length polymorphism in the serotonin transporter gene (5-HTTLPR) on cluster B personality disorder (mainly borderline disorder), but no influence on cluster C......Studies on the association between genetic polymorphisms and personality disorders have provided inconsistent results. Using the "enriched sample method," the authors of the present study aimed to assess the association between polymorphisms in the serotonergic transmitter system and comorbid...... personality disorders in patients recently diagnosed with first-episode depression. A total of 290 participants were systematically recruited via the Danish Psychiatric Central Research Register. Diagnoses of personality disorders were assessed by a SCID-II interview, and polymorphisms in the genes encoding...

  15. Association between genetic polymorphisms in the serotonergic system and comorbid personality disorders among patients with first-episode depression.

    Science.gov (United States)

    Bukh, Jens D; Bock, Camilla; Kessing, Lars V

    2014-06-01

    Studies on the association between genetic polymorphisms and personality disorders have provided inconsistent results. Using the "enriched sample method," the authors of the present study aimed to assess the association between polymorphisms in the serotonergic transmitter system and comorbid personality disorders in patients recently diagnosed with first-episode depression. A total of 290 participants were systematically recruited via the Danish Psychiatric Central Research Register. Diagnoses of personality disorders were assessed by a SCID-II interview, and polymorphisms in the genes encoding the serotonin transporter, serotonin receptors 1A, 2A, 2C, and tryptophan hydroxylase 1 were genotyped. The authors found a significant effect of the length polymorphism in the serotonin transporter gene (5-HTTLPR) on cluster B personality disorder (mainly borderline disorder), but no influence on cluster C personality disorder, and no associations between other polymorphisms and personality disorders. The study adds evidence to the effect of the serotonin transporter gene specifically on cluster B personality disorders.

  16. Anti-depression effect of licorice flavonoids from Glycyrrhiza uralensis through promotion of central serotonergic neural function in mice%甘草总黄酮提取部位抗小鼠抑郁活性可能与其增强中枢5-羟色胺能神经功能有关

    Institute of Scientific and Technical Information of China (English)

    程瑞凤; 王英华; 彭晓东; 景晶; 华冰; 薛旻秋; 陆钊罡; 赵伟鸿; 樊紫周; 果嘉; 杨卫东

    2014-01-01

    -HTP treatment were observed at 6 time points. After HTT,the mice were sacrificed quickIy,and the mono-amine oxidase(mAO)activity in the brain cortex,hippocampus and thaIamus was examined to evaIuate the antidepressant effect of fIavonoids with mAO inhibition. RESULTS Compared with the vehicIe controI,LF significantIy decreased the immobiIity period in both FST and TST(P﹤0.05). LF(50,150 and 400 mg·kg-1 )antagonized the ptosis and akinesia symptoms respectiveIy in 1 h after reserpine administration( P ﹤ 0. 05 ), but faiIed to antagonize hypothermia produced 4 h after reserpine administration. AIso,at the same dosage,LF did not synergeticaIIy produce the enhancement of death by subcutaneous injection of yohimbine at the threshoId IethaI dosage. LF(150 and 400 mg·kg-1 )couId significantIy and synergeticaIIy increase 5-HTP induced head-twitches response(P﹤0.05),but LF couId not promote mAO activity in the cortex,hippocampus and thaIamus at the same dosage. CONCLUSlON LF exerts antidepressant-Iike effect on the modeI of acute despair test. The mechanism might be reIated to direct enhancement of the serotonergic neuraI function in the brain.%目的:探讨甘草总黄酮提取部位(LF)的抗抑郁作用及可能的作用机制。方法 Km 小鼠分别每天 po给予 LF 5,30和180 mg·kg-1,连续21 d,于第1天、第7天和第21天给药后1 h进行强迫游泳实验(FST),记录4 min 内不动时间;另取 Km 小鼠,按照 FST 的实验分组处理,于第1天、第7天和第21天 po药后1 h 进行悬尾实验( TST),记录4 min 内不动时间。ICR 小鼠分别每天 po给予 LF 50,150和400 mg·kg-1,连续7 d,进行利血平诱发症状拮抗实验(ART),于末次给药后1 h采用记录小鼠运动不能、上睑下垂和监测肛温;另取 Km 小鼠,分别每天 po给予 LF 50,150和400 mg·kg-1,连续7 d,于末次给药1 h后 sc 阈致死剂量的育亨宾,观察24 h 小鼠存活情况;取 Km

  17. Leptin receptor immunoreactivity is present in ascending serotonergic and catecholaminergic neurons of the rat

    DEFF Research Database (Denmark)

    Hay-Schmidt, Anders; Helboe, Lone; Larsen, Philip J.

    2001-01-01

    Obesity, tyrosine hydroxylase, arcuate nucleus, paracentricular nucleus, raphe nuclei, leptin, serotonin, catecholamines......Obesity, tyrosine hydroxylase, arcuate nucleus, paracentricular nucleus, raphe nuclei, leptin, serotonin, catecholamines...

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

    NARCIS (Netherlands)

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

    1999-01-01

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

  19. Neurochemical coding of enteric neurons in adult and embryonic zebrafish (Danio rerio).

    Science.gov (United States)

    Uyttebroek, Leen; Shepherd, Iain T; Harrisson, Fernand; Hubens, Guy; Blust, Ronny; Timmermans, Jean-Pierre; Van Nassauw, Luc

    2010-11-01

    Although the morphology and development of the zebrafish enteric nervous system have been extensively studied, the precise neurochemical coding of enteric neurons and their proportional enteric distribution are currently not known. By using immunohistochemistry, we determined the proportional expression and coexpression of neurochemical markers in the embryonic and adult zebrafish intestine. Tyrosine hydroxylase (TH), vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP) were observed only in nerve fibers, whereas other markers were also detected in neuronal cell bodies. Calretinin and calbindin had similar distributions. In embryos, all markers, except for choline acetyltransferase (ChAT) and TH, were present from 72 hours postfertilization. Nitrergic neurons, evenly distributed and remaining constant in time, constituted the major neuronal subpopulation. The neuronal proportions of the other markers increased during development and were characterized by regional differences. In the adult, all markers examined were expressed in the enteric nervous system. A large percentage of enteric neurons displayed calbindin and calretinin, and serotonin was the only marker showing significant distribution differences in the three intestinal regions. Colocalization studies showed that serotonin was not coexpressed with any of the other markers. At least five neuronal subpopulations were determined: a serotonergic, a nitrergic noncholinergic, two cholinergic nonnitrergic subpopulations along with one subpopulation expressing both ChAT and neuronal nitric oxide synthase. Analysis of nerve fibers revealed that nitrergic neurons coexpress VIP and PACAP, and that nitrergic neurons innervate the tunica muscularis, whereas serotonergic and cholinergic nonnitrergic neurons innervate the lamina propria and the tunica muscularis.

  20. Single oral doses of (±) 3,4-methylenedioxymethamphetamine ('Ecstasy') produce lasting serotonergic deficits in non-human primates: relationship to plasma drug and metabolite concentrations.

    Science.gov (United States)

    Mueller, Melanie; Yuan, Jie; McCann, Una D; Hatzidimitriou, George; Ricaurte, George A

    2013-05-01

    Repeated doses of the popular recreational drug methylenedioxymethamphetamine (MDMA, 'Ecstasy') are known to produce neurotoxic effects on brain serotonin (5-HT) neurons but it is widely believed that typical single oral doses of MDMA are free of neurotoxic risk. Experimental and therapeutic trials with MDMA in humans are underway. The mechanisms by which MDMA produces neurotoxic effects are not understood but drug metabolites have been implicated. The aim of the present study was to assess the neurotoxic potential of a range of clinically relevant single oral doses of MDMA in a non-human primate species that metabolizes MDMA in a manner similar to humans, the squirrel monkey. A secondary objective was to explore the relationship between plasma MDMA and metabolite concentrations and lasting serotonergic deficits. Single oral doses of MDMA produced lasting dose-related serotonergic neurochemical deficits in the brains of squirrel monkeys. Notably, even the lowest dose of MDMA tested (5.7 mg/kg, estimated to be equivalent to 1.6 mg/kg in humans) produced significant effects in some brain regions. Plasma levels of MDMA engendered by neurotoxic doses of MDMA were on the order of those found in humans. Serotonergic neurochemical markers were inversely correlated with plasma concentrations of MDMA, but not with those of its major metabolites, 3,4-dihydroxymethamphetamine and 4-hydroxy-3-methoxymethamphetamine. These results suggest that single oral doses of MDMA in the range of those used by humans pose a neurotoxic risk and implicate the parent compound (MDMA), rather than one of its metabolites, in MDMA-induced 5-HT neural injury.

  1. Ontogeny of the serotonergic projection to rat neocortex: transient expression of a dense innervation to primary sensory areas.

    OpenAIRE

    D'Amato, R J; Blue, M E; Largent, B L; Lynch, D R; Ledbetter, D J; Molliver, M E; Snyder, S H

    1987-01-01

    The development of serotonergic innervation to rat cerebral cortex was characterized by immunohistochemical localization of serotonin combined with autoradiographic imaging of serotonin-uptake sites. In neonatal rat, a transient, dense, serotonergic innervation appears in all primary sensory areas of cortex. In somatosensory cortex, dense patches of serotonergic innervation are aligned with specialized cellular aggregates called barrels. The dense patches are not apparent after 3 weeks of age...

  2. Development of an integrated procedure for the detection of central nervous tissue in meat products using cholesterol and neuron-specific enolase as markers.

    Science.gov (United States)

    Lücker, E; Eigenbrodt, E; Wenisch, S; Failing, K; Leiser, R; Bülte, M

    1999-03-01

    The emergence of a new variant of Creutzfeldt-Jakob disease during the bovine spongiform encephalopathy epidemic has focused attention on the use of tissue from the central nervous system (CNS) in food. So far, the banning of CNS tissue could not be effectively controlled because procedures for detection were missing. With regard to preventive health protection and labeling law enforcement, we have developed an integrated procedure for the detection of CNS tissue in meat products. Herein, we show that antigenic characteristics of neuron-specific enolase (NSE) quantitatively survive technological treatment including severe homogenization and pressure heating. Using both poly- and monoclonal antibodies against NSE in the Western blot, bovine and porcine brain could be detected in sausages, albeit with varying sensitivity (1 to 4%). Sensitivity was increased after reduction of fat content (30 to 40%) of the samples by means of a soxhlet extraction. This made possible the detection of brain addition as low as 0.25% when using monoclonal antibodies. Immunohistology showed distribution of CNS tissue in heat-treated meat products to be homogeneous. Immunoreaction was not found to be bound to morphologically intact histological or cytological structures; however, it proved to be highly specific. The quantification of cholesterol provides a low-cost screening method for the rapid identification of meat products, suspicious with regard to CNS tissue addition. Cholesterol content increased by 26 mg per 100 g of fresh substance for each percentage of brain added to internally produced reference material. Using three different approaches (internal reference material, raw material, and field samples), a provisional cutoff point of normal cholesterol content was calculated for emulsion-type cooked sausages to be 115 mg/100 g (P < 0.05).

  3. Destruction of central noradrenergic neurones with DSP4 impairs the acquisition of temporal discrimination but does not affect memory for duration in a delayed conditional discrimination task.

    Science.gov (United States)

    al-Zahrani, S S; al-Ruwaitea, A S; Ho, M Y; Bradshaw, C M; Szabadi, E

    1997-03-01

    This experiment examined the effect of destroying central noradrenergic neurones using the selective neurotoxin N-(2-chloroethyl)-n-ethyl-2-bromobenzylamine (DSP4) on the acquisition of a temporal discrimination and on memory for duration, using a delayed conditional discrimination task. In phase I, rats that had received systemic treatment with DSP4 and vehicle-treated control rats were trained in a series of discrete trials to press lever A following a 2-s presentation of a light stimulus, and lever B following an 8-s presentation of the same stimulus. Following stimulus offset, a response on a panel placed midway between the two levers was required to initiate lever presentation; a single response on either lever resulted in withdrawal of both levers and, in the case of a "correct" response, reinforcer delivery. Both groups acquired accurate discrimination, achieving 90% correct choices within 50 sessions; the DSP4-treated group acquired accurate performance more slowly than the control group. In phase II, delays were interposed between stimulus offset and lever presentation in 50% of the trials. In the absence of a delay, discriminative accuracy was lower in the DSP4-treated group than in the control group. Accuracy declined as a function of post-stimulus delay in both groups; both groups showed a delay-dependent bias towards responding on lever A ("choose-short" bias). Neither of these effects differed significantly between the two groups. The concentrations of noradrenaline in the parietal cortex and hippocampus were reduced by 90% and 89% in the DSP4-treated group, compared to the levels in the control group, but the levels of dopamine, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid did not differ significantly between the groups. The results confirm the deleterious effect of DSP4 on the acquisition of temporal discrimination, but do not provide evidence for a role of the noradrenergic innervation of the hippocampus and neocortex in temporal working

  4. Descending serotonergic controls regulate inflammation-induced mechanical sensitivity and methyl-CpG-binding protein 2 phosphorylation in the rat superficial dorsal horn

    Directory of Open Access Journals (Sweden)

    Géranton Sandrine M

    2008-09-01

    Full Text Available Abstract Background Regulation of pain states is, in part, dependent upon plastic changes in neurones within the superficial dorsal horn. There is also compelling evidence that pain states are under the control of descending projections from the brainstem. While a number of transcription factors including Methyl-CpG-binding protein 2 (MeCP2, Zif268 and Fos have been implicated in the regulation of dorsal horn neurone sensitization following injury, modulation of their activity by descending controls has not been investigated. Results Here, we describe how descending controls regulate MeCP2 phosphorylation (P-MeCP2, known to relieve transcriptional repression by MeCP2, and Zif268 and Fos expression in the rat superficial dorsal horn, after CFA injection into the hind paw. First, we report that CFA significantly increased P-MeCP2 in Lamina I and II, from 30 min post injection, with a maximum reached after 1 h. The increase in P-MeCP2 paralleled that of Zif268 and Fos, and P-MeCP2 was expressed in large sub-populations of Zif268 and Fos expressing neurones. Serotonergic depletion of the lumbar spinal cord with 5,7 di-hydroxytryptamine creatinine sulphate (5,7-DHT reduced the inflammation evoked P-MeCP2 in the superficial dorsal horn by 57%, and that of Zif268 and Fos by 37.5% and 30% respectively. Although 5,7-DHT did not change primary thermal hyperalgesia, it significantly attenuated mechanical sensitivity seen in the first 24 h after CFA. Conclusion We conclude that descending serotonergic pathways play a crucial role in regulating gene expression in the dorsal horn and mechanical sensitivity associated with an inflammatory pain state.

  5. Neurons of human nucleus accumbens

    Directory of Open Access Journals (Sweden)

    Sazdanović Maja

    2011-01-01

    Full Text Available Background/Aim. Nucleus accumbens is a part of the ventral striatum also known as a drug active brain region, especially related with drug addiction. The aim of the study was to investigate the Golgi morphology of the nucleus accumbens neurons. Methods. The study was performed on the frontal and sagittal sections of 15 human brains by the Golgi Kopsch method. We classified neurons in the human nucleus accumbens according to their morphology and size into four types: type I - fusiform neurons; type II - fusiform neurons with lateral dendrite, arising from a part of the cell body; type III - pyramidal-like neuron; type IV - multipolar neuron. The medium spiny neurons, which are mostly noted regarding to the drug addictive conditions of the brain, correspond to the type IV - multipolar neurons. Results. Two regions of human nucleus accumbens could be clearly recognized on Nissl and Golgi preparations each containing different predominant neuronal types. Central part of nucleus accumbens, core region, has a low density of impregnated neurons with predominant type III, pyramidal-like neurons, with spines on secondary branches and rare type IV, multipolar neurons. Contrary to the core, peripheral region, shell of nucleus, has a high density of impregnated neurons predominantly contained of type I and type IV - multipolar neurons, which all are rich in spines on secondary and tertiary dendritic branches. Conclusion. Our results indicate great morphological variability of human nucleus accumbens neurons. This requires further investigations and clarifying clinical significance of this important brain region.

  6. Activation of transgenic estrogen receptor-beta by selected phytoestrogens in a stably transduced rat serotonergic cell line.

    Science.gov (United States)

    Amer, Dena A M; Kretzschmar, Georg; Müller, Nicole; Stanke, Nicole; Lindemann, Dirk; Vollmer, Günter

    2010-06-01

    Many flavonoids, a major group of phenolic plant-derived secondary metabolites, are known to possess estrogen-like bioactivities. However, little is known about their estrogenic properties in the central nervous system due to the lack of suitable cellular models expressing sufficient amounts of functional estrogen receptor beta (ERbeta). To overcome this deficit, we have created a cellular model, which is serotonergic in origin, to study properties of estrogenic substances by stably transducing RN46A-B14 cells derived from raphe nuclei region of the rat brain with a lentiviral vector encoding a human ERbeta. We clearly showed that the transgenic human ERbeta is a spontaneously expressed and a functional receptor. We have further assessed the estrogenicity of three different isoflavones and four different naringenin-type flavanones in this cell line utilizing a luciferase reporter gene assay. Genistein (GEN), Daidzein (DAI), Equol (EQ), Naringenin (NAR) and 8-prenylnaringenin (8-PN) showed strong estrogenic activity in a concentration-dependent manner as compared to 7-(O-prenyl)naringenin-4'-acetate (7-O-PN) which was only slightly estrogenic and 6-(1,1-dimethylallyl)naringenin (6-DMAN) that neither showed estrogenic nor anti-estrogenic activity in our model. All observed effects could be antagonized by the anti-estrogen fulvestrant. Moreover, co-treatment of cells with 17beta-estradiol (E2) and either GEN or DAI showed a slight additive effect as compared to EQ. On the other hand, 8-PN in addition to 7-O-PN, but not NAR and 6-DMAN, were able to slightly antagonize the responses triggered by E2. Our newly established cellular model may prove to be a useful tool in explicating basic physiological properties of ERbeta in the brain and may help unravel molecular and cellular mechanisms involved in serotonergic mood regulation by estrogen or potential plant-derived secondary metabolites.

  7. Serotonergic signaling inhibits hyperalgesia induced by spinal cord damage.

    Science.gov (United States)

    Horiuchi, Hideki; Ogata, Tadanori; Morino, Tadao; Takeba, Jun; Yamamoto, Haruyasu

    2003-02-14

    Although dysesthesia is one of the most serious problems in patients with spinal cord injury, most of them being unresponsive to conventional treatments. In this study, we established a rat thoracic spinal cord mild-compression model that revealed thermal hyperalgesia in the hind limb. The thoracic spinal cord was compressed gently, using a 20 g weight for 20 min. The withdrawal latency of the thermal stimulation of the bilateral hind-limb was monitored using Hargreaves' Plantar test apparatus. In this model, thermal-hyperalgesia was observed for 1 week after the injury. The spinal cord injury-induced thermal-hyperalgesia was mimicked by the intrathecal application of metergoline, a non-selective 5-HT antagonist, 1-(2-methoxyphenyl)-4-[4-(2-phthalimido) butyl]-piperazine hydrobromide (NAN190), a selective 5-HT1 antagonist, and 3-tropanyl-3,5-dichlorobenzoate (MDL72222), a selective 5-HT3 antagonist. Intraperitoneal application of fluvoxamine maleate, a selective serotonin reuptake inhibitor, reduced the intensity of hyperalgesia induced by spinal cord injury. The inhibitory effect of fluvoxamine maleate on thermal hyperalgesia was prevented by the application of the aforementioned nonselective or selective 5-HT receptor antagonists. Intrathecal application of fluvoxamine maleate and selective 5-HT receptor agonists, i.e., 8-hydroxy-2-(di-n-proplyamino)-tetralin hydrobromide (8-OH-DPAT: 5HT-1 selective) and 2-methyl-5-hydroxytryptamine maleate (2-m-5-HT: 5HT-3 selective), inhibited the spinal cord injury-induced hyperalgesia. These results suggest that the change in the descending serotonergic signal plays an important role in hyperalgesia after the spinal cord injury, and that the application of selective serotonin reuptake inhibitors will be one of the candidates for new therapeutic methods against post-spinal cord injury dysesthesia.

  8. Serotonergic mediated body mass index changes in Parkinson's disease.

    Science.gov (United States)

    Politis, Marios; Loane, Clare; Wu, Kit; Brooks, David J; Piccini, Paola

    2011-09-01

    More than 50% of patients with Parkinson's disease (PD) are expected to show abnormalities with their weight in a process that starts several years before the diagnosis. The serotonergic (5-HT) system has been proposed to regulate appetite and the 5-HT transporter (SERT) is a key modulator of 5-HT metabolism. Here, we hypothesized that a dysfunctional 5-HT system could be responsible for alterations of weight in PD and we sought to investigate this in vivo. Thirty four PD patients had Body Mass Index (BMI) changes monitored over a 12-month period and one positron emission tomography (PET) brain scan with (11)C-DASB, a selective marker of SERT availability, during their second clinical assessment. Results were compared with those of a group of 10 normal controls. Half (17) of the PD patients showed abnormal BMI changes over the 12-month period; 12 lost while 5 gained weight. PD patients with abnormal BMI changes showed significantly raised (11)C-DASB binding in rostral raphe nuclei, hypothalamus, caudate nucleus and ventral striatum compared to cases with no significant BMI changes. (11)C-DASB binding in other regions was similarly decreased in the PD BMI subgroups compared to normal controls. BMI gainers showed significantly raised (11)C-DASB binding in anterior cingulate cortex (ACC) compared to BMI losers. Our findings suggest that abnormal BMI changes over a 12-month period are linked with relatively raised SERT availability in PD on an overall background of decreased 5-HT function. The regions implicated are the rostral raphe nuclei and its connections to limbic and cognitive areas. It is conceivable that 5-HT agents could help alleviate abnormal changes in BMI in PD.

  9. Serotonergic Hyperactivity as a Potential Factor in Developmental, Acquired and Drug-Induced Synesthesia

    Directory of Open Access Journals (Sweden)

    Berit eBrogaard

    2013-10-01

    Full Text Available Though synesthesia research has seen a huge growth in recent decades, and tremendous progress has been made in terms of understanding the mechanism and cause of synesthesia, we are still left mostly in the dark when it comes to the mechanistic commonalities (if any among developmental, acquired and drug-induced synesthesia. We know that many forms of synesthesia involve aberrant structural or functional brain connectivity. Proposed mechanisms include direct projection and disinhibited feedback mechanisms, in which information from two otherwise structurally or functionally separate brain regions mix. We also know that synesthesia sometimes runs in families. However, it is unclear what causes its onset. Studies of psychedelic drugs, such as psilocybin, LSD and mescaline, reveal that exposure to these drugs can induce synesthesia. One neurotransmitter suspected to be central to the perceptual changes is serotonin. Excessive serotonin in the brain may cause many of the characteristics of psychedelic intoxication. Excessive serotonin levels may also play a role in synesthesia acquired after brain injury. In brain injury sudden cell death floods local brain regions with serotonin and glutamate. This neurotransmitter flooding could perhaps result in unusual feature binding. Finally, developmental synesthesia that occurs in individuals with autism may be a result of alterations in the serotonergic system, leading to a blockage of regular gating mechanisms. I conclude on these grounds that one commonality among at least some cases of acquired, developmental and drug-induced synesthesia may be the presence of excessive levels of serotonin, which increases the excitability and connectedness of sensory brain regions.

  10. Serotonin reciprocally regulates melanocortin neurons to modulate food intake.

    Science.gov (United States)

    Heisler, Lora K; Jobst, Erin E; Sutton, Gregory M; Zhou, Ligang; Borok, Erzsebet; Thornton-Jones, Zoe; Liu, Hong Yan; Zigman, Jeffrey M; Balthasar, Nina; Kishi, Toshiro; Lee, Charlotte E; Aschkenasi, Carl J; Zhang, Chen-Yu; Yu, Jia; Boss, Olivier; Mountjoy, Kathleen G; Clifton, Peter G; Lowell, Bradford B; Friedman, Jeffrey M; Horvath, Tamas; Butler, Andrew A; Elmquist, Joel K; Cowley, Michael A

    2006-07-20

    The neural pathways through which central serotonergic systems regulate food intake and body weight remain to be fully elucidated. We report that serotonin, via action at serotonin1B receptors (5-HT1BRs), modulates the endogenous release of both agonists and antagonists of the melanocortin receptors, which are a core component of the central circuitry controlling body weight homeostasis. We also show that serotonin-induced hypophagia requires downstream activation of melanocortin 4, but not melanocortin 3, receptors. These results identify a primary mechanism underlying the serotonergic regulation of energy balance and provide an example of a centrally derived signal that reciprocally regulates melanocortin receptor agonists and antagonists in a similar manner to peripheral adiposity signals.

  11. Postnatal Development of Hippocampal and Neocortical Cholinergic and Serotonergic Innervation in Rat : Effects of Nitrite-Induced Prenatal Hypoxia and Nimodipine Treatment

    NARCIS (Netherlands)

    Nyakas, C.; Buwalda, B.; Kramers, R.J.K.; Traber, J.; Luiten, P.G.M.

    1994-01-01

    Postnatal development of ingrowing cholinergic and serotonergic fiber patterns were studied in the rat hippocampus and parietal cortex employing a histochemical procedure for acetylcholinesterase as a cholinergic fiber marker, and immunocytochemistry of serotonin for serotonergic fiber staining. The

  12. Dopamine modulates two potassium currents and inhibits the intrinsic firing properties of an identified motor neuron in a central pattern generator network.

    Science.gov (United States)

    Kloppenburg, P; Levini, R M; Harris-Warrick, R M

    1999-01-01

    The two pyloric dilator (PD) neurons are components [along with the anterior burster (AB) neuron] of the pacemaker group of the pyloric network in the stomatogastric ganglion of the spiny lobster Panulirus interruptus. Dopamine (DA) modifies the motor pattern generated by the pyloric network, in part by exciting or inhibiting different neurons. DA inhibits the PD neuron by hyperpolarizing it and reducing its rate of firing action potentials, which leads to a phase delay of PD relative to the electrically coupled AB and a reduction in the pyloric cycle frequency. In synaptically isolated PD neurons, DA slows the rate of recovery to spike after hyperpolarization. The latency from a hyperpolarizing prestep to the first action potential is increased, and the action potential frequency as well as the total number of action potentials are decreased. When a brief (1 s) puff of DA is applied to a synaptically isolated, voltage-clamped PD neuron, a small voltage-dependent outward current is evoked, accompanied by an increase in membrane conductance. These responses are occluded by the combined presence of the potassium channel blockers 4-aminopyridine and tetraethylammonium. In voltage-clamped PD neurons, DA enhances the maximal conductance of a voltage-sensitive transient potassium current (IA) and shifts its Vact to more negative potentials without affecting its Vinact. This enlarges the "window current" between the voltage activation and inactivation curves, increasing the tonically active IA near the resting potential and causing the cell to hyperpolarize. Thus DA's effect is to enhance both the transient and resting K+ currents by modulating the same channels. In addition, DA enhances the amplitude of a calcium-dependent potassium current (IO(Ca)), but has no effect on a sustained potassium current (IK(V)). These results suggest that DA hyperpolarizes and phase delays the activity of the PD neurons at least in part by modulating their intrinsic postinhibitory recovery

  13. 大鼠中枢内源性镇痛系统内GABAB受体与5-HT共存神经元的观察%Co-localization of GABAB receptor and serotonin in neurons of central endogenous pain control system of rats

    Institute of Scientific and Technical Information of China (English)

    闫励; 赵华; 李云庆

    2001-01-01

    目的观察GABAB受体(GABABR)与5-HT在大鼠中脑导水管周围灰质(PAG)、中缝核簇和巨细胞网状核α部(GiA)神经元内的共存. 方法 GABABR和 5 -HT及GABABR5-HT和GABA特异性抗体的免疫荧光组织化学双重及三重染色技术. 结果 GABABR/5-HT双标神经元胞体较密集地见于中缝背核、中缝正中核、中缝桥核、中缝大核、中缝苍白核、中缝隐核. 此外,PAG和GiA内也可见双标神经元. GABA样阳性终末与GABABR/5-HT双标神经元的胞体和树突形成密切接触. 结论 PAG, 中缝核簇和GiA内的5 -HT能神经元几乎均呈GABABR样阳性;GABA能终末与GABAB受体/5-HT双标神经元形成密切接触;GABA可能通过GABAB受体调节5-HT能神经元的活动,参与对伤害性信息传递的调控.%AIM To investigate the co-localization of GABA B receptor (GABABR) and serotonin (5-HT) in neurons of the midbrain periaqueductal gray (PAG), raphe nuclei and g igantocellular reticular nucleus pars α (GiA) of the rat. METHODS Im munofluorescence histochemical double- or triple-staining technique was used with specific anti bodies against GABABR and 5-HT or GABABR, 5-HT and GABA. RESULTS Densely stained GABA BR- and 5-HT-like immunoreactive double-labelled neuronal cell bodies were observed in the dorsal raphe nucleus (DR), median raphe nucleus (MnR), pontine raphe nucleus (PnR), nucleus raphe mag nus (NRM), nucleus raphe obscurus (ROb) and nucleus raphe pallidus (RPa). Additionally, GAB ABR/5-HT double-labelled neuronal cell bodies were also found in the PAG and GiA. GABA- like immunoreactive terminals were found to be in close appositions with GABABR/5- HT double-labelled neuronal cell bodies and proximal dendrites. CONCLUSION GABABR and 5-HT co-exist in majority of the serotonergic neurons in the PAG, raphe nuclei and GiA; GABA-ergic terminals form close contacts with GABABR/5-HT double-labeled neurons; GABA might regulate the activities of serotonergic

  14. Central 5-HT4 receptor binding as biomarker of serotonergic tonus in humans

    DEFF Research Database (Denmark)

    Haahr, M E; Fisher, P M; Jensen, C G

    2014-01-01

    levels, is associated with a decline in brain 5-HT4R binding. A total of 35 healthy men were studied in a placebo-controlled, randomized, double-blind study. Participants were assigned to receive 3 weeks of oral dosing with placebo or fluoxetine, 40 mg per day. Brain 5-HT4R binding was quantified...... at baseline and at follow-up with [(11)C]SB207145 positron emission tomography (PET). Three weeks of intervention with fluoxetine was associated with a 5.2% reduction in brain 5-HT4R binding (P=0.017), whereas placebo intervention did not change 5-HT4R binding (P=0.52). Our findings are consistent...

  15. Serotonergic control of the hippocampus via local inhibitory interneurons.

    OpenAIRE

    Freund, T F; Gulyás, A I; Acsády, L.; Görcs, T; Tóth, K

    1990-01-01

    Information flow and processing in hippocampal neuronal networks is determined by a wide range of inhibitory mechanisms [e.g., feedforward or feedback, gamma-aminobutyrate (GABA) A or B receptor-mediated, perisomatic shunting, or distal dendritic inhibition], each subserving specialized functions. These forms of local inhibition are mediated by morphologically and neurochemically well-defined, mostly GABA-containing, interneurons, which control large populations of principal cells through the...

  16. Anti-hyperalgesic effects of anti-serotonergic compounds on serotonin- and capsaicin-evoked thermal hyperalgesia in the rat.

    Science.gov (United States)

    Loyd, D R; Chen, P B; Hargreaves, K M

    2012-02-17

    The peripheral serotonergic system has been implicated in the modulation of an array of pain states, from migraine to fibromyalgia; however, the mechanism by which serotonin (5HT) induces pain is unclear. Peripherally released 5HT induces thermal hyperalgesia, possibly via modulation of the transient receptor potential V1 (TRPV1) channel, which is gated by various noxious stimuli, including capsaicin. We previously reported in vitro that 5HT increases calcium accumulation in the capsaicin-sensitive population of sensory neurons with a corresponding increase in proinflammatory neuropeptide release, and both are antagonized by pretreatment with 5HT(2A) and 5HT(3) antagonists, as well as the anti-migraine drug sumatriptan. In the current study, we extended these findings in vivo using the rat hind paw thermal assay to test the hypothesis that peripheral 5HT enhances TRPV1-evoked thermal hyperalgesia that can be attenuated with 5HT(2A) and 5HT(3) receptor antagonists, as well as sumatriptan. Thermal hyperalgesia and edema were established by 5HT injection (0.1-10 nmol/100 μl) into the rat hind paw, and the latency to paw withdrawal (PWL) from noxious heat was determined. Rats were then pretreated with either 5HT before capsaicin (3 nmol/10 μl), the 5HT(2A) receptor antagonist ketanserin or the 5HT(3) receptor antagonist granisetron (0.0001-0.1 nmol/100 μl) before 5HT and/or capsaicin, or the 5HT(1B/1D) receptor agonist sumatriptan (0.01-1 nmol/100 μl) before capsaicin, and PWL was determined. We report that 5HT pretreatment enhances TRPV1-evoked thermal hyperalgesia, which is attenuated with local pretreatment with ketanserin, granisetron, or sumatriptan. We also report that peripheral 5HT induced a similar magnitude of thermal hyperalgesia in male and female rats. Overall, our results provide in vivo evidence supporting an enhancing role of 5HT on TRPV1-evoked thermal hyperalgesia, which can be attenuated by peripheral serotonergic intervention.

  17. 大鼠延髓背角内5-羟色胺、脑啡肽、γ-氨基丁酸、甘氨酸或P-物质能终末与钙结合蛋白阳性神经元间的联系%CONNECTIONS BETWEEN SEROTONERGIC, ENKEPHALINERGIC,GABAERGIC, GLYCINERGIC, SUBSTANCE P-ERGIC TERMINALS AND CALCIUM BINDING PROTEINS-CONTAINING NOCICEPTIVE NEURONS IN RAT MEDULLARY DORSAL HORN

    Institute of Scientific and Technical Information of China (English)

    李辉; 吴乐; 李云庆

    2006-01-01

    CB(calbindin-D28k),CR(calretinin)和PV(parvalbumin)是最常见的3种钙结合蛋白(calcium-binding proteins,CaBPs).本研究首先观察了面口部给予伤害性刺激诱发大鼠延髓背角(又称三叉神经脊束核尾侧亚核)神经元表达FOS蛋白的状况;然后通过免疫荧光组织化学技术检测这些神经元内是否含有CaBPs(CB、CR和PV);最后通过免疫荧光和免疫电镜染色技术观察5-HT、GABA、甘氨酸转运体2(glycine transporter 2,GlvT2)、脑啡肽(enkephalin,ENK)或SP与CaBPs/FOS双标神经元间的联系.在光镜下可观察到:(1)FOS阳性神经元在延髓背角各层均有分布,以Ⅱ层最为密集;(2)大多数CB、CR或PV阳性神经元位于Ⅱ层,余者分布在Ⅰ层和Ⅲ层;(3)5-HT、GABA、GlyT2,ENK及SP阳性纤维和终末主要位于延髓背角浅层(4)部分FOS阳性神经元同时呈CB、CR或PV阳性;(5)5-HT、GABA、GlyT2或ENK阳性终末分别与FOS/CB、FOS/CR或FOS/PV双标神经元形成密切接触;(6)SP阳性终末与5-HT、GABA、GlyT2或ENK阳性终末同时与CB、CR或PV阳性神经元形成密切接触.在电镜下观察到5-HT、GABA、GlyT2或ENK阳性终末与CB、CR或PV阳性神经元主要形成对称型(抑制性)突触联系.这些结果提示在大鼠延髓背角,5-HT、GABA、甘氨酸或ENK可能通过抑制含钙结合蛋白的伤害性感受神经元来调节面口部伤害性信息的传递.%Calbindin-D28k (CB), calretinin (CR) and parvalbumin (PV) are the most common calcium-binding proteins (CaBPs). In the present study, FOS immunoreactivity was first induced in neurons of the medullary dorsal horn (MDH) of the rat by noxious orofacial stimulation; CaBPs (CB, CR and PV) in these neurons were then identified by imumunofluorescence histochemistry, and then, in addition, afferents to CaBPs/FOS double-labeled neurons were showed by immunofluorescence histochemical staining for the γ-aminobutyric acid (GABA) , glycine transporter 2 (GlyT2) , enkephalin (ENK) , serotonin

  18. The effects of increased serotonergic activity on human sensory gating and its neural generators

    DEFF Research Database (Denmark)

    Frederiksen, Kristian Steen; Oranje, Bob; Wienberg, Malene

    2008-01-01

    of P50 suppression are sparse. OBJECTIVE: The objective of this study was to study the effects of increased serotonergic activity on parameters of P50 suppression in healthy volunteers. MATERIALS AND METHODS: In a double-blind placebo-controlled crossover design, 21 healthy male volunteers received...

  19. Carnosine reverses the aging-induced down regulation of brain regional serotonergic system.

    Science.gov (United States)

    Banerjee, Soumyabrata; Ghosh, Tushar K; Poddar, Mrinal K

    2015-12-01

    The purpose of the present investigation was to study the role of carnosine, an endogenous dipeptide biomolecule, on brain regional (cerebral cortex, hippocampus, hypothalamus and pons-medulla) serotonergic system during aging. Results showed an aging-induced brain region specific significant (a) increase in Trp (except cerebral cortex) and their 5-HIAA steady state level with an increase in their 5-HIAA accumulation and declination, (b) decrease in their both 5-HT steady state level and 5-HT accumulation (except cerebral cortex). A significant decrease in brain regional 5-HT/Trp ratio (except cerebral cortex) and increase in 5-HIAA/5-HT ratio were also observed during aging. Carnosine at lower dosages (0.5-1.0μg/Kg/day, i.t. for 21 consecutive days) didn't produce any significant response in any of the brain regions, but higher dosages (2.0-2.5μg/Kg/day, i.t. for 21 consecutive days) showed a significant response on those aging-induced brain regional serotonergic parameters. The treatment with carnosine (2.0μg/Kg/day, i.t. for 21 consecutive days), attenuated these brain regional aging-induced serotonergic parameters and restored towards their basal levels that observed in 4 months young control rats. These results suggest that carnosine attenuates and restores the aging-induced brain regional down regulation of serotonergic system towards that observed in young rats' brain regions.

  20. Dorsal border periaqueductal gray neurons project to the area directly adjacent to the central canal ependyma of the C4-T8 spinal cord in the cat

    NARCIS (Netherlands)

    Mouton, LJ; Kerstens, L; VanderWant, J; Holstege, G

    1996-01-01

    In a previous study horseradish peroxidase (HRP) injections in the upper thoracic and cervical spinal cord revealed some faintly labeled small neurons at the dorsal border of the periaqueductal gray (PAG). The present light microscopic and electronmicroscopic tracing study describes the precise loca

  1. Opposite effects of 5-HT/AKH and octopamine on the crop contractions in adult Drosophila melanogaster: Evidence of a double brain-gut serotonergic circuitry

    Science.gov (United States)

    Picciau, Lorenzo; Murru, Ludovico; Stoffolano, John G.

    2017-01-01

    This study showed that in adult Drosophila melanogaster, the type of sugar—either present within the crop lumen or in the bathing solution of the crop—had no effect on crop muscle contraction. What is important, however, is the volume within the crop lumen. Electrophysiological recordings demonstrated that exogenous applications of serotonin on crop muscles increases both the amplitude and the frequency of crop contraction rate, while adipokinetic hormone mainly enhances the crop contraction frequency. Conversely, octopamine virtually silenced the overall crop activity. The present study reports for the first time an analysis of serotonin effects along the gut-brain axis in adult D. melanogaster. Injection of serotonin into the brain between the interocellar area shows that brain applications of serotonin decrease the frequency of crop activity. Based on our results, we propose that there are two different, opposite pathways for crop motility control governed by serotonin: excitatory when added in the abdomen (i.e., directly bathing the crop) and inhibitory when supplied within the brain (i.e., by injection). Finally, our results point to a double brain-gut serotonergic circuitry suggesting that not only the brain can affect gut functions, but the gut can also affect the central nervous system. On the basis of our results, and data in the literature, a possible mechanism for these two discrete serotonergic functions is suggested. PMID:28334024

  2. An integrated serotonin and octopamine neuronal circuit directs the release of an endocrine signal to control C. elegans body fat.

    Science.gov (United States)

    Noble, Tallie; Stieglitz, Jonathan; Srinivasan, Supriya

    2013-11-01

    Serotonin (5-hydroxytryptamine, 5-HT) is an ancient and conserved neuromodulator of energy balance. Despite its importance, the neural circuits and molecular mechanisms underlying 5-HT-mediated control of body fat remain poorly understood. Here, we decipher the serotonergic neural circuit for body fat loss in C. elegans and show that the effects of 5-HT require signaling from octopamine, the invertebrate analog of adrenaline, to sustain body fat loss. Our results provide a potential molecular explanation for the long-observed potent effects of combined serotonergic and adrenergic weight loss drugs. In metabolic tissues, we find that the conserved regulatory adipocyte triglyceride lipase ATGL-1 drives serotonergic fat loss. We show that the serotonergic chloride channel MOD-1 relays a long-range endocrine signal from C. elegans body cavity neurons to control distal ATGL-1 function, via the nuclear receptor NHR-76. Our findings establish a conserved neuroendocrine axis operated by neural serotonergic and adrenergic-like signaling to regulate body fat.

  3. An Integrated Serotonin and Octopamine Neuronal Circuit Directs The Release of An Endocrine Signal to Control C. elegans Body Fat

    Science.gov (United States)

    Noble, Tallie; Stieglitz, Jonathan; Srinivasan, Supriya

    2013-01-01

    SUMMARY Serotonin (5-hydroxytryptamine, 5-HT) is an ancient and conserved neuromodulator of energy balance. Despite its importance, the neural circuits and molecular mechanisms underlying 5-HT-mediated control of body fat remain poorly understood. Here we decipher the serotonergic neural circuit for body fat loss in C. elegans and show that the effects of 5-HT require signaling from octopamine, the invertebrate analog of adrenaline, to sustain body fat loss. Our results provide a potential molecular explanation for the long-observed potent effects of combined serotonergic and adrenergic weight loss drugs. In metabolic tissues we find that the conserved regulatory adipocyte triglyceride lipase ATGL-1 drives serotonergic fat loss. We show that the serotonergic chloride channel MOD-1 relays a long-range endocrine signal via C. elegans body cavity neurons to control distal ATGL-1 function, via the nuclear receptor NHR-76. Our findings establish a conserved neuroendocrine axis operated by neural serotonergic and adrenergic-like signaling, to regulate body fat. PMID:24120942

  4. Visual input controls the functional activity of goldfish Mauthner neuron through the reciprocal synaptic mechanism.

    Science.gov (United States)

    Moshkov, Dmitry A; Shtanchaev, Rashid S; Mikheeva, Irina B; Bezgina, Elena N; Kokanova, Nadezhda A; Mikhailova, Gulnara Z; Tiras, Nadezhda R; Pavlik, Lyubov' L

    2013-03-01

    Goldfish are known to exhibit motor asymmetry due to functional asymmetry of their Mauthner neurons that induce the turns to the right or left during free swimming. It has been previously found that if the less active neuron is subjected to prolonged aimed visual stimulation via its ventral dendrite, the motor asymmetry of goldfish is inverted, testifying that this neuron becomes functionally dominant, while the size of the ventral dendrite under these conditions is reduced 2-3 times compared to its counterpart in mirror neuron. Earlier it has been also revealed that training optokinetic stimulation induces adaptation, a substantial resistance of both fish motor asymmetry and morphofunctional state of Mauthner neurons against prolonged optokinetic stimulation. The aim of this work was to study the cellular mechanisms of the effect of an unusual visual afferent input on goldfish motor asymmetry and Mauthner neuron function in norm and under adaptation. It was shown that serotonin applied onto Mauthner neurons greatly reduces their activity whereas its antagonist ondansetron increases it. Against the background of visual stimulation, serotonin strengthens functional asymmetry between neurons whereas ondansetron smoothes it. Taken together these data suggest the involvement of serotonergic excitatory synaptic transmission in the regulation of Mauthner neurons by vision. Ultrastructural study of the ventral dendrites after prolonged optokinetic stimulation has revealed depletions of numeral axo-axonal synapses with specific morphology, identified by means of immunogold label as serotonergic ones. These latter in turn are situated mainly on shaft boutons, which according to specific ultrastructural features are assigned to axo-dendritic inhibitory synapses. Thus, the excitatory serotonergic synapses seem to affect Mauthner neuron indirectly through inhibitory synapses. Further, it was morphometrically established that adaptation is accompanied by the significant

  5. Effect of a new series of bicyclic compounds with potential thymoleptic properties on the reserpine-resistant uptake mechanism of central and peripheral monoamine neurones in vivo and in vitro.

    Science.gov (United States)

    Carlsson, A; Fuxe, K; Hamberger, B; Malmfors, T

    1969-05-01

    1. Bicyclic compounds with potential thymoleptic properties (Lu-compounds) have recently become available, and their effects on the membrane pumps of the central and peripheral monoamine neurones have now been tested and compared with those of the tricyclic antidepressant drugs.2. Biochemical and histochemical in vivo studies have been performed. The possible blocking action of Lu-compounds on the noradrenaline (NA) and 5-hydroxytryptamine (5-HT) displacement caused by 4,alpha-dimethyl-metatyramine (H 77/77) and 4-methyl-alpha-ethyl-meta-tyramine (H 75/12), respectively, has been studied, and a positive result has been taken as evidence for membrane pump blocking activity. No certain effects were obtained on the 5-HT displacement induced by H 75/12, whereas a partial blockade of the NA displacement by H 77/77 in central NA neurones was obtained after most of the Lu-compounds (Lu-3-010, 3-049, 3-092, 4-012) and especially after the thiophthalane derivative Lu 5-003. The ED50 of the latter drug was around 8 mg/kg, that is, somewhere between protriptyline (ED50 4 mg/kg) and desipramine (ED50 15 mg/kg) in potency.3. Histochemical in vivo studies on the rat iris revealed that Lu 5-003 and especially the corresponding phthalane derivative Lu 3-010 were potent in blocking the uptake of alpha-methyl-NA in the adrenergic nerve terminals of the iris. The other Lu-compounds were less active. The releasing effects of the Lu-compounds on the extragranular accumulation of alpha-methyl-NA in the adrenergic terminals were weak compared with membrane blocking activity.4. In vitro studies on the central and peripheral catecholamine (CA) neurones have also been performed. In the same way as, for example, protriptyline the Lu-compounds only blocked accumulation of alpha-methyl-NA in the NA terminals but not in the dopamine (DA) nerve terminals. Lu 5-003 and Lu 3-010 were the most potent of the Lu-drugs when added in vitro. The Lu-drugs were also injected in vivo after which the effect

  6. Antinociceptive effects of neurotropin in a rat model of central neuropathic pain: DSP-4 induced noradrenergic lesion.

    Science.gov (United States)

    Kudo, Takashi; Kushikata, Tetsuya; Kudo, Mihoko; Kudo, Tsuyoshi; Hirota, Kazuyoshi

    2011-09-26

    Neurotropin is a nonprotein extract isolated from inflamed skin of rabbits inoculated with vaccinia virus, and used for treatment of neuropathic pain. In the present study, we have determined whether neurotropin could exert antinociceptive action using the central neuropathic pain model that we recently established. Rats were randomly allocated to 3 groups: Sham group (n=20), DSP-4 [N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine] group (50mg/kg ip, n=18), and DSP-4+5,7-DHT [5,7-dihydroxytryptamine] group (ip DSP-4 50mg/kg+icv 5,7-DHT 200μg, n=18). In Sham, DSP-4 and DSP-4+5,7-DHT groups, the effects of ip neurotropin (100NU/Kg) on hot-plate latency in rats with no lesion, noradrenergic neuron depletion and both noradrenergic and serotonergic neuronal depletion were studied, respectively. Rats in each group were subdivided equally to 2 subgroups: saline and neurotropin. After completion of the hot-plate tests, each rat was decapitated, the cerebral cortex was dissected from its internal structure for measurement of norepinephrine contents. Hot-plate latency significantly decreased by ∼40% 10 days after ip DSP-4 or after ip DSP-4 and 5,7-DHT. Norepinephrine contents in DSP-4 treated rats (55.6±6.3ng/ng tissue) and DSP-4+5,7-DHT treated rats (35.3±6.3ng/ng tissue) were significantly lower than those in intact rats (131.6±5.7ng/ng tissue, p<0.01). Neurotropin significantly increased the area under the curve (AUC) of the hot-plate latency in the DSP-4 and DSP-4+5,7-DHT groups but not in the Sham group. There was a significant correlation between AUC and norepinephrine contents in saline subgroup (p<0.01, r=0.597) but not in neurotropin subgroup in DSP-4 group. Neurotropin exerted an antinociceptive effect in DSP-4 induced central neuropathic pain. The present data suggest neuronal pathways other than descending inhibitory noradrenergic and serotonergic systems may be involved in neurotropin mediated antinociception.

  7. Channeling the Central Dogma.

    Science.gov (United States)

    Calabrese, Ronald L

    2014-05-21

    How do neurons and networks achieve their characteristic electrical activity, regulate this activity homeostatically, and yet show population variability in expression? In this issue of Neuron, O'Leary et al. (2014) address some of these thorny questions in this theoretical analysis that starts with the Central Dogma.

  8. Neuronal networks: enhanced feedback feeds forward.

    Science.gov (United States)

    Calabrese, Ronald L

    2012-09-25

    Modulatory projection neurons gate neuronal networks, such as those comprising motor central pattern generators; in turn, they receive feedback from the networks they gate. A recent study has shown that, in the crab stomatogastric ganglion, this feedback is also subject to modulation: the enhanced feedback feeds forward through the projection neurons to modify circuit output.

  9. Central nervous system resuscitation

    DEFF Research Database (Denmark)

    McIntosh, T K; Garde, E; Saatman, K E;

    1997-01-01

    Traumatic injury to the central nervous system induces delayed neuronal death, which may be mediated by acute and chronic neurochemical changes. Experimental identification of these injury mechanisms and elucidation of the neurochemical cascade following trauma may provide enhanced opportunities ...

  10. Central nervous system resuscitation

    DEFF Research Database (Denmark)

    McIntosh, T K; Garde, E; Saatman, K E

    1997-01-01

    Traumatic injury to the central nervous system induces delayed neuronal death, which may be mediated by acute and chronic neurochemical changes. Experimental identification of these injury mechanisms and elucidation of the neurochemical cascade following trauma may provide enhanced opportunities...

  11. [Neuronal network].

    Science.gov (United States)

    Langmeier, M; Maresová, D

    2005-01-01

    Function of the central nervous system is based on mutual relations among the nerve cells. Description of nerve cells and their processes, including their contacts was enabled by improvement of optical features of the microscope and by the development of impregnation techniques. It is associated with the name of Antoni van Leeuwenhoek (1632-1723), J. Ev. Purkyne (1787-1869), Camillo Golgi (1843-1926), and Ramón y Cajal (1852-1934). Principal units of the neuronal network are the synapses. The term synapse was introduced into neurophysiology by Charles Scott Sherrington (1857-1952). Majority of the interactions between nerve cells is mediated by neurotransmitters acting at the receptors of the postsynaptic membrane or at the autoreceptors of the presynaptic part of the synapse. Attachment of the vesicles to the presynaptic membrane and the release of the neurotransmitter into the synaptic cleft depend on the intracellular calcium concentration and on the presence of several proteins in the presynaptic element.

  12. The impact of environmental enrichment on sex-specific neurochemical circuitries - effects on brain-derived neurotrophic factor and the serotonergic system.

    Science.gov (United States)

    Chourbaji, S; Hörtnagl, H; Molteni, R; Riva, M A; Gass, P; Hellweg, R

    2012-09-18

    Experimental evidence in mice indicates that environmental conditions affect females and males differently. However, in a recent study analyzing the heterozygous mutation of brain-derived neurotrophic factor (BDNF), both sexes presented a similar emotional phenotype, which became obvious only under impoverished, but not in enriched conditions suggesting an "enrichment-induced" rescue. To investigate the basis of this behavioral "rescue" effect, we analyzed neurochemical changes (BDNF expression, serotonergic changes, and corticosterone) in the hippocampus, frontal cortex and hypothalamus of animals housed under respective conditions. In male mice, enrichment induced an increase of BDNF expression in the hippocampus of both BDNF heterozygous (BDNF(+/-)) and wild-types. Notably, in enriched-reared BDNF(+/-) mice BDNF mRNA and protein increased to levels comparable to those of wild-types in impoverished environment. In the frontal cortex of males, only wild-types presented an enrichment-induced increase of BDNF mRNA, while no effect of environment could be detected in BDNF protein levels of the male hypothalamus. A further male-specific effect of "environment" is the significant reduction of hypothalamic 5-hydroxyindoleacetic acid in enriched-housed wild-types. In female mice, environmental enrichment did not affect BDNF expression in the hippocampus and hypothalamus. However, comparable to males, an enrichment-induced increase of BDNF mRNA was detected in the frontal cortex of wild-types only. In contrast to males, no influence of environment on serotonergic parameters was observed. Male and female corticosterone levels were neither affected by "genotype" nor by "environment". In conclusion, we propose that the rescue of the emotional phenotype by environmental enrichment in BDNF(+/-) mice is directed by distinct mechanisms in males and females. Only in male BDNF(+/-) mice the rescue is related to an increase in hippocampal BDNF expression suggesting that enrichment

  13. La plasticidad neuronal y los ejercicios dinámicos en pacientes con lesión en el sistema nervioso central

    OpenAIRE

    Peluso, Gustavo

    2013-01-01

    Este trabajo pretende sumar, a la rehabilitación de pacientes lesionados del sistema nervioso, una propuesta diferente a la visión clásica de tratamiento. Simplemente tomaremos del cerebro una de sus habilidades innatas, poniéndola a favor de nuestros pacientes. "La Plasticidad neuronal", que siempre se le atribuyó al cerebro en edades tempranas donde hay nuevas conexiones sinápticas y una mielinización creciente, hoy sabemos que aunque más limitada que en niños, permanece presente en l...

  14. The serotonergic agonists quipazine, CGS-12066A, and alpha-methylserotonin alter motor activity and induce hindlimb stepping in the intact and spinal rat fetus.

    Science.gov (United States)

    Brumley, Michele R; Robinson, Scott R

    2005-06-01

    The effects of serotonergic agonists were examined in intact and spinal fetuses, using an in vivo fetal rat preparation. On Gestational Day 20, fetuses were prepared with a midthoracic or sham spinal transection. Dose-response curves were obtained for quipazine (nonselective 5-hydroxytryptamine [5-HT] agonist; 1.0-10.0 mg/kg), CGS-12066A (5-HT-sub(1B) agonist; 1.0-30.0 mg/kg), and alpha-methylserotonin (alpha-Me-5-HT; 5-HT-sub-2 agonist; 0.2-15.0 mg/kg). During a 10-min test, each of the agonists (delivered via intraperitoneal injection) influenced fetal behavior: They increased the occurrence of head movements, mouthing, and hindlimb stepping. Quipazine and alpha-Me-5-HT also promoted hindlimb activity in spinal fetuses. Thus, stimulation of the fetal 5-HT system modulates motor activity at multiple levels of the developing central nervous system.

  15. Effect of serotonergic and catecholaminergic antagonists on mild-stress-induced excessive grooming in the rat.

    Science.gov (United States)

    Rodríguez Echandía, E L; Broitman, S T; Fóscolo, M R

    1983-12-01

    Excessive grooming was induced in male rats by two ip injections of physiological saline. This mild stressful procedure did not modify open-field locomotion in 5-min trials. Methysergide (15 mg/kg) and pizotifene (5 mg/kg), serotonergic blockers, selectively prevented the grooming response to saline without affecting locomotion. Haloperidol (.4 mg/kg) also prevented the excessive grooming. However, this dopaminergic blocker impaired locomotion. The alpha- or beta-adrenoceptor antagonists phentolamine (20 mg/kg) and l-propranolol (20 mg/kg) did not prevent the excessive grooming in response to saline and did not affect locomotion. The results suggest that some serotonergic pathways in the brain are involved in the grooming response to a mild stress and support previous findings on the role of dopaminergic systems on this activity.

  16. Influence of early stress on social abilities and serotonergic functions across generations in mice.

    Directory of Open Access Journals (Sweden)

    Tamara B Franklin

    Full Text Available Exposure to adverse environments during early development is a known risk factor for several psychiatric conditions including antisocial behavior and personality disorders. Here, we induced social anxiety and altered social recognition memory in adult mice using unpredictable maternal separation and maternal stress during early postnatal life. We show that these social defects are not only pronounced in the animals directly subjected to stress, but are also transmitted to their offspring across two generations. The defects are associated with impaired serotonergic signaling, in particular, reduced 5HT1A receptor expression in the dorsal raphe nucleus, and increased serotonin level in a dorsal raphe projection area. These findings underscore the susceptibility of social behaviors and serotonergic pathways to early stress, and the persistence of their perturbation across generations.

  17. Serotonergic Mechanisms Influence the Response to Glucocorticoid Treatment in TMJ Arthritis

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    Lars Fredriksson

    2005-01-01

    Full Text Available The aims of this study were to investigate the influence of serotonin (5-HT on the effects of intra-articular injections of glucocorticoid on pain of the temporomandibular joint (TMJ in patients with inflammatory disorders of the TMJ. The pretreatment synovial fluid 5-HT was negatively, and plasma 5-HT positively, correlated to change in TMJ pain after treatment. The pretreatment plasma 5-HT was positively correlated to change in pressure-pain threshold after treatment. In conclusion, this study shows that local and systemic serotonergic mechanisms partly determine the effect of intra-articular glucocorticoid treatment on TMJ pain in patients with chronic TMJ arthritis of systemic nature, while change in pressure-pain threshold over the TMJ is influenced by systemic serotonergic mechanisms.

  18. Effects of in vitro and in vivo lead exposure on voltage-dependent calcium channels in central neurons of Lymnaea stagnalis.

    Science.gov (United States)

    Audesirk, G

    1987-01-01

    Currents through calcium channels of members of an identified cluster of neurons (B cells) in the pond snail Lymnaea stagnalis were studied under voltage clamp. The normal physiological saline was modified to maximize the visibility of voltage-dependent calcium currents and minimize contamination by other currents. Barium was used as the charge carrier for the calcium channels. Depolarizing voltage steps induce an inward current, the magnitude of which varies with the barium concentration. In brains taken from animals not exposed in vivo to lead, in vitro addition of lead acetate to the recording medium (0.25 to 14 microM) inhibits the barium current by 59 +/- 14% (mean +/- s.d.), in a manner that is independent of the lead concentration. The magnitude of the residual current still varies with the barium concentration. The voltage dependence of the current appears to be unaffected by lead. In contrast to some other calcium-channel blockers, such as cobalt, the inhibition of barium currents by in vitro lead exposure is irreversible, at least in short-term experiments. Contrary to expectations based on these in vitro results, barium currents in B cells of animals exposed to 5 microM lead for 6 to 12 weeks in vivo were approximately twice as large as barium currents in B cells from unexposed controls, when both were recorded in lead-free saline. It is possible that chronic in vivo lead exposure causes an increase in the number of calcium channels in these neurons.

  19. Serotonerge Gene und NOS1 als Risikofaktoren für gewalttätiges Verhalten

    OpenAIRE

    Eujen, Andrea

    2009-01-01

    Persönlichkeit im Allgemeinen wird, neben Umwelteinflüssen, durch genetische Komponenten beeinflusst. Bisher konnten jedoch nur wenige funktionelle Genvarianten mit Verhaltenszügen assoziiert werden. Aggressives Verhalten als spezifisches Verhaltensmuster wird durch eine Reihe von Genvariationen beeinflusst, die in serotonerge, dopaminerge und nitrinerge Regelkreise eingreifen. Neben der genetischen Komponente prädisponieren aber hier ganz erheblich auch äußere Faktoren in der Umwelt, wie z.B...

  20. Imaging Serotonergic Fibers in the Mouse Spinal Cord Using the CLARITY/CUBIC Technique.

    Science.gov (United States)

    Liang, Huazheng; Schofield, Emma; Paxinos, George

    2016-02-26

    Long descending fibers to the spinal cord are essential for locomotion, pain perception, and other behaviors. The fiber termination pattern in the spinal cord of the majority of these fiber systems have not been thoroughly investigated in any species. Serotonergic fibers, which project to the spinal cord, have been studied in rats and opossums on histological sections and their functional significance has been deduced based on their fiber termination pattern in the spinal cord. With the development of CLARITY and CUBIC techniques, it is possible to investigate this fiber system and its distribution in the spinal cord, which is likely to reveal previously unknown features of serotonergic supraspinal pathways. Here, we provide a detailed protocol for imaging the serotonergic fibers in the mouse spinal cord using the combined CLARITY and CUBIC techniques. The method involves perfusion of a mouse with a hydrogel solution and clarification of the tissue with a combination of clearing reagents. Spinal cord tissue was cleared in just under two weeks, and the subsequent immunofluorescent staining against serotonin was completed in less than ten days. With a multi-photon fluorescent microscope, the tissue was scanned and a 3D image was reconstructed using Osirix software.

  1. Chromium picolinate modulates serotonergic properties and carbohydrate metabolism in a rat model of diabetes.

    Science.gov (United States)

    Komorowski, James R; Tuzcu, Mehmet; Sahin, Nurhan; Juturu, Vijaya; Orhan, Cemal; Ulas, Mustafa; Sahin, Kazim

    2012-10-01

    Chromium picolinate (CrPic) has shown both antidepressant and antidiabetic properties. In this study, the effects of CrPic on serotonergic properties and carbohydrate metabolism in diabetic rats were evaluated. Sixty male Sprague-Dawley rats were divided into four groups. (1) The control group received only standard diet (8 % fat). (2) The CrPic group was fed standard diet and CrPic (80 μg CrPic per kilogram body mass (b.m.)/day), for 10 weeks (microgram/kilogram b.m./day). (3) The HFD/STZ group fed a high-fat diet (HFD, 40 % fat) for 2 weeks and then received streptozotocin (STZ, 40 mg/kg, i.p.) (i.v.) HFD-STZ-CrPic group treated as the previous group and then were administered CrPic. CrPic administration to HFD/STZ-treated rats increased brain chromium levels and improved all measurements of carbohydrate metabolism and serotonergic properties (P<0.001). CrPic also significantly increased levels of insulin, tryptophan, and serotonin (P<0.001) in the serum and brain, and decreased cortisol levels in the serum (P<0.01). Except chromium levels, no significant effect of CrPic supplementation was detected on the overall measured parameters in the control group. CrPic administration was well tolerated without any adverse events. The results support the use of CrPic supplementation which improves serotonergic properties of brain in diabetes.

  2. Restoration of quinine-stimulated Fos-immunoreactive neurons in the central nucleus of the amygdala and gustatory cortex following reinnervation or cross-reinnervation of the lingual taste nerves in rats.

    Science.gov (United States)

    King, Camille Tessitore; Garcea, Mircea; Spector, Alan C

    2014-08-01

    Remarkably, when lingual gustatory nerves are surgically rerouted to inappropriate taste fields in the tongue, some taste functions recover. We previously demonstrated that quinine-stimulated oromotor rejection reflexes and neural activity (assessed by Fos immunoreactivity) in subregions of hindbrain gustatory nuclei were restored if the posterior tongue, which contains receptor cells that respond strongly to bitter compounds, was cross-reinnervated by the chorda tympani nerve. Such functional recovery was not seen if instead, the anterior tongue, where receptor cells are less responsive to bitter compounds, was cross-reinnervated by the glossopharyngeal nerve, even though this nerve typically responds robustly to bitter substances. Thus, recovery depended more on the taste field being reinnervated than on the nerve itself. Here, the distribution of quinine-stimulated Fos-immunoreactive neurons in two taste-associated forebrain areas was examined in these same rats. In the central nucleus of the amygdala (CeA), a rostrocaudal gradient characterized the normal quinine-stimulated Fos response, with the greatest number of labeled cells situated rostrally. Quinine-stimulated neurons were found throughout the gustatory cortex, but a "hot spot" was observed in its anterior-posterior center in subregions approximating the dysgranular/agranular layers. Fos neurons here and in the rostral CeA were highly correlated with quinine-elicited gapes. Denervation of the posterior tongue eliminated, and its reinnervation by either nerve restored, numbers of quinine-stimulated labeled cells in the rostralmost CeA and in the subregion approximating the dysgranular gustatory cortex. These results underscore the remarkable plasticity of the gustatory system and also help clarify the functional anatomy of neural circuits activated by bitter taste stimulation.

  3. The Visual Orientation Memory of "Drosophila" Requires Foraging (PKG) Upstream of Ignorant (RSK2) in Ring Neurons of the Central Complex

    Science.gov (United States)

    Kuntz, Sara; Poeck, Burkhard; Sokolowski, Marla B.; Strauss, Roland

    2012-01-01

    Orientation and navigation in a complex environment requires path planning and recall to exert goal-driven behavior. Walking "Drosophila" flies possess a visual orientation memory for attractive targets which is localized in the central complex of the adult brain. Here we show that this type of working memory requires the cGMP-dependent protein…

  4. Serotonin modulation of cortical neurons and networks

    Directory of Open Access Journals (Sweden)

    Pau eCelada

    2013-04-01

    Full Text Available The serotonergic pathways originating in the dorsal and median raphe nuclei (DR and MnR, respectively are critically involved in cortical function. Serotonin (5-HT, acting on postsynaptic and presynaptic receptors, is involved in cognition, mood, impulse control and motor functions by 1 modulating the activity of different neuronal types, and 2 varying the release of other neurotransmitters, such as glutamate, GABA, acetylcholine and dopamine. Also, 5-HT seems to play an important role in cortical development. Of all cortical regions, the frontal lobe is the area most enriched in serotonergic axons and 5-HT receptors. 5-HT and selective receptor agonists modulate the excitability of cortical neurons and their discharge rate through the activation of several receptor subtypes, of which the 5-HT1A, 5-HT1B, 5-HT2A and 5-HT3 subtypes play a major role. Little is known, however, on the role of other excitatory receptors moderately expressed in cortical areas, such as 5-HT2C, 5-HT4, 5-HT6 and 5-HT7. In vitro and in vivo studies suggest that 5-HT1A and 5-HT2A receptors are key players and exert opposite effects on the activity of pyramidal neurons in the medial prefrontal cortex (mPFC. The activation of 5-HT1A receptors in mPFC hyperpolarizes pyramidal neurons whereas that of 5-HT2A receptors results in neuronal depolarization, reduction of the afterhyperpolarization and increase of excitatory postsynaptic currents (EPSCs and of discharge rate. 5-HT can also stimulate excitatory (5-HT2A and 5-HT3 and inhibitory (5-HT1A receptors in GABA interneurons to modulate synaptic GABA inputs onto pyramidal neurons. Likewise, the pharmacological manipulation of various 5-HT receptors alters oscillatory activity in PFC, suggesting that 5-HT is also involved in the control of cortical network activity. A better understanding of the actions of 5-HT in PFC may help to develop treatments for mood and cognitive disorders associated with an abnormal function of the

  5. Detection of Ca2+-dependent acid phosphatase activity identifies neuronal integrity in damaged rat central nervous system after application of bacterial melanin

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    Tigran R Petrosyan

    2016-01-01

    Full Text Available The study aims to confirm the neuroregenerative effects of bacterial melanin (BM on central nervous system injury using a special staining method based on the detection of Ca2+-dependent acid phosphatase activity. Twenty-four rats were randomly assigned to undergo either unilateral destruction of sensorimotor cortex (group I; n = 12 or unilateral rubrospinal tract transection at the cervical level (C3–4 (group II; n = 12. In each group, six rats were randomly selected after surgery to undergo intramuscular injection of BM solution (BM subgroup and the remaining six rats were intramuscularly injected with saline (saline subgroup. Neurological testing confirmed that BM accelerated the recovery of motor function in rats from both BM and saline subgroups. Two months after surgery, Ca2+-dependent acid phosphatase activity detection in combination with Chilingarian's calcium adenoside triphosphate method revealed that BM stimulated the sprouting of fibers and dilated the capillaries in the brain and spinal cord. These results suggest that BM can promote the recovery of motor function of rats with central nervous system injury; and detection of Ca2+-dependent acid phosphatase activity is a fast and easy method used to study the regeneration-promoting effects of BM on the injured central nervous system.

  6. Evidence for genetic influences on neurotransmitter content of identified neurones of Lymnaea stagnalis.

    Science.gov (United States)

    Audesirk, G; Audesirk, T; McCaman, R E; Ono, J K

    1985-01-01

    Neurotransmitter content was measured in two identified giant neurones in isogenic and wild-type populations of the freshwater pond snail Lymnaea stagnalis. The paired serotonergic cerebral giant neurones (LC1 and RC1) have higher transmitter levels and less variability in inbred animals than in wild-type animals. The transmitter content of the unpaired dopaminergic right pedal giant neurone (RPeD1) does not differ between inbred and wild-type animals in either level or variability. It is proposed that serotonin content of the cerebral giant neurones is under partial genetic control, and that animals of the wild-type population may possess a number of different alleles for the genes influencing serotonin levels. Inbreeding resulted in fixation of an allele promoting high serotonin levels. This particular wild-type population is probably already isogenic for genes influencing dopamine content in the right pedal giant neurone.

  7. Multi-Scale Molecular Deconstruction of the Serotonin Neuron System.

    Science.gov (United States)

    Okaty, Benjamin W; Freret, Morgan E; Rood, Benjamin D; Brust, Rachael D; Hennessy, Morgan L; deBairos, Danielle; Kim, Jun Chul; Cook, Melloni N; Dymecki, Susan M

    2015-11-18

    Serotonergic (5HT) neurons modulate diverse behaviors and physiology and are implicated in distinct clinical disorders. Corresponding diversity in 5HT neuronal phenotypes is becoming apparent and is likely rooted in molecular differences, yet a comprehensive approach characterizing molecular variation across the 5HT system is lacking, as is concomitant linkage to cellular phenotypes. Here we combine intersectional fate mapping, neuron sorting, and genome-wide RNA-seq to deconstruct the mouse 5HT system at multiple levels of granularity-from anatomy, to genetic sublineages, to single neurons. Our unbiased analyses reveal principles underlying system organization, 5HT neuron subtypes, constellations of differentially expressed genes distinguishing subtypes, and predictions of subtype-specific functions. Using electrophysiology, subtype-specific neuron silencing, and conditional gene knockout, we show that these molecularly defined 5HT neuron subtypes are functionally distinct. Collectively, this resource classifies molecular diversity across the 5HT system and discovers sertonergic subtypes, markers, organizing principles, and subtype-specific functions with potential disease relevance.

  8. NCAM-deficient mice show prominent abnormalities in serotonergic and BDNF systems in brain - Restoration by chronic amitriptyline.

    Science.gov (United States)

    Aonurm-Helm, Anu; Anier, Kaili; Zharkovsky, Tamara; Castrén, Eero; Rantamäki, Tomi; Stepanov, Vladimir; Järv, Jaak; Zharkovsky, Alexander

    2015-12-01

    Mood disorders are associated with alterations in serotonergic system, deficient BDNF (brain-derived neurotrophic factor) signaling and abnormal synaptic plasticity. Increased degradation and reduced functions of NCAM (neural cell adhesion molecule) have recently been associated with depression and NCAM deficient mice show depression-related behavior and impaired learning. The aim of the present study was to investigate potential changes in serotonergic and BDNF systems in NCAM knock-out mice. Serotonergic nerve fiber density and SERT (serotonin transporter) protein levels were robustly reduced in the hippocampus, prefrontal cortex and basolateral amygdala of adult NCAM(-)(/-) mice. This SERT reduction was already evident during early postnatal development. [(3)H]MADAM binding experiments further demonstrated reduced availability of SERT in cell membranes of NCAM(-)(/-) mice. Moreover, the levels of serotonin and its major metabolite 5-HIAA were down regulated in the brains of NCAM(-)(/-) mice. NCAM(-)(/-) mice also showed a dramatic reduction in the BDNF protein levels in the hippocampus and prefrontal cortex. This BDNF deficiency was associated with reduced phosphorylation of its receptor TrkB. Importantly, chronic administration of antidepressant amitriptyline partially or completely restored these changes in serotonergic and BDNF systems, respectively. In conclusion, NCAM deficiency lead to prominent and persistent abnormalities in brain serotonergic and BDNF systems, which likely contributes to the behavioral and neurobiological phenotype of NCAM(-/-) mice.

  9. Serotonergic modulation of astrocytic activity in the hamster suprachiasmatic nucleus.

    Science.gov (United States)

    Glass, J D; Chen, L

    1999-01-01

    The present study was undertaken to explore the effects of central serotonin receptor activation on the expression of glial fibrillary acidic protein in the suprachiasmatic nucleus of Syrian hamsters. Immunoblot and immunohistochemical procedures were used to examine the effects of systemic application of the serotonin-1A and serotonin-7 receptor agonist, (+/-)-2-dipropyl-amino-8-hydroxyl-1,2,3,4-tetrahydronaphthalene hydrobromide (8-OH-DPAT; 3.75 mg/kg) on the contents and distribution of glial fibrillary acidic protein in the suprachiasmatic nucleus. Administration of 8-OH-DPAT at midday caused a significant reduction in immunoreactive glial fibrillary acidic protein content within 1 h of injection, compared to vehicle controls. This effect was not evident 3 h after drug injection. Treatment with 8-OH-DPAT during the late dark phase had little effect on glial fibrillary acidic protein content. The 8-OH-DPAT-induced reduction in glial fibrillary acidic protein content seen at midday was blocked partially by pretreatment with the serotonin-2 and serotonin-7 receptor antagonist, ritanserin, and more substantially by pretreatment with the serotonin-1A receptor antagonist, NAN-190. Treatment with 8-OH-DPAT also caused a significant redistribution of immunoreactive glial fibrillary acidic protein, such that the dense mesh-like appearance seen in vehicle controls was significantly reduced. The 8-OH-DPAT treatment also significantly decreased expression of polysialic acid, a cell-surface molecule associated with neural plasticity. Immunoblot assessments of glial fibrillary acidic protein contents 2 h before and 1 h after lights off revealed a significant time-of-day difference in glial fibrillary acidic protein expression, with lowest levels occurring at the latter time-point, associated with maximal endogenous serotonin release in the suprachiasmatic nucleus. Collectively, these results indicate that acute plastic changes in glial fibrillary acidic protein

  10. The principal neuronal gD-type 3-O-sulfotransferases and their products in central and peripheral nervous system tissues

    Science.gov (United States)

    Lawrence, Roger; Yabe, Tomio; HajMohammadi, Sassan; Rhodes, John; McNeely, Melissa; Liu, Jian; Lamperti, Edward D.; Toselli, Paul A.; Lech, Miroslaw; Spear, Patricia G.; Rosenberg, Robert D.; Shworak, Nicholas W.

    2007-01-01

    Within the nervous system, heparan sulfate (HS) of the cell surface and extracellular matrix influences developmental, physiologic and pathologic processes. HS is a functionally diverse polysaccharide that employs motifs of sulfate groups to selectively bind and modulate various effector proteins. Specific HS activities are modulated by 3-O-sulfated glucosamine residues, which are generated by a family of seven 3-O-sulfotransferases (3-OSTs). Most isoforms we herein designate as gD-type 3-OSTs because they generate HSgD+, 3-O-sulfated motifs that bind the gD envelope protein of herpes simplex virus 1 (HSV-1) and thereby mediate viral cellular entry. Certain gD-type isoforms are anticipated to modulate neurobiologic events, because a Drosophila gD-type 3-OST is essential for a conserved neurogenic signaling pathway regulated by Notch. Information about 3-OST isoforms expressed in the nervous system of mammals is incomplete. Here, we identify the 3-OST isoforms having properties compatible with their participation in neurobiologic events. We show that 3-OST-2 and 3-OST-4 are principal isoforms of brain. We find these are gD-type enzymes, as they produce products similar to a prototypical gD-type isoform, and they can modify HS to generate receptors for HSV-1 entry into cells. Therefore, 3-OST-2 and 3-OST-4 catalyze modifications similar or identical to those made by the Drosophila gD-type 3-OST that has a role in regulating Notch signaling. We also find that 3-OST-2 and 3-OST-4 are the predominant isoforms expressed in neurons of the trigeminal ganglion, and 3-OST-2/4-type 3-O-sulfated residues occur in this ganglion and in select brain regions. Thus, 3-OST-2 and 3-OST-4 are the major neural gD-type 3-OSTs, and so are prime candidates for participating in HS-dependent neurobiologic events. PMID:17482450

  11. Loss of Kv3.1 tonotopicity and alterations in cAMP response element-binding protein signaling in central auditory neurons of hearing impaired mice.

    Science.gov (United States)

    von Hehn, Christian A A; Bhattacharjee, Arin; Kaczmarek, Leonard K

    2004-02-25

    The promoter for the kv3.1 potassium channel gene is regulated by a Ca2+-cAMP responsive element, which binds the transcription factor cAMP response element-binding protein (CREB). Kv3.1 is expressed in a tonotopic gradient within the medial nucleus of the trapezoid body (MNTB) of the auditory brainstem, where Kv3.1 levels are highest at the medial end, which corresponds to high auditory frequencies. We have compared the levels of Kv3.1, CREB, and the phosphorylated form of CREB (pCREB) in a mouse strain that maintains good hearing throughout life, CBA/J (CBA), with one that suffers early cochlear hair cell loss, C57BL/6 (BL/6). A gradient of Kv3.1 immunoreactivity in the MNTB was detected in both young (6 week) and older (8 month) CBA mice. Although no gradient of CREB was detected, pCREB-immunopositive cells were grouped together in distinct clusters along the tonotopic axis. The same pattern of Kv3.1, CREB, and pCREB localization was also found in young BL/6 mice at a time (6 weeks) when hearing is normal. In contrast, at 8 months, when hearing is impaired, the gradient of Kv3.1 was abolished. Moreover, in the older BL/6 mice there was a decrease in CREB expression along the tonotopic axis, and the pattern of pCREB labeling appeared random, with no discrete clusters of pCREB-positive cells along the tonotopic axis. Our findings are consistent with the hypothesis that ongoing activity in auditory brainstem neurons is necessary for the maintenance of Kv3.1 tonotopicity through the CREB pathway.

  12. Origin and central projections of rat dorsal penile nerve: possible direct projection to autonomic and somatic neurons by primary afferents of nonmuscle origin.

    Science.gov (United States)

    Núñez, R; Gross, G H; Sachs, B D

    1986-05-22

    Cell number, size, and somatotopic arrangement within the spinal ganglia of the cells of origin of the rat dorsal penile nerve (DPN), and their spinal cord projections, were studied by loading the proximal stump of the severed DPN with horseradish peroxidase (HRP). The DPN sensory cells were located entirely in the sixth lumbar (L6) dorsal root ganglia (DRG), in which a mean of 468 +/- 78 cells per side were observed, measuring 26.7 +/- 0.8 microns in their longest axis (range 10-65 microns) and distributed apparently randomly within the ganglia. Within the spinal cord, no retrograde label was found, i.e., no motoneurons were labeled, indicating that in the rat the DPN is formed exclusively of sensory nerve fibers. Although labeled fibers entered the cord only through L6, transganglionically transported HRP was evident in all spinal segments examined, i.e., T13-S2. Labeled fibers projected along the inner edge of the dorsal horn (medial pathway) throughout their extensive craniosacral distribution. However, laminar distribution varied with spinal segment. In the dorsal horn, terminals or preterminal axons were found in the dorsal horn marginal zone (lamina I), the substantia gelatinosa (lamina II), the nucleus proprius (laminae III and IV--the most consistent projection), Clarke's column (lamina VI), and the dorsal gray commissure. In the ventral horn, terminals were found in lamina VII and lamina IX. Label apposed to cell somas and dendrites in lamina VII may represent direct primary afferent projections onto sympathetic autonomic neurons. In lamina IX, labeled terminals delineated the somas and dendrites of cells that appeared to be motoneurons. This is the first description of an apparently monosynaptic contact onto motoneurons by a primary afferent of nonmuscle origin.

  13. A novel subset of enteric neurons revealed by ptf1a:GFP in the developing zebrafish enteric nervous system.

    Science.gov (United States)

    Uribe, Rosa A; Gu, Tiffany; Bronner, Marianne E

    2016-03-01

    The enteric nervous system, the largest division of the peripheral nervous system, is derived from vagal neural crest cells that invade and populate the entire length of the gut to form diverse neuronal subtypes. Here, we identify a novel population of neurons within the enteric nervous system of zebrafish larvae that express the transgenic marker ptf1a:GFP within the midgut. Genetic lineage analysis reveals that enteric ptf1a:GFP(+) cells are derived from the neural crest and that most ptf1a:GFP(+) neurons express the neurotransmitter 5HT, demonstrating that they are serotonergic. This transgenic line, Tg(ptf1a:GFP), provides a novel neuronal marker for a subpopulation of neurons within the enteric nervous system, and highlights the possibility that Ptf1a may act as an important transcription factor for enteric neuron development.

  14. The involvement of serotonergic system in the antidepressant effect of zinc in the forced swim test.

    Science.gov (United States)

    Szewczyk, Bernadeta; Poleszak, Ewa; Wlaź, Piotr; Wróbel, Andrzej; Blicharska, Eliza; Cichy, Agnieszka; Dybała, Małgorzata; Siwek, Agata; Pomierny-Chamioło, Lucyna; Piotrowska, Anna; Brański, Piotr; Pilc, Andrzej; Nowak, Gabriel

    2009-03-17

    Recent preclinical data indicated the antidepressant-like activity of zinc in different tests and models of depression. The present study investigates the involvement of the serotonergic system in zinc activity in the forced swim test (FST) in mice and rats. The combined treatment of sub-effective doses of zinc (hydroaspartate, 2.5 mg Zn/kg) and citalopram (15 mg/kg), fluoxetine (5 mg/kg) but not with reboxetine (2.5 mg/kg) significantly reduces the immobility time in the FST in mice. These treatments had no influence on the spontaneous locomotor activity. Moreover, while the antidepressant-like effect of zinc (5 mg/kg) in the FST was significantly blocked by pretreatment with inhibitor of serotonin synthesis, p-chlorophenylalanine (pCPA, 3x200 mg/kg), 5HT-2(A/C) receptor antagonist, ritanserin (4 mg/kg) or 5HT-1A receptor antagonist, WAY 1006335 (0.1 mg/kg), the zinc-induced reduction in the locomotor activity was not affected by these serotonin modulator agents. These results indicate the specific involvement of the serotonergic system in antidepressant but not the motion behavior of zinc in mice. Also, an increase in the swimming but not climbing parameter of the rat FST observed following zinc administration (2.5 and 5 mg Zn/kg) indicates the serotonin pathway participation. This present data indicates that the antidepressant-like activity of zinc observed in the FST involves interaction with the serotonergic system.

  15. Potential involvement of serotonergic signaling in ketamine's antidepressant actions: A critical review.

    Science.gov (United States)

    du Jardin, Kristian Gaarn; Müller, Heidi Kaastrup; Elfving, Betina; Dale, Elena; Wegener, Gregers; Sanchez, Connie

    2016-11-03

    A single i.v. infusion of ketamine, classified as an N-methyl-d-aspartate (NMDA) receptor antagonist, may alleviate depressive symptoms within hours of administration in treatment resistant depressed patients, and the antidepressant effect may last for several weeks. These unique therapeutic properties have prompted researchers to explore the mechanisms mediating the antidepressant effects of ketamine, but despite many efforts, no consensus on its antidepressant mechanism of action has been reached. Recent preclinical reports have associated the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) with the antidepressant-like action of ketamine. Here, we review the current evidence for a serotonergic role in ketamine's antidepressant effects. The pharmacological profile of ketamine may include equipotent activity on several non-NMDA targets, and the current hypotheses for the mechanisms responsible for ketamine's antidepressant activity do not appear to preclude the possibility that non-glutamate neurotransmitters are involved in the antidepressant effects. At multiple levels, the serotonergic and glutamatergic systems interact, and such crosstalk could support the notion that changes in serotonergic neurotransmission may impact ketamine's antidepressant potential. In line with these prospects, ketamine may increase 5-HT levels in the prefrontal cortex of rats, plausibly via hippocampal NMDA receptor inhibition and activation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. In addition, a number of preclinical studies suggest that the antidepressant-like effects of ketamine may depend on endogenous activation of 5-HT receptors. Recent imaging and behavioral data predominantly support a role for 5-HT1A or 5-HT1B receptors, but the full range of 5-HT receptors has currently not been systematically investigated in this context. Furthermore, the nature of any 5-HT dependent mechanism in ketamine's antidepressant effect is currently not

  16. Evidence for serotonergic modulation of progesterone-induced hyperphagia, depression and algesia in female mice.

    Science.gov (United States)

    Kaur, Gurpreet; Kulkarni, Shrinivas K

    2002-07-12

    The acute administration of the neurosteroid precursor, progesterone (10 mg/kg, s.c.) produced significant hyperphagia in female mice as observed at 0.5-, 1-, 2- and 3-h time intervals. At this dose progesterone also produced significant increase in immobility period duration in Porsolt's forced swim test and nociceptive response in hot-plate and tail-flick tests. Treatment with direct (quipazine, 5 mg/kg, i.p.) and indirect (fluoxetine, 10 mg/kg, i.p.) acting serotonergic agents per se produced significant hypophagia, decrease in immobility period and induced analgesic effect in hot-plate and tail-flick test. Further, treatment with both fluoxetine (10 mg/kg, i.p.) and quipazine (5 mg/kg, i.p.) significantly reversed progesterone-induced hyperphagia, depression and algesia in the female mice. Pretreatment with seganserin, a 5-HT(2) receptor antagonist (2 mg/kg, i.p.) significantly reversed fluoxetine and quipazine-induced antidepressant and analgesic effects. Seganserin reversed quipazine-induced hypophagia but in a replicate study it failed to reverse fluoxetine-induced hypophagia. Further, seganserin, 2 mg/kg, i.p., significantly reversed the suppressive effect of fluoxetine and quipazine on progesterone-induced hyperphagia, depression and algesia in hot-plate test. Seganserin also reversed the suppressive effect of fluoxetine and quipazine on progesterone-induced algesia in hot-plate test. These data suggest that the modulation of progesterone-induced effects by these serotonergic agents possibly involve 5-HT(2) receptor mechanisms. Further, the study underscores the use of serotonergic agents for the treatment of eating and affective disorders caused by the regular changes or disturbances of ovarian steroid levels in females.

  17. ON THE BASIS OF SYNAPTIC INTEGRATION CONSTANCY DURING GROWTH OF A NEURONAL CIRCUIT

    Directory of Open Access Journals (Sweden)

    Adriana De la Rosa

    2016-08-01

    Full Text Available We studied how a neuronal circuit composed of two neuron types connected by chemical and electrical synapses maintains constant its integrative capacities as neurons grow. For this we combined electrophysiological experiments with mathematical modeling in pairs of electrically-coupled Retzius neurons from postnatal to adult leeches. The electrically-coupled dendrites of both Retzius neurons receive a common chemical input, which produces EPSPs with varying amplitudes. Each EPSP spreads to the soma, but also crosses the electrical synapse to arrive at the soma of the coupled neuron. The leak of synaptic current across the electrical synapse reduces the amplitude of the EPSPs in proportion to the coupling ratio. In addition, summation of EPSPs generated in both neurons generates the baseline action potentials of these serotonergic neurons. To study how integration is adjusted as neurons grow we first studied the characteristics of the chemical and electrical connections onto the coupled dendrites of neuron pairs with soma diameters ranging from 21 to 75 µm. Then by feeding a mathematical model with the neuronal voltage responses to pseudorandom noise currents we obtained the values of the coupling ratio, the membrane resistance of the soma (rm and dendrites (rdend, the space constant (λ and the characteristic dendritic length (L=l/λ . We found that the EPSPs recorded from the somata were similar regardless on the neuron size. However, the amplitude of the EPSPs and the firing frequency of the neurons were inversely proportional to the coupling ratio of the neuron pair, which also was independent form the neuronal size. This data indicated that the integrative constancy relied on the passive membrane properties. We show that the growth of Retzius neurons was compensated by increasing the membrane resistance of the dendrites and therefore the λ value. By solely increasing the dendrite resistance this circuit maintains constant its integrative

  18. On the Basis of Synaptic Integration Constancy during Growth of a Neuronal Circuit

    Science.gov (United States)

    De-La-Rosa Tovar, Adriana; Mishra, Prashant K.; De-Miguel, Francisco F.

    2016-01-01

    We studied how a neuronal circuit composed of two neuron types connected by chemical and electrical synapses maintains constant its integrative capacities as neurons grow. For this we combined electrophysiological experiments with mathematical modeling in pairs of electrically-coupled Retzius neurons from postnatal to adult leeches. The electrically-coupled dendrites of both Retzius neurons receive a common chemical input, which produces excitatory postsynaptic potentials (EPSPs) with varying amplitudes. Each EPSP spreads to the soma, but also crosses the electrical synapse to arrive at the soma of the coupled neuron. The leak of synaptic current across the electrical synapse reduces the amplitude of the EPSPs in proportion to the coupling ratio. In addition, summation of EPSPs generated in both neurons generates the baseline action potentials of these serotonergic neurons. To study how integration is adjusted as neurons grow, we first studied the characteristics of the chemical and electrical connections onto the coupled dendrites of neuron pairs with soma diameters ranging from 21 to 75 μm. Then by feeding a mathematical model with the neuronal voltage responses to pseudorandom noise currents we obtained the values of the coupling ratio, the membrane resistance of the soma (rm) and dendrites (rdend), the space constant (λ) and the characteristic dendritic length (L = l/λ). We found that the EPSPs recorded from the somata were similar regardless on the neuron size. However, the amplitude of the EPSPs and the firing frequency of the neurons were inversely proportional to the coupling ratio of the neuron pair, which also was independent from the neuronal size. This data indicated that the integrative constancy relied on the passive membrane properties. We show that the growth of Retzius neurons was compensated by increasing the membrane resistance of the dendrites and therefore the λ value. By solely increasing the dendrite resistance this circuit maintains

  19. A reassessment of the role of serotonergic system in the control of feeding behavior

    OpenAIRE

    Medeiros Magda A.; Costa-e-Sousa Ricardo H.; Olivares Emerson L.; Côrtes Wellington S.; Reis Luís C.

    2005-01-01

    The role of serotonergic system in the feeding behaviorwas appraised by electrolytic lesions in the dorsal raphe nucleus (DRN) and administration of para-chlorophenylalanine (PCPA, 3 mg/5 mul, icv). Chronic evaluations were accomplished through 120 and 360 days in PCPA-injected and DRN-lesioned rats, respectively. Acute food intake was evaluated in fasted rats and submitted to injection of PCPA and hydroxytryptophan (LHTP, 30 mg/kg, ip). DRN-lesioned rats exhibited 22-80% increase in food int...

  20. Akut psykose ved ophør af langvarig tramadolbehandling − overser vi tramadols serotonerge virkning?

    DEFF Research Database (Denmark)

    Østergaard Rathe, Jette; Dideriksen, Dorthe; Carstens, Jan;

    2016-01-01

    I denne artikel præsenteres en sygehistorie, hvor en ældre kvinde får tiltagende konfusion og psykotiske symptomer en uge efter seponering af højdosis-tramadol og skift til Contalgin. Disse mulige seponeringssymptomer kan skyldes abrupt ophør af tramadols serotonerge effekt, og forfatterne...... konkluderer, at man må have skærpet opmærksomhed på atypiske bivirkninger i forbindelse med seponering af især langvarig/høj-dosering af tramadol, særligt hvis symptomerne ikke umiddelbart svinder ved morfinsubstitution....

  1. Brain serotonergic activation in growth-stunted farmed salmon: adaption versus pathology

    DEFF Research Database (Denmark)

    Vindas, Marco A.; Johansen, Ida B.; Folkedal, Ole

    2016-01-01

    Signalling systems activated under stress are highly conserved, suggesting adaptive effects of their function. Pathologies arising from continued activation of such systems may represent a mismatch between evolutionary programming and current environments. Here, we use Atlantic salmon (Salmo salar......) in aquaculture as a model to explore this stance of evolutionary-based medicine, for which empirical evidence has been lacking. Growth-stunted (GS) farmed fish were characterized by elevated brain serotonergic activation, increased cortisol production and behavioural inhibition. We make the novel observation...

  2. Appetite-suppressing effects and interactions of centrally administered corticotropin-releasing factor, urotensin I and serotonin in rainbow trout (Oncorhynchus mykiss

    Directory of Open Access Journals (Sweden)

    Van A. Ortega

    2013-10-01

    Full Text Available Corticotropin-releasing factor (CRF, urotensin I (UI and serotonin (5-HT are generally recognized as key regulators of the anorexigenic stress response in vertebrates, yet the proximal effects and potential interactions of these central messengers on food intake in salmonids are not known. Moreover, no study to date in fishes has compared the appetite-suppressing effects of CRF and UI using species-specific peptides. Therefore, the objectives of this study were to 1 assess the individual effects of synthesized rainbow trout CRF (rtCRF, rtUI as well as 5-HT on food intake in rainbow trout, and 2 determine whether the CRF and serotonergic systems interact in the regulation of food intake in this species. Intracerebroventricular (icv injections of rtCRF and rtUI both suppressed food intake in a dose-related manner but rtUI (ED50 = 17.4 ng/g body weight [BW] was significantly more potent than rtCRF (ED50 = 105.9 ng/g BW. Co-injection of either rtCRF or rtUI with the CRF receptor antagonist a-hCRF(9-41 blocked the reduction in food intake induced by CRF-related peptides. Icv injections of 5-HT also inhibited feeding in a dose-related manner (ED50 = 14.7 ng/g BW and these effects were blocked by the serotonergic receptor antagonist methysergide. While the anorexigenic effects of 5-HT were reversed by a-hCRF(9-41 co-injection, the appetite-suppressing effects of either rtCRF or rtUI were not affected by methysergide co-injection. These results identify CRF, UI and 5-HT as anorexigenic agents in rainbow trout, and suggest that 5-HT-induced anorexia may be at least partially mediated by CRF- and/or UI-secreting neurons.

  3. Immunoperoxidase detection of neuronal antigens in full-thickness whole mount preparations of hollow organs and thick sections of central nervous tissue.

    Science.gov (United States)

    Llewellyn-Smith, Ida J; Gnanamanickam, Greta J E

    2011-03-15

    Immunofluorescently stained whole mounts have proved useful for defining the innervation of the gut and large blood vessels. Nerves supplying other hollow organs are usually studied in sections, which provide much less information. Aiming to describe the entire innervation of rat uterus, we developed a method for immunoperoxidase staining of full-thickness whole mounts that allowed us to visualize all immunoreactive axons. Uterine horns were dissected out, slit open, stretched, pinned flat and fixed. Entire horns were treated with methanol/peroxide, buffered Triton X-100 and normal serum and then incubated in primary antibodies, biotinylated secondary antibodies and avidin-horseradish peroxidase (HRP), each for at least 3 days. Peroxidase reactions revealed immunoreactivity. Immunostained horns were dehydrated, infiltrated with epoxy resin, mounted on slides under Aclar coverslips and polymerized. We treated bladders, gut, major pelvic ganglia and thick sections of perfused medulla oblongata similarly to assess the applicability of the method. Using this method, we could map the entire uterine innervation provided by axons immunoreactive for a variety of antigens. We could also assess the entire tyrosine hydroxylase-immunoreactive innervation in all layers of bladder, gut and ganglia whole mounts and throughout 300 μm sections of medulla. These observations show that this method for immunoperoxidase staining reliably reveals the complete innervation of full-thickness whole mounts of hollow organs and thick sections of central nervous tissue. The method has several advantages. The resin-embedded tissue does not degrade; the immunostaining is non-fading and permanent and neurochemically defined features can be mapped at large scale without confocal microscopy.

  4. MDMA, serotonergic neurotoxicity, and the diverse functional deficits of recreational 'Ecstasy' users.

    Science.gov (United States)

    Parrott, Andrew C

    2013-09-01

    Serotonergic neurotoxicity following MDMA is well-established in laboratory animals, and neuroimaging studies have found lower serotonin transporter (SERT) binding in abstinent Ecstasy/MDMA users. Serotonin is a modulator for many different psychobiological functions, and this review will summarize the evidence for equivalent functional deficits in recreational users. Declarative memory, prospective memory, and higher cognitive skills are often impaired. Neurocognitive deficits are associated with reduced SERT in the hippocampus, parietal cortex, and prefrontal cortex. EEG and ERP studies have shown localised reductions in brain activity during neurocognitive performance. Deficits in sleep, mood, vision, pain, psychomotor skill, tremor, neurohormonal activity, and psychiatric status, have also been demonstrated. The children of mothers who take Ecstasy/MDMA during pregnancy have developmental problems. These psychobiological deficits are wide-ranging, and occur in functions known to be modulated by serotonin. They are often related to lifetime dosage, with light users showing slight changes, and heavy users displaying more pronounced problems. In summary, abstinent Ecstasy/MDMA users can show deficits in a wide range of biobehavioral functions with a serotonergic component.

  5. Colon preneoplasia after carcinogen exposure is enhanced and colonic serotonergic system is suppressed by food deprivation.

    Science.gov (United States)

    Kannen, Vinicius; Fernandes, Cleverson R; Stopper, Helga; Zanette, Dalila L; Ferreira, Frederico R; Frajacomo, Fernando T; Carvalho, Milene C; Brandão, Marcus L; Elias Junior, Jorge; Jordão Junior, Alceu Afonso; Uyemura, Sérgio Akira; Waaga-Gasser, Ana Maria; Garcia, Sérgio B

    2013-10-04

    Calorie restriction regimens usually promote health and extend life-span in mammals. This is partially related to their preventive effects against malignancies. However, certain types of nutritional restriction failed to induce beneficial effects. The American Institute of Nutrition defines calorie restriction as diets which have only 40% fewer calories, but provide normal amounts of necessary food components such as protein, vitamins and minerals; whereas, food restriction means 40% less of all dietary ingredients plus 40% less calories. Our study aimed to test the hypothesis that the latter type of food deprivation (40% less food than consumed by standard fed rats) might increase cancer risk instead of reducing it, as is generally assumed for all dietary restrictive regimens. Since the endogenous modulation of the colon serotonergic system has been observed to play a role during the early steps of carcinogenesis we also investigated whether the serotoninergic system could be involved in the food intake modulation of cancer risk. For this, rats were exposed to a carcinogen and subjected to food deprivation for 56 days. Triglyceride levels and visceral adipose tissue were reduced while hepatic and colonic lipid peroxidation was increased. This dietary restriction also decreased serotonin levels in colon, and gene expression of its intestinal transporter and receptors. Finally, the numbers of preneoplastic lesions in the colon tissue of carcinogen-exposed rats were increased. Our data suggest that food deprivation enhances formation of early tumorigenic lesions by suppressing serotonergic activity in colon tissue.

  6. The Potential Role of Cannabinoids in Modulating Serotonergic Signaling by Their Influence on Tryptophan Metabolism

    Directory of Open Access Journals (Sweden)

    Dietmar Fuchs

    2010-08-01

    Full Text Available Phytocannabinoids present in Cannabis plants are well known to exert potent anti-inflammatory and immunomodulatory effects. Previously, we have demonstrated that the psychoactive D9-tetrahydrocannabinol (THC and the non-psychotropic cannabidiol (CBD modulate mitogen-induced Th1-type immune responses in peripheral blood mononuclear cells (PBMC. The suppressive effect of both cannabinoids on mitogen-induced tryptophan degradation mediated by indoleamine-2,3-dioxygenase (IDO, suggests an additional mechanism by which antidepressive effects of cannabinoids might be linked to the serotonergic system. Here, we will review the role of tryptophan metabolism in the course of cell mediated immune responses and the relevance of cannabinoids in serotonergic signaling. We conclude that in particular the non-psychotropic CBD might be useful for the treatment of mood disorders in patients with inflammatory diseases, since this cannabinoid seems to be safe and its effects on activation-induced tryptophan degradation by CBD were more potent as compared to THC.

  7. Disturbed Serotonergic Neurotransmission and Oxidative Stress in Elderly Patients with Delirium

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    Angelique Egberts

    2015-12-01

    Full Text Available Background: Oxidative stress and disturbances in serotonergic and dopaminergic neurotransmission may play a role in the pathophysiology of delirium. Aims: In this study, we investigated levels of amino acids, amino acid ratios and levels of homovanillic acid (HVA as indicators for oxidative stress and disturbances in neurotransmission. Methods: Plasma levels of amino acids, amino acid ratios and HVA were determined in acutely ill patients aged ≥65 years admitted to the wards of Internal Medicine and Geriatrics of the Erasmus University Medical Center and the ward of Geriatrics of the Havenziekenhuis, Rotterdam, The Netherlands. Differences in the biochemical parameters between patients with and without delirium were investigated by analysis of variance in models adjusted for age, gender and comorbidities. Results: Of the 86 patients included, 23 had delirium. In adjusted models, higher mean phenylalanine/tyrosine ratios (1.34 vs. 1.14, p = 0.028, lower mean tryptophan/large neutral amino acids ratios (4.90 vs. 6.12, p = 0.021 and lower mean arginine levels (34.8 vs. 45.2 µmol/l, p = 0.022 were found in patients with delirium when compared to those without. No differences were found in HVA levels between patients with and without delirium. Conclusion: The findings of this study suggest disturbed serotonergic neurotransmission and an increased status of oxidative stress in patients with delirium.

  8. Kinetic profiling an abundantly expressed planarian serotonergic GPCR identifies bromocriptine as a perdurant antagonist

    Directory of Open Access Journals (Sweden)

    John D. Chan

    2016-12-01

    Full Text Available The diversity and uniqueness of flatworm G protein coupled receptors (GPCRs provides impetus for identifying ligands useful as tools for studying flatworm biology, or as therapeutics for treating diseases caused by parasitic flatworm infections. To catalyse this discovery process, technologies optimized for mammalian GPCR high throughput screening need be transposed for screening flatworm GPCRs. Here, we demonstrate the utility of a genetically encoded cAMP biosensor for resolving the properties of an abundantly expressed planarian serotonergic GPCR (S7.1R. Application of this methodology resolved the real time kinetics of GPCR modulation by ligands and demonstrated a marked difference in the kinetic action of antagonists at S7.1R. Notably, bromocriptine caused a protracted inhibition of S7.1R activity in vitro and a protracted paralysis of planarian movement, replicating the effect of S7.1R in vivo RNAi. The lengthy inhibition of function caused by bromocriptine at this abundantly expressed GPCR provides a useful tool to ablate serotonergic signaling in vivo, and is a noteworthy feature for exploitation as an anthelmintic vulnerability.

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

    DEFF Research Database (Denmark)

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

    2016-01-01

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

  10. Transient activation of specific neurons in mice by selective expression of the capsaicin receptor

    Science.gov (United States)

    Güler, Ali D.; Rainwater, Aundrea; Parker, Jones G.; Jones, Graham L.; Argilli, Emanuela; Arenkiel, Benjamin R.; Ehlers, Michael D.; Bonci, Antonello; Zweifel, Larry s.; Palmiter, Richard D.

    2013-01-01

    The ability to control the electrical activity of a neuronal subtype is a valuable tool in deciphering the role of discreet cell populations in complex neural circuits. Recent techniques that allow remote control of neurons are either labor intensive and invasive or indirectly coupled to neural electrical potential with low temporal resolution. Here we show the rapid, reversible and direct activation of genetically identified neuronal subpopulations by generating two inducible transgenic mouse models. Confined expression of the capsaicin receptor, TRPV1, allows cell-specific activation after peripheral or oral delivery of ligand in freely moving mice. Capsaicin-induced activation of dopaminergic or serotonergic neurons reversibly alters both physiological and behavioural responses within minutes, and lasts ~10 min. These models showcase a robust and remotely controllable genetic tool that modulates a distinct cell population without the need for invasive and labour-intensive approaches. PMID:22434189

  11. [Mirror neurons].

    Science.gov (United States)

    Rubia Vila, Francisco José

    2011-01-01

    Mirror neurons were recently discovered in frontal brain areas of the monkey. They are activated when the animal makes a specific movement, but also when the animal observes the same movement in another animal. Some of them also respond to the emotional expression of other animals of the same species. These mirror neurons have also been found in humans. They respond to or "reflect" actions of other individuals in the brain and are thought to represent the basis for imitation and empathy and hence the neurobiological substrate for "theory of mind", the potential origin of language and the so-called moral instinct.

  12. Simulation study on dynamics transition in neuronal activity during sleep cycle by using asynchronous and symmetry neural network model.

    Science.gov (United States)

    Nakao, M; Takahashi, T; Mizutani, Y; Yamamoto, M

    1990-01-01

    We have found that single neuronal activities in different regions in the brain commonly exhibit the distinct dynamics transition during sleep-waking cycle in cats. Especially, power spectral densities of single neuronal activities change their profiles from the white to the 1/f along with sleep cycle from slow wave sleep (SWS) to paradoxical sleep (PS). Each region has different neural network structure and physiological function. This suggests a globally working mechanism may be underlying the dynamics transition we concern. Pharmacological studies have shown that a change in a wide-spread serotonergic input to these regions possibly causes the neuronal dynamics transition during sleep cycle. In this paper, based on these experimental results, an asynchronous and symmetry neural network model including inhibitory input, which represents the role of the serotonergic system, is utilized to examine the reality of our idea that the inhibitory input level varying during sleep cycle induce that transition. Simulation results show that the globally applied inhibitory input can control the dynamics of single neuronal state evolution in the artificial neural network: 1/f-like power spectral density profiles result under weak inhibition, which possibly corresponds to PS, and white profiles under strong inhibition, which possibly corresponds to SWS. An asynchronous neural network is known to change its state according to its energy function. The geometrical structure of network energy function is thought to vary along with the change in inhibitory level, which is expected to cause the dynamics transition of neuronal state evolution in the network model. These simulation results support the possibility that the serotonergic system is essential for the dynamics transition of single neuronal activities during sleep cycle.

  13. Serotonergic neural links from the dorsal raphe nucleus modulate defensive behaviours organised by the dorsomedial hypothalamus and the elaboration of fear-induced antinociception via locus coeruleus pathways.

    Science.gov (United States)

    Biagioni, Audrey Francisco; de Freitas, Renato Leonardo; da Silva, Juliana Almeida; de Oliveira, Rithiele Cristina; de Oliveira, Ricardo; Alves, Vani Maria; Coimbra, Norberto Cysne

    2013-04-01

    Decrease of γ-aminobutyric acid (GABA)-mediated neurotransmission in the dorsomedial hypothalamus (DMH) evokes instinctive fear-like responses. The aim of the present study was to investigate the involvement of the serotonin (5-HT)- and norepinephrine-mediated pathways of the endogenous pain inhibitory system, including the dorsal raphe nucleus (DRN) and the locus coeruleus (LC), in the defensive responses and antinociceptive processes triggered by the blockade of GABAergic receptors in the DMH. The intra-hypothalamic microinjection of the GABA(A) receptor antagonist bicuculline (40 ng/200 nL) elicited elaborate defensive behaviours interspersed with exploratory responses. This escape behaviour was followed by significantly increased pain thresholds, a phenomenon known as fear-induced antinociception. Furthermore, at 5 and 14 days after DRN serotonin-containing neurons were damaged using the selective neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), the frequency and duration of alertness and escape behaviour evoked by the GABA(A) receptor blockade in the DMH decreased, as well as fear-induced antinociception. Pre-treatment with the non-selective 5-HT receptor antagonist methysergide, the 5-HT(2A/2C) receptor antagonist ketanserin and the 5-HT(2A) receptor selective antagonist R-96544 in the LC also decreased fear-induced antinociception, without significant changes in the expression of defensive behaviours. These data suggest that the serotonergic neurons of the DRN are directly involved in the organisation of defensive responses as well as in the elaboration of the innate fear-induced antinociception. However, serotonin-mediated inputs from the NDR to the LC modulate only fear-induced antinociception and not the defensive behaviours evoked by GABA(A) receptor blockade in the DMH.

  14. Serotonergic, noradrenergic and dopaminergic markers are related to cognitive function in adults with 22q11 deletion syndrome

    NARCIS (Netherlands)

    Evers, L.J.M.; Curfs, L.M.G.; Bakker, J.A.; Boot, E.; da Silva Alves, F.; Abeling, N.; Bierau, J.; Drukker, M.; van Amelsvoort, T.A.M.J.

    2014-01-01

    Patients with 22q11 deletion syndrome (22q11DS) have a high prevalence of psychiatric disorders and intellectual disability. At present the neurobiology underlying psychopathology in 22q11DS is still not understood. In the present study, we analyzed urinary serotonergic, dopaminergic and noradrenerg

  15. The Effect of Tongue Exercise on Serotonergic Input to the Hypoglossal Nucleus in Young and Old Rats

    Science.gov (United States)

    Behan, Mary; Moeser, Adam E.; Thomas, Cathy F.; Russell, John A.; Wang, Hao; Leverson, Glen E.; Connor, Nadine P.

    2012-01-01

    Purpose: Breathing and swallowing problems affect elderly people and may be related to age-associated tongue dysfunction. Hypoglossal motoneurons that innervate the tongue receive a robust, excitatory serotonergic (5HT) input and may be affected by aging. We used a rat model of aging and progressive resistance tongue exercise to determine whether…

  16. Neuronal boost to evolutionary dynamics.

    Science.gov (United States)

    de Vladar, Harold P; Szathmáry, Eörs

    2015-12-06

    Standard evolutionary dynamics is limited by the constraints of the genetic system. A central message of evolutionary neurodynamics is that evolutionary dynamics in the brain can happen in a neuronal niche in real time, despite the fact that neurons do not reproduce. We show that Hebbian learning and structural synaptic plasticity broaden the capacity for informational replication and guided variability provided a neuronally plausible mechanism of replication is in place. The synergy between learning and selection is more efficient than the equivalent search by mutation selection. We also consider asymmetric landscapes and show that the learning weights become correlated with the fitness gradient. That is, the neuronal complexes learn the local properties of the fitness landscape, resulting in the generation of variability directed towards the direction of fitness increase, as if mutations in a genetic pool were drawn such that they would increase reproductive success. Evolution might thus be more efficient within evolved brains than among organisms out in the wild.

  17. Neuronal boost to evolutionary dynamics

    Science.gov (United States)

    de Vladar, Harold P.; Szathmáry, Eörs

    2015-01-01

    Standard evolutionary dynamics is limited by the constraints of the genetic system. A central message of evolutionary neurodynamics is that evolutionary dynamics in the brain can happen in a neuronal niche in real time, despite the fact that neurons do not reproduce. We show that Hebbian learning and structural synaptic plasticity broaden the capacity for informational replication and guided variability provided a neuronally plausible mechanism of replication is in place. The synergy between learning and selection is more efficient than the equivalent search by mutation selection. We also consider asymmetric landscapes and show that the learning weights become correlated with the fitness gradient. That is, the neuronal complexes learn the local properties of the fitness landscape, resulting in the generation of variability directed towards the direction of fitness increase, as if mutations in a genetic pool were drawn such that they would increase reproductive success. Evolution might thus be more efficient within evolved brains than among organisms out in the wild. PMID:26640653

  18. Identifying serotonergic mechanisms underlying the corticolimbic response to threat in humans

    DEFF Research Database (Denmark)

    Fisher, Patrick M; Hariri, Ahmad R

    2013-01-01

    . Integrating these methodological approaches offers novel opportunities to identify mechanisms through which serotonin signalling contributes to differences in brain function and behaviour, which in turn can illuminate factors that confer risk for illness and inform the development of more effective treatment......A corticolimbic circuit including the amygdala and medial prefrontal cortex (mPFC) plays an important role in regulating sensitivity to threat, which is heightened in mood and anxiety disorders. Serotonin is a potent neuromodulator of this circuit; however, specific serotonergic mechanisms...... mediating these effects are not fully understood. Recent studies have evaluated molecular mechanisms mediating the effects of serotonin signalling on corticolimbic circuit function using a multi-modal neuroimaging strategy incorporating positron emission tomography and blood oxygen level...

  19. Options for patients with irritable bowel syndrome: contrasting traditional and novel serotonergic therapies.

    Science.gov (United States)

    Johanson, J F

    2004-12-01

    This article reviews the efficacy and tolerability of traditional therapies for irritable bowel syndrome (IBS) and concludes that they are limited by both poor efficacy and adverse effects. Serotonin, a neurotransmitter found mainly in the gut, appears to represent a link in IBS pathophysiological processes -- altered gut motility, abnormal intestinal secretion and visceral hypersensitivity. Recently, available treatments for IBS have targeted serotonin receptors that are involved in motor, sensory and secretory functions of the gut. Serotonergic agents, such as alosetron (a 5-HT3 receptor antagonist) and tegaserod (a selective 5-HT4 receptor partial agonist), provide global relief of the multiple symptoms of IBS with diarrhoea and IBS with constipation, respectively, and represent important additions to the IBS treatment armamentarium.

  20. Polymorphisms in serotonergic pathways influence the outcome of antidepressant therapy in psychiatric inpatients.

    Science.gov (United States)

    Staeker, Julia; Leucht, Stefan; Laika, Barbara; Steimer, Werner

    2014-01-01

    Serotonergic pathways are known to play an essential role in the effects generated by antidepressants. Polymorphisms in serotonin receptor and transporter genes have been identified as an important factor. To investigate which of these polymorphisms may be useful to predict clinical outcome, we assessed their effect in a naturalistic clinical study. We studied the influence of the 5-hydroxytryptamine transporter (5-HTT) variable number of tandem repeats (VNTR), 5-HTTLPR/rs25531 and a 5-HTR2A intron 2 SNP with regard to response and side effects in 273 psychiatric inpatients. Main clinical assessments included Clinical Global Impressions ratings, paranoid depression scale self-rating scale and Dosage Record, and Treatment Emergent Symptoms (DOTES) Scale. We found significant associations between 5-HTTLPR/rs25531 S/L(G) alleles and response and side effects in 100 patients with selective serotonin reuptake inhibitor (SSRI) treatment (p = 0.037, CGI-I ≤ 2: 0% vs. 19% and p = 0.0005, DOTES cluster c: 0.76 vs. 0.19). 5-HTT VNTR and 5-HTR2A intron 2 polymorphisms were associated significantly with adverse effects in patients with selective and nonselective SRI (5-HTT VNTR 12/12: n = 170, p = 0.0001, side effect rates: 51% vs. 19% and rs7997012 [A/A]: n = 50, p = 0.020, side effects rates: 43% vs. 11%). No impact of the polymorphisms on mirtazapine treatment was found. Our study confirms the influence of serotonergic polymorphisms at the receptor and transporter level on SSRI response and side effects, supporting previous reports based on various study designs. The effects were strong enough to be noticed clinically in this naturalistic setting. However, randomized controlled trials are warranted to provide unequivocal evidence of the clinical usefulness of pretherapeutic screening for these polymorphisms.

  1. Sexually dimorphic serotonergic dysfunction in a mouse model of Huntington's disease and depression.

    Directory of Open Access Journals (Sweden)

    Thibault Renoir

    Full Text Available Depression is the most common psychiatric disorder in Huntington's disease (HD patients. In the general population, women are more prone to develop depression and such susceptibility might be related to serotonergic dysregulation. There is yet to be a study of sexual dimorphism in the development and presentation of depression in HD patients. We investigated whether 8-week-old male and female R6/1 transgenic HD mice display depressive-like endophenotypes associated with serotonergic impairments. We also studied the behavioral effects of acute treatment with sertraline. We found that only female HD mice exhibited a decreased preference for saccharin as well as impaired emotionality-related behaviors when assessed on the novelty-suppressed feeding test (NSFT and the forced-swimming test (FST. The exaggerated immobility time displayed by female HD in the FST was reduced by acute administration of sertraline. We also report an increased response to the 5-HT(1A receptor agonist 8-OH-DPAT in inducing hypothermia and a decreased 5-HT(2A receptor function in HD animals. While tissue levels of serotonin were reduced in both male and female HD mice, we found that serotonin concentration and hydroxylase-2 (TPH2 mRNA levels were higher in the hippocampus of males compared to female animals. Finally, the antidepressant-like effects of sertraline in the FST were blunted in male HD animals. This study reveals sex-specific depressive-related behaviors during an early stage of HD prior to any cognitive and motor deficits. Our data suggest a crucial role for disrupted serotonin signaling in mediating the sexually dimorphic depression-like phenotype in HD mice.

  2. The effect of serotonergic system on nociceptin/orphanin FQ induced food intake in chicken.

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    Zendehdel, Morteza; Mokhtarpouriani, Kasra; Babapour, Vahab; Baghbanzadeh, Ali; Pourrahimi, Maryam; Hassanpour, Shahin

    2013-07-01

    The present study was designed to examine the effects of intracerebroventricular injection of para-chlorophenylalanine (PCPA) (cerebral serotonin depletive), fluoxetine (selective serotonin reuptake inhibitor), 8-OH-DPAT (5-HT1A autoreceptor agonist) and SB 242084 (5-HT2c receptor antagonist) on nociceptin/orphanin FQ (N/OFQ) induced feeding response in chickens. A guide cannula was surgically implanted into the lateral ventricle of chickens. Before the experiments, 3-h fasting periods had been given to all experimental birds. In experiment 1, chickens were injected with PCPA (1.5 μg) followed by an N/OFQ injection (16 nmol) intracerebroventricularly. In experiment 2, birds received fluoxetine (10 μg) prior to the injection of N/OFQ. In experiment 3, chickens were administered with N/OFQ after the 8-OH-DPAT administration (15.25 nmol). In experiment 4, birds were injected with SB 242084 (1.5 μg) followed by an N/OFQ injection. Cumulative food intake was measured at 3 h post injection. The results of this study show that N/OFQ increases food intake in broiler cockerels (P  0.05). Furthermore, the stimulatory effect of N/OFQ on food intake was significantly attenuated by pretreatment with fluoxetine. These results suggest that N/OFQ induced hyperphagia is mediated by serotonergic mechanisms, and possibly imply an interaction between N/OFQ and the serotonergic system (via 5-HT2C receptors) on food intake in chickens.

  3. Characterization of enteric neurons in wild-type and mutant zebrafish using semi-automated cell counting and co-expression analysis.

    Science.gov (United States)

    Simonson, Levi W; Ganz, Julia; Melancon, Ellie; Eisen, Judith S

    2013-06-01

    To characterize fluorescent enteric neurons labeled for expression of cytoplasmic markers in zebrafish mutants, we developed a new MATLAB-based program that can be trained by user input. We used the program to count enteric neurons and to analyze co-expression of the neuronal marker, Elavl, and the neuronal subtype marker, serotonin, in 3D confocal image stacks of dissected whole-mount zebrafish intestines. We quantified the entire population of enteric neurons and the serotonergic subpopulation in specific regions of the intestines of gutwrencher mutant and wild-type sibling larvae. We show a marked decrease in enteric neurons in gutwrencher mutants that is more severe at the caudal end of the intestine. We also show that gutwrencher mutants have the same number of serotonin-positive enteroendocrine cells in the intestine as wild types.

  4. Brief constant light accelerates serotonergic re-entrainment to large shifts of the daily light/dark cycle.

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    Kaur, G; Thind, R; Glass, J D

    2009-04-10

    Brief ( approximately 2 day) constant light exposure (LL(b)) in hamsters dramatically enhances circadian phase-resetting induced by the 5-HT receptor agonist, (+/-)-2-dipropyl-amino-8-hydroxyl-1,2,3,4-tetrahydronapthalene (8-OH-DPAT) and other nonphotic stimuli. The present study was undertaken to determine if LL(b) can also amplify phase-resetting responses to endogenous 5-HT and accelerate re-entrainment to large-magnitude advance and delay shifts of the light/dark (LD) cycle. First, central serotonergic activity was increased by i.p. injection of L-tryptophan+/-the 5-HT reuptake inhibitor fluoxetine. Hamsters under LD or exposed to LL(b) received vehicle or drugs during the early morning, and phase-shifts of the locomotor activity rhythm were measured after release to constant darkness. Neither drug phase-shifted animals not exposed to LL(b) (P>0.5 vs. vehicle); however in animals receiving LL(b,)L-tryptophan with and without fluoxetine produced large phase-advance shifts (means=2.5+/-0.4 h and 2.6+/-0.2 h, respectively; both Pentrainment to 10 h phase-advance and phase-delay shifts of the LD cycle were assessed. In groups not exposed to LL(b), vehicle controls re-entrained slowly to the advance and delay shifts (means=16+/-1 and 24+/-4 days, respectively), but those treated with 8-OH-DPAT re-entrained faster (means=11+/-2 and 9+/-2 days, respectively; both Pentrained slowly to the advance and delay shifts (means=15+/-2 and 25+/-3 days, respectively); however those receiving 8-OH-DPAT rapidly re-entrained to the delay and advance shifts, with the majority (75%) requiring only 1-2 days (means=2+/-1 and 4+/-2 days, respectively; both Pentrainment to a 10 h advance shift (mean=5+/-2 days; Pentrainment to large shifts of the LD cycle which offers a potential approach for treating circadian-related desynchronies.

  5. Localization of the contacts between Kenyon cells and aminergic neurons in the Drosophila melanogaster brain using SplitGFP reconstitution.

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    Pech, Ulrike; Pooryasin, Atefeh; Birman, Serge; Fiala, André

    2013-12-01

    The mushroom body of the insect brain represents a neuronal circuit involved in the control of adaptive behavior, e.g., associative learning. Its function relies on the modulation of Kenyon cell activity or synaptic transmitter release by biogenic amines, e.g., octopamine, dopamine, or serotonin. Therefore, for a comprehensive understanding of the mushroom body, it is of interest not only to determine which modulatory neurons interact with Kenyon cells but also to pinpoint where exactly in the mushroom body they do so. To accomplish the latter, we made use of the GRASP technique and created transgenic Drosophila melanogaster that carry one part of a membrane-bound splitGFP in Kenyon cells, along with a cytosolic red fluorescent marker. The second part of the splitGFP is expressed in distinct neuronal populations using cell-specific Gal4 drivers. GFP is reconstituted only if these neurons interact with Kenyon cells in close proximity, which, in combination with two-photon microscopy, provides a very high spatial resolution. We characterize spatially and microstructurally distinct contact regions between Kenyon cells and dopaminergic, serotonergic, and octopaminergic/tyraminergic neurons in all subdivisions of the mushroom body. Subpopulations of dopaminergic neurons contact complementary lobe regions densely. Octopaminergic/tyraminergic neurons contact Kenyon cells sparsely and are restricted mainly to the calyx, the α'-lobes, and the γ-lobes. Contacts of Kenyon cells with serotonergic neurons are heterogeneously distributed over the entire mushroom body. In summary, the technique enables us to localize precisely a segmentation of the mushroom body by differential contacts with aminergic neurons.

  6. Chronic alterations in monoaminergic cells in the locus coeruleus in orexin neuron-ablated narcoleptic mice.

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    Natsuko Tsujino

    Full Text Available Narcolepsy patients often suffer from insomnia in addition to excessive daytime sleepiness. Narcoleptic animals also show behavioral instability characterized by frequent transitions between all vigilance states, exhibiting very short bouts of NREM sleep as well as wakefulness. The instability of wakefulness states in narcolepsy is thought to be due to deficiency of orexins, neuropeptides produced in the lateral hypothalamic neurons, which play a highly important role in maintaining wakefulness. However, the mechanism responsible for sleep instability in this disorder remains to be elucidated. Because firing of orexin neurons ceases during sleep in healthy animals, deficiency of orexins does not explain the abnormality of sleep. We hypothesized that chronic compensatory changes in the neurophysiologica activity of the locus coeruleus (LC and dorsal raphe (DR nucleus in response to the progressive loss of endogenous orexin tone underlie the pathological regulation of sleep/wake states. To evaluate this hypothesis, we examined firing patterns of serotonergic (5-HT neurons and noradrenergic (NA neurons in the brain stem, two important neuronal populations in the regulation of sleep/wakefulness states. We recorded single-unit activities of 5-HT neurons and NA neurons in the DR nucleus and LC of orexin neuron-ablated narcoleptic mice. We found that while the firing pattern of 5-HT neurons in narcoleptic mice was similar to that in wildtype mice, that of NA neurons was significantly different from that in wildtype mice. In narcoleptic mice, NA neurons showed a higher firing frequency during both wakefulness and NREM sleep as compared with wildtype mice. In vitro patch-clamp study of NA neurons of narcoleptic mice suggested a functional decrease of GABAergic input to these neurons. These alterations might play roles in the sleep abnormality in narcolepsy.

  7. Serotonergic disturbances in autistic disorder: L-5-hydroxytryptophan administration to autistic youngsters increases the blood concentrations of serotonin in patients but not in controls.

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    Croonenberghs, Jan; Verkerk, Robert; Scharpe, Simon; Deboutte, Dirk; Maes, Michael

    2005-03-25

    Some studies have suggested that disorders in the peripheral and central metabolism of serotonin (5-HT) may play a role in the pathophysiology of autistic disorder. This study examines the whole blood concentrations of 5-HT and 5-hydroxy-indoleacetic acid (5-HIAA) in baseline conditions and during a challenge with L-5-OH-tryptophane (5-HTP; 4 mg/kg in non enteric-coated tablets), the precursor of 5-HT, in a study group of 18 male, post-pubertal, Caucasian autistic patients (age 13-19 y.; I.Q.>55) and 20 matched healthy volunteers. In baseline conditions, no significant differences in 5-HT or 5-HIAA levels could be found between autistic youngsters and normal controls. 5-HTP administration significantly increased the levels of 5-HT in autistic youngsters but not in normal controls. Following 5-HTP challenge the 5-HT levels were significantly higher in autistic patients than in healthy volunteers. After challenge with 5-HTP, no significant differences were found in the concentrations of 5-HIAA or the test substance between autistic youngsters and normal controls. Differences in the peripheral metabolism of 5-HT which may not be observed in baseline conditions but which became clear after loading with 5-HTP, suggest that an increased synthesis of 5-HT from its precursor 5-HTP might be a one factor responsible for differences in the serotonergic system between autistic post-pubertal youngsters and normal controls.

  8. Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy.

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    Martinez, Tara L; Kong, Lingling; Wang, Xueyong; Osborne, Melissa A; Crowder, Melissa E; Van Meerbeke, James P; Xu, Xixi; Davis, Crystal; Wooley, Joe; Goldhamer, David J; Lutz, Cathleen M; Rich, Mark M; Sumner, Charlotte J

    2012-06-20

    The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein and results in severe muscle weakness. In SMA mice, synaptic dysfunction of both neuromuscular junctions (NMJs) and central sensorimotor synapses precedes motor neuron cell death. To address whether this synaptic dysfunction is due to SMN deficiency in motor neurons, muscle, or both, we generated three lines of conditional SMA mice with tissue-specific increases in SMN expression. All three lines of mice showed increased survival, weights, and improved motor behavior. While increased SMN expression in motor neurons prevented synaptic dysfunction at the NMJ and restored motor neuron somal synapses, increased SMN expression in muscle did not affect synaptic function although it did improve myofiber size. Together these data indicate that both peripheral and central synaptic integrity are dependent on motor neurons in SMA, but SMN may have variable roles in the maintenance of these different synapses. At the NMJ, it functions at the presynaptic terminal in a cell-autonomous fashion, but may be necessary for retrograde trophic signaling to presynaptic inputs onto motor neurons. Importantly, SMN also appears to function in muscle growth and/or maintenance independent of motor neurons. Our data suggest that SMN plays distinct roles in muscle, NMJs, and motor neuron somal synapses and that restored function of SMN at all three sites will be necessary for full recovery of muscle power.

  9. The effects of increased central serotonergic activity on prepulse inhibition and habituation of the human startle response

    DEFF Research Database (Denmark)

    Frederiksen, Kristian Steen; Oranje, Bob; Wienberg, Malene

    2007-01-01

    modulation is currently inconsistent. In a double-blind placebo-controlled crossover design, 18 healthy male volunteers received either placebo or a dose of 10 mg of escitalopram (SSRI), after which they were tested in both PPI and habituation of the startle reflex paradigms. No significant differences...

  10. Somatic influences on subjective well-being and affective disorders: the convergence of thermosensory and central serotonergic systems

    OpenAIRE

    Raison, Charles L.; Hale, Matthew W.; Williams, Lawrence E.; Tor D Wager; Lowry, Christopher A.

    2015-01-01

    Current theories suggest that the brain is the sole source of mental illness. However, affective disorders, and major depressive disorder (MDD) in particular, may be better conceptualized as brain-body disorders that involve peripheral systems as well. This perspective emphasizes the embodied, multifaceted physiology of well-being, and suggests that afferent signals from the body may contribute to cognitive and emotional states. In this review, we focus on evidence from preclinical and clinic...

  11. Tramadol and Tramadol+Caffeine Synergism in the Rat Formalin Test Are Mediated by Central Opioid and Serotonergic Mechanisms

    OpenAIRE

    Norma Carrillo-Munguía; Ma. Eva González-Trujano; Miguel Huerta; Xochitl Trujillo; M. Irene Díaz-Reval

    2015-01-01

    Different analgesic combinations with caffeine have shown this drug to be capable of increasing the analgesic effect. Many combinations with nonsteroidal anti-inflammatory drugs (NSAIDs) have been carried out, but, in regard to opioids, only combinations with morphine and tramadol have been reported. The antinociceptive synergism mechanism of these combinations is not well understood. The purpose of the present study was to determine the participation of spinal and supraspinal opioidergic and...

  12. The effects of increased central serotonergic activity on prepulse inhibition and habituation of the human startle response

    DEFF Research Database (Denmark)

    Jensen, Kristian S; Oranje, Bob; Wienberg, Malene

    2007-01-01

    modulation is currently inconsistent. In a double-blind placebo-controlled crossover design, 18 healthy male volunteers received either placebo or a dose of 10 mg of escitalopram (SSRI), after which they were tested in both PPI and habituation of the startle reflex paradigms. No significant differences...... between the two treatments were observed on PPI, although escitalopram was found to significantly delay habituation of the ASR. In the current study, escitalopram was found to delay habituation, but it did not affect PPI in healthy male volunteers. As escitalopram is a highly specific SSRI, the results...

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

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

    2014-09-08

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

  14. Primary Neuronal Precursors in Adult Crayfish Brain: Replenishment from a Non-neuronal Source

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    Sandeman David C

    2011-06-01

    involve serotonergic mechanisms. Conclusions These results challenge our current understanding of self-renewal capacity as a defining characteristic of all adult neuronal stem cells. In addition, we suggest that in crayfish, the hematopoietic system may be a source of cells that replenish the niche stem cell pool.

  15. Denial of reward in the neonate shapes sociability and serotonergic activity in the adult rat.

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    Anastasia Diamantopoulou

    Full Text Available BACKGROUND: Manipulations of the early environment are linked to long-lasting alterations of emotionality and social capabilities. Denial of rewarding mother-pup interactions in early life of rats could serve as model for child neglect. Negative consequences for social competence in later life, accompanied by changes in the serotonergic system would be expected. In contrast, rewarding mother-pup contact should promote adequate social abilities. METHODOLOGY/PRINCIPAL FINDINGS: Male Wistar rats trained in a T-maze during postnatal days 10-13 under denial (DER or permission (RER of maternal contact were tested for play behavior in adolescence and for coping with defeat in adulthood. We estimated serotonin (5-HT levels in the brain under basal conditions and following defeat, as well as serotonin receptor 1A (5-HT1A and serotonin transporter (SERT expression. DER rats exhibited increased aggressive-like play behavior in adolescence (i.e. increased nape attacks, p<0.0001 and selected a proactive coping style during defeat in adulthood (higher sum of proactive behaviors: number of attacks, flights, rearings and defensive upright posture; p = 0.011, p<0.05 vs RER, non-handled-NH. In adulthood, they had lower 5-HT levels in both the prefrontal cortex (p<0.05 vs RER and the amygdala (p<0.05 vs NH, increased 5-HT levels following defeat (PFC p<0.0001 and decreased serotonin turnover (amygdala p = 0.008. The number of 5-HT1A immunopositive cells in the CA1 hippocampal area was increased (p<0.05 DER, vs RER, NH; SERT levels in the amygdala were elevated (p<0.05 vs RER, NH, but were lower in the prefrontal cortex (p<0.05 vs NH. CONCLUSIONS/SIGNIFICANCE: Denial of expected maternal reward early in life negatively affects sociability and the serotonergic system in a complex manner. We propose that our animal model could contribute to the identification of the neurobiological correlates of early neglect effects on social behavior and coping with challenges, but

  16. Involvement of the serotonergic system in the anxiolytic-like effect of 2-phenylethynyl butyltellurium in mice.

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    Quines, Caroline B; Da Rocha, Juliana T; Sampaio, Tuane B; Pesarico, Ana Paula; Neto, José S S; Zeni, Gilson; Nogueira, Cristina W

    2015-01-15

    Anxiety is a serious disorder with symptoms manifested at the psychological, behavioral, and physiological levels, accompanied by alterations in the serotonergic system and monoaminergic signaling. In this study, the anxiolytic-like effect of 2-phenylethynyl butyltellurium (PEBT), in three well-consolidated anxiety mouse models (light-dark test, novelty suppressed-feeding, elevated plus-maze), was investigated. The involvement of the serotonergic system, synaptosomal [(3)H] serotonin (5-HT) uptake and monoamine oxidase (MAO A and B) activities on cerebral cortices of mice, was examined. Mice received PEBT (1mg/kg, by intragastric route, i.g.) or canola oil (10 ml/kg, i.g.) 30 min before behavioral tests. The results showed that PEBT was effective in increasing the time spent by mice in the illuminated side on the light-dark box and in the open arms on the elevated plus-maze. PEBT decreased the latency to begin eating on the novelty suppressed-feeding test, indicating an anxiolytic-like effect of PEBT. Furthermore, PEBT reduced [(3)H] 5-HT uptake and selectively inhibited MAO-A activity in cerebral cortex, suggesting the involvement of the serotonergic system in the mechanism of action of this tellurium compound.

  17. Relation of central alpha-adrenoceptor and other receptors to the control of renin secretion.

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    Ganong, W F

    1983-02-01

    The location and nature of the receptors in the brain on which clonidine acts to decrease renin secretion have been investigated in dogs. Clonidine was injected into the vertebral and carotid arteries, and its effects were compared with those of norepinephrine and epinephrine when injected into the third ventricle. It was also injected intravenously (IV) after transection of the brain stem and following treatment with intraventricular 6-hydroxydopamine. The results suggest that the renin-regulating receptors are located in the brain stem in a region different from the receptors mediating the depressor response, that they are alpha 2-adrenoceptors, and that they are postsynaptic in location. Central alpha 1-adrenoceptors appear to mediate increased renin secretion. Central serotonergic receptors also mediate increased renin secretion, but it is not known how the alpha 1- and alpha 2-adrenoceptors interact with the serotonergic systems.

  18. Derivation of high purity neuronal progenitors from human embryonic stem cells.

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    Gabriel Nistor

    Full Text Available The availability of human neuronal progenitors (hNPs in high purity would greatly facilitate neuronal drug discovery and developmental studies, as well as cell replacement strategies for neurodegenerative diseases and conditions, such as spinal cord injury, stroke, Parkinson's disease, Alzheimer's disease, and Huntington's disease. Here we describe for the first time a method for producing hNPs in large quantity and high purity from human embryonic stem cells (hESCs in feeder-free conditions, without the use of exogenous noggin, sonic hedgehog or analogs, rendering the process clinically compliant. The resulting population displays characteristic neuronal-specific markers. When allowed to spontaneously differentiate into neuronal subtypes in vitro, cholinergic, serotonergic, dopaminergic and/or noradrenergic, and medium spiny striatal neurons were observed. When transplanted into the injured spinal cord the hNPs survived, integrated into host tissue, and matured into a variety of neuronal subtypes. Our method of deriving neuronal progenitors from hESCs renders the process amenable to therapeutic and commercial use.

  19. Changes in firing rate and firing pattern of midbrain dopaminergic neurons after lesioning of the dorsal raphe nucleus by 5,7-drhydroxytryptamine in adult rats

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Objective To study the effect of serotonergic efferent projection of the dorsal raphe nucleus(DRN)on the activity of substantia nigra pars compacta(SNc)and ventral tegmenta area(VTA)dopaminergic neurons after lesioning of the DRN by the neurotoxin 5,7-drhydroxytryptamine(5,7-DHT)in rat.Methods The changes in the firing rate and firing pattern of SNc and VTA dopaminergic neurons were observed with extracellular recording in control and the lesioned rats.Results The results showed that the mean firing rates o...

  20. A pharmacological analysis of serotonergic receptors: effects of their activation of blockade in learning.

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    Meneses, A; Hong, E

    1997-02-01

    1. The authors have tested several 5-HT selective agonists and antagonists (5-HT1A/1B, 5-HT2A/2B/2C, 5-HT3 or 5-HT4), an uptake inhibitor and 5-HT depletors in the autoshaping learning task. 2. The present work deals with the receptors whose stimulation increases or decreases learning. 3. Impaired consolidation of learning was observed after the presynaptic activation of 5-HT1B, 5-HT3 or 5-HT4 or the blockade of postsynaptic 5-HT2C/2B receptors. 4. In contrast, an improvement occurred after the presynaptic activation of 5-HT1A, 5-HT2C, and the blockade of presynaptic 5-HT2A, 5-HT2C and 5-HT3 receptors. 5. The blockade of postsynaptic 5-HT1A, 5-HT1B, 5-HT3 or 5-HT4 receptors and 5-HT inhibition of synthesis and its depletion did no alter learning by themselves. 6. The present data suggest that multiple pre- and postsynaptic serotonergic receptors are involved in the consolidation of learning. 7. Stimulation of most 5-HT receptors increases learning, however, some of 5-HT subtypes seem to limit the data storage. 8. Furthermore, the role of 5-HT receptors in learning seem to require an interaction with glutamatergic, GABAergic and cholinergic neurotransmission systems.

  1. Fisetin exerts antihyperalgesic effect in a mouse model of neuropathic pain: engagement of spinal serotonergic system.

    Science.gov (United States)

    Zhao, Xin; Wang, Chuang; Cui, Wu-Geng; Ma, Qing; Zhou, Wen-Hua

    2015-03-12

    Fisetin, a natural flavonoid, has been shown in our previous studies to exert antidepressant-like effect. As antidepressant drugs are clinically used to treat chronic neuropathic pain, this work aimed to investigate the potential antinociceptive efficacies of fisetin against neuropathic pain and explore mechanism(s). We subjected mice to chronic constriction injury (CCI) by loosely ligating the sciatic nerves, and Hargreaves test or von Frey test was used to assess thermal hyperalgesia or mechanical allodynia, respectively. Chronic fisetin treatment (5, 15 or 45 mg/kg, p.o.) ameliorated thermal hyperalgesia (but not mechanical allodynia) in CCI mice, concomitant with escalated levels of spinal monoamines and suppressed monoamine oxidase (MAO)-A activity. The antihyperalgesic action of fisetin was abolished by chemical depletion of spinal serotonin (5-HT) but potentiated by co-treatment with 5-HTP, a precursor of 5-HT. Moreover, intraperitoneal (i.p.) or intrathecal (i.t.) co-treatment with 5-HT7 receptor antagonist SB-258719 completely abrogated fisetin's antihyperalgesia. These findings confirm that chronic fisetin treatment exerts antinociceptive effect on thermal hyperalgesia in neuropathic mice, with spinal serotonergic system (coupled with 5-HT7) being critically involved. Of special benefit, fisetin attenuated co-morbidly behavioral symptoms of depression and anxiety (evaluated in forced swim test, novelty suppressed feeding test and light-dark test) evoked by neuropathic pain.

  2. Serotonergic, Brain Volume and Attentional Correlates of Trait Anxiety in Primates

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    Mikheenko, Yevheniia; Shiba, Yoshiro; Sawiak, Stephen; Braesicke, Katrin; Cockcroft, Gemma; Clarke, Hannah; Roberts, Angela C

    2015-01-01

    Trait anxiety is a risk factor for the development and maintenance of affective disorders, and insights into the underlying brain mechanisms are vital for improving treatment and prevention strategies. Translational studies in non-human primates, where targeted neurochemical and genetic manipulations can be made, are critical in view of their close neuroanatomical similarity to humans in brain regions implicated in trait anxiety. Thus, we characterised the serotonergic and regional brain volume correlates of trait-like anxiety in the marmoset monkey. Low- and high-anxious animals were identified by behavioral responses to a human intruder (HI) that are known to be sensitive to anxiolytic drug treatment. Extracellular serotonin levels within the amygdala were measured with in vivo microdialysis, at baseline and in response to challenge with the selective serotonin reuptake inhibitor, citalopram. Regional brain volume was assessed by structural magnetic resonance imaging. Anxious individuals showed persistent, long-term fearful responses to both a HI and a model snake, alongside sustained attention (vigilance) to novel cues in a context associated with unpredictable threat. Neurally, high-anxious marmosets showed reduced amygdala serotonin levels, and smaller volumes in a closely connected prefrontal region, the dorsal anterior cingulate cortex. These findings highlight behavioral and neural similarities between trait-like anxiety in marmosets and humans, and set the stage for further investigation of the processes contributing to vulnerability and resilience to affective disorders. PMID:25586542

  3. Pharmacological profiling an abundantly expressed schistosome serotonergic GPCR identifies nuciferine as a potent antagonist

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    John D. Chan

    2016-12-01

    Full Text Available 5-hydroxytryptamine (5-HT is a key regulator of muscle contraction in parasitic flatworms. In Schistosoma mansoni, the myoexcitatory action of 5-HT is effected through activation of a serotonergic GPCR (Sm.5HTRL, prioritizing pharmacological characterization of this target for anthelmintic drug discovery. Here, we have examined the effects of several aporphine alkaloids on the signaling activity of a heterologously expressed Sm.5HTRL construct using a cAMP biosensor assay. Four structurally related natural products – nuciferine, D-glaucine, boldine and bulbocapnine – were demonstrated to block Sm.5HTRL evoked cAMP generation with the potency of GPCR blockade correlating well with the ability of each drug to inhibit contractility of schistosomule larvae. Nuciferine was also effective at inhibiting both basal and 5-HT evoked motility of adult schistosomes. These data advance our understanding of structure-affinity relationships at Sm.5HTRL, and demonstrate the effectiveness of Sm.5HTRL antagonists as hypomotility-evoking drugs across different parasite life cycle stages.

  4. Effects of Serotonergic and Opioidergic Drugs on Escape Behaviors and Social Status of Male Crickets

    Science.gov (United States)

    Dyakonova, V. E.; Schürmann, F.-W.; Sakharov, D. A.

    We examined the effects of selective serotonin depletion and opioid ligands on social rank and related escape behavior of the cricket Gryllus bimaculatus. Establishment of social rank in a pair of males affected their escape reactions. Losers showed a lower and dominants a higher percentage of jumps in response to tactile cercal stimulation than before a fight. The serotonin-depleting drug α-methyltryptophan (AMTP) caused an activation of the escape reactivity in socially naive crickets. AMTP-treated animals also showed a lower ability to become dominants. With an initial 51.6+/-3.6% of wins in the AMTP group, the percentage decreased to 26+/-1.6% on day 5 after injection. The opiate receptor antagonist naloxone affected fight and escape similarly as AMTP. In contrast to naloxone, the opioid agonist [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin decreased escape responsiveness to cercal stimulation in naive and subordinate crickets. We suggest that serotonergic and opioid systems are involved in the dominance induced depression of escape behavior.

  5. Switching-on of serotonergic calcium signaling in activated hepatic stellate cells

    Institute of Scientific and Technical Information of China (English)

    Kyu-Sang Park; Pyo-Jin Sin; Dong Hyeon Lee; Seung-Kuy Cha; Min-Jeong Kim; Na-Hyun Kim; Soon-Koo Baik; Seong-Woo Jeong; In Deok Kong

    2011-01-01

    AIM: To investigate serotonergic Ca2+ signaling and the expression of 5-hydroxytryptamine (5-HT) receptors,as well as Ca2+ transporting proteins, in hepatic stellate cells (HSCs).METHODS: The intracellular Ca2+ concentration ([Ca2+]i)of isolated rat HSCs was measured with a fluorescence microscopic imaging system. Quantitative PCR was performed to determine the transcriptional levels of 5-HT receptors and endoplasmic reticulum (ER) proteins involved in Ca2+ storage and release in cultured rat HSCs.RESULTS: Distinct from quiescent cells, activated HSCs exhibited [Ca2+]i transients following treatment with 5-HT, which was abolished by U-73122, a phospholipase C inhibitor. Upregulation of 5-HT2A and 5-HT2B receptors,but not 5-HT3, was prominent during trans-differentiation of HSCs. Pretreatment with ritanserin, a 5-HT2 antagonist, inhibited [Ca2+]i changes upon application of 5-HT. Expression of type 1 inositol-5'-triphosphate receptor and type 2 sarcoplasmic/endoplasmic reticulum Ca2+ ATPase were also increased during activation of HSCs and serve as the major isotypes for ER Ca2+ storage and release in activated HSCs. Ca2+ binding chaperone proteins of the ER, including calreticulin, calnexin and calsequestrin, were up-regulated following activation of HSCs.CONCLUSION: The appearance of 5-HT-induced [Ca2+]i response accompanied by upregulation of metabotropic 5-HT2 receptors and Ca2+ transporting/chaperone ER proteins may participate in the activating process of HSCs.

  6. Antidepressants are selective serotonin neuronal reuptake inhibitors: 40-year history

    Directory of Open Access Journals (Sweden)

    D. S. Danilov

    2015-01-01

    Full Text Available The paper presents historical prerequisites for designing antidepressants from a group of selective serotonin neuronal reuptake inhibitors (SSRIs: to determine a lower serotonin concentration in the different tissues of depressed patients; to establish a higher serotonin concentration in the treatment of depressed patients with tricyclic antidepressants, and to formulate the serotonergic theory of depression. It also provides a consecutive account of the history of clinical introduction of individual SSRI representatives, such as fluoxetine, zimelidine, fluvoxamine, indalpine, citalopram, sertraline, paroxetine, and escitalopram. There are data from the history of studying the mechanism of SSRI action: from the theory of the importance of an increase in the concentration of serotonin in the synaptic cleft to the current understanding of complex successive intracellular rearrangements at the level of the postsynaptic neuron. The history of studying the efficacy of SSRIs in treating depression is considered in detail. Emphasis is laid on the reasons for a paradoxical difference in the evaluations of the efficiency of therapy with SSRIs versus other groups of antidepressants at different developmental stages of psychopharmacology. The role of marketing technologies in disseminating the data on the efficacy of this or that group of antidepressants is described. The practical significance of differences in individual SSRI representatives (the potency of serotonin uptake inhibition; the degree of selectivity and activity against the serotonergic system; the likelihood of an unfavorable pharmacokinetic interaction with other drugs; the half-life of elimination; the quickness of achieving a therapeutic dose is analyzed. Whether it is possible and reasonable to differentially choose different SSRI representatives in the treatment of depressions at the present stage is discussed. The authors state their belief that researches should be continued to

  7. Development and distribution of parvalbumin-positive neurons in the central pathway of the trigeminal proprioception of the rat brainstem%大鼠脑干内三叉神经本体觉中枢通路中小白蛋白样阳性神经元的分布与发育

    Institute of Scientific and Technical Information of China (English)

    庞有旺; 李金莲

    2002-01-01

    Immunohistochemical techniques were used to investigate the development and distribution of parvalbuminlike immunoreactive(PV-LI) neurons in the central pathway of the trigeminal proprioception of the rat brainstem. It was found that: ① Atembryonic day 13 (E13), PV-LI neurons were observed initially in the mesencephalic trigeminal nucleus(Vme). Most PV-LI neurons were large pseudounipolar neurons with moderate immunostaining. ②At postnatal day 3 ( P3), more neurons were labeled with intense immunostaining in the Vme, so was the Probst' s ract. ③At P10, moder- ately PV-LI neurons appeared both in the dorsomedial part of the subnucleus oralis of the spinal trigeminal nucleus (Vodm), and in the dorsomedial part of the principal sensory trigeminal nucleus (Vpdm). ④At P14, PV-LI neurons were first detected in the lateral reticular formation adjacent to the Vodm( LRF), caudolateral part of the supratrigeminal nucleus (Vsup-CL), area ventral to the motor trigeminal nucleus (AVM), and area dorsal to the superior olivery nucleus(ADO). ⑤At P21, PV-LI neurons and fibers attained the adult pattern in the Vodm-LRF, and “zone-shaped area” whichincludes the Vpdm, Vsup-CL, ADO, and AVM. The present results indicated that the istribution and development of PV-LI neurons and the formation of PV-LI fibers possibly coincided with the functional maturation of the neurons in the rat brainstem central pathway of the trigeminal proprioception during the prenatal and postnatal development stages.%应用免疫组织化学技术对脑干内三叉神经本体觉中枢通路中PV样阳性神经元的分布与发育进行了观察.结果发现:①早在胚胎13 d时,首先在三叉神经中脑核(Vme)内观察到许多含小白蛋白(Parvalbumin,PV)样阳性神经元,主要为大的假单极神经元,呈中等阳性反应.②生后3 d时,Vme内PV样阳性神经元的数量明显增多,免疫反应呈强阳性,并可观察到Probst束呈强阳性反应.③生后10 d时,在三叉

  8. Glial involvement in trigeminal central sensitization

    Institute of Scientific and Technical Information of China (English)

    Yu-feng XIE

    2008-01-01

    Recent studies have indicated that trigeminal neurons exhibit central sensitization, an increase in the excitability of neurons within the central nervous system to the extent that a normally innocuous stimulus begins to produce pain after inflamma-tion or injury, and that glial activities play a vital role in this central sensitization. The involvement of glial cells in trigeminal central sensitization contains multiple mechanisms, including interaction with glutamatergic and purinergic receptors. A better understanding of the trigeminal central sensitization mediated by glial cells will help to find potential therapeutic targets and lead to developing new analge-sics for orofacial-specific pain with higher efficiency and fewer side-effects.

  9. Epibranchial placode-derived neurons produce BDNF required for early sensory neuron development.

    Science.gov (United States)

    Harlow, Danielle E; Yang, Hui; Williams, Trevor; Barlow, Linda A

    2011-02-01

    In mice, BDNF provided by the developing taste epithelium is required for gustatory neuron survival following target innervation. However, we find that expression of BDNF, as detected by BDNF-driven β-galactosidase, begins in the cranial ganglia before its expression in the central (hindbrain) or peripheral (taste papillae) targets of these sensory neurons, and before gustatory ganglion cells innervate either target. To test early BDNF function, we examined the ganglia of bdnf null mice before target innervation, and found that while initial neuron survival is unaltered, early neuron development is disrupted. In addition, fate mapping analysis in mice demonstrates that murine cranial ganglia arise from two embryonic populations, i.e., epibranchial placodes and neural crest, as has been described for these ganglia in non-mammalian vertebrates. Only placodal neurons produce BDNF, however, which indicates that prior to innervation, early ganglionic BDNF produced by placode-derived cells promotes gustatory neuron development.

  10. Mirror neurons: their implications for group psychotherapy.

    Science.gov (United States)

    Schermer, Victor L

    2010-10-01

    Recently discovered mirror neurons in the motor cortex of the brain register the actions and intentions of both the organism and others in the environment. As such, they may play a significant role in social behavior and groups. This paper considers the potential implications of mirror neurons and related neural networks for group therapists, proposing that mirror neurons and mirror systems provide "hard-wired" support for the group therapist's belief in the centrality of relationships in the treatment process and exploring their value in accounting for group-as-a-whole phenomena. Mirror neurons further confirm the holistic, social nature of perception, action, and intention as distinct from a stimulus-response behaviorism. The implications of mirror neurons and mirroring processes for the group therapist role, interventions, and training are also discussed.

  11. Reflections on mirror neurons and speech perception.

    Science.gov (United States)

    Lotto, Andrew J; Hickok, Gregory S; Holt, Lori L

    2009-03-01

    The discovery of mirror neurons, a class of neurons that respond when a monkey performs an action and also when the monkey observes others producing the same action, has promoted a renaissance for the Motor Theory (MT) of speech perception. This is because mirror neurons seem to accomplish the same kind of one to one mapping between perception and action that MT theorizes to be the basis of human speech communication. However, this seeming correspondence is superficial, and there are theoretical and empirical reasons to temper enthusiasm about the explanatory role mirror neurons might have for speech perception. In fact, rather than providing support for MT, mirror neurons are actually inconsistent with the central tenets of MT.

  12. Effect of electro-acupuncture on nitric oxide synthase positive neurons in grey matter around the central canal in formalin-induced inflammatory hyperalgesic rats%电针对福尔马林炎性痛大鼠脊髓中央管周围灰质神经元一氧化氮合酶表达的影响

    Institute of Scientific and Technical Information of China (English)

    王泳; 马素英

    2011-01-01

    目的 探讨电针对福尔马林炎性痛大鼠脊髓中央管周围灰质神经元一氧化氮合酶(NOS)表达的影响.方法 应用还原型尼克酰胺腺嘌呤二核苷酸磷酸脱氢酶法,观察在正常情况下(正常组)、疼痛刺激下(疼痛刺激组)、电针刺激下(电针刺激组)、疼痛加电针刺激下(疼痛+电针刺激组)NOS阳性神经元在脊髓中央管周围灰质的表达.结果 正常组脊髓中央管周围灰质有少量NOS阳性细胞,疼痛刺激组NOS阳性细胞数目较正常组增多(P<0.01),电针刺激组NOS阳性细胞与正常组比较差别无统计学意义(P>O.05);疼痛+电针刺激组NOS阳性细胞数较疼痛刺激组明显减少(P<0.01),而与正常组相比差别无统计学意义(P>0.05).结论 抑制疼痛刺激引起的NOS阳性细胞数目增多,可能是电针镇痛的机制之一.%Objective To study the effect of electro-acupuncture on nitric oxide synthase ( NOS)-positive neurons a-round the central canal in formalin-induced inflammatory hyperalgesic rats. Methods Expression of NOS-positive neurons in the grey matter around the central canal in spinal cord when animal was normal, pain stimulated, electroacupuncture stimulated, or pain and electro-acupuncture stimulated was observed by nicotinamide adenine dinucletide phosphoric acid-dehydrogen-ase. Results There were a few NOS-positive neurons in the grey matter around the central canal in spinal cord in normal group;In pain stimulation group,the number of the neurons increased greatly compared with normal group( P <0. 01);There was no statistical significance in the number of NOS-positive neurons between the electro-acupuncture stimulation group and normal group(p>0.05) ;Compared with pain stimulation group,the number of NOS-positive neurons in the pain and electro-acupuncture stimulation group decreased significantly (P <0. 01), but there was no statistical significance in the number of NOS-positive neurons between the pain and

  13. Combined Norepinephrine / Serotonergic Reuptake Inhibition: Effects on Maternal Behavior, Aggression and Oxytocin in the Rat

    Directory of Open Access Journals (Sweden)

    Elizabeth Thomas Cox

    2011-06-01

    Full Text Available BACKGROUND: Few systematic studies exist on the effects of chronic reuptake of monoamine neurotransmitter systems during pregnancy on the regulation of maternal behavior, although many drugs act primarily through one or more of these systems. Previous studies examining fluoxetine and amfonelic acid treatment during gestation on subsequent maternal behavior in rodents indicated significant alterations in postpartum maternal care, aggression and oxytocin levels. In this study, we extended our studies to include chronic gestational treatment with desipramine or amitriptyline to examine differential effects of reuptake inhibition of norepinephrine and combined noradrenergic and serotonergic systems on maternal behavior, aggression, and oxytocin system changes. METHODS: Pregnant Sprague-Dawley rats were treated throughout gestation with saline or one of three doses of either desipramine, which has a high affinity for the norepinephrine monoamine transporter, or amitriptyline, an agent with high affinity for both the norepinephrine and serotonin monoamine transporters. Maternal behavior and postpartum aggression were assessed on postpartum days one and six respectively. Oxytocin levels were measured in relevant brain regions on postpartum day seven. Predictions were that amitriptyline would decrease maternal behavior and increase aggression relative to desipramine, particularly at higher doses. Amygdaloidal oxytocin was expected to decrease with increased aggression. RESULTS: Amitriptyline and desiprimine differentially reduced maternal behavior, and at higher doses reduced aggressive behavior. Hippocampal oxytocin levels were lower after treatment with either drug but were not correlated with specific behavioral effects. These results, in combination with previous findings following gestational treatment with other selective neurotransmitter reuptake inhibitors, highlight the diverse effects of multiple monoamine systems thought to be involved in

  14. Increased serotonergic innervation of lumbosacral motoneurons of rolling mouse Nagoya in correlation with abnormal hindlimb extension.

    Science.gov (United States)

    Koyanagi, Y; Sawada, K; Sakata-Haga, H; Jeong, Y-G; Fukui, Y

    2006-12-01

    Rolling Mouse Nagoya (RMN) carries a mutation in a gene encoding for alpha(1A) subunit of P/Q-type Ca(2+) channel (Ca(v)2.1). In addition to ataxia, this mutant mouse exhibits abnormal hindlimb extension, which is characterized by a sustained excessive tone of hindlimb extensor muscles. This study aimed to clarify whether serotonergic (5-HTergic) innervation of the spinal motoneurons was altered in RMN in relation to the abnormal hindlimb extension. The density of 5-HT immunoreactive fibres in the ventral horn of lumbar and sacral regions of spinal cord was significantly greater in RMN than in controls. Retrograde wheat germ agglutinin-conjugated horseradish peroxidase (WGA-HRP) labelling combined with 5-HT immunostaining revealed that the number of 5-HT immunoreactive terminals adjoining femoris quadriceps motoneurons was about 2.5-fold greater in RMN than in controls. Furthermore, 5-HT immunostaining in the lumbar cord ventral horn was examined in three other Ca(v)2.1 mutant mice (tottering, leaner and pogo) as to whether or not they showed the abnormal hindlimb extension. Among these mutants, the increased density of 5-HT immunoreactive fibres was observed in correlation with the presence of the abnormal hindlimb extension. The results suggest an increased 5-HTergic innervation of the lumbosacral motoneurons in correlation with the abnormal hindlimb extension in RMN and other Ca(v)2.1 mutant mice. As 5-HT is known to induce the sustained membrane depolarizations without continuous excitatory synaptic inputs (plateau potentials) in spinal motoneurons, the increased 5-HTergic innervation may cause the sustained excitation of hindlimb extensor motoneurons, resulting in the abnormal hindlimb extension.

  15. Wfs1-deficient mice display altered function of serotonergic system and increased behavioural response to antidepressants

    Directory of Open Access Journals (Sweden)

    Tanel eVisnapuu

    2013-07-01

    Full Text Available It has been shown that mutations in the WFS1 gene make humans more susceptible to mood disorders. Besides that, mood disorders are associated with alterations in the activity of serotonergic and noradrenergic systems. Therefore, in this study, the effects of imipramine, an inhibitor of serotonin (5-HT and noradrenaline (NA reuptake, and paroxetine, a selective inhibitor of 5-HT reuptake, were studied in tests of behavioural despair. The tail suspension test (TST and forced swimming test (FST were performed in Wfs1-deficient mice. Simultaneously, gene expression and monoamine metabolism studies were conducted to evaluate changes in 5-HT- and NA-ergic systems of Wfs1-deficient mice. The basal immobility time of Wfs1-deficient mice in TST and FST did not differ from that of their wild-type littermates. However, a significant reduction of immobility time in response to lower doses of imipramine and paroxetine was observed in homozygous Wfs1-deficient mice, but not in their wild-type littermates. In gene expression studies, the levels of 5-HT transporter (SERT were significantly reduced in the pons of homozygous animals. Monoamine metabolism was assayed separately in the dorsal and ventral striatum of naive mice and mice exposed for 30 minutes tobrightly lit motility boxes. We found that this aversive challenge caused a significant increase in the levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA, a metabolite of 5-HT, in the ventral and dorsal striatum of wild-type mice, but not in their homozygous littermates. Taken together, the blunted 5-HT metabolism and reduced levels of SERT are a likely reason for the elevated sensitivity of these mice to the action of imipramine and paroxetine. These changes in the pharmacological and neurochemical phenotype of Wfs1-deficient mice may help to explain the increased susceptibility of Wolfram syndrome patients to depressive states.

  16. Serotonergic activation of locomotor behavior and posture in one-day old rats.

    Science.gov (United States)

    Swann, Hillary E; Kempe, R Blaine; Van Orden, Ashley M; Brumley, Michele R

    2016-04-01

    The purpose of this study was to determine what dose of quipazine, a serotonergic agonist, facilitates air-stepping and induces postural control and patterns of locomotion in newborn rats. Subjects in both experiments were 1-day-old rat pups. In Experiment 1, pups were restrained and tested for air-stepping in a 35-min test session. Immediately following a 5-min baseline, pups were treated with quipazine (1.0, 3.0, or 10.0 mg/kg) or saline (vehicle control), administered intraperitoneally in a 50 μL injection. Bilateral alternating stepping occurred most frequently following treatment with 10.0 mg/kg quipazine, however the percentage of alternating steps, interlimb phase, and step period were very similar between the 3.0 and 10.0 mg/kg doses. For interlimb phase, the forelimbs and hindlimbs maintained a near perfect anti-phase pattern of coordination, with step period averaging about 1s. In Experiment 2, pups were treated with 3.0 or 10.0 mg/kg quipazine or saline, and then were placed on a surface (open field, unrestrained). Both doses of quipazine resulted in developmentally advanced postural control and locomotor patterns, including head elevation, postural stances, pivoting, crawling, and a few instances of quadrupedal walking. The 3.0 mg/kg dose of quipazine was the most effective at evoking sustained locomotion. Between the 2 experiments, behavior exhibited by the rat pup varied based on testing environment, emphasizing the role that environment and sensory cues exert over motor behavior. Overall, quipazine administered at a dose of 3.0 mg/kg was highly effective at promoting alternating limb coordination and inducing locomotor activity in both testing environments.

  17. Serotonergic effects of dotarizine in coronary artery and in oocytes expressing 5-HT2 receptors.

    Science.gov (United States)

    Montiel, C; Herrero, C J; García-Palomero, E; Renart, J; García, A G; Lomax, R B

    1997-08-01

    In strips of pig coronary arteries incubated in oxygenated Krebs-bicarbonate solution at 37 degrees C, dotarizine blocked the phasic contractions evoked by 5-HT (0.5 microM) or K+ depolarization (35 mM K+) with an IC50 of 0.22 and 3.7 microM, respectively. Flunarizine inhibited both types of contractions with IC50 values of 1.7 microM for 5-HT and 2.4 microM for K+ responses. In Xenopus oocytes injected with in vitro transcribed RNA encoding for 5-HT2A or 5-HT2C receptors, 5-HT (100 nM for 20 s) applied every 10 min caused, in both cases, a reproducible inward current through Ca2(+)-activated Cl- channels (ICl). Dotarizine inhibited the 5-HT2A response in a concentration-dependent manner, with an IC50 of 2.2 nM. In contrast, the 5-HT2C response was unaffected by 1 microM dotarizine and blocked around 62% by 10 microM of this drug. The ICl activated either by intracellular injection of inositol 1,4,5-trisphosphate (IP3) in oocytes or by direct photorelease of Ca2+ in DM-nitrophen-injected oocytes was unaffected by 10 microM dotarizine. It is concluded that dotarizine blocks 5-HT2A receptors with a high affinity; the compound is devoid of intracellular effects on any further steps of the transduction pathway (i.e., IP3 receptor). Contrary to flunarizine that blocks equally well the serotonergic and the K+ vascular responses, dotarizine exhibits 17-fold higher affinity for vascular 5-HT receptors. These findings might be relevant to an understanding of the mechanism involved in the use of dotarizine and flunarizine as prophylactic agents in migraine.

  18. Changes in firing rate and firing pattern of midbrain dopaminergic neurons after lesioning of the dorsal raphe nucleus by 5,7-drhydroxytryptamine in adult rats

    Institute of Scientific and Technical Information of China (English)

    Wang Shuang; Liu Jian; Wang Tao; Han Lingna; Zhang Qiaojun; Li Qiang

    2008-01-01

    Objective To study the effect of serotonergic efferent projection of the dorsal rophe nucleus (DRN) on the activity of substantia nigro pars compacta (SNc) and ventral tegmenta area (VTA) dopaminergic neurons after lesioning of the DRN by the neurotoxin 5,7-drhydroxytryptamine (5,7-DHT) in rot. Methods The changes in the firing rote and firing pattern of SNc and VTA dopaminergic neurons were observed with extrocellular recording in control and the lesioned rats. Results The results showed that the mean firing rotes of the fast-firing dopaminergic neurons of the SNc in control and the lesioned rots were (5.34±0. 13 ) Hz (n = 23 ) and ( 7.13±0. 49 ) Hz (n=37), respectively. The mean firing rote of the fast-firing dopaminergic neurons of the SNc in the lesioned rats was significantly increased when compared to that of control rots (P<0.01), while the mean firing rote of the slow-firing dopaminergic neurons of the SNc did not change. The mean firing rotes of dopaminergic neurons of the VTA in control and the lesioned rots were (5.27±0. 38)Hz (n=35) and (3.6±0.2)Hz (n=52), respectively. Lesioning of the DRN induced a significant decrease in the mean firing rote of dopaminergic neurons of the VTA. The firing pattern of SNc and VTA dopaminergic neurons changed towards a more bursting or irrgular firing after the lesioning. Conlusion These data suggest that the serotonergic efferent projections of the DRN significantly affect the activity of SNe and VTA dopaminergic neurons.

  19. Human mirror neuron system and its plasticity

    Institute of Scientific and Technical Information of China (English)

    Wei Chen; Tifei Yuan; Yin Wang; Jun Ding

    2008-01-01

    The mirror neuron system (MNS) was first discovered in non-human primates; these neurons fire when a monkey performs an action or observes another monkey (or even some people) performing that same action. Recent findings have suggested that neural rehabilitation might be achieved through the activation of the MNS in patients after stroke. We propose two major mechanisms (one involving adult neurogenesis and another involving brain-derived neurotrophic factor) that may underlie the activation, modulation and expe-rience-dependent plasticity in the MNS, for further study on promoting central nerve functional reconstruc-tion and rehabilitation of patients with central nervous system injury.

  20. Selective loss of alpha motor neurons with sparing of gamma motor neurons and spinal cord cholinergic neurons in a mouse model of spinal muscular atrophy.

    Science.gov (United States)

    Powis, Rachael A; Gillingwater, Thomas H

    2016-03-01

    Spinal muscular atrophy (SMA) is a neuromuscular disease characterised primarily by loss of lower motor neurons from the ventral grey horn of the spinal cord and proximal muscle atrophy. Recent experiments utilising mouse models of SMA have demonstrated that not all motor neurons are equally susceptible to the disease, revealing that other populations of neurons can also be affected. Here, we have extended investigations of selective vulnerability of neuronal populations in the spinal cord of SMA mice to include comparative assessments of alpha motor neuron (α-MN) and gamma motor neuron (γ-MN) pools, as well as other populations of cholinergic neurons. Immunohistochemical analyses of late-symptomatic SMA mouse spinal cord revealed that numbers of α-MNs were significantly reduced at all levels of the spinal cord compared with controls, whereas numbers of γ-MNs remained stable. Likewise, the average size of α-MN cell somata was decreased in SMA mice with no change occurring in γ-MNs. Evaluation of other pools of spinal cord cholinergic neurons revealed that pre-ganglionic sympathetic neurons, central canal cluster interneurons, partition interneurons and preganglionic autonomic dorsal commissural nucleus neuron numbers all remained unaffected in SMA mice. Taken together, these findings indicate that α-MNs are uniquely vulnerable among cholinergic neuron populations in the SMA mouse spinal cord, with γ-MNs and other cholinergic neuronal populations being largely spared.

  1. Regulation of neuronal lineage decisions by the HES-related bHLH protein REF-1.

    Science.gov (United States)

    Lanjuin, Anne; Claggett, Julia; Shibuya, Mayumi; Hunter, Craig P; Sengupta, Piali

    2006-02-01

    Members of the HES subfamily of bHLH proteins play crucial roles in neural patterning via repression of neurogenesis. In C. elegans, loss-of-function mutations in ref-1, a distant nematode-specific member of this subfamily, were previously shown to cause ectopic neurogenesis from postembryonic lineages. However, while the vast majority of the nervous system in C. elegans is generated embryonically, the role of REF-1 in regulating these neural lineage decisions is unknown. Here, we show that mutations in ref-1 result in the generation of multiple ectopic neuron types derived from an embryonic neuroblast. In wild-type animals, neurons derived from this sublineage are present in a left/right symmetrical manner. However, in ref-1 mutants, while the ectopically generated neurons exhibit gene expression profiles characteristic of neurons on the left, they are present only on the right side. REF-1 functions in a Notch-independent manner to regulate this ectopic lineage decision. We also demonstrate that loss of REF-1 function results in defective differentiation of an embryonically generated serotonergic neuron type. These results indicate that REF-1 functions in both Notch-dependent and independent pathways to regulate multiple developmental decisions in different neuronal sublineages.

  2. Sodium salicylate suppresses GABAergic inhibitory activity in neurons of rodent dorsal raphe nucleus.

    Directory of Open Access Journals (Sweden)

    Yan Jin

    Full Text Available Sodium salicylate (NaSal, a tinnitus inducing agent, can activate serotonergic (5-HTergic neurons in the dorsal raphe nucleus (DRN and can increase serotonin (5-HT level in the inferior colliculus and the auditory cortex in rodents. To explore the underlying neural mechanisms, we first examined effects of NaSal on neuronal intrinsic properties and the inhibitory synaptic transmissions in DRN slices of rats by using whole-cell patch-clamp technique. We found that NaSal hyperpolarized the resting membrane potential, decreased the input resistance, and suppressed spontaneous and current-evoked firing in GABAergic neurons, but not in 5-HTergic neurons. In addition, NaSal reduced GABAergic spontaneous and miniature inhibitory postsynaptic currents in 5-HTergic neurons. We next examined whether the observed depression of GABAergic activity would cause an increase in the excitability of 5-HTergic neurons using optogenetic technique in DRN slices of the transgenic mouse with channelrhodopsin-2 expressed in GABAergic neurons. When the GABAergic inhibition was enhanced by optical stimulation to GABAergic neurons in mouse DRN, NaSal significantly depolarized the resting membrane potential, increased the input resistance and increased current-evoked firing of 5-HTergic neurons. However, NaSal would fail to increase the excitability of 5-HTergic neurons when the GABAergic synaptic transmission was blocked by picrotoxin, a GABA receptor antagonist. Our results indicate that NaSal suppresses the GABAergic activities to raise the excitability of local 5-HTergic neural circuits in the DRN, which may contribute to the elevated 5-HT level by NaSal in the brain.

  3. Serotonergic and noradrenergic lesions suppress the enhancing effect of maternal exercise during pregnancy on learning and memory in rat pups.

    Science.gov (United States)

    Akhavan, M M; Emami-Abarghoie, M; Safari, M; Sadighi-Moghaddam, B; Vafaei, A A; Bandegi, A R; Rashidy-Pour, A

    2008-02-19

    The beneficial effects of exercise on learning and memory are well documented but the effects of prenatal exposure to maternal exercise on offspring are not clear yet. Using a two-trial-per-day Morris water maze for five consecutive days, succeeded by a probe trial 2 days later we showed that maternal voluntary exercise (wheel running) by pregnant rats increased the acquisition phase of the pups' learning. Maternal forced swimming by pregnant rats increased both acquisition and retention phases of the pups' learning. Also we found that the rat pups whose mother was submitted to forced-swimming during pregnancy had significantly higher brain, liver, heart and kidney weights compared with their sedentary counterparts. On the other hand we estimated the cell number of different regions of the hippocampus in the rat pups. We found that both exercise models during pregnancy increased the cell number in cornus ammonis subregion 1 (CA1) and dentate gyrus of the hippocampus in rat pups. To determine the role that noradrenergic and serotonergic neurotransmission and N-methyl-D-aspartate (NMDA) receptors hold in mediation of the maternal exercise in offspring, we used N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), p-chloroamphetamine (PCA) and MK-801 to eliminate or block the above systems, respectively. Blocking the NMDA receptors, significantly abolished learning and memory in rat pups from all three experimental groups. Elimination of noradrenergic or serotonergic input did not significantly attenuate the learning and memory in rat pups whose mothers were sedentary, while it significantly reversed the positive effects of maternal exercise during pregnancy on rat pups' learning and memory. The presented results suggest that noradrenergic and serotonergic systems in offspring brain seem to have a crucial specific role in mediating the effects of maternal physical activity during pregnancy on rat pups' cognitive function in both models of voluntary and forced exercise.

  4. Development of a mechanism-based pharmacokinetic/pharmacodynamic model to characterize the thermoregulatory effects of serotonergic drugs in mice

    Directory of Open Access Journals (Sweden)

    Xi-Ling Jiang

    2016-09-01

    Full Text Available We have shown recently that concurrent harmaline, a monoamine oxidase-A inhibitor (MAOI, potentiates serotonin (5-HT receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT-induced hyperthermia. The objective of this study was to develop an integrated pharmacokinetic/pharmacodynamic (PK/PD model to characterize and predict the thermoregulatory effects of such serotonergic drugs in mice. Physiological thermoregulation was described by a mechanism-based indirect-response model with adaptive feedback control. Harmaline-induced hypothermia and 5-MeO-DMT–elicited hyperthermia were attributable to the loss of heat through the activation of 5-HT1A receptor and thermogenesis via the stimulation of 5-HT2A receptor, respectively. Thus serotonergic 5-MeO-DMT–induced hyperthermia was readily distinguished from handling/injection stress-provoked hyperthermic effects. This PK/PD model was able to simultaneously describe all experimental data including the impact of drug-metabolizing enzyme status on 5-MeO-DMT and harmaline PK properties, and drug- and stress-induced simple hypo/hyperthermic and complex biphasic effects. Furthermore, the modeling results revealed a 4-fold decrease of apparent SC50 value (1.88–0.496 µmol/L for 5-MeO-DMT when harmaline was co-administered, providing a quantitative assessment for the impact of concurrent MAOI harmaline on 5-MeO-DMT–induced hyperthermia. In addition, the hyperpyrexia caused by toxic dose combinations of harmaline and 5-MeO-DMT were linked to the increased systemic exposure to harmaline rather than 5-MeO-DMT, although the body temperature profiles were mispredicted by the model. The results indicate that current PK/PD model may be used as a new conceptual framework to define the impact of serotonergic agents and stress factors on thermoregulation.

  5. Release of glutamate and CGRP from trigeminal ganglion neurons: Role of calcium channels and 5-HT1 receptor signaling

    Directory of Open Access Journals (Sweden)

    Hurley Joyce H

    2008-04-01

    Full Text Available Abstract Background The aberrant release of the neurotransmitters, glutamate and calcitonin-gene related peptide (CGRP, from trigeminal neurons has been implicated in migraine. The voltage-gated P/Q-type calcium channel has a critical role in controlling neurotransmitter release and has been linked to Familial Hemiplegic Migraine. Therefore, we examined the importance of voltage-dependent calcium channels in controlling release of glutamate and CGRP from trigeminal ganglion neurons isolated from male and female rats and grown in culture. Serotonergic pathways are likely involved in migraine, as triptans, a class of 5-HT1 receptor agonists, are effective in the treatment of migraine and their effectiveness may be due to inhibiting neurotransmitter release from trigeminal neurons. We also studied the effect of serotonin receptor activation on release of glutamate and CGRP from trigeminal neurons grown in culture. Results P/Q-, N- and L-type channels each mediate a significant fraction of potassium-stimulated release of glutamate and CGRP. We determined that 5-HT significantly inhibits potassium-stimulated release of both glutamate and CGRP. Serotonergic inhibition of both CGRP and glutamate release can be blocked by pertussis toxin and NAS-181, a 5-HT1B/1D antagonist. Stimulated release of CGRP is unaffected by Y-25130, a 5-HT3 antagonist and SB 200646, a 5-HT2B/2C antagonist. Conclusion These data suggest that release of both glutamate and CGRP from trigeminal neurons is controlled by calcium channels and modulated by 5-HT signaling in a pertussis-toxin dependent manner and probably via 5-HT1 receptor signaling. This is the first characterization of glutamate release from trigeminal neurons grown in culture.

  6. Hippocampal serotonin-2A receptor-immunoreactive neurons density increases after testosterone therapy in the gonadectomized male mice

    Science.gov (United States)

    Nikmahzar, Emsehgol; Ghaemi, Amir; Naseri, Gholam Reza; Moharreri, Ali Reza; Lotfinia, Ahmad Ali

    2016-01-01

    The change of steroid levels may also exert different modulatory effects on the number and class of serotonin receptors present in the plasma membrane. The effects of chronic treatment of testosterone for anxiety were examined and expression of 5-HT2A serotonergic receptor, neuron, astrocyte, and dark neuron density in the hippocampus of gonadectomized male mice was determined. Thirty-six adult male NMRI mice were randomly divided into six groups: intact-no testosterone treatment (No T), gonadectomy (GDX)-No T, GDX-Vehicle, GDX-6.25 mg/kg testosterone (T), GDX-12.5 mg/kg T, and GDX-25 mg/kg T. Anxiety-related behavior was evaluated using elevated plus maze apparatus. The animals were anesthetized after 48 hours after behavioral testing, and decapitated and micron slices were prepared for immunohistochemical as well as histopathological assessment. Subcutaneous injection of testosterone (25 mg/kg) may induce anxiogenic-like behavior in male mice. In addition, immunohistochemical data reveal reduced expression of 5-HT2A serotonergic receptor after gonadectomy in all areas of the hippocampus. However, treatment with testosterone could increase the mean number of dark neurons as well as immunoreactive neurons in CA1 and CA3 area, dose dependently. The density of 5-HT2A receptor-immunoreactive neurons may play a crucial role in the induction of anxiety like behavior. As reduction in such receptor expression have shown to significantly enhance anxiety behaviors. However, replacement of testosterone dose dependently enhances the number of 5-HT2A receptor-immunoreactive neurons and interestingly also reduced anxiety like behaviors. PMID:28127501

  7. Spiking Neurons for Analysis of Patterns

    Science.gov (United States)

    Huntsberger, Terrance

    2008-01-01

    Artificial neural networks comprising spiking neurons of a novel type have been conceived as improved pattern-analysis and pattern-recognition computational systems. These neurons are represented by a mathematical model denoted the state-variable model (SVM), which among other things, exploits a computational parallelism inherent in spiking-neuron geometry. Networks of SVM neurons offer advantages of speed and computational efficiency, relative to traditional artificial neural networks. The SVM also overcomes some of the limitations of prior spiking-neuron models. There are numerous potential pattern-recognition, tracking, and data-reduction (data preprocessing) applications for these SVM neural networks on Earth and in exploration of remote planets. Spiking neurons imitate biological neurons more closely than do the neurons of traditional artificial neural networks. A spiking neuron includes a central cell body (soma) surrounded by a tree-like interconnection network (dendrites). Spiking neurons are so named because they generate trains of output pulses (spikes) in response to inputs received from sensors or from other neurons. They gain their speed advantage over traditional neural networks by using the timing of individual spikes for computation, whereas traditional artificial neurons use averages of activity levels over time. Moreover, spiking neurons use the delays inherent in dendritic processing in order to efficiently encode the information content of incoming signals. Because traditional artificial neurons fail to capture this encoding, they have less processing capability, and so it is necessary to use more gates when implementing traditional artificial neurons in electronic circuitry. Such higher-order functions as dynamic tasking are effected by use of pools (collections) of spiking neurons interconnected by spike-transmitting fibers. The SVM includes adaptive thresholds and submodels of transport of ions (in imitation of such transport in biological

  8. General artificial neuron

    Science.gov (United States)

    Degeratu, Vasile; Schiopu, Paul; Degeratu, Stefania

    2007-05-01

    In this paper the authors present a model of artificial neuron named the general artificial neuron. Depending on application this neuron can change self number of inputs, the type of inputs (from excitatory in inhibitory or vice versa), the synaptic weights, the threshold, the type of intensifying functions. It is achieved into optoelectronic technology. Also, into optoelectronic technology a model of general McCulloch-Pitts neuron is showed. The advantages of these neurons are very high because we have to solve different applications with the same neural network, achieved from these neurons, named general neural network.

  9. Parvalbumin-immunoreactive neurons in the human claustrum.

    Science.gov (United States)

    Hinova-Palova, D V; Edelstein, L; Landzhov, B V; Braak, E; Malinova, L G; Minkov, M; Paloff, A; Ovtscharoff, W

    2014-09-01

    The morphology and distribution of parvalbumin-immunoreactive neurons (PV-ir) were studied in the human claustrum. PV-ir neurons were observed throughout the claustrum, with the highest numbers noted in the central (broadest) portion as compared with the dorsal and ventral aspects. Reaction product was evident in the neuronal perikarya, dendritic processes, and spines. In the majority of these labeled neurons, the cytoplasm was devoid of lipofuscin pigment. Cell bodies varied widely in both shape and size, ranging from oval and small, to multipolar and large. PV-ir neurons were classified into two groups, primarily based on dendritic morphology: spiny neurons with long and straight dendrites, and aspiny neurons with thin and curving dendritic processes. PV-ir fibers were seen throughout the neuropil, with many immuno-positive puncta noted.

  10. Estrogenic and serotonergic butenolides from the leaves of Piper hispidum Swingle (Piperaceae)

    Science.gov (United States)

    Michel, Joanna L; Chen, Yegao; Zhang, Hongjie; Huang, Yue; Krunic, Alecjev; Orjala, Jimmy; Veliz, Mario; Soni, Kapil K.; Soejarto, Djaja Doel; Caceres, Armando; Perez, Alice; Mahady, Gail B

    2010-01-01

    Ethnopharmacological relevance Our previous work has demonstrated that several plants in the Piperaceae family are commonly used by the Q’eqchi Maya of Livingston, Guatemala to treat amenorrhea, dysmenorrhea, and pain. Extracts of Piper hispidum Swingle (Piperaceae), bound to the estrogen (ER) and serotonin (5-HT7) receptors. Aim of the study To investigate the estrogenic and serotonergic activities of P. hispidum extracts in functionalized assays, identify the active chemical constituents in the leaf extract, and test these compounds as agonists or antagonists of ER and 5-HT7. Materials and methods The effects of the P. hispidum leaf extracts were investigated in estrogen reporter gene and endogenous gene assays in MCF-7 cells to determine if the extracts acted as an estrogen agonist or antagonist. In addition, the active compounds were isolated using ER- and 5-HT7 receptor bioassay-guided fractionation. The structures of the purified compounds were identified using high-resolution LC-MS and NMR spectroscopic methods. The ER- and 5-HT7-agonist effects of the purified chemical constituents were tested in a 2ERE-reporter gene assay in MCF-7 cells and in serotonin binding and functionalized assays. Results Three butenolides including one new compound (1) were isolated from the leaves of P. hispidum, and their structures were determined. Compound 1 bound to the serotonin receptor 5-HT7 with IC50 values of 16.1 and 8.3 μM, respectively, and using GTP shift assays, compound 1 was found to be a partial agonist of the 5-HT7 receptor. The P. hispidum leaf extracts, as well as compounds 2 and 3 enhanced the expression of estrogen responsive reporter and endogenous genes in MCF-7 cells, demonstrating estrogen agonist effects. Conclusions Extracts of P. hispidum act as agonists of the ER and 5-HT7 receptors. Compound 1, a new natural product, identified as 9, 10-methylenedioxy-5,6-Z-fadyenolide, was isolated as the 5-HT7 agonist. Compounds 2 and 3 are reported for the

  11. Reconstruction of phrenic neuron identity in embryonic stem cell-derived motor neurons.

    Science.gov (United States)

    Machado, Carolina Barcellos; Kanning, Kevin C; Kreis, Patricia; Stevenson, Danielle; Crossley, Martin; Nowak, Magdalena; Iacovino, Michelina; Kyba, Michael; Chambers, David; Blanc, Eric; Lieberam, Ivo

    2014-02-01

    Air breathing is an essential motor function for vertebrates living on land. The rhythm that drives breathing is generated within the central nervous system and relayed via specialised subsets of spinal motor neurons to muscles that regulate lung volume. In mammals, a key respiratory muscle is the diaphragm, which is innervated by motor neurons in the phrenic nucleus. Remarkably, relatively little is known about how this crucial subtype of motor neuron is generated during embryogenesis. Here, we used direct differentiation of motor neurons from mouse embryonic stem cells as a tool to identify genes that direct phrenic neuron identity. We find that three determinants, Pou3f1, Hoxa5 and Notch, act in combination to promote a phrenic neuron molecular identity. We show that Notch signalling induces Pou3f1 in developing motor neurons in vitro and in vivo. This suggests that the phrenic neuron lineage is established through a local source of Notch ligand at mid-cervical levels. Furthermore, we find that the cadherins Pcdh10, which is regulated by Pou3f1 and Hoxa5, and Cdh10, which is controlled by Pou3f1, are both mediators of like-like clustering of motor neuron cell bodies. This specific Pcdh10/Cdh10 activity might provide the means by which phrenic neurons are assembled into a distinct nucleus. Our study provides a framework for understanding how phrenic neuron identity is conferred and will help to generate this rare and inaccessible yet vital neuronal subtype directly from pluripotent stem cells, thus facilitating subsequent functional investigations.

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

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    Junlin eZhang

    2013-05-01

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

  13. Dynamic alterations of serotonergic metabolism and receptors during social isolation of low- and high-active mice.

    Science.gov (United States)

    Rilke, O; Freier, D; Jähkel, M; Oehler, J

    1998-04-01

    Alterations induced by social isolation (1 day to 18 weeks) in low- and high-active mice (LAM and HAM) were studied in respect to serotonin metabolism, [3H]-8-OH-DPAT binding of presynaptic (midbrain), postsynaptic (hippocampus) 5-HT1A receptors and [3H]-ketanserin binding of cortical 5-HT2A receptors. Individual housing of mice was associated with reduction of serotonin metabolism, depending on isolation time and brain structure. Whereas a transient decrease in the striatum and cortex was detected between 1 week and 6 weeks, reduction of cerebellar and hippocampal serotonin metabolism was found later (12-18 weeks). Serotonergic systems of HAM were found to be more reactive to environmental disturbances, and their serotonin metabolism was more affected by social isolation. Isolation-induced upregulation of cortical 5-HT2A receptors was measured only in HAM. Densities of postsynaptic 5-HT1A receptors in the hippocampus did differ either in grouped or isolated mice. However, there were significant differences in hippocampal 5-HT1A receptor affinity, especially between 1 day and 3 weeks. Transient downregulation of presynaptic 5-HT1A receptors in the midbrain was found in isolated mice between 3 and 6 weeks. These results are discussed in terms of interactions between serotonergic alterations and isolation-induced aggression.

  14. The effects of glycogen synthase kinase-3beta in serotonin neurons.

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    Wenjun Zhou

    Full Text Available Glycogen synthase kinase-3 (GSK3 is a constitutively active protein kinase in brain. Increasing evidence has shown that GSK3 acts as a modulator in the serotonin neurotransmission system, including direct interaction with serotonin 1B (5-HT1B receptors in a highly selective manner and prominent modulating effect on 5-HT1B receptor activity. In this study, we utilized the serotonin neuron-selective GSK3β knockout (snGSK3β-KO mice to test if GSK3β in serotonin neurons selectively modulates 5-HT1B autoreceptor activity and function. The snGSK3β-KO mice were generated by crossbreeding GSK3β-floxed mice and ePet1-Cre mice. These mice had normal growth and physiological characteristics, similar numbers of tryptophan hydroxylase-2 (TpH2-expressing serotonin neurons, and the same brain serotonin content as in littermate wild type mice. However, the expression of GSK3β in snGSK3β-KO mice was diminished in TpH2-expressing serotonin neurons. Compared to littermate wild type mice, snGSK3β-KO mice had a reduced response to the 5-HT1B receptor agonist anpirtoline in the regulation of serotonergic neuron firing, cAMP production, and serotonin release, whereas these animals displayed a normal response to the 5-HT1A receptor agonist 8-OH-DPAT. The effect of anpirtoline on the horizontal, center, and vertical activities in the open field test was differentially affected by GSK3β depletion in serotonin neurons, wherein vertical activity, but not horizontal activity, was significantly altered in snGSK3β-KO mice. In addition, there was an enhanced anti-immobility response to anpirtoline in the tail suspension test in snGSK3β-KO mice. Therefore, results of this study demonstrated a serotonin neuron-targeting function of GSK3β by regulating 5-HT1B autoreceptors, which impacts serotonergic neuron firing, serotonin release, and serotonin-regulated behaviors.

  15. NEURON and Python

    OpenAIRE

    Michael Hines; Davison, Andrew P.; Eilif Muller

    2009-01-01

    The NEURON simulation program now allows Python to be used, alone or in combination with NEURON's traditional Hoc interpreter. Adding Python to NEURON has the immediate benefit of making available a very extensive suite of analysis tools written for engineering and science. It also catalyzes NEURON software development by offering users a modern programming tool that is recognized for its flexibility and power to create and maintain complex programs. At the same time, nothing is lost because ...

  16. Modulation of in vivo neuronal sprouting by serotonin in the adult CNS of the snail.

    Science.gov (United States)

    Baker, M W; Croll, R P

    1996-10-01

    1. During in situ recovery from a lesion to the cerebrobuccal connective (CBC) in the snail Achatina fulica, neurons of the buccal ganglia undergo extensive regeneration and sprouting as assessed by axonal dye-fillings of the CBC. 2. These changes are preceded by the distal degeneration of severed fibres from the serotonergic metacerebral giant neuron (MCG), which results in the depletion of serotonin (5-HT) in the ipsilateral buccal ganglion. We have investigated the potential role of this depletion in causing some of the ensuing neuroplastic events. 3. Pharmacological depletion of 5-HT using either 5,7-dihydroxtryptamine or p-chlorophenylalanine in normal, unlesioned animals was found to produce supernumerary neuronal labelling similar to that seen following a lesion. 4. Systemic daily injections of 5-HT were found to partly suppress the sprouting response following the CBC lesion. For example, the contralateral, uninjured MCG which is normally induced by the lesion to sprout novel projections into the denervated ganglion, is suppressed from doing so by the 5-HT treatment. 5. These growth inhibiting effects of 5-HT upon the contralateral MCG could be antagonized by the prior administration of the 5-HT receptor blocker cyproheptadine, suggesting a specific receptor mediated action. 6. We suggest that 5-HT may play a role in governing the state of neuronal outgrowth in vivo in the CNS of the adult snail, as has been suggested by early development and neuronal cultural studies.

  17. Unraveling the central proopiomelanocortin neural circuits

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    Aaron J. Mercer

    2013-02-01

    Full Text Available Central proopiomelanocortin (POMC neurons form a potent anorexigenic network, but our understanding of the integration of this hypothalamic circuit throughout the central nervous system (CNS remains incomplete. POMC neurons extend projections along the rostrocaudal axis of the brain, and can signal with both POMC-derived peptides and fast amino acid neurotransmitters. Although recent experimental advances in circuit-level manipulation have been applied to POMC neurons, many pivotal questions still remain: How and where do POMC neurons integrate metabolic information? Under what conditions do POMC neurons release bioactive molecules throughout the CNS? Are GABA and glutamate or neuropeptides released from POMC neurons more crucial for modulating feeding and metabolism? Resolving the exact stoichiometry of signals evoked from POMC neurons under different metabolic conditions therefore remains an ongoing endeavor. In this review, we analyze the anatomical atlas of this network juxtaposed to the physiological signaling of POMC neurons both in vitro and in vivo. We also consider novel genetic tools to further characterize the function of the POMC circuit in vivo. Our goal is to synthesize a global view of the POMC network, and to highlight gaps that require further research to expand our knowledge on how these neurons modulate energy balance.

  18. Interactions between neuronal and non-neuronal cells in adult rat isolated dorsal root ganglion cells

    Institute of Scientific and Technical Information of China (English)

    NG K Y; WONG Y H; WISE H

    2008-01-01

    Objective The glial cells of the central nervous system are involved in tripartite signaling, therefore we have been investigating the relationship between sensory neurons and non-neuronal cells in isolated preparations of dorsal root ganglia (DRG). Methods The mixed cell cultures of dissociated DRG cells were separated to yield enriched fractions of IB4-positive cells (small diameter, non-peptidergic cells), IB4-negative cells (small diameter, peptidergic cells, and large diameter cells), and non-neuronal cells (principally satellite glial cells, Schwarm cells and fibroblasts). Adenylyl cyclase activity was assayed by measuring production of [3H]cAMP from cells preloaded with [3H]adenine. Results PGE2 and the PGI2 mimetic eicaprost stimulated adenylyl cyclase activity which was inhibited by ONO-AE3-208 (EP4 antagonist) or CAY10441 (IP antagonist) with estimated pA2 values of 8.9 and 8.2, respectively. Surprisingly, both PGE2 and cicaprost-stimulated [3H] cAMP production was greatest in the non-neuronal cell preparation. Furthermore, when the number of non-neuronal cells was kept constant and the number of neuronal cells was increased, we observed a progressive decrease in prostanoid-stimulated activity. Conclusions Sensory neurons appear to regulate prostanoid receptor-mediated cell signaling in non-neuronal cells within the DRG.

  19. Closing the Phenotypic Gap between Transformed Neuronal Cell Lines in Culture and Untransformed Neurons

    Science.gov (United States)

    Myers, Tereance A.; Nickerson, Cheryl A.; Kaushal, Deepak; Ott, C. Mark; HonerzuBentrup, Kerstin; Ramamurthy, Rajee; Nelman-Gonzales, Mayra; Pierson, Duane L.; Philipp, Mario T.

    2008-01-01

    Studies of neuronal dysfunction in the central nervous system (CNS) are frequently limited by the failure of primary neurons to propagate in vitro. Neuronal cell lines can be substituted for primary cells but they often misrepresent normal conditions. We hypothesized that a dimensional (3-D) cell culture system would drive the phenotype of transformed neurons closer to that of untransformed cells. In our studies comparing 3-D versus 2-dimensional (2-D) culture, neuronal SH-SY5Y (SY) cells underwent distinct morphological changes combined with a significant drop in their rate of cell division. Expression of the proto-oncogene N-myc and the RNA binding protein HuD was decreased in 3-D culture as compared to standard 2-D conditions. We observed a decline in the anti-apoptotic protein Bcl-2 in 3-D culture, coupled with increased expression of the pro-apoptotic proteins Bax and Bak. Moreover, thapsigargin (TG)-induced apoptosis was enhanced in the 3-D cells. Microarray analysis demonstrated significantly differing mRNA levels for over 700 genes in the cells of each culture type. These results indicate that a 3-D culture approach narrows the phenotypic gap between neuronal cell lines and primary neurons. The resulting cells may readily be used for in vitro research of neuronal pathogenesis.

  20. PARVALBUMIN-EXPRESSING NEURONS ON THE CENTRAL PATHWAY OF THE TRIGEMINAL PROPRIOCEPTIVE SENSATION OF THE RAT: A DOUBLE LABELING STUDY%Parvalbumin样阳性神经元大鼠三叉神经本体觉中枢通路上的分布--FG逆标与免疫组化相结合研究

    Institute of Scientific and Technical Information of China (English)

    张富兴; 李金莲; 李继硕

    2000-01-01

    Previous studies showed that the Vodm-LRF-including the dorsomedial part of the subnucleus oralis of the spinal trigeminal nucleus and its adjacent lateral reticular formation--contained the second-order neurons on the central pathway of the trigeminal proprioceptive sensation of the rat and the "zone-shaped area"-including the caudolateral part of the supratrigeminal nucleus (Vsup-CL). The dorsomedial part of principal sensory trigeminal nucleus (Vpdm) and two newly found nuclei: the areaventral to the motor trigeminal nucleus (AVM) and the area dorsal to the superior olivary nucleus (ADO)-contained the third order neurons of this pathway. Parvalbumin (PV) is one of the calcium-binding proteins, In this pathway, many PV-like immunoreactive (PV-LI) neurons were observed in Vodm LRF and the "zone-shaped arena", hut there has been no reports so far regarding whether these PV-LI neurons are projection neurons responsible for the transmission of proprioceptive information or the interneurons serving the modulatory function, in the present study, our aim was to solve the problem by a double labeling study by using retrograde tracing method combined with immunofluorescence histochemistry. The results showed that: (1) following the unilateral Fluoro-Gold (FG) injections into the ventral posteromedial nucleus (VPM) of the thalamus and the separated parts of the "zone-shaped area", viz, Vpdm, ADO and AVM, many FG-labeled neurons were always found contralaterally in the "zone-shaped area" and ipsilaterally in the Vodm-LRF, respectively; (2) in either the "zone-shaped area" or the Vodm-LRF, a substantial number of the FG retrogradely labeled neurons showed PV-LI. In the Vsup-CL, Vpdm, AVM and ADO, about 57%, 55%, 11% and 4% of the neurons projecting to the VPM of the thalamus showed pV-LI, respectively. Of the total population of PV-LI neurons in the Vsup-CL, Vpdm. AVM and ADO, about 23%, 79%, 53% and 16% were labeled by FG, respectively. Most of these PV/FG double

  1. Serotonergic Function, Two-Mode Models of Self-Regulation, and Vulnerability to Depression: What Depression Has in Common with Impulsive Aggression

    Science.gov (United States)

    Carver, Charles S.; Johnson, Sheri L.; Joormann, Jutta

    2008-01-01

    Evidence from diverse literatures supports the viewpoint that two modes of self-regulation exist, a lower-order system that responds quickly to associative cues of the moment and a higher-order system that responds more reflectively and planfully; that low serotonergic function is linked to relative dominance of the lower-order system; that how…

  2. Effects of dextromethorphan on MDMA-induced serotonergic aberration in the brains of non-human primates using [123I]-ADAM/SPECT

    Science.gov (United States)

    Ma, Kuo-Hsing; Liu, Tsung-Ta; Weng, Shao-Ju; Chen, Chien-Fu F.; Huang, Yuahn-Sieh; Chueh, Sheau-Huei; Liao, Mei-Hsiu; Chang, Kang-Wei; Sung, Chi-Chang; Hsu, Te-Hung; Huang, Wen-Sheng; Cheng, Cheng-Yi

    2016-01-01

    3,4-Methylenedioxymethamphetamine (MDMA), a common recreational drug, is known to cause serotonergic neurotoxicity in the brain. Dextromethorphan (DM) is a widely used antitussive reported to exert anti-inflammatory effect in vivo. In this study, we examined the long-term effect of MDMA on the primate serotonergic system and the protective property of DM against MDMA-induced serotonergic abnormality using single photon emission computed tomography (SPECT). Nine monkeys (Macaca cyclopis) were divided into three groups, namely control, MDMA and co-treatment (MDMA/DM). [123I]-ADAM was used as the radioligand for serotonin transporters (SERT) in SPECT scans. SERT levels of the brain were evaluated and presented as the uptake ratios (URs) of [123I]-ADAM in several regions of interest of the brain including midbrain, thalamus and striatum. We found that the URs of [123I]-ADAM were significantly lower in the brains of MDMA than control group, indicating lower brain SERT levels in the MDMA-treated monkeys. This MDMA-induced decrease in brain SERT levels could persist for over four years. However, the loss of brain SERT levels was not observed in co-treatment group. These results suggest that DM may exert a protective effect against MDMA-induced serotonergic toxicity in the brains of the non-human primate. PMID:27941910

  3. Myoanatomy and serotonergic nervous system of the ctenostome Hislopia malayensis: evolutionary trends in bodyplan patterning of ectoprocta

    Directory of Open Access Journals (Sweden)

    Wanninger Andreas

    2011-05-01

    Full Text Available Abstract Background Ectoprocta is a large lophotrochozoan clade of colonial suspension feeders comprising over 5.000 extant species. Their phylogenetic position within the Lophotrochzoa remains controversially discussed, but also the internal relationships of the major ectoproct subclades -Phylactolaemata, Stenolaemata, and Gymnolaemata - remains elusive. To gain more insight into the basic configuration of ectoproct muscle systems for phylogenetic considerations, we analysed the adult myoanatomy and the serotonergic nervous system as well as myogenesis in budding stages of the ctenostome Hislopia malayensis. Results In adults, the serotonergic nervous system is restricted to the lophophoral base with a high concentration in the cerebral ganglion and serotonergic perikarya between each pair of tentacles. Prominent smooth apertural muscles extend from the basal cystid wall to each lateral side of the vestibular wall. The musculature of the tentacle sheath consists of regular strands of smooth longitudinal muscles. Each tentacle is supplied with two bands of longitudinal muscles that show irregular striation. At the lophophoral base several muscles are present: (i Short muscle fibres that proximally diverge from a single point from where they split distally into two separate strands. (ii Proximally of the first group are smooth, longitudinal fibres that extend to the proximal-most side of the lophophoral base. (iii Smooth muscle fibres, the buccal dilatators, traverse obliquely towards the pharynx, and (iv a circular ring of smooth muscle fibres situated distally of the buccal dilatators. Retractor muscles are mainly smooth with short distal striated parts. The foregut consists mainly of striated ring musculature with only few longitudinal muscle fibres in the esophagus, while the remaining parts of the digestive tract solely exhibit smooth musculature. During budding, apertural and retractor muscles are first to appear, while the parietal muscles

  4. Effect of type-2 astrocytes on the viability of dorsal root ganglion neurons and length of neuronal processes

    Institute of Scientific and Technical Information of China (English)

    Chunling Fan; Hui Wang; Dan Chen; Xiaoxin Cheng; Kun Xiong; Xuegang Luo; Qilin Cao

    2014-01-01

    The role of type-2 astrocytes in the repair of central nervous system injury remains poorly un-derstood. In this study, using a relatively simple culture condition in vitro, type-2 astrocytes, differentiated from oligodendrocyte precursor cells by induction with bone morphogenetic pro-tein-4, were co-cultured with dorsal root ganglion neurons. We examined the effects of type-2 astrocytes differentiated from oligodendrocyte precursor cells on the survival and growth of dorsal root ganglion neurons. Results demonstrated that the number of dorsal root ganglion neurons was higher following co-culture of oligodendrocyte precursor cells and type-2 astrocytes than when cultured alone, but lower than that of neurons co-cultured with type-1 astrocytes. The length of the longest process and the length of all processes of a single neuron were shortest in neurons cultured alone, followed by neurons co-cultured with type-2 astrocytes, then neurons co-cultured with oligodendrocyte precursor cells, and longest in neurons co-cultured with type-1 astrocytes. These results indicate that co-culture with type-2 astrocytes can increase neuronal survival rate and process length. However, compared with type-1 astrocytes and oligodendrocyte precursor cells, the promotion effects of type-2 astrocytes on the growth of dorsal root ganglion neurons were weaker.

  5. Serotonergic activation of 5HT1A and 5HT2 receptors modulates sexually dimorphic communication signals in the weakly electric fish Apteronotus leptorhynchus.

    Science.gov (United States)

    Smith, G Troy; Combs, Nicole

    2008-06-01

    Serotonin modulates agonistic and reproductive behavior across vertebrate species. 5HT(1A) and 5HT(1B) receptors mediate many serotonergic effects on social behavior, but other receptors, including 5HT(2) receptors, may also contribute. We investigated serotonergic regulation of electrocommunication signals in the weakly electric fish Apteronotus leptorhynchus. During social interactions, these fish modulate their electric organ discharges (EODs) to produce signals known as chirps. Males chirp more than females and produce two chirp types. Males produce high-frequency chirps as courtship signals; whereas both sexes produce low-frequency chirps during same-sex interactions. Serotonergic innervation of the prepacemaker nucleus, which controls chirping, is more robust in females than males. Serotonin inhibits chirping and may contribute to sexual dimorphism and individual variation in chirping. We elicited chirps with EOD playbacks and pharmacologically manipulated serotonin receptors to determine which receptors regulated chirping. We also asked whether serotonin receptor activation generally modulated chirping or more specifically targeted particular chirp types. Agonists and antagonists of 5HT(1B/1D) receptors (CP-94253 and GR-125743) did not affect chirping. The 5HT(1A) receptor agonist 8OH-DPAT specifically increased production of high-frequency chirps. The 5HT(2) receptor agonist DOI decreased chirping. Receptor antagonists (WAY-100635 and MDL-11939) opposed the effects of their corresponding agonists. These results suggest that serotonergic inhibition of chirping may be mediated by 5HT(2) receptors, but that serotonergic activation of 5HT(1A) receptors specifically increases the production of high-frequency chirps. The enhancement of chirping by 5HT(1A) receptors may result from interactions with cortisol and/or arginine vasotocin, which similarly enhance chirping and are influenced by 5HT(1A) activity in other systems.

  6. Serotonergic modulation of spatial working memory: predictions from a computational network model

    Directory of Open Access Journals (Sweden)

    Maria eCano-Colino

    2013-09-01

    Full Text Available Serotonin (5-HT receptors of types 1A and 2A are massively expressed in prefrontal cortex (PFC neurons, an area associated with cognitive function. Hence, 5-HT could be effective in modulating prefrontal-dependent cognitive functions, such as spatial working memory (SWM. However, a direct association between 5-HT and SWM has proved elusive in psycho-pharmacological studies. Recently, a computational network model of the PFC microcircuit was used to explore the relationship between 5‑HT and SWM (Cano-Colino et al. 2013. This study found that both excessive and insufficient 5-HT levels lead to impaired SWM performance in the network, and it concluded that analyzing behavioral responses based on confidence reports could facilitate the experimental identification of SWM behavioral effects of 5‑HT neuromodulation. Such analyses may have confounds based on our limited understanding of metacognitive processes. Here, we extend these results by deriving three additional predictions from the model that do not rely on confidence reports. Firstly, only excessive levels of 5-HT should result in SWM deficits that increase with delay duration. Secondly, excessive 5-HT baseline concentration makes the network vulnerable to distractors at distances that were robust to distraction in control conditions, while the network still ignores distractors efficiently for low 5‑HT levels that impair SWM. Finally, 5-HT modulates neuronal memory fields in neurophysiological experiments: Neurons should be better tuned to the cued stimulus than to the behavioral report for excessive 5-HT levels, while the reverse should happen for low 5-HT concentrations. In all our simulations agonists of 5-HT1A receptors and antagonists of 5-HT2A receptors produced behavioral and physiological effects in line with global 5-HT level increases. Our model makes specific predictions to be tested experimentally and advance our understanding of the neural basis of SWM and its neuromodulation

  7. Study of a new neuron

    CERN Document Server

    Adler, Stephen Louis; Weckel, J D

    1994-01-01

    We study a modular neuron alternative to the McCulloch-Pitts neuron that arises naturally in analog devices in which the neuron inputs are represented as coherent oscillatory wave signals. Although the modular neuron can compute XOR at the one neuron level, it is still characterized by the same Vapnik-Chervonenkis dimension as the standard neuron. We give the formulas needed for constructing networks using the new neuron and training them using back-propagation. A numerical study of the modular neuron on two data sets is presented, which demonstrates that the new neuron performs at least as well as the standard neuron.

  8. A PrP(C)-caveolin-Lyn complex negatively controls neuronal GSK3β and serotonin 1B receptor.

    Science.gov (United States)

    Hernandez-Rapp, Julia; Martin-Lannerée, Séverine; Hirsch, Théo Z; Pradines, Elodie; Alleaume-Butaux, Aurélie; Schneider, Benoît; Baudry, Anne; Launay, Jean-Marie; Mouillet-Richard, Sophie

    2014-05-08

    The cellular prion protein, PrP(C), is a glycosylphosphatidylinositol-anchored protein, abundant in lipid rafts and highly expressed in the brain. While PrP(C) is much studied for its involvement under its abnormal PrP(Sc) isoform in Transmissible Spongiform Encephalopathies, its physiological role remains unclear. Here, we report that GSK3β, a multifunctional kinase whose inhibition is neuroprotective, is a downstream target of PrP(C) signalling in serotonergic neuronal cells. We show that the PrP(C)-dependent inactivation of GSK3β is relayed by a caveolin-Lyn platform located on neuronal cell bodies. Furthermore, the coupling of PrP(C) to GSK3β potentiates serotonergic signalling by altering the distribution and activity of the serotonin 1B receptor (5-HT1BR), a receptor that limits neurotransmitter release. In vivo, our data reveal an increased GSK3β kinase activity in PrP-deficient mouse brain, as well as sustained 5-HT1BR activity, whose inhibition promotes an anxiogenic behavioural response. Collectively, our data unveil a new facet of PrP(C) signalling that strengthens neurotransmission.

  9. Impact of CYP2C19 phenotypes on escitalopram metabolism and an evaluation of pupillometry as a serotonergic biomarker

    DEFF Research Database (Denmark)

    Noehr-Jensen, L; Zwisler, S; Larsen, F

    2009-01-01

    PURPOSE: To investigate the impact of cytochrome P450 2C19 (CYP2C19) phenotypes on escitalopram metabolism and to evaluate pupillometry as a serotonergic biomarker. METHODS: This was a double-blind, crossover design study with single and multiple doses of 10 mg escitalopram and placebo in panels...... of CYP2C19 extensive (EM) and poor metabolisers (PM). Pupillometry was measured by a NeurOptics Pupillometer-PLR. RESULTS: Five PM and eight EM completed the study. The CYP2C19 phenotype significantly affected the metabolism of escitalopram. The area under the time-plasma concentration curve (AUC(0......-24)) was 1.8-fold higher in PM than in EM after both single and multiple doses. Escitalopram treatment did not affect the maximum pupil size, but it did statistically significantly decrease the relative amplitude of the pupil light reflex compared to the placebo; this effect was equal in both phenotype...

  10. Cajal bodies in neurons.

    Science.gov (United States)

    Lafarga, Miguel; Tapia, Olga; Romero, Ana M; Berciano, Maria T

    2016-09-14

    Cajal is commonly regarded as the father of modern neuroscience in recognition of his fundamental work on the structure of the nervous system. But Cajal also made seminal contributions to the knowledge of nuclear structure in the early 1900s, including the discovery of the "accessory body" later renamed "Cajal body" (CB). This important nuclear structure has emerged as a center for the assembly of ribonucleoproteins (RNPs) required for splicing, ribosome biogenesis and telomere maintenance. The modern era of CB research started in the 1990s with the discovery of coilin, now known as a scaffold protein of CBs, and specific probes for small nuclear RNAs (snRNAs). In this review, we summarize what we have learned in the recent decades concerning CBs in post-mitotic neurons, thereby ruling out dynamic changes in CB functions during the cell cycle. We show that CBs are particularly prominent in neurons, where they frequently associate with the nucleolus. Neuronal CBs are transcription-dependent nuclear organelles. Indeed, their number dynamically accommodates to support the high neuronal demand for splicing and ribosome biogenesis required for sustaining metabolic and bioelectrical activity. Mature neurons have canonical CBs enriched in coilin, survival motor neuron protein and snRNPs. Disruption and loss of neuronal CBs associate with severe neuronal dysfunctions in several neurological disorders such as motor neuron diseases. In particular, CB depletion in motor neurons seems to reflect a perturbation of transcription and splicing in spinal muscular atrophy, the most common genetic cause of infant mortality.

  11. Persistently active, pacemaker-like neurons in neocortex

    Directory of Open Access Journals (Sweden)

    Morgane Le Bon-Jego

    2007-10-01

    Full Text Available The neocortex is spontaneously active, however, the origin of this self-generated, patterned activity remains unknown. To detect potential pacemaker cells, we use calcium imaging to directly identify neurons that discharge action potentials in the absence of synaptic transmissionin slices from juvenile mouse visual cortex. We characterize 60 of these neurons electrophysiologically and morphologically, finding that they belong to two classes of cells: one class composed of pyramidal neurons with a thin apical dendritic tree and a second class composed of ascending axon interneurons (Martinotti cells located in layer 5. In both types of neurons, persistent sodium currents are necessary for the generation of the spontaneous activity. Our data demonstrate that subtypes of neocortical neurons have intrinsic mechanisms to generate persistent activity. Like in central pattern generators (CPGs, these neurons may act as pacemakers to initiate or pattern spontaneous activity in the neocortex.

  12. Influence of temporal relationships between serotonergic and dopaminergic precursors on the regulation of gonadal development in birds.

    Science.gov (United States)

    Chaturvedi, Chandra Mohini; Yadav, Suneeta

    2013-09-01

    This article is focused on the effect of specific phase relation of serotonergic and dopaminergic oscillations on the gonadal responses of different avian species. These species include (i) summer breeding birds - Red headed bunting (exhibiting post-reproductive absolute photorefractoriness) and Indian Weaver bird (which lacks absolute photorefractoriness), (ii) autumn breeding - Spotted munia and Lal munia (photoperiodic responses of which are distinctly different from that of any long day birds described thus far) and (iii) domesticated Japanese quail (which under natural day length breeds in summer, exhibits relative photorefractoriness, but breeds continuously if maintained in long photoperiod). Previous experiments have shown that daily administration of serotonin precursor 5-hydroxytryptophan and dopamine precursor L-dihydroxyphenylalanine given 8h apart during progressive phase of gonadal cycle can lead to a significant decrease in gonadal activity. However, if given at an interval of 12h it leads to an increase in gonadal activity and the effect of other intervals (0-, 4-, 16- and 20-h) were not different from control. Similar effects were observed during regressive phase of the gonadal cycle of above species except in those which display absolute photorefractory phase in their breeding cycle. This shows that, gonad of such species not only develop post-reproductive photorefractoriness but also becomes insensitive to the stimulatory effects of 5-HTP and L-DOPA when given at the interval of 12h. It is suggested that, temporal phase relation of circadian serotonergic and dopaminergic oscillations is the basis of seasonality in birds and may alter the activity of neuroendocrine-gonadal axis not only under natural day length but also under experimental/different photoperiodic conditions. These results are in agreement with the internal coincidence model of photoperiodic time measurement and indicate that birds can detect specific phase relationship between the

  13. Chronic Sarpogrelate Treatment Reveals 5-HT7 Receptor in the Serotonergic Inhibition of the Rat Vagal Bradycardia.

    Science.gov (United States)

    García-Pedraza, José Ángel; García, Mónica; Martín, María Luisa; Eleno, Nélida; Morán, Asunción

    2017-01-01

    5-Hydroxytryptamine (5-HT) modulates the cardiac parasympathetic neurotransmission, inhibiting the bradyarrhythmia by 5-HT2 receptor activation. We aimed to determine whether the chronic selective 5-HT2 blockade (sarpogrelate) could modify the serotonergic modulation on vagal cardiac outflow in pithed rat. Bradycardic responses in rats treated with sarpogrelate (30 mg·kg·d; orally) were obtained by electrical stimulation of the vagal fibers (3, 6, and 9 Hz) or intravenous (IV) injections of acetylcholine (1, 5, and 10 μg/kg). 5-HT7 receptor expression was quantified by Western blot in vagus nerve and right atrium. The IV administration of 5-HT (10-200 μg/kg) dose dependently decreased the vagally induced bradycardia, and agonists 5-CT (5-HT1/7), 8-OH-DPAT (5-HT1A), or AS-19 (5-HT7) (50 μg/kg each) mimicked the 5-HT-induced inhibitory effect. Neither agonists CGS-12066B (5-HT1B), L-694,247 (5-HT1D), nor 1-phenylbiguanide (5-HT3) modified the electrically-induced bradycardic responses. Moreover, SB-258719 (5-HT7 antagonist) abolished the 5-HT-, 5-CT-, 8-OH-DPAT-, and AS-19-induced bradycardia inhibition; 5-HT or AS-19 did not modify the bradycardia induced by IV acetylcholine; and 5-HT7 receptor was expressed in both the vagus nerve and the right atrium. Our outcomes suggest that blocking chronically 5-HT2 receptors modifies the serotonergic influence on cardiac vagal neurotransmission exhibiting 5-HT as an exclusively inhibitory agent via prejunctional 5-HT7 receptor.

  14. General overview of neuronal cell culture.

    Science.gov (United States)

    Gordon, Jennifer; Amini, Shohreh; White, Martyn K

    2013-01-01

    In this introductory chapter, we provide a general overview of neuronal cell culture. This is a rapidly evolving area of research and we provide an outline and contextual framework for the different chapters of this book. These chapters were all contributed by scientists actively working in the field who are currently using state-of-the-art techniques to advance our understanding of the molecular and cellular biology of the central nervous system. Each chapter provides detailed descriptions and experimental protocols for a variety of techniques ranging in scope from basic neuronal cell line culturing to advanced and specialized methods.

  15. Deployable centralizers

    Energy Technology Data Exchange (ETDEWEB)

    Grubelich, Mark C.; Su, Jiann-Cherng; Knudsen, Steven D.

    2017-02-28

    A centralizer assembly is disclosed that allows for the assembly to be deployed in-situ. The centralizer assembly includes flexible members that can be extended into the well bore in situ by the initiation of a gas generating device. The centralizer assembly can support a large load carrying capability compared to a traditional bow spring with little or no installation drag. Additionally, larger displacements can be produced to centralize an extremely deviated casing.

  16. Noise and Neuronal Heterogeneity

    CERN Document Server

    Barber, Michael J

    2010-01-01

    We consider signal transaction in a simple neuronal model featuring intrinsic noise. The presence of noise limits the precision of neural responses and impacts the quality of neural signal transduction. We assess the signal transduction quality in relation to the level of noise, and show it to be maximized by a non-zero level of noise, analogous to the stochastic resonance effect. The quality enhancement occurs for a finite range of stimuli to a single neuron; we show how to construct networks of neurons that extend the range. The range increases more rapidly with network size when we make use of heterogeneous populations of neurons with a variety of thresholds, rather than homogeneous populations of neurons all with the same threshold. The limited precision of neural responses thus can have a direct effect on the optimal network structure, with diverse functional properties of the constituent neurons supporting an economical information processing strategy that reduces the metabolic costs of handling a broad...

  17. Mesmerising mirror neurons.

    Science.gov (United States)

    Heyes, Cecilia

    2010-06-01

    Mirror neurons have been hailed as the key to understanding social cognition. I argue that three currents of thought-relating to evolution, atomism and telepathy-have magnified the perceived importance of mirror neurons. When they are understood to be a product of associative learning, rather than an adaptation for social cognition, mirror neurons are no longer mesmerising, but they continue to raise important questions about both the psychology of science and the neural bases of social cognition.

  18. Bidirectional Microglia-Neuron Communication in the Healthy Brain

    Directory of Open Access Journals (Sweden)

    Ukpong B. Eyo

    2013-01-01

    Full Text Available Unlike other resident neural cells that are of neuroectodermal origin, microglia are resident neural cells of mesodermal origin. Traditionally recognized for their immune functions during disease, new roles are being attributed to these cells in the development and maintenance of the central nervous system (CNS including specific communication with neurons. In this review, we highlight some of the recent findings on the bidirectional interaction between neurons and microglia. We discuss these interactions along two lines. First, we review data that suggest that microglial activity is modulated by neuronal signals, focusing on evidence that (i neurons are capable of regulating microglial activation state and influence basal microglial activities; (ii classic neurotransmitters affect microglial behavior; (iii chemotactic signals attract microglia during acute neuronal injury. Next, we discuss some of the recent data on how microglia signal to neurons. Signaling mechanisms include (i direct physical contact of microglial processes with neuronal elements; (ii microglial regulation of neuronal synapse and circuit by fractalkine, complement, and DAP12 signaling. In addition, we discuss the use of microglial depletion strategies in studying the role of microglia in neuronal development and synaptic physiology. Deciphering the mechanisms of bidirectional microglial-neuronal communication provides novel insights in understanding microglial function in both the healthy and diseased brain.

  19. Optophysiological approach to resolve neuronal action potentials with high spatial and temporal resolution in cultured neurons

    Directory of Open Access Journals (Sweden)

    Stephane ePages

    2011-10-01

    Full Text Available Cell to cell communication in the central nervous system is encoded into transient and local membrane potential changes (ΔVm. Deciphering the rules that govern synaptic transmission and plasticity entails to be able to perform Vm recordings throughout the entire neuronal arborization. Classical electrophysiology is, in most cases, not able to do so within small and fragile neuronal subcompartments. Thus, optical techniques based on the use of fluorescent voltage-sensitive dyes (VSDs have been developed. However, reporting spontaneous or small ΔVm from neuronal ramifications has been challenging, in part due to the limited sensitivity and phototoxicity of VSD-based optical measurements. Here we demonstrate the use of water soluble VSD, ANNINE-6plus, with laser scanning microscopy to optically record ΔVm in cultured neurons. We show that the sensitivity (> 10 % of fluorescence change for 100 mV depolarization and time response (submillisecond of the dye allows the robust detection of action potentials (APs even without averaging, allowing the measurement of spontaneous neuronal firing patterns. In addition, we show that back-propagating APs can be recorded, along distinct dendritic sites and within dendritic spines. Importantly, our approach does not induce any detectable phototoxic effect on cultured neurons. This optophysiological approach provides a simple, minimally invasive and versatile optical method to measure electrical activity in cultured neurons with high temporal (ms resolution and high spatial (µm resolution.

  20. Histone deacetylases 1 and 2 control the progression of neural precursors to neurons during brain development

    Science.gov (United States)

    Montgomery, Rusty L.; Hsieh, Jenny; Barbosa, Ana C.; Richardson, James A.; Olson, Eric N.

    2009-01-01

    The molecular mechanism by which neural progenitor cells commit to a specified lineage of the central nervous system remains unknown. We show that HDAC1 and HDAC2 redundantly control neuronal development and are required for neuronal specification. Mice lacking HDAC1 or HDAC2 in neuronal precursors show no overt histoarchitectural phenotypes, whereas deletion of both HDAC1 and HDAC2 in developing neurons results in severe hippocampal abnormalities, absence of cerebellar foliation, disorganization of cortical neurons, and lethality by postnatal day 7. These abnormalities in brain formation can be attributed to a failure of neuronal precursors to differentiate into mature neurons and to excessive cell death. These results reveal redundant and essential roles for HDAC1 and HDAC2 in the progression of neuronal precursors to mature neurons in vivo. PMID:19380719

  1. 霍乱毒素对三氟氯氰菊酯抗性及敏感棉铃虫神经细胞L型钙通道的调节作用%Modulations by CTX of the L-type Ca2+ channels in the central neurons of the cyhalothrin-resistant and cyhalothrin-susceptible cotton bollworm, Helicoverpa armigera

    Institute of Scientific and Technical Information of China (English)

    赵强; 李杰; 刘燕强; 范贤林; 季青; 刘安西

    2006-01-01

    霍乱毒素(CTX)可激活兴奋性异三聚体G蛋白(Gαs)的α-亚基和刺激电压门控L-型钙通道,而昆虫的L-型钙通道可能是拟除虫菊酯类杀虫剂的作用靶点.为进一步探讨农业害虫对拟除虫菊酯类杀虫剂产生抗药性的作用机理,我们检测了CTX对三氟氯氰菊酯抗性及敏感棉铃虫Helicoverpa armigera中枢神经细胞电压门控L-型钙通道的调节作用.分别急性分离三氟氯氰菊酯抗性及敏感的3~4龄棉铃虫幼虫胸腹神经节细胞,并在改良的L15培养基(加入或未加入700 ng/mL的CTX)中培养12~16 h.钡离子为载流子,应用全细胞膜片钳技术记录电压门控L-型钙通道电流.结果显示,CTX可使敏感组棉铃虫神经细胞L-型钙通道的峰值电流密度增大36%、峰值电压左移5 mV,但对抗性组棉铃虫神经细胞L-型钙通道无上述作用.并且,CTX对敏感组及抗性组棉铃虫神经细胞L-型钙通道的激活电位、翻转电位、激活曲线和失活曲线等其他一些参数的影响也不明显.在无CTX作用时,所检测到的抗性组与敏感组棉铃虫神经细胞L-型钙通道的上述参数值间差异不显著.结果提示,棉铃虫神经细胞内存在Gs-腺苷酸环化酶(AC)-cAMP-蛋白激酶A (PKA)-L-型钙通道信号调节系统;与敏感棉铃虫神经细胞L-型钙通道相比,三氟氯氰菊酯抗性棉铃虫神经细胞L-型钙通道的活性相对不易受到CTX调节,这可能与昆虫对拟除虫菊酯产生抗药性的机理有关.%Cholera toxin (CTX) activates the α-subunit of stimulatory heterotrimeric G-proteins (Gαs) and stimulates voltage-gated L-type (Ca2+(L)) channels, which may be primary targets of pyrethroids. To investigate the potential mechanisms underlying the resistance to pyrethroids in agriculturally important insect pests, we examined the modulations by CTX of Ca2+(L) channels in the central neurons of the cyhalothrin-resistant (Cy-R) and cyhalothrin-susceptible (Cy-S) cotton

  2. Pacemaking Kisspeptin Neurons

    Science.gov (United States)

    Kelly, Martin J.; Zhang, Chunguang; Qiu, Jian; Rønnekleiv, Oline K.

    2013-01-01

    Kisspeptin (Kiss1) neurons are vital for reproduction. GnRH neurons express the kisspeptin receptor, GPR 54, and kisspeptins potently stimulate the release of GnRH by depolarising and inducing sustained action potential firing in GnRH neurons. As such Kiss1 neurons may be the pre-synaptic pacemaker neurons in the hypothalamic circuitry that controls reproduction. There are at least two different populations of Kiss1 neurons: one in the rostral periventricular area (RP3V) that is stimulated by oestrogens and the other in the arcuate nucleus that is inhibited by oestrogens. How each of these Kiss1 neuronal populations participate in the regulation of the reproductive cycle is currently under intense investigation. Based on electrophysiological studies in the guinea pig and mouse, Kiss1 neurons in general are capable of generating burst firing behavior. Essentially all Kiss1 neurons, which have been studied thus far in the arcuate nucleus, express the ion channels necessary for burst firing, which include hyperpolarization-activated, cyclic nucleotide gated cation (HCN) channels and the T-type calcium (Cav3.1) channels. Under voltage clamp conditions, these channels produce distinct currents that under current clamp conditions can generate burst firing behavior. The future challenge is to identify other key channels and synaptic inputs involved in the regulation of the firing properties of Kiss1 neurons and the physiological regulation of the expression of these channels and receptors by oestrogens and other hormones. The ultimate goal is to understand how Kiss1 neurons control the different phases of GnRH neurosecretion and hence reproduction. PMID:23884368

  3. Mechanosensor Channels in Mammalian Somatosensory Neurons

    Directory of Open Access Journals (Sweden)

    Patrick Delmas

    2007-09-01

    Full Text Available Mechanoreceptive sensory neurons innervating the skin, skeletal muscles andviscera signal both innocuous and noxious information necessary for proprioception, touchand pain. These neurons are responsible for the transduction of mechanical stimuli intoaction potentials that propagate to the central nervous system. The ability of these cells todetect mechanical stimuli impinging on them relies on the presence of mechanosensitivechannels that transduce the external mechanical forces into electrical and chemical signals.Although a great deal of information regarding the molecular and biophysical properties ofmechanosensitive channels in prokaryotes has been accumulated over the past two decades,less is known about the mechanosensitive channels necessary for proprioception and thesenses of touch and pain. This review summarizes the most pertinent data onmechanosensitive channels of mammalian somatosensory neurons, focusing on theirproperties, pharmacology and putative identity.

  4. Inflammatory mechanism in ischemic neuronal injury

    Institute of Scientific and Technical Information of China (English)

    Ya-Dan WEN; Hui-Ling ZHANG; Zheng-Hong QIN

    2006-01-01

    Inflammation has been implicated as a secondary mechanism underlying neuronal injury induced by ischemia.A variety of experimental models, including thromboembolic stroke, focal and global ischemia, have been used to evaluate contributions of inflammation to neuronal damage. The vasculature endothelium promotes inflammation through upregulation of adhesion molecules such as intercellular adhesion molecule (ICAM), E-selectin, and P-selectin that bind to circulating leukocytes and facilitate migration of leukocytes into the central nervous system (CNS). Once being in the CNS, leukocytes produce cytotoxic molecules that promote cell death. The response of macrophages and microglia to injury may either be beneficial by scavenging necrotic debris or be detrimental by facilitating cell death of neurons that would otherwise recover. While many studies have tested these hypotheses, the significance of inflammation in stroke models is inconclusive. This review summarizes data regarding roles of cell adhesion molecules, astrocytes, microglia and leukocytes in stroke.

  5. Microglia in neuronal plasticity: Influence of stress.

    Science.gov (United States)

    Delpech, Jean-Christophe; Madore, Charlotte; Nadjar, Agnes; Joffre, Corinne; Wohleb, Eric S; Layé, Sophie

    2015-09-01

    The central nervous system (CNS) has previously been regarded as an immune-privileged site with the absence of immune cell responses but this dogma was not entirely true. Microglia are the brain innate immune cells and recent findings indicate that they participate both in CNS disease and infection as well as facilitate normal CNS function. Microglia are highly plastic and play integral roles in sculpting the structure of the CNS, refining neuronal circuitry and connectivity, and contribute actively to neuronal plasticity in the healthy brain. Interestingly, psychological stress can perturb the function of microglia in association with an impaired neuronal plasticity and the development of emotional behavior alterations. As a result it seemed important to describe in this review some findings indicating that the stress-induced microglia dysfunction may underlie neuroplasticity deficits associated to many mood disorders. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'.

  6. Characterization of neurons of the nucleus tractus solitarius pars centralis.

    Science.gov (United States)

    Baptista, V; Zheng, Z L; Coleman, F H; Rogers, R C; Travagli, R A

    2005-08-09

    Esophageal sensory afferent inputs terminate principally in the central subnucleus of the tractus solitarius (cNTS). Neurons of the cNTS comprise two major neurochemical subpopulations. One contains neurons that are nitric oxide synthase (NOS) immunoreactive (-IR) while the other comprises neurons that are tyrosine hydroxylase (TH)-IR. We have shown recently that TH-IR neurons are involved in esophageal-distention induced gastric relaxation. We used whole cell patch clamp techniques in rat brainstem slices combined with immunohistochemical and morphological reconstructions to characterize cNTS neurons. Postrecording reconstruction of cNTS neurons revealed two morphological neuronal subtypes; one group of cells (41 out of 131 neurons, i.e., 31%) had a multipolar soma, while the other group (87 out of 131 neurons, i.e., 66%) had a bipolar soma. Of the 43 cells in which we conducted a neurochemical examination, 15 displayed TH-IR (9 with bipolar morphology, 6 with multipolar morphology) while the remaining 28 neurons did not display TH-IR (18 with bipolar morphology, 10 with multipolar morphology). Even though the range of electrophysiological properties varied significantly, morphological or neurochemical distinctions did not reveal characteristics peculiar to the subgroups. Spontaneous excitatory postsynaptic currents (sEPSC) recorded in cNTS neurons had a frequency of 1.5 +/- 0.15 events s(-1) and an amplitude of 27 +/- 1.2 pA (Vh = -50 mV) and were abolished by pretreatment with 30 muM AP-5 and 10 muM CNQX, indicating the involvement of both NMDA and non-NMDA receptors. Some cNTS neurons also received a GABAergic input that was abolished by perfusion with 30-50 muM bicuculline. In conclusion, our data show that despite the heterogeneity of morphological and neurochemical membrane properties, the electrophysiological characteristics of cNTS neurons are not a distinguishing feature.

  7. Serotonergic modulation of post-synaptic inhibition and locomotor alternating pattern in the spinal cord

    OpenAIRE

    Laurent eVinay; Florian eGackière

    2014-01-01

    The central pattern generators (CPGs) for locomotion, located in the lumbar spinal cord, are functional at birth in the rat. Their maturation occurs during the last few days preceding birth, a period during which the first projections from the brainstem start to reach the lumbar enlargement of the spinal cord. Locomotor burst activity in the mature intact spinal cord alternates between flexor and extensor motoneurons through reciprocal inhibition and between left and right sides through commi...

  8. Juvenil neuronal ceroid lipofuscinosis

    DEFF Research Database (Denmark)

    Ostergaard, J R; Hertz, Jens Michael

    1998-01-01

    Neuronal ceroid-lipofuscinosis is a group of neurodegenerative diseases which are characterized by an abnormal accumulation of lipopigment in neuronal and extraneuronal cells. The diseases can be differentiated into several subgroups according to age of onset, the clinical picture, neurophysiolog...

  9. Corticospinal mirror neurons.

    Science.gov (United States)

    Kraskov, A; Philipp, R; Waldert, S; Vigneswaran, G; Quallo, M M; Lemon, R N

    2014-01-01

    Here, we report the properties of neurons with mirror-like characteristics that were identified as pyramidal tract neurons (PTNs) and recorded in the ventral premotor cortex (area F5) and primary motor cortex (M1) of three macaque monkeys. We analysed the neurons' discharge while the monkeys performed active grasp of either food or an object, and also while they observed an experimenter carrying out a similar range of grasps. A considerable proportion of tested PTNs showed clear mirror-like properties (52% F5 and 58% M1). Some PTNs exhibited 'classical' mirror neuron properties, increasing activity for both execution and observation, while others decreased their discharge during observation ('suppression mirror-neurons'). These experiments not only demonstrate the existence of PTNs as mirror neurons in M1, but also reveal some interesting differences between M1 and F5 mirror PTNs. Although observation-related changes in the discharge of PTNs must reach the spinal cord and will include some direct projections to motoneurons supplying grasping muscles, there was no EMG activity in these muscles during action observation. We suggest that the mirror neuron system is involved in the withholding of unwanted movement during action observation. Mirror neurons are differentially recruited in the behaviour that switches rapidly between making your own movements and observing those of others.

  10. Culturing rat hippocampal neurons.

    Science.gov (United States)

    Audesirk, G; Audesirk, T; Ferguson, C

    2001-01-01

    Cultured neurons are widely used to investigate the mechanisms of neurotoxicity. Embryonic rat hippocampal neurons may be grown as described under a wide variety of conditions to suit differing experimental procedures, including electrophysiology, morphological analysis of neurite development, and various biochemical and molecular analyses.

  11. From Neural Plate to Cortical Arousal—A Neuronal Network Theory of Sleep Derived from in Vitro “Model” Systems for Primordial Patterns of Spontaneous Bioelectric Activity in the Vertebrate Central Nervous System

    Directory of Open Access Journals (Sweden)

    Michael A. Corner

    2013-05-01

    Full Text Available In the early 1960s intrinsically generated widespread neuronal discharges were discovered to be the basis for the earliest motor behavior throughout the animal kingdom. The pattern generating system is in fact programmed into the developing nervous system, in a regionally specific manner, already at the early neural plate stage. Such rhythmically modulated phasic bursts were next discovered to be a general feature of developing neural networks and, largely on the basis of experimental interventions in cultured neural tissues, to contribute significantly to their morpho-physiological maturation. In particular, the level of spontaneous synchronized bursting is homeostatically regulated, and has the effect of constraining the development of excessive network excitability. After birth or hatching, this “slow-wave” activity pattern becomes sporadically suppressed in favor of sensory oriented “waking” behaviors better adapted to dealing with environmental contingencies. It nevertheless reappears periodically as “sleep” at several species-specific points in the diurnal/nocturnal cycle. Although this “default” behavior pattern evolves with development, its essential features are preserved throughout the life cycle, and are based upon a few simple mechanisms which can be both experimentally demonstrated and simulated by computer modeling. In contrast, a late onto- and phylogenetic aspect of sleep, viz., the intermittent “paradoxical” activation of the forebrain so as to mimic waking activity, is much less well understood as regards its contribution to brain development. Some recent findings dealing with this question by means of cholinergically induced “aroused” firing patterns in developing neocortical cell cultures, followed by quantitative electrophysiological assays of immediate and longterm sequelae, will be discussed in connection with their putative implications for sleep ontogeny.

  12. From neural plate to cortical arousal-a neuronal network theory of sleep derived from in vitro "model" systems for primordial patterns of spontaneous bioelectric activity in the vertebrate central nervous system.

    Science.gov (United States)

    Corner, Michael A

    2013-05-22

    In the early 1960s intrinsically generated widespread neuronal discharges were discovered to be the basis for the earliest motor behavior throughout the animal kingdom. The pattern generating system is in fact programmed into the developing nervous system, in a regionally specific manner, already at the early neural plate stage. Such rhythmically modulated phasic bursts were next discovered to be a general feature of developing neural networks and, largely on the basis of experimental interventions in cultured neural tissues, to contribute significantly to their morpho-physiological maturation. In particular, the level of spontaneous synchronized bursting is homeostatically regulated, and has the effect of constraining the development of excessive network excitability. After birth or hatching, this "slow-wave" activity pattern becomes sporadically suppressed in favor of sensory oriented "waking" behaviors better adapted to dealing with environmental contingencies. It nevertheless reappears periodically as "sleep" at several species-specific points in the diurnal/nocturnal cycle. Although this "default" behavior pattern evolves with development, its essential features are preserved throughout the life cycle, and are based upon a few simple mechanisms which can be both experimentally demonstrated and simulated by computer modeling. In contrast, a late onto- and phylogenetic aspect of sleep, viz., the intermittent "paradoxical" activation of the forebrain so as to mimic waking activity, is much less well understood as regards its contribution to brain development. Some recent findings dealing with this question by means of cholinergically induced "aroused" firing patterns in developing neocortical cell cultures, followed by quantitative electrophysiological assays of immediate and longterm sequelae, will be discussed in connection with their putative implications for sleep ontogeny.

  13. Afferent neuronal control of type-I gonadotropin releasing hormone (GnRH neurons in the human

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    Erik eHrabovszky

    2013-09-01

    Full Text Available Understanding the regulation of the human menstrual cycle represents an important ultimate challenge of reproductive neuroendocrine research. However, direct translation of information from laboratory animal experiments to the human is often complicated by strikingly different and unique reproductive strategies and central regulatory mechanisms that can be present in even closely related animal species. In all mammals studied so far, type-I gonadotropin releasing hormone (GnRH synthesizing neurons form the final common output way from the hypothalamus in the neuroendocrine control of the adenohypophysis. Under various physiological and pathological conditions, hormonal and metabolic signals either regulate GnRH neurons directly or act on upstream neuronal circuitries to influence the pattern of pulsatile GnRH secretion into the hypophysial portal circulation. Neuronal afferents to GnRH cells convey important metabolic-, stress-, sex steroid-, lactational- and circadian signals to the reproductive axis, among other effects. This article gives an overview of the available neuroanatomical literature that described the afferent regulation of human GnRH neurons by peptidergic, monoaminergic and amino acidergic neuronal systems. Recent studies of human genetics provided evidence that central peptidergic signaling by kisspeptins and neurokinin B play particularly important roles in puberty onset and later, in the sex steroid-dependent feedback regulation of GnRH neurons. This review article places special emphasis on the topographic distribution, sexual dimorphism, aging-dependent neuroanatomical changes and plastic connectivity to GnRH neurons of the critically important human hypothalamic kisspeptin and neurokinin B systems.

  14. Glutamate and GABA in Vestibulo-Sympathetic Pathway Neurons.

    Science.gov (United States)

    Holstein, Gay R; Friedrich, Victor L; Martinelli, Giorgio P

    2016-01-01

    The vestibulo-sympathetic reflex (VSR) actively modulates blood pressure during changes in posture. This reflex allows humans to stand up and quadrupeds to rear or climb without a precipitous decline in cerebral perfusion. The VSR pathway conveys signals from the vestibular end organs to the caudal vestibular nuclei. These cells, in turn, project to pre-sympathetic neurons in the rostral and caudal ventrolateral medulla (RVLM and CVLM, respectively). The present study assessed glutamate- and GABA-related immunofluorescence associated with central vestibular neurons of the VSR pathway in rats. Retrograde FluoroGold tract tracing was used to label vestibular neurons with projections to RVLM or CVLM, and sinusoidal galvanic vestibular stimulation (GVS) was employed to activate these pathways. Central vestibular neurons of the VSR were identified by co-localization of FluoroGold and cFos protein, which accumulates in some vestibular neurons following galvanic stimulation. Triple-label immunofluorescence was used to co-localize glutamate- or GABA- labeling in the identified VSR pathway neurons. Most activated projection neurons displayed intense glutamate immunofluorescence, suggestive of glutamatergic neurotransmission. To support this, anterograde tracer was injected into the caudal vestibular nuclei. Vestibular axons and terminals in RVLM and CVLM co-localized the anterograde tracer and vesicular glutamate transporter-2 signals. Other retrogradely-labeled cFos-positive neurons displayed intense GABA immunofluorescence. VSR pathway neurons of both phenotypes were present in the caudal medial and spinal vestibular nuclei, and projected to both RVLM and CVLM. As a group, however, triple-labeled vestibular cells with intense glutamate immunofluorescence were located more rostrally in the vestibular nuclei than the GABAergic neurons. Only the GABAergic VSR pathway neurons showed a target preference, projecting predominantly to CVLM. These data provide the first

  15. Glutamate and GABA in vestibulo-sympathetic pathway neurons

    Directory of Open Access Journals (Sweden)

    Gay R Holstein

    2016-02-01

    Full Text Available The vestibulo-sympathetic reflex actively modulates blood pressure during changes in posture. This reflex allows humans to stand up and quadrupeds to rear or climb without a precipitous decline in cerebral perfusion. The vestibulo-sympathetic reflex pathway conveys signals from the vestibular end organs to the caudal vestibular nuclei. These cells, in turn, project to pre-sympathetic neurons in the rostral and caudal ventrolateral medulla (RVLM and CVLM, respectively. The present study assessed glutamate- and GABA-related immunofluorescence associated with central vestibular neurons of the vestibulo-sympathetic reflex pathway in rats. Retrograde FluoroGold tract tracing was used to label vestibular neurons with projections to RVLM or CVLM, and sinusoidal galvanic vestibular stimulation was employed to activate these pathways. Central vestibular neurons of the vestibulo-sympathetic reflex were identified by co-localization of FluoroGold and cFos protein, which accumulates in some vestibular neurons following galvanic stimulation. Triple-label immunofluorescence was used to co-localize glutamate- or GABA- labeling in the identified vestibulo-sympathetic reflex pathway neurons. Most activated projection neurons displayed intense glutamate immunofluorescence, suggestive of glutamatergic neurotransmission. To support this, anterograde tracer was injected into the caudal vestibular nuclei. Vestibular axons and terminals in RVLM and CVLM co-localized the anterograde tracer and vesicular glutamate transporter-2 signals. Other retrogradely-labeled cFos-positive neurons displayed intense GABA immunofluorescence. Vestibulo-sympathetic reflex pathway neurons of both phenotypes were present in the caudal medial and spinal vestibular nuclei, and projected to both RVLM and CVLM. As a group, however, triple-labeled vestibular cells with intense glutamate immunofluorescence were located more rostrally in the vestibular nuclei than the GABAergic neurons. Only the

  16. NEURON and Python.

    Science.gov (United States)

    Hines, Michael L; Davison, Andrew P; Muller, Eilif

    2009-01-01

    The NEURON simulation program now allows Python to be used, alone or in combination with NEURON's traditional Hoc interpreter. Adding Python to NEURON has the immediate benefit of making available a very extensive suite of analysis tools written for engineering and science. It also catalyzes NEURON software development by offering users a modern programming tool that is recognized for its flexibility and power to create and maintain complex programs. At the same time, nothing is lost because all existing models written in Hoc, including graphical user interface tools, continue to work without change and are also available within the Python context. An example of the benefits of Python availability is the use of the xml module in implementing NEURON's Import3D and CellBuild tools to read MorphML and NeuroML model specifications.

  17. Imaging calcium in neurons.

    Science.gov (United States)

    Grienberger, Christine; Konnerth, Arthur

    2012-03-08

    Calcium ions generate versatile intracellular signals that control key functions in all types of neurons. Imaging calcium in neurons is particularly important because calcium signals exert their highly specific functions in well-defined cellular subcompartments. In this Primer, we briefly review the general mechanisms of neuronal calcium signaling. We then introduce the calcium imaging devices, including confocal and two-photon microscopy as well as miniaturized devices that are used in freely moving animals. We provide an overview of the classical chemical fluorescent calcium indicators and of the protein-based genetically encoded calcium indicators. Using application examples, we introduce new developments in the field, such as calcium imaging in awake, behaving animals and the use of calcium imaging for mapping single spine sensory inputs in cortical neurons in vivo. We conclude by providing an outlook on the prospects of calcium imaging for the analysis of neuronal signaling and plasticity in various animal models.

  18. NEURON and Python

    Directory of Open Access Journals (Sweden)

    Michael Hines

    2009-01-01

    Full Text Available The NEURON simulation program now allows Python to be used, alone or in combination with NEURON's traditional Hoc interpreter. Adding Python to NEURON has the immediate benefit of making available a very extensive suite of analysis tools written for engineering and science. It also catalyzes NEURON software development by offering users a modern programming tool that is recognized for its flexibility and power to create and maintain complex programs. At the same time, nothing is lost because all existing models written in Hoc, including GUI tools, continue to work without change and are also available within the Python context. An example of the benefits of Python availability is the use of the XML module in implementing NEURON's Import3D and CellBuild tools to read MorphML and NeuroML model specifications.

  19. The role of GABA in the regulation of GnRH neurons

    Directory of Open Access Journals (Sweden)

    Miho eWatanabe

    2014-11-01

    Full Text Available Gonadotropin-releasing hormone (GnRH neurons form the final common pathway for the central regulation of reproduction. Gamma-amino butyric acid (GABA has long been implicated as one of the major players in the regulation of GnRH neurons. Although GABA is typically an inhibitory neurotransmitter in the mature adult central nervous system, most mature GnRH neurons show the unusual characteristic of being excited by GABA. While many reports have provided much insight into the contribution of GABA to the activity of GnRH neurons, the precise physiological role of the excitatory action of GABA on GnRH neurons remains elusive. This brief review presents the current knowledge of the role of GABA signaling in GnRH neuronal activity. We also discuss the modulation of GABA signaling by neurotransmitters and neuromodulators and the functional consequence of GABAergic inputs to GnRH neurons in both the physiology and pathology of reproduction.

  20. Three-dimensional distribution of sensory stimulation-evoked neuronal activity of spinal dorsal horn neurons analyzed by in vivo calcium imaging.

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    Kazuhiko Nishida

    Full Text Available The spinal dorsal horn comprises heterogeneous populations of interneurons and projection neurons, which form neuronal circuits crucial for processing of primary sensory information. Although electrophysiological analyses have uncovered sensory stimulation-evoked neuronal activity of various spinal dorsal horn neurons, monitoring these activities from large ensembles of neurons is needed to obtain a comprehensive view of the spinal dorsal horn circuitry. In the present study, we established in vivo calcium imaging of multiple spinal dorsal horn neurons by using a two-photon microscope and extracted three-dimensional neuronal activity maps of these neurons in response to cutaneous sensory stimulation. For calcium imaging, a fluorescence resonance energy transfer (FRET-based calcium indicator protein, Yellow Cameleon, which is insensitive to motion artifacts of living animals was introduced into spinal dorsal horn neurons by in utero electroporation. In vivo calcium imaging following pinch, brush, and heat stimulation suggests that laminar distribution of sensory stimulation-evoked neuronal activity in the spinal dorsal horn largely corresponds to that of primary afferent inputs. In addition, cutaneous pinch stimulation elicited activities of neurons in the spinal cord at least until 2 spinal segments away from the central projection field of primary sensory neurons responsible for the stimulated skin point. These results provide a clue to understand neuronal processing of sensory information in the spinal dorsal horn.

  1. Three-dimensional distribution of sensory stimulation-evoked neuronal activity of spinal dorsal horn neurons analyzed by in vivo calcium imaging.

    Science.gov (United States)

    Nishida, Kazuhiko; Matsumura, Shinji; Taniguchi, Wataru; Uta, Daisuke; Furue, Hidemasa; Ito, Seiji

    2014-01-01

    The spinal dorsal horn comprises heterogeneous populations of interneurons and projection neurons, which form neuronal circuits crucial for processing of primary sensory information. Although electrophysiological analyses have uncovered sensory stimulation-evoked neuronal activity of various spinal dorsal horn neurons, monitoring these activities from large ensembles of neurons is needed to obtain a comprehensive view of the spinal dorsal horn circuitry. In the present study, we established in vivo calcium imaging of multiple spinal dorsal horn neurons by using a two-photon microscope and extracted three-dimensional neuronal activity maps of these neurons in response to cutaneous sensory stimulation. For calcium imaging, a fluorescence resonance energy transfer (FRET)-based calcium indicator protein, Yellow Cameleon, which is insensitive to motion artifacts of living animals was introduced into spinal dorsal horn neurons by in utero electroporation. In vivo calcium imaging following pinch, brush, and heat stimulation suggests that laminar distribution of sensory stimulation-evoked neuronal activity in the spinal dorsal horn largely corresponds to that of primary afferent inputs. In addition, cutaneous pinch stimulation elicited activities of neurons in the spinal cord at least until 2 spinal segments away from the central projection field of primary sensory neurons responsible for the stimulated skin point. These results provide a clue to understand neuronal processing of sensory information in the spinal dorsal horn.

  2. Functional neuroanatomy of the central noradrenergic system.

    Science.gov (United States)

    Szabadi, Elemer

    2013-08-01

    The central noradrenergic neurone, like the peripheral sympathetic neurone, is characterized by a diffusely arborizing terminal axonal network. The central neurones aggregate in distinct brainstem nuclei, of which the locus coeruleus (LC) is the most prominent. LC neurones project widely to most areas of the neuraxis, where they mediate dual effects: neuronal excitation by α₁-adrenoceptors and inhibition by α₂-adrenoceptors. The LC plays an important role in physiological regulatory networks. In the sleep/arousal network the LC promotes wakefulness, via excitatory projections to the cerebral cortex and other wakefulness-promoting nuclei, and inhibitory projections to sleep-promoting nuclei. The LC, together with other pontine noradrenergic nuclei, modulates autonomic functions by excitatory projections to preganglionic sympathetic, and inhibitory projections to preganglionic parasympathetic neurones. The LC also modulates the acute effects of light on physiological functions ('photomodulation'): stimulation of arousal and sympathetic activity by light via the LC opposes the inhibitory effects of light mediated by the ventrolateral preoptic nucleus on arousal and by the paraventricular nucleus on sympathetic activity. Photostimulation of arousal by light via the LC may enable diurnal animals to function during daytime. LC neurones degenerate early and progressively in Parkinson's disease and Alzheimer's disease, leading to cognitive impairment, depression and sleep disturbance.

  3. Involvement of adrenergic and serotonergic receptors in antidepressant-like effect of urocortin 3 in a modified forced swimming test in mice.

    Science.gov (United States)

    Tanaka, Masaru; Telegdy, Gyula

    2008-11-25

    Most of the evidence suggests that peptides in the corticotropin-releasing factor (CRF) family act on CRF receptors and are involved in depressive disorders. Urocortin 3 (Ucn 3) is specific for CRF type 2 (CRF(2)) receptors and mediates anxiolytic-like action. Little is known about the roles of Ucn 3 and CRH(2) receptors on depressive disorders. The previous study revealed that Ucn 3 elicits the antidepressant-like action by shortening the immobility time and increasing both the climbing time and the swimming time. The involvement of the adrenergic and serotonergic receptors in the antidepressant-like effect of Ucn 3 (0.5μg/2μl, i.c.v.) was studied in a modified forced swimming test (FST) in mice. Mice were pretreated with a non-selective α-adrenergic receptor antagonist, phenoxybenzamine, an α(1)/α(2β)-adrenergic receptor antagonist, prazosin, an α(2)-adrenergic receptor antagonist, yohimbine, a mixed 5-HT(1)/5-HT(2) serotonergic receptor antagonist, methysergide, a non-selective 5-HT(2) serotonergic receptor antagonist, cyproheptadine or a β-adrenergic receptor antagonist, propranolol. Phenoxybenzamine prevented the effects of Ucn 3 on the immobility time. Prazosin prevented the effects of Ucn 3 on the climbing time. Yohimbine prevented the effects of Ucn 3 on the immobility, climbing and swimming times. Methysergide prevented the effects of Ucn 3 on the immobility and climbing time. Cyproheptadine prevented the effects of Ucn 3 on the swimming time. Propranolol did not change the effects of Ucn 3. The results demonstrated that the antidepressant-like effect of Ucn 3 is mediated, at least in part, by an interaction of the α-adrenergic and serotonergic receptors in a modified mouse FST.

  4. Increased depressive ratings in patients with hepatitis C receiving interferon-alpha-based immunotherapy are related to interferon-alpha-induced changes in the serotonergic system.

    Science.gov (United States)

    Bonaccorso, Stefania; Marino, Valentina; Puzella, Antonella; Pasquini, Massimo; Biondi, Massimo; Artini, Marco; Almerighi, Cristiana; Verkerk, Robert; Meltzer, Herbert; Maes, Michael

    2002-02-01

    There is now evidence that repeated administration of interferon-alpha (IFN-alpha) to patients with chronic active hepatitis and cancers induces depressive symptoms. There is also evidence that induction of the cytokine network modulates the serotonergic system and that major depression is related to activation of the cytokine network and disturbances in the serotonergic metabolism. The aims of this study were to examine the effects of IFN-alpha-based immunotherapy on the development of depressive symptoms in relation to its effects on plasma tryptophan and kynurenine and serum serotonin (5-HT). Eighteen patients affected by chronic active hepatitis C were treated with IFN-alpha (3-6 million units subcutaneously three to six times a week for 6 months) and had measurements of the previous parameters before starting immunotherapy and 2, 4, 16, and 24 weeks later. Severity of depression and anxiety were measured with the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Rating Scale for Anxiety (HAM-A) scale, respectively. Immunochemotherapy with IFN-alpha (1) significantly increased the MADRS and HAM-A scores and serum kynurenine concentrations and (2) significantly reduced plasma tryptophan and serum 5-HT concentrations. IFN-alpha-based immunotherapy significantly increased the kynurenine per tryptophan quotient, which estimates the activity of indoleamine 2,3-dioxygenase, the major tryptophan-catabolizing enzyme, which is induced by IFNs. There are significant relationships between the IFN-alpha-induced changes in the MADRS score and serum kynurenine (positive) and 5-HT (negative) concentrations. Immunotherapy with IFN-alpha significantly increases the severity of depressive symptoms. The latter is related to changes in the serotonergic system, such as depletion of serum 5-HT and induction of the catabolism of tryptophan to kynurenine. It is suggested that the IFN-alpha-induced changes in the serotonergic turnover could play a role in the

  5. WNT signaling in neuronal maturation and synaptogenesis

    Science.gov (United States)

    Rosso, Silvana B.; Inestrosa, Nibaldo C.

    2013-01-01

    The Wnt signaling pathway plays a role in the development of the central nervous system and growing evidence indicates that Wnts also regulates the structure and function of the adult nervous system. Wnt components are key regulators of a variety of developmental processes, including embryonic patterning, cell specification, and cell polarity. In the nervous system, Wnt signaling also regulates the formation and function of neuronal circuits by controlling neuronal differentiation, axon outgrowth and guidance, dendrite development, synaptic function, and neuronal plasticity. Wnt factors can signal through three very well characterized cascades: canonical or β-catenin pathway, planar cell polarity pathway and calcium pathway that control different processes. However, divergent downstream cascades have been identified to control neuronal morphogenesis. In the nervous system, the expression of Wnt proteins is a highly controlled process. In addition, deregulation of Wnt signaling has been associated with neurodegenerative diseases. Here, we will review different aspects of neuronal and dendrite maturation, including spinogenesis and synaptogenesis. Finally, the role of Wnt pathway components on Alzheimer’s disease will be revised. PMID:23847469

  6. WNT signalling in neuronal maturation and synaptogenesis

    Directory of Open Access Journals (Sweden)

    Silvana Beatriz Rosso

    2013-07-01

    Full Text Available The Wnt signaling pathway plays a role in the development of the central nervous system (CNS and growing evidence indicates that Wnts also regulates the structure and function of the adult nervous system. Wnt components are key regulators of a variety of developmental processes, including embryonic patterning, cell specification, and cell polarity. In the nervous system, Wnt signaling also regulates the formation and function of neuronal circuits by controlling neuronal differentiation, axon outgrowth and guidance, dendrite development, synaptic function and neuronal plasticity. Wnt factors can signal through three very well characterized cascades: canonical or β-catenin pathway, planar cell polarity pathway and calcium pathway that control different processes. However, divergent downstream cascades have been identified to control neuronal morphogenesis. In the nervous system, the expression of Wnt proteins is a highly controlled process. In addition, deregulation of Wnt signaling has been associated with neurodegenerative diseases. Here, we will review different aspects of neuronal and dendrite maturation, including spinogenesis and synaptogenesis. Finally, the role of Wnt pathway components on Alzheimer’s disease will be revised.

  7. Temperature integration at the AC thermosensory neurons in Drosophila.

    Science.gov (United States)

    Tang, Xin; Platt, Michael D; Lagnese, Christopher M; Leslie, Jennifer R; Hamada, Fumika N

    2013-01-16

    Temperature sensation has a strong impact on animal behavior and is necessary for animals to avoid exposure to harmful temperatures. It is now well known that thermoTRP (transient receptor potential) channels in thermosensory neurons detect a variable range of temperature stimuli. However, little is known about how a range of temperature information is relayed and integrated in the neural circuits. Here, we show novel temperature integration between two warm inputs via Drosophila TRPA channels, TRPA1 and Pyrexia (Pyx). The internal AC (anterior cell) thermosensory neurons, which express TRPA1, detect warm temperatures and mediate temperature preference behavior. We found that the AC neurons were activated twice when subjected to increasing temperatures. The first response was at ∼25°C via TRPA1 channel, which is expressed in the AC neurons. The second response was at ∼27°C via the second antennal segments, indicating that the second antennal segments are involved in the detection of warm temperatures. Further analysis reveals that pyx-Gal4-expressing neurons have synapses on the AC neurons and that mutation of pyx eliminates the second response of the AC neurons. These data suggest that AC neurons integrate both their own TRPA1-dependent temperature responses and a Pyx-dependent temperature response from the second antennal segments. Our data reveal the first identification of temperature integration, which combines warm temperature information from peripheral to central neurons and provides the possibility that temperature integration is involved in the plasticity of behavioral outputs.

  8. Behavioral plasticity through the modulation of switch neurons.

    Science.gov (United States)

    Vassiliades, Vassilis; Christodoulou, Chris

    2016-02-01

    A central question in artificial intelligence is how to design agents capable of switching between different behaviors in response to environmental changes. Taking inspiration from neuroscience, we address this problem by utilizing artificial neural networks (NNs) as agent controllers, and mechanisms such as neuromodulation and synaptic gating. The novel aspect of this work is the introduction of a type of artificial neuron we call "switch neuron". A switch neuron regulates the flow of information in NNs by selectively gating all but one of its incoming synaptic connections, effectively allowing only one signal to propagate forward. The allowed connection is determined by the switch neuron's level of modulatory activation which is affected by modulatory signals, such as signals that encode some information about the reward received by the agent. An important aspect of the switch neuron is that it can be used in appropriate "switch modules" in order to modulate other switch neurons. As we show, the introduction of the switch modules enables the creation of sequences of gating events. This is achieved through the design of a modulatory pathway capable of exploring in a principled manner all permutations of the connections arriving on the switch neurons. We test the model by presenting appropriate architectures in nonstationary binary association problems and T-maze tasks. The results show that for all tasks, the switch neuron architectures generate optimal adaptive behaviors, providing evidence that the switch neuron model could be a valuable tool in simulations where behavioral plasticity is required.

  9. Testosterone gel replacement improves sexual function in depressed men taking serotonergic antidepressants: a randomized, placebo-controlled clinical trial.

    Science.gov (United States)

    Amiaz, Revital; Pope, Harrison G; Mahne, Thomas; Kelly, John F; Brennan, Brian P; Kanayama, Gen; Weiser, Mark; Hudson, James I; Seidman, Stuart N

    2011-01-01

    Testosterone replacement is the most effective treatment for sexual dysfunction in hypogonadal men. Comorbid depression and antidepressant side effects may reduce its influence. The authors conducted a 6-week, double-blind, placebo-controlled clinical trial of testosterone gel versus placebo gel in men with major depressive disorder who were currently taking a serotonergic antidepressant and exhibited low or low-normal testosterone level. A total of 100 men were enrolled at 2 study sites (Boston, Massachusetts, USA, and Tel Aviv, Israel). The effects of testosterone augmentation on sexual functioning were determined using domain scores on the International Index of Erectile Function (IIEF). Complete pre- and posttrial IIEF data were available for 63 subjects. Men randomized to testosterone (n = 31) and placebo (n = 32) were similar in age, baseline testosterone levels, and baseline IIEF scores. At study termination, men randomized to placebo showed virtually no change from baseline in mean (95% CI) IIEF score (-0.7 [-6.5, 5.2]), whereas those receiving testosterone exhibited a substantial increase (15.8 [8.5, 23.1]). The estimated mean difference between groups was 16.8 [7.5, 26.1]; p = .001 by linear regression with adjustment for age and study site. There were also significant between-group differences in each of the 5 IIEF subscales, as well as on the single question involving ejaculatory ability (p ≤ .03 in all cases). Effect sizes in these comparisons remained little changed, and generally remained statistically significant, when we further adjusted for change in depression scores on the Montgomery Asberg Depression Rating Scale. It is notable that the subgroup of men with the highest baseline testosterone levels showed virtually the same improvement as those with lower levels, suggesting that the observed improvement was unlikely to be due simply to correction of hypogonadism alone. In depressed men with low or low-normal testosterone levels who continued

  10. Pharmacogenetics and olanzapine treatment: CYP1A2*1F and serotonergic polymorphisms influence therapeutic outcome.

    Science.gov (United States)

    Laika, B; Leucht, S; Heres, S; Schneider, H; Steimer, W

    2010-02-01

    Psychiatric pharmacotherapy with olanzapine is commonplace. We investigated the influence of CYP1A2*1F (-163A, rs762551) and serotonergic polymorphisms on olanzapine serum concentrations and clinical outcome in a naturalistic clinical setting. Included were 124 Caucasian psychiatric inpatients treated with olanzapine for at least 4 weeks with steady-state serum concentrations available for 73 patients. The CYP1A2*1F polymorphism was reported to affect the inducibility of CYP1A2. In our study population, CYP1A2*1F/*1F genotype alone resulted in a 22% reduction of dose-/body weight-normalized olanzapine serum concentrations compared to homo- and heterozygote carriers of CYP1A2*1A (both groups without inducers). This effect was independent of the well-known effect of inducing agents (here tobacco smoke and carbamazepine which led to on average 28% lower concentrations in CYP1A2*1A carriers and 26% lower concentrations in CYP1A2*1F/*1F carriers). Consistently, patients with the CYP1A2*1F/*1F genotype taking inducers had 22% lower concentrations compared to CYP1A2*1A carriers taking inducers. The influence of genotype alone remained significant after Bonferroni's post hoc test. Higher olanzapine concentrations were significantly correlated with better improvement of paranoid and depressive symptoms in patients with schizophrenic disorders (Spearman's r=0.5, P=0.026 and P=0.006, respectively). No relationship between serum concentrations and the side effects (DOTES) score was detected. However, patients with the 5-HTR2A intron 2 (rs7997012) AA genotype suffered from more pronounced side effects compared to carriers of the GA or GG genotype (P=0.018 and P=0.002). Short-term weight gain under olanzapine therapy was significantly lower for 5-HTR2C -759 T-allele carriers (P=0.011). Our data suggest that the CYP1A2*1F/*1F genotype exhibits a significant influence on olanzapine concentrations independent of other inducing factors. Thus, CYP1A2*1F genotyping may be useful for

  11. Association between 5-HT2A, TPH1 and GNB3 genotypes and response to typical neuroleptics: a serotonergic approach

    Directory of Open Access Journals (Sweden)

    Kampman Olli

    2007-05-01

    Full Text Available Abstract Background Schizophrenia is a common psychiatric disease affecting about 1% of population. One major problem in the treatment is finding the right the drug for the right patients. However, pharmacogenetic results in psychiatry can seldom be replicated. Methods We selected three candidate genes associated with serotonergic neurotransmission for the study: serotonin 2A (5-HT2A receptor gene, tryptophan hydroxylase 1 (TPH1 gene, and G-protein beta-3 subunit (GNB3 gene. We recruited 94 schizophrenia patients representing extremes in treatment response to typical neuroleptics: 43 were good responders and 51 were poor responders. The control group consisted of 392 healthy blood donors. Results We do, in part, replicate the association between 5-HT2A T102C polymorphism and response to typical neuroleptics. In female patients, C/C genotype was significantly more common in non-responders than in responders [OR = 6.04 (95% Cl 1.67–21.93, p = 0.005] or in the control population [OR = 4.16 (95% CI 1.46–11.84, p = 0.005]. TPH1 A779C C/A genotype was inversely associated with good treatment response when compared with non-responders [OR = 0.59 (95% Cl 0.36–0.98, p = 0.030] or with the controls [OR = 0.44 (95% CI 0.23–0.86, p = 0.016], and GNB3 C825T C/T genotype showed a trend-like positive association among the male patients with a good response compared with non-responders [OR = 3.48 (95% Cl 0.92–13.25, p = 0.061], and a clearer association when compared with the controls [OR = 4.95 (95% CI 1.56–15.70, p = 0.004]. Conclusion More findings on the consequences of functional polymorphisms for the role of serotonin in the development of brain and serotonergic neurotransmission are needed before more detailed hypotheses regarding susceptibility and outcome in schizophrenia can be formulated. The present results may highlight some of the biological mechanisms in different courses of schizophrenia between men and women.

  12. The role of the striatum in compulsive behavior in intact and orbitofrontal-cortex-lesioned rats: possible involvement of the serotonergic system.

    Science.gov (United States)

    Schilman, Eduardo A; Klavir, Oded; Winter, Christine; Sohr, Reinhard; Joel, Daphna

    2010-03-01

    In the signal attenuation rat model of obsessive-compulsive disorder (OCD), 'compulsive' behavior is induced by attenuating a signal indicating that a lever-press response was effective in producing food. We have recently found that lesions to the rat orbitofrontal cortex (OFC) led to an increase in compulsive lever-pressing that was prevented by systemic administration of the selective serotonin reuptake inhibitor paroxetine, and paralleled by an increase in the density of the striatal serotonin transporter. This study further explored the interaction between the OFC, the striatum, and the serotonergic system in the production of compulsive lever-pressing. Experiment 1 revealed that OFC lesions decrease the content of serotonin, dopamine, glutamate, and GABA in the striatum. Experiment 2 showed that intrastriatal administration of paroxetine blocked OFC lesion-induced increased compulsivity, but did not affect compulsive responding in intact rats. Experiments 3 and 4 found that pre-training striatal lesions had no effect on compulsive lever-pressing, whereas post-training striatal inactivation exerted an anticompulsive effect. These results strongly implicate the striatum in the expression of compulsive lever-pressing in both intact and OFC-lesioned rats. Furthermore, the results support the possibility that in a subpopulation of OCD patients a primary pathology of the OFC leads to a dysregulation of the striatal serotonergic system, which is manifested in compulsive behavior, and that antiobsessional/anticompulsive drugs exerts their effects, in these patients, by normalizing the dysfunctional striatal serotonergic system.

  13. Intrathecal nefopam-induced antinociception through activation of descending serotonergic projections involving spinal 5-HT7 but not 5-HT3 receptors.

    Science.gov (United States)

    Lee, Hyung Gon; Kim, Woong Mo; Kim, Joung Min; Bae, Hong-Beom; Choi, Jeong Il

    2015-02-05

    We examined the involvement of spinal 5-HT(5-hydroxytryptamine) receptor 3(5-HT3R) and 7(5-HT7R) as well as the overall role of descending serotonergic projections in the analgesic effects of intrathecal(i.t.) nefopam for two rat models of formalin and paw incision test. I.t. nefopam produced an antinociceptive effect in a dose-dependent manner in both tests. Lesioning the spinal serotonergic projections using i.t. 5,7-dihydroxytryptamine(5,7-DHT) did not influence the intensity of allodynia in the paw incision test, but i.t. 5,7-DHT abolished the effect of nefopam. In the formain test, i.t. 5,7-DHT alone significantly diminished the flinches, but the effect of nefopam was not affected by i.t. 5,7-DHT. Antagonism study showed that i.t. 5-HT7R antagonist, SB269970 significantly blocked the antinociceptive effect of nefopam in both tests, but i.t. 5-HT3R antagonist, ondansetron has no influence on the effect of nefopam. The present study demonstrates that descending spinal serotonergic projections play a vital role in antinociceptive effect of i.t. nefopam in the paw incision test, but indeterminate in the formalin test. In both tests, the antinociceptive effect of i.t. nefopam involves the spinal 5-HT7R, but not 5-HT3R.

  14. Identification of inputs to olivocochlear neurons using transneuronal labeling with pseudorabies virus (PRV).

    Science.gov (United States)

    Brown, M Christian; Mukerji, Sudeep; Drottar, Marie; Windsor, Alanna M; Lee, Daniel J

    2013-10-01

    Olivocochlear (OC) neurons respond to sound and provide descending input that controls processing in the cochlea. The identities of neurons in the pathways providing inputs to OC neurons are incompletely understood. To explore these pathways, the retrograde transneuronal tracer pseudorabies virus (Bartha strain, expressing green fluorescent protein) was used to label OC neurons and their inputs in guinea pigs. Labeling of OC neurons began 1 day after injection into the cochlea. On day 2 (and for longer survival times), transneuronal labeling spread to the cochlear nucleus, inferior colliculus, and other brainstem areas. There was a correlation between the numbers of these transneuronally labeled neurons and the number of labeled medial (M) OC neurons, suggesting that the spread of labeling proceeds mainly via synapses on MOC neurons. In the cochlear nucleus, the transneuronally labeled neurons were multipolar cells including the subtype known as planar cells. In the central nucleus of the inferior colliculus, transneuronally labeled neurons were of two principal types: neurons with disc-shaped dendritic fields and neurons with dendrites in a stellate pattern. Transneuronal labeling was also observed in pyramidal cells in the auditory cortex and in centers not typically associated with the auditory pathway such as the pontine reticular formation, subcoerulean nucleus, and the pontine dorsal raphe. These data provide information on the identity of neurons providing input to OC neurons, which are located in auditory as well as non-auditory centers.

  15. Bidirectional Microglia-Neuron Communication in the Healthy Brain

    OpenAIRE

    2013-01-01

    Unlike other resident neural cells that are of neuroectodermal origin, microglia are resident neural cells of mesodermal origin. Traditionally recognized for their immune functions during disease, new roles are being attributed to these cells in the development and maintenance of the central nervous system (CNS) including specific communication with neurons. In this review, we highlight some of the recent findings on the bidirectional interaction between neurons and microglia. We discuss thes...

  16. Mathematical Modeling of Subthreshold Resonant Properties in Pyloric Dilator Neurons

    OpenAIRE

    Vazifehkhah Ghaffari, Babak; Kouhnavard, Mojgan; Aihara, Takeshi; Kitajima, Tatsuo

    2015-01-01

    Various types of neurons exhibit subthreshold resonance oscillation (preferred frequency response) to fluctuating sinusoidal input currents. This phenomenon is well known to influence the synaptic plasticity and frequency of neural network oscillation. This study evaluates the resonant properties of pacemaker pyloric dilator (PD) neurons in the central pattern generator network through mathematical modeling. From the pharmacological point of view, calcium currents cannot be blocked in PD neur...

  17. Multiple domains of tetanus toxin direct entry into primary neurons

    OpenAIRE

    Blum, Faith C.; Tepp, William H.; Eric A. Johnson; Barbieri, Joseph T

    2014-01-01

    Tetanus toxin elicits spastic paralysis by cleaving VAMP-2 to inhibit neurotransmitter release in inhibitory neurons of the central nervous system. While the retrograde transport of TeNT from endosomes has been described, the initial steps that define how TeNT initiates trafficking to the retrograde system are undefined. The current study examines TeNT entry into primary cultured cortical neurons by TIRF microscopy. The initial association of TeNT with the plasma membrane was dependent upon g...

  18. Effect of methylprednisolone on mammalian neuronal networks in vitro.

    Science.gov (United States)

    Wittstock, Matthias; Rommer, Paulus S; Schiffmann, Florian; Jügelt, Konstantin; Stüwe, Simone; Benecke, Reiner; Schiffmann, Dietmar; Zettl, Uwe K

    2015-01-01

    Glucocorticosteroids (GCS) are widely used for the treatment of neurological diseases, e.g. multiple sclerosis. High levels of GCS are toxic to the central nervous system and can produce adverse effects. The effect of methylprednisolone (MP) on mammalian neuronal networks was studied in vitro. We demonstrate a dose-dependent excitatory effect of MP on cultured neuronal networks, followed by a shut-down of electrical activity using the microelectrode array technique.

  19. Pathophysiologic basis of anorexia: focus on the interaction between ghrelin dynamics and the serotonergic system.

    Science.gov (United States)

    Takeda, Hiroshi; Nakagawa, Koji; Okubo, Naoto; Nishimura, Mie; Muto, Shuichi; Ohnishi, Shunsuke; Sakamoto, Naoya; Hosono, Hidetaka; Asaka, Masahiro

    2013-01-01

    Anorexia is an important issue in the management of elderly patients with cancer because it contributes to the development of malnutrition, increases morbidity and mortality, and negatively affects patients' quality of life. This review summarizes the potential mechanisms of the development of anorexia in three animal models that mimic the situations commonly seen in elderly patients receiving chemotherapy. Cisplatin-induced anorexia is attributable to a decrease in peripheral and central ghrelin secretion caused by the stimulation of serotonin (5-hydroxytryptamine; 5-HT)2B and 5-HT2C receptors via 5-HT secretion. Age-associated anorexia is caused by an increase in plasma leptin, which results from disturbed reactivity of ghrelin in the hypothalamus and regulation of ghrelin secretion. Environmental change causes the activation of central 5-HT1B and 5-HT2C receptors and the melanocortin-4 receptor system, resulting in a decrease in circulating ghrelin levels which lowers food intake. New therapeutic approaches based on these pathophysiological mechanisms are warranted for the treatment of anorexia in cancer patients, especially elderly ones.

  20. Cdc42 regulates cofilin during the establishment of neuronal polarity

    DEFF Research Database (Denmark)

    Garvalov, Boyan K; Flynn, Kevin C; Neukirchen, Dorothee

    2007-01-01

    The establishment of polarity is an essential process in early neuronal development. Although a number of molecules controlling neuronal polarity have been identified, genetic evidence about their physiological roles in this process is mostly lacking. We analyzed the consequences of loss of Cdc42......, a central regulator of polarity in multiple systems, on the polarization of mammalian neurons. Genetic ablation of Cdc42 in the brain led to multiple abnormalities, including striking defects in the formation of axonal tracts. Neurons from the Cdc42 null animals sprouted neurites but had a strongly......-type, but not of mutant, neurons. Importantly, cofilin knockdown resulted in polarity defects quantitatively analogous to the ones seen after Cdc42 ablation. We conclude that Cdc42 is a key regulator of axon specification, and that cofilin is a physiological downstream effector of Cdc42 in this process....

  1. Conservation of 5-HT1A receptor-mediated autoinhibition of serotonin (5-HT neurons in mice with altered 5-HT homeostasis

    Directory of Open Access Journals (Sweden)

    Naozumi eAraragi

    2013-08-01

    Full Text Available Firing activity of serotonin (5-HT neurons in the dorsal raphe nucleus (DRN is controlled by inhibitory somatodendritic 5-HT1A autoreceptors. This autoinhibitory mechanism is implicated in the etiology of disorders of emotion regulation, such as anxiety disorders and depression, as well as in the mechanism of antidepressant action. Here, we investigated how persistent alterations in brain 5-HT availability affect autoinhibition in two genetically modified mouse models lacking critical mediators of serotonergic transmission: 5-HT transporter knockout (Sert -/- and tryptophan hydroxylase-2 knockout (Tph2 -/- mice. The degree of autoinhibition was assessed by loose-seal cell-attached recording in DRN slices. First, application of the 5-HT1A-selective agonist R(+-8-hydroxy-2-(di-n-propylaminotetralin showed mild sensitization and marked desensitization of 5-HT1A receptors in Tph2 -/- mice and Sert -/- mice, respectively. While 5-HT neurons from Tph2 -/- mice did not display autoinhibition in response to L-tryptophan, autoinhibition of these neurons was unaltered in Sert -/- mice despite marked desensitization of their 5-HT1A autoreceptors. When the Tph2-dependent 5-HT synthesis step was bypassed by application of 5-hydroxy-L-tryptophan (5-HTP, neurons from both Tph2 -/- and Sert -/- mice decreased their firing rates at significantly lower concentrations of 5-HTP compared to wildtype controls. Our findings demonstrate that, as opposed to the prevalent view, sensitivity of somatodendritic 5-HT1A receptors does not predict the magnitude of 5-HT neuron autoinhibition. Changes in 5-HT1A receptor sensitivity may rather be seen as an adaptive mechanism to keep autoinhibition functioning in response to extremely altered levels of extracellular 5-HT resulting from targeted inactivation of mediators of serotonergic signaling.

  2. Single neuron computation

    CERN Document Server

    McKenna, Thomas M; Zornetzer, Steven F

    1992-01-01

    This book contains twenty-two original contributions that provide a comprehensive overview of computational approaches to understanding a single neuron structure. The focus on cellular-level processes is twofold. From a computational neuroscience perspective, a thorough understanding of the information processing performed by single neurons leads to an understanding of circuit- and systems-level activity. From the standpoint of artificial neural networks (ANNs), a single real neuron is as complex an operational unit as an entire ANN, and formalizing the complex computations performed by real n

  3. Active properties of neuronal dendrites.

    Science.gov (United States)

    Johnston, D; Magee, J C; Colbert, C M; Cristie, B R

    1996-01-01

    Dendrites of neurons in the central nervous system are the principal sites for excitatory synaptic input. Although little is known about their function, two disparate perspectives have arisen to describe the activity patterns inherent to these diverse tree-like structures. Dendrites are thus considered either passive or active in their role in integrating synaptic inputs. This review follows the history of dendritic research from before the turn of the century to the present, with a primary focus on the hippocampus. A number of recent techniques, including high-speed fluorescence imaging and dendritic patch clamping, have provided new information and perspectives about the active properties of dendrites. The results support previous notions about the dendritic propagation of action potentials and also indicate which types of voltage-gated sodium and calcium channels are expressed and functionally active in dendrites. Possible roles for the active properties of dendrites in synaptic plasticity and integration are also discussed.

  4. Anatomy and Physiology of the Thick-tufted Layer 5 Pyramidal Neuron

    Directory of Open Access Journals (Sweden)

    Srikanth eRamaswamy

    2015-06-01

    Full Text Available The thick-tufted layer 5 (TTL5 pyramidal neuron is one of the most extensively studied neuron types in the mammalian neocortex and has become a benchmark for understanding information processing in excitatory neurons. By virtue of having the widest local axonal and dendritic arborization, the TTL5 neuron encompasses various local neocortical neurons and thereby defines the dimensions of neocortical microcircuitry. The TTL5 neuron integrates input across all neocortical layers and is the principal output pathway funneling information flow to subcortical structures. Several studies over the past decades have investigated the anatomy, physiology, synaptology, and pathophysiology of the TTL5 neuron. This review summarizes key discoveries and identifies potential avenues of research to facilitate an integrated and unifying understanding on the role of a central neuron in the neocortex.

  5. Neuromorphic silicon neuron circuits

    Directory of Open Access Journals (Sweden)

    Giacomo eIndiveri

    2011-05-01

    Full Text Available Hardware implementations of spiking neurons can be extremely useful for a large variety of applications, ranging from high-speed modeling of large-scale neural systems to real-time behaving systems, to bidirectional brain-machine interfaces. The specific circuit solutions used to implement silicon neurons depend on the application requirements. In this paper we describe the most common building blocks and techniques used to implement these circuits, and present an overview of a wide range of neuromorphic silicon neurons, which implement different computational models, ranging from biophysically realistic and conductance based Hodgkin-Huxley models to bi-dimensional generalized adaptive Integrate and Fire models. We compare the different design methodologies used for each silicon neuron design described, and demonstrate their features with experimental results, measured from a wide range of fabricated VLSI chips.

  6. Motor neurone disease.

    Science.gov (United States)

    2016-03-23

    Essential facts Motor neurone disease describes a group of related diseases, affecting the neurones in the brain and spinal cord. Progressive, incurable and life-limiting, MND is rare, with about 1,100 people developing it each year in the UK and up to 5,000 people affected at any one time. One third of people will die within a year of diagnosis and more than half within two years. About 5% to 10% are alive at ten years.

  7. Neuronal network of panic disorder: the role of the neuropeptide cholecystokinin.

    Science.gov (United States)

    Zwanzger, P; Domschke, K; Bradwejn, J

    2012-09-01

    Panic disorder (PD) is characterized by panic attacks, anticipatory anxiety and avoidance behavior. Its pathogenesis is complex and includes both neurobiological and psychological factors. With regard to neurobiological underpinnings, anxiety in humans seems to be mediated through a neuronal network, which involves several distinct brain regions, neuronal circuits and projections as well as neurotransmitters. A large body of evidence suggests that the neuropeptide cholecystokinin (CCK) might be an important modulator of this neuronal network. Key regions of the fear network, such as amygdala, hypothalamus, peraqueductal grey, or cortical regions seem to be connected by CCKergic pathways. CCK interacts with several anxiety-relevant neurotransmitters such as the serotonergic, GABA-ergic and noradrenergic system as well as with endocannabinoids, NPY and NPS. In humans, administration of CCK-4 reliably provokes panic attacks, which can be blocked by antipanic medication. Also, there is some support for a role of the CCK system in the genetic pathomechanism of PD with particularly strong evidence for the CCK gene itself and the CCK-2R (CCKBR) gene. Thus, it is hypothesized that genetic variants in the CCK system might contribute to the biological basis for the postulated CCK dysfunction in the fear network underlying PD. Taken together, a large body of evidence suggests a possible role for the neuropeptide CCK in PD with regard to neuroanatomical circuits, neurotransmitters and genetic factors. This review article proposes an extended hypothetical model for human PD, which integrates preclinical and clinical findings on CCK in addition to existing theories of the pathogenesis of PD.

  8. Neuron division or enucleation.

    Science.gov (United States)

    Sotnikov, O S; Laktionova, A A; Solovieva, I A; Krasnova, T V

    2010-10-01

    The classical Bielschowsky-Gross neurohistological method was used to reproduce all the morphological phenomena interpreted by many authors as signs of neuron division, budding, and fission. It is suggested that these signs are associated with the effects of enucleation, which occurs in many cells of other tissue types in response to a variety of chemical and physical treatments. Studies were performed using neurons isolated from the mollusk Lymnaea stagnalis and exposed in tissue culture to the actin microfilament inhibitor cytochalasin B. Phase contrast time-lapse video recording over periods of 4-8 h demonstrated nuclear displacement, ectopization, and budding, to the level of almost complete fission of the neuron body. This repeats the pattern seen in static fixed preparations in "normal" conditions and after different experimental treatments. Budding of the cytoplasm was also sometimes seen at the early stages of the experiments. Control experiments in which cultured neurons were exposed to the solvent for cytochalasin B, i.e., dimethylsulfoxide (DMSO), did not reveal any changes in neurons over a period of 8 h. We take the view that the picture previously interpreted as neuron division and fission can be explained in terms of the inhibition of actin microfilaments, sometimes developing spontaneously in cells undergoing individual metabolic changes preventing the maintenance of cytoskeleton stability.

  9. NeuronBank: A Tool for Cataloging Neuronal Circuitry.

    Science.gov (United States)

    Katz, Paul S; Calin-Jageman, Robert; Dhawan, Akshaye; Frederick, Chad; Guo, Shuman; Dissanayaka, Rasanjalee; Hiremath, Naveen; Ma, Wenjun; Shen, Xiuyn; Wang, Hsui C; Yang, Hong; Prasad, Sushil; Sunderraman, Rajshekhar; Zhu, Ying

    2010-01-01

    The basic unit of any nervous system is the neuron. Therefore, understanding the operation of nervous systems ultimately requires an inventory of their constituent neurons and synaptic connectivity, which form neural circuits. The presence of uniquely identifiable neurons or classes of neurons in many invertebrates has facilitated the construction of cellular-level connectivity diagrams that can be generalized across individuals within a species. Homologous neurons can also be recognized across species. Here we describe NeuronBank.org, a web-based tool that we are developing for cataloging, searching, and analyzing neuronal circuitry within and across species. Information from a single species is represented in an individual branch of NeuronBank. Users can search within a branch or perform queries across branches to look for similarities in neuronal circuits across species. The branches allow for an extensible ontology so that additional characteristics can be added as knowledge grows. Each entry in NeuronBank generates a unique accession ID, allowing it to be easily cited. There is also an automatic link to a Wiki page allowing an encyclopedic explanation of the entry. All of the 44 previously published neurons plus one previously unpublished neuron from the mollusc, Tritonia diomedea, have been entered into a branch of NeuronBank as have 4 previously published neurons from the mollusc, Melibe leonina. The ability to organize information about neuronal circuits will make this information more accessible, ultimately aiding research on these important models.

  10. NeuronBank: a tool for cataloging neuronal circuitry

    Directory of Open Access Journals (Sweden)

    Paul S Katz

    2010-04-01

    Full Text Available The basic unit of any nervous system is the neuron. Therefore, understanding the operation of nervous systems ultimately requires an inventory of their constituent neurons and synaptic connectivity, which form neural circuits. The presence of uniquely identifiable neurons or classes of neurons in many invertebrates has facilitated the construction of cellular-level connectivity diagrams that can be generalized across individuals within a species. Homologous neurons can also be recognized across species. Here we describe NeuronBank.org, a web-based tool that we are developing for cataloging, searching, and analyzing neuronal circuitry within and across species. Information from a single species is represented in an individual branch of NeuronBank. Users can search within a branch or perform queries across branches to look for similarities in neuronal circuits across species. The branches allow for an extensible ontology so that additional characteristics can be added as knowledge grows. Each entry in NeuronBank generates a unique accession ID, allowing it to be easily cited. There is also an automatic link to a Wiki page allowing an encyclopedic explanation of the entry. All of the 44 previously published neurons plus one previously unpublished neuron from the mollusc, Tritonia diomedea, have been entered into a branch of NeuronBank as have 4 previously published neurons from the mollusc, Melibe leonina. The ability to organize information about neuronal circuits will make this information more accessible, ultimately aiding research on these important models.

  11. NeuronBank: A Tool for Cataloging Neuronal Circuitry

    Science.gov (United States)

    Katz, Paul S.; Calin-Jageman, Robert; Dhawan, Akshaye; Frederick, Chad; Guo, Shuman; Dissanayaka, Rasanjalee; Hiremath, Naveen; Ma, Wenjun; Shen, Xiuyn; Wang, Hsui C.; Yang, Hong; Prasad, Sushil; Sunderraman, Rajshekhar; Zhu, Ying

    2010-01-01

    The basic unit of any nervous system is the neuron. Therefore, understanding the operation of nervous systems ultimately requires an inventory of their constituent neurons and synaptic connectivity, which form neural circuits. The presence of uniquely identifiable neurons or classes of neurons in many invertebrates has facilitated the construction of cellular-level connectivity diagrams that can be generalized across individuals within a species. Homologous neurons can also be recognized across species. Here we describe NeuronBank.org, a web-based tool that we are developing for cataloging, searching, and analyzing neuronal circuitry within and across species. Information from a single species is represented in an individual branch of NeuronBank. Users can search within a branch or perform queries across branches to look for similarities in neuronal circuits across species. The branches allow for an extensible ontology so that additional characteristics can be added as knowledge grows. Each entry in NeuronBank generates a unique accession ID, allowing it to be easily cited. There is also an automatic link to a Wiki page allowing an encyclopedic explanation of the entry. All of the 44 previously published neurons plus one previously unpublished neuron from the mollusc, Tritonia diomedea, have been entered into a branch of NeuronBank as have 4 previously published neurons from the mollusc, Melibe leonina. The ability to organize information about neuronal circuits will make this information more accessible, ultimately aiding research on these important models. PMID:20428500

  12. Hearing loss alters serotonergic modulation of intrinsic excitability in auditory cortex.

    Science.gov (United States)

    Rao, Deepti; Basura, Gregory J; Roche, Joseph; Daniels, Scott; Mancilla, Jaime G; Manis, Paul B

    2010-11-01

    Sensorineural hearing loss during early childhood alters auditory cortical evoked potentials in humans and profoundly changes auditory processing in hearing-impaired animals. Multiple mechanisms underlie the early postnatal establishment of cortical circuits, but one important set of developmental mechanisms relies on the neuromodulator serotonin (5-hydroxytryptamine [5-HT]). On the other hand, early sensory activity may also regulate the establishment of adultlike 5-HT receptor expression and function. We examined the role of 5-HT in auditory cortex by first investigating how 5-HT neurotransmission and 5-HT(2) receptors influence the intrinsic excitability of layer II/III pyramidal neurons in brain slices of primary auditory cortex (A1). A brief application of 5-HT (50 μM) transiently and reversibly decreased firing rates, input resistance, and spike rate adaptation in normal postnatal day 12 (P12) to P21 rats. Compared with sham-operated animals, cochlear ablation increased excitability at P12-P21, but all the effects of 5-HT, except for the decrease in adaptation, were eliminated in both sham-operated and cochlear-ablated rats. At P30-P35, cochlear ablation did not increase intrinsic excitability compared with shams, but it did prevent a pronounced decrease in excitability that appeared 10 min after 5-HT application. We also tested whether the effects on excitability were mediated by 5-HT(2) receptors. In the presence of the 5-HT(2)-receptor antagonist, ketanserin, 5-HT significantly decreased excitability compared with 5-HT or ketanserin alone in both sham-operated and cochlear-ablated P12-P21 rats. However, at P30-P35, ketanserin had no effect in sham-operated and only a modest effect cochlear-ablated animals. The 5-HT(2)-specific agonist 5-methoxy-N,N-dimethyltryptamine also had no effect at P12-P21. These results suggest that 5-HT likely regulates pyramidal cell excitability via multiple receptor subtypes with opposing effects. These data also show that

  13. Aspartame affects the electrical activity of projection neurons in central nervous system by inhibiting the calcium channel current in Drosophila%阿斯巴甜抑制钙通道电流影响果蝇中枢投射神经元电活动

    Institute of Scientific and Technical Information of China (English)

    王琦; 齐旻悦; 吴诗哲; 顾怀宇

    2016-01-01

    目的:从突触水平检验不同浓度的阿斯巴甜对果蝇中枢神经元影响及作用机制,为进一步探究阿斯巴甜生物安全性提供支持。方法采用膜片钳全细胞记录的方法,通过离子通道的阻断与分离,分别记录给药前后果蝇投射神经元(PN)的胆碱能突触微小兴奋性电流(mEPSC)、钙离子通道电流和钙通道瞬时电流密度,统计并分析mEPSC幅值和频率,以及钙通道电流峰值和瞬时电流密度。结果与给药前相比,8μg/ml阿斯巴甜会降低果蝇PN的mEPSC频率(t=22.05,P<0.01)、钙电流峰值(t=5.01,P<0.01)和瞬时电流密度(t=2.68,P<0.05);2μg/ml阿斯巴甜会降低果蝇PN的mEPSC频率(t=3.15,P<0.05),其他实验指标差异则无统计学意义(P>0.05)。结论一定浓度的阿斯巴甜可影响果蝇中枢投射神经元的电活动,并且该作用可能是通过影响钙电流而实现的。%Objective To study the effect of different concentrations of aspartame in Drosophila central nervous system , especially to the electrical activity of projection neuron (PN), and evaluate the biological security of aspartame and neural mechanism. Methods The whole-cell electrophysiological signals of projection neurons in Drosophila was detected by patch clamp. The recordings of mini excitatory postsynaptic currents (mEPSC) and calcium currents were performed in both pre-and post-of aspartame treatment. Results Aspartame treatments with 8 μg/ml could reduce the frequency of mEPSC (t=22.05, P0.05) at the same time. In addition, there have no statistically significant in aspartame treatments with 2μg/ml experimental groups except for the frequency of mEPSC (t=3.15, P<0.05). Conclusion There has a range of aspartame concentration can significantly affect the electrical activity of projection neurons in Drosophila central nervous system, which could be effective via the calcium

  14. The Possible Neuronal Mechanism of Acupuncture: Morphological Evidence of the Neuronal Connection between Groin A-Shi Point and Uterus

    Directory of Open Access Journals (Sweden)

    Chun-Yen Chen

    2013-01-01

    Full Text Available Somatovisceral reflex suggested that the somatic stimulation could affect visceral function like acupuncture which treats diseases by stimulating acupoints. The neuronal connection between somatic point and visceral organ was not clear. Uterine pain referred to the groin region has long been recognized clinically. Wesselmann, using neurogenic plasma extravasation method, showed that uterine pain was referred to the groin region through a neuronal mechanism (Wesselmann and Lai 1997. This connection could be considered through the somatovisceral reflex pathway. However, the relay center of this pathway is still not clearly identified. In the present study, bee venom was injected in the groin region to induce central Fos expression to map the sensory innervation of groin region. Pseudorabies virus (PrV, a transneuronal tracer, was injected in the uterus to identify the higher motor control of the uterus. Immunohistochemistry staining revealed the Fos expression and PrV-infected double-labeled neurons in the nucleus of solitary tract (NTS, the dorsal motor nucleus of vagus (DMX, and the paraventricular hypothalamic nucleus (PVN. These results suggest a somatoparasympathetic neuronal connection (groin-spinal dorsal horn-NTS/DMX-uterus and a somatosympathetic neuronal connection (groin-spinal dorsal horn-NTS-PVN-uterus. These two neuronal connections could be the prerequisites to the neuronal basis of the somatovisceral reflex and also the neuronal mechanism of acupuncture.

  15. Serotonergic modulation of post-synaptic inhibition and locomotor alternating pattern in the spinal cord

    Directory of Open Access Journals (Sweden)

    Laurent eVinay

    2014-08-01

    Full Text Available The central pattern generators (CPGs for locomotion, located in the lumbar spinal cord, are functional at birth in the rat. Their maturation occurs during the last few days preceding birth, a period during which the first projections from the brainstem start to reach the lumbar enlargement of the spinal cord. Locomotor burst activity in the mature intact spinal cord alternates between flexor and extensor motoneurons through reciprocal inhibition and between left and right sides through commisural inhibitory interneurons. By contrast, all motor bursts are in phase in the fetus. The alternating pattern disappears after neonatal spinal cord transection which suppresses supraspinal influences upon the locomotor networks. This article will review the role of serotonin (5-HT, in particular 5-HT2 receptors, in shaping the alternating pattern. For instance, pharmacological activation of these receptors restores the left-right alternation after injury. Experiments aimed at either reducing the endogenous level of serotonin in the spinal cord or blocking the activation of 5-HT2 receptors.We then describe recent evidence that the action of 5-HT2 receptors is mediated, at least in part, through a modulation of chloride homeostasis. The postsynaptic action of GABA and glycine depends on the intracellular concentration of chloride ions which is regulated by a protein in the plasma membrane, the K+-Cl− cotransporter (KCC2 extruding both K+ and Cl− ions. Absence or reduction of KCC2 expression leads to a depolarizing action of GABA and glycine and a marked reduction in the strength of postsynaptic inhibition. This latter situation is observed early during development and in several pathological conditions, such as after spinal cord injury, thereby causing spasticity and chronic pain. It was recently shown that specific activation of 5-HT2A receptors is able to up-regulate KCC2, restore endogenous inhibition and reduce spasticity.

  16. Characterization of astrocytic and neuronal benzodiazepine receptors

    Energy Technology Data Exchange (ETDEWEB)

    Bender, A.S.

    1988-01-01

    Primary cultures of astrocytes and neurons express benzodiazepine receptors. Neuronal benzodiazepine receptors were of high-affinity, K{sub D} values were 7.5-43 nM and the densities of receptors (B{sub max}) were 924-4131 fmol/mg protein. Astrocytes posses a high-affinity benzodiazepine receptor, K{sub D} values were 6.6-13 nM. The B{sub max} values were 6,033-12,000 fmol/mg protein. The pharmacological profile of the neuronal benzodiazepine receptor was that of the central-type benzodiazepine receptor, where clonazepam has a high-affinity and Ro 5-4864 (4{prime}-chlorodiazepam) has a low-affinity. Whereas astrocytic benzoidazepine receptor was characteristic of the so called peripheral-type benzodiazepine receptors, which shows a high-affinity towards Ro 5-4863, and a low-affinity towards clonazepam. The astrocytic benzodiazepine receptors was functionally correlated with voltage dependent calcium channels, since dihydropyridines and benzodiazepines interacted with ({sup 3}H) diazepam and ({sup 3}H) nitrendipine receptors with the same rank order of potency, showing a statistically significant correlation. No such correlation was observed in neurons.

  17. Kisspeptin-GPR54-GnRH神经元轴在雌性大鼠中枢性性早熟中的作用%Effect of Kisspeptin-GPR54-GnRH neuron axis in central precocious puberty of female rats

    Institute of Scientific and Technical Information of China (English)

    王海莲; 葛伟; 薛江

    2012-01-01

    目的 探讨Kisspeptin-GPR54 -GnRH神经元轴在雌性大鼠中枢性性早熟(CPP)中的作用.方法 选择雌性SD大鼠50只,随机分为对照1组(正常青春前期)、对照2组(正常青春早期)、对照3组(正常青春中期)、实验1组(性早熟青春早期)、实验2组(性早熟青春中期)各10只.实验组皮下注射N-甲基-DL-天冬氨酸(NMA)建立CPP模型.观察各组阴道开放时间及性周期,测量其子宫指数、卵巢指数、卵巢黄体出现个数、子宫壁厚度和血清黄体生成素;用Real-Time RT-PCR法检测下丘脑中的KISS-1 mRNA、GPR54 mRNA、促性腺激素释放激素(GnRH) mRNA表达;在电镜下观察各组下丘脑内分泌神经元的超微结构.结果 实验组性发育起始时间早于对照组,实验组各检查指标明显高于对照1组(P均<0.05),实验1组与对照2组、实验2组与对照3组比较均无统计学差异.随着青春期发育,实验组和对照组大鼠下丘脑中KISS-1 mRNA、GPR54 mRNA、GnRH mRNA表达均逐渐升高,下丘脑内分泌神经元代谢逐渐活跃,分泌旺盛.结论 应用NMA可建立理想的雌性大鼠CPP模型,随着大鼠青春期发育,其下丘脑中的KISS-1 mRNA、GPR54 mRNA、GnRH mRNA表达逐渐升高;提示Kisspeptin-GPR54-GnRH神经元轴在CPP的发生、发展中起重要作用.%Objective To study the effect of Kisspeptin-GPR54-GnRH neuron axis in central precocious puberty (CPP) of female rats. Methods Fifty female rats were randomly assigned to five groups, the first control group (normal prepuberty) , the second control group (early phase of normal puberty) , the third control group (metaphase of normal puberty) , the first experimental group (early phase of precocious puberty), the second experimental group (metaphase of precocious puberty) , ten rats in each group. Experimental group received subcutaneous injection of N-methyl-DL-aspartale acid (NMA) in order to establish the central precocious puberty model. The vaginal open and

  18. A comparison of experience-dependent locomotory behaviors and biogenic amine neurons in nematode relatives of Caenorhabditis elegans

    Directory of Open Access Journals (Sweden)

    Sternberg Paul W

    2010-02-01

    Full Text Available Abstract Background Survival of an animal depends on its ability to match its responses to environmental conditions. To generate an optimal behavioral output, the nervous system must process sensory information and generate a directed motor output in response to stimuli. The nervous system should also store information about experiences to use in the future. The diverse group of free-living nematodes provides an excellent system to study macro- and microevolution of molecular, morphological and behavioral character states associated with such nervous system function. We asked whether an adaptive behavior would vary among bacterivorous nematodes and whether differences in the neurotransmitter systems known to regulate the behavior in one species would reflect differences seen in the adaptive behavior among those species. Caenorhabditis elegans worms slow in the presence of food; this 'basal' slowing is triggered by dopaminergic mechanosensory neurons that detect bacteria. Starved worms slow more dramatically; this 'enhanced' slowing is regulated by serotonin. Results We examined seven nematode species with known phylogenetic relationship to C. elegans for locomotory behaviors modulated by food (E. coli, and by the worm's recent history of feeding (being well-fed or starved. We found that locomotory behavior in some species was modulated by food and recent feeding experience in a manner similar to C. elegans, but not all the species tested exhibited these food-modulated behaviors. We also found that some worms had different responses to bacteria other than E. coli. Using histochemical and immunological staining, we found that dopaminergic neurons were very similar among all species. For instance, we saw likely homologs of four bilateral pairs of dopaminergic cephalic and deirid neurons known from C. elegans in all seven species examined. In contrast, there was greater variation in the patterns of serotonergic neurons. The presence of presumptive

  19. [Central nervous system malformations: neurosurgery correlates].

    Science.gov (United States)

    Jiménez-León, Juan C; Betancourt-Fursow, Yaline M; Jiménez-Betancourt, Cristina S

    2013-09-06

    Congenital malformations of the central nervous system are related to alterations in neural tube formation, including most of the neurosurgical management entities, dysraphism and craniosynostosis; alterations of neuronal proliferation; megalencefaly and microcephaly; abnormal neuronal migration, lissencephaly, pachygyria, schizencephaly, agenesis of the corpus callosum, heterotopia and cortical dysplasia, spinal malformations and spinal dysraphism. We expose the classification of different central nervous system malformations that can be corrected by surgery in the shortest possible time and involving genesis mechanisms of these injuries getting better studied from neurogenic and neuroembryological fields, this involves connecting innovative knowledge areas where alteration mechanisms in dorsal induction (neural tube) and ventral induction (telencephalization) with the current way of correction, as well as the anomalies of cell proliferation and differentiation of neuronal migration and finally the complex malformations affecting the posterior fossa and current possibilities of correcting them.

  20. The effects of AP521, a novel anxiolytic drug, in three anxiety models and on serotonergic neural transmission in rats.

    Science.gov (United States)

    Kasahara, Ken-Ichi; Hashimoto, Shinji; Hattori, Tsuyoshi; Kawasaki, Koh; Tsujita, Ryuichi; Nakazono, Osamu; Takao, Katsuyuki; Kawakubo, Hiromu; Nagatani, Tadashi

    2015-01-01

    We investigated the anxiolytic effects and mechanism of action of a new anxiolytic drug, (R)-piperonyl-1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridine-3- carboxamide hydrochloride (AP521). AP521 showed equal or more potent anxiolytic-like effects compared with diazepam, a benzodiazepine receptor agonist, or tandospirone, a partial 5-hydroxytryptamine (5-HT)1A receptor agonist, in three rat anxiety models; the Vogel-type conflict test, elevated plus maze test, and conditioned fear stress test. Although AP521 did not bind to the benzodiazepine receptor, it did bind to 5-HT1A, 5-HT1B, 5-HT1D, 5-HT5A and 5-HT7 receptors, and showed agonist activity for the human 5-HT1A receptor expressed in HEK293 cells. Tandospirone, which can stimulate the presynaptic 5-HT1A receptors in the raphe, tended to decrease extracellular 5-HT concentration in the medial prefrontal cortex (mPFC) in rats. In contrast, AP521 increased extracellular 5-HT concentration. In addition, AP521 enhanced the anti-freezing effect of citalopram, a selective serotonin reuptake inhibitor, in the fear conditioning model in rats and enhanced the citalopram-caused increase of the extracellular 5-HT concentration in the mPFC. These results suggest that AP521 exhibits potent anxiolytic effects by acting as a postsynaptic 5-HT1A receptor agonist and by enhancing serotonergic neural transmission in the mPFC by a novel mechanism of action.

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