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Sample records for dysfunction central cholinergic

  1. Glutamatergic and central cholinergic dysfunction in the CA1, CA2 and CA3 fields on spatial learning and memory in chronic cerebral ischemia-Induced vascular dementia of rats.

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    Cao, Yanjing; Gou, Zengmei; Du, Yifeng; Fan, Yongjun; Liang, Lizhen; Yan, Yongxing; Lin, Ping; Jin, Mudan; Du, Yifenf

    2016-05-04

    Chronic cerebral ischemia (CCI) is associated with cognitive decline in aging, vascular dementia and Alzheimer's disease. Substantial evidence has shown that chronic cerebral ischemia may cause cognitive impairment, but the underlying neurobiological mechanism is poorly understood so far. In the present study, we used a rat model of chronic cerebral ischemia by permanent bilateral common carotid artery occlusion (BCCAO) to investigate the alterations of glutamatergic and central cholinergic dysfunction, and their causal relationship with the cognitive deficits induced by chronic cerebral ischemia. We found that BCCAO rats exhibited spatial learning and memory impairments dysfunction 3 month after BCCAO. Meanwhile, vGluT levels as well as glutamatergic and central cholinergic positive neurons in the hippocampus CA1-3 field significantly decreased. The protection of glutamergic and cholinergic neurons or regulating glutamate and central cholinergic levels in hippocampal subregion may have beneficial effects on cognitive impairments associated with the possible mechanism in CCI-induced vascular dementia.

  2. Central cholinergic regulation of respiration: nicotinic receptors

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    Xuesi M SHAO; Jack L FELDMAN

    2009-01-01

    Nicotinic acetylcholine receptors (nAChRs) are expressed in brainstem and spinal cord regions involved in the control of breathing. These receptors mediate central cholinergic regulation of respiration and effects of the exogenous ligand nicotine on respiratory pattern. Activation of a4* nAChRs in the preBotzinger Complex (preBotC), an essential site for normal respiratory rhythm generation in mammals, modulates excitatory glutamatergic neurotransmission and depolarizes preBotC inspiratory neurons, leading to increases in respiratory frequency. nAChRs are also present in motor nuclei innervating respiratory muscles. Activation of post- and/or extra-synaptic a4* nAChRs on hypoglossal (XII) motoneurons depolarizes these neurons, potentiating tonic and respiratory-related rhythmic activity. As perinatal nicotine exposure may contribute to the pathogenesis of sudden infant death syndrome (SIDS), we discuss the effects of perinatal nicotine exposure on development of the cholinergic and other neurotransmitter systems involved in control of breathing. Advances in understanding of the mechanisms underlying central cholinergic/nicotinic modulation of respiration provide a pharmacological basis for exploiting nAChRs as therapeutic targets for neurological disorders related to neural control of breathing such as sleep apnea and SIDS.

  3. Cholinergic dysfunction and amnesia in patients with Wernicke-Korsakoff syndrome: a transcranial magnetic stimulation study.

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    Nardone, Raffaele; Bergmann, Jürgen; De Blasi, Pierpaolo; Kronbichler, Martin; Kraus, Jörg; Caleri, Francesca; Tezzon, Frediano; Ladurner, Gunther; Golaszewski, Stefan

    2010-03-01

    The specific neurochemical substrate underlying the amnesia in patients with Wernicke-Korsakoff syndrome (WKS) is still poorly defined. Memory impairment has been linked to dysfunction of neurons in the cholinergic system. A transcranial magnetic stimulation (TMS) protocol, the short latency afferent inhibition (SAI), may give direct information about the function of some cholinergic pathways in the human motor cortex. In the present study, we measured SAI in eight alcoholics with WKS and compared the data with those from a group of age-matched healthy individuals; furthermore, we correlated the individual SAI values of the WKS patients with memory and other cognitive functions. Mean SAI was significantly reduced in WKS patients when compared with the controls. SAI was increased after administration of a single dose of donezepil in a subgroup of four patients. The low score obtained in the Rey Complex Figure delayed recall test, the Digit Span subtest of the Wechsler Adult Intelligence Scale-Revised (WAIS-R) and the Corsi's Block Span subtest of the WAIS-R documented a severe impairment in the anterograde memory and short-term memory. None of the correlations between SAI values and these neuropsychological tests reached significance. We provide physiological evidence of cholinergic involvement in WKS. However, this putative marker of central cholinergic activity did not significantly correlate with the memory deficit in our patients. These findings suggest that the cholinergic dysfunction does not account for the memory disorder and that damage to the cholinergic system is not sufficient to cause a persisting amnesic syndrome in WKS.

  4. Cognitive impairment as a central cholinergic deficit in patients with Myasthenia Gravis

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    Antonia Kaltsatou

    2015-06-01

    Conclusions: VCmax and ACmax are governed mainly by the action of the Parasympathetic Nervous System, through acetylcholine. The results of this study demonstrate that the CNS may be affected in MG and support the hypothesis that MG has central cholinergic effects manifested by cognitive dysfunction.

  5. Cholinergic Signaling Exerts Protective Effects in Models of Sympathetic Hyperactivity-Induced Cardiac Dysfunction

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    Gavioli, Mariana; Lara, Aline; Almeida, Pedro W. M.; Lima, Augusto Martins; Damasceno, Denis D.; Rocha-Resende, Cibele; Ladeira, Marina; Resende, Rodrigo R.; Martinelli, Patricia M.; Melo, Marcos Barrouin; Brum, Patricia C.; Fontes, Marco Antonio Peliky; Souza Santos, Robson A.; Prado, Marco A. M.; Guatimosim, Silvia

    2014-01-01

    Cholinergic control of the heart is exerted by two distinct branches; the autonomic component represented by the parasympathetic nervous system, and the recently described non-neuronal cardiomyocyte cholinergic machinery. Previous evidence has shown that reduced cholinergic function leads to deleterious effects on the myocardium. Yet, whether conditions of increased cholinergic signaling can offset the pathological remodeling induced by sympathetic hyperactivity, and its consequences for these two cholinergic axes are unknown. Here, we investigated two models of sympathetic hyperactivity: i) the chronic beta-adrenergic receptor stimulation evoked by isoproterenol (ISO), and ii) the α2A/α2C-adrenergic receptor knockout (KO) mice that lack pre-synaptic adrenergic receptors. In both models, cholinergic signaling was increased by administration of the cholinesterase inhibitor, pyridostigmine. First, we observed that isoproterenol produces an autonomic imbalance characterized by increased sympathetic and reduced parasympathetic tone. Under this condition transcripts for cholinergic proteins were upregulated in ventricular myocytes, indicating that non-neuronal cholinergic machinery is activated during adrenergic overdrive. Pyridostigmine treatment prevented the effects of ISO on autonomic function and on the ventricular cholinergic machinery, and inhibited cardiac remodeling. α2A/α2C-KO mice presented reduced ventricular contraction when compared to wild-type mice, and this dysfunction was also reversed by cholinesterase inhibition. Thus, the cardiac parasympathetic system and non-neuronal cardiomyocyte cholinergic machinery are modulated in opposite directions under conditions of increased sympathetic drive or ACh availability. Moreover, our data support the idea that pyridostigmine by restoring ACh availability is beneficial in heart disease. PMID:24992197

  6. Cholinergic signaling exerts protective effects in models of sympathetic hyperactivity-induced cardiac dysfunction.

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    Mariana Gavioli

    Full Text Available Cholinergic control of the heart is exerted by two distinct branches; the autonomic component represented by the parasympathetic nervous system, and the recently described non-neuronal cardiomyocyte cholinergic machinery. Previous evidence has shown that reduced cholinergic function leads to deleterious effects on the myocardium. Yet, whether conditions of increased cholinergic signaling can offset the pathological remodeling induced by sympathetic hyperactivity, and its consequences for these two cholinergic axes are unknown. Here, we investigated two models of sympathetic hyperactivity: i the chronic beta-adrenergic receptor stimulation evoked by isoproterenol (ISO, and ii the α2A/α2C-adrenergic receptor knockout (KO mice that lack pre-synaptic adrenergic receptors. In both models, cholinergic signaling was increased by administration of the cholinesterase inhibitor, pyridostigmine. First, we observed that isoproterenol produces an autonomic imbalance characterized by increased sympathetic and reduced parasympathetic tone. Under this condition transcripts for cholinergic proteins were upregulated in ventricular myocytes, indicating that non-neuronal cholinergic machinery is activated during adrenergic overdrive. Pyridostigmine treatment prevented the effects of ISO on autonomic function and on the ventricular cholinergic machinery, and inhibited cardiac remodeling. α2A/α2C-KO mice presented reduced ventricular contraction when compared to wild-type mice, and this dysfunction was also reversed by cholinesterase inhibition. Thus, the cardiac parasympathetic system and non-neuronal cardiomyocyte cholinergic machinery are modulated in opposite directions under conditions of increased sympathetic drive or ACh availability. Moreover, our data support the idea that pyridostigmine by restoring ACh availability is beneficial in heart disease.

  7. Central cholinergic control of vasopressin release in conscious rats

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    Iitake, K.; Share, L.; Ouchi, Y.; Crofton, J.T.; Brooks, D.P.

    1986-08-01

    Intracerebroventricular (icv) administration of carbachol into conscious rats evoked a substantial increase in vasopressin secretion and blood pressure in a dose-dependent manner. These effects were blocked by pretreatment with the muscarinic blocker, atropine (10 g icv), but not by the nicotinic blocker, hexamethonium (10 g icv). Hexamethonium did, however, block the increase in blood pressure, the decrease in heart rate, and they very small elevation in the plasma vasopressin concentration induced by nicotine (10 g icv). These results indicate that stimulation of either central nicotinic or muscarinic receptors can affect the cardiovascular system and suggest that the cholinergic stimulation of vasopressin secretion may involve primarily muscarinic receptors in the conscious rat.

  8. Houttuynia cordata Improves Cognitive Deficits in Cholinergic Dysfunction Alzheimer's Disease-Like Models.

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    Huh, Eugene; Kim, Hyo Geun; Park, Hanbyeol; Kang, Min Seo; Lee, Bongyong; Oh, Myung Sook

    2014-05-01

    Cognitive impairment is a result of dementia of diverse causes, such as cholinergic dysfunction and Alzheimer's disease (AD). Houttuynia cordata Thunb. (Saururaceae) has long been used as a traditional herbal medicine. It has biological activities including protective effects against amyloid beta (Aβ) toxicity, via regulation of calcium homeostasis, in rat hippocampal cells. To extend previous reports, we investigated the effects of water extracts of H. cordata herb (HCW) on tauopathies, also involving calcium influx. We then confirmed the effects of HCW in improving memory impairment and neuronal damage in mice with Aβ-induced neurotoxicity. We also investigated the effects of HCW against scopolamine-induced cholinergic dysfunction in mice. In primary neuronal cells, HCW inhibited the phosphorylation of tau by regulating p25/p35 expression in Aβ-induced neurotoxicity. In mice with Aβ-induced neurotoxicity, HCW improved cognitive impairment, as assessed with behavioral tasks, such as novel object recognition, Y-maze, and passive avoidance tasks. HCW also inhibited the degeneration of neurons in the CA3 region of the hippocampus in Aβ-induced neurotoxicity. Moreover, HCW, which had an IC50 value of 79.7 μg/ml for acetylcholinesterase inhibition, ameliorated scopolamine-induced cognitive impairment significantly in Y-maze and passive avoidance tasks. These results indicate that HCW improved cognitive impairment, due to cholinergic dysfunction, with inhibitory effects against tauopathies and cholinergic antagonists, suggesting that HCW may be an interesting candidate to investigate for the treatment of AD.

  9. Selective blockade of central m1 muscarinic cholinergic receptors with pirenzepine impairs cardiovascular and respiratory function in rats with acute hemorrhage.

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    Kovalenko, N Ya; Matsievskii, D D

    2006-09-01

    Ultrasound studies showed that selective antagonist of central M1 muscarinic cholinergic receptors pirenzepine (50 mg/kg intravenously) causes transitory hypotension and respiratory depression in anesthetized intact rats. The M1 receptor antagonist had no effect on cardiac output and portal blood flow. Pretreatment with pirenzepine increased the sensitivity of rats with acute massive hemorrhage to circulatory hypoxia. After blockade of central M1 muscarinic cholinergic receptors, the posthemorrhagic period was characterized by primary decompensation of blood pressure, portal blood flow, and respiration and development of low cardiac output syndrome. The animals died over the first minutes after bleeding arrest. Our results indicate that central M1 muscarinic cholinergic receptors act as shock-limiting cholinergic structures under conditions of posthemorrhagic changes in systemic and portal blood flow, as well as during respiratory dysfunction.

  10. Cognitive impairment as a central cholinergic deficit in patients with Myasthenia Gravis.

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    Kaltsatou, Antonia; Fotiou, Dimitris; Tsiptsios, Dimitris; Orologas, Anastasios

    2015-06-01

    The purpose of this study was to investigate with neurophysiological and neuropsychological methods such as pupillometry, cognitive test and Hamilton Depression Rating Scale (HAM-D) the hypothesis of Central Nervous System (CNS) cholinergic involvement in patients with Myasthenia Gravis (MG). Thirty-two patients (32) with MG and a mean age of 51.1 ± 17.2 volunteered to participate in this investigation, while thirty-three (33) healthy subjects with a mean age of 50.2 ± 14.8 served as controls. All subjects underwent pupillometric measurements and performed the Wechsler Memory Scale (WMS) and HAM-D. The pupillometric indices studied were: 1) latency for the onset of constriction (T1), 2) maximum constriction velocity (VCmax) and 3) maximum constriction acceleration (ACmax). T1 was found significantly increased by 21.7% (p WMS by 41.6% (p System, through acetylcholine. The results of this study demonstrate that the CNS may be affected in MG and support the hypothesis that MG has central cholinergic effects manifested by cognitive dysfunction.

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

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    Srivastava, Pranay [CSIR-Indian Institute of Toxicology Research, Post Box 80, MG Marg, Lucknow 226 001 (India); Yadav, Rajesh S. [CSIR-Indian Institute of Toxicology Research, Post Box 80, MG Marg, Lucknow 226 001 (India); Department of Crimnology and Forensic Science, Harisingh Gour University, Sagar 470 003 (India); Chandravanshi, Lalit P.; Shukla, Rajendra K.; Dhuriya, Yogesh K.; Chauhan, Lalit K.S. [CSIR-Indian Institute of Toxicology Research, Post Box 80, MG Marg, Lucknow 226 001 (India); Dwivedi, Hari N. [Babu Banarasi Das University, BBD City, Faizabad Road, Lucknow 227 015 (India); Pant, Aditiya B. [CSIR-Indian Institute of Toxicology Research, Post Box 80, MG Marg, Lucknow 226 001 (India); Khanna, Vinay K., E-mail: vkkhanna1@gmail.com [CSIR-Indian Institute of Toxicology Research, Post Box 80, MG Marg, Lucknow 226 001 (India)

    2014-09-15

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

  12. Catalpol Induces Neuroprotection and Prevents Memory Dysfunction through the Cholinergic System and BDNF

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    Dong Wan

    2013-01-01

    Full Text Available To investigate the role and mechanism of catalpol on neuroprotective effects and memory enhancing effects simultaneously, neuroprotective effects of catalpol were assessed by neurological deficits score, TTC staining, and cerebral blood flow detecting. Morris water maze was employed to investigate its effects on learning and memory and then clarify its possible mechanisms relating the central cholinergic system and BDNF. Edaravone and oxiracetam were used for positive control drugs based on its different action. Results showed that catalpol and edaravone significantly facilitated neurological function recovery, reduced infarction volume, and increased cerebral blood flow in stroke mice. Catalpol and oxiracetam decreased the escape latency significantly and increased the numbers of crossing platform obviously. The levels of ACh, ChAT, and BDNF in catalpol group were increased in a dose-dependent manner, and AChE declined with a U-shaped dose-response curve. Moreover, the levels of muscarinic AChR subtypes M1 and M2 in hippocampus were considerably raised by catalpol. These results demonstrated that catalpol may be useful for neuroprotection and memory enhancement, and the mechanism may be related to the central cholinergic system.

  13. Central cholinergic activation of a vagus nerve-to-spleen circuit alleviates experimental colitis.

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

    2014-03-01

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

  14. Mangifera indica Fruit Extract Improves Memory Impairment, Cholinergic Dysfunction, and Oxidative Stress Damage in Animal Model of Mild Cognitive Impairment

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    Jintanaporn Wattanathorn

    2014-01-01

    Full Text Available To date, the effective preventive paradigm against mild cognitive impairment (MCI is required. Therefore, we aimed to determine whether Mangifera indica fruit extract, a substance possessing antioxidant and cognitive enhancing effects, could improve memory impairment, cholinergic dysfunction, and oxidative stress damage in animal model of mild cognitive impairment. Male Wistar rats, weighing 180–200 g, were orally given the extract at doses of 12.5, 50, and 200 mg·kg−1 BW for 2 weeks before and 1 week after the bilateral injection of AF64A (icv. At the end of study, spatial memory, cholinergic neurons density, MDA level, and the activities of SOD, CAT, and GSH-Px enzymes in hippocampus were determined. The results showed that all doses of extract could improve memory together with the decreased MDA level and the increased SOD and GSH-Px enzymes activities. The increased cholinergic neurons density in CA1 and CA3 of hippocampus was also observed in rats treated with the extract at doses of 50 and 200 mg·kg−1 BW. Therefore, our results suggested that M. indica, the potential protective agent against MCI, increased cholinergic function and the decreased oxidative stress which in turn enhanced memory. However, further researches are essential to elucidate the possible active ingredients and detail mechanism.

  15. Red Dermographism in Autism Spectrum Disorders: A Clinical Sign of Cholinergic Dysfunction?

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    Lemonnier, E.; Grandgeorge, M.; Jacobzone-Leveque, C.; Bessaguet, C.; Peudenier, S.; Misery, L.

    2013-01-01

    The authors hypothesised that red dermographism--a skin reaction involving the cholinergic system--is more frequent in children with autism spectrum disorders (ASDs) than in children exhibiting typical development. We used a dermatological examination to study red dermographism in this transverse study, which compared forty six children with ASDs…

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

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    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.

  17. Memory and learning seems to be related to cholinergic dysfunction in the JE rat model.

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    Chauhan, Prashant Singh; Misra, Usha Kant; Kalita, Jayantee; Chandravanshi, Lalit Pratap; Khanna, Vinay Kumar

    2016-03-15

    Cognitive changes have been known in encephalitis but in Japanese encephalitis (JE) such studies are limited. This study aims at evaluating the spatial memory and learning and correlate with markers of cholinergic activity in the brain.12day old Wistar rats were inoculated with dose of 3×10(6)pfu/ml of JE virus. On 10, 33 and 48days post-inoculation (dpi), spatial memory and learning was assessed by Y maze. Brain biopsies from frontal cortex, corpus striatum, hippocampus and cerebellum were taken. Muscarinic cholinergic receptor was assayed by Quinuclidinyl benzylate (H3-QNB) binding, CHRM2 gene expression by real time PCR and choline acetyl transferase (ChAT) by Western blot. Spatial learning and memory showed significant decline in rats inoculated with JEV on 10 and 33dpi (47.5%, pJE Virus.

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

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    Leite-Panissi C.R.A.

    2004-01-01

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

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

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    Balázs Hangya

    2017-04-01

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

  20. The involvement of the central cholinergic system in the pressor and bradycardic effects of centrally administrated melittin in normotensive conscious rats.

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    Yalcin, Murat; Erturk, Melih

    2007-04-01

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

  1. Irinotecan-Induced Gastrointestinal Dysfunction Is Associated with Enteric Neuropathy, but Increased Numbers of Cholinergic Myenteric Neurons

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    Rachel M. McQuade

    2017-06-01

    Full Text Available Gastrointestinal dysfunction is a common side-effect of chemotherapy leading to dose reductions and treatment delays. These side-effects may persist up to 10 years post-treatment. A topoisomerase I inhibitor, irinotecan (IRI, commonly used for the treatment of colorectal cancer, is associated with severe acute and delayed-onset diarrhea. The long-term effects of IRI may be due to damage to enteric neurons innervating the gastrointestinal tract and controlling its functions. Balb/c mice received intraperitoneal injections of IRI (30 mg/kg−1 3 times a week for 14 days, sham-treated mice received sterile water (vehicle injections. In vivo analysis of gastrointestinal transit via serial x-ray imaging, facal water content, assessment of gross morphological damage and immunohistochemical analysis of myenteric neurons were performed at 3, 7 and 14 days following the first injection and at 7 days post-treatment. Ex vivo colonic motility was analyzed at 14 days following the first injection and 7 days post-treatment. Mucosal damage and inflammation were found following both short and long-term treatment with IRI. IRI-induced neuronal loss and increases in the number and proportion of ChAT-IR neurons and the density of VAChT-IR fibers were associated with changes in colonic motility, gastrointestinal transit and fecal water content. These changes persisted in post-treatment mice. Taken together this work has demonstrated for the first time that IRI-induced inflammation, neuronal loss and altered cholinergic expression is associated with the development of IRI-induced long-term gastrointestinal dysfunction and diarrhea.

  2. Sodium Tanshinone IIA Sulfonate Attenuates Scopolamine-Induced Cognitive Dysfunctions via Improving Cholinergic System

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    Qing-Qing Xu

    2016-01-01

    Full Text Available Sodium Tanshinone IIA sulfonate (STS is a derivative of Tanshinone IIA (Tan IIA. Tan IIA has been reported to possess neuroprotective effects against Alzheimer’s disease (AD. However, whether STS possesses effect on AD remains unclear. This study aims to estimate whether STS could protect against scopolamine- (SCOP- induced learning and memory deficit in Kunming mice. Morris water maze results showed that oral administration of STS (10 mg/kg and 20 mg/kg and Donepezil shortened escape latency, increased crossing times of the original position of the platform, and increased the time spent in the target quadrant. STS decreased the activity of acetylcholinesterase (AChE and increased the activity of choline acetyltransferase (ChAT in the hippocampus and cortex of SCOP-treated mice. Oxidative stress results showed that STS increased the activity of superoxide dismutase (SOD and decreased the levels of malondialdehyde (MDA and reactive oxygen species (ROS in hippocampus and cortex. In addition, western blot was carried out to detect the expression of apoptosis related proteins (Bcl-2, Bax, and Caspase-3. STS upregulated the protein expression of Bcl-2 and downregulated the proteins expression of Bax and Caspase-3. These results indicated that STS might become a promising therapeutic candidate for attenuating AD-like pathological dysfunction.

  3. Electroacupuncture at Zusanli (ST36 Prevents Intestinal Barrier and Remote Organ Dysfunction following Gut Ischemia through Activating the Cholinergic Anti-Inflammatory-Dependent Mechanism

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    Sen Hu

    2013-01-01

    Full Text Available This study investigated the protective effect and mechanism of electroacupuncture at ST36 points on the intestinal barrier dysfunction and remote organ injury after intestinal ischemia and reperfusion injury in rats. Rats were subjected to gut ischemia for 30 min, and then received electroacupuncture for 30 min with or without abdominal vagotomy or intraperitoneal administration of cholinergic α7 nicotinic acetylcholine receptor (α7nAChR inhibitor. Then we compared its effects with electroacupuncture at nonchannel points, vagal nerve stimulation, or intraperitoneal administration of cholinergic agonist. Cytokine levels in plasma and tissue of intestine, lung, and liver were assessed 60 min after reperfusion. Intestinal barrier injury was detected by histology, gut injury score, the permeability to 4 kDa FITC-dextran, and changes in tight junction protein ZO-1 using immunofluorescence and Western blot. Electroacupuncture significantly lowered the levels of tumor necrosis factor-α and interleukin-8 in plasma and organ tissues, decreased intestinal permeability to FITC-dextran, and prevented changes in ZO-1 protein expression and localization. However, abdominal vagotomy or intraperitoneal administration of cholinergic α7nAChR inhibitor reversed these effects of electroacupuncture. These findings suggest that electroacupuncture attenuates the systemic inflammatory response through protection of intestinal barrier integrity after intestinal ischemia injury in the presence of an intact vagus nerve.

  4. Targeting the Cholinergic System to Develop a Novel Therapy for Huntington's Disease.

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    D'Souza, Gary X; Waldvogel, Henry J

    2016-12-15

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

  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. Central Auditory Nervous System Dysfunction in Echolalic Autistic Individuals.

    Science.gov (United States)

    Wetherby, Amy Miller; And Others

    1981-01-01

    The results showed that all the Ss had normal hearing on the monaural speech tests; however, there was indication of central auditory nervous system dysfunction in the language dominant hemisphere, inferred from the dichotic tests, for those Ss displaying echolalia. (Author)

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

    Directory of Open Access Journals (Sweden)

    B. Cam-Etoz

    2012-03-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-03-02

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

  9. Central cholinergic involvement in sequential behavior: impairments of performance by atropine in a serial multiple choice task for rats.

    Science.gov (United States)

    Fountain, Stephen B; Rowan, James D; Wollan, Michael O

    2013-11-01

    Two experiments examined whether muscarinic cholinergic systems play a role in rats' ability to perform well-learned highly-structured serial response patterns, particularly focusing on rats' performance on pattern elements learned by encoding rules versus by acquisition of stimulus-response (S-R) associations. Rats performed serial patterns of responses in a serial multiple choice task in an 8-lever circular array for hypothalamic brain-stimulation reward. Two experiments examined the effects of atropine, a centrally-acting muscarinic cholinergic receptor antagonist, on rats' ability to perform pattern elements where responses were controlled by rules versus elements, such as rule-inconsistent "violation elements" and elements following "phrasing cues," where responses were controlled by associative cues. In Experiment 1, 3-element chunks of both patterns were signaled by pauses that served as phrasing cues before chunk-boundary elements, but one pattern also included a violation element that was inconsistent with pattern structure. Once rats reached a high criterion of performance, the drug challenge was intraperitoneal injection of a single dose of 50 mg/kg atropine sulfate. Atropine impaired performance on elements learned by S-R learning, namely, chunk-boundary elements and the violation element, but had no effect on performance of rule-based within-chunk elements. In Experiment 2, patterns were phrased and unphrased perfect patterns (i.e., without violation elements). To control for peripheral effects of atropine, rats were treated with a series of doses of either centrally-acting atropine or peripherally-acting atropine methyl nitrate (AMN), which does not cross the blood-brain barrier. Once rats reached a high criterion, the drug challenges were on alternate days in the order 50, 25, and 100 mg/kg of either atropine sulfate or AMN. Atropine, but not AMN, impaired performance in the phrased perfect pattern for pattern elements where S-R associations were

  10. Cholinergic receptor blockade by scopolamine and mecamylamine exacerbates global cerebral ischemia induced memory dysfunction in C57BL/6J mice.

    Science.gov (United States)

    Ray, R S; Rai, S; Katyal, A

    2014-12-01

    Global cerebral ischemia/reperfusion (GCI/R) injury encompasses complex pathophysiological sequalae, inducing loss of hippocampal neurons and behavioural deficits. Progressive neuronal death and memory dysfunctions culminate from several different mechanisms like oxidative stress, excitotoxicity, neuroinflammation and cholinergic hypofunction. Experimental evidences point to the beneficial effects of cholinomimetic agents such as rivastigmine and galantamine in improving memory outcomes following GCI/R injury. However, the direct implications of muscarinic and nicotinic receptor blockade during global cerebral ischemia/reperfusion injury have not been investigated. Therefore, we evaluated the relative involvement of muscarinic and nicotinic receptors in spatial/associative memory functions and neuronal damage during global cerebral ischemia reperfusion injury. The outcomes of present study support the idea that preservation of both muscarinic and nicotinic receptor functions is essential to alleviate hippocampal neuronal death in CA1 region following global cerebral ischemia/reperfusion injury.

  11. Serum anticholinergic activity and cerebral cholinergic dysfunction: An EEG study in frail elderly with and without delirium

    Directory of Open Access Journals (Sweden)

    Driessen Martin

    2008-09-01

    Full Text Available Abstract Background Delirium increases morbidity, mortality and healthcare costs especially in the elderly. Serum anticholinergic activity (SAA is a suggested biomarker for anticholinergic burden and delirium risk, but the association with cerebral cholinergic function remains unclear. To clarify this relationship, we prospectively assessed the correlation of SAA with quantitative electroencephalography (qEEG power, delirium occurrence, functional and cognitive measures in a cross-sectional sample of acutely hospitalized elderly (> 80 y with high dementia and delirium prevalence. Methods 61 consecutively admitted patients over 80 years underwent an extensive clinical and neuropsychological evaluation. SAA was determined by using radio receptor assay as developed by Tune, and standard as well as quantitative EEGs were obtained. Results 15 patients had dementia with additional delirium (DD according to expert consensus using DSM-IV criteria, 31 suffered from dementia without delirium (D, 15 were cognitively unimpaired (CU. SAA was clearly detectable in all patients but one (mean 10.9 ± 7.1 pmol/ml, but was not associated with expert-panel approved delirium diagnosis or cognitive functions. Delirium-associated EEG abnormalities included occipital slowing, peak power and alpha decrease, delta and theta power increase and slow wave ratio increase during active delirious states. EEG measures correlated significantly with cognitive performance and delirium severity, but not with SAA levels. Conclusion In elderly with acute disease, EEG parameters reliable indicate delirium, but SAA does not seem to reflect cerebral cholinergic function as measured by EEG and is not related to delirium diagnosis.

  12. Cholinergic dermographism.

    Science.gov (United States)

    Mayou, S C; Kobza Black, A; Eady, R A; Greaves, M W

    1986-09-01

    We report a patient with cholinergic urticaria in whom stroking the skin produced a band of erythema studded with the small weals characteristics of cholinergic urticaria. This response was suppressed by pre-treatment with topical scopolamine. Light and electron microscopy of the weal showed mast cell degranulation and a moderate mononuclear cell infiltrate.

  13. Erectile dysfunction and central obesity: an Italian perspective

    Directory of Open Access Journals (Sweden)

    Giovanni Corona

    2014-08-01

    Full Text Available Erectile dysfunction (ED is a frequent complication of obesity. The aim of this review is to critically analyze the framework of obesity and ED, dissecting the connections between the two pathological entities. Current clinical evidence shows that obesity, and in particular central obesity, is associated with both arteriogenic ED and reduced testosterone (T levels. It is conceivable that obesity-associated hypogonadism and increased cardiovascular risk might partially justify the higher prevalence of ED in overweight and obese individuals. Conversely, the psychological disturbances related to obesity do not seem to play a major role in the pathogenesis of obesity-related ED. However, both clinical and preclinical data show that the association between ED and visceral fat accumulation is independent from known obesity-associated comorbidities. Therefore, how visceral fat could impair penile microcirculation still remains unknown. This point is particularly relevant since central obesity in ED subjects categorizes individuals at high cardiovascular risk, especially in the youngest ones. The presence of ED in obese subjects might help healthcare professionals in convincing them to initiate a virtuous cycle, where the correction of sexual dysfunction will be the reward for improved lifestyle behavior. Unsatisfying sexual activity represents a meaningful, straightforward motivation for consulting healthcare professionals, who, in turn, should take advantage of the opportunity to encourage obese patients to treat, besides ED, the underlying unfavorable conditions, thus not only restoring erectile function, but also overall health.

  14. In vivo cholinergic circuit evaluation in frontotemporal and Alzheimer dementias.

    Science.gov (United States)

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

    2006-04-11

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

  15. Libidibia ferrea mature seeds promote antinociceptive effect by peripheral and central pathway: possible involvement of opioid and cholinergic receptors.

    Science.gov (United States)

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

    2014-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Luis Armando Sawada

    2014-01-01

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

  17. Central respiratory failure during acute organophosphate poisoning.

    Science.gov (United States)

    Carey, Jennifer L; Dunn, Courtney; Gaspari, Romolo J

    2013-11-01

    Organophosphate (OP) pesticide poisoning is a global health problem with over 250,000 deaths per year. OPs affect neuronal signaling through acetylcholine (Ach) neurotransmission via inhibition of acetylcholinesterase (AChE), leading to accumulation of Ach at the synaptic cleft and excessive stimulation at post-synaptic receptors. Mortality due to OP agents is attributed to respiratory dysfunction, including central apnea. Cholinergic circuits are integral to many aspects of the central control of respiration, however it is unclear which mechanisms predominate during acute OP intoxication. A more complete understanding of the cholinergic aspects of both respiratory control as well as neural modification of pulmonary function is needed to better understand OP-induced respiratory dysfunction. In this article, we review the physiologic mechanisms of acute OP exposure in the context of the known cholinergic contributions to the central control of respiration. We also discuss the potential central cholinergic contributions to the known peripheral physiologic effects of OP intoxication.

  18. The Riley-Day syndrome. Familial dysautonomy, central autonomic dysfunction.

    Science.gov (United States)

    François, J

    1977-01-01

    The Riley-Day syndrome is characterized by a dysfunction of the autonomous nervous system, sensory disturbances, neurological disorders, psychical anomalies and important ophthalmological symptoms, such as absence of tears, corneal anaesthesia, keratinized conjunctiva and cornea; myosis after instillation of methacholine. The diagnosis is based on the absence of fungiform papillae of the tongue and the absence of reaction after intradermic injection of histamine. The inheritance is autosomal recessive. The disease results probably from an enzymatic insufficiency.

  19. [Involvement of cross interaction between central cholinergic and histaminergic systems in the nucleus tractus solitarius in regulating carotid sinus baroreceptor reflex].

    Science.gov (United States)

    Hu, Li-Xun; Zhang, Guo-Xing; Zhang, Yu-Ying; Zhao, Hong-Fen; Yu, Kang-Ying; Wang, Guo-Qing

    2013-12-25

    The carotid sinus baroreceptor reflex (CSR) is an important approach for regulating arterial blood pressure homeostasis instantaneously and physiologically. Activation of the central histaminergic or cholinergic systems results in CSR functional inhibitory resetting. However, it is unclear whether two systems at the nucleus tractus solitarius (NTS) level display cross interaction to regulate the CSR or not. In the present study, the left or right carotid sinus region was isolated from the systemic circulation in Sprague-Dawley rats (sinus nerve was reserved) anesthetized with pentobarbital sodium. Respective intubation was conducted into one side isolated carotid sinus and into the femoral artery for recording the intracarotid sinus pressure (ISP) and mean arterial pressure (MAP) simultaneously with pressure transducers connection in vivo. ISP was set at the level of 0 mmHg to eliminate the effect of initial internal pressure of the carotid sinus on the CSR function. To trigger CSR, the ISP was quickly elevated from 0 mmHg to 280 mmHg in a stepwise manner (40 mmHg) which was added at every step for over 4 s, and then ISP returned to 0 mmHg in similar steps. The original data of ISP and corresponding MAP were fitted to a modified logistic equation with five parameters to obtain the ISP-MAP, ISP-Gain relationship curves and the CSR characteristic parameters, which were statistically compared and analyzed separately. Under the precondition of no influence on the basic levels of the artery blood pressure, the effects and potential regulatory mechanism of preceding microinjection with different cholinoceptor antagonists, the selective cholinergic M1 receptor antagonist, i.e., pirenzepine (PRZ), the M2 receptor antagonist, i.e., methoctramine (MTR) or the N1 receptor antagonist, i.e., hexamethonium (HEX) into the NTS on the changes in function of CSR induced by intracerebroventricular injection (i.c.v.) of histamine (HA) in rats were observed. Meanwhile, the actions and

  20. Sympathetic dysfunction of central origin in patients with ALS

    DEFF Research Database (Denmark)

    Karlsborg, M; Andersen, E B; Wiinberg, N;

    2003-01-01

    Amyotrophic lateral sclerosis (ALS) is a severe, progressive disease affecting both the central and peripheral parts of the motor nervous system. Some studies have shown unequivocal indications of a more disseminated disease also affecting the autonomic nervous system. We therefore evaluated...

  1. Sympathetic dysfunction of central origin in patients with ALS

    DEFF Research Database (Denmark)

    Karlsborg, M; Andersen, E B; Wiinberg, N

    2003-01-01

    Amyotrophic lateral sclerosis (ALS) is a severe, progressive disease affecting both the central and peripheral parts of the motor nervous system. Some studies have shown unequivocal indications of a more disseminated disease also affecting the autonomic nervous system. We therefore evaluated...

  2. INTRAHIPPOCAMPAL ADMINISTRATION OF IBOTENIC ACID INDUCED CHOLINERGIC DYSFUNCTION via NR2A/NR2B EXPRESSION: IMPLICATIONS OF RESVERATROL AGAINST ALZHEIMER DISEASE PATHOPHYSIOLOGY

    Directory of Open Access Journals (Sweden)

    Chennakesavan eKarthick

    2016-04-01

    Full Text Available Although several drugs revealed moderate amelioration of symptoms, none of them have sufficient potency to prevent or reverse the progression towards Alzheimer’s disease (AD pathology. Resveratrol (RSV, a polyphenolic compound has shown an outstanding therapeutic effect on a broad spectrum of diseases like age-associated neurodegeneration, inflammation etc. The present study was thus conducted to assess the therapeutic efficacy of RSV in ameliorating the deleterious effects of Ibotenic acid (IBO in male Wistar rats. Stereotactic intrahippocampal administration of IBO (5µg/µl lesioned rats impairs cholinergic transmission, learning and memory performance that is rather related to AD and thus chosen as a suitable model to understand the drug efficacy in preventing AD pathophysiology. Since IBO is an agonist of glutamate, it is expected to exhibit an excitotoxic effect by altering glutamatergic receptors like NMDA receptor. The current study displayed significant alterations in the mRNA expression of NR2A and NR2B subunits of NMDA receptors, and further it is surprising to note that cholinergic receptors decreased in expression particularly α7-nAChR with increased m1AChR. RSV administration (20mg/kg body weight, i.p significantly reduced these changes in IBO induced rats. Glutamatergic and cholinergic receptor alterations were associated with significant changes in the behavioral parameters of rats induced by IBO. While RSV improved spatial learning performance, attenuated immobility and improvised open field activity in IBO induced rats. NR2B activation in the present study might mediate cell death through oxidative stress that form the basis of abnormal behavioral pattern in IBO induced rats. Interestingly, RSV that could efficiently encounter oxidative stress have significantly decreased stress markers viz., nitrite, PCO, and MDA levels by enhancing antioxidant status. Histopathological analysis displayed significant reduction in the

  3. Intrahippocampal Administration of Ibotenic Acid Induced Cholinergic Dysfunction via NR2A/NR2B Expression: Implications of Resveratrol against Alzheimer Disease Pathophysiology.

    Science.gov (United States)

    Karthick, Chennakesavan; Periyasamy, Sabapathy; Jayachandran, Kesavan S; Anusuyadevi, Muthuswamy

    2016-01-01

    Although several drugs revealed moderate amelioration of symptoms, none of them have sufficient potency to prevent or reverse the progression toward Alzheimer's disease (AD) pathology. Resveratrol (RSV), a polyphenolic compound has shown an outstanding therapeutic effect on a broad spectrum of diseases like age-associated neurodegeneration, inflammation etc. The present study was thus conducted to assess the therapeutic efficacy of RSV in ameliorating the deleterious effects of Ibotenic acid (IBO) in male Wistar rats. Stereotactic intrahippocampal administration of IBO (5 μg/μl) lesioned rats impairs cholinergic transmission, learning and memory performance that is rather related to AD and thus chosen as a suitable model to understand the drug efficacy in preventing AD pathophysiology. Since IBO is an agonist of glutamate, it is expected to exhibit an excitotoxic effect by altering glutamatergic receptors like NMDA receptor. The current study displayed significant alterations in the mRNA expression of NR2A and NR2B subunits of NMDA receptors, and further it is surprising to note that cholinergic receptors decreased in expression particularly α7-nAChR with increased m1AChR. RSV administration (20 mg/kg body weight, i.p.) significantly reduced these changes in IBO induced rats. Glutamatergic and cholinergic receptor alterations were associated with significant changes in the behavioral parameters of rats induced by IBO. While RSV improved spatial learning performance, attenuated immobility, and improvised open field activity in IBO induced rats. NR2B activation in the present study might mediate cell death through oxidative stress that form the basis of abnormal behavioral pattern in IBO induced rats. Interestingly, RSV that could efficiently encounter oxidative stress have significantly decreased stress markers viz., nitrite, PCO, and MDA levels by enhancing antioxidant status. Histopathological analysis displayed significant reduction in the hippocampal

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

    NARCIS (Netherlands)

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

    2001-01-01

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

  5. Cognitive and Emotional Dysfunction after Central Pontine Myelinolysis

    Directory of Open Access Journals (Sweden)

    Tatia M. C. Lee

    2003-01-01

    Full Text Available The case of a 67-year-old right-handed Chinese man with Central Pontine Myelinolysis [CPM] is described to illustrate the resulting cognitive and emotional disturbances. A comparison of the data in this report with that in published studies suggests that ethnicity does not seem to have much effect on the symptoms of CPM. Possible underlying neural-pathological mechanisms are discussed. This case further substantiates the speculation that the brainstem plays a role in higher cognitive processes and emotional regulation.

  6. Sexual Dysfunction in Patients with Diabetes Mellitus: The Role of a "Central" Neuropathy.

    Science.gov (United States)

    Nofzinger

    1997-01-01

    Sexual behavior involves the complex integration of higher intellectual function, such as associative memory and the experience of drives and motivations, with basic instinctual or reflexive physiological responses coordinated at the spinal level. Previous research in diabetic sexual dysfunction has largely focused on diabetic male erectile dysfunction, emphasizing a peripheral vasculopathy or neuropathy as etiologic factors, although ignoring the more complex neuropsychiatric components of sexual behavior. Following a review of the basic physiology of sexual behavior and evidence in support of a peripheral vasculopathy and/or a peripheral autonomic neuropathy in the cause of diabetic sexual dysfunction, emphasis will then shift to the role of a "central" neuropathy as a contributing component of diabetic sexual dysfunction. Evidence in support of such a view will come from a variety of studies, ranging from basic neuroscience research on forebrain mechanisms of sexual function to the functional brain imaging of human rapid eye movement (REM) sleep, a brain state known to be associated with the periodic occurrence of penile tumescence. An integrative perspective of this research will identify major candidate structures within the brain that may be dysfunctional in diabetic patients and may contribute to the profound sexual dysfunction that characterizes this condition. Major findings as well as deficits in our understanding of the effects of diabetes on female sexual dysfunction will also be highlighted, followed by suggestions for future research in this largely understudied area.

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

    Directory of Open Access Journals (Sweden)

    Anju TR

    2010-02-01

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

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

    NARCIS (Netherlands)

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

    2011-01-01

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

  9. Successful use of albuterol in a patient with central core disease and mitochondrial dysfunction

    OpenAIRE

    2010-01-01

    Albuterol, a selective beta-adrenergic agonist, has been used experimentally in combination with exercise therapy in a few inherited neuromuscular disorders to increase muscle strength and muscle volume . We report on a 9-year-old boy with central core disease and mitochondrial dysfunction due to compound heterozygous RYR1 mutations receiving albuterol treatment for 1 year. Throughout the period of albuterol administration, the patient underwent an aerobic exercise regime of training sessions...

  10. Metabolic Dysfunction in Parkinson's Disease: Bioenergetics, Redox Homeostasis and Central Carbon Metabolism.

    Science.gov (United States)

    Anandhan, Annadurai; Jacome, Maria S; Lei, Shulei; Hernandez-Franco, Pablo; Pappa, Aglaia; Panayiotidis, Mihalis I; Powers, Robert; Franco, Rodrigo

    2017-07-01

    The loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the accumulation of protein inclusions (Lewy bodies) are the pathological hallmarks of Parkinson's disease (PD). PD is triggered by genetic alterations, environmental/occupational exposures and aging. However, the exact molecular mechanisms linking these PD risk factors to neuronal dysfunction are still unclear. Alterations in redox homeostasis and bioenergetics (energy failure) are thought to be central components of neurodegeneration that contribute to the impairment of important homeostatic processes in dopaminergic cells such as protein quality control mechanisms, neurotransmitter release/metabolism, axonal transport of vesicles and cell survival. Importantly, both bioenergetics and redox homeostasis are coupled to neuro-glial central carbon metabolism. We and others have recently established a link between the alterations in central carbon metabolism induced by PD risk factors, redox homeostasis and bioenergetics and their contribution to the survival/death of dopaminergic cells. In this review, we focus on the link between metabolic dysfunction, energy failure and redox imbalance in PD, making an emphasis in the contribution of central carbon (glucose) metabolism. The evidence summarized here strongly supports the consideration of PD as a disorder of cell metabolism. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Central vestibular dysfunction in an otorhinolaryngological vestibular unit: incidence and diagnostic strategy.

    Science.gov (United States)

    Mostafa, Badr E; Kahky, Ayman O El; Kader, Hisham M Abdel; Rizk, Michael

    2014-07-01

    Introduction Vertigo can be due to a variety of central and peripheral causes. The relative incidence of central causes is underestimated. This may have an important impact of the patients' management and prognosis. Objective The objective of this work is to determine the incidence of central vestibular disorders in patients presenting to a vestibular unit in a tertiary referral academic center. It also aims at determining the best strategy to increase the diagnostic yield of the patients' visit. Methods This is a prospective observational study on 100 consecutive patients with symptoms suggestive of vestibular dysfunction. All patients completed a structured questionnaire and received bedside and vestibular examination and neuroimaging as required. Results There were 69 women and 31 men. Their ages ranged between 28 and 73 (mean 42.48 years). Provisional videonystagmography (VNG) results were: 40% benign paroxysmal positional vertigo (BPPV), 23% suspicious of central causes, 18% undiagnosed, 15% Meniere disease, and 4% vestibular neuronitis. Patients with an unclear diagnosis or central features (41) had magnetic resonance imaging (MRI) and Doppler studies. Combining data from history, VNG, and imaging studies, 23 patients (23%) were diagnosed as having a central vestibular lesion (10 with generalized ischemia/vertebra basilar insufficiency, 4 with multiple sclerosis, 4 with migraine vestibulopathy, 4 with phobic postural vertigo, and 1 with hyperventilation-induced nystagmus). Conclusions Combining a careful history with clinical examination, VNG, MRI, and Doppler studies decreases the number of undiagnosed cases and increases the detection of possible central lesions.

  12. Central Vestibular Dysfunction in an Otorhinolaryngological Vestibular Unit: Incidence and Diagnostic Strategy

    Directory of Open Access Journals (Sweden)

    Mostafa, Badr E.

    2014-03-01

    Full Text Available Introduction Vertigo can be due to a variety of central and peripheral causes. The relative incidence of central causes is underestimated. This may have an important impact of the patients' management and prognosis. Objective The objective of this work is to determine the incidence of central vestibular disorders in patients presenting to a vestibular unit in a tertiary referral academic center. It also aims at determining the best strategy to increase the diagnostic yield of the patients' visit. Methods This is a prospective observational study on 100 consecutive patients with symptoms suggestive of vestibular dysfunction. All patients completed a structured questionnaire and received bedside and vestibular examination and neuroimaging as required. Results There were 69 women and 31 men. Their ages ranged between 28 and 73 (mean 42.48 years. Provisional videonystagmography (VNG results were: 40% benign paroxysmal positional vertigo (BPPV, 23% suspicious of central causes, 18% undiagnosed, 15% Meniere disease, and 4% vestibular neuronitis. Patients with an unclear diagnosis or central features (41 had magnetic resonance imaging (MRI and Doppler studies. Combining data from history, VNG, and imaging studies, 23 patients (23% were diagnosed as having a central vestibular lesion (10 with generalized ischemia/vertebra basilar insufficiency, 4 with multiple sclerosis, 4 with migraine vestibulopathy, 4 with phobic postural vertigo, and 1 with hyperventilation-induced nystagmus. Conclusions Combining a careful history with clinical examination, VNG, MRI, and Doppler studies decreases the number of undiagnosed cases and increases the detection of possible central lesions.

  13. Do children with central venous line (CVL dysfunction have increased risk of symptomatic thromboembolism compared to those without CVL-dysfunction, while on cancer therapy?

    Directory of Open Access Journals (Sweden)

    Halton Jacqueline

    2012-07-01

    Full Text Available Abstract Background Thromboembolism (TE and infection are two common complications of central venous line (CVL. Thrombotic CVL-dysfunction is a common, yet less studied, complication of CVL. Two retrospective studies have reported significant association of CVL-dysfunction and TE. Recent studies indicate association of CVL-related small clot with infection. Infection is the most common cause of non-cancer related mortality in children with cancer. We and others have shown reduced overall survival (OS in children with cancer and CVL-dysfunction compared to those without CVL-dysfunction. Despite these observations, to date there are no prospective studies to evaluate the clinical significance of CVL-dysfunction and it’s impact on the development of TE, infection, or outcome of children with cancer. Study design This is a prospective, analytical cohort study conducted at five tertiary care pediatric oncology centers in Ontario. Children (≤ 18 years of age with non-central nervous system cancers and CVL will be eligible for the study. Primary outcome measure is symptomatic TE and secondary outcomes are infection, recurrence of cancer and death due to any cause. Data will be analyzed using regression analyses. Discussion The overall objective is to delineate the relationship between CVL-dysfunction, infection and TE. The primary aim is to evaluate the role of CVL-dysfunction as a predictor of symptomatic TE in children with cancer. We hypothesize that children with CVL-dysfunction have activation of the coagulation system resulting in an increased risk of symptomatic TE. The secondary aims are to study the impact of CVL-dysfunction on the rate of infection and the survival [OS and event free survival (EFS] of children with cancer. We postulate that patients with CVL-dysfunction have an occult CVL-related clot which acts as a microbial focus with resultant increased risk of infection. Further, CVL-dysfunction by itself or in combination with

  14. Contribution of the Cholinergic System to Verbal Memory Performance in Mild Cognitive Impairment.

    Science.gov (United States)

    Peter, Jessica; Lahr, Jacob; Minkova, Lora; Lauer, Eliza; Grothe, Michel J; Teipel, Stefan; Köstering, Lena; Kaller, Christoph P; Heimbach, Bernhard; Hüll, Michael; Normann, Claus; Nissen, Christoph; Reis, Janine; Klöppel, Stefan

    2016-06-18

    Acetylcholine is critically involved in modulating learning and memory function, which both decline in neurodegeneration. It remains unclear to what extent structural and functional changes in the cholinergic system contribute to episodic memory dysfunction in mild cognitive impairment (MCI), in addition to hippocampal degeneration. A better understanding is critical, given that the cholinergic system is the main target of current symptomatic treatment in mild to moderate Alzheimer's disease. We simultaneously assessed the structural and functional integrity of the cholinergic system in 20 patients with MCI and 20 matched healthy controls and examined their effect on verbal episodic memory via multivariate regression analyses. Mediating effects of either cholinergic function or hippocampal volume on the relationship between cholinergic structure and episodic memory were computed. In MCI, a less intact structure and function of the cholinergic system was found. A smaller cholinergic structure was significantly correlated with a functionally more active cholinergic system in patients, but not in controls. This association was not modulated by age or disease severity, arguing against compensational processes. Further analyses indicated that neither functional nor structural changes in the cholinergic system influence verbal episodic memory at the MCI stage. In fact, those associations were fully mediated by hippocampal volume. Although the cholinergic system is structurally and functionally altered in MCI, episodic memory dysfunction results primarily from hippocampal neurodegeneration, which may explain the inefficiency of cholinergic treatment at this disease stage.

  15. Reduced cholinergic olfactory centrifugal inputs in patients with neurodegenerative disorders and MPTP-treated monkeys.

    Science.gov (United States)

    Mundiñano, Iñaki-Carril; Hernandez, Maria; Dicaudo, Carla; Ordoñez, Cristina; Marcilla, Irene; Tuñon, Maria-Teresa; Luquin, Maria-Rosario

    2013-09-01

    Olfactory impairment is a common feature of neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). Olfactory bulb (OB) pathology in these diseases shows an increased number of olfactory dopaminergic cells, protein aggregates and dysfunction of neurotransmitter systems. Since cholinergic denervation might be a common underlying pathophysiological feature, the objective of this study was to determine cholinergic innervation of the OB in 27 patients with histological diagnosis of PD (n = 5), AD (n = 14), DLB (n = 8) and 8 healthy control subjects. Cholinergic centrifugal inputs to the OB were clearly reduced in all patients, the most significant decrease being in the DLB group. We also studied cholinergic innervation of the OB in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys (n = 7) and 7 intact animals. In MPTP-monkeys, we found that cholinergic innervation of the OB was reduced compared to control animals (n = 7). Interestingly, in MPTP-monkeys, we also detected a loss of cholinergic neurons and decreased dopaminergic innervation in the horizontal limb of the diagonal band, which is the origin of the centrifugal cholinergic input to the OB. All these data suggest that cholinergic damage in the OB might contribute, at least in part, to the olfactory dysfunction usually exhibited by these patients. Moreover, decreased cholinergic input to the OB found in MPTP-monkeys suggests that dopamine depletion in itself might reduce the cholinergic tone of basal forebrain cholinergic neurons.

  16. Striatal cholinergic interneuron regulation and circuit effects

    Directory of Open Access Journals (Sweden)

    Sean Austin Lim

    2014-10-01

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

  17. Radioiodinated 2-hydroxy-3-(4-iodophenyl)-1-(4-phenylpiperidinyl)propane: potential radiotracer for mapping central cholinergic innervation in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Efange, S.M.N.; Dutta, A.K.; Michelson, R.H.; Thomas, J.R.; Boudreau, R.J. (Minnesota Univ., Minneapolis, MN (United States)); Kung, H.F.; Billings, J. (Pennsylvania Univ., Philadelphia, PA (United States). Dept. of Radiology)

    1992-04-01

    Radioiodinated 2-hydroxy-3-(4-iodophenyl)-1-(4-phenylpiperidinyl)propane, (4-HIPP), was synthesized and evaluated as a simple vesamicol-like radiotracer for mapping cholinergic pathways in the brain. Both enantiomers of 4-HIPP exhibit significant accumulation (approx. 2% of injected dose) and prolonged retention (t[sub 1/2] > 3h) within the rat brain. The accumulation of radioiodinated 4-HIPP in the rat brain was reduced by up to 70% in the presence of vesamicol and its analogs. The levorotary isomer (-)-4-[[sup 123]I]HIPP exhibits significant accumulation in the monkey brain, with a half-life of about 9 h. Radioiodinated 4-HIPP may therefore be a useful tool for studying cholinergic pathways in the brain. (author).

  18. Drug-induced sexual dysfunction.

    Science.gov (United States)

    Aldridge, S A

    1982-01-01

    Commonly used drugs that may cause sexual dysfunction are reviewed. The anatomy and physiology of the normal sexual response are reviewed. The influence of drugs on neurogenic, hormonal, and vascular mechanisms may result in diminished libido, impotence, ejaculatory and orgasmic difficulties, inhibited vaginal lubrication, menstrual irregularities, and gynecomastia in men or painful breast enlargement in women. Parasympatholytic agents, which interfere with cholinergic transmission, may affect erectile potency, while adrenergic inhibiting agents may interfere with ejaculatory control. Central nervous system depressants or sedating drugs, drugs producing hyperprolactinemia, and antiandrogenic drugs also may affect the normal sexual response. Drugs such as antihypertensive and antipsychotic agents may induce sexual dysfunction that can result in patient noncompliance. Usually, drug-induced side effects are reversible with discontinuation of the offending agent.

  19. Chronic treatment with taurine after intracerebroventricular streptozotocin injection improves cognitive dysfunction in rats by modulating oxidative stress, cholinergic functions and neuroinflammation.

    Science.gov (United States)

    Reeta, K H; Singh, Devendra; Gupta, Y K

    2017-03-08

    The present study investigated the neuroprotective effects of taurine, an essential amino acid for growth and development of central nervous system. Intracerebroventricular streptozotocin (ICV-STZ) model of cognitive impairment was used in male Wistar rats (270 ± 20 g). Morris water maze, elevated plus maze and passive avoidance paradigm were used to assess cognitive performance. Taurine (40, 60 and 120 mg/kg) was administered orally for 28 days following STZ administration on day 1. Oxidative stress parameters (malondialdehyde, glutathione, nitric oxide and superoxide dismutase) and cholinesterases (acetylcholinesterase and butyrylcholinesterase) activity were measured at end of the study in the cortex and hippocampus. Levels of TNF-α, IL-1β, expression of rho kinase-II (ROCK-II), glycogen synthase kinase-3β (GSK-3β) and choline acetyltransferase (ChAT) were studied in cortex and hippocampus. STZ caused significant cognitive impairment as compared to normal control. Chronic administration of taurine attenuated STZ-induced cognitive impairment. Increased oxidative stress and increased levels of TNF-α, IL-1β induced by STZ were also significantly attenuated by taurine. Taurine significantly (p < 0.05) decreased the STZ-induced increased expression of ROCK-II in cortex and hippocampus. Further, STZ-induced increased activity of cholinesterases was significantly (p < 0.001) mitigated by taurine. STZ decreased the expression of ChAT in hippocampus which was significantly (p < 0.05) reversed by taurine. However, GSK-3β expression was not altered by either STZ or taurine. The present study indicates that taurine exerts a neuroprotective role against STZ-induced cognitive impairment in rats. This effect is probably mediated by modulating oxidative stress, cholinesterases, inflammatory cytokines and expression of ROCK-II. Thus, this study suggests a potential of chronic taurine administration in cognitive impairment of Alzheimer's type.

  20. Is epicardial adipose tissue, another measure of central obesity, correlated with erectile dysfunction?

    Directory of Open Access Journals (Sweden)

    Chih-Wei Tsao

    2016-01-01

    Full Text Available Background: This study investigated the correlation between epicardial adipose tissue (EAT, a measure of central obesity, and sexual function in males with vasculogenic erectile dysfunction (ED. Materials and Methods: The study was a cross-sectional study of selected males with ED aged <75 years who attended the Urology Outpatient Department of Tri-Service General Hospital. Sixty subjects were included in the study, which employed biochemical data, anthropometric indexes, echocardiography, and questionnaires. Biochemical lipid profiles and associated inflammation markers were recorded. The anthropometric indexes included general and central obesity and bioelectrical impedance analysis. Echocardiography results were assessed by a single experienced cardiologist and included epicardial and pericardial fat thickness measurements. Sexual function was evaluated using the International Index of Erectile Function-5 (IIEF-5 score. Results: According to the analysis of variance and multivariate logistic regression, only the erectile hardness score (EHS was statistically positively correlated with the IIEF-5 score. All other anthropometric indexes and echocardiography parameters, including EAT thickness, pericardial adipose tissue thickness, and ejection fraction (EF, were not significantly associated with sexual function. Conclusions: Only EHS was statistically associated with sexual function in the male subjects with ED. The anthropometric indexes and EAT thickness, a measure of central obesity, were not significantly correlated with sexual function in the male patients with ED.

  1. Central Autonomic Dysfunction Delays Recovery of Fingolimod Induced Heart Rate Slowing.

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    Max J Hilz

    Full Text Available In multiple sclerosis (MS patients, Fingolimod may induce prolonged heart-rate slowing which might be caused by MS-related central autonomic lesions.To evaluate whether MS-patients with prolonged heart-rate slowing (> six hours upon Fingolimod show cardiovascular-autonomic dysfunction before Fingolimod-initiation.Before Fingolimod-initiation, we recorded electrocardiographic RR-intervals (RRIs and blood-pressure (BP at rest, upon standing-up, during metronomic deep-breathing, Valsalva-maneuver, and "sustained-handgrip-exercise" in 21 patients with relapsing-remitting MS, and 20 healthy persons. We calculated sympathetic and parasympathetic cardiovascular parameters, including low- (LF and high-frequency (HF powers of RRI- and BP-oscillations, RRI-RMSSDs, RRI- and BP-changes during handgrip-exercise, parasympathetic heart-rate-slowing in relation to BP-overshoot after Valsalva-strain-release. We compared values of healthy persons and patients with and without prolonged heart-rate slowing after Fingolimod-initiation (ANOVA; significance: p<0.05.Upon Fingolimod-initiation, 7/21 patients had prolonged HR-slowing. Before Fingolimod, these patients had higher resting BP and higher BP increase during handgrip-exercise than had the other participants (p<0.05. They did not reduce parasympathetic HR-parameters upon standing-up. After Valsalva-strain-release, their parasympathetic HR-slowing in response to BP-overshoot was four times higher than in the other participants (p<0.05.The autonomic cardiovascular dysfunction in MS-patients with delayed HR-re-acceleration upon Fingolimod-initiation suggests that MS-related central autonomic lesions compromise HR-re-acceleration upon Fingolimod.German Clinical Trial Register DRKS00004548 http://drks-neu.uniklinik-freiburg.de/drks_web/setLocale_EN.do.

  2. Pharmacological characteristics of catalepsy induced by intracerebroventricular administration of histamine in mice: the importance of muscarinic step in central cholinergic neurons.

    Science.gov (United States)

    Onodera, K; Shinoda, H

    1991-05-01

    Histamine-induced catalepsy was antagonized potently by scopolamine, an antimuscarinic drug, and partially blocked by sparteine. Neither methylatropine nor antinicotinic drugs could reverse histamine-induced catalepsy. These results indicate the greater importance of muscarinic receptors rather than their nicotinic counterparts in histamine-induced catalepsy. Various antiparkinson drugs, i.e. biperiden and trihexyphenidyl, which have antimuscarinic activity or dopamine agonists, i.e. L-dopa, amantadine and bromocriptine, could antagonize the histamine-induced catalepsy to various degrees. Thus, catalepsy induced by icv histamine can be evoked not only by an activation of the histamine receptor, but also indirectly due to cholinergic and dopaminergic imbalance.

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

    DEFF Research Database (Denmark)

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

    2017-01-01

    subjects for more than 1 year after at least moderate traumatic brain injury. Ten of the subjects were respondents and 7 nonrespondents to cholinergic medication. DESIGN:: Cholinergic function was assessed with [methyl-C] N-methylpiperidyl-4-acetate-PET (C-MP4A-PET), which reflects the activity...... was notably lower throughout the cortex in both respondents and nonrespondents, without significant differences between them. CONCLUSION:: Our study suggests that frontal cholinergic dysfunction is associated with the clinical response to cholinergic stimulation in patients with traumatic brain injury....

  4. Cholinergic imaging in dementia spectrum disorders

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-07-15

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

  5. Cholinergic systems mediate action from movement to higher consciousness.

    Science.gov (United States)

    Woolf, Nancy J; Butcher, Larry L

    2011-08-10

    There is a fundamental link between cholinergic neurotransmitter function and overt and covert actions. Major cholinergic systems include peripheral motor neurons organizing skeletal muscle movements into overt behaviors and cholinergic neurons in the basal forebrain and mesopontine regions that mediate covert actions realized as states of consciousness, arousal, selective attention, perception, and memory. Cholinergic interneurons in the striatum appear to integrate conscious and unconscious actions. Neural network models involving cholinergic neurons, as well as neurons using other neurotransmitters, emphasize connective circuitry as being responsible for both motor programs and neural correlates of higher consciousness. This, however, is only a partial description. At a more fundamental level lie intracellular mechanisms involving the cytoskeleton, which are common to both muscle contraction and neuroplastic responses in targets of central cholinergic cells attendant with higher cognition. Acetylcholine, acting through nicotinic receptors, triggers interactions between cytoskeletal proteins in skeletal muscle cells, as has been long known. There is also evidence that acetylcholine released at central sites acts through muscarinic and nicotinic receptors to initiate responses in actin and microtubule proteins. These effects and their implications for cholinergic involvement in higher cognition are explored in this review.

  6. Hypothalamic pituitary dysfunction in acute nonmycobacterial infections of central nervous system

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    Dinesh K Dhanwal

    2011-01-01

    Full Text Available Background and Objective: Acute and chronic central nervous system (CNS infections are not uncommon in tropical countries and are associated with high morbidity and mortality if specific targeted therapy is not instituted in time. Effects of tubercular meningitis, a form of chronic meningitis on hypothalamic pituitary axis, are well known both at the time of diagnosis and after few months to years of illness. However, there are few reports of pituitary dysfunction in subjects with acute CNS infections. Therefore, this study was aimed at evaluating the pituitary hormonal profile in patients with nonmycobacterial acute meningitis at the time of presentation. Materials and Methods: This prospective case series study included 30 untreated adult patients with acute meningitis, meningoencephalitis, or encephalitis, due to various nonmycobacterial agents, admitted and registered with Lok Nayak Hospital, Maulana Aazd Medical College, New Delhi, between September 2007 and March 2009. Patients with preexisting endocrine diseases, tubercular meningitis and patients on steroids were carefully excluded from the study. The basal pituitary hormonal profile was measured by the electrochemilumniscence technique for serum cortisol, luetinizing hormone (LH, follicular stimulating hormone (FSH, prolactin (PRL, thyrotropin (TSH, free tri-iodothyronine (fT3, and free thyroxine (fT4. Results: The cases (n = 30 comprised of patients with acute pyogenic meningitis (n = 23, viral meningoencephalitis (n = 4, brain abscess (n = 2, and cryptococcal meningitis (n = 1. The mean age of patients was 28.97 ± 11.306 years. Out of 30 patients, 14 (46.7% were males and 16 (58.1% were females. Adrenal insufficiency both absolute and relative was seen in seven (23.3% and hyperprolactinemia was seen in nine (30.0% of the patients. One study subject had central hypothyroidism and seven (23.3 showed low levels of LH and/or FSH. None of patients showed clinical features suggestive of

  7. Amyloid-β depresses excitatory cholinergic synaptic transmission in Drosophila

    Institute of Scientific and Technical Information of China (English)

    Liqun Fang; Jingjing Duan; Dongzhi Ran; Zihao Fan; Ying Yan; Naya Huang; Huaiyu Gu; Yulan Zhu

    2012-01-01

    Objective Decline,disruption,or alterations of nicotinic cholinergic mechanisms contribute to cognitive dysfunctions like Alzheimer's disease (AD).Although amyloid-β (Aβ) aggregation is a pathological hallmark of AD,the mechanisms by which Aβ peptides modulate cholinergic synaptic transmission and memory loss remain obscure.This study was aimed to investigate the potential synaptic modulation by Aβ of the cholinergic synapses between olfactory receptor neurons and projection neurons (PNs) in the olfactory lobe of the fruit fly.Methods Cholinergic spontaneous and miniature excitatory postsynaptic current (mEPSC) were recorded with whole-cell patch clamp from PNs in Drosophila AD models expressing Aβ40,Aβ42,or Aβ42Arc peptides in neural tissue.Results In fly pupae (2 days before eclosion),overexpression of Aβ42 or Aβ42Arc,but not Aβ40,led to a significant decrease of mEPSC frequency,while overexpression of Aβ40,Aβ42,or Aβ42Arc had no significant effect on mEPSC amplitude.In contrast,Pavlovian olfactory associative learning and lifespan assays showed that both short-term memory and lifespan were decreased in the Drosophila models expressing Aβ40,Aβ42,or Aβ42Arc.Conclusion Both electrophysiological and behavioral results showed an effect of Aβ peptide on cholinergic synaptic transmission and suggest a possible mechanism by which Aβ peptides cause cholinergic neuron degeneration and the consequent memory loss.

  8. Cholinergic Abnormalities, Endosomal Alterations and Up-Regulation of Nerve Growth Factor Signaling in Niemann-Pick Type C Disease

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    Cabeza Carolina

    2012-03-01

    Full Text Available Abstract Background Neurotrophins and their receptors regulate several aspects of the developing and mature nervous system, including neuronal morphology and survival. Neurotrophin receptors are active in signaling endosomes, which are organelles that propagate neurotrophin signaling along neuronal processes. Defects in the Npc1 gene are associated with the accumulation of cholesterol and lipids in late endosomes and lysosomes, leading to neurodegeneration and Niemann-Pick type C (NPC disease. The aim of this work was to assess whether the endosomal and lysosomal alterations observed in NPC disease disrupt neurotrophin signaling. As models, we used i NPC1-deficient mice to evaluate the central cholinergic septo-hippocampal pathway and its response to nerve growth factor (NGF after axotomy and ii PC12 cells treated with U18666A, a pharmacological cellular model of NPC, stimulated with NGF. Results NPC1-deficient cholinergic cells respond to NGF after axotomy and exhibit increased levels of choline acetyl transferase (ChAT, whose gene is under the control of NGF signaling, compared to wild type cholinergic neurons. This finding was correlated with increased ChAT and phosphorylated Akt in basal forebrain homogenates. In addition, we found that cholinergic neurons from NPC1-deficient mice had disrupted neuronal morphology, suggesting early signs of neurodegeneration. Consistently, PC12 cells treated with U18666A presented a clear NPC cellular phenotype with a prominent endocytic dysfunction that includes an increased size of TrkA-containing endosomes and reduced recycling of the receptor. This result correlates with increased sensitivity to NGF, and, in particular, with up-regulation of the Akt and PLC-γ signaling pathways, increased neurite extension, increased phosphorylation of tau protein and cell death when PC12 cells are differentiated and treated with U18666A. Conclusions Our results suggest that the NPC cellular phenotype causes neuronal

  9. Persistent Postural-Perceptual Dizziness: A Matter of Higher, Central Dysfunction?

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    Dagny Holle

    Full Text Available Persistent postural-perceptual dizziness (PPPD is the most common vestibular disorder in the age group between 30 and 50 years. It is considered to be based on a multisensory maladjustment involving alterations of sensory response pattern including vestibular, visual and motion stimuli. Previous data supported a link between vestibular and pain mechanism. The aim of the study was to investigate whether other sensory inputs such as pain stimuli might be altered in terms of a more widespread central perception dysfunction in this disorder.Nociceptive blink reflex was measured in 27 patients with PPPD and compared with 27 healthy, age and gender matched controls. The habituation of the R2 component of the blink reflex was evaluated as the percentage area-under-the curve (AUC decrease in ten consecutive blocks of five averaged rectified responses. Additionally, clinical characteristics were evaluated.In patients with PPPD a lack of habituation was observed compared to healthy controls. Relative AUC decreased between the first and the tenth block by 19.48% in PPPD patients and by 31.63% (p = 0.035 in healthy controls. There was no correlation between clinical data (course of disease, comorbid depression, medication, trigger factors or electrophysiological data (perception threshold, pain threshold, stimulus intensity and habituation pattern. No trigeminal sensitization in terms of facilitation of absolute values could be detected.Our study results supports the hypothesis of the multisensory dimension of impaired sensory processing in patients with PPPD extends beyond vestibular/visual motion stimuli and reflexive postural/oculomotor control mechanisms to other sensory inputs such as pain perception in terms of a more generalized disturbed habituation pattern.

  10. Nematode cholinergic pharmacology

    Energy Technology Data Exchange (ETDEWEB)

    Segerberg, M.A.

    1989-01-01

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

  11. Cholinergic drugs as diagnostic and therapeutic tools in affective disorders.

    Science.gov (United States)

    Berger, M; Riemann, D; Krieg, C

    1991-01-01

    The hypothesis of a significant involvement of the cholinergic system in the pathogenesis of affective disorders still lacks strong experimental support. This is mainly because of missing specific peripheral markers of the central nervous activity of the cholinergic system and the lack of specific cholinergic agonists and antagonists without severe peripheral side effects. As the direct cholinergic agonist RS 86 seems to be more suitable because of its minor side effects, long half-life and oral applicability, it was tested for its antimanic property and its effect on the hypothalamo-pituitary adrenal system and the rapid eye movement (REM) sleep-generating system. RS 86 exhibited antimanic and REM sleep-inducing properties, but failed to stimulate the cortisol system.

  12. Glucocorticoid programing of the mesopontine cholinergic system.

    Science.gov (United States)

    Borges, Sónia; Coimbra, Bárbara; Soares-Cunha, Carina; Ventura-Silva, Ana P; Pinto, Luisa; Carvalho, Miguel M; Pêgo, José-Miguel; Rodrigues, Ana João; Sousa, Nuno

    2013-01-01

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

  13. Glucocorticoid programming of the mesopontine cholinergic system

    Directory of Open Access Journals (Sweden)

    Sónia eBorges

    2013-12-01

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

  14. Convergent effects on cell signaling mechanisms mediate the actions of different neurobehavioral teratogens: alterations in cholinergic regulation of protein kinase C in chick and avian models.

    Science.gov (United States)

    Yanai, Joseph; Beer, Avital; Huleihel, Rabab; Izrael, Michal; Katz, Sofia; Levi, Yaarit; Rozenboim, Israel; Yaniv, Shiri P; Slotkin, Theodore A

    2004-10-01

    Although the actions of heroin on central nervous system (CNS) development are mediated through opioid receptors, the net effects converge on dysfunction of cholinergic systems. We explored the mechanisms underlying neurobehavioral deficits in mouse and avian (chick, Cayuga duck) models. In mice, prenatal heroin exposure (10 mg/kg on gestation days 9-18) elicited deficits in behaviors related to hippocampal cholinergic innervation, characterized by concomitant pre- and postsynaptic hyperactivity, but ending in a reduction of basal levels of protein kinase C (PKC) isoforms betaII and gamma and their desensitization to cholinergic receptor-induced activation. PKCalpha, which is not involved in the behaviors studied, was unaffected. Because mammalian models possess inherent confounding factors from maternal effects, we conducted parallel studies using avian embryos, evaluating hyperstriatal nucleus (intermedial part of the hyperstriatum ventrale, IMHV)-related, filial imprinting behavior. Heroin injection to the eggs (20 mg/kg) on incubation days 0 and 5 diminished the post-hatch imprinting ability and reduced PKCg and bII content in the IMHV membrane fraction. Two otherwise unrelated agents that converge on cholinergic systems, chlorpyrifos and nicotine, elicited the same spectrum of effects on PKC isoforms and imprinting but had more robust actions. Pharmacological characterization also excluded direct effects of opioid receptors on the expression of imprinting; instead, it indicated participation of serotonergic innervation. The avian models can provide rapid screening of neuroteratogens, exploration of common mechanisms of behavioral disruption, and the potential design of therapies to reverse neurobehavioral deficits.

  15. Central and peripheral effects of arecoline in patients with autonomic failure.

    Science.gov (United States)

    Polinsky, R J; Brown, R T; Curras, M T; Baser, S M; Baucom, C E; Hooper, D R; Marini, A M

    1991-01-01

    Increased plasma adrenalin (A) levels following arecoline in normal subjects and patients with multiple system atrophy (MSA) may result from nicotinic adrenal stimulation. Lack of this response in patients with pure autonomic failure (PAF) is consistent with peripheral sympathetic dysfunction. The mechanisms underlying diminished plasma corticotropin (ACTH) responses to arecoline may differ in patients with autonomic failure. Hypothalamic, cholinergic degeneration could prevent the response in MSA whereas patients with PAF do not manifest the normal increase in A which may be required to elicit an ACTH response. The appearance and exacerbation of tremor, vertigo, and pathological affect in the MSA group suggest that some central cholinergic receptors remain functional. PMID:1659617

  16. Cholinergic Neurons Excite Cortically Projecting Basal Forebrain GABAergic Neurons

    Science.gov (United States)

    Yang, Chun; McKenna, James T.; Zant, Janneke C.; Winston, Stuart; Basheer, Radhika

    2014-01-01

    The basal forebrain (BF) plays an important role in the control of cortical activation and attention. Understanding the modulation of BF neuronal activity is a prerequisite to treat disorders of cortical activation involving BF dysfunction, such as Alzheimer's disease. Here we reveal the interaction between cholinergic neurons and cortically projecting BF GABAergic neurons using immunohistochemistry and whole-cell recordings in vitro. In GAD67-GFP knock-in mice, BF cholinergic (choline acetyltransferase-positive) neurons were intermingled with GABAergic (GFP+) neurons. Immunohistochemistry for the vesicular acetylcholine transporter showed that cholinergic fibers apposed putative cortically projecting GABAergic neurons containing parvalbumin (PV). In coronal BF slices from GAD67-GFP knock-in or PV-tdTomato mice, pharmacological activation of cholinergic receptors with bath application of carbachol increased the firing rate of large (>20 μm diameter) BF GFP+ and PV (tdTomato+) neurons, which exhibited the intrinsic membrane properties of cortically projecting neurons. The excitatory effect of carbachol was blocked by antagonists of M1 and M3 muscarinic receptors in two subpopulations of BF GABAergic neurons [large hyperpolarization-activated cation current (Ih) and small Ih, respectively]. Ion substitution experiments and reversal potential measurements suggested that the carbachol-induced inward current was mediated mainly by sodium-permeable cation channels. Carbachol also increased the frequency of spontaneous excitatory and inhibitory synaptic currents. Furthermore, optogenetic stimulation of cholinergic neurons/fibers caused a mecamylamine- and atropine-sensitive inward current in putative GABAergic neurons. Thus, cortically projecting, BF GABAergic/PV neurons are excited by neighboring BF and/or brainstem cholinergic neurons. Loss of cholinergic neurons in Alzheimer's disease may impair cortical activation, in part, through disfacilitation of BF cortically

  17. Cholinergic connectivity: it’s implications for psychiatric disorders.

    Directory of Open Access Journals (Sweden)

    Elizabeth eScarr

    2013-05-01

    Full Text Available Acetylcholine has been implicated in both the pathophysiology and treatment of a number of psychiatric disorders, with most of the data related to its role and therapeutic potential focussing on schizophrenia. However, there is little thought given to the consequences of the documented changes in the cholinergic system and how they may affect the functioning of the brain. This review looks at the cholinergic system and its interactions with the intrinsic neurotransmitters glutamate and gamma-amino butyric acid as well as those with the projection neurotransmitters most implicated in the pathophysiologies of psychiatric disorders; dopamine and serotonin. In addition, with the recent focus on the role of factors normally associated with inflammation in the pathophysiologies of psychiatric disorders, links between the cholinergic system and these factors will also be examined. These interfaces are put into context, primarily for schizophrenia, by looking at the changes in each of these systems in the disorder and exploring, theoretically, whether the changes are interconnected with those seen in the cholinergic system. Thus, this review will provide a comprehensive overview of the connectivity between the cholinergic system and some of the major areas of research into the pathophysiologies of psychiatric disorders, resulting in a critical appraisal of the potential outcomes of a dysregulated central cholinergic system.

  18. Central Vestibular Dysfunction in an Otorhinolaryngological Vestibular Unit: Incidence and Diagnostic Strategy

    OpenAIRE

    2014-01-01

    Introduction  Vertigo can be due to a variety of central and peripheral causes. The relative incidence of central causes is underestimated. This may have an important impact of the patients' management and prognosis. Objective  The objective of this work is to determine the incidence of central vestibular disorders in patients presenting to a vestibular unit in a tertiary referral academic center. It also aims at determining the best strategy to increase the diagnostic yield of th...

  19. Cytosolic triglycerides and oxidative stress in central obesity : the missing link between excessive atherosclerosis, endothelial dysfunction, and beta-cell failure?

    NARCIS (Netherlands)

    Bakker, SJL; IJzerman, RG; Teerlink, T; Westerhoff, HV; Gans, ROB; Heine, RJ

    2000-01-01

    Central obesity is increasingly recognized as a risk factor for atherosclerosis and type 2 diabetes mellitus. Here we present a hypothesis that may explain the excess atherosclerosis, endothelial dysfunction and progressive beta-cell failure. Central obesity is associated with increased cytosolic tr

  20. Cytosolic triglycerides and oxidative stress in central obesity : the missing link between excessive atherosclerosis, endothelial dysfunction, and beta-cell failure?

    NARCIS (Netherlands)

    Bakker, SJL; IJzerman, RG; Teerlink, T; Westerhoff, HV; Gans, ROB; Heine, RJ

    2000-01-01

    Central obesity is increasingly recognized as a risk factor for atherosclerosis and type 2 diabetes mellitus. Here we present a hypothesis that may explain the excess atherosclerosis, endothelial dysfunction and progressive beta-cell failure. Central obesity is associated with increased cytosolic tr

  1. Hemispheric Lateralization of Bilaterally Presented Homologous Visual and Auditory Stimuli in Normal Adults, Normal Children, and Children with Central Auditory Dysfunction

    Science.gov (United States)

    Bellis, Teri James; Billiet, Cassie; Ross, Jody

    2008-01-01

    Two experiments were conducted to examine the performance of normal adults, normal children, and children diagnosed with central auditory dysfunction presumed to involve the interhemispheric pathways on a dichotic digits test in common clinical use for the diagnosis of central auditory processing disorder (CAPD) and its corresponding visual…

  2. [Cholinergic system of the heart].

    Science.gov (United States)

    Kučera, Matej; Hrabovská, Anna

    2015-12-01

    The cholinergic system of the heart can be either of neuronal or non-neuronal origin. The neuronal cholinergic system in the heart is represented by preganglionic parasympathetic pathways, intracardiac parasympathetic ganglia and postganglionic parasympathetic neurons projecting to the atria, SA node and AV node. The non-neuronal cholinergic system consists of cardiomyocytes that have complete equipment for synthesis and secretion of acetylcholine. Current knowledge suggests that the non-neuronal cholinergic system in the heart affects the regulation of the heart during sympathetic activation. The non-neuronal cholinergic system of the heart plays also a role in the energy metabolism of cardimyocites. Acetylcholine of both neuronal and non-neuronal origin acts in the heart through muscarinic and nicotinic receptors. The effect of acetylcholine in the heart is terminated by cholinesterases acetylcholinesterase and butyrylcholinesterase. Recently, papers suggest that the increased cholinergic tone in the heart by cholinesterase inhibitors has a positive effect on some cardiovascular disorders such as heart failure. For this reason, the cholinesterase inhibitors might be used in the treatment of certain cardiovascular disorders in the future.

  3. Dysfunctional astrocytes as key players in the pathogenesis of central nervous system disorders

    NARCIS (Netherlands)

    De Keyser, Jacques; Mostert, Jop P.; Koch, Marcus W.

    2008-01-01

    Once considered little more than the glue that holds neurons in place, astrocytes are now becoming appreciated for the key roles they play in central nervous system functions. They supply neurons and oligodendrocytes with substrates for energy metabolism, control extracellular water and electrolyte

  4. Dysfunctional astrocytes as key players in the pathogenesis of central nervous system disorders

    NARCIS (Netherlands)

    De Keyser, Jacques; Mostert, Jop P.; Koch, Marcus W.

    2008-01-01

    Once considered little more than the glue that holds neurons in place, astrocytes are now becoming appreciated for the key roles they play in central nervous system functions. They supply neurons and oligodendrocytes with substrates for energy metabolism, control extracellular water and electrolyte

  5. [Modulation of the cholinergic system during inflammation].

    Science.gov (United States)

    Nezhinskaia, G I; Vladykin, A L; Sapronov, N S

    2008-01-01

    This review describes the effects of realization of the central and peripheral "cholinergic antiinflammatory pathway" in a model of endotoxic and anaphylactic shock. Under endotoxic shock conditions, a pharmacological correction by means of the central m-cholinomimetic action (electrical stimulation of the distal ends of nervus vagus after bilateral cervical vagotomy, surgical implantation of the stimulant devise, activation of efferent vagal neurons by means of muscarinic agonist) is directed toward the elimination of LPS-induced hypotension. During the anaphylaxis, peripheral effects of the cholinergic system induced by blocking m-AChR on the target cells (neuronal and non-neuronal lung cells) and acetylcholinesterase inhibition are related to suppression of the bronchoconstrictor response. The role of immune system in the pathogenesis of endotoxic shock is associated with the production of proinflammatory cytokines by macrophages, increase in IgM concentration, and complement activation, while the role in the pathogenesis of anaphylactic shock is associated with IgE, IgG1 augmentation. Effects of B cell stimulation may be important in hypoxia and in the prophylaxis of stress ulcers and other diseases. Plasma proteins can influence the effects of the muscarinic antagonist methacine: IgG enhance its action while albumin and CRP abolish it.

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

    Directory of Open Access Journals (Sweden)

    Dawe Gavin S

    2009-06-01

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

  7. Physical urticarias and cholinergic urticaria.

    Science.gov (United States)

    Abajian, Marina; Schoepke, Nicole; Altrichter, Sabine; Zuberbier, Torsten; Zuberbier, H C Torsten; Maurer, Marcus

    2014-02-01

    Physical urticarias are a unique subgroup of chronic urticaria in which urticarial responses can be reproducibly induced by different specific physical stimuli acting on the skin. These conditions include urticaria factitia/symptomatic dermographism, delayed pressure urticaria, cold contact urticaria, heat contact urticaria, solar urticaria, and vibratory urticaria/angioedema. Physical urticarias and cholinergic urticarias are diagnosed based on the patients' history and provocation tests including trigger threshold testing where possible. Treatment is mainly symptomatic. Many patients benefit from avoiding eliciting triggers, and desensitization to these triggers can be helpful in some physical urticarias and in cholinergic urticaria.

  8. Central plasticity and dysfunction elicited by aural deprivation in the critical period.

    Science.gov (United States)

    Chen, Zhiji; Yuan, Wei

    2015-01-01

    The acoustic signal is crucial for animals to obtain information from the surrounding environment. Like other sensory modalities, the central auditory system undergoes adaptive changes (i.e., plasticity) during the developmental stage as well as other stages of life. Owing to its plasticity, auditory centers may be susceptible to various factors, such as medical intervention, variation in ambient acoustic signals and lesion of the peripheral hearing organ. There are critical periods during which auditory centers are vulnerable to abnormal experiences. Particularly in the early postnatal development period, aural inputs are essential for functional maturity of auditory centers. An aural deprivation model, which can be achieved by attenuating or blocking the peripheral acoustic afferent input to the auditory center, is ideal for investigating plastic changes of auditory centers. Generally, auditory plasticity includes structural and functional changes, some of which can be irreversible. Aural deprivation can distort tonotopic maps, disrupt the binaural integration, reorganize the neural network and change the synaptic transmission in the primary auditory cortex or at lower levels of the auditory system. The regulation of specific gene expression and the modified signal pathway may be the deep molecular mechanism of these plastic changes. By studying this model, researchers may explore the pathogenesis of hearing loss and reveal plastic changes of the auditory cortex, facilitating the therapeutic advancement in patients with severe hearing loss. After summarizing developmental features of auditory centers in auditory deprived animals and discussing changes of central auditory remodeling in hearing loss patients, we aim at stressing the significant of an early and well-designed auditory training program for the hearing rehabilitation.

  9. Cholinergic systems are essential for late-stage maturation and refinement of motor cortical circuits.

    Science.gov (United States)

    Ramanathan, Dhakshin S; Conner, James M; Anilkumar, Arjun A; Tuszynski, Mark H

    2015-03-01

    Previous studies reported that early postnatal cholinergic lesions severely perturb early cortical development, impairing neuronal cortical migration and the formation of cortical dendrites and synapses. These severe effects of early postnatal cholinergic lesions preclude our ability to understand the contribution of cholinergic systems to the later-stage maturation of topographic cortical representations. To study cholinergic mechanisms contributing to the later maturation of motor cortical circuits, we first characterized the temporal course of cortical motor map development and maturation in rats. In this study, we focused our attention on the maturation of cortical motor representations after postnatal day 25 (PND 25), a time after neuronal migration has been accomplished and cortical volume has reached adult size. We found significant maturation of cortical motor representations after this time, including both an expansion of forelimb representations in motor cortex and a shift from proximal to distal forelimb representations to an extent unexplainable by simple volume enlargement of the neocortex. Specific cholinergic lesions placed at PND 24 impaired enlargement of distal forelimb representations in particular and markedly reduced the ability to learn skilled motor tasks as adults. These results identify a novel and essential role for cholinergic systems in the late refinement and maturation of cortical circuits. Dysfunctions in this system may constitute a mechanism of late-onset neurodevelopmental disorders such as Rett syndrome and schizophrenia.

  10. Sex differences in brain cholinergic activity in MSG-obese rats submitted to exercise.

    Science.gov (United States)

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

    2011-11-01

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

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

    Directory of Open Access Journals (Sweden)

    Costa eVakalopoulos

    2013-11-01

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

  12. Both pre- and post-synaptic alterations contribute to aberrant cholinergic transmission in superior cervical ganglia of APP(-/-) mice.

    Science.gov (United States)

    Cai, Zhao-Lin; Zhang, Jia-Jia; Chen, Ming; Wang, Jin-Zhao; Xiao, Peng; Yang, Li; Long, Cheng

    2016-11-01

    Though amyloid precursor protein (APP) can potentially be cleaved to generate the pathological amyloid β peptide (Aβ), APP itself plays an important role in regulating neuronal activity. APP deficiency causes functional impairment in cholinergic synaptic transmission and cognitive performance. However, the mechanisms underlying altered cholinergic synaptic transmission in APP knock-out mice (APP(-/-)) are poorly understood. In this study, we conducted in vivo extracellular recording to investigate cholinergic compound action potentials (CAPs) of the superior cervical ganglion (SCG) in APP(-/-) and littermate wild-type (WT) mice. Our results demonstrate that APP not only regulates presynaptic activity, but also affects postsynaptic function at cholinergic synapses in SCG. APP deficiency reduces the number of vesicles in presynaptic terminalsand attenuatesthe amplitude of CAPs, likely due to dysfunction of high-affinity choline transporters. Pharmacological and biochemical examination showed that postsynaptic responsesmediated by α4β2 and α7 nicotinic acetylcholine receptors are reduced in the absence of APP. Our research provides evidences on how APP regulates cholinergic function and therefore may help to identify potential therapeutic targets to treat cholinergic dysfunction associated with Alzheimer's disease pathogenesis.

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

    Directory of Open Access Journals (Sweden)

    Kevin P Grace

    2015-09-01

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

  14. Evaluating the Evidence Surrounding Pontine Cholinergic Involvement in REM Sleep Generation.

    Science.gov (United States)

    Grace, Kevin P; Horner, Richard L

    2015-01-01

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

  15. Acute and chronic effects of clozapine on cholinergic transmission in cultured mouse superior cervical ganglion neurons.

    Science.gov (United States)

    Saur, Taixiang; Cohen, Bruce M; Ma, Qi; Babb, Suzann M; Buttner, Edgar A; Yao, Wei-Dong

    Cholinergic dysfunction contributes to cognitive deficits in schizophrenia. The atypical antipsychotic clozapine improves cognition in patients with schizophrenia, possibly through modulation of the cholinergic system. However, little is known about specific underlying mechanisms. We investigated the acute and chronic effects of clozapine on cholinergic synaptic transmission in cultured superior cervical ganglion (SCG) neurons. Spontaneous excitatory postsynaptic currents (sEPSCs) were detected and were reversibly inhibited by the nicotinic receptor antagonist d-tubocurarine, confirming that the synaptic responses were primarily mediated by nicotinic receptors. Bath application of clozapine at therapeutic concentrations rapidly and reversely inhibited both the amplitude and frequency of sEPSCs in a concentration-dependent manner, without changing either rise or decay time, suggesting that clozapine effects have both presynaptic and postsynaptic origins. The acute effects of clozapine on sEPSCs were recapitulated by chronic treatment of SCG cultures with similar concentrations of clozapine, as clozapine treatment for 4 d reduced the frequency and amplitude of sEPSCs without affecting their kinetics. Cell survival analysis indicated that SCG neuron cell counts after chronic clozapine treatment were comparable to the control group. These results demonstrate that therapeutic concentrations of clozapine suppress nicotinic synaptic transmission in SCG cholinergic synapses, a simple in vitro preparation of cholinergic transmission.

  16. Dysfunctional Neurotransmitter Systems in Fibromyalgia, Their Role in Central Stress Circuitry and Pharmacological Actions on These Systems

    Directory of Open Access Journals (Sweden)

    Susanne Becker

    2012-01-01

    Full Text Available Fibromyalgia is considered a stress-related disorder, and hypo- as well as hyperactive stress systems (sympathetic nervous system and hypothalamic-pituitary-adrenal axis have been found. Some observations raise doubts on the view that alterations in these stress systems are solely responsible for fibromyalgia symptoms. Cumulative evidence points at dysfunctional transmitter systems that may underlie the major symptoms of the condition. In addition, all transmitter systems found to be altered in fibromyalgia influence the body's stress systems. Since both transmitter and stress systems change during chronic stress, it is conceivable that both systems change in parallel, interact, and contribute to the phenotype of fibromyalgia. As we outline in this paper, subgroups of patients might exhibit varying degrees and types of transmitter dysfunction, explaining differences in symptomatoloy and contributing to the heterogeneity of fibromyalgia. The finding that not all fibromyalgia patients respond to the same medications, targeting dysfunctional transmitter systems, further supports this hypothesis.

  17. PET study of cholinergic system in the brain

    Energy Technology Data Exchange (ETDEWEB)

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

    1999-01-01

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

  18. Cholinergic degeneration is associated with increased plaque deposition and cognitive impairment in APPswe/PS1dE9 mice

    DEFF Research Database (Denmark)

    Laursen, Bettina; Mørk, Arne; Plath, Niels

    2013-01-01

    Cholinergic dysfunction and deposition of plaques containing amyloid ß-peptides (Aß) are two of the characteristics of Alzheimer's disease. Here, we combine APPswe/PS1dE9 (APP/PS1) mice with the cholinergic immunotoxin mu p75-saporin (SAP) to integrate partial basal forebrain cholinergic degenera......Cholinergic dysfunction and deposition of plaques containing amyloid ß-peptides (Aß) are two of the characteristics of Alzheimer's disease. Here, we combine APPswe/PS1dE9 (APP/PS1) mice with the cholinergic immunotoxin mu p75-saporin (SAP) to integrate partial basal forebrain cholinergic...... APP/PS1 mice in a behavioural paradigm addressing working memory. Conversely, the performance of Wt mice was unaffected by SAP treatment. Choline acetyltransferase activity was reduced in the hippocampus and frontal cortex following SAP treatment. The selective effect of a mild SAP lesion in APP/PS1...... mice was not due to a more extensive cholinergic degeneration since the reduction in choline acetyltransferase activity was similar following SAP treatment in APP/PS1 mice and Wt. Interestingly, plaque load was significantly increased in SAP treated APP/PS1 mice relative to sham lesioned APP/PS1 mice...

  19. Developmental specification of forebrain cholinergic neurons.

    Science.gov (United States)

    Allaway, Kathryn C; Machold, Robert

    2017-01-01

    Striatal cholinergic interneurons and basal forebrain cholinergic projection neurons, which together comprise the forebrain cholinergic system, regulate attention, memory, reward pathways, and motor activity through the neuromodulation of multiple brain circuits. The importance of these neurons in the etiology of neurocognitive disorders has been well documented, but our understanding of their specification during embryogenesis is still incomplete. All forebrain cholinergic projection neurons and interneurons appear to share a common developmental origin in the embryonic ventral telencephalon, a region that also gives rise to GABAergic projection neurons and interneurons. Significant progress has been made in identifying the key intrinsic and extrinsic factors that promote a cholinergic fate in this precursor population. However, how cholinergic interneurons and projection neurons differentiate from one another during development, as well as how distinct developmental programs contribute to heterogeneity within those two classes, is not yet well understood. In this review we summarize the transcription factors and signaling molecules known to play a role in the specification and early development of striatal and basal forebrain cholinergic neurons. We also discuss the heterogeneity of these populations and its possible developmental origins. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Intermittent hypoxia from obstructive sleep apnea may cause neuronal impairment and dysfunction in central nervous system: the potential roles played by microglia

    Directory of Open Access Journals (Sweden)

    Yang Q

    2013-08-01

    Full Text Available Qingchan Yang,1,* Yan Wang,2,* Jing Feng,2 Jie Cao,2 Baoyuan Chen2 1Graduate School of Tianjin Medical University, 2Respiratory Department, Tianjin Medical University General Hospital, Tianjin, People's Republic of China *These authors contributed equally to this work Abstract: Obstructive sleep apnea (OSA is a common condition characterized by repetitive episodes of complete (apnea or partial (hypopnea obstruction of the upper airway during sleep, resulting in oxygen desaturation and arousal from sleep. Intermittent hypoxia (IH resulting from OSA may cause structural neuron damage and dysfunction in the central nervous system (CNS. Clinically, it manifests as neurocognitive and behavioral deficits with oxidative stress and inflammatory impairment as its pathophysiological basis, which are mediated by microglia at the cellular level. Microglia are dominant proinflammatory cells in the CNS. They induce CNS oxidative stress and inflammation, mainly through mitochondria, reduced nicotinamide adenine dinucleotide phosphate oxidase, and the release of excitatory toxic neurotransmitters. The balance between neurotoxic versus protective and anti- versus proinflammatory microglial factors might determine the final roles of microglia after IH exposure from OSA. Microglia inflammatory impairments will continue and cascade persistently upon activation, ultimately resulting in clinically significant neuron damage and dysfunction in the CNS. In this review article, we summarize the mechanisms of structural neuron damage in the CNS and its concomitant dysfunction due to IH from OSA, and the potential roles played by microglia in this process. Keywords: intermittent hypoxia, obstructive sleep apnea, microglia, inflammation, apoptosis

  1. Neurogenic bowel dysfunction in patients with spinal cord injury, myelomeningocele, multiple sclerosis and Parkinson's disease

    Institute of Scientific and Technical Information of China (English)

    Richard A Awad

    2011-01-01

    Exciting new features have been described concerning neurogenic bowel dysfunction, including interactions between the central nervous system, the enteric nervous system, axonal injury, neuronal loss, neurotransmission of noxious and non-noxious stimuli, and the fields of gastroenterology and neurology. Patients with spinal cord injury, myelomeningocele, multiple sclerosis and Parkinson's disease present with serious upper and lower bowel dysfunctions characterized by constipation, incontinence, gastrointestinal motor dysfunction and altered visceral sensitivity. Spinal cord injury is associated with severe autonomic dysfunction, and bowel dysfunction is a major physical and psychological burden for these patients. An adult myelomeningocele patient commonly has multiple problems reflecting the multisystemic nature of the disease. Multiple sclerosis is a neurodegenerative disorder in which axonal injury, neuronal loss, and atrophy of the central nervous system can lead to permanent neurological damage and clinical disability. Parkinson's disease is a multisystem disorder involving dopaminergic, noradrenergic, serotoninergic and cholinergic systems, characterized by motor and non-motor symptoms. Parkinson's disease affects several neuronal structures outside the substantia nigra, among which is the enteric nervous system. Recent reports have shown that the lesions in the enteric nervous system occur in very early stages of the disease, even before the involvement of the central nervous system. This has led to the postulation that the enteric nervous system could be critical in the pathophysiology of Parkinson's disease, as it could represent the point of entry for a putative environmental factor to initiate the pathological process. This review covers the data related to the etiology, epidemiology, clinical expression, pathophysiology, genetic aspects, gastrointestinal motor dysfunction, visceral sensitivity, management, prevention and prognosis of neurogenic bowel

  2. Evaluation of cholinergic markers in Alzheimer's disease and in a model of cholinergic deficit

    OpenAIRE

    2005-01-01

    Cognitive deficits in neuropsychiatric disorders, such as Alzheimer's disease (AD), have been closely related to cholinergic deficits. We have compared different markers of cholinergic function to assess the best biomarker of cognitive deficits associated to cholinergic hypoactivity. In post-mortem frontal cortex from AD patients, acetylcholine (ACh) levels, cholinacetyltransferase (ChAT) and acetylcholinesterase (AChE) activity were all reduced compared to controls. Both ChAT and AChE activi...

  3. White Matter Damage in the Cholinergic System Contributes to Cognitive Impairment in Subcortical Vascular Cognitive Impairment, No Dementia

    Science.gov (United States)

    Liu, Qing; Zhu, Zude; Teipel, Stefan J.; Yang, Jianwei; Xing, Yi; Tang, Yi; Jia, Jianping

    2017-01-01

    Cholinergic deficiency has been implicated in the pathogenesis of vascular cognitive impairment (VCI), but the extent of involvement and underlying mechanism remain unclear. In this study, targeting the early stage of VCI, we determined regional atrophy within the basal forebrain and deficiency in cholinergic pathways in 25 patients with vascular cognitive impairment no dementia (VCIND) compared to 24 healthy elderly subjects. By applying stereotaxic cytoarchitectonic maps of the nucleus basalis of Meynert (NbM), no significant atrophy was identified in VCIND. Using probabilistic tractography analysis, our study tracked the two major white matter tracks which map to cholinergic pathways. We identified significantly lower fractional anisotropy (FA) in VCIND. Mediation analysis demonstrated that FA in the tracked pathways could fully account for the executive dysfunction, and partly mediate the memory and global cognition impairment. Our study suggests that the fibers mapped to the cholinergic pathways, but not the NbM, are significantly impaired in VCIND. MRI-based in vivo tracking of cholinergic pathways together with NbM measurement may become a valuable in vivo marker for evaluating the cholinergic system in cognitive disorders. PMID:28289381

  4. Dysfunction of subtelomeric methylation and telomere length in gallstone disease and gallbladder cancer patients of North Central India.

    Science.gov (United States)

    Poojary, Satish S; Mishra, Gunja; Gupta, Sanjiv; Shrivastav, Braj Raj; Tiwari, Pramod Kumar

    2016-05-01

    Telomeres play an important role in cancer progression. Recently it has been shown that subtelomeric methylation negatively regulates telomere length in various diseases, including cancers. Here, we evaluated the influence of subtelomeric methylation in telomere dysfunction in gallbladder cancer (GBC), and whether this dysfunction is affected by the presence of gallstones. Relative telomere length and subtelomeric methylation levels were assessed using monochrome multiplex quantitative polymerase chain reaction and bisulfite sequencing, respectively, in different gallbladder tissue types including different grades of GBC, gallstones and adjacent non-tumor. We found telomere length to shorten significantly in overall GBC, but specifically in early grade cancer. We also found D4Z4 and DNF92 subtelomeric sequences to be hypermethylated and hypomethylated, respectively, in GBC; however, their methylation levels differed significantly, only in early grade cancer. We could not find any specific correlation between subtelomeric methylation and telomere length in GBC. Interestingly, telomere length and subtelomeric methylation differed significantly in GBC without gallstones but not in GBC with gallstones. This study, thus, suggests that telomere dysfunction and changes in methylation levels may occur earlier in the progression of GBC, while the presence of gallstones may have no influence on telomere length as well as on methylation levels. © 2016 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

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

    DEFF Research Database (Denmark)

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

    2004-01-01

    Aspirin and paracetamol have been shown to suppress non-inflammatory pain conditions like thermal, visceral and mechanical pain in mice and rats. The non-inflammatory antinociception appears to be mediated by central receptor mechanisms, such as the cholinergic system. In this study, we tested th...

  6. Gastrointestinal dysfunction and dopaminergic, cholinergic neurotransmitte changes of myenteric plexus in a rodent model of Parkinson' s disease%帕金森病大鼠胃肠功能障碍和肌间神经丛多巴胺能、胆碱能神经递质的变化

    Institute of Scientific and Technical Information of China (English)

    朱红灿; 赵静; 段东晓; 罗常月; 李倩倩; 张华; 任秀花; 臧卫东

    2011-01-01

    Objective To observe the gastrointestinal dysfunction and the changes of dopaminergic and cholinergic neurons in the myenteric plexuses of Sprague-Dawley (SD) rats model with parkinson' s disease (PD). Methods A rat model of PD was induced by 6-hydroxydopamine (6-OHDA). The one-h fecal output, stool water content and residual solid food in the stomach at 2 h after feeding were measured.Contractile activity of isolated antrum and colon smooth muscle were recorded. Changes in tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT) in the gastrointestinal myenteric plexus were studied by immunohistochemistry. Changes in TH and ChAT mRNA levels in the gastric antrum and colon tissue were determined by reverse transcription-polymerase chain reaction ( RT-PCR). Results In the 6-OHDA group, the wet weight, dry weight and water content of the feces within 1 h were (1. 047 ± 0. 124) g,(0. 812 ±0.093) g, (22.442 ±1. 180)% respectively, which were lower than in the control group (P<0.01); The percentage of residual solid food was (72. 316 ±3. 834)% , that was higher than in the control group (P <0. 01); The contractile amplitude of gastric antrum and colon smooth muscle strips was (0. 824 ±0. 152) g and (1. 541 ±0. 103) g respectively, that were lower than in the control group (P <0.01);The average integrated absorbance values of TH-positive areas in the myenteric plexus of gastric antrum and colon tissue were 147. 74 ± 13. 92 and 150. 45 ± 10. 09 respectively, that were higher than in the control group (P <0. 01); There was no significant difference in ChAT immunoreactivity between 6-OHDA group (109. 36 ± 3. 37 and 104. 73 ± 5. 93) and control group ( P > 0. 05); The mRNA expression levels of TH in the gastric antrum and colon tissue were 0. 662 ±0. 011 and 0. 585 ±0.012 respectively, that were lower than in the control group (P < 0. 01). There was no significant difference in ChAT mRNA expression levels between 6-OHDA group (1.157 ± 0. 037

  7. Illuminating the role of cholinergic signaling in circuits of attention and emotionally salient behaviors

    Directory of Open Access Journals (Sweden)

    Antonio eLuchicchi

    2014-10-01

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

  8. The cholinergic REM induction test with RS 86 after scopolamine pretreatment in healthy subjects.

    Science.gov (United States)

    Riemann, D; Hohagen, F; Fleckenstein, P; Schredl, M; Berger, M

    1991-09-01

    A shortened latency of rapid eye movement (REM) sleep is one of the most stable biological abnormalities described in depressive patients. According to the reciprocal interaction model of non-REM and REM sleep regulation, REM sleep disinhibition at the beginning of the night in depression is a consequence of heightened central nervous system cholinergic transmitter activity in relation to aminergic transmitter activity. A recent study has indicated that muscarinic supersensitivity, rather than quantitatively enhanced cholinergic activity, may be the primary cause of REM sleep abnormalities in depression. The present study tested this hypothesis by treating healthy volunteers for 3 days with a cholinergic antagonist (scopolamine) in the morning, in an effort to induce muscarinic receptor supersensitivity. On the last day of scopolamine administration, RS 86, an orally active cholinergic agonist, was administered before bedtime to test whether this procedure would induce sleep onset REM periods. Whereas scopolamine treatment tended to advance REM sleep and to heighten REM density in healthy controls in comparison to NaCl administration, the additional cholinergic stimulation did not provoke further REM sleep disinhibition. This result underlines the need to take a hypofunction of aminergic transmitter systems into account in attempts to explain the pronounced advance of REM sleep typically seen in depressives.

  9. Inflammatory bowel diseases: a dysfunction of brain-gut interactions?

    Science.gov (United States)

    Bonaz, B

    2013-09-01

    The gut has the capacity to function as an autonomous organ. However, in normal conditions, the gut and the central nervous system talk to each other through the autonomic nervous system (ANS), represented by the sympathetic (i.e. the splanchnic nerves) and the parasympathetic nervous system (i.e. the vagus nerve and the sacral parasympathetic pelvic nerves). The brain is able to integrate inputs coming from the digestive tract inside a central autonomic network organized around the hypothalamus, limbic system and cerebral cortex and in return to modify the ANS and the hypothalamic pituitary adrenal axis (HPA axis). An abnormal functioning of these brain-gut interactions has been described in irritable bowel syndrome (IBS) classically considered as a biopsychosocial model where stress plays a promoting role. Inflammatory bowel diseases (IBD) result from an inappropriate inflammatory response to intestinal microbes in a genetically susceptible host. In this article we review the current knowledge on the possible involvement of a dysfunction of brain-gut interactions in the pathogeny of IBD as represented by a dysfunction of the ANS, an abnormal HPA axis and cholinergic anti-inflammatory pathway, a deleterious effect of stress and depression as well as an abnormal coupling of the prefrontal cortex-amygdala complex and an abnormal relation between the microbiota and the brain as pro-inflammatory factors. Therapeutic approaches with the aim to restore an equilibrium of these brain-gut interactions are of interest.

  10. Correlative study on the cognitive dysfunction of patients with myasthenia gravis

    Institute of Scientific and Technical Information of China (English)

    Wenli Chen; Wenmin Wang; Yi Wang

    2006-01-01

    BACKGROUND: Myasthenia gravis (MG) is considered as a peripheral neuromuscular disorder. Some investigations demonstrate that MG affects central nervous system (CNS), and there are disorders in cognitive function, affection, sleep, mental status and others; however, there are also some different standpoints. Some questions are still disputed, such as whether or not MG exists in the CNS and cognitive function is impaired.DATA SOURCES; Using the terms of "myasthenia gravis, neuropsychological test, memory, central, brain,cognitive dysfunction and so on", we searched the Medline database for the articles about CNS involved in MG, nerve and neuropsychology as well as cognitive function, which were published in the English language between January 198,5 and December 2004. Meanwhile, we also searched CNKI database by inputting "myasthenia gravis, neuropsychology and cognitive function" in Chinese for articles about involved neuropsychology and cognitive function which were published between October 1995 and June 2006 in the Chinese language.STUDY SElECTroN: Data were checked in the first trial, and articles about the influences of MG on CNS,neuropsychology, cognitive function and central cholinergic function were selected, then those were obviously unrelated with above criteria were excluded. Articles which expound the influences of MG on neuropsychology and cognitive were included, but those with repeated contents were also excluded.DATA EXTRACTTON: A total of 89 related English articles and 34 Chinese articles were collected, including 43studies on involved CNS and 32 studies on involved central cholinergic function and cholinergic receptor.Sixty-three literatures were about neuropsychology and cognitive function, which were closely related with this article. Seventy-two articles met inclusive criteria and 66 were excluded. Thirty of sevetty-two were chosen for analysis.DATA SYNTHESrs: MG is an autoimmune disease of muscular diseased fatigue induced by transmission

  11. Dysautonomia due to reduced cholinergic neurotransmission causes cardiac remodeling and heart failure.

    Science.gov (United States)

    Lara, Aline; Damasceno, Denis D; Pires, Rita; Gros, Robert; Gomes, Enéas R; Gavioli, Mariana; Lima, Ricardo F; Guimarães, Diogo; Lima, Patricia; Bueno, Carlos Roberto; Vasconcelos, Anilton; Roman-Campos, Danilo; Menezes, Cristiane A S; Sirvente, Raquel A; Salemi, Vera M; Mady, Charles; Caron, Marc G; Ferreira, Anderson J; Brum, Patricia C; Resende, Rodrigo R; Cruz, Jader S; Gomez, Marcus Vinicius; Prado, Vania F; de Almeida, Alvair P; Prado, Marco A M; Guatimosim, Silvia

    2010-04-01

    Overwhelming evidence supports the importance of the sympathetic nervous system in heart failure. In contrast, much less is known about the role of failing cholinergic neurotransmission in cardiac disease. By using a unique genetically modified mouse line with reduced expression of the vesicular acetylcholine transporter (VAChT) and consequently decreased release of acetylcholine, we investigated the consequences of altered cholinergic tone for cardiac function. M-mode echocardiography, hemodynamic experiments, analysis of isolated perfused hearts, and measurements of cardiomyocyte contraction indicated that VAChT mutant mice have decreased left ventricle function associated with altered calcium handling. Gene expression was analyzed by quantitative reverse transcriptase PCR and Western blotting, and the results indicated that VAChT mutant mice have profound cardiac remodeling and reactivation of the fetal gene program. This phenotype was attributable to reduced cholinergic tone, since administration of the cholinesterase inhibitor pyridostigmine for 2 weeks reversed the cardiac phenotype in mutant mice. Our findings provide direct evidence that decreased cholinergic neurotransmission and underlying autonomic imbalance cause plastic alterations that contribute to heart dysfunction.

  12. Mitochondrial dysfunction as a central actor in intellectual disability-related diseases: an overview of Down syndrome, autism, Fragile X and Rett syndrome.

    Science.gov (United States)

    Valenti, Daniela; de Bari, Lidia; De Filippis, Bianca; Henrion-Caude, Alexandra; Vacca, Rosa Anna

    2014-10-01

    Clinical manifestations typical of mitochondrial diseases are often present in various genetic syndromes associated with intellectual disability, a condition leading to deficit in cognitive functions and adaptive behaviors. Until now, the causative mechanism leading to intellectual disability is unknown and the progression of the condition is poorly understood. We first report latest advances on genetic and environmental regulation of mitochondrial function and its role in brain development. Starting from the structure, function and regulation of the oxidative phosphorylation apparatus, we review how mitochondrial biogenesis and dynamics play a central role in neurogenesis and neuroplasticity. We then discuss how dysfunctional mitochondria and alterations in reactive oxygen species homeostasis are potentially involved in the pathogenesis of various neurodevelopmental syndromes with a special focus on Down, Rett, Fragile X syndromes and autism spectrum disorders. Finally, we review and suggest novel therapeutic approaches aimed at improving intellectual disability by activating mitochondrial function and reducing oxidative stress to amiliorate the quality of life in the subjects affected.

  13. Decreased elastic energy storage, not increased material stiffness, characterizes central artery dysfunction in fibulin-5 deficiency independent of sex.

    Science.gov (United States)

    Ferruzzi, J; Bersi, M R; Uman, S; Yanagisawa, H; Humphrey, J D

    2015-03-01

    Central artery stiffness has emerged over the past 15 years as a clinically significant indicator of cardiovascular function and initiator of disease. Loss of elastic fiber integrity is one of the primary contributors to increased arterial stiffening in aging, hypertension, and related conditions. Elastic fibers consist of an elastin core and multiple glycoproteins; hence defects in any of these constituents can adversely affect arterial wall mechanics. In this paper, we focus on mechanical consequences of the loss of fibulin-5, an elastin-associated glycoprotein involved in elastogenesis. Specifically, we compared the biaxial mechanical properties of five central arteries-the ascending thoracic aorta, descending thoracic aorta, suprarenal abdominal aorta, infrarenal abdominal aorta, and common carotid artery-from male and female wild-type and fibulin-5 deficient mice. Results revealed that, independent of sex, all five regions in the fibulin-5 deficient mice manifested a marked increase in structural stiffness but also a marked decrease in elastic energy storage and typically an increase in energy dissipation, with all differences being most dramatic in the ascending and abdominal aortas. Given that the primary function of large arteries is to store elastic energy during systole and to use this energy during diastole to work on the blood, fibulin-5 deficiency results in a widespread diminishment of central artery function that can have significant effects on hemodynamics and cardiac function.

  14. Cholinergic regulation of the vasopressin neuroendocrine system

    Energy Technology Data Exchange (ETDEWEB)

    Michels, K.M.

    1987-01-01

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

  15. Cholinergic profiles in the Goettingen miniature pig (Sus scrofa domesticus) brain.

    Science.gov (United States)

    Mahady, Laura J; Perez, Sylvia E; Emerich, Dwaine F; Wahlberg, Lars U; Mufson, Elliott J

    2017-02-15

    Central cholinergic structures within the brain of the even-toed hoofed Goettingen miniature domestic pig (Sus scrofa domesticus) were evaluated by immunohistochemical visualization of choline acetyltransferase (ChAT) and the low-affinity neurotrophin receptor, p75(NTR) . ChAT-immunoreactive (-ir) perikarya were seen in the olfactory tubercle, striatum, medial septal nucleus, vertical and horizontal limbs of the diagonal band of Broca, and the nucleus basalis of Meynert, medial habenular nucleus, zona incerta, neurosecretory arcuate nucleus, cranial motor nuclei III and IV, Edinger-Westphal nucleus, parabigeminal nucleus, pedunculopontine nucleus, and laterodorsal tegmental nucleus. Cholinergic ChAT-ir neurons were also found within transitional cortical areas (insular, cingulate, and piriform cortices) and hippocampus proper. ChAT-ir fibers were seen throughout the dentate gyrus and hippocampus, in the mediodorsal, laterodorsal, anteroventral, and parateanial thalamic nuclei, the fasciculus retroflexus of Meynert, basolateral and basomedial amygdaloid nuclei, anterior pretectal and interpeduncular nuclei, as well as select laminae of the superior colliculus. Double immunofluorescence demonstrated that virtually all ChAT-ir basal forebrain neurons were also p75(NTR) -positive. The present findings indicate that the central cholinergic system in the miniature pig is similar to other mammalian species. Therefore, the miniature pig may be an appropriate animal model for preclinical studies of neurodegenerative diseases where the cholinergic system is compromised. J. Comp. Neurol. 525:553-573, 2017. © 2016 Wiley Periodicals, Inc.

  16. Rabbit Forebrain cholinergic system : Morphological characterization of nuclei and distribution of cholinergic terminals in the cerebral cortex and hippocampus

    NARCIS (Netherlands)

    Varga, C; Hartig, W; Grosche, J; Luiten, PGM; Seeger, J; Brauer, K; Harkany, T; Härtig, Wolfgang; Keijser, Jan N.

    2003-01-01

    Although the rabbit brain, in particular the basal forebrain cholinergic system, has become a common model for neuropathological changes associated with Alzheimer's disease, detailed neuroanatomical studies on the morphological organization of basal forebrain cholinergic nuclei and on their output p

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

    NARCIS (Netherlands)

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

    2011-01-01

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

  18. Cholinergic modulation of cognition: Insights from human pharmacological functional neuroimaging

    Science.gov (United States)

    Bentley, Paul; Driver, Jon; Dolan, Raymond J.

    2011-01-01

    Evidence from lesion and cortical-slice studies implicate the neocortical cholinergic system in the modulation of sensory, attentional and memory processing. In this review we consider findings from sixty-three healthy human cholinergic functional neuroimaging studies that probe interactions of cholinergic drugs with brain activation profiles, and relate these to contemporary neurobiological models. Consistent patterns that emerge are: (1) the direction of cholinergic modulation of sensory cortex activations depends upon top-down influences; (2) cholinergic hyperstimulation reduces top-down selective modulation of sensory cortices; (3) cholinergic hyperstimulation interacts with task-specific frontoparietal activations according to one of several patterns, including: suppression of parietal-mediated reorienting; decreasing ‘effort’-associated activations in prefrontal regions; and deactivation of a ‘resting-state network’ in medial cortex, with reciprocal recruitment of dorsolateral frontoparietal regions during performance-challenging conditions; (4) encoding-related activations in both neocortical and hippocampal regions are disrupted by cholinergic blockade, or enhanced with cholinergic stimulation, while the opposite profile is observed during retrieval; (5) many examples exist of an ‘inverted-U shaped’ pattern of cholinergic influences by which the direction of functional neural activation (and performance) depends upon both task (e.g. relative difficulty) and subject (e.g. age) factors. Overall, human cholinergic functional neuroimaging studies both corroborate and extend physiological accounts of cholinergic function arising from other experimental contexts, while providing mechanistic insights into cholinergic-acting drugs and their potential clinical applications. PMID:21708219

  19. GABAergic actions on cholinergic laterodorsal tegmental neurons

    DEFF Research Database (Denmark)

    Kohlmeier, K A; Kristiansen, Uffe

    2010-01-01

    Cholinergic neurons of the pontine laterodorsal tegmentum (LDT) play a critical role in regulation of behavioral state. Therefore, elucidation of mechanisms that control their activity is vital for understanding of how switching between wakefulness, sleep and anesthetic states is effectuated....... Therefore, we studied the actions of GABA agonists and antagonists on cholinergic LDT cells by performing patch clamp recordings in mouse brain slices. Under conditions where detection of Cl(-) -mediated events was optimized, GABA induced gabazine (GZ)-sensitive inward currents in the majority of LDT...

  20. Postnatal lead exposure and the cholinergic system: effects on cholinergically mediated behaviors and cholinergic development and plasticity in the hippocampus

    Energy Technology Data Exchange (ETDEWEB)

    Alfano, D.P.

    1982-01-01

    A review of previous evidence suggested the possibility of a functional association between the behavioral effect of early lead (Pb) exposure, hippocampal damage and cholinergic deficiency. To further assess this possibility, Long-Evans hooded rat pups were exposed to Pb for the first 25 postnatal days via the maternal milk. Beginning at 65 days of age, animals were tested on behavioral tasks sensitive to both Pb exposure and cholinergic deficiency. Exposure to both levels of Pb impaired passive avoidance acquisition and produced lower rates of spontaneous alternation. The anticholinergic scopolamine (0.4 mg/kg) impaired passive avoidance acquisition, lowered the rate of spontaneous alternation and decreased open field activity scores in control animals. At 30 days of age, the brains of High Pb and control animals were processed for acetylcholinesterase (AChE) histochemistry. Morphometric evaluation of the molecular layer of the hippocampal dentate gyrus indicated no effects of Pb on the development of the cholinergic innervation of this brain region. The results provide strong evidence for the involvement of deficient cholinergic functioning in the behavioral changes observed following postnatal Pb exposure. Further, these findings indicate that a decrease in neuroanatomical plasticity may be a critical brain mechanism underlying the learning deficits observed following exposure to Pb.

  1. Sleep pattern and learning in knockdown mice with reduced cholinergic neurotransmission

    Directory of Open Access Journals (Sweden)

    C.M. Queiroz

    2013-01-01

    Full Text Available Impaired cholinergic neurotransmission can affect memory formation and influence sleep-wake cycles (SWC. In the present study, we describe the SWC in mice with a deficient vesicular acetylcholine transporter (VAChT system, previously characterized as presenting reduced acetylcholine release and cognitive and behavioral dysfunctions. Continuous, chronic ECoG and EMG recordings were used to evaluate the SWC pattern during light and dark phases in VAChT knockdown heterozygous (VAChT-KDHET, n=7 and wild-type (WT, n=7 mice. SWC were evaluated for sleep efficiency, total amount and mean duration of slow-wave, intermediate and paradoxical sleep, as well as the number of awakenings from sleep. After recording SWC, contextual fear-conditioning tests were used as an acetylcholine-dependent learning paradigm. The results showed that sleep efficiency in VAChT-KDHET animals was similar to that of WT mice, but that the SWC was more fragmented. Fragmentation was characterized by an increase in the number of awakenings, mainly during intermediate sleep. VAChT-KDHET animals performed poorly in the contextual fear-conditioning paradigm (mean freezing time: 34.4±3.1 and 44.5±3.3 s for WT and VAChT-KDHET animals, respectively, which was followed by a 45% reduction in the number of paradoxical sleep episodes after the training session. Taken together, the results show that reduced cholinergic transmission led to sleep fragmentation and learning impairment. We discuss the results on the basis of cholinergic plasticity and its relevance to sleep homeostasis. We suggest that VAChT-KDHET mice could be a useful model to test cholinergic drugs used to treat sleep dysfunction in neurodegenerative disorders.

  2. Central arterial stiffness and diastolic dysfunction are associated with insulin resistance and abdominal obesity in young women but polycystic ovary syndrome does not confer additional risk.

    Science.gov (United States)

    Rees, E; Coulson, R; Dunstan, F; Evans, W D; Blundell, H L; Luzio, S D; Dunseath, G; Halcox, J P; Fraser, A G; Rees, D A

    2014-09-01

    Are arterial stiffness, carotid intima-media thickness and diastolic dysfunction increased in young women with polycystic ovary syndrome (PCOS) independently of the effects of obesity? Insulin resistance and central obesity are associated with subclinical cardiovascular dysfunction in young women, but a diagnosis of PCOS does not appear to confer additional risk at this age. Some studies have shown that young women with PCOS may have increased measures of cardiovascular risk, including arterial stiffness, carotid intima-media thickness and myocardial dysfunction. However, it is difficult to establish how much of this risk is due to PCOS per se and how much is due to obesity and insulin resistance, which are common in PCOS and themselves associated with greater vascular risk. This cross-sectional study comprised 84 women with PCOS and 95 healthy volunteers, aged 16-45 years. The study was conducted in a university hospital. Subjects underwent a comprehensive assessment of body composition (including computed tomography (CT) assessment of visceral fat; VF), measurements of arterial stiffness (aortic pulse wave velocity; aPWV), common carotid intima-media thickness (ccIMT), diastolic function (longitudinal tissue velocity; e':a') and endocrinological measures. A sample size of 80 in each group gave 80% power for detecting a difference of 0.45 m/s in aPWV or a difference of 0.25 in e':a'. After adjustment for age and body mass index (BMI), PCOS subjects had a greater insulin response (insulin area under the curve-IAUC) following glucose challenge (adjusted difference [AD] 35 900 pmol min/l, P obesity. Obesity thus represents the greatest modifiable risk factor for cardiovascular disease in young women with PCOS and lifestyle measures which target weight reduction are critical. This study received no specific grant support from any funding body. The authors have no conflicts of interest to declare. © The Author 2014. Published by Oxford University Press on behalf of

  3. Rabbit forebrain cholinergic system: morphological characterization of nuclei and distribution of cholinergic terminals in the cerebral cortex and hippocampus.

    Science.gov (United States)

    Varga, Csaba; Härtig, Wolfgang; Grosche, Jens; Keijser, Jan; Luiten, Paul G M; Seeger, Johannes; Brauer, Kurt; Harkany, Tibor

    2003-06-09

    Although the rabbit brain, in particular the basal forebrain cholinergic system, has become a common model for neuropathological changes associated with Alzheimer's disease, detailed neuroanatomical studies on the morphological organization of basal forebrain cholinergic nuclei and on their output pathways are still awaited. Therefore, we performed quantitative choline acetyltransferase (ChAT) immunocytochemistry to localize major cholinergic nuclei and to determine the number of respective cholinergic neurons in the rabbit forebrain. The density of ChAT-immunoreactive terminals in layer V of distinct neocortical territories and in hippocampal subfields was also measured. Another cholinergic marker, the low-affinity neurotrophin receptor (p75(NTR)), was also employed to identify subsets of cholinergic neurons. Double-immunofluorescence labeling of ChAT and p75(NTR), calbindin D-28k (CB), parvalbumin, calretinin, neuronal nitric oxide synthase (nNOS), tyrosine hydroxylase, or substance P was used to elucidate the neuroanatomical borders of cholinergic nuclei and to analyze the neurochemical complexity of cholinergic cell populations. Cholinergic projection neurons with heterogeneous densities were found in the medial septum, vertical and horizontal diagonal bands of Broca, ventral pallidum, and magnocellular nucleus basalis (MBN)/substantia innominata (SI) complex; cholinergic interneurons were observed in the caudate nucleus, putamen, accumbens nucleus, and olfactory tubercule, whereas the globus pallidus was devoid of cholinergic nerve cells. Cholinergic interneurons were frequently present in the hippocampus and to a lesser extent in cerebral cortex. Cholinergic projection neurons, except those localized in SI, abundantly expressed p75(NTR), and a subset of cholinergic neurons in posterior MBN was immunoreactive for CB and nNOS. A strict laminar distribution pattern of cholinergic terminals was recorded both in the cerebral cortex and in CA1-CA3 and dentate gyrus

  4. Central Serotonin-2A (5-HT2A Receptor Dysfunction in Depression and Epilepsy: The Missing Link?

    Directory of Open Access Journals (Sweden)

    Bruno Pierre Guiard

    2015-03-01

    Full Text Available 5-Hydroxytryptamine 2A receptors (5-HT2A-Rs are G-protein coupled receptors. In agreement with their location in the brain, they have been implicated not only in various central physiological functions including memory, sleep, nociception, eating and reward behaviors, but also in many neuropsychiatric disorders. Interestingly, a bidirectional link between depression and epilepsy is suspected since patients with depression and especially suicide attempters have an increased seizure risk, while a significant percentage of epileptic patients suffer from depression. Such epidemiological data led us to hypothesize that both pathologies may share common anatomical and neurobiological alteration of the 5-HT2A signaling. After a brief presentation of the pharmacological properties of the 5-HT2A-Rs, this review illustrates how these receptors may directly or indirectly control neuronal excitability in most networks involved in depression and epilepsy through interactions with the monoaminergic, GABAergic and glutamatergic neurotransmissions. It also synthetizes the preclinical and clinical evidence demonstrating the role of these receptors in antidepressant and antiepileptic responses.

  5. Effect of central muscarinic receptors on passive-avoidance learning deficits induced by prenatal pentylenetetrazol kindling in male offspring.

    Science.gov (United States)

    Pourmotabbed, A; Mahmoodi, G; Mahmoodi, S; Mohammadi-Farani, A; Nedaei, S E; Pourmotabbed, T; Pourmotabbed, T

    2014-10-24

    Occurrence of the epileptic seizures during gestation might affect the neurodevelopment of the fetus resulting in cognitive problems for the child later in life. We have previously reported that prenatal pentylenetetrazol (PTZ)-kindling induces learning and memory deficits in the children born to kindled mothers, later in life but the mechanisms involved in this processes are unknown. The cholinergic system plays a major role in learning and memory. The present study was performed to investigate the possible involvement of central muscarinic cholinergic receptors on learning and memory deficits induced by prenatal PTZ-kindling in male offspring. Pregnant Wistar rats were kindled by repetitive i.p. injection of 25mg/kg of PTZ on day 13 of their pregnancy. The effect of intracerebroventricular (ICV) microinjection of scopolamine and pilocarpine, muscarinic cholinergic receptors antagonist and agonist, respectively on passive-avoidance learning of pups were tested at 12weeks of age using shuttle-box apparatus. Our data showed that the retention latencies of pups that received scopolamine (2 or 3μg) were significantly reduced compared to those received normal saline (pkindled dams and suggest a central mechanism for the cognitive and memory dysfunction, associated with seizures during pregnancy.

  6. Evaluation of the radial artery applanation tonometry technology for continuous noninvasive blood pressure monitoring compared with central aortic blood pressure measurements in patients with multiple organ dysfunction syndrome.

    Science.gov (United States)

    Meidert, Agnes S; Huber, Wolfgang; Hapfelmeier, Alexander; Schöfthaler, Miriam; Müller, Johannes N; Langwieser, Nicolas; Wagner, Julia Y; Schmid, Roland M; Saugel, Bernd

    2013-12-01

    We compared blood pressure (BP) measurements obtained using radial artery applanation tonometry with invasive BP measurements using a catheter placed in the abdominal aorta through the femoral artery in patients with multiple organ dysfunction syndrome (MODS). In 23 intensive care unit patients with MODS, we simultaneously assessed BP values for 15 minutes per patient using radial artery applanation tonometry (T-Line TL-200 pro device; Tensys Medical Inc, San Diego, Calif) and the arterial catheter (standard-criterion technique). A total of 2879 averaged 10-beat epochs were compared using Bland-Altman plots. The mean difference ± SD (with corresponding 95% limits of agreement) between radial artery applanation tonometry-derived BP and invasively assessed BP was +1.0 ± 5.5 mm Hg (-9.9 to +11.8 mm Hg) for mean arterial pressure, -3.3 ± 11.2 mm Hg (-25.3 to +18.6 mm Hg) for systolic arterial pressure, and +4.9 ± 7.0 mm Hg (-8.8 to +18.6 mm Hg) for diastolic arterial pressure, respectively. In intensive care unit patients with MODS, mean arterial pressure and diastolic arterial pressure can be determined accurately and precisely using radial artery applanation tonometry compared with central aortic values obtained using a catheter placed in the abdominal aorta through the femoral artery. Although systolic arterial pressure could also be derived accurately, wider 95% limits of agreement suggest lower precision for determination of systolic arterial pressure. © 2013.

  7. Mitochondrial dysfunction and organophosphorus compounds

    Energy Technology Data Exchange (ETDEWEB)

    Karami-Mohajeri, Somayyeh [Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of); Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Kerman University of Medical Sciences, Kerman (Iran, Islamic Republic of); Abdollahi, Mohammad, E-mail: Mohammad.Abdollahi@UToronto.Ca [Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of)

    2013-07-01

    Organophosphorous (OPs) pesticides are the most widely used pesticides in the agriculture and home. However, many acute or chronic poisoning reports about OPs have been published in the recent years. Mitochondria as a site of cellular oxygen consumption and energy production can be a target for OPs poisoning as a non-cholinergic mechanism of toxicity of OPs. In the present review, we have reviewed and criticized all the evidences about the mitochondrial dysfunctions as a mechanism of toxicity of OPs. For this purpose, all biochemical, molecular, and morphological data were retrieved from various studies. Some toxicities of OPs are arisen from dysfunction of mitochondrial oxidative phosphorylation through alteration of complexes I, II, III, IV and V activities and disruption of mitochondrial membrane. Reductions of adenosine triphosphate (ATP) synthesis or induction of its hydrolysis can impair the cellular energy. The OPs disrupt cellular and mitochondrial antioxidant defense, reactive oxygen species generation, and calcium uptake and promote oxidative and genotoxic damage triggering cell death via cytochrome C released from mitochondria and consequent activation of caspases. The mitochondrial dysfunction induced by OPs can be restored by use of antioxidants such as vitamin E and C, alpha-tocopherol, electron donors, and through increasing the cytosolic ATP level. However, to elucidate many aspect of mitochondrial toxicity of Ops, further studies should be performed. - Highlights: • As a non-cholinergic mechanism of toxicity, mitochondria is a target for OPs. • OPs affect action of complexes I, II, III, IV and V in the mitochondria. • OPs reduce mitochondrial ATP. • OPs promote oxidative and genotoxic damage via release of cytochrome C from mitochondria. • OP-induced mitochondrial dysfunction can be restored by increasing the cytosolic ATP.

  8. Profound Olfactory Dysfunction in Myasthenia Gravis

    Science.gov (United States)

    Leon-Sarmiento, Fidias E.; Bayona, Edgardo A.; Bayona-Prieto, Jaime; Osman, Allen; Doty, Richard L.

    2012-01-01

    In this study we demonstrate that myasthenia gravis, an autoimmune disease strongly identified with deficient acetylcholine receptor transmission at the post-synaptic neuromuscular junction, is accompanied by a profound loss of olfactory function. Twenty-seven MG patients, 27 matched healthy controls, and 11 patients with polymiositis, a disease with peripheral neuromuscular symptoms analogous to myasthenia gravis with no known central nervous system involvement, were tested. All were administered the University of Pennsylvania Smell Identification Test (UPSIT) and the Picture Identification Test (PIT), a test analogous in content and form to the UPSIT designed to control for non-olfactory cognitive confounds. The UPSIT scores of the myasthenia gravis patients were markedly lower than those of the age- and sex-matched normal controls [respective means (SDs) = 20.15 (6.40) & 35.67 (4.95); p<0.0001], as well as those of the polymiositis patients who scored slightly below the normal range [33.30 (1.42); p<0.0001]. The latter finding, along with direct monitoring of the inhalation of the patients during testing, implies that the MG-related olfactory deficit is unlikely due to difficulties sniffing, per se. All PIT scores were within or near the normal range, although subtle deficits were apparent in both the MG and PM patients, conceivably reflecting influences of mild cognitive impairment. No relationships between performance on the UPSIT and thymectomy, time since diagnosis, type of treatment regimen, or the presence or absence of serum anti-nicotinic or muscarinic antibodies were apparent. Our findings suggest that MG influences olfactory function to the same degree as observed in a number of neurodegenerative diseases in which central nervous system cholinergic dysfunction has been documented. PMID:23082113

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

    Directory of Open Access Journals (Sweden)

    L M Jordan

    2014-11-01

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

  10. Coordinate High-Frequency Pattern of Stimulation and Calcium Levels Control the Induction of LTP in Striatal Cholinergic Interneurons

    Science.gov (United States)

    Bonsi, Paola; De Persis, Cristiano; Calabresi, Paolo; Bernardi, Giorgio; Pisani, Antonio

    2004-01-01

    Current evidence appoints a central role to cholinergic interneurons in modulating striatal function. Recently, a long-term potentiation (LTP) of synaptic transmission has been reported to occur in these neurons. The relationship between the pattern of cortico/thalamostriatal fibers stimulation, the consequent changes in the intracellular calcium…

  11. Cholinergic interneurons in the dorsal and ventral striatum: anatomical and functional considerations in normal and diseased conditions.

    Science.gov (United States)

    Gonzales, Kalynda K; Smith, Yoland

    2015-09-01

    Striatal cholinergic interneurons (ChIs) are central for the processing and reinforcement of reward-related behaviors that are negatively affected in states of altered dopamine transmission, such as in Parkinson's disease or drug addiction. Nevertheless, the development of therapeutic interventions directed at ChIs has been hampered by our limited knowledge of the diverse anatomical and functional characteristics of these neurons in the dorsal and ventral striatum, combined with the lack of pharmacological tools to modulate specific cholinergic receptor subtypes. This review highlights some of the key morphological, synaptic, and functional differences between ChIs of different striatal regions and across species. It also provides an overview of our current knowledge of the cellular localization and function of cholinergic receptor subtypes. The future use of high-resolution anatomical and functional tools to study the synaptic microcircuitry of brain networks, along with the development of specific cholinergic receptor drugs, should help further elucidate the role of striatal ChIs and permit efficient targeting of cholinergic systems in various brain disorders, including Parkinson's disease and addiction.

  12. Right Cervical Vagotomy Aggravates Viral Myocarditis in Mice Via the Cholinergic Anti-inflammatory Pathway

    Science.gov (United States)

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

    2017-01-01

    The autonomic nervous system dysfunction with increased sympathetic activity and withdrawal of vagal activity may play an important role in the pathogenesis of viral myocarditis. The vagus nerve can modulate the immune response and control inflammation through a ‘cholinergic anti-inflammatory pathway’ dependent on the α7-nicotinic acetylcholine receptor (α7nAChR). Although the role of β-adrenergic stimulation on viral myocarditis has been investigated in our pervious studies, the direct effect of vagal tone in this setting has not been yet studied. Therefore, in the present study, we investigated the effects of cervical vagotomy in a murine model of viral myocarditis. In a coxsackievirus B3 murine myocarditis model (Balb/c), effects of right cervical vagotomy and nAChR agonist nicotine on echocardiography, myocardial histopathology, viral RNA, and proinflammatory cytokine levels were studied. We found that right cervical vagotomy inhibited the cholinergic anti-inflammatory pathway, aggravated myocardial lesions, up-regulated the expression of TNF-α, IL-1β, and IL-6, and worsened the impaired left ventricular function in murine viral myocarditis, and these changes were reversed by co-treatment with nicotine by activating the cholinergic anti-inflammatory pathway. These results indicate that vagal nerve plays an important role in mediating the anti-inflammatory effect in viral myocarditis, and that cholinergic stimulation with nicotine also plays its peripheral anti-inflammatory role relying on α7nAChR, without requirement for the integrity of vagal nerve in the model. The findings suggest that vagus nerve stimulation mediated inhibition of the inflammatory processes likely provide important benefits in myocarditis treatment. PMID:28197102

  13. Acetylcholinesterase loosens the brain's cholinergic anti-inflammatory response and promotes epileptogenesis

    Directory of Open Access Journals (Sweden)

    Yehudit eGnatek

    2012-05-01

    Full Text Available Recent studies show a key role of brain inflammation in epilepsy. However, the mechanisms controlling brain immune response are only partly understood. In the periphery, acetylcholine (ACh release by the vagus nerve restrains inflammation by inhibiting the activation of leukocytes. Recent reports suggested a similar anti-inflammatory effect for ACh in the brain. Since brain cholinergic dysfunction are documented in epileptic animals, we explored changes in brain cholinergic gene expression and associated immune response during pilocarpine-induced epileptogenesis. Levels of acetylcholinesterase (AChE and inflammatory markers were measured using real-time RT-PCR, in-situ hybridization and immunostaining in wild type (WT and transgenic mice over-expressing the "synaptic" splice variant AChE-S (TgS. One month following pilocarpine, mice were video-monitored for spontaneous seizures. To test directly the effect of ACh on the brain's innate immune response, cytokines expression levels were measured in acute brain slices treated with cholinergic agents. We report a robust upregulation of AChE as early as 48 hrs following pilocarpine-induced status epilepticus (SE. AChE was expressed in hippocampal neurons, microglia and endothelial cells but rarely in astrocytes. TgS mice overexpressing AChE showed constitutive increased microglial activation, elevated levels of pro-inflammatory cytokines 48 hrs after SE and accelerated epileptogenesis compared to their WT counterparts. Finally we show a direct, muscarine-receptor dependant, nicotine-receptor independent anti-inflammatory effect of ACh in brain slices maintained ex vivo. Our work demonstrates for the first time, that ACh directly suppresses brain innate immune response and that AChE up-regulation after SE is associated with enhanced immune response, facilitating the epileptogenic process. Our results highlight the cholinergic system as a potential new target for the prevention of seizures and epilepsy.

  14. Rabbit Forebrain cholinergic system: Morphological characterization of nuclei and distribution of cholinergic terminals in the cerebral cortex and hippocampus

    OpenAIRE

    C. Varga; Hartig, W.; Grosche, J.; Luiten, PGM; Seeger, J.; K. Brauer; Harkany, T.; Härtig, Wolfgang; Keijser, Jan N.

    2003-01-01

    Although the rabbit brain, in particular the basal forebrain cholinergic system, has become a common model for neuropathological changes associated with Alzheimer's disease, detailed neuroanatomical studies on the morphological organization of basal forebrain cholinergic nuclei and on their output pathways are still awaited. Therefore, we performed quantitative choline acetyltransferase (ChAT) immunocytochemistry to localize major cholinergic nuclei and to determine the number of respective c...

  15. Nicotine protects kidney from renal ischemia/reperfusion injury through the cholinergic anti-inflammatory pathway.

    Directory of Open Access Journals (Sweden)

    Claude Sadis

    Full Text Available Kidney ischemia/reperfusion injury (I/R is characterized by renal dysfunction and tubular damages resulting from an early activation of innate immunity. Recently, nicotine administration has been shown to be a powerful inhibitor of a variety of innate immune responses, including LPS-induced toxaemia. This cholinergic anti-inflammatory pathway acts via the alpha7 nicotinic acetylcholine receptor (alpha7nAChR. Herein, we tested the potential protective effect of nicotine administration in a mouse model of renal I/R injury induced by bilateral clamping of kidney arteries. Renal function, tubular damages and inflammatory response were compared between control animals and mice receiving nicotine at the time of ischemia. Nicotine pretreatment protected mice from renal dysfunction in a dose-dependent manner and through the alpha7nAChR, as attested by the absence of protection in alpha7nAChR-deficient mice. Additionally, nicotine significantly reduced tubular damages, prevented neutrophil infiltration and decreased productions of the CXC-chemokine KC, TNF-alpha and the proinflammatory high-mobility group box 1 protein. Reduced tubular damage in nicotine pre-treated mice was associated with a decrease in tubular cell apoptosis and proliferative response as attested by the reduction of caspase-3 and Ki67 positive cells, respectively. All together, these data highlight that nicotine exerts a protective anti-inflammatory effect during kidney I/R through the cholinergic alpha7nAChR pathway. In addition, this could provide an opportunity to overcome the effect of surgical cholinergic denervation during kidney transplantation.

  16. Synthesis and evaluation of radiolabeled piperazine derivatives of vesamicol as SPECT agents for cholinergic neurons

    Energy Technology Data Exchange (ETDEWEB)

    Bando, Kazunori E-mail: bkazunori@drl.co.jp; Taguchi, Kazumi; Ginoza, Yasushi; Naganuma, Tomoyoshi; Tanaka, Yoshitomo; Koike, Katsuo; Takatoku, Keizo

    2001-04-01

    To diagnose and investigate neurodegenerative diseases affecting cholinergic neuron density, piperazine derivatives of vesamicol were synthesized and evaluated. Previously, we reported that trans-5-iodo-2-hydroxy-3-[4-phenylpiperazinyl] tetralin (DRC140, 1) possessed high selectivity for vesicular acetylcholine transporter (VAChT). In present study of the effect of alkyl substituents, we observed that the introduction of a methyl group into the ortho or meta positions of the phenyl group of 1 increased affinity for VAChT. trans-5-Iodo-2-hydroxy-3-[4-[2-methylphenyl] piperazinyl]tetralin (2) displayed high affinity and specificity for VAChT. The regional distributions of radioactivity in the rat brain correlated well with known patterns of central cholinergic innervation. [{sup 123}I]2 is a potentially useful compound for SPECT imaging.

  17. Brain cholinergic involvement during the rapid development of tolerance to morphine

    Science.gov (United States)

    Wahba, Z. Z.; Oriaku, E. T.; Soliman, S. F. A.

    1987-01-01

    The effect of repeated administration of morphine on the activities of the cholinergic enzymes, choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), in specific brain regions were studied in rats treated with 10 mg/kg morphine for one or two days. Repeated administration of morphine was associated with a decline in the degree of analgesia produced and with a significant increase of AChE activity of the medulla oblongata. A single injection of morphine resulted in a significant decline in ChAT activity in the hypothalamus, cerebellum, and medulla oblongata regions. After two consecutive injections, no decline in ChAT was observed in these regions, while in the cerebral cortex the second administration elicited a significant decline. The results suggest that the development of tolerance to morphine may be mediated through changes in ChAT activity and lend support to the involvement of the central cholinergic system in narcotic tolerance.

  18. Hypothalamic dysfunction

    Science.gov (United States)

    ... common causes of hypothalamic dysfunction are surgery, traumatic brain injury, tumors, and radiation. Other causes include: Anorexia nervosa or bulimia Bleeding Genetic disorders that cause iron ...

  19. Studies on the pharmacology of central cholinergic nerve terminals

    Energy Technology Data Exchange (ETDEWEB)

    Lapchak, P.A.

    1988-01-01

    The presynaptic regulation of acetylcholine (ACh) synthesis and release in the mammalian brain was studied. Vasoactive intestinal peptide (VIP) increased Ach synthesis by rat hippocampal slices; this effect was time-, concentration- and calcium-dependent. The VIP-induced increase in ACh synthesis was independent of either an alteration of high affinity choline uptake or altered ACh release. Activation of presynaptic opiate receptors by selective opiate agonists causes a concentration-dependent inhibition of potassium-evoked Ach release from rat and guinea-pig hippocampus, striatum and cerebral cortex; spontaneous ACh release was not affected by any opiate drug tested. ({sup 3}H)N-Methylcarbamylcholine (MCC) binds specifically to nicotinic binding sites in the rat brain; activation of nicotinic receptors in the rat hippocampus and frontal cortex by MCC or nicotine causes a dose-dependent facilitation of spontaneous ACh release. Chronic administration of nicotine to rats results in the upregulation of ({sup 3}H)MCC/nicotinic binding sites in certain regions of the rat brain; associated with the upregulation of the density of nicotinic sites was a concomitant down-regulation of functional nicotinic autoreceptors. This latter effect was reversible upon removal of nicotine, however, the time course of recovery of nicotinic auto-receptor function appears to be different from that of alterations of ({sup 3}H)MCC binding site number.

  20. Cholinergic interneurons control local circuit activity and cocaine conditioning.

    Science.gov (United States)

    Witten, Ilana B; Lin, Shih-Chun; Brodsky, Matthew; Prakash, Rohit; Diester, Ilka; Anikeeva, Polina; Gradinaru, Viviana; Ramakrishnan, Charu; Deisseroth, Karl

    2010-12-17

    Cholinergic neurons are widespread, and pharmacological modulation of acetylcholine receptors affects numerous brain processes, but such modulation entails side effects due to limitations in specificity for receptor type and target cell. As a result, causal roles of cholinergic neurons in circuits have been unclear. We integrated optogenetics, freely moving mammalian behavior, in vivo electrophysiology, and slice physiology to probe the cholinergic interneurons of the nucleus accumbens by direct excitation or inhibition. Despite representing less than 1% of local neurons, these cholinergic cells have dominant control roles, exerting powerful modulation of circuit activity. Furthermore, these neurons could be activated by cocaine, and silencing this drug-induced activity during cocaine exposure (despite the fact that the manipulation of the cholinergic interneurons was not aversive by itself) blocked cocaine conditioning in freely moving mammals.

  1. Cholinergic Neurotransmission: Function and Dysfunction, International Cholinergic Symposium (8th) Held at Montreal (Quebec) on 26-30 July 1992

    Science.gov (United States)

    1992-12-31

    Georgina Rodr~auez de Lores Arnaiz. Instituto do Biologia Celular , Facultad do Medicina, Universidad do Buenos Aires, Paraguay 2155 - 1121 Buenos Aires...CNS distribution of receptorsI 4:00 - 5:30 Session 3: Molecular aspects of receptors 5:30 - 6:00 Posters/Coffee Break 6:00 - 7:30 Session 4: Molecular ...Session 6: ACh turnover and release 4:00 - 5:30 Session 7: Molecular aspects of ACh release 5:30 - 6:00 Posters/Coffee Break 6:00 - 7:30 Session 8

  2. Pharmacological identification of cholinergic receptor subtypes on Drosophila melanogaster larval heart.

    Science.gov (United States)

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

    2016-01-01

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

  3. ROLE OF CHOLINERGIC SYSTEM ON THE CONSTRUCTION OF MEMORY AND ITS INTERACTION WITH DOPAMINERGIC SYSTEM

    Directory of Open Access Journals (Sweden)

    F. Z. Zangeneh

    2006-07-01

    Full Text Available The central cholinergic system has been associated with cognitive function and memory and acetylcholine plays an important role during the early stages of memory consolidation. In this study, after training mice were tested with one way active avoidance procedure and retention were tested at 4, 8, 12, 16 and 24 hours of training and compared with non-shocked mice, in which it took 24 hours, a suitable time for retention test. Low dose administration of arecoline and physostigmine pre-training, immediate post-training and before retrieval showed that muscarinic agonist arecoline can potentiated memory in post trained and retrieval phases and reversible cholinesterase inhibitor physostigmine potentiated memory only in retrieval phase. Scopolamine disrupted acetylcholine potentiation only in retrieval phase. In the second part of this study, the effect of dopaminergic system was investigated. Low dose of apomorphine and D2 agonist bromocriptine potentiated memory when administered immediately post-training, and D2 antagonist sulpiride impaired memory. When the cholinergic system was blocked by scopolamine immediately post-training, apomorphine and bromocriptine potentiated memory and sulpiride impaired it. In conclusion, these results suggest that, cholinergic system in retrieval phase is very critical and there was no interaction between the two systems in the post-training phase.

  4. Cholinergic modulation of Pavlovian fear conditioning in rats: differential effects of intrahippocampal infusion of mecamylamine and methyllycaconitine.

    Science.gov (United States)

    Vago, David R; Kesner, Raymond P

    2007-03-01

    The cholinergic system has consistently been implicated in Pavlovian fear conditioning. Considerable work has been done to localize specific nicotinic receptor subtypes in the hippocampus and determine their functional importance; however, the specific function of many of these subtypes has yet to be determined. An alpha7 nicotinic antagonist methyllycaconitine (MLA) (35 microg), and a broad spectrum non-alpha7 nicotinic antagonist mecamylamine (35 microg) was injected directly into the dorsal hippocampus or overlying cortex either 15 min pre-, 1 min post-, or 6h post-fear conditioning. One week after conditioning, retention of contextual and cue (tone) conditioning were assessed. A significant impairment in retention of contextual fear was observed when mecamylamine was injected 15 min pre- and 1 min post-conditioning. No significant impairment was observed when mecamylamine was injected 6h post-conditioning. Likewise, a significant impairment in retention of contextual fear was observed when MLA was injected 1 min post-conditioning; however, in contrast, MLA did not show any significant impairments when injected 15 min pre-conditioning, but did show a significant impairment when injected 6h post-conditioning. There were no significant impairments observed when either drug was injected into overlying cortex. No significant impairments were observed in cue conditioning for either drug. In general, specific temporal dynamics involved in nicotinic receptor function were found relative to time of receptor dysfunction. The results indicate that the greatest deficits in long-term retention (1 week) of contextual fear are produced by central infusion of MLA minutes to hours post-conditioning or mecamylamine within minutes of conditioning.

  5. Rapid desensitization with autologous sweat in cholinergic urticaria.

    Science.gov (United States)

    Kozaru, Takeshi; Fukunaga, Atsushi; Taguchi, Kumiko; Ogura, Kanako; Nagano, Tohru; Oka, Masahiro; Horikawa, Tatsuya; Nishigori, Chikako

    2011-09-01

    The majority of patients with cholinergic urticaria presents with strong hypersensitivity to autologous sweat. Patients with severe cholinergic urticaria are frequently resistant to H(1) antagonists which are used in conventional therapies for various types of urticaria. It has been reported that desensitization using partially purified sweat antigen was effective in a patient with cholinergic urticaria. The aim of this study is to determine the usefulness of rapid desensitization with autologous sweat in severe cholinergic urticaria, because rapid desensitization has proven to be a quick and effective immunotherapy for allergies to various allergens. Six patients with severe cholinergic urticaria who are resistant to H(1) antagonists and have sweat hypersensitivity were enrolled in a rapid desensitization protocol. In all six patients, the responses for skin tests with autologous sweat were attenuated after rapid desensitization with autologous sweat. Two of the three cholinergic urticaria patients showed reduced histamine release with autologous sweat after the rapid desensitization with autologous sweat. Further, the rapid desensitization and subsequent maintenance treatment reduced the symptoms in five of the six patients. This study provides evidence that rapid desensitization with autologous sweat is beneficial for treating cholinergic urticaria patients resistant to conventional therapy who have sweat hypersensitivity.

  6. Local cholinergic and non-cholinergic neural pathways to the rat supraoptic nucleus

    Energy Technology Data Exchange (ETDEWEB)

    Meeker, M.L.

    1986-01-01

    An estimated two thirds of the input to the supraoptic nucleus of the rat hypothalamus (SON) including a functionally significant cholinergic innervation, arise from local sources of unknown origin. The sources of these inputs were identified utilizing Golgi-Cox, retrograde tracing, choline acetyltransferase immunocytochemistry and anterograde tracing methodologies. Multipolar Golgi impregnated neurons located dorsal and lateral to the SON extend spiney processes into the nucleus. Injections of the retrograde tracers, wheat germ agglutinin or wheat germ agglutinin-horseradish peroxidase, into the SON labeled cells bilaterally in the arcuate nucleus, and ipsilaterally in the lateral hypothalamus, anterior hypothalamus, nucleus of the diagonal band, subfornical organ, medial preoptic area, lateral preoptic area and in the region dorsolateral to the nucleus. Immunocytochemistry for choline acetyltransferase revealed cells within the ventro-caudal portion of cholinergic cell group, Ch4, which cluster dorsolateral to the SON, and extend axon- and dendrite-like processes into the SON. Cells double-labeled by choline acetyltransferase immunocytochemistry and retrograde tracer injections into the SON are localized within the same cholinergic cell group dorsolateral to the SON. Injections of the anterograde tracer, Phaseolus vulgaris-leucoagglutinin, deposited dorsolateral to the SON results in labeled pre-and post-synaptic processes within the SON. The identification and characterization of endogenous immunoglobulin within the SON and other neurons innervating areas lacking a blood-brain barrier established a novel and potentially important system for direct communication of the supraoptic cells with blood-borne constitutents.

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

    Directory of Open Access Journals (Sweden)

    Prashant Tiwari

    2013-10-01

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

  8. Voiding dysfunction - A review

    Directory of Open Access Journals (Sweden)

    Sripathi V

    2005-01-01

    Full Text Available In a child who is toilet trained the sudden onset of daytime wetting with frequency or urgency is alarming to the parents. Initially this subject was subdivided into a number of descriptive clinical conditions which led to a lot of confusion in recognition and management. Subsequently, the term elimination dysfunction was coined by Stephen Koff to emphasise the association between recurrent urinary infection, wetting, constipation and bladder overactivity. From a urodynamic point of view, in voiding dysfunction, there is either detrusor overactivity during bladder filling or dyssynergic action between the detrusor and the external sphincter during voiding. Identifying a given condition as a ′filling phase dysfunction′ or ′voiding phase dysfunction′ helps to provide appropriate therapy. Objective clinical criteria should be used to define voiding dysfunction. These include bladder wall thickening, large capacity bladder and infrequent voiding, bladder trabeculation and spinning top deformity of the urethra and a clinically demonstrated Vincent′s curtsy. The recognition and treatment of constipation is central to the adequate treatment of voiding dysfunction. Transcutaneous electric nerve stimuation for the treatment of detrusor overactivity, biofeedback with uroflow EMG to correct dyssynergic voiding, and behavioral therapy all serve to correct voiding dysfunction in its early stages. In established neurogenic bladder disease the use of Botulinum Toxin A injections into the detrusor or the external sphincter may help in restoring continence especially in those refractory to drug therapy. However in those children in whom the upper tracts are threatened, augmentation of the bladder may still be needed.

  9. Thyroid function, Alzheimer's disease and postoperative cognitive dysfunction: a tale of dangerous liaisons?

    Science.gov (United States)

    Mafrica, Federica; Fodale, Vincenzo

    2008-05-01

    Hypothyroidism and hyperthyroidism are commonly present conditions in adults, leading to neurological symptoms, affecting the central and peripheral nervous system, and to neurocognitive impairment. Several studies investigated a possible association between Alzheimer's disease (AD) and thyroid dysfunctions. Increasing evidence supports an extensive interrelationship between thyroid hormones and the cholinergic system, which is selectively and early affected in AD. Moreover, thyroid hormones negatively regulate expression of the amyloid-beta protein precursor (AbetaPP), which plays a key role in the development of AD. A condition, the so called euthyroid sick syndrome (ESS), characterized by reduced serum T_{3} and T_{4} concentrations without increased serum thyroid stimulation hormone secretion, occurs within hours after major surgery. After surgery, elderly patients often exhibit a transient, reversible state of cognitive alterations. Delirium occurs in 10-26% of general medical patients over 65, and it is associated with a significant increase in morbidity and mortality. Modifications in thyroid hormone functioning may take place as a consequence of psycho-physical stress caused by surgery, and probably as a consequence of reduced conversion of T4 into T3 by the liver engaged in metabolizing anesthetic drugs. Therefore, modifications of thyroid hormones post-surgery, might play a role in the pathogenesis of postoperative cognitive dysfunction.

  10. Male Gender Role Dysfunction

    OpenAIRE

    Daig, Isolde

    2010-01-01

    Background: Men have a higher alcohol and cigarette consumption than women, they use more drugs, they have twice as high a suicide rate and only a minority of men attend on preventive medical checkups. Hypotheses: The central questions of the present study pertained to the identification of dysfunctional aspects of a male self concept and the possible correlations with risk behaviour of men in different age stages. One possible explanation for this high risk behaviour may be higher mascul...

  11. BMI, HOMA-IR, and Fasting Blood Glucose Are Significant Predictors of Peripheral Nerve Dysfunction in Adult Overweight and Obese Nondiabetic Nepalese Individuals: A Study from Central Nepal

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    Lekhjung Thapa

    2016-01-01

    Full Text Available Objective. Nondiabetic obese individuals have subclinical involvement of peripheral nerves. We report the factors predicting peripheral nerve function in overweight and obese nondiabetic Nepalese individuals. Methodology. In this cross-sectional study, we included 50 adult overweight and obese nondiabetic volunteers without features of peripheral neuropathy and 50 healthy volunteers to determine the normative nerve conduction data. In cases of abnormal function, the study population was classified on the basis of the number of nerves involved, namely, “<2” or “≥2.” Multivariable logistic regression analysis was carried out to predict outcomes. Results. Fasting blood glucose (FBG was the significant predictor of motor nerve dysfunction (P=0.039, 95% confidence interval (CI = 1.003–1.127. Homeostatic model assessment of insulin resistance (HOMA-IR was the significant predictor (P=0.019, 96% CI = 1.420–49.322 of sensory nerve dysfunction. Body mass index (BMI was the significant predictor (P=0.034, 95% CI = 1.018–1.577 in case of ≥2 mixed nerves’ involvement. Conclusion. FBG, HOMA-IR, and BMI were significant predictors of peripheral nerve dysfunction in overweight and obese Nepalese individuals.

  12. Disruption of cardiac cholinergic neurons enhances susceptibility to ventricular arrhythmias

    Science.gov (United States)

    Jungen, Christiane; Scherschel, Katharina; Eickholt, Christian; Kuklik, Pawel; Klatt, Niklas; Bork, Nadja; Salzbrunn, Tim; Alken, Fares; Angendohr, Stephan; Klene, Christiane; Mester, Janos; Klöcker, Nikolaj; Veldkamp, Marieke W.; Schumacher, Udo; Willems, Stephan; Nikolaev, Viacheslav O.; Meyer, Christian

    2017-01-01

    The parasympathetic nervous system plays an important role in the pathophysiology of atrial fibrillation. Catheter ablation, a minimally invasive procedure deactivating abnormal firing cardiac tissue, is increasingly becoming the therapy of choice for atrial fibrillation. This is inevitably associated with the obliteration of cardiac cholinergic neurons. However, the impact on ventricular electrophysiology is unclear. Here we show that cardiac cholinergic neurons modulate ventricular electrophysiology. Mechanical disruption or pharmacological blockade of parasympathetic innervation shortens ventricular refractory periods, increases the incidence of ventricular arrhythmia and decreases ventricular cAMP levels in murine hearts. Immunohistochemistry confirmed ventricular cholinergic innervation, revealing parasympathetic fibres running from the atria to the ventricles parallel to sympathetic fibres. In humans, catheter ablation of atrial fibrillation, which is accompanied by accidental parasympathetic and concomitant sympathetic denervation, raises the burden of premature ventricular complexes. In summary, our results demonstrate an influence of cardiac cholinergic neurons on the regulation of ventricular function and arrhythmogenesis. PMID:28128201

  13. Suppression of glucocorticoid secretion enhances cholinergic transmission in rat hippocampus.

    Science.gov (United States)

    Mizoguchi, Kazushige; Shoji, Hirotaka; Ikeda, Ryuji; Tanaka, Yayoi; Maruyama, Wakako; Tabira, Takeshi

    2008-08-15

    We previously demonstrated that suppression of glucocorticoid secretion by adrenalectomy (ADX) impaired prefrontal cortex-sensitive working memory, but not reference memory. Since the cholinergic system in the hippocampus is also involved in these memories, we examined the effects of glucocorticoid suppression on cholinergic transmission in the rat hippocampus. A microdialysis study revealed that ADX did not affect the basal acetylcholine release, but enhanced the KCl-evoked response. This enhanced response was reversed by the corticosterone replacement treatment. The extracellular choline concentrations increased under both basal and KCl-stimulated conditions in the ADX rats, and these increases were also reversed by the corticosterone replacement. These results indicate that suppression of glucocorticoid secretion enhances cholinergic transmission in the hippocampus in response to stimuli. It is possible that this enhanced cholinergic transmission may not contribute to the ADX-induced working memory impairment, but it may be involved in maintenance of reference memory.

  14. Striatal cholinergic interneurons Drive GABA release from dopamine terminals.

    Science.gov (United States)

    Nelson, Alexandra B; Hammack, Nora; Yang, Cindy F; Shah, Nirao M; Seal, Rebecca P; Kreitzer, Anatol C

    2014-04-01

    Striatal cholinergic interneurons are implicated in motor control, associative plasticity, and reward-dependent learning. Synchronous activation of cholinergic interneurons triggers large inhibitory synaptic currents in dorsal striatal projection neurons, providing one potential substrate for control of striatal output, but the mechanism for these GABAergic currents is not fully understood. Using optogenetics and whole-cell recordings in brain slices, we find that a large component of these inhibitory responses derive from action-potential-independent disynaptic neurotransmission mediated by nicotinic receptors. Cholinergically driven IPSCs were not affected by ablation of striatal fast-spiking interneurons but were greatly reduced after acute treatment with vesicular monoamine transport inhibitors or selective destruction of dopamine terminals with 6-hydroxydopamine, indicating that GABA release originated from dopamine terminals. These results delineate a mechanism in which striatal cholinergic interneurons can co-opt dopamine terminals to drive GABA release and rapidly inhibit striatal output neurons.

  15. Erectile dysfunction.

    Science.gov (United States)

    Wylie, Kevan

    2008-01-01

    Erectile dysfunction is a common problem affecting sexual function in men. Approximately one in 10 men over the age of 40 is affected by this condition and the incidence is age related. Erectile dysfunction is a sentinel marker for several reversible conditions including peripheral and coronary vascular disease, hypertension and diabetes mellitus. Endothelial dysfunction is a common factor between the disease states. Concurrent conditions such as depression, late-onset hypogonadism, Peyronie's disease and lower urinary tract symptoms may significantly worsen erectile function, other sexual and relationship issues and penis dysmorphophobia. A focused physical examination and baseline laboratory investigations are mandatory. Management consists of initiating modifiable lifestyle changes, psychological and psychosexual/couples interventions and pharmacological and other interventions. In combination and with treatment of concurrent comorbid states, these interventions will often bring about successful resolution of symptoms and avoid the need for surgical interventions.

  16. Personalized genetics of the cholinergic blockade of neuroinflammation.

    Science.gov (United States)

    Simchovitz, Alon; Heneka, Michael T; Soreq, Hermona

    2017-03-21

    Acetylcholine signaling is essential for cognitive functioning and blocks inflammation. To maintain homeostasis, cholinergic signaling is subjected to multi-leveled and bidirectional regulation by both proteins and non-coding microRNAs ('CholinomiRs'). CholinomiRs coordinate the cognitive and inflammatory aspects of cholinergic signaling by targeting major cholinergic transcripts including the acetylcholine hydrolyzing enzyme acetylcholinesterase (AChE). Notably, AChE inhibitors are the only currently approved line of treatment for Alzheimer's disease patients. Since cholinergic signaling blocks neuroinflammation which is inherent to Alzheimer's disease, genomic changes modifying AChE's properties and its susceptibility to inhibitors and/or to CholinomiRs regulation may affect the levels and properties of inflammasome components such as NLRP3. This calls for genomic-based medicine approaches based on genotyping of both coding and non-coding single nucleotide polymorphisms (SNPs) in the genes involved in cholinergic signaling. An example is a SNP in a recognition element for the primate-specific microRNA-608 within the 3' untranslated region of the AChE transcript. Carriers of the minor allele of that SNP present massively elevated brain AChE levels, increased trait anxiety and inflammation, accompanied by perturbed CholinomiR-608 regulatory networks and elevated prefrontal activity under exposure to stressful insults. Several additional SNPs in the AChE and other cholinergic genes await further studies, and might likewise involve different CholinomiRs and pathways including those modulating the initiation and progression of neurodegenerative diseases. CholinomiRs regulation of the cholinergic system thus merits in-depth interrogation and is likely to lead to personalized medicine approaches for achieving better homeostasis in health and disease. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms.

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

    Directory of Open Access Journals (Sweden)

    Marta Navarrete

    2012-02-01

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

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

    Directory of Open Access Journals (Sweden)

    Jolien Schaeverbeke

    2017-01-01

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

  19. Immunohistochemical localisation of cholinergic muscarinic receptor subtype 1 (M1r) in the guinea pig and human enteric nervous system.

    Science.gov (United States)

    Harrington, A M; Hutson, J M; Southwell, B R

    2007-07-01

    Little is known regarding the location of cholinergic muscarinic receptor 1 (M1r) in the ENS, even though physiological data suggest that M1rs are central to cholinergic neurotransmission. This study localised M1rs in the ENS of the guinea pig ileum and human colon using fluorescence immunohistochemistry and RT-PCR in human colon. Double labelling using antibodies against neurochemical markers was used to identify neuron subytpes bearing M1r. M1r immunoreactivity (IR) was present on neurons in the myenteric and submucosal ganglia. The two antibodies gave similar M1r-IR patterns and M1r-IR was abolished upon antibody preabsorption. M1r-IR was present on cholinergic and nNOS-IR nerve cell bodies in both guinea pig and human myenteric neurons. Presynaptic M1r-IR was present on NOS-IR and VAChT-IR nerve fibres in the circular muscle in the human colon. In the submucosal ganglia, M1r-IR was present on a population of neurons that contained cChAT-IR, but did not contain NPY-IR or calretinin-IR. M1r-IR was present on endothelial cells of blood vessels in the submucosal plexus. The localisation of M1r-IR in the guinea pig and human ENS shown in this study agrees with physiological studies. M1r-IR in cholinergic and nitrergic neurons and nerve fibres indicate that M1rs have a role in both cholinergic and nitrergic transmission. M1r-IR present in submucosal neurons suggests a role in mediating acetylcholine's effect on submucosal sensory and secretomotor/vasodilator neurons. M1r-IR present on blood vessel endothelial cells suggests that M1rs may also mediate acetylcholine's direct effect on vasoactivation.

  20. In vivo functional neurochemistry of human cortical cholinergic function during visuospatial attention

    Science.gov (United States)

    Lindner, Michael; Bell, Tiffany; Iqbal, Somya; Mullins, Paul Gerald

    2017-01-01

    Cortical acetylcholine is involved in key cognitive processes such as visuospatial attention. Dysfunction in the cholinergic system has been described in a number of neuropsychiatric disorders. Levels of brain acetylcholine can be pharmacologically manipulated, but it is not possible to directly measure it in vivo in humans. However, key parts of its biochemical cascade in neural tissue, such as choline, can be measured using magnetic resonance spectroscopy (MRS). There is evidence that levels of choline may be an indirect but proportional measure of acetylcholine availability in brain tissue. In this study, we measured relative choline levels in the parietal cortex using functional (event-related) MRS (fMRS) during performance of a visuospatial attention task, with a modelling approach verified using simulated data. We describe a task-driven interaction effect on choline concentration, specifically driven by contralateral attention shifts. Our results suggest that choline MRS has the potential to serve as a proxy of brain acetylcholine function in humans. PMID:28192451

  1. Erectile dysfunction

    African Journals Online (AJOL)

    that increase blood flow to the penis. The blood ... The pressure of the blood in the chambers makes the ... What are the risk factors for erectile dysfunction? The most .... losing excessive weight and increasing physical activity, may improve the ...

  2. Monitoring cholinergic activity during attentional performance in mice heterozygous for the choline transporter: a model of cholinergic capacity limits.

    Science.gov (United States)

    Paolone, Giovanna; Mallory, Caitlin S; Koshy Cherian, Ajeesh; Miller, Thomas R; Blakely, Randy D; Sarter, Martin

    2013-12-01

    Reductions in the capacity of the human choline transporter (SLC5A7, CHT) have been hypothesized to diminish cortical cholinergic neurotransmission, leading to risk for cognitive and mood disorders. To determine the acetylcholine (ACh) release capacity of cortical cholinergic projections in a mouse model of cholinergic hypofunction, the CHT+/- mouse, we assessed extracellular ACh levels while mice performed an operant sustained attention task (SAT). We found that whereas SAT-performance-associated increases in extracellular ACh levels of CHT+/- mice were significantly attenuated relative to wildtype littermates, performance on the SAT was normal. Tetrodotoxin-induced blockade of neuronal excitability reduced both dialysate ACh levels and SAT performance similarly in both genotypes. Likewise, lesions of cholinergic neurons abolished SAT performance in both genotypes. However, cholinergic activation remained more vulnerable to the reverse-dialyzed muscarinic antagonist atropine in CHT+/- mice. Additionally, CHT+/- mice displayed greater SAT-disrupting effects of reverse dialysis of the nAChR antagonist mecamylamine. Receptor binding assays revealed a higher density of α4β2* nAChRs in the cortex of CHT+/- mice compared to controls. These findings reveal compensatory mechanisms that, in the context of moderate cognitive challenges, can overcome the performance deficits expected from the significantly reduced ACh capacity of CHT+/- cholinergic terminals. Further analyses of molecular and functional compensations in the CHT+/- model may provide insights into both risk and resiliency factors involved in cognitive and mood disorders.

  3. Predominant Glandular Cholinergic Dysautonomia in Patients with Primary Sjögren’s Syndrome

    Science.gov (United States)

    Imrich, Richard; Alevizos, Ilias; Bebris, Lolita; Goldstein, David S.; Holmes, Courtney S.; Illei, Gabor G.; Nikolov, Nikolay P.

    2015-01-01

    Objectives The autonomic nervous system (ANS) modulates exocrine gland function. Available data show poor correlation between the degree of exocrine gland function and destruction in primary Sjögren’s syndrome (pSS) suggesting other mechanisms, such as autonomic dysfunction may be important in these patients. We performed a comprehensive analysis of sympathoneural and sympathetic cholinergic function in well-characterized patients with pSS. Methods 21 pSS patients (mean±SE age 44±3 years) and in 13 healthy controls (51±2 years) were assessed during orthostasis and intravenous injection of edrophonium (10 mg). The postganglionic sympathetic cholinergic system was evaluated by assessing sweat production by the quantitative sudomotor axon reflex test (QSART). Gastric empting testing assessed the gastro-intestinal ANS in pSS patients. Results Velocity index and acceleration index were significantly higher (p<0.05) in pSS compared to controls before and during the orthostatic and edrophonium tests. Other hemodynamic and neurochemical parameters did not differ between pSS patients and controls during the orthostasis and edrophonium test, however, edrophonium-induced saliva increment was lower in pSS (p=0.002). Abnormally low sweat production was found in four (N=4) pSS patients but in none of the controls in the QSART. Gastric empting was delayed in 53 % of pSS patients. Conclusion We observed subtle differences in several ANS domains, including gastrointestinal and sympathocholinergic system suggesting a complex ANS dysfunction in pSS. The impact was the largest on the exocrine glands with subtle differences in the cardiac parasympathetic function independent of glandular inflammation and atrophy, suggesting an alternative pathogenesis mechanism of the disease in pSS. PMID:25622919

  4. Effects of Tiantai Ⅰ on the activity of central cholinergic system in mice with spontaneous Alzheimer disease%天泰1号对自发老年性痴呆模型中枢胆碱能系统活性的影响

    Institute of Scientific and Technical Information of China (English)

    吴正治; 李明; 李耀芳; 贾秀琴; 张永锋

    2006-01-01

    BACKGROUND: Tiantai I consists of gastrodia, Chinese angelica root, areca seed. It has been considered as the roles of invigorating the liver, nourishing marrow, heightening the intelligence and causing resuscitation. OBJECTIVE: To observe the effects of Tiantai Ⅰ on the abilities of learn ing and memory and the activity of central cholinergic system in mice with spontaneous Alzheimer disease. DESIGN: A randomized control observation. SETTING: Shenzhen Institute of Integrated Chinese and Western Medicine. MATERIALS: Male Kunming mice of 13 months old were raised to 21 months old, of which 52 with spontaneous Alzheimer disease were screened. They were randomly divided into blank control group, western drug control group, Tiantai Ⅰ 6.80 and 20.41 g/kg groups, 13 mice in each group. Another 13 aged mice with normal learning and memory abilities were selected as the normal control group at the same time. METHODS: Mice in the western drug control group were treated with 0.6 mg/Kg Hydergine, those in the Tiantai Ⅰ 6.80 and 20.41 g/kg groups were given intragastric administration of Tiantai Ⅰ of 6.80 and 20.41 g/kg, respectively, and those in the normal control group and blank control group were given double distilled water of the same volume. The learning and memory results were examined by the step-down test. Freezing sections of brain tissue were prepared, acetylcholinesterase (AChE) fiber was showed according to the Hedreen method, and choline acetyltransferase (ChAT) was detected with Burt and Silver methods, the automatic image analysis system for biomedical application was applied in the quantitative analysis of AChE fiber and ChAT activity. MAIN OUTCOME MEASURES: ① Effect of Tiantai Ⅰ on the abilities of learning and memory in mice with Alzheimer disease; ② AChE fiber area density in temporal cortex and hippocampal CA1 region; ③ ChAT ac tivity in Meynert nuclei of basal forebrain. RESULTS: ① Tiantai Ⅰ in ameliorating the abilities of learning

  5. Dysfunctional Families: One Central Theme in Two Fictional Works of Tony Morrison, Song of Solomon and Sula Familias Disfuncionales: Un Tema Central en Dos Novelas de Toni Morrison, Canción de Salomón y Sula

    OpenAIRE

    Luís Fernando Gómez R.

    2009-01-01

    Toni Morrison, Nobel Prize winner (1993), has been recognized as one of the most prominent novelists in the USA today. Her novels Song of Solomon and Sula rank enormous and original literary creativity through which she shows what it means to survive as an individual in the black families of America. Hence, this article explores the desperation and vulnerabilities of children who grow up in dysfunctional families and how they experience trauma and pain from their parents' unconventional actio...

  6. Intrinsic cholinergic neurons in the hippocampus: fact or artefact?

    Directory of Open Access Journals (Sweden)

    Jan Krzysztof Blusztajn

    2016-03-01

    Full Text Available It is generally agreed that hippocampal acetylcholine (ACh is synthesized and released exclusively from the terminals of the long-axon afferents whose cell bodies reside in the medial septum and diagonal band. The search for intrinsic cholinergic neurons in the hippocampus has a long history; however evidence for the existence of these neurons has been inconsistent, with most investigators failing to detect them using in situ hybridization or immunohistochemical staining of the cholinergic markers, choline acetyltransferase (CHAT or vesicular acetylcholine transporter (VACHT. Advances in the use of bacterial artificial chromosome (BAC transgenic mice expressing a reporter protein under the control of the genomic elements of the Chat gene (Chat-BAC mice have facilitated studies of cholinergic neurons. Such mice show robust and faithful expression of the reporter proteins in all known cholinergic cell populations. The availability of the Chat-BAC mice re-ignited interest in hippocampal cholinergic interneurons, because a small number of such reporter-expressing cells is frequently observed in the hippocampus of these mice. However, to date, attempts to confirm that these neurons co-express the endogenous cholinergic markers CHAT or VACHT, or release ACh, have been unsuccessful. Without such confirmatory evidence it is best to conclude that there are no cholinergic neurons in the hippocampus. Similar considerations apply to other BAC transgenic lines, whose utility as a discovery tool for cell populations heretofore not known to express the genes of interest encoded by the BACs, must be validated by methods that detect expression of the endogenous genes.

  7. Oral Dysfunction

    OpenAIRE

    鈴木, 規子; スズキ, ノリコ; Noriko, SUZUKI

    2004-01-01

    The major oral functions can be categorized as mastication, swallowing, speech and respiratory functions. Dysfunction of these results in dysphagia, speech disorders and abnormal respiration (such as Sleep Apnea). These functions relate to dentistry in the occurrence of : (1) oral preparatory and oral phases, (2) articulation disorders and velopharyngeal incompetence (VPI), and (3) mouth breathing, respiratory and blowing disorders. These disorders are related to oral and maxillofacial diseas...

  8. A Study of Magnetic Motor Evoked Potentials in the Central Nervous System Dysfunction Model of Myasthenia Gravis%大鼠重症肌无力中枢损害运动诱发电位研究

    Institute of Scientific and Technical Information of China (English)

    张旭; 夏君慧; 孙成超; 叶好好

    2000-01-01

    Objective To explore the relation of acetylcholine receptor antibodies(AChRAb) and dysfunction of central neuvous system (CNS) motor transmission in myasthenia gravis(MG) . Methods IgG purified from MG patient sera was injected into the lateral cerebroventricular system before and after application of motor evoked potential(MEP) examination .Results Intracerebroventricular administration of AChRAb produced loss of MEP wave or prolongation of the latency of the MEP wave,compared to injection of IgG purified from healthy control . Conclusion It is concluded that intracerebroventricular administration of AChRAb causes dysfunction of motor pulse transmission in rats . Present study has further demonstrated that AChRAb cause CNS dysfunction .%目的 探讨乙酰胆碱受体抗体(AChRAb)与中枢神经系统(CNS)运动传导通路之间的关系。方法 从AChRAb阳性的全身型重症肌无力(MG)患者血清中提取纯化IgG,然后注入大鼠侧脑室,观察其对运动诱发电位(MEP)的影响。结果 注入大鼠侧脑室内的AChRAb可致大鼠MEP异常,表现为MEP波消失或潜伏期延长。结论 本研究进一步证实MG患者的AChRAb不仅可以作用于NMJ处的AChR,而且还可作用于大鼠CNS,致CNS运动传导通路功能异常。

  9. The cone dysfunction syndromes

    Science.gov (United States)

    Aboshiha, Jonathan; Dubis, Adam M; Hardcastle, Alison J; Michaelides, Michel

    2016-01-01

    The cone dysfunction syndromes are a heterogeneous group of inherited, predominantly stationary retinal disorders characterised by reduced central vision and varying degrees of colour vision abnormalities, nystagmus and photophobia. This review details the following conditions: complete and incomplete achromatopsia, blue-cone monochromatism, oligocone trichromacy, bradyopsia and Bornholm eye disease. We describe the clinical, psychophysical, electrophysiological and imaging findings that are characteristic to each condition in order to aid their accurate diagnosis, as well as highlight some classically held notions about these diseases that have come to be challenged over the recent years. The latest data regarding the genetic aetiology and pathological changes observed in the cone dysfunction syndromes are discussed, and, where relevant, translational avenues of research, including completed and anticipated interventional clinical trials, for some of the diseases described herein will be presented. Finally, we briefly review the current management of these disorders. PMID:25770143

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

    Directory of Open Access Journals (Sweden)

    Dusica Bajic

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

  11. Cholinergic and adrenergic influence on the teleost heart in vivo.

    Science.gov (United States)

    Axelsson, M; Ehrenström, F; Nilsson, S

    1987-01-01

    The tonical cholinergic and adrenergic influence on the heart rate was investigated in vivo in seven species of marine teleosts (pollack, Pollachius pollachius; cuckoo wrasse, Labrus mixtus; ballan wrasse, Labrus berggylta; five-bearded rockling, Ciliata mustela; tadpole fish, Raniceps raninus; eel-pout, Zoarces viviparus and short-spined sea scorpion, Myoxocephalus scor pius) during rest and, in two of the species (P. pollachius and L. mixtus), also during moderate swimming exercise in a Blazka-type swim tunnel. Ventral aortic blood pressure and heart rate were recorded via a catheter implanted in an afferent branchial artery, and the influence of the cholinergic and adrenergic tonus on the heart rate was assessed by injection of atropine and sotalol respectively. During rest the adrenergic tonus was higher than the cholinergic tonus in all species except L. berggylta, where the reverse was true. In P. pollachius and L. mixtus, exercise appeared to produce a lowering of the cholinergic tonus on the heart and, possibly, a slight increase of the adrenergic tonus. The nature of the adrenergic tonus (humoral or neural) is not clear, but the low plasma concentrations of catecholamines both during rest and exercise could be interpreted in favour of a mainly neural adrenergic tonus on the teleost heart. These experiments are compatible with the view that both a cholinergic inhibitory tonus and an adrenergic excitatory tonus are general features in the control of the teleost heart in vivo, both at rest and during moderate swimming exercise.

  12. The clinical analysis of central neurological dysfunctions in primary Sjogren's syndrome: 4 cases report%原发性干燥综合征中枢神经系统损害4例分析

    Institute of Scientific and Technical Information of China (English)

    姚晓萍; 李智文; 林仕芳

    2012-01-01

    目的 探讨原发性干燥综合征中枢神经系统损害的临床特点,以提高其早期诊断、治疗效果.方法 回顾性分析4例原发性干燥综合征中枢神经系统损害患者的临床特征、诊疗情况,并结合国内外相关文献进行分析.结果 4例患者均为女性,年龄30~52岁.3例患者中枢神经系统损害表现先于干燥综合征诊断,1例患者先诊断干燥综合征后出现中枢神经系统损害.1例患者出现脊髓损害表现,2例患者为脑实质损害表现,1例具有脊髓、脑、视神经损害表现.4例患者MR均表现为点状或小片状长T1长T2信号影.治疗上1例患者单用糖皮质激素,其余3例患者均合用免疫抑制剂,治疗后病情均好转,随访无再新发中枢神经系统损害表现.结论 对不能用其他原因解释的中枢神经系统损害,尤其是中老年女性,应警惕原发性干燥综合征的可能.重视干燥综合征症状的询问,加深对干燥综合征中枢神经系统损害临床表现的认识,进行相关检查,以提高早期诊断、治疗效果,减少患者的致残率.%Objective To explore the clinical features of central neurological dysfunctions in primary Sjogren' s syndrome , and to improve its early diagnosis and treatment. Methods Retrospective review the clinical features, diagnosis and treatment in four patients of central neurological dysfunctions in primary Sjogren s syndrome, and analyze the relative literatures. Results The four patients were female, aged from 30 years old to 52 years old. Three patients of them presented the manifestation of central nervous system damage ahead of the diagnosis of Sjogren' s syndrome. One patient with spinal cord injury , two patients with brain parenchymal damage, and one patient with spinal cord injury, brain parenchyma and optic nerve damage. All of the patients showed punctate or small pieces of long Tl, T2 signal intensity in the MR examination. In terms of treatment, one patient was treated

  13. [Central visual fields in pure alexia "without hemianopsia"--visual dysfunction in the right hemifield, and alexia for "kana" words in the left].

    Science.gov (United States)

    Uchiyama, S; Uchiyama, C

    1991-10-01

    Following a left occipito-temporal subcortical hematoma, a 57-year-old, right-handed man developed pure alexia that was more prominent in kana words, especially in kana nonwords, than in kanji letters. Although a kinetic perimetry with a Goldmann perimeter showed his visual fields to be full, a static perimetry with a Humphrey visual field analyzer disclosed decreased visual sensitivity in the right visual field in its central 30 degrees. In addition, a tachnistoscopic examination with Landolt rings revealed his visual acuity (the ability of two points discrimination) to have decreased in the right half of his central visual filed in its 3 degrees. In the right central vision, he was unable to recognize the letters, pictures or colors presented by the tachistoscope. Concerning the reading, the more letters in kana words or the higher the number of strokes in kanji letters, the more difficulty he experienced in orally reading both kana and kanji. On the contrary, in the left central vision, kanji reading was not so affected by an increased number of strokes as the kana-word reading which became difficult when the number of the letters increased. CT scan showed subcortical hematoma in the left occipitotemporal region. Magnetic resonance imaging 3 months after onset revealed a localized injury in the region between the left postero-inferior temporal lobe and the infero-lateral occipital lobe, including the fusiform gyrus. None of the splenium, the lingual gyrus or the optic area were affected. The spared structures also included the angular gyrus, the Wernicke area and their subcortical white matter.(ABSTRACT TRUNCATED AT 250 WORDS)

  14. The influence of different metabolic syndrome definitions in predicting vasculogenic erectile dysfunction: is there a role for the index of central obesity?

    Science.gov (United States)

    Carvalho, H N; Campos Costa, I M; Campos Costa, I N; Botelho, F; Tomada, N

    2013-09-01

    Analyze the capacity of ICO, the ratio of waist circumference (WC) and height, in predicting hemodynamic impairment in Erectile Dysfunction (ED) patients, independently and integrated in Metabolic Syndrome (MetS) definitions. Four hundred and eighty-five ED patients followed in Urology consult from January 2008 until March 2012 were evaluated by a standardized protocol: health questionnaire, anthropometric measurements (AM), blood pressure and analysis, and Penile Duplex Doppler Ultrasound (PDDU) exam. Associations between AM and MetS definitions, including ATPIII, IDF and a new definition replacing WC by ICO in ATPIII MetS definition (ModATPIII), and PDDU were calculated. ICO was the measure of obesity more strongly correlated with diminished mean Peak Systolic Velocity (mPSV) (r = -0.189, p ICO ≥ 0.60 (a nationally obtained ratio) in ATPIII MetS definition (ModATPIII). Patients with ModATPIII had lower mPSV when compared to non-MetS patients (30.8 versus 37.1, p ICO revealed potential value to predict PDDU changes in a MetS context. However, IDF definition presented a stronger correlation with arteriogenic ED. Although longitudinal studies are necessary to confirm this hypothesis, our study highlights the importance of different MetS definitions for ED assessment.

  15. Morphine dependence and withdrawal induced changes in cholinergic signaling

    Science.gov (United States)

    Neugebauer, Nichole M.; Einstein, Emily B.; Lopez, Maria B.; McClure-Begley, Tristan D.; Mineur, Yann S.; Picciotto, Marina R.

    2013-01-01

    Cholinergic signaling is thought to be involved in morphine dependence and withdrawal, but the specific mechanisms involved remain unclear. The current study aimed to identify alterations in the cholinergic system that may contribute to the development of morphine dependence and withdrawal. Acetylcholinesterase (AChE) activity and [3H]-epibatidine binding were evaluated in order to determine if morphine dependence and withdrawal induces alterations in cholinergic signaling or expression of high affinity nicotinic acetylcholine receptors (nAChRs) in the midbrain (MB), medial habenula (MHb) and interpeduncular nucleus (IPN). The effect of cholinergic signaling through nAChRs on morphine-withdrawal induced jumping behavior was then determined. Lastly, the contribution of β4-containing nAChRs receptors in the MHb to morphine-withdrawal induced jumping behavior and neuronal activity as indicated by c-fos expression was assessed. Chronic morphine administration decreased AChE activity in MB and MHb, an effect that was no longer present following precipitated withdrawal. Morphine dependent mice showed increased nicotinic acetylcholine receptor (nAChR) levels in MB. Further, nicotine (0.4 mg/kg) and lobeline (3 mg/kg) decreased jumping behavior while mecamylamine (1 mg/kg) had no effect. Knock-down of β4 subunit-containing nAChRs in the MHb attenuated c-fos activation, but did not decrease morphine withdrawal-induced jumping. Thus, morphine withdrawal induces cholinergic signaling in the MHb, but this does not appear to be responsible for the effects of cholinergic drugs on somatic signs of opiate withdrawal, as measured by jumping behavior. PMID:23651795

  16. Interaction of nerve agent antidotes with cholinergic systems.

    Science.gov (United States)

    Soukup, O; Tobin, G; Kumar, U K; Binder, J; Proska, J; Jun, D; Fusek, J; Kuca, K

    2010-01-01

    The poisoning with organophosphorus compounds represents a life threatening danger especially in the time of terroristic menace. No universal antidote has been developed yet and other therapeutic approaches not related to reactivation of acetylcholinesterase are being investigated. This review describes the main features of the cholinergic system, cholinergic receptors, cholinesterases and their inhibitors. It also focuses on the organophosphorus nerve agents, their properties, effects and a large part describes various possibilities in treatments, mainly traditional oxime therapies based on reactivation of AChE. Furthermore, non-cholinesterase coupled antidotal effects of the oximes are thoroughly discussed. These antidotal effects principally include oxime interactions with muscarinic and nicotinic receptors.

  17. Basal Forebrain Cholinergic System and Orexin Neurons: Effects on Attention

    Science.gov (United States)

    Villano, Ines; Messina, Antonietta; Valenzano, Anna; Moscatelli, Fiorenzo; Esposito, Teresa; Monda, Vincenzo; Esposito, Maria; Precenzano, Francesco; Carotenuto, Marco; Viggiano, Andrea; Chieffi, Sergio; Cibelli, Giuseppe; Monda, Marcellino; Messina, Giovanni

    2017-01-01

    The basal forebrain (BF) cholinergic system has an important role in attentive functions. The cholinergic system can be activated by different inputs, and in particular, by orexin neurons, whose cell bodies are located within the postero-lateral hypothalamus. Recently the orexin-producing neurons have been proved to promote arousal and attention through their projections to the BF. The aim of this review article is to summarize the evidence showing that the orexin system contributes to attentional processing by an increase in cortical acetylcholine release and in cortical neurons activity. PMID:28197081

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1990-10-12

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

  19. Interleukin-6 impairs chronotropic responsiveness to cholinergic stimulation and decreases heart rate variability in mice.

    Science.gov (United States)

    Hajiasgharzadeh, Khalil; Mirnajafi-Zadeh, Javad; Mani, Ali R

    2011-12-30

    Heart rate variability is reduced in several clinical settings associated with systemic inflammation. The underlying mechanism of decreased heart rate variability during systemic inflammation is unknown. It appears that the inflammatory cytokines might play a role, since epidemiologic studies has shown that circulating levels of interleukine-6 (IL-6) correlate significantly with indexes of depressed heart rate variability in various clinical conditions. The present investigation was carried out to study the peripheral and central effects of IL-6 on heart rate dynamic in mice. Adult male BALB/c mice were used in the study. RT-PCR was performed to study the expression of IL-6 receptor in mouse atrial and the results showed that gp130 mRNA was detectable in the atrium. The effect of IL-6 was also studies on chronotropic responsiveness of isolated atria to adrenergic and cholinergic stimulations. Incubation of isolated atria with 10 ng/ml of IL-6 was associated with a significant hypo-responsiveness to cholinergic stimulation (log IC₅₀ of carbacholine changed from -6.26±0.10 in controls to -5.59±0.19 following incubation with IL-6, Pheart rate variability parameters (SDNN, SD1, and SD2). While intracerebroventricular injection of IL-6 (50 ng/mouse) had no significant effect on heart rate variability parameters. These data are in line with a peripheral role for IL-6 in the genesis of decreased heart rate variability during systemic inflammation.

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

    Energy Technology Data Exchange (ETDEWEB)

    Lane, J.D.

    1989-11-30

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

  1. Unprotected daily sun exposure is differently associated with central adiposity and beta-cell dysfunction by gender: The Korean national health and nutrition examination survey (KNHANES) V

    Energy Technology Data Exchange (ETDEWEB)

    Ohn, Jung Hun [Division of Endocrinology and Metabolism, Department of Internal Medicine, Hallym University College of Medicine, Chuncheon (Korea, Republic of); Kwon, In Ho [Department of Dermatology, Hallym University Dongtan Sacred Heart Hospital, Hwaseong (Korea, Republic of); Park, Juri; Ryu, Ohk Hyun; Lee, Seong Jin; Kim, Doo-Man; Ihm, Sung-Hee; Choi, Moon-Gi; Yoo, Hyung Joon [Division of Endocrinology and Metabolism, Department of Internal Medicine, Hallym University College of Medicine, Chuncheon (Korea, Republic of); Hong, Eun-Gyoung, E-mail: hegletter@hallym.or.kr [Division of Endocrinology and Metabolism, Department of Internal Medicine, Hallym University College of Medicine, Chuncheon (Korea, Republic of)

    2014-08-15

    Background: Ultraviolet irradiation by sun exposure has been associated with both harms and benefits to metabolic health. Objective: The objective of this study was to determine whether unprotected daily sun exposure is associated with the prevalence of diabetes and explore the underlying mechanism. Methods: We analyzed the Korean National Health and Nutrition Survey V from 2010 to 2011. Participants 19–60 years of age were asked about the average amount of time they had been exposed to direct sunlight per day since the age of 19. We categorized participants into three groups with different levels of lifetime daily sun exposure and explored the association of sun exposure with the prevalence of diabetes. Results: The risk of diabetes was higher in subjects with more than 5 h of unprotected sun exposure per day, with an odds ratio of 2.39 (95% CI 1.75–3.25), compared to those with less than 2 h of sun exposure, and the association remained significant after adjusting for diabetes risk factors. Long-term sun exposure was associated with increased central obesity and the possibility of an increase in visceral adiposity, especially among women, and with decrease in beta cell function and peripheral adiposity or percent body fat in men. Conclusions: Our study provides a cutoff for upper limit of sun exposure and suggests unprotected daily sun exposure for more than 5 h should be avoided to prevent diabetes. Increased central adiposity and decreased beta cell function were observed in women and men, respectively, who had long-term unprotected daily sun exposure. - Highlights: • Sun exposure for more than 5 h per day is associated with diabetes risk. • Insulin resistance associated with visceral adiposity may play a role in women. • Insulin secretory defect may explain diabetes risk in men.

  2. Muscarinic and dopaminergic receptor subtypes on striatal cholinergic interneurons

    Energy Technology Data Exchange (ETDEWEB)

    Dawson, V.L.; Dawson, T.M.; Wamsley, J.K. (Neuropsychiatric Research Institute, Fargo, ND (USA))

    1990-12-01

    Unilateral stereotaxic injection of small amounts of the cholinotoxin, AF64A, caused minimal nonselective tissue damage and resulted in a significant loss of the presynaptic cholinergic markers (3H)hemicholinium-3 (45% reduction) and choline acetyltransferase (27% reduction). No significant change from control was observed in tyrosine hydroxylase or tryptophan hydroxylase activity; presynaptic neuronal markers for dopamine- and serotonin-containing neurons, respectively. The AF64A lesion resulted in a significant reduction of dopamine D2 receptors as evidenced by a decrease in (3H)sulpiride binding (42% reduction) and decrease of muscarinic non-M1 receptors as shown by a reduction in (3H)QNB binding in the presence of 100 nM pirenzepine (36% reduction). Saturation studies revealed that the change in (3H)sulpiride and (3H)QNB binding was due to a change in Bmax not Kd. Intrastriatal injection of AF64A failed to alter dopamine D1 or muscarinic M1 receptors labeled with (3H)SCH23390 and (3H)pirenzepine, respectively. In addition, no change in (3H)forskolin-labeled adenylate cyclase was observed. These results demonstrate that a subpopulation of muscarinic receptors (non-M1) are presynaptic on cholinergic interneurons (hence, autoreceptors), and a subpopulation of dopamine D2 receptors are postsynaptic on cholinergic interneurons. Furthermore, dopamine D1, muscarinic M1 and (3H)forskolin-labeled adenylate cyclase are not localized to striatal cholinergic interneurons.

  3. Cellular mechanisms underlying spatiotemporal features of cholinergic retinal waves

    Science.gov (United States)

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

    2012-01-01

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

  4. Cypermethrin Poisoning and Anti-cholinergic Medication- A Case Report

    Directory of Open Access Journals (Sweden)

    Dr Sudip Parajuli

    2006-07-01

    Full Text Available A 30 years old male was brought to emergency department of Manipal Teaching Hospital, Pokhara, Nepal with alleged history of consumption of pyrethroid compound ‘cypermethrin’. It was found to be newer insecticide poisoning reported in Nepal. We reported this case to show effectiveness of anti-cholinergic like hyosciane and chlorpheniramine maleate in the treatment of cypermethrin poisoning.

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

    NARCIS (Netherlands)

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

    2011-01-01

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

  6. The catecholaminergic-cholinergic balance hypothesis of bipolar disorder revisited.

    Science.gov (United States)

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

    2015-04-15

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

  7. Selective optogenetic stimulation of cholinergic axons in neocortex.

    Science.gov (United States)

    Kalmbach, Abigail; Hedrick, Tristan; Waters, Jack

    2012-04-01

    Acetylcholine profoundly affects neocortical function, being involved in arousal, attention, learning, memory, sensory and motor function, and plasticity. The majority of cholinergic afferents to neocortex are from neurons in nucleus basalis. Nucleus basalis also contains projecting neurons that release other transmitters, including GABA and possibly glutamate. Hence, electrical stimulation of nucleus basalis evokes the release of a mixture of neurotransmitters in neocortex, and this lack of selectivity has impeded research on cholinergic signaling in neocortex. We describe a method for the selective stimulation of cholinergic axons in neocortex. We used the Cre-lox system and a viral vector to express the light-activated protein channelrhodopsin-2 in cholinergic neurons in nucleus basalis and their axons in neocortex. Labeled neurons depolarized on illumination with blue light but were otherwise unchanged. In anesthetized mice, illumination of neocortex desynchronized the local field potential, indicating that light evoked release of ACh. This novel technique will enable many new studies of the cellular, network, and behavioral physiology of ACh in neocortex.

  8. Dysfunctional Families: One Central Theme in Two Fictional Works of Tony Morrison, Song of Solomon and Sula Familias Disfuncionales: Un Tema Central en Dos Novelas de Toni Morrison, Canción de Salomón y Sula

    Directory of Open Access Journals (Sweden)

    Luís Fernando Gómez R.

    2009-06-01

    Full Text Available Toni Morrison, Nobel Prize winner (1993, has been recognized as one of the most prominent novelists in the USA today. Her novels Song of Solomon and Sula rank enormous and original literary creativity through which she shows what it means to survive as an individual in the black families of America. Hence, this article explores the desperation and vulnerabilities of children who grow up in dysfunctional families and how they experience trauma and pain from their parents' unconventional actions and behaviors. The article accounts of the irregular experiences that the main characters of these two novels have to confront at hostile homes as they grow up changed, different from other children, and lack the essential educational guidance that prepare them for adulthood. Children are forced to assume unnatural roles within their families and, consequently, become dysfunctional members of society.En la actualidad, Toni Morrison, ganadora del premio Nóbel (1993, ha sido reconocida como una de las novelistas más prominentes de los Estados Unidos. Sus novelas Canción de Salomón y Sula gozan de poseer una enorme creatividad literaria a través de la cual presenta lo que significa sobrevivir como un miembro de las familias de raza negra en Norteamérica. Por ello, este artículo explora las vulnerabilidades de niños que crecen dentro de familias disfuncionales y de cómo sufren afectivamente a causa de las acciones y comportamientos poco convencionales de sus padres. El artículo discute las experiencias irregulares que los personajes principales de estas dos novelas tienen que enfrentar en hogares hostiles a medida que crecen diferentes a otros niños, carentes de la orientación educativa esencial que los prepare para la vida adulta. Los menores de edad son obligados a asumir roles anormales dentro de sus familias y en consecuencia se convierten en miembros disfuncionales de la sociedad.

  9. Brainstem cholinergic modulation of muscle tone in infant rats.

    Science.gov (United States)

    Gall, Andrew J; Poremba, Amy; Blumberg, Mark S

    2007-06-01

    In week-old rats, lesions of the dorsolateral pontine tegmentum (DLPT) and nucleus pontis oralis (PnO) have opposing effects on nuchal muscle tone. Specifically, pups with DLPT lesions exhibit prolonged bouts of nuchal muscle atonia (indicative of sleep) and pups with PnO lesions exhibit prolonged bouts of high nuchal muscle tone (indicative of wakefulness). Here we test the hypothesis that nuchal muscle tone is modulated, at least in part, by cholinergically mediated interactions between these two regions. First, in unanesthetized pups, we found that chemical infusion of the cholinergic agonist carbachol (22 mm, 0.1 microL) within the DLPT produced high muscle tone. Next, chemical lesions of the PnO were used to produce a chronic state of high nuchal muscle tone, at which time the cholinergic antagonist scopolamine (10 mm, 0.1 microL) was infused into the DLPT. Scopolamine effectively decreased nuchal muscle tone, thus suggesting that lesions of the PnO increase muscle tone via cholinergic activation of the DLPT. Using 2-deoxyglucose autoradiography, metabolic activation throughout the DLPT was observed after PnO lesions. Finally, consistent with the hypothesis that PnO inactivation produces high muscle tone, infusion of the sodium channel blocker lidocaine (2%) into the PnO of unanesthetized pups produced rapid increases in muscle tone. We conclude that, even early in infancy, the DLPT is critically involved in the regulation of muscle tone and behavioral state, and that its activity is modulated by a cholinergic mechanism that is directly or indirectly controlled by the PnO.

  10. Cholinergically mediated augmentation of cerebral perfusion in Alzheimer's disease and related cognitive disorders: the cholinergic-vascular hypothesis.

    NARCIS (Netherlands)

    Claassen, J.A.H.R.; Jansen, R.W.M.M.

    2006-01-01

    The treatment of Alzheimer's disease (AD) with cholinesterase inhibitors (ChEIs) is based on the cholinergic hypothesis. This hypothesis fails to account for the global nature of the clinical effects of ChEIs, for the replication of these effects in other dementias, and for the strong and

  11. 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.

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

    Directory of Open Access Journals (Sweden)

    Benedikt Zujalovic

    2015-01-01

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

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

    Science.gov (United States)

    Hu, Rongfeng; Jin, Sen; He, Xiaobin; Xu, Fuqiang; Hu, Ji

    2016-01-01

    The basal forebrain cholinergic system (BFCS) robustly modulates many important behaviors, such as arousal, attention, learning and memory, through heavy projections to cortex and hippocampus. However, the presynaptic partners governing BFCS activity still remain poorly understood. Here, we utilized a recently developed rabies virus-based cell-type-specific retrograde tracing system to map the whole-brain afferent inputs of the BFCS. We found that the BFCS receives inputs from multiple cortical areas, such as orbital frontal cortex, motor cortex, and insular cortex, and that the BFCS also receives dense inputs from several subcortical nuclei related to motivation and stress, including lateral septum, central amygdala, paraventricular nucleus of hypothalamus, dorsal raphe, and parabrachial nucleus. Interestingly, we found that the BFCS receives inputs from the olfactory areas and the entorhinal–hippocampal system. These results greatly expand our knowledge about the connectivity of the mouse BFCS and provided important preliminary indications for future exploration of circuit function. PMID:27777554

  14. Mitochondrial Dysfunction in Parkinson's Disease

    Directory of Open Access Journals (Sweden)

    P. C. Keane

    2011-01-01

    Full Text Available Parkinson's disease (PD is a progressive, neurodegenerative condition that has increasingly been linked with mitochondrial dysfunction and inhibition of the electron transport chain. This inhibition leads to the generation of reactive oxygen species and depletion of cellular energy levels, which can consequently cause cellular damage and death mediated by oxidative stress and excitotoxicity. A number of genes that have been shown to have links with inherited forms of PD encode mitochondrial proteins or proteins implicated in mitochondrial dysfunction, supporting the central involvement of mitochondria in PD. This involvement is corroborated by reports that environmental toxins that inhibit the mitochondrial respiratory chain have been shown to be associated with PD. This paper aims to illustrate the considerable body of evidence linking mitochondrial dysfunction with neuronal cell death in the substantia nigra pars compacta (SNpc of PD patients and to highlight the important need for further research in this area.

  15. Cholinergic modulation of auditory P3 event-related potentials as indexed by CHRNA4 and CHRNA7 genotype variation in healthy volunteers.

    Science.gov (United States)

    Hyde, Molly; Choueiry, Joëlle; Smith, Dylan; de la Salle, Sara; Nelson, Renee; Impey, Danielle; Baddeley, Ashley; Aidelbaum, Robert; Millar, Anne; Knott, Verner

    2016-06-03

    Schizophrenia (SZ) is a psychiatric disorder characterized by cognitive dysfunction within the realm of attentional processing. Reduced P3a and P3b event-related potentials (ERPs), indexing involuntary and voluntary attentional processing respectively, have been consistently observed in SZ patients who also express prominent cholinergic deficiencies. The involvement of the brain's cholinergic system in attention has been examined for several decades; however, further inquiry is required to further comprehend how abnormalities in this system affect neighbouring neurotransmitter systems and contribute to neurocognitive deficits. The objective of this pilot study was to examine the moderating role of the CHRNA4 (rs1044396), CHRNA7 (rs3087454), and SLC5A7 (rs1013940) genes on ERP indices of attentional processing in healthy volunteers (N=99; Caucasians and non-Caucasians) stratified by genotype and assessed using the auditory P300 "oddball" paradigm. Results indicated significantly greater P3a and P3b-indexed attentional processing for CT (vs. CC) CHRNA4 carriers and greater P3b for AA (vs. CC) CHRNA7 carriers. SLC5A7 allelic variants did not show significant differences in P3a and P3b processing. These findings expand our knowledge on the moderating effect of cholinergic genes on attention and could help inform targeted drug developments aimed at restoring attention deficits in SZ patients.

  16. Endothelial dysfunction in morbid obesity.

    Science.gov (United States)

    Mauricio, Maria Dolores; Aldasoro, Martin; Ortega, Joaquin; Vila, José María

    2013-01-01

    Morbid obesity is a chronic multifunctional disease characterized by an accumulation of fat. Epidemiological studies have shown that obesity is associated with cardiovascular and metabolic disorders. Endothelial dysfunction, as defined by an imbalance between relaxing and contractile endothelial factors, plays a central role in the pathogenesis of these cardiometabolic diseases. Diminished bioavailability of nitric oxide (NO) contributes to endothelial dysfunction and impairs endothelium- dependent vasodilatation. But this is not the only mechanism that drives to endothelial dysfunction. Obesity has been associated with a chronic inflammatory process, atherosclerosis, and oxidative stress. Moreover levels of asymmetrical dimethyl-L-arginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), are elevated in obesity. On the other hand, increasing prostanoid-dependent vasoconstriction and decreasing vasodilator prostanoids also lead to endothelial dysfunction in obesity. Other mechanisms related to endothelin-1 (ET-1) or endothelium derived hyperpolarizing factor (EDHF) have been proposed. Bariatric surgery (BS) is a safe and effective means to achieve significant weight loss, but its use is limited only to patients with severe obesity including morbid obesity. BS also proved efficient in endothelial dysfunction reduction improving cardiovascular and metabolic comorbidities associated with morbid obesity such as diabetes, coronary artery disease, nonalcoholic fatty liver disease and cancer. This review will provide a brief overview of the mechanisms that link obesity with endothelial dysfunction, and how weight loss is a cornerstone treatment for cardiovascular comorbidities obesity-related. A better understanding of the mechanisms of obesity-induced endothelial dysfunction may help develop new therapeutic strategies to reduce cardiovascular morbidity and mortality.

  17. Mathematical modelling of the enteric nervous network. 1: Cholinergic neuron.

    Science.gov (United States)

    Miftakhov, R N; Wingate, D L

    1994-01-01

    A mathematical model is proposed to describe the coupled electrochemical mechanisms of nerve-pulse transmission via cholinergic synapse. Based on pharmacological and morphophysiological data, the model describes the dynamics of the propagation of the electric signal along the unmyelinated geometrically non-uniform axon of the neuron and the chemical mechanisms of the transformation of the electrical signal in the synaptic zone into the postsynaptic output. The combined nonlinear system of partial and ordinary differential equations has been obtained and solved numerically. The results of numerical simulation of the function of the cholinergic neuron quantitatively and qualitatively describe the dynamics of Ca2+ ions influx into the terminal, acetylcholine release from the vesicles, accumulation of its free fraction, diffusion into the synaptic cleft, and binding with the receptors on the postsynaptic structures with the generation of the fast excitatory postsynaptic potential. They are in good agreement with the observed experimental findings.

  18. Cholinergic modulation of the hippocampal region and memory function.

    Science.gov (United States)

    Haam, Juhee; Yakel, Jerrel L

    2017-08-01

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

  19. Modulation of the Cholinergic Mechanisms in the Bronchial Smooth Muscle.

    Science.gov (United States)

    1984-06-01

    Ginsborg and Hirst, 1q72; Sawynok and Jhamandas, 1976), although theopylline has not shown to be a specific adenosine receptor antagonist in all the tissues... theopylline and other cyclic nucletide phosphodiesterase inhibitors. Acta Pharmacol. Toxicol. 45, 336-344. Fredholm, B.B. and P. Hedqvist, 1980...51 mM) evoked release of [3H]-Ach from cholinergic nerves in the bronchial smooth muscle. The effect of theopylline (I mM) on the response to

  20. Atopic predisposition in cholinergic urticaria patients and its implications.

    Science.gov (United States)

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

    2016-12-01

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

  1. Cholinergic Urticaria with Anaphylaxis: An Underrecognized Clinical Entity.

    Science.gov (United States)

    Vadas, Peter; Sinilaite, Angela; Chaim, Marcus

    2016-01-01

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

  2. BRAINSTEM CHOLINERGIC MODULATION OF MUSCLE TONE IN INFANT RATS

    OpenAIRE

    Gall, Andrew J.; Poremba, Amy; Blumberg, Mark S.

    2007-01-01

    In week-old rats, lesions of the dorsolateral pontine tegmentum (DLPT) and nucleus pontis oralis (PnO) have opposing effects on nuchal muscle tone. Specifically, pups with DLPT lesions exhibit prolonged bouts of nuchal muscle atonia (indicative of sleep) and pups with PnO lesions exhibit prolonged bouts of high nuchal muscle tone (indicative of wakefulness). Here we test the hypothesis that nuchal muscle tone is modulated, at least in part, by cholinergically mediated interactions between the...

  3. Dopaminergic and Cholinergic Modulation of Striatal Tyrosine Hydroxylase Interneurons

    OpenAIRE

    Ibáñez-Sandoval, Osvaldo; Xenias, Harry S.; Tepper, James M.; Koós, Tibor

    2015-01-01

    The recent electrophysiological characterization of TH-expressing GABAergic interneurons (THINs) in the neostriatum revealed an unexpected degree of diversity of interneurons in this brain area (Ibáñez-Sandoval et al., 2010, Unal et al., 2011, 2013). Despite being relatively few in number, THINs may play a significant role in transmitting and distributing extra- and intrastriatal neuromodulatory signals in the striatal circuitry. Here we investigated the dopaminergic and cholinergic regulatio...

  4. Basal forebrain cholinergic input is not essential for lesion-induced plasticity in mature auditory cortex.

    Science.gov (United States)

    Kamke, Marc R; Brown, Mel; Irvine, Dexter R F

    2005-11-23

    The putative role of the basal forebrain cholinergic system in mediating lesion-induced plasticity in topographic cortical representations was investigated. Cholinergic immunolesions were combined with unilateral restricted cochlear lesions in adult cats, demonstrating the consequence of cholinergic depletion on lesion-induced plasticity in primary auditory cortex (AI). Immunolesions almost eliminated the cholinergic input to AI, while cochlear lesions produced broad high-frequency hearing losses. The results demonstrate that the near elimination of cholinergic input does not disrupt reorganization of the tonotopic representation of the lesioned (contralateral) cochlea in AI and does not affect the normal representation of the unlesioned (ipsilateral) cochlea. It is concluded that cholinergic basal forebrain input to AI is not essential for the occurrence of lesion-induced plasticity in AI.

  5. Segregated cholinergic transmission modulates dopamine neurons integrated in distinct functional circuits.

    Science.gov (United States)

    Dautan, Daniel; Souza, Albert S; Huerta-Ocampo, Icnelia; Valencia, Miguel; Assous, Maxime; Witten, Ilana B; Deisseroth, Karl; Tepper, James M; Bolam, J Paul; Gerdjikov, Todor V; Mena-Segovia, Juan

    2016-08-01

    Dopamine neurons in the ventral tegmental area (VTA) receive cholinergic innervation from brainstem structures that are associated with either movement or reward. Whereas cholinergic neurons of the pedunculopontine nucleus (PPN) carry an associative/motor signal, those of the laterodorsal tegmental nucleus (LDT) convey limbic information. We used optogenetics and in vivo juxtacellular recording and labeling to examine the influence of brainstem cholinergic innervation of distinct neuronal subpopulations in the VTA. We found that LDT cholinergic axons selectively enhanced the bursting activity of mesolimbic dopamine neurons that were excited by aversive stimulation. In contrast, PPN cholinergic axons activated and changed the discharge properties of VTA neurons that were integrated in distinct functional circuits and were inhibited by aversive stimulation. Although both structures conveyed a reinforcing signal, they had opposite roles in locomotion. Our results demonstrate that two modes of cholinergic transmission operate in the VTA and segregate the neurons involved in different reward circuits.

  6. Animal model of vascular dementia and its cholinergic mechanism

    Institute of Scientific and Technical Information of China (English)

    FAN Wen-hui; LI Lu-si; LIU Zhi-rong; ZHU Hong-yan; CHEN Kang-ning

    2001-01-01

    Objective: To establish a model of vascular dementia (VD) in aging rats and study primarily the cholinergic mechanism of hypomnesia. Methods: Chronic hypoperfusion of cerebral blood flow (CBF) in the forebrain was performed in aging rats with permanent bilateral common carotid arteries occlusion (PBCCAO). Then the rats were tested with a computerized shuttle-training case. The changes of cerebrovascular system were observed with digital subtraction angiography (DSA). The brain tissues were studied with immunohistochemical method with cholinergic acetyltransferase (ChAT) as a marker. Results: The cognitive function of rats was obviously reduced in 2 months after chronic cerebral hypoperfusion and became worse 2 months later, showing a more marked decrease of ChAT positive neurons and fibers in CA1 of the hippocampus as compared with the rats of the control, which had a significant positive correlation with memory ability. Conclusion: This rat model is successfully established to imitate human VD induced with chronic cerebral hypoperfusion. The mechanism of the hypomnesia of VD might be the impairment of cholinergic neurons in frontal cortex and hippocampus.

  7. Modulatory compartments in cortex and local regulation of cholinergic tone.

    Science.gov (United States)

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

    2016-09-01

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

  8. Cholinergic control of visual categorisation in macaques

    Directory of Open Access Journals (Sweden)

    Nikolaos C. Aggelopoulos

    2011-11-01

    Full Text Available Acetylcholine (ACh is a neurotransmitter acting via muscarinic and nicotinic receptors that is implicated in several cognitive functions and impairments, such as Alzheimer’s disease. It is believed to especially affect the acquisition of new information, which is particularly important when behaviour needs to be adapted to new situations and to novel sensory events. Categorisation, the process of assigning stimuli to a category, is a cognitive function that also involves information acquisition. The role of ACh on categorisation has not been previously studied. We have examined the effects of scopolamine, an antagonist of muscarinic ACh receptors, on visual categorisation in macaque monkeys using familiar and novel stimuli. When the peripheral effects of scopolamine on the parasympathetic nervous system were controlled for, categorisation performance was disrupted following systemic injections of scopolamine. This impairment was observed only when the stimuli that needed to be categorised had not been seen before. In other words, the monkeys were not impaired by the central action of scopolamine in categorising a set of familiar stimuli (stimuli which they had categorised successfully in previous sessions. Categorisation performance also deteriorated as the stimulus became less salient by an increase in the level of visual noise. However, scopolamine did not cause additional performance disruptions for difficult categorisation judgements at lower coherence levels. Scopolamine, therefore, specifically affects the assignment of new exemplars to established cognitive categories, presumably by impairing the processing of novel information. Since we did not find an effect of scopolamine in the categorisation of familiar stimuli, scopolamine had no significant central action on other cognitive functions such as perception, attention, memory or executive control within the context of our categorisation task.

  9. Heart failure causes cholinergic transdifferentiation of cardiac sympathetic nerves via gp130-signaling cytokines in rodents.

    Science.gov (United States)

    Kanazawa, Hideaki; Ieda, Masaki; Kimura, Kensuke; Arai, Takahide; Kawaguchi-Manabe, Haruko; Matsuhashi, Tomohiro; Endo, Jin; Sano, Motoaki; Kawakami, Takashi; Kimura, Tokuhiro; Monkawa, Toshiaki; Hayashi, Matsuhiko; Iwanami, Akio; Okano, Hideyuki; Okada, Yasunori; Ishibashi-Ueda, Hatsue; Ogawa, Satoshi; Fukuda, Keiichi

    2010-02-01

    Although several cytokines and neurotrophic factors induce sympathetic neurons to transdifferentiate into cholinergic neurons in vitro, the physiological and pathophysiological roles of this remain unknown. During congestive heart failure (CHF), sympathetic neural tone is upregulated, but there is a paradoxical reduction in norepinephrine synthesis and reuptake in the cardiac sympathetic nervous system (SNS). Here we examined whether cholinergic transdifferentiation can occur in the cardiac SNS in rodent models of CHF and investigated the underlying molecular mechanism(s) using genetically modified mice. We used Dahl salt-sensitive rats to model CHF and found that, upon CHF induction, the cardiac SNS clearly acquired cholinergic characteristics. Of the various cholinergic differentiation factors, leukemia inhibitory factor (LIF) and cardiotrophin-1 were strongly upregulated in the ventricles of rats with CHF. Further, LIF and cardiotrophin-1 secreted from cultured failing rat cardiomyocytes induced cholinergic transdifferentiation in cultured sympathetic neurons, and this process was reversed by siRNAs targeting Lif and cardiotrophin-1. Consistent with the data in rats, heart-specific overexpression of LIF in mice caused cholinergic transdifferentiation in the cardiac SNS. Further, SNS-specific targeting of the gene encoding the gp130 subunit of the receptor for LIF and cardiotrophin-1 in mice prevented CHF-induced cholinergic transdifferentiation. Cholinergic transdifferentiation was also observed in the cardiac SNS of autopsied patients with CHF. Thus, CHF causes target-dependent cholinergic transdifferentiation of the cardiac SNS via gp130-signaling cytokines secreted from the failing myocardium.

  10. Acupuncture Stimulation Alleviates Corticosterone-Induced Impairments of Spatial Memory and Cholinergic Neurons in Rats

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    Bombi Lee

    2012-01-01

    Full Text Available The purpose of this study was to examine whether acupuncture improves spatial cognitive impairment induced by repeated corticosterone (CORT administration in rats. The effect of acupuncture on the acetylcholinergic system was also investigated in the hippocampus. Male rats were subcutaneously injected with CORT (5 mg/kg once daily for 21 days. Acupuncture stimulation was performed at the HT7 (Sinmun acupoint for 5 min before CORT injection. HT7 acupoint is located at the end of transverse crease of ulnar wrist of forepaw. In CORT-treated rats, reduced spatial cognitive function was associated with significant increases in plasma CORT level (+36% and hippocampal CORT level (+204% compared with saline-treated rats. Acupuncture stimulation improved the escape latency for finding the platform in the Morris water maze. Consistently, the acupuncture significantly alleviated memory-associated decreases in cholinergic immunoreactivity and mRNA expression of BDNF and CREB in the hippocampus. These findings demonstrate that stimulation of HT7 acupoint produced significant neuroprotective activity against the neuronal impairment and memory dysfunction.

  11. UNILATERAL MYDRIASIS WITH CHOLINERGIC SUPER SENSITIVITY: A DIAGNOSTIC DILEMMA - A CASE SERIES REPORT

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    Sandhya

    2014-05-01

    Full Text Available Pupillary abnormalities are a common feature of general ophthalmic practice. It often causes confusion as they can be manifestations of local and/ or systemic diseases. These diseases may range from vision threatening to life endangering to innocuous ones. A keen observational and clinical skill can help the ophthalmologist in diagnosis & timely referral when necessary. We report 3 cases of acquired mydriasis, with cholinergic supersensitivity. The short history poses a diagnostic dilemma as to whether it is Adie’s Tonic pupil or a harbinger of a serious neurological problem. 2 of the patients with mydriasis were younger, 32 & 35 years of age, presenting with recent onset of blurring of Vision for distance and difficulty in reading. The 3rd patient was a 45 year old presbyope who presented with sudden drop in near vision in one eye. Our cases raise several important question regarding so-called “benign pupillary dilation of the young” and its relationship with Adie‘s tonic pupil. Demonstration of probable transient parasympathetic dysfunction suggests that pharmacologic testing with dilute pilocarpine should be considered in patients reporting with near vision problems with isolated unilateral recent onset mydriasis which is probably intermittent. Thorough history and basic clinical neurological examination are mandatory. The importance of timely referral to neurologist must be borne in mind always in such cases.

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

    Science.gov (United States)

    Kosovicheva, Anna A; Sheremata, Summer L; Rokem, Ariel; Landau, Ayelet N; Silver, Michael A

    2012-01-01

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

  13. Cholinergic regulation of the evoked quantal release at frog neuromuscular junction

    Science.gov (United States)

    Nikolsky, Eugeny E; Vyskočil, František; Bukharaeva, Ella A; Samigullin, Dmitry; Magazanik, Lev G

    2004-01-01

    The effects of cholinergic drugs on the quantal contents of the nerve-evoked endplate currents (EPCs) and the parameters of the time course of quantal release (minimal synaptic latency, main modal value of latency histogram and variability of synaptic latencies) were studied at proximal, central and distal regions of the frog neuromuscular synapse. Acetylcholine (ACh, 5 × 10−4 m), carbachol (CCh, 1 × 10−5 m) or nicotine (5 × 10−6 m) increased the numbers of EPCs with long release latencies mainly in the distal region of the endplate (90–120 μm from the last node of Ranvier), where the synchronization of transmitter release was the most pronounced. The parameters of focally recorded motor nerve action potentials were not changed by either ACh or CCh. The effects of CCh and nicotine on quantal dispersion were reduced substantially by 5 × 10−7 m (+)tubocurarine (TC). The muscarinic agonists, oxotremorine and the propargyl ester of arecaidine, as well as antagonists such as pirenzepine, AF-DX 116 and methoctramine, alone or in combination, did not affect the dispersion of the release. Muscarinic antagonists did not block the dispersion action of CCh. Cholinergic drugs either decreased the quantal content mo (muscarinic agonist, oxotremorine M, and nicotinic antagonist, TC), or decreased mo and dispersed the release (ACh, CCh and nicotine). The effects on mo were not related either to the endplate region or to the initial level of release dispersion. It follows that the mechanisms regulating the amount and the time course of transmitter release are different and that, among other factors, they are altered by presynaptic nicotinic receptors. PMID:15254150

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

    Directory of Open Access Journals (Sweden)

    Anna A. Kosovicheva

    2012-09-01

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

  15. Changes in brain MicroRNAs contribute to cholinergic stress reactions.

    Science.gov (United States)

    Meerson, Ari; Cacheaux, Luisa; Goosens, Ki Ann; Sapolsky, Robert M; Soreq, Hermona; Kaufer, Daniela

    2010-01-01

    Mental stress modifies both cholinergic neurotransmission and alternative splicing in the brain, via incompletely understood mechanisms. Here, we report that stress changes brain microRNA (miR) expression and that some of these stress-regulated miRs regulate alternative splicing. Acute and chronic immobilization stress differentially altered the expression of numerous miRs in two stress-responsive regions of the rat brain, the hippocampal CA1 region and the central nucleus of the amygdala. miR-134 and miR-183 levels both increased in the amygdala following acute stress, compared to unstressed controls. Chronic stress decreased miR-134 levels, whereas miR-183 remained unchanged in both the amygdala and CA1. Importantly, miR-134 and miR-183 share a common predicted mRNA target, encoding the splicing factor SC35. Stress was previously shown to upregulate SC35, which promotes the alternative splicing of acetylcholinesterase (AChE) from the synapse-associated isoform AChE-S to the, normally rare, soluble AChE-R protein. Knockdown of miR-183 expression increased SC35 protein levels in vitro, whereas overexpression of miR-183 reduced SC35 protein levels, suggesting a physiological role for miR-183 regulation under stress. We show stress-induced changes in miR-183 and miR-134 and suggest that, by regulating splicing factors and their targets, these changes modify both alternative splicing and cholinergic neurotransmission in the stressed brain.

  16. Neuropharmacological Treatment of Mental Dysfunction in Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Patrick McNamara

    2006-01-01

    Full Text Available Many patients with Parkinson's Disease (PD experience significant cognitive and mood impairment -even early in the course of the disease. These mental impairments are only partially responsive to levodopa treatment and are often as disabling as the motor impairment, particularly in mid and late stages of the disease. Investigators have recently begun a search for new agents that can effectively treat mental dysfunction of PD. Although there have been only a handful of properly controlled clinical trials of interventions targeted at amelioration of mental dysfunction in PD, progress has been made. Based on the available evidence, targeting catecholaminergic and cholinergic function may be an effective strategy for amelioration of cognitve, mood and psychiatric disturbances in PD.

  17. [Hypothalamic dysfunction in obesity].

    Science.gov (United States)

    van de Sande-Lee, Simone; Velloso, Licio A

    2012-08-01

    Obesity, defined as abnormal or excessive fat accumulation that may impair life quality, is one of the major public health problems worldwide. It results from an imbalance between food intake and energy expenditure. The control of energy balance in animals and humans is performed by the central nervous system (CNS) by means of neuroendocrine connections, in which circulating peripheral hormones, such as leptin and insulin, provide signals to specialized neurons of the hypothalamus reflecting body fat stores, and induce appropriate responses to maintain the stability of these stores. The majority of obesity cases are associated with central resistance to both leptin and insulin actions. In experimental animals, high-fat diets can induce an inflammatory process in the hypothalamus, which impairs leptin and insulin intracellular signaling pathways, and results in hyperphagia, decreased energy expenditure and, ultimately, obesity. Recent evidence obtained from neuroimaging studies and assessment of inflammatory markers in the cerebrospinal fluid of obese subjects suggests that similar alterations may be also present in humans. In this review, we briefly present the mechanisms involved with the loss of homeostatic control of energy balance in animal models of obesity, and the current evidence of hypothalamic dysfunction in obese humans.

  18. Posterior Tibial Tendon Dysfunction

    Science.gov (United States)

    .org Posterior Tibial Tendon Dysfunction Page ( 1 ) Posterior tibial tendon dysfunction is one of the most common problems of the foot and ankle. It occurs when the posterior tibial tendon becomes inflamed or torn. As a result, the ...

  19. Female Sexual Dysfunction

    Science.gov (United States)

    ... Endocrinologist Search Featured Resource Menopause Map™ View Female Sexual Dysfunction February 2012 Download PDFs English Espanol Editors ... Resources Mayo Clinic Cleveland Clinic What is female sexual dysfunction (FSD)? Many women have a low sex ...

  20. Medial-to-lateral gradient of neostriatal NGF receptors: relationship to cholinergic neurons and NGF-like immunoreactivity.

    Science.gov (United States)

    Altar, C A; Dugich-Djordjevic, M; Armanini, M; Bakhit, C

    1991-03-01

    High-affinity binding sites for recombinant human NGF (rhNGF) were studied in the caudate-putamen of the adult rat and rabbit. Displaceable 125I-rhNGF binding sites were densely distributed throughout the caudate-putamen and were 2-3-fold more prevalant in the ventrolateral and lateral than in the medial caudate-putamen. The amount of nondisplaceable binding did not vary throughout the caudate-putamen. The medial-to-lateral receptor gradient was correlated (r = +0.99) with a 2-3-fold medial-to-lateral increase in ChAT activity. In contrast, NGF-like immunoreactivity (NGF-LI) was prevalent but uniformly distributed in the caudate-putamen. Lesions of intrinsic cholinergic neurons by quinolinic acid produced extensive gliosis in the medial, central, and lateral caudate-putamen, yet 125I-rhNGF binding was decreased in each of these regions. The activity of ChAT and 125I-rhNGF binding throughout the caudate-putamen were each decreased by 40% following quinolinic acid. Binding was not changed after 70-77% dopamine nerve terminal depletions induced by 6-hydroxydopamine, demonstrating a nonglial, nondopaminergic locus for striatal NGF binding sites. The cholinergiclike topography of NGF binding sites throughout the intact caudate-putamen, the parallel decreases of cholinergic neurons and NGF binding sites following intrinsic neuronal loss, and the uniform neostriatal gradient of NGF-LI are consistent with the trophic role of endogenous NGF for cholinergic interneurons of the caudate-putamen.

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

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    V. Brusasco

    2006-12-01

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

  2. Novel aspects of cholinergic regulation of colonic ion transport

    Science.gov (United States)

    Bader, Sandra; Diener, Martin

    2015-01-01

    Nicotinic receptors are not only expressed by excitable tissues, but have been identified in various epithelia. One aim of this study was to investigate the expression of nicotinic receptors and their involvement in the regulation of ion transport across colonic epithelium. Ussing chamber experiments with putative nicotinic agonists and antagonists were performed at rat colon combined with reverse transcription polymerase chain reaction (RT-PCR) detection of nicotinic receptor subunits within the epithelium. Dimethylphenylpiperazinium (DMPP) and nicotine induced a tetrodotoxin-resistant anion secretion leading to an increase in short-circuit current (Isc) across colonic mucosa. The response was suppressed by the nicotinic receptor antagonist hexamethonium. RT-PCR experiments revealed the expression of α2, α4, α5, α6, α7, α10, and β4 nicotinic receptor subunits in colonic epithelium. Choline, the product of acetylcholine hydrolysis, is known for its affinity to several nicotinic receptor subtypes. As a strong acetylcholinesterase activity was found in colonic epithelium, the effect of choline on Isc was examined. Choline induced a concentration-dependent, tetrodotoxin-resistant chloride secretion which was, however, resistant against hexamethonium, but was inhibited by atropine. Experiments with inhibitors of muscarinic M1 and M3 receptors revealed that choline-evoked secretion was mainly due to a stimulation of epithelial M3 receptors. Although choline proved to be only a partial agonist, it concentration-dependently desensitized the response to acetylcholine, suggesting that it might act as a modulator of cholinergically induced anion secretion. Thus the cholinergic regulation of colonic ion transport – up to now solely explained by cholinergic submucosal neurons stimulating epithelial muscarinic receptors – is more complex than previously assumed. PMID:26236483

  3. Cholinergic Interneurons Underlie Spontaneous Dopamine Release in Nucleus Accumbens.

    Science.gov (United States)

    Yorgason, Jordan T; Zeppenfeld, Douglas M; Williams, John T

    2017-02-22

    The release of dopamine from terminals in the NAc is regulated by a number of factors, including voltage-gated ion channels, D2-autoreceptors, and nAChRs. Cholinergic interneurons (CINs) drive dopamine release through activation of nAChRs on dopamine terminals. Using cyclic voltammetry in mouse brain slices, nAChR-dependent spontaneous dopamine transients and the mechanisms underlying the origin were examined in the NAc. Spontaneous events were infrequent (0.3 per minute), but the rate and amplitude were increased after blocking Kv channels with 4-aminopyridine. Although the firing frequency of CINs was increased by blocking glutamate reuptake with TBOA and the Sk blocker apamin, only 4-aminopyridine increased the frequency of dopamine transients. In contrast, inhibition of CIN firing with the μ/δ selective opioid [Met(5)]enkephalin (1 μm) decreased spontaneous dopamine transients. Cocaine increased the rate and amplitude of dopamine transients, suggesting that the activity of the dopamine transporter limits the detection of these events. In the presence of cocaine, the rate of spontaneous dopamine transients was further increased after blocking D2-autoreceptors. Blockade of muscarinic receptors had no effect on evoked dopamine release, suggesting that feedback inhibition of acetylcholine release was not involved. Thus, although spontaneous dopamine transients are reliant on nAChRs, the frequency was not strictly governed by the activity of CINs. The increase in frequency of spontaneous dopamine transients induced by cocaine was not due to an increase in cholinergic tone and is likely a product of an increase in detection resulting from decreased dopamine reuptake.SIGNIFICANCE STATEMENT The actions of dopamine in the NAc are thought to be responsible for endogenous reward and the reinforcing properties of drugs of abuse, such as psychostimulants. The present work examines the mechanisms underlying nAChR-induced spontaneous dopamine release. This study

  4. Mechanisms mediating cholinergic antral circular smooth muscle contraction in rats

    Science.gov (United States)

    Wrzos, Helena F; Tandon, Tarun; Ouyang, Ann

    2004-01-01

    AIM: To investigate the pathway (s) mediating rat antral circular smooth muscle contractile responses to the cholinomimetic agent, bethanechol and the subtypes of muscarinic receptors mediating the cholinergic contraction. METHODS: Circular smooth muscle strips from the antrum of Sprague-Dawley rats were mounted in muscle baths in Krebs buffer. Isometric tension was recorded. Cumulative concentration-response curves were obtained for (+)-cis-dioxolane (cD), a nonspecific muscarinic agonist, at 10-8-10-4 mol/L, in the presence of tetrodotoxin (TTX, 10-7 mol/L). Results were normalized to cross sectional area. A repeat concentration-response curve was obtained after incubation of the muscle for 90 min with antagonists for M1 (pirenzepine), M2 (methoctramine) and M3 (darifenacin) muscarinic receptor subtypes. The sensitivity to PTX was tested by the ip injection of 100 mg/kg of PTX 5 d before the experiment. The antral circular smooth muscles were removed from PTX-treated and non-treated rats as strips and dispersed smooth muscle cells to identify whether PTX-linked pathway mediated the contractility to bethanechol. RESULTS: A dose-dependent contractile response observed with bethanechol, was not affected by TTX. The pretreatment of rats with pertussis toxin decreased the contraction induced by bethanechol. Lack of calcium as well as the presence of the L-type calcium channel blocker, nifedipine, also inhibited the cholinergic contraction, with a reduction in response from 2.5 ± 0.4 g/mm2 to 1.2 ± 0.4 g/mm2 (P methocramine (M2) > pirenzepine (M1). CONCLUSION: The muscarinic receptors-dependent contraction of rat antral circular smooth muscles was linked to the signal transduction pathway(s) involving pertussis-toxin sensitive GTP-binding proteins and to extracellular calcium via L-type voltage gated calcium channels. The presence of the residual contractile response after the treatment with nifedipine, suggests that an additional pathway could mediate the

  5. Mechanisms mediating cholinergic antral circular smooth muscle contraction in rats

    Institute of Scientific and Technical Information of China (English)

    Helena F Wrzos; Tarun Tandon; Ann Ouyang

    2004-01-01

    AIM: To investigate the pathway (s) mediating rat antral circular smooth muscle contractile responses to the cholinomimetic agent, bethanechol and the subtypes of muscarinic receptors mediating the cholinergic contraction.METHODS: Circular smooth muscle strips from the antrum of Sprague-Dawley rats were mounted in muscle baths in Krebs buffer. Isometric tension was recorded. Cumulative concentration-response curves were obtained for (+)-cisdioxolane (cD), a nonspecific muscarinic agonist, at 10-8-10-4 mol/L, in the presence of tetrodotoxin (TTX, 10-7 mol/L).Results were normalized to cross sectional area. A repeat concentration-response curve was obtained after incubation of the muscle for 90 min with antagonists for M1 (pirenzepine),M2 (methoctramine) and M3 (darifenacin) muscarinic receptor subtypes. The sensitivity to PTX was tested by the ip injection of 100 mg/kg of PTX 5 d before the experiment. The antral circular smooth muscles were removed from PTX-treated and non-treated rats as strips and dispersed smooth muscle cells to identify whether PTX-linked pathway mediated the contractility to bethanechol.RESULTS: A dose-dependent contractile response observed with bethanechol, was not affected by TTX. The pretreatment of rats with pertussis toxin decreased the contraction induced by bethanechol. Lack of calcium as Well as the presence of the L-type calcium channel blocker, nifedipine, also inhibited the cholinergic contraction, with a reduction in response from 2.5±0.4 g/mm2 to 1.2±0.4 g/mm2 (P<0.05). The doseresponse curves were shifted to the right by muscarinic antagonists in the following order of affinity: darifenacin(M3)>methocramine (M2)>pirenzepine (M1).CONCLUSION: The muscarinic receptors-dependent contraction of rat antral circular smooth muscles was linked to the signal transduction pathway(s) involving pertussis-toxin sensitive GTP-binding proteins and to extracellular calcium via L-type voltage gated calcium channels. The presence of the

  6. 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.

  7. Ultrastructural localization of cholinergic muscarinic receptors in rat brain cortical capillaries

    NARCIS (Netherlands)

    Luiten, PGM; deJong, GI; VanderZee, EA; vanDijken, H; Dijken, H. van

    1996-01-01

    Cholinergic innervation of the cerebrovasculature is known to regulate vascular tone, perfusion rate and permeability of the microvascular wall. Notably the cholinergic innervation of cerebral capillaries is of interest since these capillaries form the blood-brain barrier. Although there is a genera

  8. A cellular and regulatory map of the cholinergic nervous system of C. elegans.

    Science.gov (United States)

    Pereira, Laura; Kratsios, Paschalis; Serrano-Saiz, Esther; Sheftel, Hila; Mayo, Avi E; Hall, David H; White, John G; LeBoeuf, Brigitte; Garcia, L Rene; Alon, Uri; Hobert, Oliver

    2015-12-25

    Nervous system maps are of critical importance for understanding how nervous systems develop and function. We systematically map here all cholinergic neuron types in the male and hermaphrodite C. elegans nervous system. We find that acetylcholine (ACh) is the most broadly used neurotransmitter and we analyze its usage relative to other neurotransmitters within the context of the entire connectome and within specific network motifs embedded in the connectome. We reveal several dynamic aspects of cholinergic neurotransmitter identity, including a sexually dimorphic glutamatergic to cholinergic neurotransmitter switch in a sex-shared interneuron. An expression pattern analysis of ACh-gated anion channels furthermore suggests that ACh may also operate very broadly as an inhibitory neurotransmitter. As a first application of this comprehensive neurotransmitter map, we identify transcriptional regulatory mechanisms that control cholinergic neurotransmitter identity and cholinergic circuit assembly.

  9. Cholinergic deficiency involved in vascular dementia:possible mechanism and strategy of treatment

    Institute of Scientific and Technical Information of China (English)

    Juan WANG; Hai-yan ZHANG; Xi-can TANG

    2009-01-01

    Vascular dementia (VaD) is a progressive neurodegenerative disease with a high prevalence.Several studies have recently reported that VaD patients present cholinergic deficits in the brain and cerebrospinal fluid (CSF) that may be closely related to the pathophysiology of cognitive impairment.Moreover,cholinergic therapies have shown promising effects on cognitive improvement in VaD patients.The precise mechanisms of these cholinergic agents are currently not fully understood;however,accumulating evidence indicates that these drugs may act through the cholinergic anti-inflammatory pathway,in which the efferent vagus nerve signals suppress pro-inflammatory cytokine release and inhibit inflammation,although regulation of oxidative stress and energy metabolism,alleviation of apoptosis may also be involved.In this paper,we provide a brief overview of the cholinergic treatment strategy for VaD and its relevant mechanisms of anti-inflammation.

  10. The cholinergic anti-inflammatory pathway delays TLR-induced skin allograft rejection in mice: cholinergic pathway modulates alloreactivity.

    Directory of Open Access Journals (Sweden)

    Claude Sadis

    Full Text Available Activation of innate immunity through Toll-like receptors (TLR can abrogate transplantation tolerance by revealing hidden T cell alloreactivity. Separately, the cholinergic anti-inflammatory pathway has the capacity to dampen macrophage activation and cytokine release during endotoxemia and ischemia reperfusion injury. However, the relevance of the α7 nicotinic acetylcholine receptor (α7nAChR-dependent anti-inflammatory pathway in the process of allograft rejection or maintenance of tolerance remains unknown. The aim of our study is to investigate whether the cholinergic pathway could impact T cell alloreactivity and transplant outcome in mice. For this purpose, we performed minor-mismatched skin allografts using donor/recipient combinations genetically deficient for the α7nAChR. Minor-mismatched skin grafts were not rejected unless the mice were housed in an environment with endogenous pathogen exposure or the graft was treated with direct application of imiquimod (a TLR7 ligand. The α7nAChR-deficient recipient mice showed accelerated rejection compared to wild type recipient mice under these conditions of TLR activation. The accelerated rejection was associated with enhanced IL-17 and IFN-γ production by alloreactive T cells. An α7nAChR-deficiency in the donor tissue facilitated allograft rejection but not in recipient mice. In addition, adoptive T cell transfer experiments in skin-grafted lymphopenic animals revealed a direct regulatory role for the α7nAChR on T cells. Taken together, our data demonstrate that the cholinergic pathway regulates alloreactivity and transplantation tolerance at multiple levels. One implication suggested by our work is that, in an organ transplant setting, deliberate α7nAChR stimulation of brain dead donors might be a valuable approach for preventing donor tissue inflammation prior to transplant.

  11. The cholinergic anti-inflammatory pathway delays TLR-induced skin allograft rejection in mice: cholinergic pathway modulates alloreactivity.

    Science.gov (United States)

    Sadis, Claude; Detienne, Sophie; Vokaer, Benoît; Charbonnier, Louis-Marie; Lemaître, Philippe; Spilleboudt, Chloé; Delbauve, Sandrine; Kubjak, Carole; Flamand, Véronique; Field, Kenneth A; Goldman, Michel; Benghiat, Fleur S; Le Moine, Alain

    2013-01-01

    Activation of innate immunity through Toll-like receptors (TLR) can abrogate transplantation tolerance by revealing hidden T cell alloreactivity. Separately, the cholinergic anti-inflammatory pathway has the capacity to dampen macrophage activation and cytokine release during endotoxemia and ischemia reperfusion injury. However, the relevance of the α7 nicotinic acetylcholine receptor (α7nAChR)-dependent anti-inflammatory pathway in the process of allograft rejection or maintenance of tolerance remains unknown. The aim of our study is to investigate whether the cholinergic pathway could impact T cell alloreactivity and transplant outcome in mice. For this purpose, we performed minor-mismatched skin allografts using donor/recipient combinations genetically deficient for the α7nAChR. Minor-mismatched skin grafts were not rejected unless the mice were housed in an environment with endogenous pathogen exposure or the graft was treated with direct application of imiquimod (a TLR7 ligand). The α7nAChR-deficient recipient mice showed accelerated rejection compared to wild type recipient mice under these conditions of TLR activation. The accelerated rejection was associated with enhanced IL-17 and IFN-γ production by alloreactive T cells. An α7nAChR-deficiency in the donor tissue facilitated allograft rejection but not in recipient mice. In addition, adoptive T cell transfer experiments in skin-grafted lymphopenic animals revealed a direct regulatory role for the α7nAChR on T cells. Taken together, our data demonstrate that the cholinergic pathway regulates alloreactivity and transplantation tolerance at multiple levels. One implication suggested by our work is that, in an organ transplant setting, deliberate α7nAChR stimulation of brain dead donors might be a valuable approach for preventing donor tissue inflammation prior to transplant.

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

    Directory of Open Access Journals (Sweden)

    Maya Kaufman

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

  13. A Reaction-Diffusion Model of Cholinergic Retinal Waves

    Science.gov (United States)

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

    2014-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Huan Wang

    2015-01-01

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

  15. THE ROLE OF PARASYMPATHETIC AUTONOMIC REGULATION IN ENSURING OF RATS’ RESISTANCE IN THE MODEL OF MULTIPLE ORGAN DYSFUNCTION SYNDROM

    Directory of Open Access Journals (Sweden)

    I. A. Khrypachenko

    2015-06-01

    Full Text Available To assess contribution of autonomic regulation in multiple organ dysfunction syndrome (MODS survival ensuring and to test hypothesis about possible correction of clinical course by modulating the activity of parasympathetic influences we performed experiments on rats’ model of the MODS. It was determined that nonresistant animals differentiated by less intensity of parasympathetic regulation response. It was revealed that stimulation of cholinergic system decrease lethality in rats, and inhibits the power of high frequency regulatory effects on the heart rate.

  16. Effects of beta-amyloid protein on M1 and M2 subtypes of muscarinic acetylcholine receptors in the medial septum-diagonal band complex of the rat: relationship with cholinergic, GABAergic, and calcium-binding protein perikarya.

    Science.gov (United States)

    González, Iván; Arévalo-Serrano, Juan; Sanz-Anquela, José Miguel; Gonzalo-Ruiz, Alicia

    2007-06-01

    Cortical cholinergic dysfunction has been correlated with the expression and processing of beta-amyloid precursor protein. However, it remains unclear as to how cholinergic dysfunction and beta-amyloid (Abeta) formation and deposition might be related to one another. Since the M1- and M2 subtypes of muscarinic acetylcholine receptors (mAChRs) are considered key molecules that transduce the cholinergic message, the purpose of the present study was to assess the effects of the injected Abeta peptide on the number of M1mAchR- and M2mAChR-immunoreactive cells in the medial septum-diagonal band (MS-nDBB) complex of the rat. Injections of Abeta protein into the retrosplenial cortex resulted in a decrease in M1mAChR and M2mAChR immunoreactivity in the MS-nDBB complex. Quantitative analysis revealed a significant reduction in the number of M1mAChR- and M2mAChR-immunoreactive cells in the medial septum nucleus (MS) and in the horizontal nucleus of the diagonal band of Broca (HDB) as compared to the corresponding hemisphere in control animals and with that seen in the contralateral hemisphere, which corresponds to the PBS-injected side. Co-localization studies showed that the M1mAChR protein is localized in GABA-immunoreactive cells of the MS-nDBB complex, in particular those of the MS nucleus, while M2mAChR protein is localized in both the cholinergic and GABAergic cells. Moreover, GABAergic cells containing M2mAChR are mainly localized in the MS nucleus, while cholinergic cells containing M2mAChR are localized in the MS and the HDB nuclei. Our findings suggest that Abeta induces a reduction in M1mAChR- and M2mAChR-containing cells, which may contribute to impairments of cholinergic and GABAergic transmission in the MS-nDBB complex.

  17. Involvement of dopaminergic and cholinergic pathways in the induction of yawning and genital grooming by the aqueous extract of Saccharum officinarum L. (sugarcane) in rats.

    Science.gov (United States)

    Gamberini, Maria T; Gamberini, Maria C; Nasello, Antonia G

    2015-01-01

    Yawning, associated with genital grooming, is a physiological response that may be used for elucidating the mechanism of action of drugs. Preliminary analysis showed that aqueous extract (AE) of Saccharum induced yawns in rats. So, we aimed to quantify these behavioral responses and investigate the pharmacological mechanisms involved in these actions. During 120 min, after AE administration, the yawns and the genital grooming were quantified at 10 min intervals. Since dopaminergic and cholinergic pathways are implied in these responses, AE were evaluated in the presence of haloperidol 0.5 mg/kg and atropine 2 mg/kg. AE 0.5 g/kg increased the yawns, effect that was blocked both by haloperidol and atropine. Genital grooming could only be stimulated by AE 0.5 g/kg when dopaminergic receptors were blocked by haloperidol. However, it was inhibited when atropine was previously administered. So, we demonstrated a central action of Saccharum and it was postulated that neural circuits with the participation of dopaminergic and cholinergic pathways are involved. The fact that AE is comprised of innumerous compounds could justify the extract's distinct responses. Also, we cannot disregard the presence of different neural circuits that count on the participation of dopaminergic and cholinergic pathways and could be activated by the same induction agent.

  18. Increase in cholinergic modulation with pyridostigmine induces anti-inflammatory cell recruitment soon after acute myocardial infarction in rats.

    Science.gov (United States)

    Rocha, Juraci Aparecida; Ribeiro, Susan Pereira; França, Cristiane Miranda; Coelho, Otávio; Alves, Gisele; Lacchini, Silvia; Kallás, Esper Georges; Irigoyen, Maria Cláudia; Consolim-Colombo, Fernanda M

    2016-04-15

    We tested the hypothesis that an increase in the anti-inflammatory cholinergic pathway, when induced by pyridostigmine (PY), may modulate subtypes of lymphocytes (CD4+, CD8+, FOXP3+) and macrophages (M1/M2) soon after myocardial infarction (MI) in rats. Wistar rats, randomly allocated to receive PY (40 mg·kg(-1)·day(-1)) in drinking water or to stay without treatment, were followed for 4 days and then were subjected to ligation of the left coronary artery. The groups-denominated as the pyridostigmine-treated infarcted (IP) and infarcted control (I) groups-were submitted to euthanasia 3 days after MI; the heart was removed for immunohistochemistry, and the peripheral blood and spleen were collected for flow cytometry analysis. Noninfarcted and untreated rats were used as controls (C Group). Echocardiographic measurements were registered on the second day after MI, and heart rate variability was measured on the third day after MI. The infarcted groups had similar MI areas, degrees of systolic dysfunction, blood pressures, and heart rates. Compared with the I Group, the IP Group showed a significant higher parasympathetic modulation and a lower sympathetic modulation, which were associated with a small, but significant, increase in diastolic function. The IP Group showed a significant increase in M2 macrophages and FOXP3(+)cells in the infarcted and peri-infarcted areas, a significantly higher frequency of circulating Treg cells (CD4(+)CD25(+)FOXP3(+)), and a less extreme decrease in conventional T cells (CD25(+)FOXP3(-)) compared with the I Group. Therefore, increasing cholinergic modulation with PY induces greater anti-inflammatory cell recruitment soon after MY in rats.

  19. Warfarin for improvement the cuffed central venous catheter dysfunction and clinical analysis%华法令对于带涤纶套中央静脉导管功能不良的改善及临床分析

    Institute of Scientific and Technical Information of China (English)

    汤小芳; 严连喜; 李康峰; 石平; 王成双; 孔若曦; 严宁; 周玉坤

    2016-01-01

    目的 观察口服华法令对于因血栓及纤维蛋白鞘而至涤纶套中央静脉导管置入后功能不良的改善并行临床分析.方法 59例带卡夫隧道导管患者,分为A组(28例)口服华法令1.5~3mg/d抗凝,对照组B组(31例)口服阿司匹林100mg/d抗凝,两组常规普通肝素封管.记录导管透析中血流量、回血静脉压,记录透析前后尿素氮、肌酐、超滤等,计算透析尿素清除指数,评估透析效果,定期检测非透析状态下国际标准化比值.比较导管留存时间、导管中位留存时间,并观察两组出血、导管相关性血流感染等并发症.观察一年时间.结果 A、B两组透析前后肌酐、尿素氮水平变化存在统计学差异,A组尿素清除指数均达标,A、B两组透析中血流量、回血静脉压比较存在统计学差异.A、B两组透析后比较肌酐、尿素氮水平、尿素清除指数以及国际标准化比值也存在统计学差异,且两组导管留存时间亦存在统计学差异.A组国际标准化比值维持在(2.00±0.93)之间,A、B两组未见出血、导管相关性血流感染并发症.结论 带卡夫中央静脉导管置后常规口服中等剂量华法令抗凝配合肝素封管较口服阿司匹林更能改善因血栓及纤维蛋白鞘而至导管功能不良,延长导管留存时间,且并发症少.但本研究样本量偏少,观察时间偏短,仍需进一步临床验证以证实口服华法令在带卡夫隧道导管置入后临床安全性及有效性.%Objectives To observe the improvement of warfarin for cuffed central venous catheter dysfunction due to thrombus and fibrin sheath and to carry on the clinical analysis.Methods 59 patients with cuffed central venous catheter were divided into group A (28 cases) and control group B (31 cases),patients in the group A were given warfarin 1.5 ~3mg/d,and patients in the control group B were given aspirin 100mg/d.The heparin was used to sealed tube in two groups.Catheter hemodialysis

  20. Cholinergic enhancement of visual attention and neural oscillations in the human brain.

    Science.gov (United States)

    Bauer, Markus; Kluge, Christian; Bach, Dominik; Bradbury, David; Heinze, Hans Jochen; Dolan, Raymond J; Driver, Jon

    2012-03-06

    Cognitive processes such as visual perception and selective attention induce specific patterns of brain oscillations. The neurochemical bases of these spectral changes in neural activity are largely unknown, but neuromodulators are thought to regulate processing. The cholinergic system is linked to attentional function in vivo, whereas separate in vitro studies show that cholinergic agonists induce high-frequency oscillations in slice preparations. This has led to theoretical proposals that cholinergic enhancement of visual attention might operate via gamma oscillations in visual cortex, although low-frequency alpha/beta modulation may also play a key role. Here we used MEG to record cortical oscillations in the context of administration of a cholinergic agonist (physostigmine) during a spatial visual attention task in humans. This cholinergic agonist enhanced spatial attention effects on low-frequency alpha/beta oscillations in visual cortex, an effect correlating with a drug-induced speeding of performance. By contrast, the cholinergic agonist did not alter high-frequency gamma oscillations in visual cortex. Thus, our findings show that cholinergic neuromodulation enhances attentional selection via an impact on oscillatory synchrony in visual cortex, for low rather than high frequencies. We discuss this dissociation between high- and low-frequency oscillations in relation to proposals that lower-frequency oscillations are generated by feedback pathways within visual cortex. Copyright © 2012 Elsevier Ltd. All rights reserved.

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

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    Florian Groessl

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

  2. Huperzine A protects sepsis associated encephalopathy by promoting the deficient cholinergic nervous function.

    Science.gov (United States)

    Zhu, Sen-Zhi; Huang, Wei-Ping; Huang, Lin-Qiang; Han, Yong-Li; Han, Qian-Peng; Zhu, Gao-Feng; Wen, Miao-Yun; Deng, Yi-Yu; Zeng, Hong-Ke

    2016-09-19

    Neuroinflammatory deregulation in the brain plays a crucial role in the pathogenesis of sepsis associated encephalopathy (SAE). Given the mounting evidence of anti-inflammatory and neuroprotective effects of the cholinergic nervous system, it is surprising that there is little information about its changes in the brain during sepsis. To elucidate the role of the cholinergic nervous system in SAE, hippocampal choline acetyltransferase, muscarinic acetylcholine receptor-1, acetylcholinesterase and acetylcholine were evaluated in LPS-induced sepsis rats. Expression of pro-inflammatory cytokines, neuronal apoptosis, and animal cognitive performance were also assessed. Furthermore, therapeutic effects of the acetylcholinesterase inhibitor Huperzine A (HupA) on the hippocampal cholinergic nervous function and neuroinflammation were evaluated. A deficiency of the cholinergic nervous function was revealed in SAE, accompanied with over-expressed pro-inflammatory cytokines, increase in neuronal apoptosis and brain cognitive impairment. HupA remarkably promoted the deficient cholinergic nervous function and attenuated the abnormal neuroinflammation in SAE, paralleled with the recovery of brain function. We suggest that the deficiency of the cholinergic nervous function and the abnormal neuroinflammation are synergistically implicated in the pathogenesis of SAE. Thus, HupA is a potential therapeutic candidate for SAE, as it improves the deficient cholinergic nervous function and exerts anti-inflammatory action.

  3. Synaptic connectivity of the cholinergic axons in the olfactory bulb of the cynomolgus monkey

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    Teresa eLiberia

    2015-03-01

    Full Text Available The olfactory bulb of mammals receives cholinergic afferents from the horizontal limb of the diagonal band of Broca. At present, the synaptic connectivity of the cholinergic axons on the circuits of the olfactory bulb has only been investigated in the rat. In this report, we analyze the synaptic connectivity of the cholinergic axons in the olfactory bulb of the cynomolgus monkey (Macaca fascicularis. Our aim is to investigate whether the cholinergic innervation of the bulbar circuits is phylogenetically conserved between macrosmatic and microsmatic mammals. Our results demonstrate that the cholinergic axons form synaptic contacts on interneurons. In the glomerular layer, their main targets are the periglomerular cells, which receive axo-somatic and axo-dendritic synapses. In the inframitral region, their main targets are the granule cells, which receive synaptic contacts on their dendritic shafts and spines. Although the cholinergic boutons were frequently found in close vicinity of the dendrites of principal cells, we have not found synaptic contacts on them. From a comparative perspective, our data indicate that the synaptic connectivity of the cholinergic circuits is highly preserved in the olfactory bulb of macrosmatic and microsmatic mammals.

  4. 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

    Science.gov (United States)

    Ishibashi, Masaru; Gumenchuk, Iryna; Kang, Bryan; Steger, Catherine; Lynn, Elizabeth; Molina, Nancy E.; Eisenberg, Leonard M.; Leonard, Christopher S.

    2015-01-01

    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 gamma. PMID

  5. Orexin Receptor Activation Generates Gamma Band Input to Cholinergic and Serotonergic Arousal System Neurons and Drives an Intrinsic Ca(2+)-Dependent Resonance in LDT and PPT Cholinergic Neurons.

    Science.gov (United States)

    Ishibashi, Masaru; Gumenchuk, Iryna; Kang, Bryan; Steger, Catherine; Lynn, Elizabeth; Molina, Nancy E; Eisenberg, Leonard M; Leonard, Christopher S

    2015-01-01

    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, Ca(2+)-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 Ca(2+)-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 Ca(2+)-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 Ca(2+) 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 gamma.

  6. 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.

    Directory of Open Access Journals (Sweden)

    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

  7. Obesity and Metabolic Syndrome Affect the Cholinergic Transmission a nd Cognitive Functions.

    Science.gov (United States)

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

    2017-01-01

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

  8. Glial response in the rat models of functionally distinct cholinergic neuronal denervations.

    Science.gov (United States)

    Bataveljic, Danijela; Petrovic, Jelena; Lazic, Katarina; Saponjic, Jasna; Andjus, Pavle

    2015-02-01

    Alzheimer's disease (AD) involves selective loss of basal forebrain cholinergic neurons, particularly in the nucleus basalis (NB). Similarly, Parkinson's disease (PD) might involve the selective loss of pedunculopontine tegmental nucleus (PPT) cholinergic neurons. Therefore, lesions of these functionally distinct cholinergic centers in rats might serve as models of AD and PD cholinergic neuropathologies. Our previous articles described dissimilar sleep/wake-state disorders in rat models of AD and PD cholinergic neuropathologies. This study further examines astroglial and microglial responses as underlying pathologies in these distinct sleep disorders. Unilateral lesions of the NB or the PPT were induced with rats under ketamine/diazepam anesthesia (50 mg/kg i.p.) by using stereotaxically guided microinfusion of the excitotoxin ibotenic acid (IBO). Twenty-one days after the lesion, loss of cholinergic neurons was quantified by nicotinamide adenine dinucleotide phosphate-diaphorase histochemistry, and the astroglial and microglial responses were quantified by glia fibrillary acidic protein/OX42 immunohistochemistry. This study demonstrates, for the first time, the anatomofunctionally related astroglial response following unilateral excitotoxic PPT cholinergic neuronal lesion. Whereas IBO NB and PPT lesions similarly enhanced local astroglial and microglial responses, astrogliosis in the PPT was followed by a remote astrogliosis within the ipslilateral NB. Conversely, there was no microglial response within the NB after PPT lesions. Our results reveal the rostrorostral PPT-NB astrogliosis after denervation of cholinergic neurons in the PPT. This hierarchically and anatomofunctionally guided PPT-NB astrogliosis emerged following cholinergic neuronal loss greater than 17% throughout the overall rostrocaudal PPT dimension.

  9. Structural basis for cholinergic regulation of neural circuits in the mouse olfactory bulb.

    Science.gov (United States)

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

    2017-02-15

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

  10. Development of cardiac parasympathetic neurons, glial cells, and regional cholinergic innervation of the mouse heart.

    Science.gov (United States)

    Fregoso, S P; Hoover, D B

    2012-09-27

    Very little is known about the development of cardiac parasympathetic ganglia and cholinergic innervation of the mouse heart. Accordingly, we evaluated the growth of cholinergic neurons and nerve fibers in mouse hearts from embryonic day 18.5 (E18.5) through postnatal day 21(P21). Cholinergic perikarya and varicose nerve fibers were identified in paraffin sections immunostained for the vesicular acetylcholine transporter (VAChT). Satellite cells and Schwann cells in adjacent sections were identified by immunostaining for S100β calcium binding protein (S100) and brain-fatty acid binding protein (B-FABP). We found that cardiac ganglia had formed in close association to the atria and cholinergic innervation of the atrioventricular junction had already begun by E18.5. However, most cholinergic innervation of the heart, including the sinoatrial node, developed postnatally (P0.5-P21) along with a doubling of the cross-sectional area of cholinergic perikarya. Satellite cells were present throughout neonatal cardiac ganglia and expressed primarily B-FABP. As they became more mature at P21, satellite cells stained strongly for both B-FABP and S100. Satellite cells appeared to surround most cardiac parasympathetic neurons, even in neonatal hearts. Mature Schwann cells, identified by morphology and strong staining for S100, were already present at E18.5 in atrial regions that receive cholinergic innervation at later developmental times. The abundance and distribution of S100-positive Schwann cells increased postnatally along with nerve density. While S100 staining of cardiac Schwann cells was maintained in P21 and older mice, Schwann cells did not show B-FABP staining at these times. Parallel development of satellite cells and cholinergic perikarya in the cardiac ganglia and the increase in abundance of Schwann cells and varicose cholinergic nerve fibers in the atria suggest that neuronal-glial interactions could be important for development of the parasympathetic nervous

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

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    Diana eSimon

    2013-06-01

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

  12. Tolerance of nestin+ cholinergic neurons in the basal forebrain against colchicine-induced cytotoxicity

    Institute of Scientific and Technical Information of China (English)

    Jing Yu; Kaihua Guo; Dongpei Li; Jinhai Duan; Juntao Zou; Junhua Yang; Zhibin Yao

    2011-01-01

    In the present study we injected colchicine into the lateral ventricle of Sprague-Dawley rats to investigate the effects of colchicine on the number of different-type neurons in the basal forebrain and to search for neurons resistant to injury. After colchicine injection, the number of nestin+ cholinergic neurons was decreased at 1 day, but increased at 3 days and peaked at 14-28 days. The quantity of nestin- cholinergic neurons, parvalbumin-positive neurons and choline acetyl transferase-positive neurons decreased gradually. Our results indicate that nestin+ cholinergic neurons possess better tolerance to colchicine-induced neurotoxicity.

  13. Dysfunction of G Protein-Coupled Receptor Kinases in Alzheimer’'s Disease

    Directory of Open Access Journals (Sweden)

    William Z. Suo

    2010-01-01

    Full Text Available Although mutations and variations of several genes have been identified to be involved in Alzheimer's disease (AD, the efforts towards understanding the pathogenic mechanisms of the disease still have a long journey to go. One such effort is to identify the signal transduction deficits, for which previous studies have suggested that the central problems appear to be at the interface between G proteins and their coupled receptors. G protein-coupled receptor kinases (GRKs are a small family of serine/threonine protein kinases primarily acting at the “receptor-G protein interface””. Recent studies have indicated the possible involvement of GRK, primarily GRK2 and GRK5, dysfunction in the pathogenesis of AD. It seems that mild, soluble, β-amyloid accumulation can lead to a reduced membrane (functional and an elevated cytosolic GRK2/5. The increased cytosolic GRK2 appears to be colocalized with damaged mitochondria and neurofibrillary tangles. Moreover, the total levels of GRK2, not only in the brain, but also in peripheral blood samples, are increased in a manner inversely correlated with the patient's cognitive levels. The deficiency of GRK5, on the other hand, impairs presynaptic M2 autoreceptor desensitization, which leads to a reduced acetylcholine release, axonal/synaptic degenerative changes, and associated amnestic, mild cognitive impairment. It also promotes an evil cycle to further increase Beta-amyloid accumulation and exaggerates brain inflammation, possibly even the basal forebrain cholinergic degeneration. Therefore, continuous efforts in this direction are necessary before translating the knowledge to any therapeutic strategies.

  14. The Role of Gut Microflora and the Cholinergic Anti-inflammatory Neuroendocrine System in Diabetes Mellitus.

    Science.gov (United States)

    Parekh, Parth J; Nayi, Vipul R; Johnson, David A; Vinik, Aaron I

    2016-01-01

    The obesity epidemic has drastically impacted the state of health care in the United States. Paralleling this epidemic is the incidence of diabetes mellitus, with a notable shift toward a much younger age of onset. While central to the pathogenesis of diabetes associated with obesity is the role of inflammation attributed to "adiposopathy." Emerging data suggest that changes in sympathetic/parasympathetic balance regulated by the brain precede changes in the inflammatory cascade. It has now been established that the gut microflora contributes significantly to the activation and inhibition of autonomic control and impact the set of the neuroinflammatory inhibitory reflex mediated by the cholinergic nervous system. There has been a paradigm shift toward further investigating commensal bacteria in the pathogenesis of obesity and diabetes mellitus and its complications, as dysbiosis is thought to play a pivotal role in diabetic-associated disorders. This paper is intended to evaluate the role of intestinal dysbiosis in the pathogenesis of diabetes mellitus and examine the potential for restoration of balance via use of probiotics.

  15. Behavioral and biochemical effects of neonicotinoid thiamethoxam on the cholinergic system in rats.

    Science.gov (United States)

    Rodrigues, K J A; Santana, M B; Do Nascimento, J L M; Picanço-Diniz, D L W; Maués, L A L; Santos, S N; Ferreira, V M M; Alfonso, M; Durán, R; Faro, L R F

    2010-01-01

    Thiamethoxam is a neonicotinoid insecticide, a group of pesticides that acts selectively on insect nicotinic acetylcholine receptors (nAChRs), with only a little action on mammalian nAChRs. Nevertheless, the selectivity of neonicotinoids for the insect nAChRs may change when these substances are metabolized. Therefore, we aimed to determine the potential effects of thiamethoxam on mammalian brain, testing the performance in the open field and elevated plus-maze of rats exposed to this insecticide and, in order to establish the neurochemical endpoints, we measured the acetylcholinesterase activity in different brain regions (hippocampus, striatum and cortex) and the high-affinity choline uptake (HACU) in synaptosomes from rat hippocampus. Treated animals received thiamethoxam (25, 50 or 100mg/kg) for 7 consecutive days. The results showed that treatment with thiamethoxam induced an increase in the anxiety behavior at two doses (50 or 100mg/kg). Moreover, there was a significant decrease in both HACU and acetylcholinesterase activity. Our hypothesis is that thiamethoxam (or its metabolites) could be acting on the central rats nAChRs. This would produce an alteration on the cholinergic transmission, modulating the anxiety behavior, acetylcholinesterase levels and HACU.

  16. Production of adenosine from extracellular ATP at the striatal cholinergic synapse.

    Science.gov (United States)

    James, S; Richardson, P J

    1993-01-01

    The components of the ectonucleotidase pathway at the immunoaffinity-purified striatal cholinergic synapse have been studied. The ecto-ATPase (EC 3.6.1.15) had a Km of 131 microM, whereas the ecto-ADPase (EC 3.6.1.6) had a Km of 58 microM, was Ca(2+)-dependent, and was inhibited by the ATP analogue 5'-adenylylimidodiphosphate (AMPPNP). The ecto-5'-nucleotidase (EC 3.1.3.5) had a Km of 21 microM, was inhibited by AMPPNP and alpha,beta-methylene ADP, and by a specific antiserum. The Vmax values of the ATPase, ADPase, and 5'-nucleotidase enzymes present at this synapse were in a ratio of 30:14:1. Very little ecto-adenylate kinase activity was detected on these purified synapses. The intraterminal 5'-nucleotidase enzyme, which amounted to 40% of the total 5'-nucleotidase activity, was inhibited by AMPPNP, alpha,beta-methylene ADP, and the antiserum, and also had the same kinetic properties as the ectoenzyme. The time course of ATP degradation to adenosine outside the nerve terminals showed a delay, followed by a period of sustained adenosine production. The delay in adenosine production was proportional to the initial ATP concentration, was a consequence of feedforward inhibition of the ADPase and 5'-nucleotidase, and was inversely proportional to the ecto-5'-nucleotidase activity. The function and characteristics of this pathway and the central role of 5'-nucleotidase in the regulation of extraterminal adenosine concentrations are discussed.

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

    Directory of Open Access Journals (Sweden)

    Flávia Franceli de Brito Passos

    2015-01-01

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

  18. Effects of cholinergic and noradrenergic agents on locomotion in the mudpuppy (Necturus maculatus).

    Science.gov (United States)

    Fok, M; Stein, R B

    2002-08-01

    Some neurotransmitters act consistently on the central pattern generator (CPG) for locomotion in a wide range of vertebrates. In contrast, acetylcholine (ACh) and noradrenaline (NA) have various effects on locomotion in different preparations. The roles of ACh and NA have not been studied in amphibian walking, so we examined their effects in an isolated spinal cord preparation of the mudpuppy ( Necturus maculatus). This preparation contains a CPG that produces locomotor activity when N-methyl- D-aspartic acid (NMDA), an excitatory amino acid agonist, is added to the bath. The addition of carbachol, a long acting ACh agonist, to the bath disrupted the walking rhythm induced by NMDA, while not changing the level of activity in flexor and extensor motoneurons. Adding clonidine, an alpha(2)-noradrenergic agonist, had no effect on the NMDA-induced walking rhythm. Physostigmine, an ACh-esterase inhibitor, disrupted the walking rhythm, presumably by potentiating the effects of endogenously released ACh. Atropine, an ACh antagonist that binds to muscarinic ACh receptors, blocked the effects of carbachol, indicating that the action is mediated, at least in part, by muscarinic receptors. In the absence of carbachol, atropine had no effect. Locomotion was not induced by carbachol, atropine or clonidine in a resting spinal cord preparation. Cholinergic actions do not seem to be essential to the CPG for walking in the mudpuppy, but ACh may convert a rhythmic walking state to a more tonic state with occasional bursts of EMG activity for postural adjustments.

  19. The Role of Gut Microflora and the Cholinergic Anti-inflammatory Neuroendocrine System in Diabetes Mellitus

    Science.gov (United States)

    Parekh, Parth J.; Nayi, Vipul R.; Johnson, David A.; Vinik, Aaron I.

    2016-01-01

    The obesity epidemic has drastically impacted the state of health care in the United States. Paralleling this epidemic is the incidence of diabetes mellitus, with a notable shift toward a much younger age of onset. While central to the pathogenesis of diabetes associated with obesity is the role of inflammation attributed to “adiposopathy.” Emerging data suggest that changes in sympathetic/parasympathetic balance regulated by the brain precede changes in the inflammatory cascade. It has now been established that the gut microflora contributes significantly to the activation and inhibition of autonomic control and impact the set of the neuroinflammatory inhibitory reflex mediated by the cholinergic nervous system. There has been a paradigm shift toward further investigating commensal bacteria in the pathogenesis of obesity and diabetes mellitus and its complications, as dysbiosis is thought to play a pivotal role in diabetic-associated disorders. This paper is intended to evaluate the role of intestinal dysbiosis in the pathogenesis of diabetes mellitus and examine the potential for restoration of balance via use of probiotics. PMID:27375553

  20. Cholinergic urethral brush cells are widespread throughout placental mammals.

    Science.gov (United States)

    Deckmann, Klaus; Krasteva-Christ, Gabriela; Rafiq, Amir; Herden, Christine; Wichmann, Judy; Knauf, Sascha; Nassenstein, Christina; Grevelding, Christoph G; Dorresteijn, Adriaan; Chubanov, Vladimir; Gudermann, Thomas; Bschleipfer, Thomas; Kummer, Wolfgang

    2015-11-01

    We previously identified a population of cholinergic epithelial cells in murine, human and rat urethrae that exhibits a structural marker of brush cells (villin) and expresses components of the canonical taste transduction signaling cascade (α-gustducin, phospholipase Cβ2 (PLCβ2), transient receptor potential cation channel melanostatin 5 (TRPM5)). These cells serve as sentinels, monitoring the chemical composition of the luminal content for potentially hazardous compounds such as bacteria, and initiate protective reflexes counteracting further ingression. In order to elucidate cross-species conservation of the urethral chemosensory pathway we investigated the occurrence and molecular make-up of urethral brush cells in placental mammals. We screened 11 additional species, at least one in each of the five mammalian taxonomic units primates, carnivora, perissodactyla, artiodactyla and rodentia, for immunohistochemical labeling of the acetylcholine synthesizing enzyme, choline acetyltransferase (ChAT), villin, and taste cascade components (α-gustducin, PLCβ2, TRPM5). Corresponding to findings in previously investigated species, urethral epithelial cells with brush cell shape were immunolabeled in all 11 mammals. In 8 species, immunoreactivities against all marker proteins and ChAT were observed, and double-labeling immunofluorescence confirmed the cholinergic nature of villin-positive and chemosensory (TRPM5-positive) cells. In cat and horse, these cells were not labeled by the ChAT antiserum used in this study, and unspecific reactions of the secondary antiserum precluded conclusions about ChAT-expression in the bovine epithelium. These data indicate that urethral brush cells are widespread throughout the mammalian kingdom and evolved not later than about 64.5millionyears ago.

  1. Impact of basal forebrain cholinergic inputs on basolateral amygdala neurons.

    Science.gov (United States)

    Unal, Cagri T; Pare, Denis; Zaborszky, Laszlo

    2015-01-14

    In addition to innervating the cerebral cortex, basal forebrain cholinergic (BFc) neurons send a dense projection to the basolateral nucleus of the amygdala (BLA). In this study, we investigated the effect of near physiological acetylcholine release on BLA neurons using optogenetic tools and in vitro patch-clamp recordings. Adult transgenic mice expressing cre-recombinase under the choline acetyltransferase promoter were used to selectively transduce BFc neurons with channelrhodopsin-2 and a reporter through the injection of an adeno-associated virus. Light-induced stimulation of BFc axons produced different effects depending on the BLA cell type. In late-firing interneurons, BFc inputs elicited fast nicotinic EPSPs. In contrast, no response could be detected in fast-spiking interneurons. In principal BLA neurons, two different effects were elicited depending on their activity level. When principal BLA neurons were quiescent or made to fire at low rates by depolarizing current injection, light-induced activation of BFc axons elicited muscarinic IPSPs. In contrast, with stronger depolarizing currents, eliciting firing above ∼ 6-8 Hz, these muscarinic IPSPs lost their efficacy because stimulation of BFc inputs prolonged current-evoked afterdepolarizations. All the effects observed in principal neurons were dependent on muscarinic receptors type 1, engaging different intracellular mechanisms in a state-dependent manner. Overall, our results suggest that acetylcholine enhances the signal-to-noise ratio in principal BLA neurons. Moreover, the cholinergic engagement of afterdepolarizations may contribute to the formation of stimulus associations during fear-conditioning tasks where the timing of conditioned and unconditioned stimuli is not optimal for the induction of synaptic plasticity.

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

    Directory of Open Access Journals (Sweden)

    Susan D Motts

    2010-10-01

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

  3. Measures of Autonomic Dysfunction in Diabetic and Idiopathic Gastroparesis

    Science.gov (United States)

    Mohammad, Mohammad Khalid; Pepper, Dominique J.; Kedar, Archana; Bhaijee, Feriyl; Familoni, Babajide; Rashed, Hani; Cutts, Teresa; Abell, Thomas L.

    2016-01-01

    Background Gastroparesis is a condition classically characterized by delayed gastric emptying and is associated with considerable morbidity. While the etiology of gastroparesis remains elusive, autonomic dysfunction may play an important role, especially as many patients with gastroparesis also have diabetes. The aim of this study was to determine whether measures of autonomic function differ between adults with diabetic gastroparesis (DG) and adults with idiopathic gastroparesis (IG). Methods Tests of systemic autonomic function were performed among 20 adults with GD (six men and 14 women, mean age: 42 years) and 21 adults with IG (seven men and 14 women, mean age: 37 years). Measures included vagal cholinergics by R-R interval percentage variation (RRI-PV) and sympathetic adrenergics by vasoconstriction to cold (VC) and postural adjustment ratio (PAR). The two groups were compared using Wilcoxon rank sum tests and linear regression analysis (STATA 10.0). Results In univariate analysis, the following autonomic measures differed significantly between DG and IG: VC (P = 0.004), PAR (P = 0.045), VC + PAR (P = 0.002) and RRI-PV (P < 0.001). In multivariate analysis (P = 0.002, R2 = 0.55), only RRI-PV (adjusted odds ratio (aOR): 1.02, 95% confidence interval (CI): 1.01 - 1.03) differed significantly between DG and IG patients. Conclusions Vagal cholinergics are affected to a greater degree in DG compared to IG, suggesting that impaired vagal tone is not a universal mechanism for gastroparesis. PMID:27785328

  4. Mitochondrial Dysfunction in Lysosomal Storage Disorders

    Directory of Open Access Journals (Sweden)

    Mario de la Mata

    2016-10-01

    Full Text Available Lysosomal storage diseases (LSDs describe a heterogeneous group of rare inherited metabolic disorders that result from the absence or loss of function of lysosomal hydrolases or transporters, resulting in the progressive accumulation of undigested material in lysosomes. The accumulation of substances affects the function of lysosomes and other organelles, resulting in secondary alterations such as impairment of autophagy, mitochondrial dysfunction, inflammation and apoptosis. LSDs frequently involve the central nervous system (CNS, where neuronal dysfunction or loss results in progressive neurodegeneration and premature death. Many LSDs exhibit signs of mitochondrial dysfunction, which include mitochondrial morphological changes, decreased mitochondrial membrane potential (ΔΨm, diminished ATP production and increased generation of reactive oxygen species (ROS. Furthermore, reduced autophagic flux may lead to the persistence of dysfunctional mitochondria. Gaucher disease (GD, the LSD with the highest prevalence, is caused by mutations in the GBA1 gene that results in defective and insufficient activity of the enzyme β-glucocerebrosidase (GCase. Decreased catalytic activity and/or instability of GCase leads to accumulation of glucosylceramide (GlcCer and glucosylsphingosine (GlcSph in the lysosomes of macrophage cells and visceral organs. Mitochondrial dysfunction has been reported to occur in numerous cellular and mouse models of GD. The aim of this manuscript is to review the current knowledge and implications of mitochondrial dysfunction in LSDs.

  5. Vascular endothelial dysfunction and pharmacological treatment

    Institute of Scientific and Technical Information of China (English)

    Jin; Bo; Su

    2015-01-01

    The endothelium exerts multiple actions involving regulation of vascular permeability and tone, coagulation and fibrinolysis, inflammatory and immunological reactions and cell growth. Alterations of one or more such actions may cause vascular endothelial dysfunction. Different risk factors such as hypercholesterolemia, homocystinemia, hyperglycemia, hypertension, smo-king, inflammation, and aging contribute to the development of endothelial dysfunction. Mechanisms underlying endothelial dysfunction are multiple, including impaired endothelium-derived vasodilators, enhanced endothelium-derived vasoconstrictors, over production of reactive oxygen species and reactive nitrogen species, activation of inflammatory and immune reactions, and imbalance of coagulation and fibrinolysis. Endothelial dysfunction occurs in many cardiovascular diseases, which involves different mechanisms, depending on specific risk factors affecting the disease. Among these mechanisms, a reduction in nitric oxide(NO) bioavailability plays a central role in the development of endothelial dysfunction because NO exerts diverse physiological actions, including vasodilation, anti-inflammation, antiplatelet, antiproliferation and antimigration. Experimental and clinical studies have demonstrated that a variety of currently used or investigational drugs, such as angiotensin-converting enzyme inhibitors, angiotensin AT1 receptors blockers, angiotensin-(1-7), antioxidants, beta-blockers, calcium channel blockers, endothelial NO synthase enhancers, phosphodiesterase 5 inhibitors, sphingosine-1-phosphate and statins, exert endothelial protective effects. Due to the difference in mechanisms of action, these drugs need to be used according to specific mechanisms underlying endothelial dysfunction of the disease.

  6. The association of cholinergic and cold-induced urticaria: diagnosis and management

    Science.gov (United States)

    Torabi, Bahar; Ben-Shoshan, Moshe

    2015-01-01

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

  7. Transplantation of cholinergic neural stem cells in a mouse model of Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    WANG Qing-hua; XU Ru-xiang; Seigo Nagao

    2005-01-01

    @@ It is believed that the degeneration of cholinergic cells in the nucleus basalis of Meynert (NBM) and the loss of cortical cholinergic innervation cause dementia of Alzheimer's disease (AD).1 Currently available therapeutic interventions are mainly aimed at alleviating the cholinergic deficits. Unfortunately, these strategies do not prevent the disease, but instead offer limited symptomatic improvement.2 A recent study demonstrated that transplantation of in vitro expanded neural stem cells (NSCs) in an animal model of Parkinson's disease (PD) resulted in functional recovery of the animals to some extent,2 suggesting that such neural precursors might offer a useful future therapy for AD. In this study, we tried to find whether mouse embryonic stem (ES) cell derived cholinergic NSCs grafted in the prefrontal and parietal cortex have effects on the disruption of spatial memory following development of lesion in NBM.

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

    Directory of Open Access Journals (Sweden)

    Mekkattukunnel Andrews

    2014-12-01

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

  9. Optogenetic activation of cholinergic neurons in the PPT or LDT induces REM sleep.

    Science.gov (United States)

    Van Dort, Christa J; Zachs, Daniel P; Kenny, Jonathan D; Zheng, Shu; Goldblum, Rebecca R; Gelwan, Noah A; Ramos, Daniel M; Nolan, Michael A; Wang, Karen; Weng, Feng-Ju; Lin, Yingxi; Wilson, Matthew A; Brown, Emery N

    2015-01-13

    Rapid eye movement (REM) sleep is an important component of the natural sleep/wake cycle, yet the mechanisms that regulate REM sleep remain incompletely understood. Cholinergic neurons in the mesopontine tegmentum have been implicated in REM sleep regulation, but lesions of this area have had varying effects on REM sleep. Therefore, this study aimed to clarify the role of cholinergic neurons in the pedunculopontine tegmentum (PPT) and laterodorsal tegmentum (LDT) in REM sleep generation. Selective optogenetic activation of cholinergic neurons in the PPT or LDT during non-REM (NREM) sleep increased the number of REM sleep episodes and did not change REM sleep episode duration. Activation of cholinergic neurons in the PPT or LDT during NREM sleep was sufficient to induce REM sleep.

  10. Impairment of the nerve growth factor pathway driving amyloid accumulation in cholinergic neurons: the incipit of the Alzheimer′s disease story?

    Directory of Open Access Journals (Sweden)

    Viviana Triaca

    2016-01-01

    Full Text Available The current idea behind brain pathology is that disease is initiated by mild disturbances of common physiological processes. Overtime, the disruption of the neuronal homeostasis will determine irreversible degeneration and neuronal apoptosis. This could be also true in the case of nerve growth factor (NGF alterations in sporadic Alzheimer′s disease (AD, an age-related pathology characterized by cholinergic loss, amyloid plaques and neurofibrillary tangles. In fact, the pathway activated by NGF, a key neurotrophin for the metabolism of basal forebrain cholinergic neurons (BFCN, is one of the first homeostatic systems affected in prodromal AD. NGF signaling dysfunctions have been thought for decades to occur in AD late stages, as a mere consequence of amyloid-driven disruption of the retrograde axonal transport of neurotrophins to BFCN. Nowadays, a wealth of knowledge is potentially opening a new scenario: NGF signaling impairment occurs at the onset of AD and correlates better than amyloid load with cognitive decline. The recent acceleration in the characterization of anatomical, functional and molecular profiles of early AD is aimed at maximizing the efficacy of existing treatments and setting novel therapies. Accordingly, the elucidation of the molecular events underlying APP metabolism regulation by the NGF pathway in the septo-hippocampal system is crucial for the identification of new target molecules to slow and eventually halt mild cognitive impairment (MCI and its progression toward AD.

  11. Generation of Cholinergic and Dopaminergic Interneurons from Human Pluripotent Stem Cells as a Relevant Tool for In Vitro Modeling of Neurological Disorders Pathology and Therapy

    Directory of Open Access Journals (Sweden)

    Anna Ochalek

    2016-01-01

    Full Text Available The cellular and molecular bases of neurological diseases have been studied for decades; however, the underlying mechanisms are not yet fully elucidated. Compared with other disorders, diseases of the nervous system have been very difficult to study mainly due to the inaccessibility of the human brain and live neurons in vivo or in vitro and difficulties in examination of human postmortem brain tissue. Despite the availability of various genetically engineered animal models, these systems are still not adequate enough due to species variation and differences in genetic background. Human induced pluripotent stem cells (hiPSCs reprogrammed from patient somatic cells possess the potential to differentiate into any cell type, including neural progenitor cells and postmitotic neurons; thus, they open a new area to in vitro modeling of neurological diseases and their potential treatment. Currently, many protocols for generation of various neuronal subtypes are being developed; however, most of them still require further optimization. Here, we highlight accomplishments made in the generation of dopaminergic and cholinergic neurons, the two subtypes most affected in Alzheimer’s and Parkinson’s diseases and indirectly affected in Huntington’s disease. Furthermore, we discuss the potential role of hiPSC-derived neurons in the modeling and treatment of neurological diseases related to dopaminergic and cholinergic system dysfunction.

  12. Impairment of the nerve growth factor pathway driving amyloid accumulation in cholinergic neurons:the incipit of the Alzheimer’s disease story?

    Institute of Scientific and Technical Information of China (English)

    Viviana Triaca; Pietro Calissano

    2016-01-01

    The current idea behind brain pathology is that disease is initiated by mild disturbances of common physiological processes. Overtime, the disruption of the neuronal homeostasis will determine irreversible degeneration and neuronal apoptosis. hTis could be also true in the case of nerve growth factor (NGF) al-terations in sporadic Alzheimer’s disease (AD), an age-related pathology characterized by cholinergic loss, amyloid plaques and neurofibrillary tangles. In fact, the pathway activated by NGF, a key neurotrophin for the metabolism of basal forebrain cholinergic neurons (BFCN), is one of the ifrst homeostatic systems affected in prodromal AD. NGF signaling dysfunctions have been thought for decades to occur in AD late stages, as a mere consequence of amyloid-driven disruption of the retrograde axonal transport of neuro-trophins to BFCN. Nowadays, a wealth of knowledge is potentially opening a new scenario: NGF signaling impairment occurs at the onset of AD and correlates better than amyloid load with cognitive decline. hTe recent acceleration in the characterization of anatomical, functional and molecular proifles of early AD is aimed at maximizing the efficacy of existing treatments and setting novel therapies. Accordingly, the elucidation of the molecular events underlying APP metabolism regulation by the NGF pathway in the sep-to-hippocampal system is crucial for the identiifcation of new target molecules to slow and eventually halt mild cognitive impairment (MCI) and its progression toward AD.

  13. Partial BACE1 reduction in a Down syndrome mouse model blocks Alzheimer-related endosomal anomalies and cholinergic neurodegeneration: role of APP-CTF.

    Science.gov (United States)

    Jiang, Ying; Rigoglioso, Andrew; Peterhoff, Corrinne M; Pawlik, Monika; Sato, Yutaka; Bleiwas, Cynthia; Stavrides, Philip; Smiley, John F; Ginsberg, Stephen D; Mathews, Paul M; Levy, Efrat; Nixon, Ralph A

    2016-03-01

    β-amyloid precursor protein (APP) and amyloid beta peptide (Aβ) are strongly implicated in Alzheimer's disease (AD) pathogenesis, although recent evidence has linked APP-βCTF generated by BACE1 (β-APP cleaving enzyme 1) to the development of endocytic abnormalities and cholinergic neurodegeneration in early AD. We show that partial BACE1 genetic reduction prevents these AD-related pathological features in the Ts2 mouse model of Down syndrome. Partially reducing BACE1 by deleting one BACE1 allele blocked development of age-related endosome enlargement in the medial septal nucleus, cerebral cortex, and hippocampus and loss of choline acetyltransferase (ChAT)-positive medial septal nucleus neurons. BACE1 reduction normalized APP-βCTF elevation but did not alter Aβ40 and Aβ42 peptide levels in brain, supporting a critical role in vivo for APP-βCTF in the development of these abnormalities. Although ameliorative effects of BACE1 inhibition on β-amyloidosis and synaptic proteins levels have been previously noted in AD mouse models, our results highlight the additional potential value of BACE1 modulation in therapeutic targeting of endocytic dysfunction and cholinergic neurodegeneration in Down syndrome and AD.

  14. Cholinergic basal forebrain structures are involved in the mediation of the arousal effect of noradrenaline.

    Science.gov (United States)

    Lelkes, Zoltán; Porkka-Heiskanen, Tarja; Stenberg, Dag

    2013-12-01

    Cholinergic basal forebrain structures are implicated in cortical arousal and regulation of the sleep-wake cycle. Cholinergic neurones are innervated by noradrenergic terminals, noradrenaline excites them via alpha-1 receptors and microinjection of noradrenaline into the basal forebrain enhances wakefulness. However, it is not known to what extent the cholinergic versus non-cholinergic basal forebrain projection neurones contribute to the arousing effects of noradrenaline. To elucidate the roles of cholinergic basal forebrain structures we administered methoxamine, an alpha-1-adrenergic agonist into the basal forebrain, in intact animals and again after selective destruction of the basal forebrain cholinergic cells by 192 IgG-saporin. In eight male Han-Wistar rats implanted with electroencephalogram/electromyogram electrodes, a microdialysis probe targeted into the basal forebrain was perfused with artificial cerebrospinal fluid for 6 h on a baseline day, and with cerebrospinal fluid in the first and with methoxamine in the second 3-h period of the subsequent day. The sleep-wake activity was recorded for 24 h on both days. Saporin was then injected into the basal forebrain and 2 weeks later the same experimental schedule (with cerebrospinal fluid and methoxamine) was repeated. In the intact animals, methoxamine exhibited a robust arousing effect and non-rapid eye movement (NREM) and REM sleep was suppressed. Lesioning of the basal forebrain cholinergic neurones abolished almost completely the NREM sleep-suppressing effect of methoxamine, whereas the REM sleep-suppressing effect remained intact. Thus, the basal forebrain cholinergic neurones mediate, at least in part, cortical arousal and non-REM sleep-suppression, but they are not involved in the REM sleep-suppressing effects of noradrenaline. © 2013 European Sleep Research Society.

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

    DEFF Research Database (Denmark)

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

    2011-01-01

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

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

    DEFF Research Database (Denmark)

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

    2011-01-01

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

  17. Acetylcholinesterase in central vocal control nuclei of the zebra finch (Taeniopygia guttata)

    Indian Academy of Sciences (India)

    Monika Sadananda

    2004-06-01

    The distribution of acetylcholinesterase (AChE) in the central vocal control nuclei of the zebra finch was studied using enzyme histochemistry. AChE fibres and cells are intensely labelled in the forebrain nucleus area X, strongly labelled in high vocal centre (HVC) perikarya, and moderately to lightly labelled in the somata and neuropil of vocal control nuclei robust nucleus of arcopallium (RA), medial magnocellular nucleus of the anterior nidopallium (MMAN) and lateral magnocellular nucleus of the anterior nidopallium (LMAN). The identified sites of cholinergic and/or cholinoceptive neurons are similar to the cholinergic presence in vocal control regions of other songbirds such as the song sparrow, starling and another genus of the zebra finch (Poephila guttata), and to a certain extent in parallel vocal control regions in vocalizing birds such as the budgerigar. AChE presence in the vocal control system suggests innervation by either afferent projecting cholinergic systems and/or local circuit cholinergic neurons. Co-occurrence with choline acetyltransferase (ChAT) indicates efferent cholinergic projections. The cholinergic presence in parts of the zebra finch vocal control system, such as the area X, that is also intricately wired with parts of the basal ganglia, the descending fibre tracts and brain stem nuclei could underlie this circuitry’s involvement in sensory processing and motor control of song.

  18. Nerve growth factor metabolic dysfunction in Down's syndrome brains.

    Science.gov (United States)

    Iulita, M Florencia; Do Carmo, Sonia; Ower, Alison K; Fortress, Ashley M; Flores Aguilar, Lisi; Hanna, Michael; Wisniewski, Thomas; Granholm, Ann-Charlotte; Buhusi, Mona; Busciglio, Jorge; Cuello, A Claudio

    2014-03-01

    Basal forebrain cholinergic neurons play a key role in cognition. This neuronal system is highly dependent on NGF for its synaptic integrity and the phenotypic maintenance of its cell bodies. Basal forebrain cholinergic neurons progressively degenerate in Alzheimer's disease and Down's syndrome, and their atrophy contributes to the manifestation of dementia. Paradoxically, in Alzheimer's disease brains, the synthesis of NGF is not affected and there is abundance of the NGF precursor, proNGF. We have shown that this phenomenon is the result of a deficit in NGF's extracellular metabolism that compromises proNGF maturation and exacerbates its subsequent degradation. We hypothesized that a similar imbalance should be present in Down's syndrome. Using a combination of quantitative reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting and zymography, we investigated signs of NGF metabolic dysfunction in post-mortem brains from the temporal (n = 14), frontal (n = 34) and parietal (n = 20) cortex obtained from subjects with Down's syndrome and age-matched controls (age range 31-68 years). We further examined primary cultures of human foetal Down's syndrome cortex (17-21 gestational age weeks) and brains from Ts65Dn mice (12-22 months), a widely used animal model of Down's syndrome. We report a significant increase in proNGF levels in human and mouse Down's syndrome brains, with a concomitant reduction in the levels of plasminogen and tissue plasminogen activator messenger RNA as well as an increment in neuroserpin expression; enzymes that partake in proNGF maturation. Human Down's syndrome brains also exhibited elevated zymogenic activity of MMP9, the major NGF-degrading protease. Our results indicate a failure in NGF precursor maturation in Down's syndrome brains and a likely enhanced proteolytic degradation of NGF, changes which can compromise the trophic support of basal forebrain cholinergic neurons. The alterations in pro

  19. Basal forebrain neurons suppress amygdala kindling via cortical but not hippocampal cholinergic projections in rats.

    Science.gov (United States)

    Ferencz, I; Leanza, G; Nanobashvili, A; Kokaia, M; Lindvall, O

    2000-06-01

    Intraventricular administration of the immunotoxin 192 IgG-saporin in rats has been shown to cause a selective loss of cholinergic afferents to the hippocampus and cortical areas, and to facilitate seizure development in hippocampal kindling. Here we demonstrate that this lesion also accelerates seizure progression when kindling is induced by electrical stimulations in the amygdala. However, whereas intraventricular 192 IgG-saporin facilitated the development of the initial stages of hippocampal kindling, the same lesion promoted the late stages of amygdala kindling. To explore the role of various parts of the basal forebrain cholinergic system in amygdala kindling, selective lesions of the cholinergic projections to either hippocampus or cortex were produced by intraparenchymal injections of 192 IgG-saporin into medial septum/vertical limb of the diagonal band or nucleus basalis, respectively. Cholinergic denervation of the cortical regions caused acceleration of amygdala kindling closely resembling that observed after the more widespread lesion induced by intraventricular 192 IgG-saporin. In contrast, removal of the cholinergic input to the hippocampus had no effect on the development of amygdala kindling. These data indicate that basal forebrain cholinergic neurons suppress kindling elicited from amygdala, and that this dampening effect is mediated via cortical but not hippocampal projections.

  20. Cholinergic Depletion in Alzheimer’s Disease Shown by [18F]FEOBV Autoradiography

    Directory of Open Access Journals (Sweden)

    Maxime J. Parent

    2013-01-01

    Full Text Available Rationale. Alzheimer’s Disease (AD is a neurodegenerative condition characterized in part by deficits in cholinergic basalocortical and septohippocampal pathways. [18F]Fluoroethoxybenzovesamicol ([18F]FEOBV, a Positron Emission Tomography ligand for the vesicular acetylcholine transporter (VAChT, is a potential molecular agent to investigate brain diseases associated with presynaptic cholinergic losses. Purpose. To demonstrate this potential, we carried out an [18F]FEOBV autoradiography study to compare postmortem brain tissues from AD patients to those of age-matched controls. Methods. [18F]FEOBV autoradiography binding, defined as the ratio between regional grey and white matter, was estimated in the hippocampus (13 controls, 8 AD and prefrontal cortex (13 controls, 11 AD. Results. [18F]FEOBV binding was decreased by 33% in prefrontal cortex, 25% in CA3, and 20% in CA1. No changes were detected in the dentate gyrus of the hippocampus, possibly because of sprouting or upregulation toward the resilient glutamatergic neurons of the dentate gyrus. Conclusion. This is the first demonstration of [18F]FEOBV focal binding changes in cholinergic projections to the cortex and hippocampus in AD. Such cholinergic synaptic (and more specifically VAChT alterations, in line with the selective basalocortical and septohippocampal cholinergic losses documented in AD, indicate that [18F]FEOBV is indeed a promising ligand to explore cholinergic abnormalities in vivo.

  1. Impact of the NGF maturation and degradation pathway on the cortical cholinergic system phenotype.

    Science.gov (United States)

    Allard, Simon; Leon, Wanda C; Pakavathkumar, Prateep; Bruno, Martin A; Ribeiro-da-Silva, Alfredo; Cuello, A Claudio

    2012-02-08

    Cortical cholinergic atrophy plays a significant role in the cognitive loss seen with aging and in Alzheimer's disease (AD), but the mechanisms leading to it remain unresolved. Nerve growth factor (NGF) is the neurotrophin responsible for the phenotypic maintenance of basal forebrain cholinergic neurons in the mature and fully differentiated CNS. In consequence, its implication in cholinergic atrophy has been suspected; however, no mechanistic explanation has been provided. We have previously shown that the precursor of NGF (proNGF) is cleaved extracellularly by plasmin to form mature NGF (mNGF) and that mNGF is degraded by matrix metalloproteinase 9. Using cognitive-behavioral tests, Western blotting, and confocal and electron microscopy, this study demonstrates that a pharmacologically induced chronic failure in extracellular NGF maturation leads to a reduction in mNGF levels, proNGF accumulation, cholinergic degeneration, and cognitive impairment in rats. It also shows that inhibiting NGF degradation increases endogenous levels of the mature neurotrophin and increases the density of cortical cholinergic boutons. Together, the data point to a mechanism explaining cholinergic loss in neurodegenerative conditions such as AD and provide a potential therapeutic target for the protection or restoration of this CNS transmitter system in aging and AD.

  2. Lesions of the basal forebrain cholinergic system in mice disrupt idiothetic navigation.

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    Adam S Hamlin

    Full Text Available Loss of integrity of the basal forebrain cholinergic neurons is a consistent feature of Alzheimer's disease, and measurement of basal forebrain degeneration by magnetic resonance imaging is emerging as a sensitive diagnostic marker for prodromal disease. It is also known that Alzheimer's disease patients perform poorly on both real space and computerized cued (allothetic or uncued (idiothetic recall navigation tasks. Although the hippocampus is required for allothetic navigation, lesions of this region only mildly affect idiothetic navigation. Here we tested the hypothesis that the cholinergic medial septo-hippocampal circuit is important for idiothetic navigation. Basal forebrain cholinergic neurons were selectively lesioned in mice using the toxin saporin conjugated to a basal forebrain cholinergic neuronal marker, the p75 neurotrophin receptor. Control animals were able to learn and remember spatial information when tested on a modified version of the passive place avoidance test where all extramaze cues were removed, and animals had to rely on idiothetic signals. However, the exploratory behaviour of mice with cholinergic basal forebrain lesions was highly disorganized during this test. By contrast, the lesioned animals performed no differently from controls in tasks involving contextual fear conditioning and spatial working memory (Y maze, and displayed no deficits in potentially confounding behaviours such as motor performance, anxiety, or disturbed sleep/wake cycles. These data suggest that the basal forebrain cholinergic system plays a specific role in idiothetic navigation, a modality that is impaired early in Alzheimer's disease.

  3. Origin and immunolesioning of cholinergic basal forebrain innervation of cat primary auditory cortex.

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    Kamke, Marc R; Brown, Mel; Irvine, Dexter R F

    2005-08-01

    Numerous studies have implicated the cholinergic basal forebrain (cBF) in the modulation of auditory cortical responses. This study aimed to accurately define the sources of cBF input to primary auditory cortex (AI) and to assess the efficacy of a cholinergic immunotoxin in cat. Three anaesthetized cats received multiple injections of horseradish-peroxidase conjugated wheatgerm-agglutin into physiologically identified AI. Following one to two days survival, tetramethylbenzidine histochemistry revealed the greatest number of retrogradely labeled cells in ipsilateral putamen, globus pallidus and internal capsule, and smaller numbers in more medial nuclei of the basal forebrain (BF). Concurrent choline acetyltransferase immunohistochemistry showed that almost 80% of the retrogradely labeled cells in BF were cholinergic, with the vast majority of these cells arising from the more lateral BF nuclei identified above. In the second part of the study, unilateral intraparenchymal injections of the cholinergic immunotoxin ME20.4-SAP were made into the putamen/globus pallidus nuclei of six cats. Immuno- and histochemistry revealed a massive reduction in the number of cholinergic cells in and around the targeted area, and a corresponding reduction in the density of cholinergic fibers in auditory cortex. These results are discussed in terms of their implications for investigations of the role of the cBF in cortical plasticity.

  4. Hippocampal cholinergic interneurons visualized with the choline acetyltransferase promoter: anatomical distribution, intrinsic membrane properties, neurochemical characteristics, and capacity for cholinergic modulation

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    Feng eYi; Elizabeth eCatudio-Garrett; Robert eGabriel; Marta eWilhelm; Ferenc eErdelyi; Gabor eSzabo; Karl eDeisseroth; Josh eLawrence

    2015-01-01

    Release of acetylcholine (ACh) in the hippocampus (HC) occurs during exploration, arousal, and learning. Although the medial septum-diagonal band of Broca (MS-DBB) is the major extrinsic source of cholinergic input to the HC, cholinergic neurons intrinsic to the HC also exist but remain poorly understood. Here, ChAT-tauGFP and ChAT-CRE/Rosa26YFP (ChAT-Rosa) mice were examined in HC. The HC of ChAT-tauGFP mice was densely innervated with GFP-positive axons, often accompanied by large GFP-posit...

  5. Hippocampal “cholinergic interneurons” visualized with the choline acetyltransferase promoter: anatomical distribution, intrinsic membrane properties, neurochemical characteristics, and capacity for cholinergic modulation

    OpenAIRE

    Yi, Feng; Catudio-Garrett, Elizabeth; Gábriel, Robert; Wilhelm, Marta; Erdelyi, Ferenc; Szabo, Gabor; Deisseroth, Karl; Lawrence, Josh

    2015-01-01

    Release of acetylcholine (ACh) in the hippocampus (HC) occurs during exploration, arousal, and learning. Although the medial septum-diagonal band of Broca (MS-DBB) is the major extrinsic source of cholinergic input to the HC, cholinergic neurons intrinsic to the HC also exist but remain poorly understood. Here, ChAT-tauGFP and ChAT-CRE/Rosa26YFP (ChAT-Rosa) mice were examined in HC. The HC of ChAT-tauGFP mice was densely innervated with GFP-positive axons, often accompanied by large GFP-posit...

  6. Cognitive dysfunction and its determinants in patients with neurocysticercosis

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    Vinod Varghese

    2016-01-01

    Full Text Available Introduction: Neurocysticercosis (NCC is the most common parasitic infection of man. In addition to a headache, seizures, and focal deficits, this is associated with significant cognitive dysfunction. Many studies revealed that the number and location of lesions are not always responsible for cognitive dysfunction. Cholinesterase and pseudocholinesterase are found in the walls of the cysticercus which could contribute to cholinergic depletion and thus cognitive dysfunction. Patients and Methods: A total of 43 patients who presented with NCC were evaluated for cognitive deficits, as well as cholinesterase levels in cerebrospinal fluid (CSF with control CSF from patients undergoing spinal anesthesia. Blood levels of interleukin-10 and tumor necrosis factor alpha were also estimated and correlated with cognitive deficits. Results: There is a mild increase in the acetylcholinesterase in CSF of patients compared to controls, but it did not correlate with cognitive deficits. There is an increase in interleukins to a significant level which correlates with vesicular stage of the organism and cognitive impairment. The number of lesions also correlated with cognitive impairment even though the location did not. The domains of cognitive deficits seen are sustained attention, category fluency, verbal working memory, planning, set shifting, verbal learning, visual memory, and construction. Discussion and Conclusion: NCC is associated with multi-domain cognitive impairment correlates with vescicular stage, proinflammatory cytokines and number of lesions but not location, vesicular stage, and proinflammatory cytokines.

  7. Cognitive Dysfunction and its Determinants in Patients with Neurocysticercosis

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    Varghese, Vinod; Chandra, Sadanandavalli Retnaswami; Christopher, Rita; Rajeswaran, Jamuna; Prasad, Chandrajit; Subasree, R.; Issac, Thomas Gregor

    2016-01-01

    Introduction: Neurocysticercosis (NCC) is the most common parasitic infection of man. In addition to a headache, seizures, and focal deficits, this is associated with significant cognitive dysfunction. Many studies revealed that the number and location of lesions are not always responsible for cognitive dysfunction. Cholinesterase and pseudocholinesterase are found in the walls of the cysticercus which could contribute to cholinergic depletion and thus cognitive dysfunction. Patients and Methods: A total of 43 patients who presented with NCC were evaluated for cognitive deficits, as well as cholinesterase levels in cerebrospinal fluid (CSF) with control CSF from patients undergoing spinal anesthesia. Blood levels of interleukin-10 and tumor necrosis factor alpha were also estimated and correlated with cognitive deficits. Results: There is a mild increase in the acetylcholinesterase in CSF of patients compared to controls, but it did not correlate with cognitive deficits. There is an increase in interleukins to a significant level which correlates with vesicular stage of the organism and cognitive impairment. The number of lesions also correlated with cognitive impairment even though the location did not. The domains of cognitive deficits seen are sustained attention, category fluency, verbal working memory, planning, set shifting, verbal learning, visual memory, and construction. Discussion and Conclusion: NCC is associated with multi-domain cognitive impairment correlates with vescicular stage, proinflammatory cytokines and number of lesions but not location, vesicular stage, and proinflammatory cytokines. PMID:27114627

  8. Chronic pelvic floor dysfunction.

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    Hartmann, Dee; Sarton, Julie

    2014-10-01

    The successful treatment of women with vestibulodynia and its associated chronic pelvic floor dysfunctions requires interventions that address a broad field of possible pain contributors. Pelvic floor muscle hypertonicity was implicated in the mid-1990s as a trigger of major chronic vulvar pain. Painful bladder syndrome, irritable bowel syndrome, fibromyalgia, and temporomandibular jaw disorder are known common comorbidities that can cause a host of associated muscular, visceral, bony, and fascial dysfunctions. It appears that normalizing all of those disorders plays a pivotal role in reducing complaints of chronic vulvar pain and sexual dysfunction. Though the studies have yet to prove a specific protocol, physical therapists trained in pelvic dysfunction are reporting success with restoring tissue normalcy and reducing vulvar and sexual pain. A review of pelvic anatomy and common findings are presented along with suggested physical therapy management.

  9. Female Sexual Dysfunction

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    ... to be comfortable with your sexuality, improve your self-esteem and accept your body. Try practicing these healthy ... mayoclinic.org/diseases-conditions/female-sexual-dysfunction/basics/definition/CON-20027721 . Mayo Clinic Footer Legal Conditions and ...

  10. Spinal Cord Dysfunction (SCD)

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    Department of Veterans Affairs — The Spinal Cord Dysfunction (SCD) module supports the maintenance of local and national registries for the tracking of patients with spinal cord injury and disease...

  11. Basal ganglia dysfunction

    Science.gov (United States)

    ... ganglia dysfunction. They include: Dystonia (muscle tone problems) Huntington disease (disorder in which nerve cells in certain parts ... ed. Philadelphia, PA: Elsevier Mosby; 2013:chap 20. Review Date 5/30/2016 Updated by: Amit M. ...

  12. Sexual Dysfunction in Women

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    Brown, Pamela

    1989-01-01

    Sexual dysfunction takes place in the context of women's lives and affects their sexuality and self-esteem. Awareness of these influences are vital to the management of the dysfunction and the promotion of positive sexuality. The family physician's contribution to both the prevention and management of sexual concerns includes an awareness of societal influences and facilitation of a woman's sense of her own power and control over her life.

  13. Replicated Risk Nicotinic Cholinergic Receptor Genes for Nicotine Dependence

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    Lingjun Zuo

    2016-11-01

    Full Text Available It has been hypothesized that the nicotinic acetylcholine receptors (nAChRs play important roles in nicotine dependence (ND and influence the number of cigarettes smoked per day (CPD in smokers. We compiled the associations between nicotinic cholinergic receptor genes (CHRNs and ND/CPD that were replicated across different studies, reviewed the expression of these risk genes in human/mouse brains, and verified their expression using independent samples of both human and mouse brains. The potential functions of the replicated risk variants were examined using cis-eQTL analysis or predicted using a series of bioinformatics analyses. We found replicated and significant associations for ND/CPD at 19 SNPs in six genes in three genomic regions (CHRNB3-A6, CHRNA5-A3-B4 and CHRNA4. These six risk genes are expressed in at least 18 distinct areas of the human/mouse brain, with verification in our independent human and mouse brain samples. The risk variants might influence the transcription, expression and splicing of the risk genes, alter RNA secondary or protein structure. We conclude that the replicated associations between CHRNB3-A6, CHRNA5-A3-B4, CHRNA4 and ND/CPD are very robust. More research is needed to examine how these genetic variants contribute to the risk for ND/CPD.

  14. Replicated Risk Nicotinic Cholinergic Receptor Genes for Nicotine Dependence

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    Zuo, Lingjun; Garcia-Milian, Rolando; Guo, Xiaoyun; Zhong, Chunlong; Tan, Yunlong; Wang, Zhiren; Wang, Jijun; Wang, Xiaoping; Kang, Longli; Lu, Lu; Chen, Xiangning; Li, Chiang-Shan R.; Luo, Xingguang

    2016-01-01

    It has been hypothesized that the nicotinic acetylcholine receptors (nAChRs) play important roles in nicotine dependence (ND) and influence the number of cigarettes smoked per day (CPD) in smokers. We compiled the associations between nicotinic cholinergic receptor genes (CHRNs) and ND/CPD that were replicated across different studies, reviewed the expression of these risk genes in human/mouse brains, and verified their expression using independent samples of both human and mouse brains. The potential functions of the replicated risk variants were examined using cis-eQTL analysis or predicted using a series of bioinformatics analyses. We found replicated and significant associations for ND/CPD at 19 SNPs in six genes in three genomic regions (CHRNB3-A6, CHRNA5-A3-B4 and CHRNA4). These six risk genes are expressed in at least 18 distinct areas of the human/mouse brain, with verification in our independent human and mouse brain samples. The risk variants might influence the transcription, expression and splicing of the risk genes, alter RNA secondary or protein structure. We conclude that the replicated associations between CHRNB3-A6, CHRNA5-A3-B4, CHRNA4 and ND/CPD are very robust. More research is needed to examine how these genetic variants contribute to the risk for ND/CPD. PMID:27827986

  15. Photocolorimetric Biosensor for Detection of Cholinergic Organophosphorus Compounds

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    Kamila Vymazalová

    2012-11-01

    Full Text Available To detect nerve agents in practice, the analytical methods such as gas, liquid and thin-layer chromatography, mass spectrometry or capillary electrophoresis are usually used. Apart from these analytical methods, we developed an analytical device (tape photocolorimetric biosensor based on the modified Ellman's cholinesterase biochemical reaction for multidetection of cholinergic organophosphorus compounds. Enzyme butyrylcholinesterase was used as a biorecognizing component and its activity was evaluated by red, blue, green (RGB sensor. This method eliminates errors in the evaluation and provides automatic data collection with their subsequent evaluation. The unique method of dosing allows appropriate dispensing of reagents in microlitres volumes and the whole system is simple to operate. Suitability of the constructed biosensors was evaluated using the six organophosphates (Tabun, sarin, Soman, cyclosin, VX and R33 compound. Biosensor showed the ability to measure substances at concentrations ranging between ~ 1×10-8 mg/l - 1×10-6 mg/l in the air, according to their inhibition effect.Defence Science Journal, 2012, 62(6, pp.399-403, DOI:http://dx.doi.org/10.14429/dsj.62.2589

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

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    Ehren L Newman

    2012-06-01

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

  17. Characterization of muscarinic cholinergic receptor subtypes in human peripheral lung

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    Bloom, J.W.; Halonen, M.; Yamamura, H.I.

    1988-02-01

    The authors have characterized the muscarinic cholinergic receptor subtypes in human peripheral lung membranes using the selective muscarinic antagonist (/sup 3/H)pirenzepine ((/sup 3/H)PZ) and the classical muscarinic antagonist (/sup 3/H)(-)-quinuclidinyl benzilate. High-affinity binding with pharmacologic specificity was demonstrated for both radioligands. The high affinity Kd for (/sup 3/H)PZ binding determined from saturation isotherms was 5.6 nM, and the Kd for (/sup 3/H)(-)-quinuclidinyl benzilate binding was 14.3 pM. Approximately 62% of the total muscarinic binding sites in human peripheral lung bind (/sup 3/H)PZ with high affinity. There was no significant effect of the guanine nucleotide, guanyl-5'-yl imidodiphosphate, on the inhibition of (/sup 3/H)(-)-quinyclidinyl benzilate binding by the muscarinic agonist carbachol in peripheral lung membranes. If the muscarinic receptor with high affinity for PZ has an important role in bronchoconstriction, its characterization could result in the development of more selective bronchodilators.

  18. Replicated Risk Nicotinic Cholinergic Receptor Genes for Nicotine Dependence.

    Science.gov (United States)

    Zuo, Lingjun; Garcia-Milian, Rolando; Guo, Xiaoyun; Zhong, Chunlong; Tan, Yunlong; Wang, Zhiren; Wang, Jijun; Wang, Xiaoping; Kang, Longli; Lu, Lu; Chen, Xiangning; Li, Chiang-Shan R; Luo, Xingguang

    2016-11-07

    It has been hypothesized that the nicotinic acetylcholine receptors (nAChRs) play important roles in nicotine dependence (ND) and influence the number of cigarettes smoked per day (CPD) in smokers. We compiled the associations between nicotinic cholinergic receptor genes (CHRNs) and ND/CPD that were replicated across different studies, reviewed the expression of these risk genes in human/mouse brains, and verified their expression using independent samples of both human and mouse brains. The potential functions of the replicated risk variants were examined using cis-eQTL analysis or predicted using a series of bioinformatics analyses. We found replicated and significant associations for ND/CPD at 19 SNPs in six genes in three genomic regions (CHRNB3-A6, CHRNA5-A3-B4 and CHRNA4). These six risk genes are expressed in at least 18 distinct areas of the human/mouse brain, with verification in our independent human and mouse brain samples. The risk variants might influence the transcription, expression and splicing of the risk genes, alter RNA secondary or protein structure. We conclude that the replicated associations between CHRNB3-A6, CHRNA5-A3-B4,CHRNA4 and ND/CPD are very robust. More research is needed to examine how these genetic variants contribute to the risk for ND/CPD.

  19. Progressive cholinergic decline in Alzheimer's Disease: consideration for treatment with donepezil 23 mg in patients with moderate to severe symptomatology

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    Cummings Jeffrey

    2011-02-01

    Full Text Available Abstract Of the estimated 5.3 million people with Alzheimer's disease in the United States, more than half would be classified as having moderate or severe disease. Alzheimer's disease is a progressive disorder with the moderate to severe stages generally characterized by significant cognitive, functional, and behavioral dysfunction. Unsurprisingly, these advanced stages are often the most challenging for both patients and their caregivers/families. Symptomatic treatments for moderate to severe Alzheimer's disease are approved in the United States and include the acetylcholinesterase inhibitor donepezil and the glutamate receptor antagonist memantine. Progressive symptomatic decline is nevertheless inevitable even with the available therapies, and therefore additional treatment options are urgently needed for this segment of the Alzheimer's disease population. An immediate-release formulation of donepezil has been available at an approved dose of 5-10 mg/d for the past decade. Recently, the United States Food and Drug Administration approved a higher-dose (23 mg/d donepezil formulation, which provides more gradual systemic absorption, a longer time to maximum concentration (8 hours versus the immediate-release formulation (3 hours, and higher daily concentrations. Herein, we review (1 the scientific data on the importance of cholinergic deficits in Alzheimer's disease treatment strategies, (2 the rationale for the use of higher-dose acetylcholinesterase inhibitors in patients with advanced disease, and (3 recent clinical evidence supporting the use of higher-dose donepezil in patients with moderate to severe Alzheimer's disease.

  20. Whole-brain mapping of inputs to projection neurons and cholinergic interneurons in the dorsal striatum.

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    Guo, Qingchun; Wang, Daqing; He, Xiaobin; Feng, Qiru; Lin, Rui; Xu, Fuqiang; Fu, Ling; Luo, Minmin

    2015-01-01

    The dorsal striatum integrates inputs from multiple brain areas to coordinate voluntary movements, associative plasticity, and reinforcement learning. Its projection neurons consist of the GABAergic medium spiny neurons (MSNs) that express dopamine receptor type 1 (D1) or dopamine receptor type 2 (D2). Cholinergic interneurons account for a small portion of striatal neuron populations, but they play important roles in striatal functions by synapsing onto the MSNs and other local interneurons. By combining the modified rabies virus with specific Cre- mouse lines, a recent study mapped the monosynaptic input patterns to MSNs. Because only a small number of extrastriatal neurons were labeled in the prior study, it is important to reexamine the input patterns of MSNs with higher labeling efficiency. Additionally, the whole-brain innervation pattern of cholinergic interneurons remains unknown. Using the rabies virus-based transsynaptic tracing method in this study, we comprehensively charted the brain areas that provide direct inputs to D1-MSNs, D2-MSNs, and cholinergic interneurons in the dorsal striatum. We found that both types of projection neurons and the cholinergic interneurons receive extensive inputs from discrete brain areas in the cortex, thalamus, amygdala, and other subcortical areas, several of which were not reported in the previous study. The MSNs and cholinergic interneurons share largely common inputs from areas outside the striatum. However, innervations within the dorsal striatum represent a significantly larger proportion of total inputs for cholinergic interneurons than for the MSNs. The comprehensive maps of direct inputs to striatal MSNs and cholinergic interneurons shall assist future functional dissection of the striatal circuits.

  1. Neuroligin 2 is expressed in synapses established by cholinergic cells in the mouse brain.

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    Virág T Takács

    Full Text Available Neuroligin 2 is a postsynaptic protein that plays a critical role in the maturation and proper function of GABAergic synapses. Previous studies demonstrated that deletion of neuroligin 2 impaired GABAergic synaptic transmission, whereas its overexpression caused increased inhibition, which suggest that its presence strongly influences synaptic function. Interestingly, the overexpressing transgenic mouse line showed increased anxiety-like behavior and other behavioral phenotypes, not easily explained by an otherwise strengthened GABAergic transmission. This suggested that other, non-GABAergic synapses may also express neuroligin 2. Here, we tested the presence of neuroligin 2 at synapses established by cholinergic neurons in the mouse brain using serial electron microscopic sections double labeled for neuroligin 2 and choline acetyltransferase. We found that besides GABAergic synapses, neuroligin 2 is also present in the postsynaptic membrane of cholinergic synapses in all investigated brain areas (including dorsal hippocampus, somatosensory and medial prefrontal cortices, caudate putamen, basolateral amygdala, centrolateral thalamic nucleus, medial septum, vertical- and horizontal limbs of the diagonal band of Broca, substantia innominata and ventral pallidum. In the hippocampus, the density of neuroligin 2 labeling was similar in GABAergic and cholinergic synapses. Moreover, several cholinergic contact sites that were strongly labeled with neuroligin 2 did not resemble typical synapses, suggesting that cholinergic axons form more synaptic connections than it was recognized previously. We showed that cholinergic cells themselves also express neuroligin 2 in a subset of their input synapses. These data indicate that mutations in human neuroligin 2 gene and genetic manipulations of neuroligin 2 levels in rodents will potentially cause alterations in the cholinergic system as well, which may also have a profound effect on the functional properties

  2. Anticholinesterase Effects on Number and Function of Brain Muscarinic Receptors and Central Cholinergic Activity: Drug Intervention.

    Science.gov (United States)

    1986-04-11

    chloride; pirenzepine ;scopolamine;N-methyL- scopolamine; McN-A-343; quinpiroLe; putative neurotransmitters;dopamine;noradrenaline; glutamate;serotonin... pirenzepine /( H)QNB competition experiments revealed the presence of two muscarinic receptor subtypes :-1, . . - the high affinity site,and M-2...also to occur through activation of the M-2 type, e.g. pretreatment with pirenzepine , a selective and potent M- 1 receptor antagonist failed to block

  3. Multiple sclerosis and sexual dysfunction

    Institute of Scientific and Technical Information of China (English)

    Zhen-Ni Guo; Si-Yuan He; Hong-Liang Zhang; Jiang Wu; Yi Yang

    2012-01-01

    Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system characterized by episodic and progressive neurologic dysfunction resulting from inflammatory and autoimmune reactions.The underlying pathogenesis of MS remains largely unclear.However,it is currently accepted as a T cell-mediated autoimmune disease.Among other clinical manifestations,sexual dysfunction (SD) is a painful but still underreported and underdiagnosed symptom of the disorder.SD in MS patients may result from a complex set of conditions and may be associated with multiple anatomic,physiologic,biologic,medical and psychological factors.SD arises primarily from lesions affecting the neural pathways involved in physiologic function.In addition,psychological factors,the side effects of medications and physical symptoms such as fatigue,muscular weakness,menstrual changes,pain and concerns about bladder and bowel incontinence may also be involved.Since MS primarily affects young people,SD secondary to MS may have a great impact on quality of life.Thus,maintaining a healthy sexual life with MS is an important priority.The treatment of SD requires multidisciplinary teamwork and cooperation among specialists,individual patients,partners and the society.

  4. Animal models of erectile dysfunction

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    Snehlata V Gajbhiye

    2015-01-01

    Full Text Available Animal models have contributed to a great extent to understanding and advancement in the field of sexual medicine. Many current medical and surgical therapies in sexual medicine have been tried based on these animal models. Extensive literature search revealed that the compiled information is limited. In this review, we describe various experimental models of erectile dysfunction (ED encompassing their procedures, variables of assessment, advantages and disadvantages. The search strategy consisted of review of PubMed based articles. We included original research work and certain review articles available in PubMed database. The search terms used were "ED and experimental models," "ED and nervous stimulation," "ED and cavernous nerve stimulation," "ED and central stimulation," "ED and diabetes mellitus," "ED and ageing," "ED and hypercholesteremia," "ED and Peyronie′s disease," "radiation induced ED," "telemetric recording," "ED and mating test" and "ED and non-contact erection test."

  5. Flibanserin for female sexual dysfunction.

    Science.gov (United States)

    Reviriego, C

    2014-08-01

    Hypoactive sexual desire disorder (HSDD) is the most commonly described form of female sexual dysfunction. There is currently no pharmacological therapy approved to treat HSDD, and therefore, there is an unmet medical need for the development of efficacious treatment alternatives. Flibanserin is a novel, non-hormonal drug for the treatment of HSDD in pre- and postmenopausal women, although the application submitted to the U.S. Food and Drug Administration by Sprout Pharmaceuticals is only for premenopausal women. Flibanserin works by correcting an imbalance of the levels of the neurotransmitters that affect sexual desire. More specifically, flibanserin increases dopamine and norepinephrine, both responsible for sexual excitement, and decreases serotonin, responsible for sexual inhibition. Clinically, flibanserin has exhibited some encouraging results in terms of its ability to increase the frequency of satisfying sexual events, and the intensity of sexual desire. However, adverse events such as dizziness, nausea, fatigue and somnolence, typical of a centrally acting drug, are also frequently related to flibanserin treatment.

  6. An increase in intracelluar free calcium ions modulated by cholinergic receptors in rat facial nucleus

    Institute of Scientific and Technical Information of China (English)

    SUN Da-wei; ZHOU Rui; LI Na; ZHANG Qiu-gui; ZHU Fu-gao

    2009-01-01

    Background Ca2+in the central nervous system plays important roles in brain physiology, including neuronal survival and regeneration in rats with injured facial motoneurons. The present research was to study the modulations of intracellular free Ca2+ concentrations by cholinergic receptors in rat facial nucleus, and the mechanisms of the modulations. Methods The fluorescence intensity of facial nucleus in Fluo-3 AM loaded acute brainstem slices was detected by applying intracellular free Ca2+ measurement technique via confocal laser scanning microscope. The changes of fluorescence intensity of facial nucleus indicate the average changes of intracellular free Ca2+ levels of the neurons. Results Acetylcholine was effective at increasing the fluorescence intensity of facial nucleus. Muscarine chlorlde induced a marked increase of fluorescence intensity in a concentration dependent fashion. The enhancement of fluorescence intensity by muscarine chloride was significantly reduced by thapsigargin (depletor of intracellular Ca2+ store; P0.05). And the increase of fluorescence intensity was also significantly inhibited by pirenzepine (M1 subtype selective antagonist; P0.05).Conclusions The data provide the evidence that muscarinic receptors may induce the increase of intracellular free Ca2+ levels through the Ca2+ release of intracellular Ca2+ stores, in a manner related to M1 and M3 subtypes of muscarinic receptors in rat facial nucleus. Nicotine may increase intracellular free Ca2+ concentrations via the influx of extracellular Ca2+ mainly across L-type voltage-gated Ca2+ channels, in a manner related to the α4β2 subtype of nicotinic receptors.

  7. Cholinergic Enhancement of Cell Proliferation in the Postnatal Neurogenic Niche of the Mammalian Spinal Cord.

    Science.gov (United States)

    Corns, Laura F; Atkinson, Lucy; Daniel, Jill; Edwards, Ian J; New, Lauryn; Deuchars, Jim; Deuchars, Susan A

    2015-09-01

    The region surrounding the central canal (CC) of the spinal cord is a highly plastic area, defined as a postnatal neurogenic niche. Within this region are ependymal cells that can proliferate and differentiate to form new astrocytes and oligodendrocytes following injury and cerebrospinal fluid contacting cells (CSFcCs). The specific environmental conditions, including the modulation by neurotransmitters that influence these cells and their ability to proliferate, are unknown. Here, we show that acetylcholine promotes the proliferation of ependymal cells in mice under both in vitro and in vivo conditions. Using whole cell patch clamp in acute spinal cord slices, acetylcholine directly depolarized ependymal cells and CSFcCs. Antagonism by specific nicotinic acetylcholine receptor (nAChR) antagonists or potentiation by the α7 containing nAChR (α7*nAChR) modulator PNU 120596 revealed that both α7*nAChRs and non-α7*nAChRs mediated the cholinergic responses. Using the nucleoside analogue EdU (5-ethynyl-2'-deoxyuridine) as a marker of cell proliferation, application of α7*nAChR modulators in spinal cord cultures or in vivo induced proliferation in the CC region, producing Sox-2 expressing ependymal cells. Proliferation also increased in the white and grey matter. PNU 120596 administration also increased the proportion of cells coexpressing oligodendrocyte markers. Thus, variation in the availability of acetylcholine can modulate the rate of proliferation of cells in the ependymal cell layer and white and grey matter through α7*nAChRs. This study highlights the need for further investigation into how neurotransmitters regulate the response of the spinal cord to injury or during aging.

  8. Hormonal and cholinergic influences on pancreatic lysosomal and digestive enzymes in rats.

    Science.gov (United States)

    Evander, A; Ihse, I; Lundquist, I

    1983-01-01

    Hormonal and cholinergic influences on lysosomal and digestive enzyme activities in pancreatic tissue were studied in normal adult rats. Hormonal stimulation by the cholecystokinin analogue, caerulein, induced a marked enhancement of the activities of cathepsin D and N-acetyl-beta-D-glucosaminidase in pancreatic tissue, whereas the activities of amylase and lipase tended to decrease. Acid phosphatase activity was not affected. Further, caerulein was found to induce a significant increase of cathepsin D output in bile-pancreatic juice. This output largely parallelled that of amylase. Cholinergic stimulation by the muscarinic agonist carbachol, at a dose level giving the same output of amylase as caerulein, did not affect pancreatic activities of cathepsin D and N-acetyl-beta-D-glucosaminidase. Further, cholinergic stimulation induced an increase of amylase activity and a slight decrease of acid phosphatase activity in pancreatic tissue. Lipase activity was not affected. No apparent effect on cathepsin D output in bile-pancreatic juice was encountered after cholinergic stimulation. The activities of neither the digestive nor the lysosomal enzymes were influenced by the administration of secretin. The results suggest a possible lysosomal involvement in caerulein-induced secretion and/or inactivation of pancreatic digestive enzymes, whereas cholinergic stimulation seems to act through different mechanisms.

  9. Caffeine elicits c-Fos expression in horizontal diagonal band cholinergic neurons.

    Science.gov (United States)

    Reznikov, Leah R; Pasumarthi, Ravi K; Fadel, Jim R

    2009-12-09

    Caffeine is a widely self-administered psychostimulant with purported neuroprotective and procognitive effects in rodent models of aging. The cholinergic basal forebrain is important for arousal and attention and is implicated in age-related cognitive decline. Accordingly, we determined the effects of caffeine on cholinergic neuron activation in the rat basal forebrain. Young adult (age 2 months) male rats were treated with caffeine (0, 10, or 50 mg/kg) and killed 2 h later. Caffeine significantly increased c-Fos expression in cholinergic neurons of the horizontal limb of the diagonal band of Broca but not other basal forebrain regions such as the medial septum or substantia innominata. The horizontal limb of the diagonal band of Broca provides cholinergic innervation to the olfactory bulb, suggesting that deficits in this structure may contribute to diminished olfactory function observed in Alzheimer's disease patients. These results suggest that part of the cognitive-enhancing effects of caffeine may be mediated through activation of this part of the cholinergic basal forebrain.

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

    Directory of Open Access Journals (Sweden)

    Licurgo Benemann Almeida

    2016-11-01

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

  11. Cholinergic involvement in Alzheimer's disease. A link with NGF maturation and degradation.

    Science.gov (United States)

    Cuello, A Claudio; Bruno, Martin A; Allard, Simon; Leon, Wanda; Iulita, M Florencia

    2010-01-01

    Basal forebrain cholinergic neurons are highly dependent on nerve growth factor (NGF) supply for the maintenance of their cholinergic phenotype as well as their cholinergic synaptic integrity. The precursor form of NGF, proNGF, abounds in the CNS and is highly elevated in Alzheimer's disease. In order to obtain a deeper understanding of the NGF biology in the CNS, we have performed a series of ex vivo and in vivo investigations to elucidate the mechanisms of release, maturation and degradation of this neurotrophin. In this short review, we describe this NGF metabolic pathway, its significance for the maintenance of basal cholinergic neurons, and its dysregulation in Alzheimer's disease. We are proposing that the conversion of proNGF to mature NGF occurs in the extracellular space by the coordinated action of zymogens, convertases, and endogenous regulators, which are released in the extracellular space in an activity-dependent fashion. We further discuss our findings of a diminished conversion of the NGF precursor molecule to its mature form in Alzheimer's disease as well as an augmented degradation of mature NGF. These combined effects on NGF metabolism would explain the well-known cholinergic atrophy found in Alzheimer's disease and would offer new therapeutic opportunities aimed at correcting the NGF dysmetabolism along with Abeta-induced inflammatory responses.

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

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    Yi Lv

    2014-01-01

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

  13. Chronic Cerebral Ischaemia Forms New Cholinergic Mechanisms of Learning and Memory

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    E. I. Zakharova

    2010-01-01

    Full Text Available The purpose of this research was a comparative analysis of cholinergic synaptic organization following learning and memory in normal and chronic cerebral ischaemic rats in the Morris water maze model. Choline acetyltransferase and protein content were determined in subpopulations of presynapses of “light” and “heavy” synaptosomal fractions of the cortex and the hippocampus, and the cholinergic projective and intrinsic systems of the brain structures were taken into consideration. We found a strong involvement of cholinergic systems, both projective and intrinsic, in all forms of cognition. Each form of cognition had an individual cholinergic molecular profile and the cholinergic synaptic compositions in the ischaemic rat brains differed significantly from normal ones. Our data demonstrated that under ischaemic conditions, instead of damaged connections new key synaptic relationships, which were stable against pathological influences and able to restore damaged cognitive functions, arose. The plasticity of neurochemical links in the individual organization of certain types of cognition gave a new input into brain pathology and can be used in the future for alternative corrections of vascular and other degenerative dementias.

  14. 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

  15. Effects of L-DOPA/benserazide co-treatment on colonic excitatory cholinergic motility and enteric inflammation following dopaminergic nigrostriatal neurodegeneration.

    Science.gov (United States)

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

    2017-09-01

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

  16. Cav2-type calcium channels encoded by cac regulate AP-independent neurotransmitter release at cholinergic synapses in adult Drosophila brain.

    Science.gov (United States)

    Gu, Huaiyu; Jiang, Shaojuan Amy; Campusano, Jorge M; Iniguez, Jorge; Su, Hailing; Hoang, Andy An; Lavian, Monica; Sun, Xicui; O'Dowd, Diane K

    2009-01-01

    Voltage-gated calcium channels containing alpha1 subunits encoded by Ca(v)2 family genes are critical in regulating release of neurotransmitter at chemical synapses. In Drosophila, cac is the only Ca(v)2-type gene. Cacophony (CAC) channels are localized in motor neuron terminals where they have been shown to mediate evoked, but not AP-independent, release of glutamate at the larval neuromuscular junction (NMJ). Cultured embryonic neurons also express CAC channels, but there is no information about the properties of CAC-mediated currents in adult brain nor how these channels regulate transmission in central neural circuits where fast excitatory synaptic transmission is predominantly cholinergic. Here we report that wild-type neurons cultured from late stage pupal brains and antennal lobe projection neurons (PNs) examined in adult brains, express calcium currents with two components: a slow-inactivating current sensitive to the spider toxin Plectreurys toxin II (PLTXII) and a fast-inactivating PLTXII-resistant component. CAC channels are the major contributors to the slow-inactivating PLTXII-sensitive current based on selective reduction of this component in hypomorphic cac mutants (NT27 and TS3). Another characteristic of cac mutant neurons both in culture and in whole brain recordings is a reduced cholinergic miniature excitatory postsynaptic current frequency that is mimicked in wild-type neurons by acute application of PLTXII. These data demonstrate that cac encoded Ca(v)2-type calcium channels regulate action potential (AP)-independent release of neurotransmitter at excitatory cholinergic synapses in the adult brain, a function not predicted from studies at the larval NMJ.

  17. Neurogenic voiding dysfunction.

    Science.gov (United States)

    Georgopoulos, Petros; Apostolidis, Apostolos

    2017-05-01

    This review aims to analyze and discuss all recently published articles associated with neurogenic voiding discussion providing readers with the most updated knowledge and trigger for further research. They include the proposal of a novel classification system for the pathophysiology of neurogenic lower urinary tract dysfunction (NLUTD) which combines neurological defect in a distinct anatomic location, and data on bowel dysfunction, autonomic dysreflexia and urine biomarkers; review of patient-reported outcome measures in NLUTD; review of the criteria for the diagnosis of clinically significant urinary infections; novel research findings on the pathophysiology of NLUTD; and review of data on minimally and more invasive treatments. Despite the extended evidence base on NLUTD, there is a paucity of high-quality new research concerning voiding dysfunction as opposed to storage problems. The update aims to inform clinicians about new developments in clinical practice, as well as ignite discussion for further clinical and basic research in the aforementioned areas of NLUTD.

  18. Biology of Sexual Dysfunction

    Directory of Open Access Journals (Sweden)

    Anil Kumar Mysore Nagaraj

    2009-05-01

    Full Text Available Sexual activity is a multifaceted activity, involving complex interactions between the nervous system, the endocrine system, the vascular system and a variety of structures that are instrumental in sexual excitement, intercourse and satisfaction. Sexual function has three components i.e., desire, arousal and orgasm. Many sexual dysfunctions can be categorized according to the phase of sexual response that is affected. In actual clinical practice however, sexual desire, arousal and orgasmic difficulties more often than not coexist, suggesting an integration of phases. Sexual dysfunction can result from a wide variety of psychological and physiological causes including derangements in the levels of sex hormones and neurotrensmitters. This review deals with the biology of different phases of sexual function as well as implications of hormones and neurotransmitters in sexual dysfunction

  19. Central cholinesterase inhibition enhances glutamatergic synaptic transmission.

    Science.gov (United States)

    Kozhemyakin, Maxim; Rajasekaran, Karthik; Kapur, Jaideep

    2010-04-01

    Central cholinergic overstimulation results in prolonged seizures of status epilepticus in humans and experimental animals. Cellular mechanisms of underlying seizures caused by cholinergic stimulation remain uncertain, but enhanced glutamatergic transmission is a potential mechanism. Paraoxon, an organophosphate cholinesterase inhibitor, enhanced glutamatergic transmission on hippocampal granule cells synapses by increasing the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in a concentration-dependent fashion. The amplitude of mEPSCs was not increased, which suggested the possibility of enhanced action potential-dependent release. Analysis of EPSCs evoked by minimal stimulation revealed reduced failures and increased amplitude of evoked responses. The ratio of amplitudes of EPSCs evoked by paired stimuli was also altered. The effect of paraoxon on glutamatergic transmission was blocked by the muscarinic antagonist atropine and partially mimicked by carbachol. The nicotinic receptor antagonist α -bungarotoxin did not block the effects of paraoxon; however, nicotine enhanced glutamatergic transmission. These studies suggested that cholinergic overstimulation enhances glutamatergic transmission by enhancing neurotransmitter release from presynaptic terminals.

  20. A model of cholinergic modulation in olfactory bulb and piriform cortex.

    Science.gov (United States)

    de Almeida, Licurgo; Idiart, Marco; Linster, Christiane

    2013-03-01

    In this work we investigate in a computational model how cholinergic inputs to the olfactory bulb (OB) and piriform cortex (PC) modulate odor representations. We use experimental data derived from different physiological studies of ACh modulation of the bulbar and cortical circuitry and the interaction between these two areas. The results presented here indicate that cholinergic modulation in the OB significantly increases contrast and synchronization in mitral cell output. Each of these effects is derived from distinct neuronal interactions, with different groups of interneurons playing different roles. Both bulbar modulation effects contribute to more stable learned representations in PC, with pyramidal networks trained with cholinergic-modulated inputs from the bulb exhibiting more robust learning than those trained with unmodulated bulbar inputs. This increased robustness is evidenced as better recovery of memories from corrupted patterns and lower-concentration inputs as well as increased memory capacity.

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

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    Roger Cachope

    2012-07-01

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

  2. Cholinergic Neurons - Keeping Check on Amyloid beta in the Cerebral Cortex

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    Saak V. Ovsepian

    2013-12-01

    Full Text Available The physiological relevance of the uptake of ligands with no apparent trophic functions via the p75 neurotrophin receptor (p75NTR remains unclear. Herein, we propose a homeostatic role for this in clearance of amyloid β (Aβ in the brain. We hypothesize that uptake of Aβ in conjunction with p75NTR followed by its degradation in lysosomes endows cholinergic basalo-cortical projections enriched in this receptor a facility for maintaining physiological levels of Aβ in target areas. Thus, in addition to the diffuse modulator influence and channeling of extra-thalamic signals, cholinergic innervations could supply the cerebral cortex with an elaborate system for Aβ drainage. Interpreting the emerging relationship of new molecular data with established role of cholinergic modulator system in regulating cortical network dynamics should provide new insights into the brain physiology and mechanisms of neuro-degenerative diseases.

  3. Cholinergic neuromuscular junctions in Brachionus calyciflorus and Lecane quadridentata (Rotifera:Monogononta)

    Institute of Scientific and Technical Information of China (English)

    Ignacio Alejandro Prez-Legaspi; Alma Lilin Guerrero-Barrera; Ivn Jos Galvn-Mendoza; Jos Luis Quintanar; Roberto Rico-Martnez

    2014-01-01

    Objective:To identify the presence of joint muscular and cholinergic systems in two freshwater rotifer species, Brachionus calyciflorus and Lecane quadridentata. Methods: The muscle actin fibers were stained with phalloidin-linked fluorescent dye, and acetylcholine was detected with Amplex Red Acetylcholine/Acetylcholinesterase Assay Kit, and then confocal scanning laser microscopy was used. Results:The musculature of Brachionus calyciflorus showed a pattern similar to other species of the same genus, while that of Lecane quadridentata was different from other rotifer genera described previously. The cholinergic system was determined by co-localization of both muscles and acetylcholine labels in the whole rotifer, suggesting the presence of neuromuscular junctions. Conclusions: The distribution pattern of muscular and acetylcholine systems showed considerable differences between the two species that might be related to different adaptations to particular ecological niches. The confirmation of a cholinergic system in rotifers contributes to the development of potential neuro-pharmacological and toxicological studies using rotifers as model organism.

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

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    Keming Zhou

    2017-05-01

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

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

    DEFF Research Database (Denmark)

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

    2005-01-01

    Urotensin II (UII) is a cyclic neuropeptide with strong vasoconstrictive activity in the peripheral vasculature. UII receptor mRNA is also expressed in the CNS, in particular in cholinergic neurons located in the mesopontine tegmental area, including the pedunculopontine tegmental (PPT) and lateral...... dorsal tegmental nuclei. This distribution suggests that the UII system is involved in functions regulated by acetylcholine, such as the sleep-wake cycle. Here, we tested the hypothesis that UII influences cholinergic PPT neuron activity and alters rapid eye movement (REM) sleep patterns in rats. Local...... blood flow. Moreover, whole-cell recordings from rat-brain slices show that UII selectively excites cholinergic PPT neurons via an inward current and membrane depolarization that were accompanied by membrane conductance decreases. This effect does not depend on action potential generation or fast...

  6. Acupuncture for erectile dysfunction: a systematic review protocol

    OpenAIRE

    Cui, Xiaoming; Li, Xiaoli; Peng, Weina; Zhou, Jing; Yu, Jinna; Ye, Yongming; Liu, Zhishun

    2015-01-01

    Introduction This systematic review protocol aims to provide a protocol for assessing the safety and effectiveness of acupuncture for the treatment of erectile dysfunction(ED). Previous systematic reviews did not draw convincing conclusions owing to high heterogeneity and few included randomised controlled trials, so it is necessary to reassess the efficacy and safety of acupuncture for ED. Methods and analysis Eight electronic databases will be searched: the Cochrane Central Register of Cont...

  7. Muscarinic signaling influences the patterning and phenotype of cholinergic amacrine cells in the developing chick retina

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    Fischer Andy J

    2008-02-01

    Full Text Available Abstract Background Many studies in the vertebrate retina have characterized the differentiation of amacrine cells as a homogenous class of neurons, but little is known about the genes and factors that regulate the development of distinct types of amacrine cells. Accordingly, the purpose of this study was to characterize the development of the cholinergic amacrine cells and identify factors that influence their development. Cholinergic amacrine cells in the embryonic chick retina were identified by using antibodies to choline acetyltransferase (ChAT. Results We found that as ChAT-immunoreactive cells differentiate they expressed the homeodomain transcription factors Pax6 and Islet1, and the cell-cycle inhibitor p27kip1. As differentiation proceeds, type-II cholinergic cells, displaced to the ganglion cell layer, transiently expressed high levels of cellular retinoic acid binding protein (CRABP and neurofilament, while type-I cells in the inner nuclear layer did not. Although there is a 1:1 ratio of type-I to type-II cells in vivo, in dissociated cell cultures the type-I cells (ChAT-positive and CRABP-negative out-numbered the type-II cells (ChAT and CRABP-positive cells by 2:1. The relative abundance of type-I to type-II cells was not influenced by Sonic Hedgehog (Shh, but was affected by compounds that act at muscarinic acetylcholine receptors. In addition, the abundance and mosaic patterning of type-II cholinergic amacrine cells is disrupted by interfering with muscarinic signaling. Conclusion We conclude that: (1 during development type-I and type-II cholinergic amacrine cells are not homotypic, (2 the phenotypic differences between these subtypes of cells is controlled by the local microenvironment, and (3 appropriate levels of muscarinic signaling between the cholinergic amacrine cells are required for proper mosaic patterning.

  8. Sox2 regulates cholinergic amacrine cell positioning and dendritic stratification in the retina.

    Science.gov (United States)

    Whitney, Irene E; Keeley, Patrick W; St John, Ace J; Kautzman, Amanda G; Kay, Jeremy N; Reese, Benjamin E

    2014-07-23

    The retina contains two populations of cholinergic amacrine cells, one positioned in the ganglion cell layer (GCL) and the other in the inner nuclear layer (INL), that together comprise ∼1/2 of a percent of all retinal neurons. The present study examined the genetic control of cholinergic amacrine cell number and distribution between these two layers. The total number of cholinergic amacrine cells was quantified in the C57BL/6J and A/J inbred mouse strains, and in 25 recombinant inbred strains derived from them, and variations in their number and ratio (GCL/INL) across these strains were mapped to genomic loci. The total cholinergic amacrine cell number was found to vary across the strains, from 27,000 to 40,000 cells, despite little variation within individual strains. The number of cells was always lower within the GCL relative to the INL, and the sizes of the two populations were strongly correlated, yet there was variation in their ratio between the strains. Approximately 1/3 of that variation in cell ratio was mapped to a locus on chromosome 3, where Sex determining region Y box 2 (Sox2) was identified as a candidate gene due to the presence of a 6-nucleotide insertion in the protein-coding sequence in C57BL/6J and because of robust and selective expression in cholinergic amacrine cells. Conditionally deleting Sox2 from the population of nascent cholinergic amacrine cells perturbed the normal ratio of cells situated in the GCL versus the INL and induced a bistratifying morphology, with dendrites distributed to both ON and OFF strata within the inner plexiform layer.

  9. Adenosine Inhibits the Excitatory Synaptic Inputs to Basal Forebrain Cholinergic, GABAergic and Parvalbumin Neurons in mice

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    Chun eYang

    2013-06-01

    Full Text Available Coffee and tea contain the stimulants caffeine and theophylline. These compounds act as antagonists of adenosine receptors. Adenosine promotes sleep and its extracellular concentration rises in association with prolonged wakefulness, particularly in the basal forebrain (BF region involved in activating the cerebral cortex. However, the effect of adenosine on identified BF neurons, especially non-cholinergic neurons, is incompletely understood. Here we used whole-cell patch-clamp recordings in mouse brain slices prepared from two validated transgenic mouse lines with fluorescent proteins expressed in GABAergic or parvalbumin (PV neurons to determine the effect of adenosine. Whole-cell recordings were made BF cholinergic neurons and from BF GABAergic & PV neurons with the size (>20 µm and intrinsic membrane properties (prominent H-currents corresponding to cortically projecting neurons. A brief (2 min bath application of adenosine (100 μM decreased the frequency but not the amplitude of spontaneous excitatory postsynaptic currents in all groups of BF cholinergic, GABAergic and PV neurons we recorded. In addition, adenosine decreased the frequency of miniature EPSCs in BF cholinergic neurons. Adenosine had no effect on the frequency of spontaneous inhibitory postsynaptic currents in cholinergic neurons or GABAergic neurons with large H-currents but reduced them in a group of GABAergic neurons with smaller H-currents. All effects of adenosine were blocked by a selective, adenosine A1 receptor antagonist, cyclopentyltheophylline (CPT, 1 μM. Adenosine had no postsynaptic effects. Taken together, our work suggests that adenosine promotes sleep by an A1-receptor mediated inhibition of glutamatergic inputs to cortically-projecting cholinergic and GABA/PV neurons. Conversely, caffeine and theophylline promote attentive wakefulness by inhibiting these A1 receptors in BF thereby promoting the high-frequency oscillations in the cortex required for

  10. Ventral tegmental area cholinergic mechanisms mediate behavioral responses in the forced swim test.

    Science.gov (United States)

    Addy, N A; Nunes, E J; Wickham, R J

    2015-07-15

    Recent studies revealed a causal link between ventral tegmental area (VTA) phasic dopamine (DA) activity and pro-depressive and antidepressant-like behavioral responses in rodent models of depression. Cholinergic activity in the VTA has been demonstrated to regulate phasic DA activity, but the role of VTA cholinergic mechanisms in depression-related behavior is unclear. The goal of this study was to determine whether pharmacological manipulation of VTA cholinergic activity altered behavioral responding in the forced swim test (FST) in rats. Here, male Sprague-Dawley rats received systemic or VTA-specific administration of the acetylcholinesterase inhibitor, physostigmine (systemic; 0.06 or 0.125mg/kg, intra-cranial; 1 or 2μg/side), the muscarinic acetylcholine receptor (AChR) antagonist scopolamine (2.4 or 24μg/side), or the nicotinic AChR antagonist mecamylamine (3 or 30μg/side), prior to the FST test session. In control experiments, locomotor activity was also examined following systemic and intra-cranial administration of cholinergic drugs. Physostigmine administration, either systemically or directly into the VTA, significantly increased immobility time in FST, whereas physostigmine infusion into a dorsal control site did not alter immobility time. In contrast, VTA infusion of either scopolamine or mecamylamine decreased immobility time, consistent with an antidepressant-like effect. Finally, the VTA physostigmine-induced increase in immobility was blocked by co-administration with scopolamine, but unaltered by co-administration with mecamylamine. These data show that enhancing VTA cholinergic tone and blocking VTA AChRs has opposing effects in FST. Together, the findings provide evidence for a role of VTA cholinergic mechanisms in behavioral responses in FST.

  11. Organization of cholinergic, catecholaminergic, serotonergic and orexinergic nuclei in three strepsirrhine primates: Galago demidoff, Perodicticus potto and Lemur catta.

    Science.gov (United States)

    Calvey, Tanya; Patzke, Nina; Kaswera-Kyamakya, Consolate; Gilissen, Emmanuel; Bertelsen, Mads F; Pettigrew, John D; Manger, Paul R

    2015-12-01

    The nuclear organization of the cholinergic, catecholaminergic, serotonergic and orexinergic systems in the brains of three species of strepsirrhine primates is presented. We aimed to investigate the nuclear complement of these neural systems in comparison to those of simian primates, megachiropterans and other mammalian species. The brains were coronally sectioned and immunohistochemically stained with antibodies against choline acetyltransferase, tyrosine hydroxylase, serotonin and orexin-A. The nuclei identified were identical among the strepsirrhine species investigated and identical to previous reports in simian primates. Moreover, a general similarity to other mammals was found, but specific differences in the nuclear complement highlighted potential phylogenetic interrelationships. The central feature of interest was the structure of the locus coeruleus complex in the primates, where a central compactly packed core (A6c) of tyrosine hydroxylase immunopositive neurons was surrounded by a shell of less densely packed (A6d) tyrosine hydroxylase immunopositive neurons. This combination of compact and diffuse divisions of the locus coeruleus complex is only found in primates and megachiropterans of all the mammalian species studied to date. This neural character, along with variances in a range of other neural characters, supports the phylogenetic grouping of primates with megachiropterans as a sister group. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Co-expression of alpha7 and beta2 nicotinic acetylcholine receptor subunit mRNAs within rat brain cholinergic neurons.

    Science.gov (United States)

    Azam, L; Winzer-Serhan, U; Leslie, F M

    2003-01-01

    Nicotine enhances cognitive and attentional processes through stimulation of the basal forebrain cholinergic system. Although muscarinic cholinergic autoreceptors have been well characterized, pharmacological characterization of nicotinic autoreceptors has proven more difficult. The present study used double-labeling in situ hybridization to determine expression of nicotinic acetylcholine receptor (nAChR) subunit mRNAs within basal forebrain cholinergic neurons in order to gain information about possible nAChR autoreceptor properties. Cholinergic cells of the mesopontine tegmentum and striatal interneurons were also examined, as were septohippocampal GABAergic neurons that interact with cholinergic neurons to regulate hippocampal activity. alpha7 and beta2 nAChR mRNAs were found to be co-expressed in almost all cholinergic cells and in the majority of GABAergic neurons examined. alpha4 nAChR mRNA expression was restricted to cholinergic cells of the nucleus basalis magnocellularis, and to non-cholinergic cells of the medial septum and mesopontine tegmentum. These data suggest possible regional differences in the pharmacological properties of nicotinic autoreceptors on cholinergic cells. Whereas most cholinergic cells express rapidly desensitizing alpha7 homomers or alpha7beta2 heteromers, cortical projection neurons may also express a pharmacologically distinct alpha4beta2 nAChR subtype. There may also be differential nAChR regulation of cholinergic and non-cholinergic cells within the mesopontine tegmentum that are implicated in acquisition of nicotine self-administration.

  13. Contribution of the cholinergic basal forebrain to proactive interference from stored odor memories during associative learning in rats.

    Science.gov (United States)

    De Rosa, E; Hasselmo, M E; Baxter, M G

    2001-04-01

    E. De Rosa and M. E. Hasselmo (2000) demonstrated that 0.25 mg/kg scopolamine (SCOP) selectively increased proactive interference (PI) from stored odor memories during learning. In the present study, rats with bilateral cholinergic lesions limited to the horizontal limb of the diagonal band of Broca, made with 192 IgG-saporin, were not impaired in acquiring the same olfactory discrimination task relative to control rats. Rats with bilateral 192 IgG-saporin lesions to all basal forebrain cholinergic nuclei (BF) also showed no impairment in acquisition of this task. However, the BF-saporin rats were hypersensitive to oxotremorine-induced hypothermia and demonstrated an increased sensitivity to PI following a low dose of SCOP (0.125 mg/kg) relative to control rats. The results suggest that weaker cholinergic modulation after cholinergic BF lesions makes the system more sensitive to PI during blockade of the remaining cholinergic elements.

  14. Neonatal treatment with scopolamine butylbromide prevents metabolic dysfunction in male rats

    Science.gov (United States)

    Malta, Ananda; Souza, Aline Amenencia de; Ribeiro, Tatiane Aparecida; Francisco, Flávio Andrade; Pavanello, Audrei; Prates, Kelly Valério; Tófolo, Laize Peron; Miranda, Rosiane Aparecida; Oliveira, Júlio Cezar de; Martins, Isabela Peixoto; Previate, Carina; Gomes, Rodrigo Mello; Franco, Claudinéia Conationi da Silva; Natali, Maria Raquel Marçal; Palma-Rigo, Kesia; Mathias, Paulo Cezar de Freitas

    2016-01-01

    We tested whether treatment with a cholinergic antagonist could reduce insulin levels in early postnatal life and attenuate metabolic dysfunctions induced by early overfeeding in adult male rats. Wistar rats raised in small litters (SLs, 3 pups/dam) and normal litters (NLs, 9 pups/dam) were used in models of early overfeeding and normal feeding, respectively. During the first 12 days of lactation, animals in the SL and NL groups received scopolamine butylbromide (B), while the controls received saline (S) injections. The drug treatment decreased insulin levels in pups from both groups, and as adults, these animals showed improvements in glucose tolerance, insulin sensitivity, vagus nerve activity, fat tissue accretion, insulinemia, leptinemia, body weight gain and food intake. Low glucose and cholinergic insulinotropic effects were observed in pancreatic islets from both groups. Low protein expression was observed for the muscarinic M3 acetylcholine receptor subtype (M3mAChR), although M2mAChR subtype expression was increased in SL-B islets. In addition, beta-cell density was reduced in drug-treated rats. These results indicate that early postnatal scopolamine butylbromide treatment inhibits early overfeeding-induced metabolic dysfunctions in adult rats, which might be caused by insulin decreases during lactation, associated with reduced parasympathetic activity and expression of M3mAChR in pancreatic islets. PMID:27561682

  15. Dexmedetomidine controls systemic cytokine levels through the cholinergic anti-inflammatory pathway.

    Science.gov (United States)

    Xiang, Hui; Hu, Bo; Li, Zhifeng; Li, Jianguo

    2014-10-01

    %, Pdexmedetomidine significantly attenuated the cytokine response after lipopolysaccharide (LPS) induced endotoxemia (TNF-alpha, IL-1beta, IL-6, Pdexmedetomidine failed to suppress cytokine response in α-bungarotoxin group and vagotomy group (TNF-alpha, IL-1beta, IL-6, P>0.05, respectively). Furthermore, preemptive administration of dexmedetomidine significantly increased the discharge frequency of cervical vagus nerves in comparison with sterile saline treatment (Pdexmedetomidine increases the activity of cervical vagus nerve and have the ability to successfully improve survival in experimental endotoxemia by inhibiting the inflammatory cytokines release. However, administration of dexmedetomidine to vagotomy or α7 nAChR antagonist pretreatment mice failed to suppress TNF levels, indicating that the vagus nerve and α7nAChR-mediated cholinergic anti-inflammatory pathway is required for the anti-inflammatory effect of dexmedetomidine. These findings show that central alpha-2 agonist dexmedetomidine suppresses systemic inflammation through vagal- and α7nAChR-dependent mechanism.

  16. Dichotomous Distribution of Putative Cholinergic Interneurons in Mouse Accessory Olfactory Bulb

    Science.gov (United States)

    Marking, Sarah; Krosnowski, Kurt; Ogura, Tatsuya; Lin, Weihong

    2017-01-01

    Sensory information processing in the olfactory bulb (OB) relies on diverse populations of bulbar interneurons. In rodents, the accessory OB (AOB) is divided into two bulbar regions, the anterior (aAOB) and posterior (pAOB), which differ substantially in their circuitry connections and associated behaviors. We previously identified and characterized a large number of morphologically diverse cholinergic interneurons in the main OB (MOB) using transgenic mice to visualize the cell bodies of choline acetyltransferase (ChAT-expressing neurons and immunolabeling (Krosnowski et al., 2012)). However, whether there are cholinergic neurons in the AOB is controversial and there is no detailed characterization of such neurons. Using the same line of ChAT(bacterial artificial chromosome, BAC)-enhanced green fluorescent protein (eGFP) transgenic mice, we investigated cholinergic neurons in the AOB. We found significant differences in the number and location of GFP-expressing (GFP+), putative cholinergic interneurons between the aAOB and pAOB. The highest numbers of GFP+ interneurons were found in the aAOB glomerular layer (aGL) and pAOB mitral/tufted cell layer (pMCL). We also noted a high density of GFP+ interneurons encircling the border region of the pMCL. Interestingly, a small subset of glomeruli in the middle of the GL receives strong MCL GFP+ nerve processes. These local putative cholinergic-innervated glomeruli are situated just outside the aGL, setting the boundary between the pGL and aGL. Many but not all GFP+ neurons in the AOB were weakly labeled with antibodies against ChAT and vesicular acetylcholine transporter (VAChT). We further determined if these GFP+ interneurons differ from other previously characterized interneuron populations in the AOB and found that AOB GFP+ interneurons express neither GABAergic nor dopaminergic markers and most also do not express the glutamatergic marker. Similar to the cholinergic interneurons of the MOB, some AOB GFP+ interneurons

  17. Thalamic cholinergic innervation is spared in Alzheimer disease compared to Parkinsonian disorders

    Science.gov (United States)

    Kotagal, Vikas; Müller, Martijn L.T.M.; Kaufer, Daniel I.; Koeppe, Robert A.; Bohnen, Nicolaas I.

    2012-01-01

    OBJECTIVE There are two major sources of cholinergic projections in the brain. The nucleus basalis of Meynert provides the principal cholinergic input of the cortical mantle and the pedunculopontine nucleus-laterodorsal tegmental complex (PPN-LDTC; hereafter referred to as PPN) provides the major cholinergic input to the thalamus. Cortical cholinergic denervation has previously been shown to be part of Alzheimer and parkinsonian dementia but there is less information about subcortical thalamic cholinergic denervation. We investigated thalamic cholinergic afferent integrity by measuring PPN-Thalamic (PPN-Thal) acetylcholinesterase (AChE) activity via PET imaging in Alzheimer (AD), Parkinson disease without dementia (PD), Parkinson disease with dementia (PDD) and dementia with Lewy bodies (DLB). METHODS AD (n=13; mean age 75.4±5.5), PD (n=11; age 71.4±6.4), PDD (n=6; age 70.8±4.7), DLB (n=6; age 68.0±8.6) and normal controls (NC; n=14; age 69.0±7.5) subjects underwent AChE [11C]-methyl-4-piperidinyl propionate (PMP) PET imaging. PPN-Thal PET data were analyzed using the Nagatsuka method. RESULTS There were no significant differences in mean age between the groups (F=1.86, p=0.134). Kruskal-Wallis testing demonstrated a significant group effect for PPN-Thal AChE hydrolysis rates (F=9.62, P<0.0001). Compared to NC, reduced thalamic k3 hydrolysis rate was noted in subjects with PDD (−19.8%; AChE k3 hydrolysis rates 0.1072±0.0143 min−1), DLB (−17.4%; 0.1103±0.0112 min−1) and PD (−12.8%; 0.1165±0.0114 min−1). Each of these 3 subgroups were statistically different from AD subjects (−0.7%; 0.1326±0.0095 min−1) who showed relatively spared thalamic k3 hydrolysis rates which were comparable to NC (0.1336±0.0142 min−1). CONCLUSIONS Thalamic cholinergic denervation is present in PD, PDD, and DLB but not in AD. Neurodegenerative involvement of thalamic cholinergic afferent projections may contribute to disease-specific motor and cognitive

  18. Developmental and neurochemical features of cholinergic neurons in the murine cerebral cortex

    Directory of Open Access Journals (Sweden)

    Becchetti Andrea

    2009-03-01

    Full Text Available Abstract Background The existence and role of intrinsic cholinergic cells in the cerebral cortex is controversial, because of their variable localization and morphology in different mammalian species. We have applied choline acetyltransferase (ChAT immunocytochemistry to study the distribution of cholinergic neurons in the murine cerebral cortex, in the adult and during postnatal development. For more precise neurochemical identification of these neurons, the possible colocalization of ChAT with different markers of cortical neuronal populations has been analyzed by confocal microscopy. This method was also used to verify the relationship between cholinergic cells and cortical microvessels. Results ChAT positive cells appeared at the end of the first postnatal week. Their density dramatically increased at the beginning of the second postnatal week, during which it remained higher than in perinatal and adult stages. In the adult neocortex, cholinergic neurons were particularly expressed in the somatosensory area, although their density was also significant in visual and auditory areas. ChAT positive cells tended to be scarce in other regions. They were mainly localized in the supragranular layers and displayed a fusiform/bipolar morphology. The colocalization of ChAT with pyramidal neuron markers was negligible. On the other hand, more than half of the cholinergic neurons contained calretinin, but none of them expressed parvalbumin or calbindin. However, only a fraction of the ChAT positive cells during development and very few in adulthood turned out to be GABAergic, as judged from expression of GABA and its biosynthetic enzymes GAD67/65. Consistently, ChAT showed no localization with interneurons expressing green fluorescent protein under control of the GAD67 promoter in the adult neocortex. Finally, the cortical cholinergic cells often showed close association with the microvessel walls, as identified with the gliovascular marker aquaporin 4

  19. Diastolic dysfunction in cirrhosis

    DEFF Research Database (Denmark)

    Møller, Søren; Wiese, Signe Skovgaard; Halgreen, Hanne

    2016-01-01

    Development of esophageal varices, ascites, and hepatic nephropathy is among the major complications of cirrhosis. The presence of cirrhotic cardiomyopathy, which includes a left ventricular diastolic dysfunction (DD), seems to deteriorate the course of the disease and the prognosis. Increased st...

  20. Female sexual dysfunction

    DEFF Research Database (Denmark)

    Giraldi, Annamaria; Wåhlin-Jacobsen, Sarah

    2016-01-01

    Female sexual dysfunction (FSD) is a controversial condition, which has prompted much debate regarding its aetiology, components, and even its existence. Our inability to work together as clinicians, psychologists, patients, and advocates hinders our understanding of FSD, and we will only improve...

  1. Mitochondrial Dysfunction in Cancer

    Directory of Open Access Journals (Sweden)

    Michelle L Boland

    2013-12-01

    Full Text Available A mechanistic understanding of how mitochondrial dysfunction contributes to cell growth and tumorigenesis is emerging beyond Warburg as an area of research that is under-explored in terms of its significance for clinical management of cancer. Work discussed in this review focuses less on the Warburg effect and more on mitochondria and how dysfunctional mitochondria modulate cell cycle, gene expression, metabolism, cell viability and other more conventional aspects of cell growth and stress responses. There is increasing evidence that key oncogenes and tumor suppressors modulate mitochondrial dynamics through important signaling pathways and that mitochondrial mass and function vary between tumors and individuals but the sigificance of these events for cancer are not fully appreciated. We explore the interplay between key molecules involved in mitochondrial fission and fusion and in apoptosis, as well as in mitophagy, biogenesis and spatial dynamics and consider how these distinct mechanisms are coordinated in response to physiological stresses such as hypoxia and nutrient deprivation. Importantly, we examine how deregulation of these processes in cancer has knockon effects for cell proliferation and growth. Scientifically, there is also scope for defining what mitochondria dysfunction is and here we address the extent to which the functional consequences of such dysfunction can be determined and exploited for cancer diagnosis and treatment.

  2. Shared Parenting Dysfunction.

    Science.gov (United States)

    Turkat, Ira Daniel

    2002-01-01

    Joint custody of children is the most prevalent court ordered arrangement for families of divorce. A growing body of literature indicates that many parents engage in behaviors that are incompatible with shared parenting. This article provides specific criteria for a definition of the Shared Parenting Dysfunction. Clinical aspects of the phenomenon…

  3. Age-dependent loss of cholinergic neurons in learning and memory-related brain regions and impaired learning in SAMP8 mice with trigeminal nerve damage

    Institute of Scientific and Technical Information of China (English)

    Yifan He; Jihong Zhu; Fang Huang; Liu Qin; Wenguo Fan; Hongwen He

    2014-01-01

    The tooth belongs to the trigeminal sensory pathway. Dental damage has been associated with impairments in the central nervous system that may be mediated by injury to the trigeminal nerve. In the present study, we investigated the effects of damage to the inferior alveolar nerve, an important peripheral nerve in the trigeminal sensory pathway, on learning and memory be-haviors and structural changes in related brain regions, in a mouse model of Alzheimer’s disease. Inferior alveolar nerve transection or sham surgery was performed in middle-aged (4-month-old) or elderly (7-month-old) senescence-accelerated mouse prone 8 (SAMP8) mice. When the middle-aged mice reached 8 months (middle-aged group 1) or 11 months (middle-aged group 2), and the elderly group reached 11 months, step-down passive avoidance and Y-maze tests of learn-ing and memory were performed, and the cholinergic system was examined in the hippocampus (Nissl staining and acetylcholinesterase histochemistry) and basal forebrain (choline acetyltrans-ferase immunohistochemistry). In the elderly group, animals that underwent nerve transection had fewer pyramidal neurons in the hippocampal CA1 and CA3 regions, fewer cholinergic ifbers in the CA1 and dentate gyrus, and fewer cholinergic neurons in the medial septal nucleus and vertical limb of the diagonal band, compared with sham-operated animals, as well as showing impairments in learning and memory. Conversely, no signiifcant differences in histology or be-havior were observed between middle-aged group 1 or group 2 transected mice and age-matched sham-operated mice. The present ifndings suggest that trigeminal nerve damage in old age, but not middle age, can induce degeneration of the septal-hippocampal cholinergic system and loss of hippocampal pyramidal neurons, and ultimately impair learning ability. Our results highlight the importance of active treatment of trigeminal nerve damage in elderly patients and those with Alzheimer’s disease, and

  4. Brain dysfunction in mild to moderate hypoxia.

    Science.gov (United States)

    Gibson, G E; Pulsinelli, W; Blass, J P; Duffy, T E

    1981-06-01

    Hypoxia is commonly invoked to explain alterations in mental function, particularly in patients with cardiac pulmonary failure. The effects of acute graded hypoxia or higher integrative functions are well documented experimentally in man. Hypoxia in experimental animal models demonstrates that the pathophysiology is complex. In mild to moderate hypoxia, in contrast to severe hypoxia and to ischemia, the supply of energy for the brain is not impaired; cerebral levels of adenosine triphosphate (ATP) and adenylate energy charge are normal. In contrast, the turnover of several neurotransmitters is altered by mild hypoxia. For example, acetylcholine synthesis is reduced proportionally to the reduction in carbohydrate oxidation. This relationship holds in vitro and with several in vivo models of hypoxia. Pharmacologic and physiologic studies in man and experimental animals are consistent with acetylcholine having an important role in mediating the cerebral effects of mild hypoxia. These observations raise the possibility that treatments directed to cholinergic or other central neurotransmitter systems may benefit patients with cerebral syndromes secondary to chronic hypoxia.

  5. Cognitive dysfunction after cardiovascular surgery

    DEFF Research Database (Denmark)

    Funder, K S; Steinmetz, J; Rasmussen, L S

    2009-01-01

    This review describes the incidence, risk factors, and long-term consequences of cognitive dysfunction after cardiovascular surgery. Postoperative cognitive dysfunction (POCD) is increasingly being recognized as an important complication, especially in the elderly. A highly sensitive neuropsychol...

  6. Tiliacora triandra, an Anti-Intoxication Plant, Improves Memory Impairment, Neurodegeneration, Cholinergic Function, and Oxidative Stress in Hippocampus of Ethanol Dependence Rats

    Directory of Open Access Journals (Sweden)

    Nattaporn Phunchago

    2015-01-01

    Full Text Available Oxidative stress plays an important role in brain dysfunctions induced by alcohol. Since less therapeutic agent against cognitive deficit and brain damage induced by chronic alcohol consumption is less available, we aimed to assess the effect of Tiliacora triandra extract, a plant possessing antioxidant activity, on memory impairment, neuron density, cholinergic function, and oxidative stress in hippocampus of alcoholic rats. Male Wistar rats were induced ethanol dependence condition by semivoluntary intake of alcohol for 15 weeks. Alcoholic rats were orally given T. triandra at doses of 100, 200, and 400 mg·kg−1BW for 14 days. Memory assessment was performed every 7 days while neuron density, activities of AChE, SOD, CAT, and GSH-Px and, MDA level in hippocampus were assessed at the end of study. Interestingly, the extract mitigated the increased escape latency, AChE and MDA level. The extract also mitigated the decreased retention time, SOD, CAT, and GSH-Px activities, and neurons density in hippocampus induced by alcohol. These data suggested that the extract improved memory deficit in alcoholic rats partly via the decreased oxidative stress and the suppression of AChE. Therefore, T. triandra is the potential reagent for treating brain dysfunction induced by alcohol. However, further researches are necessary to understand the detail mechanism and possible active ingredient.

  7. Hepatitis C Virus-Induced Mitochondrial Dysfunctions

    Directory of Open Access Journals (Sweden)

    Birke Bartosch

    2013-03-01

    Full Text Available Chronic hepatitis C is characterized by metabolic disorders and a microenvironment in the liver dominated by oxidative stress, inflammation and regeneration processes that lead in the long term to hepatocellular carcinoma. Many lines of evidence suggest that mitochondrial dysfunctions, including modification of metabolic fluxes, generation and elimination of oxidative stress, Ca2+ signaling and apoptosis, play a central role in these processes. However, how these dysfunctions are induced by the virus and whether they play a role in disease progression and neoplastic transformation remains to be determined. Most in vitro studies performed so far have shown that several of the hepatitis C virus (HCV proteins localize to mitochondria, but the consequences of these interactions on mitochondrial functions remain contradictory, probably due to the use of artificial expression and replication systems. In vivo studies are hampered by the fact that innate and adaptive immune responses will overlay mitochondrial dysfunctions induced directly in the hepatocyte by HCV. Thus, the molecular aspects underlying HCV-induced mitochondrial dysfunctions and their roles in viral replication and the associated pathology need yet to be confirmed in the context of productively replicating virus and physiologically relevant in vitro and in vivo model systems.

  8. Central presbycusis: an emerging view.

    Science.gov (United States)

    Gates, George A

    2012-07-01

    Age-related dysfunction of the central auditory system (central presbycusis) is common but rarely looked for by those who provide aural rehabilitation. Patients who complain of difficulty hearing in noise--the key symptom of central presbycusis--are generally disadvantaged with conventional rehabilitation. This symptom should be documented with commercially available speech-in-noise tests, which use materials that are uncomplicated to administer. Those patients who perform poorly on such tests should have a customized rehabilitation program aimed at optimizing their remaining communication abilities. Otolaryngologists who provide auditory rehabilitation may wish to consider expanding their practices to meet the communication needs of older patients with central presbycusis. Central presbycusis is an emerging area for basic and clinical research in auditory neurotology, particularly in the relation of cognitive dysfunction to impaired auditory processing.

  9. Melanocortins protect against multiple organ dysfunction syndrome in mice

    Science.gov (United States)

    Bitto, Alessandra; Polito, Francesca; Altavilla, Domenica; Irrera, Natasha; Giuliani, Daniela; Ottani, Alessandra; Minutoli, Letteria; Spaccapelo, Luca; Galantucci, Maria; Lodi, Renzo; Guzzo, Giuseppe; Guarini, Salvatore; Squadrito, Francesco

    2011-01-01

    BACKGROUND AND PURPOSE Melanocortins reverse circulatory shock and improve survival by counteracting the systemic inflammatory response, and through the activation of the vagus nerve-mediated cholinergic anti-inflammatory pathway. To gain insight into the potential therapeutic value of melanocortins against multiple organ damage following systemic inflammatory response, here we investigated the effects of the melanocortin analogue [Nle4, D-Phe7]α-MSH (NDP-α-MSH) in a widely used murine model of multiple organ dysfunction syndrome (MODS). EXPERIMENTAL APPROACH MODS was induced in mice by a single intraperitoneal injection of lipopolysaccharide followed, 6 days later (= day 0), by zymosan. After MODS or sham MODS induction, animals were randomized to receive intraperitoneally NDP-α-MSH (340 µg·kg−1 day) or saline for up to 16 days. Additional groups of MODS mice were concomitantly treated with the melanocortin MC4 receptor antagonist HS024, or the nicotinic acetylcholine receptor antagonist chlorisondamine, and NDP-α-MSH. KEY RESULTS At day 7, in the liver and lung NDP-α-MSH, significantly reduced mRNA expression of tumour necrosis factor-α (TNF-α), increased mRNA expression of interleukin-10 and improved the histological picture, as well as reduced TNF-α plasma levels; furthermore, NDP-α-MSH dose-dependently increased survival rate, as assessed throughout the 16 day observation period. HS024 and chlorisondamine prevented all the beneficial effects of NDP-α-MSH in MODS mice. CONCLUSIONS AND IMPLICATIONS These data indicate that NDP-α-MSH protects against experimental MODS by counteracting the systemic inflammatory response, probably through brain MC4 receptor-triggered activation of the cholinergic anti-inflammatory pathway. These findings reveal previously undescribed effects of melanocortins and could have clinical relevance in the MODS setting. PMID:21039420

  10. What Is a Dysfunctional School?

    Science.gov (United States)

    Bergman, M. M.

    2013-01-01

    Whether or not a school is dysfunctional depends largely on how dysfunctionality in schools is defined and measured. Dysfunctionality, as any construct, is subject to definition and interpretation, and it is thus always marked by perspectivism. But regardless of the definition games occasionally played by academics, some form of reality takes…

  11. Lesson Nine Sinus node dysfunction

    Institute of Scientific and Technical Information of China (English)

    鲁端; 吴文烈

    2004-01-01

    @@ Sinus node dysfunction most often is found in the elderly as an isolated phenomenon. Although interruption of the blood supply to the sinus node may produce dysfunction, the correlation between obstruction of the sinus node artery and clinical evidence of sinus node dysfunction is poor.

  12. Hippocampal P3-like auditory event-related potentials are disrupted in a rat model of cholinergic degeneration in Alzheimer's disease: reversal by donepezil treatment.

    Science.gov (United States)

    Laursen, Bettina; Mørk, Arne; Kristiansen, Uffe; Bastlund, Jesper Frank

    2014-01-01

    P300 (P3) event-related potentials (ERPs) have been suggested to be an endogenous marker of cognitive function and auditory oddball paradigms are frequently used to evaluate P3 ERPs in clinical settings. Deficits in P3 amplitude and latency reflect some of the neurological dysfunctions related to several psychiatric and neurological diseases, e.g., Alzheimer's disease (AD). However, only a very limited number of rodent studies have addressed the back-translational validity of the P3-like ERPs as suitable markers of cognition. Thus, the potential of rodent P3-like ERPs to predict pro-cognitive effects in humans remains to be fully validated. The current study characterizes P3-like ERPs in the 192-IgG-SAP (SAP) rat model of the cholinergic degeneration associated with AD. Following training in a combined auditory oddball and lever-press setup, rats were subjected to bilateral intracerebroventricular infusion of 1.25 μg SAP or PBS (sham lesion) and recording electrodes were implanted in hippocampal CA1. Relative to sham-lesioned rats, SAP-lesioned rats had significantly reduced amplitude of P3-like ERPs. P3 amplitude was significantly increased in SAP-treated rats following pre-treatment with 1 mg/kg donepezil. Infusion of SAP reduced the hippocampal choline acetyltransferase activity by 75%. Behaviorally defined cognitive performance was comparable between treatment groups. The present study suggests that AD-like deficits in P3-like ERPs may be mimicked by the basal forebrain cholinergic degeneration induced by SAP. SAP-lesioned rats may constitute a suitable model to test the efficacy of pro-cognitive substances in an applied experimental setup.

  13. Learning history and cholinergic modulation in the dorsal hippocampus are necessary for rats to infer the status of a hidden event.

    Science.gov (United States)

    Fast, Cynthia D; Flesher, M Melissa; Nocera, Nathanial A; Fanselow, Michael S; Blaisdell, Aaron P

    2016-06-01

    Identifying statistical patterns between environmental stimuli enables organisms to respond adaptively when cues are later observed. However, stimuli are often obscured from detection, necessitating behavior under conditions of ambiguity. Considerable evidence indicates decisions under ambiguity rely on inference processes that draw on past experiences to generate predictions under novel conditions. Despite the high demand for this process and the observation that it deteriorates disproportionately with age, the underlying mechanisms remain unknown. We developed a rodent model of decision-making during ambiguity to examine features of experience that contribute to inference. Rats learned either a simple (positive patterning) or complex (negative patterning) instrumental discrimination between the illumination of one or two lights. During test, only one light was lit while the other relevant light was blocked from physical detection (covered by an opaque shield, rendering its status ambiguous). We found experience with the complex negative patterning discrimination was necessary for rats to behave sensitively to the ambiguous test situation. These rats behaved as if they inferred the presence of the hidden light, responding differently than when the light was explicitly absent (uncovered and unlit). Differential expression profiles of the immediate early gene cFos indicated hippocampal involvement in the inference process while localized microinfusions of the muscarinic antagonist, scopolamine, into the dorsal hippocampus caused rats to behave as if only one light was present. That is, blocking cholinergic modulation prevented the rat from inferring the presence of the hidden light. Collectively, these results suggest cholinergic modulation mediates recruitment of hippocampal processes related to past experiences and transfer of these processes to make decisions during ambiguous situations. Our results correspond with correlations observed between human brain

  14. HIPP neurons in the dentate gyrus mediate the cholinergic modulation of background context memory salience.

    Science.gov (United States)

    Raza, Syed Ahsan; Albrecht, Anne; Çalışkan, Gürsel; Müller, Bettina; Demiray, Yunus Emre; Ludewig, Susann; Meis, Susanne; Faber, Nicolai; Hartig, Roland; Schraven, Burkhart; Lessmann, Volkmar; Schwegler, Herbert; Stork, Oliver

    2017-08-04

    Cholinergic neuromodulation in the hippocampus controls the salience of background context memory acquired in the presence of elemental stimuli predicting an aversive reinforcement. With pharmacogenetic inhibition we here demonstrate that hilar perforant path-associated (HIPP) cells of the dentate gyrus mediate the devaluation of background context memory during Pavlovian fear conditioning. The salience adjustment is sensitive to reduction of hilar neuropeptide Y (NPY) expression via dominant negative CREB expression in HIPP cells and to acute blockage of NPY-Y1 receptors in the dentate gyrus during conditioning. We show that NPY transmission and HIPP cell activity contribute to inhibitory effects of acetylcholine in the dentate gyrus and that M1 muscarinic receptors mediate the cholinergic activation of HIPP cells as well as their control of background context salience. Our data provide evidence for a peptidergic local circuit in the dentate gyrus that mediates the cholinergic encoding of background context salience during fear memory acquisition.Intra-hippocampal circuits are essential for associating a background context with behaviorally salient stimuli and involve cholinergic modulation at SST(+) interneurons. Here the authors show that the salience of the background context memory is modulated through muscarinic activation of NPY(+) hilar perforant path associated interneurons and NPY signaling in the dentate gyrus.

  15. A Computational Model of How Cholinergic Interneurons Protect Striatal-Dependent Learning

    Science.gov (United States)

    Ashby, F. Gregory; Crossley, Matthew J.

    2011-01-01

    An essential component of skill acquisition is learning the environmental conditions in which that skill is relevant. This article proposes and tests a neurobiologically detailed theory of how such learning is mediated. The theory assumes that a key component of this learning is provided by the cholinergic interneurons in the striatum known as…

  16. Decreased number of parvalbumin and cholinergic interneurons in the striatum of individuals with Tourette syndrome.

    Science.gov (United States)

    Kataoka, Yuko; Kalanithi, Paul S A; Grantz, Heidi; Schwartz, Michael L; Saper, Clifford; Leckman, James F; Vaccarino, Flora M

    2010-02-01

    Corticobasal ganglia neuronal ensembles bring automatic motor skills into voluntary control and integrate them into ongoing motor behavior. A 5% decrease in caudate (Cd) nucleus volume is the most consistent structural finding in the brain of patients with Tourette syndrome (TS), but the cellular abnormalities that underlie this decrease in volume are unclear. In this study the density of different types of interneurons and medium spiny neurons (MSNs) in the striatum was assessed in the postmortem brains of 5 TS subjects as compared with normal controls (NC) by unbiased stereological analyses. TS patients demonstrated a 50%-60% decrease of both parvalbumin (PV)+ and choline acetyltransferase (ChAT)+ cholinergic interneurons in the Cd and the putamen (Pt). Cholinergic interneurons were decreased in TS patients in the associative and sensorimotor regions but not in the limbic regions of the striatum, such that the normal gradient in density of cholinergic cells (highest in associative regions, intermediate in sensorimotor and lowest in limbic regions) was abolished. No significant difference was present in the densities of medium-sized calretinin (CR)+ interneurons, MSNs, and total neurons. The selective deficit of PV+ and cholinergic striatal interneurons in TS subjects may result in an impaired cortico/thalamic control of striatal neuron firing in TS.

  17. Cholinergic Septo-Hippocampal Innervation Is Required for Trace Eyeblink Classical Conditioning

    Science.gov (United States)

    Fontan-Lozano, Angela; Troncoso, Julieta; Munera, Alejandro; Carrion, Angel Manuel; Delgado-Garcia, Jose Maria

    2005-01-01

    We studied the effects of a selective lesion in rats, with 192-IgG-saporin, of the cholinergic neurons located in the medial septum/diagonal band (MSDB) complex on the acquisition of classical and instrumental conditioning paradigms. The MSDB lesion induced a marked deficit in the acquisition, but not in the retrieval, of eyeblink classical…

  18. Deficits in attentional control: cholinergic mechanisms and circuitry-based treatment approaches.

    Science.gov (United States)

    Sarter, Martin; Paolone, Giovanna

    2011-12-01

    The cognitive control of attention involves maintaining task rules in working memory (or "online"), monitoring reward and error rates, filtering distractors, and suppressing prepotent, and competitive responses. Weak attentional control increases distractibility and causes attentional lapses, impulsivity, and attentional fatigue. Levels of tonic cholinergic activity (changes over tens of seconds or minutes) modulate cortical circuitry as a function of the demands on cognitive control. Increased cholinergic modulation enhances the representation of cues, by augmenting cue-evoked activity in thalamic glutamatergic afferents, thereby increasing the rate of detection. Such cholinergic modulation is mediated primarily via α4β2* nicotinic acetylcholine receptors. Animal experiments and clinical trials in adult patients with ADHD indicate that attentional symptoms and disorders may benefit from drugs that stimulate this receptor. Tonic cholinergic modulation of cue-evoked glutamatergic transients in prefrontal regions is an essential component of the brain's executive circuitry. This circuitry model guides the development of treatments of deficits in attentional control. PsycINFO Database Record (c) 2011 APA, all rights reserved.

  19. FER-1/Dysferlin promotes cholinergic signaling at the neuromuscular junction in C. elegans and mice

    Directory of Open Access Journals (Sweden)

    Predrag Krajacic

    2013-10-01

    Dysferlin is a member of the evolutionarily conserved ferlin gene family. Mutations in Dysferlin lead to Limb Girdle Muscular Dystrophy 2B (LGMD2B, an inherited, progressive and incurable muscle disorder. However, the molecular mechanisms underlying disease pathogenesis are not fully understood. We found that both loss-of-function mutations and muscle-specific overexpression of C. elegans fer-1, the founding member of the Dysferlin gene family, caused defects in muscle cholinergic signaling. To determine if Dysferlin-dependent regulation of cholinergic signaling is evolutionarily conserved, we examined the in vivo physiological properties of skeletal muscle synaptic signaling in a mouse model of Dysferlin-deficiency. In addition to a loss in muscle strength, Dysferlin −/− mice also exhibited a cholinergic deficit manifested by a progressive, frequency-dependent decrement in their compound muscle action potentials following repetitive nerve stimulation, which was observed in another Dysferlin mouse model but not in a Dysferlin-independent mouse model of muscular dystrophy. Oral administration of Pyridostigmine bromide, a clinically used acetylcholinesterase inhibitor (AchE.I known to increase synaptic efficacy, reversed the action potential defect and restored in vivo muscle strength to Dysferlin −/− mice without altering muscle pathophysiology. Our data demonstrate a previously unappreciated role for Dysferlin in the regulation of cholinergic signaling and suggest that such regulation may play a significant pathophysiological role in LGMD2B disease.

  20. Cholinergic Septo-Hippocampal Innervation Is Required for Trace Eyeblink Classical Conditioning

    Science.gov (United States)

    Fontan-Lozano, Angela; Troncoso, Julieta; Munera, Alejandro; Carrion, Angel Manuel; Delgado-Garcia, Jose Maria

    2005-01-01

    We studied the effects of a selective lesion in rats, with 192-IgG-saporin, of the cholinergic neurons located in the medial septum/diagonal band (MSDB) complex on the acquisition of classical and instrumental conditioning paradigms. The MSDB lesion induced a marked deficit in the acquisition, but not in the retrieval, of eyeblink classical…

  1. Reexposure to nicotine during withdrawal increases the pacemaking activity of cholinergic habenular neurons

    Science.gov (United States)

    Görlich, Andreas; Antolin-Fontes, Beatriz; Ables, Jessica L.; Frahm, Silke; Ślimak, Marta A.; Dougherty, Joseph D.; Ibañez-Tallon, Inés

    2013-01-01

    The discovery of genetic variants in the cholinergic receptor nicotinic CHRNA5-CHRNA3-CHRNB4 gene cluster associated with heavy smoking and higher relapse risk has led to the identification of the midbrain habenula–interpeduncular axis as a critical relay circuit in the control of nicotine dependence. Although clear roles for α3, β4, and α5 receptors in nicotine aversion and withdrawal have been established, the cellular and molecular mechanisms that participate in signaling nicotine use and contribute to relapse have not been identified. Here, using translating ribosome affinity purification (TRAP) profiling, electrophysiology, and behavior, we demonstrate that cholinergic neurons, but not peptidergic neurons, of the medial habenula (MHb) display spontaneous tonic firing of 2–10 Hz generated by hyperpolarization-activated cyclic nucleotide-gated (HCN) pacemaker channels and that infusion of the HCN pacemaker antagonist ZD7288 in the habenula precipitates somatic and affective signs of withdrawal. Further, we show that a strong, α3β4-dependent increase in firing frequency is observed in these pacemaker neurons upon acute exposure to nicotine. No change in the basal or nicotine-induced firing was observed in cholinergic MHb neurons from mice chronically treated with nicotine. We observe, however, that, during withdrawal, reexposure to nicotine doubles the frequency of pacemaking activity in these neurons. These findings demonstrate that the pacemaking mechanism of cholinergic MHb neurons controls withdrawal, suggesting that the heightened nicotine sensitivity of these neurons during withdrawal may contribute to smoking relapse. PMID:24082085

  2. Modulation of cholinergic airway reactivity and nitric oxide production by endogenous arginase activity

    NARCIS (Netherlands)

    Meurs, Herman; Hamer, M.A M; Pethe, S; Vadon-Le Goff, S; Boucher, J.-L; Zaagsma, Hans

    2000-01-01

    1 Cholinergic airway constriction is functionally antagonized by agonist-induced constitutive nitric oxide synthase (cNOS)-derived nitric oxide (NO). Since cNOS and arginase, which hydrolyzes L-arginine to L-ornithine and urea, use L-arginine as a common substrate, competition between both enzymes f

  3. In vivo labeling of rabbit cholinergic basal forebrain neurons with fluorochromated antibodies

    NARCIS (Netherlands)

    Hartig, W; Varga, C; Kacza, J; Grosche, J; Seeger, J; Luiten, PGM; Brauer, K; Harkany, T; Härtig, Wolfgang

    2002-01-01

    Cholinergic basal forebrain neurons (CBFN) expressing the low-affinity neurotrophin receptor p75 (p75(NTR)) were previously selectively labeled in vivo with carbocyanine 3 (Cy3)-tagged anti-p75(NTR), but the applied 192IgG-conjugates recognized p75(NTR) only in rat The antibody ME 20.4 raised agains

  4. Cholinergic excitation in mouse primary vs. associative cortex: region-specific magnitude and receptor balance.

    Science.gov (United States)

    Tian, Michael K; Bailey, Craig D C; Lambe, Evelyn K

    2014-08-01

    Cholinergic stimulation of the cerebral cortex is essential for tasks requiring attention; however, there is still some debate over which cortical regions are required for such tasks. There is extensive cholinergic innervation of both primary and associative cortices, and transient release of acetylcholine (ACh) is detected in deep layers of the relevant primary and/or associative cortex, depending on the nature of the attention task. Here, we investigated the electrophysiological effects of ACh in layer VI, the deepest layer, of the primary somatosensory cortex, the primary motor cortex, and the associative medial prefrontal cortex. Layer VI pyramidal neurons are a major source of top-down modulation of attention, and we found that the strength and homogeneity of their direct cholinergic excitation was region-specific. On average, neurons in the primary cortical regions showed weaker responses to ACh, mediated by a balance of contributions from both nicotinic and muscarinic ACh receptors. Conversely, neurons in the associative medial prefrontal cortex showed significantly stronger excitation by ACh, mediated predominantly by nicotinic receptors. The greatest diversity of responses to ACh was found in the primary somatosensory cortex, with only a subset of neurons showing nicotinic excitation. In a mouse model with attention deficits only under demanding conditions, cholinergic excitation was preserved in primary cortical regions but not in the associative medial prefrontal cortex. These findings demonstrate that the effect of ACh is not uniform throughout the cortex, and suggest that its ability to enhance attention performance may involve different cellular mechanisms across cortical regions.

  5. GABAERGIC MODULATION OF STRIATAL CHOLINERGIC INTERNEURONS - AN IN-VIVO MICRODIALYSIS STUDY

    NARCIS (Netherlands)

    DEBOER, P; WESTERINK, BHC

    1994-01-01

    Striatal cholinergic interneurons have been shown to receive input from striatal gamma-aminobutyric acid (GABA)-containing cell elements. GABA is known to act on two different types of receptors, the GABA(A) and the GABA(B) receptor. Using in vivo microdialysis, we have studied the effect of intrast

  6. Cholinergic involvement in vascular and glucoregulatory actions of insulin in rats.

    Science.gov (United States)

    Lévesque, Martin; Santuré, Marta; Pitre, Maryse; Nadeau, André; Bachelard, Hélène

    2006-02-01

    This study was designed to test the glucose metabolic and vasodilator actions of insulin in rats and its relation to cholinergic system-dependent mechanisms. The first group of rats had pulsed Doppler flow probes and intravascular catheters implanted to determine blood pressure, heart rate, and regional blood flows. Insulin sensitivity was assessed by the euglycemic-hyperinsulinemic clamp technique carried out in the absence or presence of atropine. The second group of rats was used to determine the cholinergic contribution to in vivo insulin-mediated glucose utilization in individual muscles. Glucose uptake was examined by using [(3)H]2-deoxy-D-glucose. Muscarinic cholinergic blockade was found to significantly (P = 0.002) reduce insulin sensitivity and to completely abrogate the renal (P = 0.008) and hindquarter (P = 0.02) vasodilator responses to euglycemic infusion of insulin. A significant reduction in insulin-stimulated in vivo glucose uptake was also noted in soleus (P = 0.006), quadriceps (P = 0.03), gastrocnemius (P = 0.02), and extensor digitorum longus (EDL) (P = 0.001) muscles, when insulin was infused at a rate of 4 mU . kg(-1) . min(-1), whereas at the rate of 16 mU . kg(-1) . min(-1), a significant reduction in glucose uptake was only observed in EDL (P = 0.03) and quadriceps (P = 0.01) muscles. Together, these results demonstrate a potential role for cholinergic involvement with physiological insulin actions in glucose clearance and blood flow regulation in rats.

  7. Hippocampal cholinergic interneurons visualized with the choline acetyltransferase promoter: anatomical distribution, intrinsic membrane properties, neurochemical characteristics, and capacity for cholinergic modulation

    Directory of Open Access Journals (Sweden)

    Feng eYi

    2015-03-01

    Full Text Available Release of acetylcholine (ACh in the hippocampus (HC occurs during exploration, arousal, and learning. Although the medial septum-diagonal band of Broca (MS-DBB is the major extrinsic source of cholinergic input to the HC, cholinergic neurons intrinsic to the HC also exist but remain poorly understood. Here, ChAT-tauGFP and ChAT-CRE/Rosa26YFP (ChAT-Rosa mice were examined in HC. The HC of ChAT-tauGFP mice was densely innervated with GFP-positive axons, often accompanied by large GFP-positive structures, some of which were Neurotrace/DAPI-negative and likely represent large axon terminals. In the HC of ChAT-Rosa mice, ChAT-YFP cells were Neurotrace-positive and more abundant in CA3 and dentate gyrus than CA1 with partial overlapping with calretinin/VIP. Moreover, an anti-ChAT antibody consistently showed ChAT immunoreactivity in ChAT-YFP cells from MS-DBB but rarely from HC. Furthermore, ChAT-YFP cells from CA1 stratum radiatum/stratum lacunosum moleculare (SR/SLM exhibited a stuttering firing phenotype but a delayed firing phenotype in stratum pyramidale (SP of CA3. Input resistance and capacitance were also different between CA1 SR/LM and CA3 SP ChAT-YFP cells. Bath application of ACh increased firing frequency in all ChAT-YFP cells; however, cholinergic modulation was larger in CA1 SR/SLM than CA3 SP ChAT-YFP cells. Finally, CA3 SP ChAT-YFP cells exhibited a wider AP half-width and weaker cholinergic modulation than YFP-negative CA3 pyramidal cells. Consistent with CRE expression in a subpopulation of principal cells, optogenetic stimulation evoked glutamatergic postsynaptic currents in CA1 SR/SLM interneurons. In conclusion, the presence of fluorescently labeled hippocampal cells common to both ChAT-Rosa and ChAT-tauGFP mice are in good agreement with previous reports on the existence of cholinergic interneurons, but both transgenic mouse lines exhibited unexpected anatomical features that departed considerably from earlier observations.

  8. Hippocampal "cholinergic interneurons" visualized with the choline acetyltransferase promoter: anatomical distribution, intrinsic membrane properties, neurochemical characteristics, and capacity for cholinergic modulation.

    Science.gov (United States)

    Yi, Feng; Catudio-Garrett, Elizabeth; Gábriel, Robert; Wilhelm, Marta; Erdelyi, Ferenc; Szabo, Gabor; Deisseroth, Karl; Lawrence, Josh

    2015-01-01

    Release of acetylcholine (ACh) in the hippocampus (HC) occurs during exploration, arousal, and learning. Although the medial septum-diagonal band of Broca (MS-DBB) is the major extrinsic source of cholinergic input to the HC, cholinergic neurons intrinsic to the HC also exist but remain poorly understood. Here, ChAT-tauGFP and ChAT-CRE/Rosa26YFP (ChAT-Rosa) mice were examined in HC. The HC of ChAT-tauGFP mice was densely innervated with GFP-positive axons, often accompanied by large GFP-positive structures, some of which were Neurotrace/DAPI-negative and likely represent large axon terminals. In the HC of ChAT-Rosa mice, ChAT-YFP cells were Neurotrace-positive and more abundant in CA3 and dentate gyrus than CA1 with partial overlap with calretinin/VIP. Moreover, an anti-ChAT antibody consistently showed ChAT immunoreactivity in ChAT-YFP cells from MS-DBB but rarely from HC. Furthermore, ChAT-YFP cells from CA1 stratum radiatum/stratum lacunosum moleculare (SR/SLM) exhibited a stuttering firing phenotype but a delayed firing phenotype in stratum pyramidale (SP) of CA3. Input resistance and capacitance were also different between CA1 SR/LM and CA3 SP ChAT-YFP cells. Bath application of ACh increased firing frequency in all ChAT-YFP cells; however, cholinergic modulation was larger in CA1 SR/SLM than CA3 SP ChAT-YFP cells. Finally, CA3 SP ChAT-YFP cells exhibited a wider AP half-width and weaker cholinergic modulation than YFP-negative CA3 pyramidal cells. Consistent with CRE expression in a subpopulation of principal cells, optogenetic stimulation evoked glutamatergic postsynaptic currents in CA1 SR/SLM interneurons. In conclusion, the presence of fluorescently labeled hippocampal cells common to both ChAT-tauGFP and ChAT-Rosa mice are in good agreement with previous reports on the existence of cholinergic interneurons, but both transgenic mouse lines exhibited unexpected anatomical features that departed considerably from earlier observations.

  9. Dysfunctional Uterine Bleeding

    OpenAIRE

    1987-01-01

    Dysfunctional uterine bleeding (DUB) is defined as abnormal uterine bleeding that results from an ovarian endocrinopathy. It may be associated with ovulatory and anovulatory cycles. The diagnosis of DUB depends on a thorough history and physical examination to exclude organic disorders. In older women, endometrial biopsy should be done before starting therapy. The treatment depends on an understanding of the menstrual cycle. In less urgent cases, anovulatory cycles are managed using progester...

  10. Biology of Sexual Dysfunction

    OpenAIRE

    MN, Anil Kumar; Pai, NB; Rao, S; Rao, TSS; Goyal, N.

    2009-01-01

    Sexual activity is a multifaceted activity, involving complex interactions between the nervous system, the endocrine system, the vascular system and a variety of structures that are instrumental in sexual excitement, intercourse and satisfaction. Sexual function has three components i.e., desire, arousal and orgasm. Many sexual dysfunctions can be categorized according to the phase of sexual response that is affected. In actual clinical practice however, sexual desire, arousal and orgasmic di...

  11. Thyroid dysfunction and subfertility.

    Science.gov (United States)

    Cho, Moon Kyoung

    2015-12-01

    The thyroid hormones act on nearly every cell in the body. Moreover, the thyroid gland continuously interacts with the ovaries, and the thyroid hormones are involved in almost all phases of reproduction. Thyroid dysfunctions are relatively common among women of reproductive age, and can affect fertility in various ways, resulting in anovulatory cycles, high prolactin levels, and sex hormone imbalances. Undiagnosed and untreated thyroid disease can be a cause of subfertility. Subclinical hypothyroidism (SCH), also known as mild thyroid failure, is diagnosed when peripheral thyroid hormone levels are within the normal reference laboratory range, but serum thyroid-stimulating hormone levels are mildly elevated. Thyroid autoimmunity (TAI) is characterized by the presence of anti-thyroid antibodies, which include anti-thyroperoxidase and anti-thyroglobulin antibodies. SCH and TAI may remain latent, asymptomatic, or even undiagnosed for an extended period. It has also been demonstrated that controlled ovarian hyperstimulation has a significant impact on thyroid function, particularly in women with TAI. In the current review, we describe the interactions between thyroid dysfunctions and subfertility, as well as the proper work-up and management of thyroid dysfunctions in subfertile women.

  12. Expression and localization of pChAT as a novel method to study cholinergic innervation of rat adrenal gland.

    Science.gov (United States)

    Elnasharty, Mohamed A; Sayed-Ahmed, Ahmed

    2014-10-01

    Cholinergic innervation of the rat adrenal gland has been analyzed previously using cholinergic markers including acetylcholinesterase (AChE), choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT). In the present study, we demonstrate putative cholinergic neurons in the rat adrenal gland using an antibody to pChAT, which is the product of a splice variant of ChAT mRNA that is preferentially localized in peripheral cholinergic nerves. Most of the ganglionic neurons as well as small single sporadic neurons in the adrenal gland were stained intensely for pChAT. The density of pChAT-immunoreactive (IR) fibers was distinct in the adrenal cortex and medulla. AChE-, cChAT- and VAChT-immunoreactivities were also observed in some cells and fibers of the adrenal medulla, while the cortex had few positive nerve fibers. These results indicate that ganglionic neurons of the adrenal medulla and nerve fibers heterogeneously express cholinergic markers, especially pChAT. Furthermore, the innervation of the adrenal gland, cortex and medulla, by some cholinergic fibers provides additional morphological evidence for a significant role of cholinergic mechanisms in adrenal gland functions.

  13. Cholinergic markers in the cortex and hippocampus of some animal species and their correlation to Alzheimer's disease.

    Science.gov (United States)

    Orta-Salazar, E; Cuellar-Lemus, C A; Díaz-Cintra, S; Feria-Velasco, A I

    2014-10-01

    The cholinergic system includes neurons located in the basal forebrain and their long axons that reach the cerebral cortex and the hippocampus. This system modulates cognitive function. In Alzheimer's disease (AD) and ageing, cognitive impairment is associated with progressive damage to cholinergic fibres, which leads us to the cholinergic hypothesis for AD. The AD produces alterations in the expression and activity of acetyltransferase (ChAT) and acetyl cholinesterase (AChE), enzymes specifically related to cholinergic system function. Both proteins play a role in cholinergic transmission, which is altered in both the cerebral cortex and the hippocampus due to ageing and AD. Dementia disorders are associated with the severe destruction and disorganisation of the cholinergic projections extending to both structures. Specific markers, such as anti-ChAT and anti-AChE antibodies, have been used in light immunohistochemistry and electron microscopy assays to study this system in adult members of certain animal species. This paper reviews the main immunomorphological studies of the cerebral cortex and hippocampus in some animal species with particular emphasis on the cholinergic system and its relationship with the AD. Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

  14. [Beyond immunopathogenesis. Insulin resistance and "epidermal dysfunction"].

    Science.gov (United States)

    Boehncke, W-H; Boehncke, S; Buerger, C

    2012-03-01

    Insulin is a central player in the regulation of metabolic as well as non-metabolic cells: inefficient signal transduction (insulin resistance) not only represents the cornerstone in the pathogenesis of type 2 diabetes mellitus, but also drives atherosclerosis through inducing endothelial dysfunction. Last but not least epidermal homeostasis depends on insulin. We summarize the effects of insulin on proliferation and differentiation of human keratinocytes as well as the relevance of cytokine-induced insulin resistance for alterations in epidermal homeostasis characteristic for psoriasis. Kinases involved in both insulin- as well as cytokine-receptor signaling represent potential targets for innovative therapeutics. Such small molecules would primarily normalize "epidermal dysfunction", thus complementing the immunomodulatory strategies of today's biologics.

  15. Postlesion estradiol treatment increases cortical cholinergic innervations via estrogen receptor-α dependent nonclassical estrogen signaling in vivo.

    Science.gov (United States)

    Koszegi, Zsombor; Szego, Éva M; Cheong, Rachel Y; Tolod-Kemp, Emeline; Ábrahám, István M

    2011-09-01

    17β-Estradiol (E2) treatment exerts rapid, nonclassical actions via intracellular signal transduction system in basal forebrain cholinergic (BFC) neurons in vivo. Here we examined the effect of E2 treatment on lesioned BFC neurons in ovariectomized mice and the role of E2-induced nonclassical action in this treatment. Mice given an N-methyl-d-aspartic acid (NMDA) injection into the substantia innominata-nucleus basalis magnocellularis complex (SI-NBM) exhibited cholinergic cell loss in the SI-NBM and ipsilateral cholinergic fiber loss in the cortex. A single injection of E2 after NMDA lesion did not have an effect on cholinergic cell loss in the SI-NBM, but it restored the ipsilateral cholinergic fiber density in the cortex in a time- and dose-dependent manner. The most effective cholinergic fiber restoration was observed with 33 ng/g E2 treatment at 1 h after NMDA lesion. The E2-induced cholinergic fiber restoration was absent in neuron-specific estrogen receptor-α knockout mice in vivo. Selective activation of nonclassical estrogen signaling in vivo by estren induced E2-like restorative actions. Selective blockade of the MAPK or protein kinase A pathway in vivo prevented E2's ability to restore cholinergic fiber loss. Finally, studies in intact female mice revealed an E2-induced restorative effect that was similar to that of E2-treated ovariectomized mice. These observations demonstrate that a single E2 treatment restores the BFC fiber loss in the cortex, regardless of endogenous E2 levels. They also reveal the critical role of nonclassical estrogen signaling via estrogen receptor-α and protein kinase A-MAPK pathways in E2-induced restorative action in the cholinergic system in vivo.

  16. Endogenous cholinergic input to the pontine REM sleep generator is not required for REM sleep to occur.

    Science.gov (United States)

    Grace, Kevin P; Vanstone, Lindsay E; Horner, Richard L

    2014-10-22

    Initial theories of rapid eye movement (REM) sleep generation posited that induction of the state required activation of the pontine subceruleus (SubC) by cholinergic inputs. Although the capacity of cholinergic neurotransmission to contribute to REM sleep generation has been established, the role of cholinergic inputs in the generation of REM sleep is ultimately undetermined as the critical test of this hypothesis (local blockade of SubC acetylcholine receptors) has not been rigorously performed. We used bilateral microdialysis in freely behaving rats (n = 32), instrumented for electroencephalographic and electromyographic recording, to locally manipulate neurotransmission in the SubC with select drugs. As predicted, combined microperfusion of D-AP5 (glutamate receptor antagonist) and muscimol (GABAA receptor agonist) in the SubC virtually eliminated REM sleep. However, REM sleep was not reduced by scopolamine microperfusion in this same region, at a concentration capable of blocking the effects of cholinergic receptor stimulation. This result suggests that transmission of REM sleep drive to the SubC is acetylcholine-independent. Although SubC cholinergic inputs are not majorly involved in REM sleep generation, they may perform a minor function in the reinforcement of transitions into REM sleep, as evidenced by increases in non-REM-to-REM sleep transition duration and failure rate during cholinergic receptor blockade. Cholinergic receptor antagonism also attenuated the normal increase in hippocampal θ oscillations that characterize REM sleep. Using computational modeling, we show that our in vivo results are consistent with a mutually excitatory interaction between the SubC and cholinergic neurons where, importantly, cholinergic neuron activation is gated by SubC activity.

  17. Cholinergic depletion in nucleus accumbens impairs mesocortical dopamine activation and cognitive function in rats.

    Science.gov (United States)

    Laplante, François; Zhang, Zi-Wei; Huppé-Gourgues, Frédéric; Dufresne, Marc M; Vaucher, Elvire; Sullivan, Ron M

    2012-11-01

    In rats, selective depletion of the cholinergic interneurons in the ventral striatum (nucleus accumbens or N.Acc.) results in heightened behavioural sensitivity to amphetamine and impaired sensorimotor gating processes, suggesting a hyper-responsiveness to dopamine (DA) activity in the N.Acc. We hypothesized that local cholinergic depletion may also trigger distal functional alterations, particularly in prefrontal cortex (PFC). Adult male Sprague-Dawley rats were injected bilaterally in the N.Acc. with an immunotoxin targeting choline acetyltransferase. Two weeks later, cognitive function was assessed using the delayed alternation paradigm in the T-maze. The rats were then implanted with voltammetric recording electrodes in the ventromedial PFC to measure in vivo extracellular DA release in response to mild tail pinch stress. The PFC was also examined for density of tyrosine hydroxylase (TH)-labelled varicosities. In another cohort of control and lesioned rats, we measured post mortem tissue content of DA. Depletion of cholinergic neurons (restricted to N.Acc.) significantly impaired delayed alternation performance across delay intervals. While (basal) post mortem indices of PFC DA function were unaffected by N.Acc. lesions, in vivo mesocortical DA activation was markedly reduced; this deficit correlated significantly with cognitive impairments. TH-labelled varicosities however, were unaffected in cortical layer V relative to controls. These data suggest that selective depletion of cholinergic interneurons in N.Acc. triggers widespread functional impairments in mesocorticolimbic DA function and cognition. The possible relevance of these findings is also discussed in relation to schizophrenia, where reduced density of cholinergic neurons in ventral striatum has been reported. Copyright © 2012 Elsevier Ltd. All rights reserved.

  18. Measurement of functional cholinergic innervation in rat heart with a novel vesamicol receptor ligand

    Energy Technology Data Exchange (ETDEWEB)

    Coffeen, Paul R.; Efange, S.M.N.; Haidet, George C.; McKnite, Scott; Langason, Rosemary B.; Khare, A.B.; Pennington, Jennifer; Lurie, Keith G

    1996-10-01

    Regional differences in cholinergic activity in the cardiac conduction system have been difficult to study. We tested the utility of (+)-m-[{sup 125}I]iodobenzyl)trozamicol(+)-[{sup 125}I]MIBT), a novel radioligand that binds to the vesamicol receptor located on the synaptic vesicle in presynaptic cholinergic neurons, as a functional marker of cholinergic activity in the conduction system. The (+)-[{sup 125}I]MIBT was injected intravenously into four rats. Three hours later, the rats were killed and their hearts were frozen. Quantitative autoradiography was performed on 20-micron-thick sections that were subsequently stained for acetylcholinesterase to identify specific conduction-system elements. Marked similarities existed between (+)-[{sup 125}I]MIBT uptake and acetylcholinesterase-positive regions. Optical densitometric analysis of regional (+)-[{sup 125}I]MIBT uptake revealed significantly greater (+)-[{sup 125}I]MIBT binding (nCi/mg) in the atrioventricular node (AVN) and His bundle regions compared with other conduction and contractile elements (AVN: 3.43 {+-} 0.37; His bundle: 2.16 {+-} 0.30; right bundle branch: 0.95 {+-} 0.13; right atrium: 0.68 {+-} 0.05; right ventricle: 0.57 {+-} 0.03; and left ventricle: 0.57 {+-} 0.03; p < 0.05 comparing conduction elements with ventricular muscle). This study demonstrates that (+)-[{sup 125}I]MIBT binds avidly to cholinergic nerve tissue innervating specific conduction-system elements. Thus, (+)-[{sup 125}I]MIBT may be a useful functional marker in studies on cholinergic innervation in the cardiac conduction system.

  19. Sexual dysfunction with antihypertensive drugs.

    Science.gov (United States)

    Prisant, L M; Carr, A A; Bottini, P B; Solursh, D S; Solursh, L P

    1994-04-11

    The relationship of antihypertensive drugs have a long history of association with sexual dysfunction; however, this relationship is poorly documented. There appears to be a higher rate of sexual dysfunction in untreated hypertensive men compared with normotensive men. Sexual dysfunction increases with age and is associated with physical and emotional symptoms. There are few studies assessing sexual dysfunction with female and African-American hypertensive patients. Sexual dysfunction is associated with impairment of quality of life and noncompliance. Since group data may hide individual drug effects, baseline data should be collected on all patients before initiating therapy with any antihypertensive agent. Although questionnaires may not provide objective information on sexual dysfunction, the response rate to direct questioning may be less than the response rate on a questionnaire and may be affected by the gender or race of the interviewer. Research protocols using a double-blind, placebo-controlled design should assess sexual dysfunction in men and women in a standardized fashion.

  20. Hyperbaric Oxygen Prevents Cognitive Impairments in Mice Induced by D-Galactose by Improving Cholinergic and Anti-apoptotic Functions.

    Science.gov (United States)

    Chen, Chunxia; Huang, Luying; Nong, Zhihuan; Li, Yaoxuan; Chen, Wan; Huang, Jianping; Pan, Xiaorong; Wu, Guangwei; Lin, Yingzhong

    2017-01-11

    Our previous study demonstrated that hyperbaric oxygen (HBO) improved cognitive impairments mainly by regulating oxidative stress, inflammatory responses and aging-related gene expression. However, a method for preventing cognitive dysfunction has yet to be developed. In the present study, we explored the protective effects of HBO on the cholinergic system and apoptosis in D-galactose (D-gal)-treated mice. A model of aging was established via systemic intraperitoneal injection of D-gal daily for 8 weeks. HBO was administered during the last 2 weeks of D-gal injection. Our results showed that HBO in D-gal-treated mice significantly improved behavioral performance on the open field test and passive avoidance task. Studies on the potential mechanisms of this effect showed that HBO significantly reduced oxidative stress and blocked the nuclear factor-κB pathway. Moreover, HBO significantly increased the levels of choline acetyltransferase and acetylcholine and decreased the activity of acetylcholinesterase in the hippocampus. Furthermore, HBO markedly increased expression of the anti-apoptosis protein Bcl-2 and glial fibrillary acidic protein meanwhile decreased expression of the pro-apoptosis proteins Bax and caspase-3. Importantly, there was a significant reduction in expression of Aβ-related genes, such as amyloid precursor protein, β-site amyloid cleaving enzyme-1 and cathepsin B mRNA. These decreases were accompanied by significant increases in expression of neprilysin and insulin-degrading enzyme mRNA. Moreover, compared with the Vitamin E group, HBO combined with Vitamin E exhibited significant difference in part of the above mention parameters. These findings suggest that HBO may act as a neuroprotective agent in preventing cognitive impairments.

  1. Vascular dysfunctions following spinal cord injury.

    Science.gov (United States)

    Popa, Constantin; Popa, Florian; Grigorean, Valentin Titus; Onose, Gelu; Sandu, Aurelia Mihaela; Popescu, Mihai; Burnei, Gheorghe; Strambu, Victor; Sinescu, Crina

    2010-01-01

    The aim of this article is to analyze the vascular dysfunctions occurring after spinal cord injury (SCI). Vascular dysfunctions are common complications of SCI. Cardiovascular disturbances are the leading causes of morbidity and mortality in both acute and chronic stages of SCI. Neuroanatomy and physiology of autonomic nervous system, sympathetic and parasympathetic, is reviewed. SCI implies disruption of descendent pathways from central centers to spinal sympathetic neurons, originating in intermediolateral nuclei of T1-L2 cord segments. Loss of supraspinal control over sympathetic nervous system results in reduced overall sympathetic activity below the level of injury and unopposed parasympathetic outflow through intact vagal nerve. SCI associates significant vascular dysfunction. Spinal shock occurs during the acute phase following SCI and it is a transitory suspension of function and reflexes below the level of the injury. Neurogenic shock, part of spinal shock, consists of severe arterial hypotension and bradycardia. Autonomic dysreflexia appears during the chronic phase, after spinal shock resolution, and it is a life-threatening syndrome of massive imbalanced reflex sympathetic discharge occurring in patients with SCI above the splanchnic sympathetic outflow (T5-T6). Arterial hypotension with orthostatic hypotension occurs in both acute and chronic phases. The etiology is multifactorial. We described a few factors influencing the orthostatic hypotension occurrence in SCI: sympathetic nervous system dysfunction, low plasma catecholamine levels, rennin-angiotensin-aldosterone activity, peripheral alpha-adrenoceptor hyperresponsiveness, impaired function of baroreceptors, hyponatremia and low plasmatic volume, cardiovascular deconditioning, morphologic changes in sympathetic neurons, plasticity within spinal circuits, and motor deficit leading to loss of skeletal muscle pumping activity. Additional associated cardiovascular concerns in SCI, such as deep vein

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

    Directory of Open Access Journals (Sweden)

    Luiz O.S. Leiria

    2015-05-01

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

  3. Sleep apnoea and metabolic dysfunction

    Directory of Open Access Journals (Sweden)

    Maria R. Bonsignore

    2013-09-01

    Full Text Available Obstructive sleep apnoea (OSA is a highly prevalent condition often associated with central obesity. In the past few years, several studies have analysed the potential independent contribution of OSA to the pathogenesis of metabolic abnormalities, including type 2 diabetes, the metabolic syndrome and non-alcoholic fatty liver disease. New perspectives in OSA patient care have been opened by the promotion of lifestyle interventions, such as diet and exercise programmes that could improve both OSA and the metabolic profile. The rich clinical literature on this subject, together with the growing amount of data on pathophysiological mechanisms provided by animal studies using the chronic intermittent hypoxia model, urged the organising Committee of the Sleep and Breathing meeting to organise a session on sleep apnoea and metabolic dysfunction, in collaboration with the European Association for the Study of Diabetes. This review summarises the state-of-the-art lectures presented in the session, more specifically the relationship between OSA and diabetes, the role of OSA in the metabolic consequences of obesity, and the effects of lifestyle interventions on nocturnal respiratory disturbances and the metabolic profile in OSA patients.

  4. Diabetic bladder dysfunction

    Institute of Scientific and Technical Information of China (English)

    Guiming Liu; Firouz Daneshgari

    2014-01-01

    Objective To review studies on diabetic bladder dysfunction (DBD),a common and bothersome complication of diabetes mellitus.Data sources We performed a search of the English literature through PubMed.The key words used were "diabetes" and "bladder dysfunction" or "cystopathy".Our own data and perspective are included in the discussion.Study selection Studies containing data relevant to DBD were selected.Because of the limited length of this article,we also referenced reviews that contain comprehensive amalgamations of relevant literature.Results The classic symptoms of DBD are decreased bladder sensation,increased bladder capacity,and impaired bladder emptying with resultant elevated post-void residual urine.However,recent clinical and experimental evidence indicate a strong presence of storage problems such as urge incontinence in diabetes.Recent studies of DBD in animal models of type 1 diabetes have revealed temporal effects of diabetes,causing an early phase of compensatory bladder function and a later phase of decompensated bladder function.The pathophysiology of DBD is multifactorial,including disturbances of the detrusor,urothelium,autonomic nerves,and urethra.Polyuria and hyperglycemia play important but distinctive roles in induction of bladder dysfunction in type 1 diabetes.Polyuria causes significant bladder hypertrophy in the early stage of diabetes,whereas oxidative stress in the bladder caused by chronic hyperglycemia may play an important role in the late stage failure of bladder function.Conclusions DBD includes time-dependent and mixed manifestations.The pathological alterations include muscle,nerve,and urothelium.Polyuria and hyperglycemia independently contribute to the pathogenesis of DBD.Treatments for DBD are limited.Future clinical studies on DBD in type 1 and type 2 diabetes should be investigated separately.Animal studies of DBD in type 2 diabetes are needed,from the natural history to mechanisms.Further understanding of the molecular

  5. Mitochondrial dysfunction in autism.

    Science.gov (United States)

    Legido, Agustín; Jethva, Reena; Goldenthal, Michael J

    2013-09-01

    Using data of the current prevalence of autism as 200:10,000 and a 1:2000 incidence of definite mitochondrial (mt) disease, if there was no linkage of autism spectrum disorder (ASD) and mt disease, it would be expected that 1 in 110 subjects with mt disease would have ASD and 1 in 2000 individuals with ASD would have mt disease. The co-occurrence of autism and mt disease is much higher than these figures, suggesting a possible pathogenetic relationship. Such hypothesis was initially suggested by the presence of biochemical markers of abnormal mt metabolic function in patients with ASD, including elevation of lactate, pyruvate, or alanine levels in blood, cerebrospinal fluid, or brain; carnitine level in plasma; and level of organic acids in urine, and by demonstrating impaired mt fatty acid β-oxidation. More recently, mtDNA genetic mutations or deletions or mutations of nuclear genes regulating mt function have been associated with ASD in patients or in neuropathologic studies on the brains of patients with autism. In addition, the presence of dysfunction of the complexes of the mt respiratory chain or electron transport chain, indicating abnormal oxidative phosphorylation, has been reported in patients with ASD and in the autopsy samples of brains. Possible pathogenetic mechanisms linking mt dysfunction and ASD include mt activation of the immune system, abnormal mt Ca(2+) handling, and mt-induced oxidative stress. Genetic and epigenetic regulation of brain development may also be disrupted by mt dysfunction, including mt-induced oxidative stress. The role of the purinergic system linking mt dysfunction and ASD is currently under investigation. In summary, there is genetic and biochemical evidence for a mitochondria (mt) role in the pathogenesis of ASD in a subset of children. To determine the prevalence and type of genetic and biochemical mt defects in ASD, there is a need for further research using the latest genetic technology such as next

  6. Depression and erectile dysfunction.

    Science.gov (United States)

    Makhlouf, Antoine; Kparker, Ashay; Niederberger, Craig S

    2007-11-01

    Depression and erectile dysfunction (ED) clearly are associated. Although urologists and psychiatrists have long recognized that antidepressant medications affect erectile function negatively, the interplay between the two conditions remains underappreciated. Psychiatrists may be reluctant to question a patient in detail about ED, and urologists seldom perform a formal assessment of the presence of depression in patients who have ED. This article gives a quick overview of the relationship between these two conditions and provides the clinician with the knowledge required to effectively manage ED with comorbid depression.

  7. Amyloid-β peptides act as allosteric modulators of cholinergic signalling through formation of soluble BAβACs.

    Science.gov (United States)

    Kumar, Rajnish; Nordberg, Agneta; Darreh-Shori, Taher

    2016-01-01

    Amyloid-β peptides, through highly sophisticated enzymatic machinery, are universally produced and released in an action potential synchronized manner into the interstitial fluids in the brain. Yet no native functions are attributed to amyloid-β. The amyloid-β hypothesis ascribes just neurotoxicity properties through build-up of soluble homomeric amyloid-β oligomers or fibrillar deposits. Apolipoprotein-ε4 (APOE4) allele is the only confirmed genetic risk factor of sporadic Alzheimer's disease; once more it is unclear how it increases the risk of Alzheimer's disease. Similarly, central cholinergic signalling is affected selectively and early in the Alzheimer's disease brain, again why cholinergic neurons show this sensitivity is still unclear. However, the three main known Alzheimer's disease risk factors, advancing age, female gender and APOE4, have been linked to a high apolipoprotein-E and accumulation of the acetylcholine degrading enzyme, butyrylcholinesterase in cerebrospinal fluids of patients. Furthermore, numerous reports indicate that amyloid-β interacts with butyrylcholinesterase and apolipoprotein-E. We have proposed that this interaction leads to formation of soluble ultrareactive acetylcholine-hydrolyzing complexes termed BAβACs, to adjust at demand both synaptic and extracellular acetylcholine signalling. This hypothesis predicted presence of acetylcholine-synthesizing enzyme, choline acetyltransferase in extracellular fluids to allow maintenance of equilibrium between breakdown and synthesis of acetylcholine through continuous in situ syntheses. A recent proof-of-concept study led to the discovery of this enzyme in the human extracellular fluids. We report here that apolipoprotein-E, in particular ε4 isoprotein acts as one of the strongest endogenous anti-amyloid-β fibrillization agents reported in the literature. At biological concentrations, apolipoprotein-E prevented amyloid-β fibrillization for at least 65 h. We show that amyloid

  8. Detection of visual signals by rats: effects of chlordiazepoxide and cholinergic and adrenergic drugs on sustained attention.

    Science.gov (United States)

    Bushnell, P J; Oshiro, W M; Padnos, B K

    1997-12-01

    Central cholinergic and adrenergic pathways support the attentional processes necessary for detecting and reporting temporally unpredictable stimuli. To assess the functional effects of pharmacological manipulations of these pathways, male Long-Evans rats performed a two-choice, discrete-trial signal-detection task in which food was provided for pressing one lever after presentation of a signal (a 300-ms light flash), and for pressing a second lever at the end of a trial lacking a signal. Seven signal intensities were presented during each 1-h session in a pseudo-random order across three 100-trial blocks. After acquisition of a stable performance baseline, the acute effects of chlordiazepoxide (0, 3, 5, 8 mg/kg i.p.), pilocarpine (0, 1.0, 1.8, 3.0 mg/kg s.c.), scopolamine 0, 0.030, 0.056, 0.100 mg/kg s.c.), nicotine (0, 0.08, 0.25, 0.75 mg/kg s.c.), mecamylamine (0, 1.8, 3.0, 5.6 mg/kg i.p.), clonidine (0, 0.003, 0.010, 0.030 mg/kg s.c.), and idazoxan (0, 1, 3, 10 mg/kg s.c.) were assessed. Five measures of performance were analyzed: response failures; the proportion of "hits" [P(hit): the proportion of correct responses on signal trials]; the proportion of "false alarms" [P(fa): the proportion of incorrect responses on non-signal trials]; and response times (RT) for hits and for correct rejections. All drugs which slowed responding affected RT for hits and correct rejections equivalently, suggesting little or no influence of motor slowing on choice accuracy. Chlordiazepoxide reduced P(hit) at low signal intensities only, without affecting P(fa) or RT, consistent with sensory impairment (reduced visual sensitivity). All other drugs except nicotine reduced P(hit) at high signal intensities preferentially, suggesting a non-visual source of the impairment. Scopolamine, mecamylamine and clonidine affected both P(hit) and P(fa); pilocarpine and idazoxan reduced P(hit) without affecting P(fa). Nicotine at 0.75 mg/kg decreased P(hit) in the first block of trials; at 0

  9. Age-related changes in nicotine response of cholinergic and non-cholinergic laterodorsal tegmental neurons: implications for the heightened adolescent susceptibility to nicotine addiction.

    Science.gov (United States)

    Christensen, Mark H; Ishibashi, Masaru; Nielsen, Michael L; Leonard, Christopher S; Kohlmeier, Kristi A

    2014-10-01

    The younger an individual starts smoking, the greater the likelihood that addiction to nicotine will develop, suggesting that neurobiological responses vary across age to the addictive component of cigarettes. Cholinergic neurons of the laterodorsal tegmental nucleus (LDT) are importantly involved in the development of addiction, however, the effects of nicotine on LDT neuronal excitability across ontogeny are unknown. Nicotinic effects on LDT cells across different age groups were examined using calcium imaging and whole-cell patch clamping. Within the youngest age group (P7-P15), nicotine induced larger intracellular calcium transients and inward currents. Nicotine induced a greater number of excitatory synaptic currents in the youngest animals, whereas larger amplitude inhibitory synaptic events were induced in cells from the oldest animals (P15-P34). Nicotine increased neuronal firing of cholinergic cells to a greater degree in younger animals, possibly linked to development associated differences found in nicotinic effects on action potential shape and afterhyperpolarization. We conclude that in addition to age-associated alterations of several properties expected to affect resting cell excitability, parameters affecting cell excitability are altered by nicotine differentially across ontogeny. Taken together, our data suggest that nicotine induces a larger excitatory response in cholinergic LDT neurons from the youngest animals, which could result in a greater excitatory output from these cells to target regions involved in development of addiction. Such output would be expected to be promotive of addiction; therefore, ontogenetic differences in nicotine-mediated increases in the excitability of the LDT could contribute to the differential susceptibility to nicotine addiction seen across age.

  10. S100b Counteracts Neurodegeneration of Rat Cholinergic Neurons in Brain Slices after Oxygen-Glucose Deprivation

    Directory of Open Access Journals (Sweden)

    Daniela Serbinek

    2010-01-01

    Full Text Available Alzheimer's disease is a severe chronic neurodegenerative disorder characterized by beta-amyloid plaques, tau pathology, cerebrovascular damage, inflammation, reactive gliosis, and cell death of cholinergic neurons. The aim of the present study is to test whether the glia-derived molecule S100b can counteract neurodegeneration of cholinergic neurons after oxygen-glucose deprivation (OGD in organotypic brain slices of basal nucleus of Meynert. Our data showed that 3 days of OGD induced a marked decrease of cholinergic neurons (60% of control, which could be counteracted by 50 μg/mL recombinant S100b. The effect was dose and time dependent. Application of nerve growth factor or fibroblast growth factor-2 was less protective. C-fos-like immunoreactivity was enhanced 3 hours after OGD indicating metabolic stress. We conclude that S100b is a potent neuroprotective factor for cholinergic neurons during ischemic events.

  11. Antidepressant-like properties of sildenafil in a genetic rat model of depression: Role of cholinergic cGMP-interactions

    DEFF Research Database (Denmark)

    Liebenberg, Nico; Brink, Christiaan; Brand, Linda

    2008-01-01

    a strategy for the treatment of depression, using a PDE5 inhibitor in the presence of cholinergic inhibition. Sildenafil-induced augmentation of imipramine, an antidepressant with inherent anticholinergic properties, concurs with this suggestion, and highlights the potential clinical value...

  12. The subcellular distribution of [3H]-CGS 21680 binding sites in the rat striatum: copurification with cholinergic nerve terminals.

    Science.gov (United States)

    James, S; Richardson, P J

    1993-08-01

    The subcellular distribution of the adenosine A2a receptor in rat striatum has been investigated using specific binding of the A2a-selective ligand [3H]-CGS 21680. After subcellular fractionation, the distribution of [3H]-CGS 21680 binding was similar to that of the cholinergic nerve terminal marker acetylcholinesterase rather than the more general membrane marker 5'-nucleotidase, with 42% of binding associated with the synaptosomal sub-fraction and 19% with a light membrane fraction. Binding of [3H]-CGS 21680 was also found to co-purify with the cholinergic nerve terminal marker choline acetyltransferase during immunoaffinity purification of striatal cholinergic nerve terminals. These results demonstrate that some adenosine A2a receptors are present on cholinergic nerve terminals in rat striatum.

  13. Cholinergic neuronal lesions in the medial septum and vertical limb of the diagonal bands of Broca induce contextual fear memory generalization and impair acquisition of fear extinction.

    Science.gov (United States)

    Knox, Dayan; Keller, Samantha M

    2016-06-01

    Previous research has shown that the ventral medial prefrontal cortex (vmPFC) and hippocampus (Hipp) are critical for extinction memory. Basal forebrain (BF) cholinergic input to the vmPFC and Hipp is critical for neural function in these substrates, which suggests BF cholinergic neurons may be critical for extinction memory. In order to test this hypothesis, we applied cholinergic lesions to different regions of the BF and observed the effects these lesions had on extinction memory. Complete BF cholinergic lesions induced contextual fear memory generalization, and this generalized fear was resistant to extinction. Animals with complete BF cholinergic lesions could not acquire cued fear extinction. Restricted cholinergic lesions in the medial septum and vertical diagonal bands of Broca (MS/vDBB) mimicked the effects that BF cholinergic lesions had on contextual fear memory generalization and acquisition of fear extinction. Cholinergic lesions in the horizontal diagonal band of Broca and nucleus basalis (hDBB/NBM) induced a small deficit in extinction of generalized contextual fear memory with no accompanying deficits in cued fear extinction. The results of this study reveal that MS/vDBB cholinergic neurons are critical for inhibition and extinction of generalized contextual fear memory, and via this process, may be critical for acquisition of cued fear extinction. Further studies delineating neural circuits and mechanisms through which MS/vDBB cholinergic neurons facilitate these emotional memory processes are needed. © 2015 Wiley Periodicals, Inc.

  14. Vascular dysfunction in preeclampsia.

    Science.gov (United States)

    Brennan, Lesley J; Morton, Jude S; Davidge, Sandra T

    2014-01-01

    Preeclampsia is a complex disorder which affects an estimated 5% of all pregnancies worldwide. It is diagnosed by hypertension in the presence of proteinuria after the 20th week of pregnancy and is a prominent cause of maternal morbidity and mortality. As delivery is currently the only known treatment, preeclampsia is also a leading cause of preterm delivery. Preeclampsia is associated with maternal vascular dysfunction, leading to serious cardiovascular risk both during and following pregnancy. Endothelial dysfunction, resulting in increased peripheral resistance, is an integral part of the maternal syndrome. While the cause of preeclampsia remains unknown, placental ischemia resulting from aberrant placentation is a fundamental characteristic of the disorder. Poor placentation is believed to stimulate the release of a number of factors including pro- and antiangiogenic factors and inflammatory activators into the maternal systemic circulation. These factors are critical mediators of vascular function and impact the endothelium in distinctive ways, including enhanced endothelial oxidative stress. The mechanisms of action and the consequences on the maternal vasculature will be discussed in this review.

  15. Age-related changes in nicotine response of cholinergic and non-cholinergic laterodorsal tegmental neurons: implications for the heightened adolescent susceptibility to nicotine addiction

    DEFF Research Database (Denmark)

    Christensen, Mark Holm; Ishibashi, Masaru; Nielsen, Michael Linnemann;

    2014-01-01

    in the development of addiction, however, the effects of nicotine on LDT neuronal excitability across ontogeny are unknown. Nicotinic effects on LDT cells across different age groups were examined using calcium imaging and whole-cell patch clamping. Within the youngest age group (P7–P15), nicotine induced larger...... intracellular calcium transients and inward currents. Nicotine induced a greater number of excitatory synaptic currents in the youngest animals, whereas larger amplitude inhibitory synaptic events were induced in cells from the oldest animals (P15–P34). Nicotine increased neuronal firing of cholinergic cells...

  16. Knockdown of Myo-Inositol Transporter SMIT1 Normalizes Cholinergic and Glutamatergic Function in an Immortalized Cell Line Established from the Cerebral Cortex of a Trisomy 16 Fetal Mouse, an Animal Model of Human Trisomy 21 (Down Syndrome).

    Science.gov (United States)

    Cárdenas, Ana María; Fernández-Olivares, Paola; Díaz-Franulic, Ignacio; González-Jamett, Arlek M; Shimahara, Takeshi; Segura-Aguilar, Juan; Caviedes, Raúl; Caviedes, Pablo

    2017-07-10

    The Na(+)/myo-inositol cotransporter (SMIT1) is overexpressed in human Down syndrome (DS) and in trisomy 16 fetal mice (Ts16), an animal model of the human condition. SMIT1 overexpression determines increased levels of intracellular myo-inositol, a precursor of phophoinositide synthesis. SMIT1 is overexpressed in CTb cells, an immortalized cell line established from the cerebral cortex of a Ts16 mouse fetus. CTb cells exhibit impaired cytosolic Ca(2+) signals in response to glutamatergic and cholinergic stimuli (increased amplitude and delayed time-dependent kinetics in the decay post-stimulation), compared to our CNh cell line, derived from the cerebral cortex of a euploid animal. Considering the role of myo-inositol in intracellular signaling, we normalized SMIT1 expression in CTb cells using specific mRNA antisenses. Forty-eight hours post-transfection, SMIT1 levels in CTb cells reached values comparable to those of CNh cells. At this time, decay kinetics of Ca(2+) signals induced by either glutamate, nicotine, or muscarine were accelerated in transfected CTb cells, to values similar to those of CNh cells. The amplitude of glutamate-induced cytosolic Ca(2+) signals in CTb cells was also normalized. The results suggest that SMIT1 overexpression contributes to abnormal cholinergic and glutamatergic Ca(2+) signals in the trisomic condition, and knockdown of DS-related genes in our Ts16-derived cell line could constitute a relevant tool to study DS-related neuronal dysfunction.

  17. Inositol 1,4,5-Triphosphate Drives Glutamatergic and Cholinergic Inhibition Selectively in Spiny Projection Neurons in the Striatum

    OpenAIRE

    Clements, Michael A; Swapna, Immani; Morikawa, Hitoshi

    2013-01-01

    The striatum is critically involved in the selection of appropriate actions in a constantly changing environment. The spiking activity of striatal spiny projection neurons (SPNs), driven by extrinsic glutamatergic inputs, is shaped by local GABAergic and cholinergic networks. For example, it is well established that different types of GABAergic interneurons, activated by extrinsic glutamatergic and local cholinergic inputs, mediate powerful feedforward inhibition of SPN activity. In this stud...

  18. The Role of Basal Forebrain in Rat Somatosensory Cortex: Impact on Cholinergic Innervation, Sensory Information Processing, and Tactile Discrimination

    Science.gov (United States)

    1993-05-28

    noradrenergic neurons, as well as from the cholinergic neurons of the brainstem tegmentum (Jones and Cuello , 1989). This suggests that final control over...Jones, B. E., & Cuello , A. C. (1989). Afferents to the basal forebrain cholinergic cell area from pontomesencephalic- catecholamine, serotonin, and...organization in mouse barrel cortex. Brain Research, 165, 327-332. 160 Sofroniew, M. V., Eckenstein, Fo, Thoenen, Ho, & Cuello , A. C. (1982

  19. Acute renal dysfunction in liver diseases

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Renal dysfunction is common in liver diseases, either as part of multiorgan involvement in acute illness or secondary to advanced liver disease. The presence of renal impairment in both groups is a poor prognostic indicator. Renal failure is often multifactorial and can present as pre-renal or intrinsic renal dysfunction. Obstructive or post renal dysfunction only rarely complicates liver disease. Hepatorenal syndrome (MRS) is a unique form of renal failure associated with advanced liver disease or cirrhosis, and is characterized by functional renal impairment without significant changes in renal histology. Irrespective of the type of renal failure, renal hypoperfusion is the central pathogenetic mechanism, due either to reduced perfusion pressure or increased renal vascular resistance. Volume expansion, avoidance of precipitating factors and treatment of underlying liver disease constitute the mainstay of therapy to prevent and reverse renal impairment. Splanchnic vasoconstrictor agents, such as terlipressin, along with volume expansion, and early placement of transjugular intrahepatic portosystemic shunt (TIPS) may be effective in improving renal function in HRS. Continuous renal replacement therapy (CRRT) and molecular absorbent recirculating system (MARS) in selected patients may be life saving while awaiting liver transplantation.

  20. Understanding Muscle Dysfunction in Chronic Fatigue Syndrome

    Directory of Open Access Journals (Sweden)

    Gina Rutherford

    2016-01-01

    Full Text Available Introduction. Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME is a debilitating disorder of unknown aetiology, characterised by severe disabling fatigue in the absence of alternative diagnosis. Historically, there has been a tendency to draw psychological explanations for the origin of fatigue; however, this model is at odds with findings that fatigue and accompanying symptoms may be explained by central and peripheral pathophysiological mechanisms, including effects of the immune, oxidative, mitochondrial, and neuronal pathways. For example, patient descriptions of their fatigue regularly cite difficulty in maintaining muscle activity due to perceived lack of energy. This narrative review examined the literature for evidence of biochemical dysfunction in CFS/ME at the skeletal muscle level. Methods. Literature was examined following searches of PUB MED, MEDLINE, and Google Scholar, using key words such as CFS/ME, immune, autoimmune, mitochondria, muscle, and acidosis. Results. Studies show evidence for skeletal muscle biochemical abnormality in CFS/ME patients, particularly in relation to bioenergetic dysfunction. Discussion. Bioenergetic muscle dysfunction is evident in CFS/ME, with a tendency towards an overutilisation of the lactate dehydrogenase pathway following low-level exercise, in addition to slowed acid clearance after exercise. Potentially, these abnormalities may lead to the perception of severe fatigue in CFS/ME.

  1. Understanding Muscle Dysfunction in Chronic Fatigue Syndrome.

    Science.gov (United States)

    Rutherford, Gina; Manning, Philip; Newton, Julia L

    2016-01-01

    Introduction. Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a debilitating disorder of unknown aetiology, characterised by severe disabling fatigue in the absence of alternative diagnosis. Historically, there has been a tendency to draw psychological explanations for the origin of fatigue; however, this model is at odds with findings that fatigue and accompanying symptoms may be explained by central and peripheral pathophysiological mechanisms, including effects of the immune, oxidative, mitochondrial, and neuronal pathways. For example, patient descriptions of their fatigue regularly cite difficulty in maintaining muscle activity due to perceived lack of energy. This narrative review examined the literature for evidence of biochemical dysfunction in CFS/ME at the skeletal muscle level. Methods. Literature was examined following searches of PUB MED, MEDLINE, and Google Scholar, using key words such as CFS/ME, immune, autoimmune, mitochondria, muscle, and acidosis. Results. Studies show evidence for skeletal muscle biochemical abnormality in CFS/ME patients, particularly in relation to bioenergetic dysfunction. Discussion. Bioenergetic muscle dysfunction is evident in CFS/ME, with a tendency towards an overutilisation of the lactate dehydrogenase pathway following low-level exercise, in addition to slowed acid clearance after exercise. Potentially, these abnormalities may lead to the perception of severe fatigue in CFS/ME.

  2. Postoperative cognitive dysfunction and neuroinflammation; Cardiac surgery and abdominal surgery are not the same

    NARCIS (Netherlands)

    Hovens, Iris B.; van Leeuwen, Barbara L.; Mariani, Massimo A.; Kraneveld, Aletta D.; Schoemaker, Regien G.

    Postoperative cognitive dysfunction (POCD) is a debilitating surgical complication, with cardiac surgery patients at particular risk. To gain insight in the mechanisms underlying the higher incidence of POCD after cardiac versus non-cardiac surgery, systemic and central inflammatory changes,

  3. Differential effects of selective lesions of cholinergic and dopaminergic neurons on serotonin-type 1 receptors in rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Quirion, R.; Richard, J.

    1987-01-01

    Serotonin (5-HT)-type1 receptor binding sites are discretely distributed in rat brain. High densities of (3H)5-HT1 binding sites are especially located in areas enriched with cholinergic and dopaminergic innervation, such as the substantia innominata/ventral pallidum, striatum, septal nuclei, hippocampus and substantia nigra. The possible association of (3H)5-HT1 binding sites with cholinergic or dopaminergic cell bodies and/or nerve fiber terminals was investigated by selective lesions of the substantia innominata/ventral pallidum-cortical and septohippocampal cholinergic pathways and the nigrostriatal dopaminergic projection. (3H)5-HT1 receptor binding sites are possibly located on cholinergic cell bodies in the ventral pallidum-cortical pathway since (3H)5-HT1 binding in the substantia innominata/ventral pallidal area was markedly decreased following kainic acid lesions. Fimbriaectomies markedly decreased (3H)5-HT1 binding in the hippocampus, suggesting the presence of 5-HT1 binding sites on cholinergic nerve fiber terminals in the septohippocampal pathway. Lesions of the nigrostriatal dopaminergic projection did not modify (3H)5-HT1 binding in the substantia nigra and the striatum, suggesting that 5-HT1 receptors are not closely associated with dopaminergic cell bodies and nerve terminals in this pathway. These results demonstrate differential association between 5-HT1 receptors and cholinergic and dopaminergic innervation in rat brain.

  4. Functional and laminar dissociations between muscarinic and nicotinic cholinergic neuromodulation in the tree shrew primary visual cortex.

    Science.gov (United States)

    Bhattacharyya, Anwesha; Bießmann, Felix; Veit, Julia; Kretz, Robert; Rainer, Gregor

    2012-04-01

    Acetylcholine is an important neuromodulator involved in cognitive function. The impact of cholinergic neuromodulation on computations within the cortical microcircuit is not well understood. Here we investigate the effects of layer-specific cholinergic drug application in the tree shrew primary visual cortex during visual stimulation with drifting grating stimuli of varying contrast and orientation. We describe differences between muscarinic and nicotinic cholinergic effects in terms of both the layer of cortex and the attribute of visual representation. Nicotinic receptor activation enhanced the contrast response in the granular input layer of the cortex, while tending to reduce neural selectivity for orientation across all cortical layers. Muscarinic activation modestly enhanced the contrast response across cortical layers, and tended to improve orientation tuning. This resulted in highest orientation selectivity in the supra- and infragranular layers, where orientation selectivity was already greatest in the absence of pharmacological stimulation. Our results indicate that laminar position plays a crucial part in functional consequences of cholinergic stimulation, consistent with the differential distribution of cholinergic receptors. Nicotinic receptors function to enhance sensory representations arriving in the cortex, whereas muscarinic receptors act to boost the cortical computation of orientation tuning. Our findings suggest close homology between cholinergic mechanisms in tree shrew and primate visual cortices.

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

    DEFF Research Database (Denmark)

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

    2015-01-01

    A cholinergic (muscarinic) contribution to the initial circulatory response to exercise in humans remains controversial. Herein, we posit that this may be due to exercise mode with a cholinergic contribution being important during isometric handgrip exercise, where the hyperemic response...... of the muscle is relatively small compared with the onset of leg cycling, where a marked increase in muscle blood flow rapidly occurs as a consequence of multiple redundant mechanisms. We recorded blood pressure (BP; brachial artery), stroke volume (pulse contour analysis), cardiac output, and systemic vascular...... resistance (SVR) in young healthy males, while performing either 20 s of isometric handgrip contraction at 40% maximum voluntary contraction (protocol 1; n = 9) or 20 s of low-intensity leg cycling exercise (protocol 2; n = 8, 42 ± 8 W). Exercise trials were conducted under control (no drug) conditions...

  6. Evidence for dopamine D-2 receptors on cholinergic interneurons in the rat caudate-putamen

    Energy Technology Data Exchange (ETDEWEB)

    Dawson, V.L.; Dawson, T.M.; Filloux, F.M.; Wamsley, J.K.

    1988-01-01

    The aziridinium ion of ethylcholine (AF64A) is a neurotoxin that has demonstrated selectivity for cholinergic neurons. Unilateral stereotaxic injection of AF64A into the caudate-putamen of rats, resulted in a decrease in dopamine D-2 receptors as evidenced by a decrease in (/sup 3/H)-sulpiride binding. Dopamine D-1 receptors, labeled with (/sup 3/H)-SCH 23390, were unchanged. The efficacy of the lesion was demonstrated by the reduction of Na/sup +/-dependent high affinity choline uptake sites labeled with (/sup 3/H)-hemicholinium-3. These data indicate that a population of D-2 receptors are postsynaptic on cholinergic interneurons within the striatum of rat brain.

  7. Induction of cholinergic differentiation by 5-azacytidine in NG108-15 neuronal cells.

    Science.gov (United States)

    Aizawa, Shu; Sensui, Naoto; Yamamuro, Yutaka

    2009-01-28

    The DNA-demethylating agent 5-azacytidine (5-azaC) causes extensive genomic demethylation of 5-methyl-cytosine residues and reduces DNA methyltransferase activity in cells. This study evaluated the effect of 5-azaC on neuronal differentiation in proliferating NG108-15 neuronal cells, which exhibit cholinergic traits. The expression of choline acetyltransferase, an enzyme responsible for acetylcholine synthesis, was increased at both the mRNA and protein level, and neurite outgrowth was markedly induced with an increase of neurofilament-heavy chain protein, in the 5-azaC-treated cells. These findings show that global DNA demethylation markedly induces the expression of the neurotransmitter phenotype and morphological differentiation in NG108-15 neuronal cells as a model for cholinergic neuron.

  8. Cholinergic impact on neuroplasticity drives muscarinic M1 receptor mediated differentiation into neurons.

    Science.gov (United States)

    Benninghoff, Jens; Rauh, Werner; Brantl, Victor; Schloesser, Robert J; Moessner, Rainald; Möller, Hans-Jürgen; Rujescu, Dan

    2013-04-01

    Increasing evidence indicates that canonical neurotransmitters act as regulatory signals during neuroplasticity. Here, we report that muscarinic cholinergic neurotransmission stimulates differentiation of adult neural stem cells in vitro. Adult neural stem cells (ANSC) dissociated from the adult mouse hippocampus were expanded in culture with basic fibroblast growth factor (BFGF) and epidermal growth factor (EGF). Carbachol (CCh), an analog of acetylcholine (ACh) significantly enhanced de novo differentiation into neurons on bFGF- and EGF-deprived stem cells as shown by the percentage of TUJ1 positive cells. By contrast, pirenzepine (PIR), a muscarinic M1 receptor antagonist, reduced the generation of neurons. Activation of cholinergic signaling drives the de novo differentiation of uncommitted stem cells into neurons. These effects appear to be predominantly mediated via the muscarinic M1 receptor subtype.

  9. The role of efferent cholinergic transmission for the insulinotropic and glucagonostatic effects of GLP-1

    DEFF Research Database (Denmark)

    Plamboeck, Astrid; Veedfald, Simon; Deacon, Carolyn F

    2015-01-01

    The importance of vagal efferent signaling for the insulinotropic and glucagonostatic effects of glucagon-like peptide-1 (GLP-1) was investigated in a randomized single-blinded study. Healthy male participants (n = 10) received atropine to block vagal cholinergic transmission or saline infusions...... on separate occasions. At t = 15 min, plasma glucose was clamped at 6 mmol/l. GLP-1 was infused at a low dose (0.3 pmol·kg(-1)·min(-1)) from t = 45-95 min and at a higher dose (1 pmol·kg(-1)·min(-1)) from t = 95-145 min. Atropine blocked muscarinic, cholinergic transmission, as evidenced by an increase...... in heart rate [peak: 70 ± 2 (saline) vs. 90 ± 2 (atropine) beats/min, P atropine) pmol/l × min, P

  10. A kinetic model for the frequency dependence of cholinergic modulation at hippocampal GABAergic synapses.

    Science.gov (United States)

    Stone, Emily; Haario, Heikki; Lawrence, J Josh

    2014-12-01

    In this paper we use a simple model of presynaptic neuromodulation of GABA signaling to decipher paired whole-cell recordings of frequency dependent cholinergic neuromodulation at CA1 parvalbumin-containing basket cell (PV BC)-pyramidal cell synapses. Variance-mean analysis is employed to normalize the data, which is then used to estimate parameters in the mathematical model. Various parameterizations and hidden parameter dependencies are investigated using Markov Chain Monte Carlo (MCMC) parameter estimation techniques. This analysis reveals that frequency dependence of cholinergic modulation requires both calcium-dependent recovery from depression and mAChR-induced inhibition of presynaptic calcium entry. A reduction in calcium entry into the presynaptic terminal in the kinetic model accounted for the frequency-dependent effects of mAChR activation.

  11. A cholinergic receptor gene (CHRM2) affects event-related oscillations.

    Science.gov (United States)

    Jones, Kevin A; Porjesz, Bernice; Almasy, Laura; Bierut, Laura; Dick, Danielle; Goate, Alison; Hinrichs, Anthony; Rice, John P; Wang, Jen C; Bauer, Lance O; Crowe, Raymond; Foroud, Tatiana; Hesselbrock, Victor; Kuperman, Samuel; Nurnberger, John; O'Connor, Sean J; Rohrbaugh, John; Schuckit, Marc A; Tischfield, Jay; Edenberg, Howard J; Begleiter, Henri

    2006-09-01

    We report genetic linkage and association findings which implicate the gene encoding the muscarinic acetylcholine receptor M2 (CHRM2) in the modulation of a scalp-recorded electrophysiological phenotype. The P3 (P300) response was evoked using a three-stimulus visual oddball paradigm and a phenotype that relates to the energy in the theta band (4-5 Hz) was analyzed. Studies have shown that similar electrophysiological measures represent cognitive correlates of attention, working memory, and response selection; a role has been suggested for the ascending cholinergic pathway in the same functions. The results of our genetic association tests, combined with knowledge regarding the presence of presynaptic cholinergic M2 autoreceptors in the basal forebrain, indicate that the cognitive processes required by the experiment may in part be mediated by inhibitory neural networks. These findings underscore the utility of electrophysiology and neurogenetics in the understanding of cognitive function and the study of brain-related disorders.

  12. Administration of NaHS attenuates footshock-induced pathologies and emotional and cognitive dysfunction in triple transgenic Alzheimer’s mice

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    Hei-Jen eHuang

    2015-11-01

    Full Text Available Alzheimer's disease (AD is characterized by progressive cognitive decline and neuropsychiatric symptoms. Increasing evidence indicates that environmental risk factors in young adults may accelerate cognitive loss in AD and that hydrogen sulfide (H2S may represent an innovative treatment to slow the progression of AD. Therefore, the aim of this study was to evaluate the effects of NaHS, an H2S donor, in a triple transgenic AD mouse model (3×Tg-AD under footshock with situational reminders (SRs. Inescapable footshock with SRs induced anxiety and cognitive dysfunction as well as a decrease in the levels of plasma H2S and GSH and an increase in IL-6 levels in 3×Tg-AD mice. Under footshock with SR stimulus, amyloid deposition, tau protein hyperphosphorylation, and microgliosis were highly increased in the stress-responsive brain structures, including the hippocampus and amygdala, of the AD mice. Oxidative stress, inflammatory response, and β-site APP cleaving enzyme 1 (BACE1 levels were also increased, and the level of inactivated glycogen synthase kinase-3β (GSK3β (pSer9 was decreased in the hippocampi of AD mice subjected to footshock with SRs. Furthermore, the numbers of cholinergic neurons in the medial septum/diagonal band of Broca (MS/DB and noradrenergic neurons in the locus coeruleus (LC were also decreased in the 3×Tg-AD mice under footshock with SRs. These biochemical hallmarks and pathological presentations were all alleviated by the semi-acute administration of NaHS in the AD mice. Together, these findings suggest that footshock with SRs induces the impairment of spatial cognition and emotion, which involve pathological changes in the peripheral and central systems, including the hippocampus, MS/DB, LC, and BLA, and that the administration of NaHS may be a candidate strategy to ameliorate the progression of neurodegeneration.

  13. Protective effect of berberine, an isoquinoline alkaloid ameliorates ethanol-induced oxidative stress and memory dysfunction in rats.

    Science.gov (United States)

    Patil, Shaktipal; Tawari, Santosh; Mundhada, Dharmendra; Nadeem, Sayyed

    2015-09-01

    Memory impairment induced by ethanol in rats is a consequence of changes in the CNS that are secondary to impaired oxidative stress and cholinergic dysfunction. Treatment with antioxidants and cholinergic agonists are reported to produce beneficial effects in this model. Berberine, an isoquinoline alkaloid is reported to exhibit antioxidant effect and cholinesterase (ChE) inhibitor activity. However, no report is available on the influence of berberine on ethanol-induced memory impairment. Therefore, we tested its influence against cognitive dysfunction in ethanol-induced rats using Morris water maze paradigm. Lipid peroxidation and glutathione levels as parameter of oxidative stress and cholinesterase (ChE) activity as a marker of cholinergic function were assessed in the cerebral cortex and hippocampus. Forty five days after ethanol treated rats showed a severe deficit in learning and memory associated with increased lipid peroxidation, decreased glutathione, and elevated ChE activity. In contrast, chronic treatment with berberine (25-100mg/kg, p.o., once a day for 45days) improved cognitive performance, and lowered oxidative stress and ChE activity in ethanol treated rats. In another set of experiments, berberine (100mg/kg) treatment during training trials also improved learning and memory, and lowered oxidative stress and ChE activity. Chronic treatment (45days) with vitamin C, and donepezil during training trials also improved ethanol-induced memory impairment and reduced oxidative stress and/or cholinesterase activity. In conclusion, the present study demonstrates that treatment with berberine prevents the changes in oxidative stress and ChE activity, and consequently memory impairment in ethanol treated rats.

  14. A bio-behavioural investigation into the role of the cholinergic system in stress / Ilse Groenewald

    OpenAIRE

    Groenewald, Ilse

    2006-01-01

    Posttraumatic stress disorder (PTSD) is an anxiety disorder that may follow exposure to severe emotional trauma and presents with various symptoms of anxiety, hyperarousal and cognitive anomalies. Interestingly, only 10-30% of an exposed population will go on to develop full-blown PTSD. Cholinergic neurotransmission is implicated in anxiety as well as other typical manifestations of PTSD, particularly cognitive changes. The frontal cortex and hippocampus regulate and in turn ar...

  15. Origin of the slow afterhyperpolarization and slow rhythmic bursting in striatal cholinergic interneurons.

    Science.gov (United States)

    Wilson, Charles J; Goldberg, Joshua A

    2006-01-01

    Striatal cholinergic interneurons recorded in slices exhibit three different firing patterns: rhythmic single spiking, irregular bursting, and rhythmic bursting. The rhythmic single-spiking pattern is governed mainly by a prominent brief afterhyperpolarization (mAHP) that follows single spikes. The mAHP arises from an apamin-sensitive calcium-dependent potassium current. A slower AHP (sAHP), also present in these neurons, becomes prominent during rhythmic bursting or driven firing. Although not apamin sensitive, the sAHP is caused by a calcium-dependent potassium conductance. It is not present after blockade of calcium current with cadmium or after calcium is removed from the media or when intracellular calcium is buffered with bis-(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. It reverses at the potassium equilibrium potential. It can be generated by subthreshold depolarizations and persists after blockade of sodium currents by tetrodotoxin. It is slow, being maximal approximately 1 s after depolarization onset, and takes several seconds to decay. It requires >300-ms depolarizations to become maximally activated. Its voltage sensitivity is sigmoidal, with a half activation voltage of -40 mV. We conclude the sAHP is a high-affinity apamin-insensitive calcium-dependent potassium conductance, triggered by calcium currents partly activated at subthreshold levels. In combination with those calcium currents, it accounts for the slow oscillations seen in a subset of cholinergic interneurons exhibiting rhythmic bursting. In all cholinergic interneurons, it contributes to the slowdown or pause in firing that follows driven activity or prolonged subthreshold depolarizations and is therefore a candidate mechanism for the pause response observed in cholinergic neurons in vivo.

  16. Nonequilibrium Calcium Dynamics Regulate the Autonomous Firing Pattern of Rat Striatal Cholinergic Interneurons

    OpenAIRE

    Goldberg, Joshua A.; Teagarden, Mark A.; Foehring, Robert C.; Wilson, Charles J.

    2009-01-01

    Striatal cholinergic interneurons discharge rhythmically in two patterns associated with different afterhyperpolarization timescales, each dictated by a different calcium-dependent potassium current. Single spiking depends on a medium-duration afterhyperpolarization (mAHP) generated by rapid SK currents that are associated with N-type calcium channels. Periodic bursting is driven by a delayed and slowly decaying afterhyperpolarization (sAHP) current associated with L-type channels. Using calc...

  17. Striatal cholinergic interneurons and D2 receptor-expressing GABAergic medium spiny neurons regulate tardive dyskinesia.

    Science.gov (United States)

    Bordia, Tanuja; Zhang, Danhui; Perez, Xiomara A; Quik, Maryka

    2016-12-01

    Tardive dyskinesia (TD) is a drug-induced movement disorder that arises with antipsychotics. These drugs are the mainstay of treatment for schizophrenia and bipolar disorder, and are also prescribed for major depression, autism, attention deficit hyperactivity, obsessive compulsive and post-traumatic stress disorder. There is thus a need for therapies to reduce TD. The present studies and our previous work show that nicotine administration decreases haloperidol-induced vacuous chewing movements (VCMs) in rodent TD models, suggesting a role for the nicotinic cholinergic system. Extensive studies also show that D2 dopamine receptors are critical to TD. However, the precise involvement of striatal cholinergic interneurons and D2 medium spiny neurons (MSNs) in TD is uncertain. To elucidate their role, we used optogenetics with a focus on the striatum because of its close links to TD. Optical stimulation of striatal cholinergic interneurons using cholineacetyltransferase (ChAT)-Cre mice expressing channelrhodopsin2-eYFP decreased haloperidol-induced VCMs (~50%), with no effect in control-eYFP mice. Activation of striatal D2 MSNs using Adora2a-Cre mice expressing channelrhodopsin2-eYFP also diminished antipsychotic-induced VCMs, with no change in control-eYFP mice. In both ChAT-Cre and Adora2a-Cre mice, stimulation or mecamylamine alone similarly decreased VCMs with no further decline with combined treatment, suggesting nAChRs are involved. Striatal D2 MSN activation in haloperidol-treated Adora2a-Cre mice increased c-Fos(+) D2 MSNs and decreased c-Fos(+) non-D2 MSNs, suggesting a role for c-Fos. These studies provide the first evidence that optogenetic stimulation of striatal cholinergic interneurons and GABAergic MSNs modulates VCMs, and thus possibly TD. Moreover, they suggest nicotinic receptor drugs may reduce antipsychotic-induced TD. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Neurostimulation of the cholinergic anti-inflammatory pathway ameliorates disease in rat collagen-induced arthritis.

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    Yaakov A Levine

    Full Text Available INTRODUCTION: The inflammatory reflex is a physiological mechanism through which the nervous system maintains immunologic homeostasis by modulating innate and adaptive immunity. We postulated that the reflex might be harnessed therapeutically to reduce pathological levels of inflammation in rheumatoid arthritis by activating its prototypical efferent arm, termed the cholinergic anti-inflammatory pathway. To explore this, we determined whether electrical neurostimulation of the cholinergic anti-inflammatory pathway reduced disease severity in the collagen-induced arthritis model. METHODS: Rats implanted with vagus nerve cuff electrodes had collagen-induced arthritis induced and were followed for 15 days. Animals underwent active or sham electrical stimulation once daily from day 9 through the conclusion of the study. Joint swelling, histology, and levels of cytokines and bone metabolism mediators were assessed. RESULTS: Compared with sham treatment, active neurostimulation of the cholinergic anti-inflammatory pathway resulted in a 52% reduction in ankle diameter (p = 0.02, a 57% reduction in ankle diameter (area under curve; p = 0.02 and 46% reduction overall histological arthritis score (p = 0.01 with significant improvements in inflammation, pannus formation, cartilage destruction, and bone erosion (p = 0.02, accompanied by numerical reductions in systemic cytokine levels, not reaching statistical significance. Bone erosion improvement was associated with a decrease in serum levels of receptor activator of NF-κB ligand (RANKL from 132±13 to 6±2 pg/mL (mean±SEM, p = 0.01. CONCLUSIONS: The severity of collagen-induced arthritis is reduced by neurostimulation of the cholinergic anti-inflammatory pathway delivered using an implanted electrical vagus nerve stimulation cuff electrode, and supports the rationale for testing this approach in human inflammatory disorders.

  19. Novel GABAergic circuits mediate the reinforcement-related signals of striatal cholinergic interneurons

    OpenAIRE

    English, Daniel F.; Ibanez-Sandoval, Osvaldo; Stark, Eran; Tecuapetla, Fatuel; Buzsaki, Gyorgy; Deisseroth, Karl; Tepper, James M.; Koos, Tibor

    2011-01-01

    Neostriatal cholinergic interneurons are believed to play an important role in reinforcement mediated learning and response selection by signaling the occurrence and motivational value of behaviorally relevant stimuli through precisely timed multiphasic population responses. An important problem is to understand how these signals regulate the functioning of the neostriatum. Here we describe the synaptic organization of a novel circuit that involves direct nicotinic excitation of GABAergic int...

  20. Progressive posterior cortical dysfunction

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    Fábio Henrique de Gobbi Porto

    Full Text Available Abstract Progressive posterior cortical dysfunction (PPCD is an insidious syndrome characterized by prominent disorders of higher visual processing. It affects both dorsal (occipito-parietal and ventral (occipito-temporal pathways, disturbing visuospatial processing and visual recognition, respectively. We report a case of a 67-year-old woman presenting with progressive impairment of visual functions. Neurologic examination showed agraphia, alexia, hemispatial neglect (left side visual extinction, complete Balint's syndrome and visual agnosia. Magnetic resonance imaging showed circumscribed atrophy involving the bilateral parieto-occipital regions, slightly more predominant to the right . Our aim was to describe a case of this syndrome, to present a video showing the main abnormalities, and to discuss this unusual presentation of dementia. We believe this article can contribute by improving the recognition of PPCD.

  1. Cycling and erectile dysfunction

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    Ina Šibli

    2015-01-01

    Full Text Available Abstract: For many years medical studies have implicated bicycle riding is causing erectile dysfunction (ED in association with higher perineal pressure. This review focuses upon epidemiological studies assesing the impact of cycling on ED, pathogenesis of ED in cyclists  as well as on research considering changes of perineal pressure, hemodynamics, and nerve conduction when cycling. Investigestors were also interested in different saddle sizes, materials and geometry and also in the impact of saddle and riders position on changes to the perineum. Research on female cyclists is very limited but indicates similar genitourinary disorders as in male cyclists. We also review  research on preventative and therapeutic options regarding bicycle riding and ED.

  2. Neuropsychological Dysfunction among HIV Infected Drug Abusers

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    Ramani S. Durvasula

    2006-01-01

    Full Text Available Human immunodeficiency virus (HIV has been documented to cause direct and indirect central nervous system dysfunction that can be observed as a progressive decline in neuropsychological functioning in a large proportion of persons with HIV and AIDS. Neuropsychological decline in individuals with HIV is characterized by cognitive and motor slowing, attentional deficits, executive dysfunction and memory impairment (characterized by intact recognition and deficits in learning and delayed recall. Dementia occurs in a relatively small proportion of HIV infected individuals, though milder NP deficits are observed in 30-50% of persons with advanced disease. Recent evidence suggests that drug users, especially stimulant users, are at risk for accelerated progression of their HIV disease, including a greater risk of neuropsychological dysfunction. Methamphetamine may potentiate HIV Tat protein mediated neurotoxicity giving rise to striatal proinflammatory cytokine stimulation and activation of redox-regulated transcription factors. Oxidative stress due to mitochondrial dysfunction is another candidate process underlying the synergistic effects of stimulant use and HIV. Damage to neurotransmitter systems including the dopaminergic, serotonergic and glutamatergic systems which are affected by both stimulant use and HIV is an alternate explanation. Methamphetamine has also been shown to impede the effectiveness of HAART, which could then in turn allow for more rapid HIV disease progression. A greater prevalence of psychiatric disorders, particularly mood, anxiety and substance use disorders are also observed in HIV positive samples relative to the general population. The changing nature of the HIV pandemic is an ongoing challenge to investigators and clinicians working in this field. Emerging issues requiring additional attention are study of the interactive effects of normal aging and HIV on neurocognition as well as study of the effects of co

  3. Lesions of cholinergic pedunculopontine tegmental nucleus neurons fail to affect cocaine or heroin self-administration or conditioned place preference in rats.

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    Stephan Steidl

    Full Text Available Cholinergic input to the ventral tegmental area (VTA is known to contribute to reward. Although it is known that the pedunculopontine tegmental nucleus (PPTg provides an important source of excitatory input to the dopamine system, the specific role of PPTg cholinergic input to the VTA in cocaine reward has not been previously determined. We used a diphtheria toxin conjugated to urotensin-II (Dtx::UII, the endogenous ligand for urotensin-II receptors expressed by PPTg cholinergic but not glutamatergic or GABAergic cells, to lesion cholinergic PPTg neurons. Dtx::UII toxin infusion resulted in the loss of 95.78 (±0.65% of PPTg cholinergic cells but did not significantly alter either cocaine or heroin self-administration or the development of cocaine or heroin conditioned place preferences. Thus, cholinergic cells originating in PPTg do not appear to be critical for the rewarding effects of cocaine or of heroin.

  4. Novel information on the non-neuronal cholinergic system in orthopedics provides new possible treatment strategies for inflammatory and degenerative diseases

    Directory of Open Access Journals (Sweden)

    Sture Forsgren

    2009-07-01

    Full Text Available Anti-cholinergic agents are used in the treatment of several pathological conditions. Therapy regimens aimed at up-regulating cholinergic functions, such as treatment with acetylcholinesterase inhibitors, are also currently prescribed. It is now known that not only is there a neuronal cholinergic system but also a non-neuronal cholinergic system in various parts of the body. Therefore, interference with the effects of acetylcholine (ACh brought about by the local production and release of ACh should also be considered. Locally produced ACh may have proliferative, angiogenic, wound-healing, and immunomodulatory functions. Interestingly, cholinergic stimulation may lead to anti-inflammatory effects. Within this review, new findings for the locomotor system of a more widespread non-neuronal cholinergic system than previously expected will be discussed in relation to possible new treatment strategies. The conditions discussed are painful and degenerative tendon disease (tendinopathy/tendinosis, rheumatoid arthritis, and osteoarthritis.

  5. Vagotomy diminishes obesity in cafeteria rats by decreasing cholinergic potentiation of insulin release.

    Science.gov (United States)

    Balbo, Sandra Lucinei; Ribeiro, Rosane Aparecida; Mendes, Mariana Carla; Lubaczeuski, Camila; Maller, Ana Claudia Paiva Alegre; Carneiro, Everardo Magalhães; Bonfleur, Maria Lúcia

    2016-12-01

    Herein, we investigated whether subdiaphragmatic vagotomy has benefits on obesity, body glucose homeostasis, and insulin secretion in cafeteria (CAF)-obese rats. Wistar rats were fed a standard or CAF diet for 12 weeks. Subsequently, CAF rats were randomly submitted to truncal vagotomy (CAF Vag) or sham operation (CAF Sham). CAF Sham rats were hyperphagic, obese, and presented metabolic disturbances, including hyperinsulinemia, glucose intolerance, insulin resistance, hyperglycemia, and hypertriglyceridemia. Twelve weeks after vagotomy, CAF Vag rats presented reductions in body weight and perigonadal fat stores. Vagotomy did not modify glucose tolerance but normalized fed glycemia, insulinemia, and insulin sensitivity. Isolated islets from CAF Sham rats secreted more insulin in response to the cholinergic agent, carbachol, and when intracellular cyclic adenine monophosphate (cAMP) is enhanced by forskolin or 3-isobutyl-1-methylxanthine. Vagotomy decreased glucose-induced insulin release due to a reduction in the cholinergic action on β-cells. This effect also normalized islet secretion in response to cAMP. Therefore, vagotomy in rats fed on a CAF-style diet effectively decreases adiposity and restores insulin sensitivity. These effects were mainly associated with the lack of cholinergic action on the endocrine pancreas, which decreases insulinemia and may gradually reduce fat storage and improve insulin sensitivity.

  6. Acetylcholine content and viability of cholinergic neurons are influenced by the activity of protein histidine phosphatase.

    Science.gov (United States)

    Eißing, Anna; Fischer, Daniel; Rauch, Ilka; Baumann, Anne; Schebb, Nils-Helge; Karst, Uwe; Rose, Karsten; Klumpp, Susanne; Krieglstein, Josef

    2012-03-21

    The first mammalian protein histidine phosphatase (PHP) was discovered in the late 90s of the last century. One of the known substrates of PHP is ATP-citrate lyase (ACL), which is responsible--amongst other functions--for providing acetyl-CoA for acetylcholine synthesis in neuronal tissues. It has been shown in previous studies that PHP downregulates the activity of ACL by dephosphorylation. According to this our present work focused on the influence of PHP activity on the acetylcholine level in cholinergic neurons. The amount of PHP in SN56 cholinergic neuroblastoma cells was increased after overexpression of PHP by using pIRES2-AcGFP1-PHP as a vector. We demonstrated that PHP overexpression reduced the acetylcholine level and induced cell death. The acetylcholine content of SN56 cells was measured by fast liquid chromatography-tandem mass spectrometry method. Overexpression of the inactive H53A-PHP mutant also induced cell damage, but in a significantly reduced manner. However, this overexpression of the inactive PHP mutant did not change the acetylcholine content of SN56 cells significantly. In contrast, PHP downregulation, performed by RNAi-technique, did not induce cell death, but significantly increased the acetylcholine content in SN56 cells. We could show for the first time that PHP downregulation increased the acetylcholine level in SN56 cells. This might be a potential therapeutic strategy for diseases involving cholinergic deficits like Alzheimer's disease.

  7. Acetylcholine content and viability of cholinergic neurons are influenced by the activity of protein histidine phosphatase

    Directory of Open Access Journals (Sweden)

    Eißing Anna

    2012-03-01

    Full Text Available Abstract Background The first mammalian protein histidine phosphatase (PHP was discovered in the late 90s of the last century. One of the known substrates of PHP is ATP-citrate lyase (ACL, which is responsible - amongst other functions - for providing acetyl-CoA for acetylcholine synthesis in neuronal tissues. It has been shown in previous studies that PHP downregulates the activity of ACL by dephosphorylation. According to this our present work focused on the influence of PHP activity on the acetylcholine level in cholinergic neurons. Results The amount of PHP in SN56 cholinergic neuroblastoma cells was increased after overexpression of PHP by using pIRES2-AcGFP1-PHP as a vector. We demonstrated that PHP overexpression reduced the acetylcholine level and induced cell death. The acetylcholine content of SN56 cells was measured by fast liquid chromatography-tandem mass spectrometry method. Overexpression of the inactive H53A-PHP mutant also induced cell damage, but in a significantly reduced manner. However, this overexpression of the inactive PHP mutant did not change the acetylcholine content of SN56 cells significantly. In contrast, PHP downregulation, performed by RNAi-technique, did not induce cell death, but significantly increased the acetylcholine content in SN56 cells. Conclusions We could show for the first time that PHP downregulation increased the acetylcholine level in SN56 cells. This might be a potential therapeutic strategy for diseases involving cholinergic deficits like Alzheimer's disease.

  8. Targeted ablation of cholinergic interneurons in the dorsolateral striatum produces behavioral manifestations of Tourette syndrome.

    Science.gov (United States)

    Xu, Meiyu; Kobets, Andrew; Du, Jung-Chieh; Lennington, Jessica; Li, Lina; Banasr, Mounira; Duman, Ronald S; Vaccarino, Flora M; DiLeone, Ralph J; Pittenger, Christopher

    2015-01-20

    Gilles de la Tourette syndrome (TS) is characterized by tics, which are transiently worsened by stress, acute administration of dopaminergic drugs, and by subtle deficits in motor coordination and sensorimotor gating. It represents the most severe end of a spectrum of tic disorders that, in aggregate, affect ∼ 5% of the population. Available treatments are frequently inadequate, and the pathophysiology is poorly understood. Postmortem studies have revealed a reduction in specific striatal interneurons, including the large cholinergic interneurons, in severe disease. We tested the hypothesis that this deficit is sufficient to produce aspects of the phenomenology of TS, using a strategy for targeted, specific cell ablation in mice. We achieved ∼ 50% ablation of the cholinergic interneurons of the striatum, recapitulating the deficit observed in patients postmortem, without any effect on GABAergic markers or on parvalbumin-expressing fast-spiking interneurons. Interneuron ablation in the dorsolateral striatum (DLS), corresponding roughly to the human putamen, led to tic-like stereotypies after either acute stress or d-amphetamine challenge; ablation in the dorsomedial striatum, in contrast, did not. DLS interneuron ablation also led to a deficit in coordination on the rotorod, but not to any abnormalities in prepulse inhibition, a measure of sensorimotor gating. These results support the causal sufficiency of cholinergic interneuron deficits in the DLS to produce some, but not all, of the characteristic symptoms of TS.

  9. Cholinergic neuromuscular junctions in Brachionus calyciflorus and Lecane quadridentata (Rotifera: Monogononta

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    Ignacio Alejandro Pérez-Legaspi

    2014-05-01

    Full Text Available Objective: To identify the presence of joint muscular and cholinergic systems in two freshwater rotifer species, Brachionus calyciflorus and Lecane quadridentata. Methods: The muscle actin fibers were stained with phalloidin-linked fluorescent dye, and acetylcholine was detected with Amplex Red Acetylcholine/Acetylcholinesterase Assay Kit, and then confocal scanning laser microscopy was used. Results: The musculature of Brachionus calyciflorus showed a pattern similar to other species of the same genus, while that of Lecane quadridentata was different from other rotifer genera described previously. The cholinergic system was determined by co-localization of both muscles and acetylcholine labels in the whole rotifer, suggesting the presence of neuromuscular junctions. Conclusions: The distribution pattern of muscular and acetylcholine systems showed considerable differences between the two species that might be related to different adaptations to particular ecological niches. The confirmation of a cholinergic system in rotifers contributes to the development of potential neuro-pharmacological and toxicological studies using rotifers as model organism.

  10. High-affinity binding of (/sup 3/H)acetylcholine to muscarinic cholinergic receptors

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    Kellar, K.J.; Martino, A.M.; Hall, D.P. Jr.; Schwartz, R.D.; Taylor, R.L.

    1985-06-01

    High-affinity binding of (/sup 3/H)acetylcholine to muscarinic cholinergic sites in rat CNS and peripheral tissues was measured in the presence of cytisin, which occupies nicotinic cholinergic receptors. The muscarinic sites were characterized with regard to binding kinetics, pharmacology, anatomical distribution, and regulation by guanyl nucleotides. These binding sites have characteristics of high-affinity muscarinic cholinergic receptors with a Kd of approximately 30 nM. Most of the muscarinic agonist and antagonist drugs tested have high affinity for the (/sup 3/H)acetylcholine binding site, but pirenzepine, an antagonist which is selective for M-1 receptors, has relatively low affinity. The ratio of high-affinity (/sup 3/H)acetylcholine binding sites to total muscarinic binding sites labeled by (/sup 3/H)quinuclidinyl benzilate varies from 9 to 90% in different tissues, with the highest ratios in the pons, medulla, and heart atrium. In the presence of guanyl nucleotides, (/sup 3/H) acetylcholine binding is decreased, but the extent of decrease varies from 40 to 90% in different tissues, with the largest decreases being found in the pons, medulla, cerebellum, and heart atrium. The results indicate that (/sup 3/H)acetylcholine binds to high-affinity M-1 and M-2 muscarinic receptors, and they suggest that most M-2 sites have high affinity for acetylcholine but that only a small fraction of M-1 sites have such high affinity.

  11. Effects of histamine and cholinergic systems on memory retention of passive avoidance learning in rats.

    Science.gov (United States)

    Eidi, Maryam; Zarrindast, Mohammad-Reza; Eidi, Akram; Oryan, Shahrbanoo; Parivar, Kazem

    2003-03-28

    In the present study, the effects of the histamine and cholinergic systems on memory retention in adult male rats were investigated. Post-training intracerebroventricular injections were carried out in all the experiments. Cholinoceptor agonist, acetylcholine (1-10 microg/rat) or nicotine (1-10 microg/rat), increased, while a cholinoceptor antagonist, scopolamine (5-20 microg/rat), decreased memory retention. The response to acetylcholine was attenuated by scopolamine. Administration of histamine (5-20 microg/rat) reduced, but the histamine H(1) receptor antagonist, pyrilamine (10-50 microg/rat), and the histamine H(2) receptor antagonist, cimetidine (1-50 microg/rat), increased memory retention in rats. The histamine receptor antagonists attenuated the response to histamine. Histamine reduced the acetylcholine- or nicotine-induced enhancement. The histamine receptor antagonists enhanced the nicotine- or acetylcholine-induced response. Histamine potentiated the inhibitory effect induced by scopolamine. It is concluded that histaminergic and cholinergic systems have opposing effects on memory retention. Also, the histaminergic system elicits an interaction with the cholinergic system in memory retention.

  12. THE ROLE OF VENTRAL MIDLINE THALAMUS IN CHOLINERGIC-BASED RECOVERY IN THE AMNESTIC RAT

    Science.gov (United States)

    Bobal, Michael G.; Savage, Lisa M.

    2014-01-01

    The thalamus is a critical node for several pathways involved in learning and memory. Damage to the thalamus by trauma, disease or malnourishment can impact the effectiveness of the prefrontal cortex (PFC) and hippocampus (HPC) and lead to a profound amnesia state. Using the pyrithiamine-induced thiamine deficiency (PTD) rat model of human Wernicke-Korsakoff syndrome, we tested the hypothesis that co-infusion of the acetylcholinesterase inhibitor physostigmine across the PFC and HPC would recover spatial alternation performance in PTD rats. When cholinergic tone was increased by dual injections across the PFC-HPC, spontaneous alternation performance in PTD rats was recovered. In addition, we tested a second hypothesis that two ventral midline thalamic nuclei, the rhomboid nucleus and nucleus reuniens (Rh-Re), form a critical node needed for the recovery of function observed when cholinergic tone was increased across the PFC and HPC. By using the GABAA agonist muscimol to temporarily deactivate the Rh-Re the recovery of alternation behavior obtained in the PTD model by cholinergic stimulation across the PFC-HPC was blocked. In control pair-fed (PF) rats, inactivation of the Rh-Re impaired spontaneous alternation. However, when inactivation of the Rh-Re co-occurred with physostigmine infusions across the PFC-HPC, PF rats had normal performance. These results further demonstrate that the Rh-Re is critical in facilitating interactions between the HPC and PFC, but other redundant pathways also exist. PMID:25446352

  13. Effects of diazinon on the lymphocytic cholinergic system of Nile tilapia fish (Oreochromis niloticus).

    Science.gov (United States)

    Toledo-Ibarra, G A; Díaz-Resendiz, K J G; Pavón-Romero, L; Rojas-García, A E; Medina-Díaz, I M; Girón-Pérez, M I

    2016-08-01

    Fish rearing under intensive farming conditions can be easily disturbed by pesticides, substances that have immunotoxic properties and may predispose to infections. Organophosphorus pesticides (OPs) are widely used in agricultural activities; however, the mechanism of immunotoxicity of these substances is unclear. The aim of this study was to evaluate the effect of diazinon pesticides (OPs) on the cholinergic system of immune cells as a possible target of OP immunotoxicity. We evaluated ACh levels and cholinergic (nicotinic and muscarinic) receptor concentration. Additionally, AChE activity was evaluated in mononuclear cells of Nile tilapia (Oreochromis niloticus), a freshwater fish mostly cultivated in tropical regions around the world. The obtained results indicate that acute exposure to diazinon induces an increase in ACh concentration and a decrease in nAChR and mAChR concentrations and AChE activity in fish immune cells, This suggests that the non-neuronal lymphocytic cholinergic system may be the main target in the mechanism of OP immunotoxicity. This study contributes to the understanding of the mechanisms of immunotoxicity of pollutants and may help to take actions for animal health improvement.

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

    Science.gov (United States)

    Vianna, Lauro C; Fadel, Paul J; Secher, Niels H; Fisher, James P

    2015-04-01

    A cholinergic (muscarinic) contribution to the initial circulatory response to exercise in humans remains controversial. Herein, we posit that this may be due to exercise mode with a cholinergic contribution being important during isometric handgrip exercise, where the hyperemic response of the muscle is relatively small compared with the onset of leg cycling, where a marked increase in muscle blood flow rapidly occurs as a consequence of multiple redundant mechanisms. We recorded blood pressure (BP; brachial artery), stroke volume (pulse contour analysis), cardiac output, and systemic vascular resistance (SVR) in young healthy males, while performing either 20 s of isometric handgrip contraction at 40% maximum voluntary contraction (protocol 1; n = 9) or 20 s of low-intensity leg cycling exercise (protocol 2; n = 8, 42 ± 8 W). Exercise trials were conducted under control (no drug) conditions and following cholinergic blockade (glycopyrrolate). Under control conditions, isometric handgrip elicited an initial increase in BP (+5 ± 2 mmHg at 3 s and +3 ± 1 mmHg at 10 s, P mechanism is important for the BP and SVR responses at the onset of isometric handgrip exercise in humans.

  15. Cholinergic enhancement augments magnitude and specificity of visual perceptual learning in healthy humans.

    Science.gov (United States)

    Rokem, Ariel; Silver, Michael A

    2010-10-12

    Learning through experience underlies the ability to adapt to novel tasks and unfamiliar environments. However, learning must be regulated so that relevant aspects of the environment are selectively encoded. Acetylcholine (ACh) has been suggested to regulate learning by enhancing the responses of sensory cortical neurons to behaviorally relevant stimuli. In this study, we increased synaptic levels of ACh in the brains of healthy human subjects with the cholinesterase inhibitor donepezil (trade name: Aricept) and measured the effects of this cholinergic enhancement on visual perceptual learning. Each subject completed two 5 day courses of training on a motion direction discrimination task, once while ingesting 5 mg of donepezil before every training session and once while placebo was administered. We found that cholinergic enhancement augmented perceptual learning for stimuli having the same direction of motion and visual field location used during training. In addition, perceptual learning with donepezil was more selective to the trained direction of motion and visual field location. These results, combined with previous studies demonstrating an increase in neuronal selectivity following cholinergic enhancement, suggest a possible mechanism by which ACh augments neural plasticity by directing activity to populations of neurons that encode behaviorally relevant stimulus features.

  16. Developmental Neurotoxicity of Tobacco Smoke Directed Toward Cholinergic and Serotonergic Systems: More Than Just Nicotine.

    Science.gov (United States)

    Slotkin, Theodore A; Skavicus, Samantha; Card, Jennifer; Stadler, Ashley; Levin, Edward D; Seidler, Frederic J

    2015-09-01

    Tobacco smoke contains thousands of compounds in addition to nicotine, a known neuroteratogen. We evaluated the developmental neurotoxicity of tobacco smoke extract (TSE) administered to pregnant rats starting preconception and continued through the second postnatal week. We simulated nicotine concentrations encountered with second-hand smoke, an order of magnitude below those seen in active smokers, and compared TSE with an equivalent dose of nicotine alone, and to a 10-fold higher nicotine dose. We conducted longitudinal evaluations in multiple brain regions, starting in adolescence (postnatal day 30) and continued to full adulthood (day 150). TSE exposure impaired presynaptic cholinergic activity, exacerbated by a decrement in nicotinic cholinergic receptor concentrations. Although both nicotine doses produced presynaptic cholinergic deficits, these were partially compensated by hyperinnervation and receptor upregulation, effects that were absent with TSE. TSE also produced deficits in serotonin receptors in females that were not seen with nicotine. Regression analysis showed a profound sex difference in the degree to which nicotine could account for overall TSE effects: whereas the 2 nicotine doses accounted for 36%-46% of TSE effects in males, it accounted for only 7%-13% in females. Our results show that the adverse effects of TSE on neurodevelopment exceed those that can be attributed to just the nicotine present in the mixture, and further, that the sensitivity extends down to levels commensurate with second-hand smoke exposure. Because nicotine itself evoked deficits at low exposures, "harm reduction" nicotine products do not eliminate the potential for neurodevelopmental damage.

  17. Dysfunctional anger and sexual violence.

    Science.gov (United States)

    Ahmed, A G

    2014-06-01

    Sexual offenses with or without aggression attract attention from the popular media and the scientific community. Empirical research suggests a relationship between anger and sexual violence. This article describes the key themes of dysfunctional anger and sexual violence, and how dysfunctional anger relates to sexual fantasies, sexual offending, and sexual recidivism. The implications of the findings for clinical practice and future research are discussed.

  18. Defining sphincter of oddi dysfunction

    DEFF Research Database (Denmark)

    Funch-Jensen, P

    1996-01-01

    Sphincter of Oddi (SO) dysmotility may give rise to pain. The golden standard for the demonstration of SO dysfunction is endoscopic manometry. A number of abnormalities are observed in patients with postcholecystectomy pain and in patients with idiopathic recurrent pancreatitis. Criteria for defi...... for defining SO dysfunction and the possible mechanisms for the precipitation of pain are discussed....

  19. Bladder Dysfunction and Vesicoureteral Reflux

    Directory of Open Access Journals (Sweden)

    Ulla Sillén

    2008-01-01

    Full Text Available In this overview the influence of functional bladder disturbances and of its treatment on the resolution of vesicoureteral reflux (VUR in children is discussed. Historically both bladder dysfunction entities, the overactive bladder (OAB and the dysfunctional voiding (DV, have been described in conjunction with VUR. Treatment of the dysfunction was also considered to influence spontaneous resolution in a positive way. During the last decades, however, papers have been published which could not support these results. Regarding the OAB, a prospective study with treatment of the bladder overactivity with anticholinergics, did not influence spontaneous resolution rate in children with a dysfunction including also the voiding phase, DV and DES (dysfunctional elimination syndrome, most studies indicate a negative influence on the resolution rate of VUR in children, both before and after the age for bladder control, both with and without treatment. However, a couple of uncontrolled studies indicate that there is a high short-term resolution rate after treatment with flow biofeedback. It should be emphasized that the voiding phase dysfunctions (DV and DES are more severe than the genuine filling phase dysfunction (OAB, with an increased frequency of UTI and renal damage in the former groups. To be able to answer the question if treatment of bladder dysfunction influence the resolution rate of VUR in children, randomized controlled studies must be performed.

  20. Mitochondrial Dysfunction in Metabolic Syndrome and Asthma

    Directory of Open Access Journals (Sweden)

    Ulaganathan Mabalirajan

    2013-01-01

    Full Text Available Though severe or refractory asthma merely affects less than 10% of asthma population, it consumes significant health resources and contributes significant morbidity and mortality. Severe asthma does not fell in the routine definition of asthma and requires alternative treatment strategies. It has been observed that asthma severity increases with higher body mass index. The obese-asthmatics, in general, have the features of metabolic syndrome and are progressively causing a significant burden for both developed and developing countries thanks to the westernization of the world. As most of the features of metabolic syndrome seem to be originated from central obesity, the underlying mechanisms for metabolic syndrome could help us to understand the pathobiology of obese-asthma condition. While mitochondrial dysfunction is the common factor for most of the risk factors of metabolic syndrome, such as central obesity, dyslipidemia, hypertension, insulin resistance, and type 2 diabetes, the involvement of mitochondria in obese-asthma pathogenesis seems to be important as mitochondrial dysfunction has recently been shown to be involved in airway epithelial injury and asthma pathogenesis. This review discusses current understanding of the overlapping features between metabolic syndrome and asthma in relation to mitochondrial structural and functional alterations with an aim to uncover mechanisms for obese-asthma.

  1. Muscle dysfunction in cancer patients

    DEFF Research Database (Denmark)

    Christensen, Jesper Frank; Jones, L W; Andersen, J L

    2014-01-01

    implications of muscle dysfunction in cancer patients. The efficacy of exercise training to prevent and/or mitigate cancer-related muscle dysfunction is also discussed. DESIGN: We identified 194 studies examining muscular outcomes in cancer patients by searching PubMed and EMBASE databases. RESULTS: Muscle...... dysfunction is evident across all stages of the cancer trajectory. The causes of cancer-related muscle dysfunction are complex, but may involve a wide range of tumor-, therapy- and/or lifestyle-related factors, depending on the clinical setting of the individual patient. The main importance of muscle...... dysfunction in cancer patients lies in the correlation to vital clinical end points such as cancer-specific and all-cause mortality, therapy complications and quality of life (QoL). Such associations strongly emphasize the need for effective therapeutic countermeasures to be developed and implemented...

  2. [Podocyte dysfunction and proteinuria

    NARCIS (Netherlands)

    Vogtländer, N.P.J.; Rietjens, S.J.; Vlag, J. van der; Berden, J.H.M.

    2004-01-01

    Podocytes play a central role in the pathogenesis of several glomerular diseases. In recent years, this has been revealed by molecular analysis of a number of rare hereditary renal diseases. Podocytes contain three domains: the domain bound to the glomerular basement membrane (GBM), the domain of th

  3. The role of muscarinic cholinergic signaling in cost-benefit decision making

    Science.gov (United States)

    Fobbs, Wambura

    Animals regularly face decisions that affect both their immediate success and long term survival. Such decisions typically involve some form of cost-benefit analysis and engage a number of high level cognitive processes, including learning, memory and motivational influences. While decision making has been a focus of study for over a century, it's only in the last 20 years that researchers have begun to identify functional neural circuits that subserve different forms of cost-benefit decision making. Even though the cholinergic system is both functionally and anatomically positioned to modulate cost-benefit decision circuits, the contribution of the cholinergic system to decision making has been little studied. In this thesis, I investigated the cognitive and neural contribution of muscarinic cholinergic signaling to cost-benefit decision making. I, first, re-examined the effects of systemic administration of 0.3 mg/kg atropine on delay and probability discounting tasks and found that blockade of muscarinic acetylcholine receptors by atropine induced suboptimal choices (impulsive and risky) in both tasks. Since the effect on delay discounting was restricted to the No Cue version of the delay discounting task, I concluded that muscarinic cholinergic signaling mediates both forms of cost-benefit decision making and is selectively engaged when decisions require valuation of reward options whose costs are not externally signified. Second, I assessed the impact of inactivating the nucleus basalis (NBM) on both forms decision making and the effect of injecting atropine locally into the orbitofrontal cortex (OFC), basolateral amygdala (BLA), or nucleus accumbens (NAc) core during the No Cue version of the delay discounting task. I discovered that although NBM inactivation failed to affect delay discounting, it induced risk aversion in the probability discounting task; and blockade of intra- NAc core, but not intra-OFC or intra-BLA, muscarinic cholinergic signaling lead to

  4. Effects of prenatal ethanol exposure on central dopamine and Met-enkephalin system ontogeny

    Energy Technology Data Exchange (ETDEWEB)

    Hand, D.E.

    1987-01-01

    The effect of utero ethanol exposure on the development of central neurotransmitter systems was examined in rat offspring of dams that consumed liquid diets containing 35% ethanol derived calories either before and during pregnancy (E-P and P), or exclusively during gestation (E-Preg). Autoradiography of tritiated ligand receptor binding was used to rapidly screen neurotransmitter receptors in cholinergic, dopaminergic, serotonergic, noradrenergic, GABAergic, and opiatergic systems. The results led to a more comprehensive study of (1) the dopaminergic D-2 receptor binding using (/sup 3/H)spiroperidol, and (2) the opiatergic mu and delta receptor binding defined by (/sup 3/H)Met-enkephalin. Significant reductions in (/sup 3/H)spiroperidol binding were found in the 15 day old E-Preg caudate-putamen, which may be related to reductions in neurotransmission and increased locomotor activity. This provides a link between the hyperactivity reported in animal models and children with fetal alcohol syndrome (FAS) and its attenuation by drugs that facilitate dopaminergic transmission. Significant reductions were also seen in D-2 receptor binding in the inferior colliculus, which may be related to the functional deficits in the auditory processing of information by hyperactive children and the changes in the auditory evoked potentials of FAS children found at the level of that structure. The hyperactivity and auditory dysfunction improve with age, consistent with the trend in binding of (/sup 3/H)spiroperidol to D-2 receptors. The D-2 receptor binding in the E-P and P group was normal in nearly all brain regions which suggests that ethanol exposure begun during pregnancy may be more harmful than when initiated before pregnancy.

  5. Involvement of mu(1)-opioid receptors and cholinergic neurotransmission in the endomorphins-induced impairment of passive avoidance learning in mice.

    Science.gov (United States)

    Ukai, Makoto; Lin, Hui Ping

    2002-02-01

    The effects of naloxonazine, a mu(1)-opioid receptor antagonist, and physostigmine, a cholinesterase inhibitor, on the endomorphins-induced impairment of passive avoidance learning were investigated in mice. Endomorphin-1 (10 microg) and endomorphin-2 (10 microg) significantly impaired passive avoidance learning, while naloxonazine (35 mg/kg, s.c.), a mu(1)-opioid receptor antagonist, which alone failed to influence passive avoidance learning significantly inhibited the endomorphin-1 (10 microg)- but not endomorphin-2 (10 microg)-induced disturbance of such learning. A rather nonselective higher dose (50 mg/kg, s.c.) of naloxonazine almost completely antagonized the endomorphin-1 (10 microg)- and endomorphin-2 (10 microg)-induced impairment of passive avoidance learning. In contrast, physostigmine (0.025 and 0.05 mg/kg, i.p.) significantly reversed the endomorphin-1 (10 microg)- and endomorphin-2 (10 microg)-induced disturbance of passive avoidance learning, whereas physostigmine (0.025 and 0.05 mg/kg, i.p.) alone did not influence such learning. These results suggest that endomorphin-1 but not endomorphin-2 impairs learning and memory resulting from cholinergic dysfunction, and from activation of mu(1)-opioid receptors.

  6. Cholinergic Stimulation Prevents the Development of Autoimmune Diabetes: Evidence for the Modulation of Th17 Effector Cells via an IFNγ-Dependent Mechanism

    Science.gov (United States)

    George, Junu A.; Bashir, Ghada; Qureshi, Mohammed M.; Mohamed, Yassir A.; Azzi, Jamil; al-Ramadi, Basel K.; Fernández-Cabezudo, Maria J.

    2016-01-01

    Type I diabetes (T1D) results from T cell-mediated damage of pancreatic β-cells and loss of insulin production. The cholinergic anti-inflammatory pathway represents a physiological link connecting the central nervous and immune systems via vagus nerve, and functions to control the release of proinflammatory cytokines. Using the multiple low-dose streptozotocin (MLD-STZ) model to induce experimental autoimmune diabetes, we investigated the potential of regulating the development of hyperglycemia through administration of paraoxon, a highly specific acetylcholinesterase inhibitor (AChEI). We demonstrate that pretreatment with paraoxon prevented hyperglycemia in STZ-treated C57BL/6 mice. This correlated with a reduction in T cell infiltration into pancreatic islets and preservation of the structure and functionality of β-cells. Gene expression analysis of pancreatic tissue revealed that increased peripheral cholinergic activity prevented STZ-mediated loss of insulin production, this being associated with a reduction in IL-1β, IL-6, and IL-17 proinflammatory cytokines. Intracellular cytokine analysis in splenic T cells demonstrated that inhibition of AChE led to a shift in STZ-induced immune response from a predominantly disease-causing IL-17-expressing Th17 cells to IFNγ-positive Th1 cells. Consistent with this conclusion, inhibition of AChE failed to prevent STZ-induced hyperglycemia in IFNγ-deficient mice. Our results provide mechanistic evidence for the prevention of murine T1D by inhibition of AChE and suggest a promising strategy for modulating disease severity. PMID:27790217

  7. [Female sexual dysfunction].

    Science.gov (United States)

    Luria, Mijal

    2009-09-01

    Female sexual problems are common, frequently overlooked and have a significant impact on the lives of women. Research in the last decade has brought to the understanding and recognition of a number of standpoints, mainly the broad range of normative function. In 2003, the American Urological Association Foundation convened an international committee of experts in the field of women's sexuality, to reconsider the existing definitions of women's sexual dysfunction. Based on the circular response cycle developed by Basson, the group emphasized motivations that might move a woman from being sexually "neutral" to making a decision to be sexual with her partner, as a normative alternative to the need for spontaneous sexual desire as the trigger for sexual behavior. Etiology may stem from medical as well as psychological factors, thus assessment must include a complete evaluation. Treatment includes psycho-education, improvement of interpersonal communication, cognitive behavioral treatment and elucidation and treatment of medical problems, if necessary. Several pharmacological treatments are under investigation, with modest results and uncertainties about their long term safety. This review presents the female sexual response as it is understood today and the current diagnostic and therapeutic understandings and directions.

  8. [Thyroid dysfunction during pregnancy].

    Science.gov (United States)

    Díez, Juan J; Iglesias, Pedro; Donnay, Sergio

    2015-10-21

    Recent clinical practice guidelines on thyroid dysfunction and pregnancy have changed health care provided to pregnant women, although their recommendations are under constant revision. Trimester- and area-specific reference ranges for serum thyroid-stimulating hormone are required for proper diagnosis of hypothyroidism and hyperthyroidism. There is no doubt on the need of therapy for overt hypothyroidism, while therapy for subclinical hypothyroidism is controversial. Further research is needed to settle adverse effects of isolated hypothyroxinemia and thyroid autoimmunity. Differentiation between hyperthyroidism due to Graves' disease and the usually self-limited gestational transient thyrotoxicosis is critical. It is also important to recognize risk factors for postpartum thyroiditis. Supplementation with iodine is recommended to maintain adequate iodine nutrition during pregnancy and avoid serious consequences in offspring. Controversy remains about universal screening for thyroid disease during pregnancy or case-finding in high-risk women. Opinions of some scientific societies and recent cost-benefit studies favour universal screening. Randomized controlled studies currently under development should reduce the uncertainties that still remain in this area. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  9. Multiple organ dysfunction syndrome.

    Science.gov (United States)

    Ramírez, Michelle

    2013-01-01

    Initially known as multiple system organ failure, the term multiple organ dysfunction syndrome (MODS) was first described in the 1960s in adults with bleeding, respiratory failure, and sepsis. It is defined as "the development of potentially reversible physiologic derangement involving two or more organ systems not involved in the disorder that resulted in ICU admission, and arising in the wake of a potentially life threatening physiologic insult."(3) There are many risk factors predisposing to MODS; however, the most common risk factors are shock due to any cause, sepsis, and tissue hypoperfusion. A dysregulated immune response, or immuneparalysis, in which the homeostasis between pro-inflammatory and anti-inflammatory reaction is lost is thought to be key in the development of MODS. The clinical course and evolution of MODS is dependent on a combination of acquired and genetic factors. There are several nonspecific therapies for the prevention and resolution of MODS, mostly care is supportive. Mortality from MODS in septic pediatric patients varies between 11% and 54%. © 2013 Published by Mosby, Inc.

  10. Markers of erectile dysfunction

    Directory of Open Access Journals (Sweden)

    Kelvin P Davies

    2008-01-01

    Full Text Available With the development and marketing of oral pharmacotherapy that is both noninvasive and successful in treating erectile dysfunction (ED, the quest to identify markers of organic ED lost ground. Indeed, the multi-factorial nature of ED may have led many researchers to conclude that searching for a universal marker of ED was futile. However, the realization that ED is strongly correlated with the overall health of men, and may act as a predictor for the development of cardiovascular disease (CVD and diabetes, has stimulated interest in identifying genes that can distinguish organic ED. In addition, the potential ability to suggest to the patient that ED is reversible (i.e., psychogenic with a simple test would be of significance to both the physician and patient, as well as for reimbursement issues for therapy by insurance companies. Such a marker may also act as a non-subjective measure of the degree of ED and the efficacy of treatment. This review discusses the importance of identifying such markers and recent work identifying potential markers in human patients.

  11. DIASTOLIC DYSFUNCTION: A REVIEW

    Directory of Open Access Journals (Sweden)

    Rajat

    2016-01-01

    Full Text Available INTRODUCTION Diastolic heart failure is an underestimated pathology. Epidemiological and clinical studies suggest that HF with a preserved ejection fraction will become the more common form of HF which clinicians will encounter. Symptomatic treatment focuses on the reduction in pulmonary congestion and the improvement in LV filling. Specific treatment is actually lacking, but encouraging data are emerging concerning the use of renin–angiotensin–aldosterone axis blockers, nitric oxide donors, or, very recently, new agents specifically targeting actin–myosin cross-bridges. It is generally considered to have a somewhat better prognosis than systolic HF, but frequency of hospitalizations is comparable in systolic and diastolic HF. 1 Despite the recognition of its importance, definition and diagnostic criteria of diastolic dysfunction and diastolic HF remain controversial. AIMS AND OBJECTIVES This review focus of definition, diagnosis and management of diastolic heart failure with it prognosis. MATERIAL AND METHODS We have studied various guidelines, articles, reviews using given keywords, along with our experience in management of diastolic heart failure in 2015. The articles and the references were reviewed keeping in mind about the simplified management offered to the patient.

  12. Psychoanalysis: a dysfunctional family?

    Science.gov (United States)

    Grosskurth, P

    1998-01-01

    The discussion opens with an account of the author's mother's bizarre family in which a strong, charismatic grandmother maintained absolute control over her large family by encouraging a neurotic dependence in them through daily reports of their complaints. Getting interested in psychoanalysis in an effort to understand the dynamics of this dysfunctional family, the author, a biographer, turned to the study of Melanie Klein, becoming entranced by her ideas. Her research also revealed how Klein had discouraged her followers from developing ideas that diverged in any way from her own. Her portrait of the pioneer analyst provoked intense indignation. A similar pattern of absolute loyalty to his person and theories was to be found in Freud's Secret Committee, formed primarily as a means of getting rid of Jung who had been showing disturbing signs of independence. When Ferenczi and Rank began to pursue independent lines of enquiry in their work, they too were though to be undermining the foundations of classical psychoanalysis. Finally, the author concludes that though there have been sorry incidents in psychoanalysis, we should be mature enough to accept both the contributions of the early pioneers and the realizations that new ideas must be permitted to evolve.

  13. Endothelial dysfunction: EDCF revisited

    Institute of Scientific and Technical Information of China (English)

    PAUL M Vanhoutte

    2008-01-01

    Endothelial cells can initiate contraction (constriction) of the vascular smooth muscle cells that surround them. Such endothelium-dependent, acute increases in contractile tone can be due to the withdrawal of the production of nitric oxide, to the production of vasoconstrictor peptides (angiotensin Ⅱ, endothelin-1), to the formation of oxygen-derived free radicals(superoxide anions) and/or the release of vasoconstrictor metabolites of arachidonic acid. The latter have been termed endothelium-derived contracting factor (EDCF) as they can contribute to moment-to-moment changes in contractile activity of the underlying vascular smooth muscle cells. To judge from animal experiments, EDCF-mediated responses are exacerbated when the production of nitric oxide is impaired as well as by aging, spontaneous hypertension and diabetes. To judge from human studies, they contribute to the blunting of endothelium-dependent vasodilatations in aged subjects and essential hypertensive patients. Since EDCF causes vasoconstriction by activation of the TP-receptors on the vascular smooth muscle cells, selective antagonists at these receptors prevent endothelium-dependent contractions, and curtail the endothelial dysfunction in hypertension and diabetes.

  14. [Characteristics of postpartum thyroid dysfunction].

    Science.gov (United States)

    Argatska, A; Nonchev, B; Obretsova, M; Pehlivanov, B

    2015-01-01

    The risk factors and mechanisms for the development of postpartum thyroid dysfunction have been widely discussed. However data on patients suffered spontaneous or induced abortion during early pregnancy are scarce. To reveal the characteristics of thyroid dysfunction in women after an abortion in the first trimester of pregnancy. A total of 28 women (18 euthyroid, 10 with thyroid dysfunction), mean age 30.46 ± 1.01 years following abortion in the first trimester have been included in the study. Thyroid-stimulating hormone (TSH), free triiodthyronine (FT3), free thyroxine (FT4), thyreoglobulin antibodies (TgAb), thyroid peroxidase antibodies (TPOAb) were measured and ultrasound assessment of the thyroid was performed 3 and 9 months after the interruption of pregnancy. Hypothyroidism was found in 6 of the women with thyroid dysfunction and thyrotoxicosis--in 4. Clinical features of thyroid dysfunction were observed in 3 patients while in the remaining 7 cases, diagnosis was made on the basis of hormonal levels. Positive titers of thyroid autoantibodies were detected in the majority of the cases with functional disordes. In 6 patients thyroid dysfunction was transient and in 4 hormonal abnormalities persisted on by the 9th month after the abortion. The comparative analysis showed that the volume of the thyroid gland and the degree of hypoehogenicity were significantly higher in patients with thyroid dysfunction compared to euthyroid women. Thyroid dysfunction after abortion in the first trimester is mainly of autoimmune pathogenesis and its characteristics do not differ from those of postpartum thyroiditis. In the majority of patients these disorders are subclinical and may remain unrecognized. A close active follow up of patients at increased risk of functional thyroid disorders after an abortion is required in order to prevent morbidity and identify the cases developing permanent thyroid dysfunction.

  15. Sacroiliac joint dysfunction in athletes.

    Science.gov (United States)

    Brolinson, P Gunnar; Kozar, Albert J; Cibor, Greg

    2003-02-01

    The sacroiliac (SI) joint is a common source of low back pain in the general population. Because it is the link between the lower extremities and the spine, it sustains even higher loads during athletic activity, predisposing athletes to a greater probability of joint dysfunction and pain. The diagnosis and treatment of SI joint dysfunction remains controversial, due to complex anatomy and biomechanics, and a lack of universally accepted nomenclature and terminology, consistently reliable clinical tests and imaging studies, and consistently effective treatments. This article clarifies these issues by presenting a model of SI joint anatomy and function, a systematic approach to the diagnosis of dysfunction, and a comprehensive treatment plan.

  16. Strapping for temporomandibular joint dysfunction

    Directory of Open Access Journals (Sweden)

    Babu Abraham

    2008-01-01

    Full Text Available Temporomandibular joint dysfunction (TMJD is a common problem seen in many of the dental clinics. Management of this depends on an accurate diagnosis of the cause for the TMJD. Physical therapy and rehabilitation play a vital role in the management of these dysfunctions. Physical therapy is useful in treating post-traumatic stiffness of the TMJ while strapping of the TMJ for a dysfunction along with conventional physical therapy is of benefit in terms of reduction in click, decrease in pain, and an improvement in function.

  17. Strapping for temporomandibular joint dysfunction.

    Science.gov (United States)

    Babu, Abraham Samuel; John, Sandhya Mary; Unni, Amith

    2008-01-01

    Temporomandibular joint dysfunction (TMJD) is a common problem seen in many of the dental clinics. Management of this depends on an accurate diagnosis of the cause for the TMJD. Physical therapy and rehabilitation play a vital role in the management of these dysfunctions. Physical therapy is useful in treating post-traumatic stiffness of the TMJ while strapping of the TMJ for a dysfunction along with conventional physical therapy is of benefit in terms of reduction in click, decrease in pain, and an improvement in function.

  18. Central nervous system dysfunction in obesity-induced hypertension.

    Science.gov (United States)

    Head, Geoffrey A; Lim, Kyungjoon; Barzel, Benjamin; Burke, Sandra L; Davern, Pamela J

    2014-09-01

    The activation of the sympathetic nervous system is a major mechanism underlying both human and experimental models of obesity-related hypertension. While insulin and the adipokine leptin have long been thought to contribute to obesity-related neurogenic mechanisms, the evidence is now very strong that they play a major role, shown particularly in animal studies using selective receptor antagonists. There is not just maintenance of leptin's sympatho-excitatory actions as previously suggested but considerable amplification particularly in renal sympathetic nervous activity. Importantly, these changes are not dependent on short-term elevation or reduction in plasma leptin or insulin, but require some weeks to develop indicating a slow "neural adaptivity" within hypothalamic signalling. These effects can be carried across generations even when offspring are raised on a normal diet. A better understanding of the underlying mechanism should be a high research priority given the prevalence of obesity not just in the current population but also for future generations.

  19. Immunolocalization of choline acetyltransferase of common type in the central brain mass of Octopus vulgaris.

    Science.gov (United States)

    Casini, A; Vaccaro, R; D'Este, L; Sakaue, Y; Bellier, J P; Kimura, H; Renda, T G

    2012-07-19

    Acetylcholine, the first neurotransmitter to be identified in the vertebrate frog, is widely distributed among the animal kingdom. The presence of a large amount of acetylcholine in the nervous system of cephalopods is well known from several biochemical and physiological studies. However, little is known about the precise distribution of cholinergic structures due to a lack of a suitable histochemical technique for detecting acetylcholine. The most reliable method to visualize the cholinergic neurons is the immunohistochemical localization of the enzyme choline acetyltransferase, the synthetic enzyme of acetylcholine. Following our previous study on the distribution patterns of cholinergic neurons in the Octopus vulgaris visual system, using a novel antibody that recognizes choline acetyltransferase of the common type (cChAT), now we extend our investigation on the octopus central brain mass. When applied on sections of octopus central ganglia, immunoreactivity for cChAT was detected in cell bodies of all central brain mass lobes with the notable exception of the subfrontal and subvertical lobes. Positive varicosed nerves fibers where observed in the neuropil of all central brain mass lobes.

  20. Immunolocalization of choline acetyltransferase of common type in the central brain mass of Octopus vulgaris

    Directory of Open Access Journals (Sweden)

    A. Casini

    2012-07-01

    Full Text Available Acetylcholine, the first neurotransmitter to be identified in the vertebrate frog, is widely distributed among the animal kingdom. The presence of a large amount of acetylcholine in the nervous system of cephalopods is well known from several biochemical and physiological studies. However, little is known about the precise distribution of cholinergic structures due to a lack of a suitable histochemical technique for detecting acetylcholine. The most reliable method to visualize the cholinergic neurons is the immunohistochemical localization of the enzyme choline acetyltransferase, the synthetic enzyme of acetylcholine. Following our previous study on the distribution patterns of cholinergic neurons in the Octopus vulgaris visual system, using a novel antibody that recognizes choline acetyltransferase of the common type (cChAT, now we extend our investigation on the octopus central brain mass. When applied on sections of octopus central ganglia, immunoreactivity for cChAT was detected in cell bodies of all central brain mass lobes with the notable exception of the subfrontal and subvertical lobes. Positive varicosed nerves fibers where observed in the neuropil of all central brain mass lobes.

  1. Cholinergic neurons regulate secretion of glial cell line-derived neurotrophic factor by skeletal muscle cells in culture.

    Science.gov (United States)

    Vianney, John-Mary; Spitsbergen, John M

    2011-05-16

    Glial cell line-derived neurotrophic factor (GDNF) has been identified as a potent survival factor for both central and peripheral neurons. GDNF has been shown to be a potent survival factor for motor neurons during programmed cell death and continuous treatment with GDNF maintains hyperinnervation of skeletal muscle in adulthood. However, little is known about factors regulating normal production of endogenous GDNF in skeletal muscle. This study aimed to examine the role that motor neurons play in regulating GDNF secretion by skeletal muscle. A co-culture of skeletal muscle cells (C2C12) and cholinergic neurons, glioma×neuroblastoma hybrid cells (NG108-15) were used to create nerve-muscle interactions in vitro. Acetylcholine receptors (AChRs) on nerve-myotube co-cultures were blocked with alpha-bungarotoxin (α-BTX). GDNF protein content in cells and in culture medium was analyzed by enzyme-linked immunosorbant assay (ELISA) and western blotting. GDNF localization was examined by immunocytochemistry. The nerve-muscle co-culture study indicated that the addition of motor neurons to skeletal muscle cells reduced the secretion of GDNF by skeletal muscle. The results also showed that blocking AChRs with α-BTX reversed the action of neural cells on GDNF secretion by skeletal muscle. Although ELISA results showed no GDNF in differentiated NG108-15 cells grown alone, immunocytochemical analysis showed that GDNF was localized in NG108-15 cells co-cultured with C2C12 myotubes. These results suggest that motor neurons may be regulating their own supply of GDNF secreted by skeletal muscle and that activation of AChRs may be involved in this process. Copyright © 2011 Elsevier B.V. All rights reserved.

  2. Studies on effects of Emblica officinalis (Amla) on oxidative stress and cholinergic function in scopolamine induced amnesia in mice.

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    Golechha, Mahaveer; Bhatia, Jagriti; Arya, Dharmveer Singh

    2012-01-01

    and anti-cholinesterase activity. It may be useful for the treament of cognitive impairments induced by cholinergic dysfunction. Its potential in the management of dementia and Azheimer disease needs to be further explored.

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

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    Cecilia Tubert

    2016-09-01

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

  4. Improvements in Memory after Medial Septum Stimulation Are Associated with Changes in Hippocampal Cholinergic Activity and Neurogenesis

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    Da Un Jeong

    2014-01-01

    Full Text Available Deep brain stimulation (DBS has been found to have therapeutic effects in patients with dementia, but DBS mechanisms remain elusive. To provide evidence for the effectiveness of DBS as a treatment for dementia, we performed DBS in a rat model of dementia with intracerebroventricular administration of 192 IgG-saporins. We utilized four groups of rats, group 1, unlesioned control; group 2, cholinergic lesion; group 3, cholinergic lesion plus medial septum (MS electrode implantation (sham stimulation; group 4, cholinergic lesions plus MS electrode implantation and stimulation. During the probe test in the water maze, performance of the lesion group decreased for measures of time spent and the number of swim crossings over the previous platform location. Interestingly, the stimulation group showed an equivalent performance to the normal group on all measures. And these are partially reversed by the electrode implantation. Acetylcholinesterase activity in the hippocampus was decreased in lesion and implantation groups, whereas activity in the stimulation group was not different from the normal group. Hippocampal neurogenesis was increased in the stimulation group. Our results revealed that DBS of MS restores spatial memory after damage to cholinergic neurons. This effect is associated with an increase in hippocampal cholinergic activity and neurogenesis.

  5. Histaminergic modulation of cholinergic release from the nucleus basalis magnocellularis into insular cortex during taste aversive memory formation.

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    Liliana Purón-Sierra

    Full Text Available The ability of acetylcholine (ACh to alter specific functional properties of the cortex endows the cholinergic system with an important modulatory role in memory formation. For example, an increase in ACh release occurs during novel stimulus processing, indicating that ACh activity is critical during early stages of memory processing. During novel taste presentation, there is an increase in ACh release in the insular cortex (IC, a major structure for taste memory recognition. There is extensive evidence implicating the cholinergic efferents of the nucleus basalis magnocellularis (NBM in cortical activity changes during learning processes, and new evidence suggests that the histaminergic system may interact with the cholinergic system in important ways. However, there is little information as to whether changes in cholinergic activity in the IC are modulated during taste memory formation. Therefore, in the present study, we evaluated the influence of two histamine receptor subtypes, H1 in the NBM and H3 in the IC, on ACh release in the IC during conditioned taste aversion (CTA. Injection of the H3 receptor agonist R-α-methylhistamine (RAMH into the IC or of the H1 receptor antagonist pyrilamine into the NBM during CTA training impaired subsequent CTA memory, and simultaneously resulted in a reduction of ACh release in the IC. This study demonstrated that basal and cortical cholinergic pathways are finely tuned by histaminergic activity during CTA, since dual actions of histamine receptor subtypes on ACh modulation release each have a significant impact during taste memory formation.

  6. GABAA receptors are located in cholinergic terminals in the nucleus pontis oralis of the rat: implications for REM sleep control.

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    Liang, Chang-Lin; Marks, Gerald A

    2014-01-16

    The oral pontine reticular formation (PnO) of rat is one region identified in the brainstem as a rapid eye movement (REM) sleep induction zone. Microinjection of GABA(A) receptor antagonists into PnO induces a long lasting increase in REM sleep, which is similar to that produced by cholinergic agonists. We previously showed that this REM sleep-induction can be completely blocked by a muscarinic antagonist, indicating that the REM sleep-inducing effect of GABA(A) receptor antagonism is dependent upon the local cholinergic system. Consistent with these findings, it has been reported that GABA(A) receptor antagonists microdialyzed into PnO resulted in increased levels of acetylcholine. We hypothesize that GABA(A) receptors located on cholinergic boutons in the PnO are responsible for the REM sleep induction by GABA(A) receptor antagonists through blocking GABA inhibition of acetylcholine release. Cholinergic, varicose axon fibers were studied in the PnO by immunofluorescence and confocal, laser scanning microscopy. Immunoreactive cholinergic boutons were found to be colocalized with GABA(A) receptor subunit protein γ2. This finding implicates a specific subtype and location of GABA(A) receptors in PnO of rat in the control of REM sleep.

  7. Cognitive dysfunction in spinocerebellar ataxias

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    Helio Afonso Ghizoni Teive

    Full Text Available Abstract Spinocerebellar ataxias (SCAs comprise a heterogeneous group of complex neurodegenerative diseases, characterized by the presence of progressive cerebellar ataxia, associated or otherwise with ophthalmoplegia, pyramidal signs, extrapyramidal features, pigmentary retinopathy, peripheral neuropathy, cognitive dysfunction and dementia. Objective: To verify the presence of cognitive dysfunction among the main types of SCA described in the literature. Methods: the review was conducted using the search system of the PUBMED and OMIM databases. Results: Cognitive dysfunction occurs in a considerable proportion of SCA, particularly in SCA 3, which is the most frequent form of SCA worldwide. Dementia has been described in several other types of SCA such as SCA 2, SCA 17 and DRPLA. Mental retardation is a specific clinical feature of SCA 13. Conclusions: The role of the cerebellum in cognitive functions has been observed in different types of SCAs which can manifest varying degrees of cognitive dysfunction, dementia and mental retardation.

  8. Executive Dysfunction in Geriatric Depression

    National Research Council Canada - National Science Library

    Lockwood, Kathryn A; Alexopoulos, George S; van Gorp, Wilfred G

    2002-01-01

    OBJECTIVE: The purpose of this study was to characterize the neuropsychological presentation of geriatric depression and to determine whether depression-related executive dysfunction is more pronounced during advanced age. METHOD...

  9. Thyroid dysfunction and pregnancy outcomes

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    Nazarpour, Sima; Ramezani Tehrani, Fahimeh; Simbar, Masoumeh; Azizi, Fereidoun

    2015-01-01

    Background: Pregnancy has a huge impact on the thyroid function in both healthy women and those that have thyroid dysfunction. The prevalence of thyroid dysfunction in pregnant women is relatively high. Objective: The objective of this review was to increase awareness and to provide a review on adverse effect of thyroid dysfunction including hyperthyroidism, hypothyroidism and thyroid autoimmune positivity on pregnancy outcomes. Materials and Methods: In this review, Medline, Embase and the Cochrane Library were searched with appropriate keywords for relevant English manuscript. We used a variety of studies, including randomized clinical trials, cohort (prospective and retrospective), case-control and case reports. Those studies on thyroid disorders among non-pregnant women and articles without adequate quality were excluded. Results: Overt hyperthyroidism and hypothyroidism has several adverse effects on pregnancy outcomes. Overt hyperthyroidism was associated with miscarriage, stillbirth, preterm delivery, intrauterine growth retardation, low birth weight, preeclampsia and fetal thyroid dysfunction. Overt hypothyroidism was associated with abortion, anemia, pregnancy-induced hypertension, preeclampsia, placental abruption, postpartum hemorrhage, premature birth, low birth weight, intrauterine fetal death, increased neonatal respiratory distress and infant neuro developmental dysfunction. However the adverse effect of subclinical hypothyroidism, and thyroid antibody positivity on pregnancy outcomes was not clear. While some studies demonstrated higher chance of placental abruption, preterm birth, miscarriage, gestational hypertension, fetal distress, severe preeclampsia and neonatal distress and diabetes in pregnant women with subclinical hypothyroidism or thyroid autoimmunity; the other ones have not reported these adverse effects. Conclusion: While the impacts of overt thyroid dysfunction on feto-maternal morbidities have been clearly identified and its long

  10. Thyroid dysfunction and pregnancy outcomes

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    Sima Nazarpour

    2015-07-01

    Full Text Available Background: Pregnancy has a huge impact on the thyroid function in both healthy women and those that have thyroid dysfunction. The prevalence of thyroid dysfunction in pregnant women is relatively high. Objective: The objective of this review was to increase awareness and to provide a review on adverse effect of thyroid dysfunction including hyperthyroidism, hypothyroidism and thyroid autoimmune positivity on pregnancy outcomes. Materials and Methods: In this review, Medline, Embase and the Cochrane Library were searched with appropriate keywords for relevant English manuscript. We used a variety of studies, including randomized clinical trials, cohort (prospective and retrospective, case-control and case reports. Those studies on thyroid disorders among non-pregnant women and articles without adequate quality were excluded. Results: Overt hyperthyroidism and hypothyroidism has several adverse effects on pregnancy outcomes. Overt hyperthyroidism was associated with miscarriage, stillbirth, preterm delivery, intrauterine growth retardation, low birth weight, preeclampsia and fetal thyroid dysfunction. Overt hypothyroidism was associated with abortion, anemia, pregnancy-induced hypertension, preeclampsia, placental abruption, postpartum hemorrhage, premature birth, low birth weight, intrauterine fetal death, increased neonatal respiratory distress and infant neuro developmental dysfunction. However the adverse effect of subclinical hypothyroidism, and thyroid antibody positivity on pregnancy outcomes was not clear. While some studies demonstrated higher chance of placental abruption, preterm birth, miscarriage, gestational hypertension, fetal distress, severe preeclampsia and neonatal distress and diabetes in pregnant women with subclinical hypothyroidism or thyroid autoimmunity; the other ones have not reported these adverse effects. Conclusion: While the impacts of overt thyroid dysfunction on feto-maternal morbidities have been clearly

  11. Effects of bone morphogenetic protein-4 on spatial memory and cholinergic expression in the dentate gyrus after fornix-fimbria transection in rats

    Institute of Scientific and Technical Information of China (English)

    Lei Liu; Yilong Xue; Jingkun Pan; Yazhuo Hu; Yuhong Gao; Yun Luo

    2008-01-01

    , Morris water maze test was performed in all rats to test spatial memory. Time-to-platform and swim-path length were recorded. Immunohistochemical staining of cholinergic neurons was performed on brain sections containing dentate gyrus. The area covered by ChAT-positive cells was analyzed using an Image-prog-plus image analysis software. MAIN OUTCOME MEASURES: Area covered by ChAT-positive cells in the dentate gyrus. Time-to-platform and swim path-length.RESULTS: Twenty-seven rats were included in the final analysis. In the Alzheimer's disease group, the area covered by ChAT-positive cells was significantly smaller compared with the normal control group (F = 76.03, P < 0.01). The area covered by ChAT-positive cells was significantly larger in the BMP-4- Alzheimer's disease group than in the model group (F = 35.17, P < 0.05), but significantly smaller than in the normal control group (F = 40.17, P < 0.05). Time-to-platform and swim-path length were significantly longer in the Alzheimer's disease group than in the normal control group (F =24.62 and 631.58, respectively, both P < 0.05). Time-to-platform and swim-path length were significantly shorter in the BMP4-Alzheimer's disease group compared with the model group (F = 22.06 and 606.89, respectively P < 0.05).CONCLUSION: Injection of BMP-4 into the dentate gyrus of Alzheimer's disease model rats alleviates central cholinergic system injury and concomitantly improves spatial memory.

  12. Intricate paths of cells and networks becoming "Cholinergic" in the embryonic chicken retina.

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    Thangaraj, Gopenath; Greif, Alexander; Bachmann, Gesine; Layer, Paul G

    2012-10-01

    Choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) are the decisive enzymatic activities regulating the availability of acetylcholine (ACh) at a given synaptic or nonsynaptic locus. The only cholinergic cells of the mature inner retina are the so-called starburst amacrine cells (SACs). A type-I SAC, found at the outer border of the inner plexiform layer (IPL), forms a synaptic subband "a" within the IPL, while a type-II SAC located at the inner IPL border projects into subband "d." Applying immunohistochemistry for ChAT and AChE on sections of the chicken retina, we here have revealed intricate relationships of how retinal networks became dominated by AChE or by ChAT reactivities. AChE+ cells were first detectable in an embryonic day (E)4 retina, while ChAT appeared 1 day later in the very same cells; at this stage all are Brn3a+, a marker for ganglion cells (GCs). On either side of a faint AChE+ band, indicating the future IPL, pairs of ChAT+ /AChE- /Brn3a- cells appeared between E7/8. Type-I cells had increased ChAT and lost AChE; type-II cells presented less ChAT, but some AChE on their surfaces. Direct neighbors of SACs tended to express much AChE. Along with maturation, subband "a" presented more ChAT but less AChE; in subband "d" this pattern was reversed. In conclusion, the two retinal cholinergic networks segregate out from one cell pool, become locally opposed to each other, and become dominated by either synthesis or degradation of ACh. These "cholinergic developmental divergences" may also have significant physiologic consequences.

  13. Excitatory and inhibitory actions of isoflurane on the cholinergic ascending arousal system of the rat.

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    Dong, Hai-Long; Fukuda, Satoru; Murata, Eri; Higuchi, Takashi

    2006-01-01

    The cholinergic arousal systems are known to critically regulate the state of consciousness. The aim of this study was to determine the effect of isoflurane on the inhibitory or excitatory neurotransmitters efflux in important nuclei within the cholinergic arousal system using in vivo intracerebral microdialysis. The efflux of glutamate, gamma-aminobutyric acid (GABA), or acetylcholine in the posterior hypothalamus (PH), the basal forebrain (BF), and the somatosensory cortex (S1BF) of rats was detected using intracerebral microdialysis under an awake condition and at 0.5-2.0 minimum alveolar concentration (MAC) isoflurane anesthesia. The intrabasalis perfusion of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate on the cortical acetylcholine effluxes was also examined under both conditions. Isoflurane had no influence on the glutamate and GABA efflux in the PH, whereas in the BF, it dose-dependently increased glutamate efflux and decreased GABA efflux. A transient increase in glutamate efflux at 1.0 MAC and a decrease in GABA at 0.5-1.5 MAC were observed in the S1BF. Isoflurane dose-dependently decreased acetylcholine efflux in the S1BF. Perfusion of the BF with AMPA increased acetylcholine efflux in the S1BF with electroencephalographic activation during 0.75 MAC isoflurane anesthesia, suggesting an inhibitory action of isoflurane on AMPA receptors in the BF. However, N-methyl-D-aspartate had no effect on these parameters. Isoflurane induces both excitatory and inhibitory actions in the cholinergic arousal system. The predominant inhibitory action of isoflurane over its excitatory action at the BF would result in the decrease in the acetylcholine efflux in the S1BF.

  14. The cholinergic system is involved in regulation of the development of the hematopoietic system.

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    Serobyan, Naira; Jagannathan, Suchitra; Orlovskaya, Irina; Schraufstatter, Ingrid; Skok, Marina; Loring, Jeanne; Khaldoyanidi, Sophia

    2007-05-30

    Gene expression profiling demonstrated that components of the cholinergic system, including choline acetyltransferase, acetylcholinesterase and nicotinic acetylcholine receptors (nAChRs), are expressed in embryonic stem cells and differentiating embryoid bodies (EBs). Triggering of nAChRs expressed in EBs by nicotine resulted in activation of MAPK and shifts of spontaneous differentiation toward hemangioblast. In vivo, non-neural nAChRs are detected early during development in fetal sites of hematopoiesis. Similarly, in vivo exposure of the developing embryo to nicotine resulted in higher numbers of hematopoietic progenitors in fetal liver. However postpartum, the number of hematopoietic stem/progenitor cells (HSPC) was decreased, suggesting an impaired colonization of the fetal bone marrow with HSPCs. This correlated with increased number of circulating HSPC and decreased expression of CXCR4 that mediates migration of circulating cells into the bone marrow regulatory niche. In addition, protein microarrays demonstrated that nicotine changed the profile of cytokines produced in the niche. While the levels of IL1alpha, IL1beta, IL2, IL9 and IL10 were not changed, the production of hematopoiesis-supportive cytokines including G-CSF, GM-CSF, IL3, IL6 and IGFBP-3 was decreased. This correlated with the decreased repopulating ability of HSPC in vivo and diminished hematopoietic activity in bone marrow cultures treated with nicotine. Interestingly, nicotine stimulated the production of IL4 and IL5, implying a possible role of the cholinergic system in pathogenesis of allergic diseases. Our data provide evidence that the nicotine-induced imbalance of the cholinergic system during gestation interferes with normal development and provides the basis for negative health outcomes postpartum in active and passive smokers.

  15. Effects of septal cholinergic lesion on rat exploratory behavior in an open-field

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    M.R. Lamprea

    2003-02-01

    Full Text Available The medial septum participates in the modulation of exploratory behavior triggered by novelty. Also, selective lesions of the cholinergic component of the septohippocampal system alter the habituation of rats to an elevated plus-maze without modifying anxiety indices. We investigated the effects of the intraseptal injection of the cholinergic immunotoxin 192 IgG-saporin (SAP on the behavior of rats in an open-field. Thirty-nine male Wistar rats (weight: 194-230 g were divided into three groups, non-injected controls and rats injected with either saline (0.5 µl or SAP (237.5 ng/0.5 µl. Twelve days after surgery, the animals were placed in a square open-field (120 cm and allowed to freely explore for 5 min. After the test, the rats were killed by decapitation and the septum, hippocampus and frontal cortex were removed and assayed for acetylcholinesterase activity. SAP increased acetylcholinesterase activity in the septum, hippocampus and frontal cortex and decreased the total distance run (9.15 ± 1.51 m in comparison to controls (13.49 ± 0.91 m. The time spent in the center and at the periphery was not altered by SAP but the distance run was reduced during the first and second minutes (2.43 ± 0.36 and 1.75 ± 0.34 m compared to controls (4.18 ± 0.26 and 3.14 ± 0.25 m. SAP-treated rats showed decreased but persistent exploration throughout the session. These results suggest that septohippocampal cholinergic mechanisms contribute to at least two critical processes, one related to the motivation to explore new environments and the other to the acquisition and storage of spatial information (i.e., spatial memory.

  16. Protection of early phase hepatic ischemia-reperfusion injury by cholinergic agonists

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    Roth Robert

    2006-02-01

    Full Text Available Abstract Background Cytokine production is critical in ischemia/reperfusion (IR injury. Acetylcholine binds to macrophages and inhibits cytokine synthesis, through the cholinergic anti-inflammatory pathway. This study examined the role of the cholinergic pathway in cytokine production and hepatic IR- injury. Methods Adult male mice underwent 90-min of partial liver ischemia followed by reperfusion. The AChR agonists (1,1-dimethyl-4-phenyl-L-pioperazinium-iodide [DMPP], and nicotine or saline-vehicle were administered i.p. before ischemia. Plasma cytokine tumor necrosis factor (TNF-α, macrophage inflammatory protein-2, and Interleukin-6 were measured. Liver injury was assessed by plasma alanine transaminase (ALT and liver histopathology. Results A reperfusion time-dependent hepatocellular injury occurred as was indicated by increased plasma-ALT and histopathology. The injury was associated with marked elevation of plasma cytokines/chemokines. Pre-ischemic treatment of mice with DMPP or nicotine significantly decreased plasma-ALT and cytokines after 3 h of reperfusion. After 6 h of reperfusion, the protective effect of DMPP decreased and reached a negligible level by 24 h of reperfusion, despite significantly low levels of plasma cytokines. Histopathology showed markedly diminished hepatocellular injury in DMPP- and nicotine-pretreated mice during the early-phase of hepatic-IR, which reached a level comparable to saline-treated mice at late-phase of IR. Conclusion Pharmacological modulation of the cholinergic pathway provides a means to modulate cytokine production and to delay IR-induced heaptocellular injury.

  17. Dopamine-galanin receptor heteromers modulate cholinergic neurotransmission in the rat ventral hippocampus

    Science.gov (United States)

    Moreno, Estefanía; Vaz, Sandra H.; Cai, Ning-Sheng; Ferrada, Carla; Quiroz, César; Barodia, Sandeep; Kabbani, Nadine; Canela, Enric I.; McCormick, Peter J.; Lluis, Carme; Franco, Rafael; Ribeiro, Joaquim A; Sebastião, Ana M.; Ferré, Sergi

    2011-01-01

    Previous studies have shown that dopamine and galanin modulate cholinergic transmission in the hippocampus, but little is known about the mechanisms involved and their possible interactions. By using resonance energy transfer techniques in transfected mammalian cells we demonstrated the existence of heteromers between the dopamine D1-like receptors (D1 and D5) and galanin Gal1, but not Gal2 receptors. Within the D1-Gal1 and D5-Gal1 receptor heteromers, dopamine receptor activation potentiated and dopamine receptor blockade counteracted MAPK activation induced by stimulation of Gal1 receptors, while Gal1 receptor activation or blockade did not modify D1-like receptor-mediated MAPK activation. Ability of a D1-like receptor antagonist to block galanin-induced MAPK activation (cross-antagonism) was used as a “biochemical fingerprint” of D1-like-Gal1 receptor heteromers, allowing their identification in the rat ventral hippocampus. The functional role of D1-like-Gal receptor heteromers was demonstrated in synaptosomes from rat ventral hippocampus, where galanin facilitated acetylcholine release, but only with co-stimulation of D1-like receptors. Electrophysiological experiments in rat ventral hippocampal slices showed that these receptor interactions modulate hippocampal synaptic transmission. Thus, a D1-like receptor agonist, that was ineffective when administered alone, turned an inhibitory effect of galanin into an excitatory effect, an interaction that required cholinergic neurotransmission. Altogether, our results strongly suggest that D1-like-Gal1 receptor heteromers act as processors that integrate signals of two different neurotransmitters, dopamine and acetylcholine, to modulate hippocampal cholinergic neurotransmission. PMID:21593325

  18. Ventral tegmental area GABA projections pause accumbal cholinergic interneurons to enhance associative learning.

    Science.gov (United States)

    Brown, Matthew T C; Tan, Kelly R; O'Connor, Eoin C; Nikonenko, Irina; Muller, Dominique; Lüscher, Christian

    2012-12-20

    The ventral tegmental area (VTA) and nucleus accumbens (NAc) are essential for learning about environmental stimuli associated with motivationally relevant outcomes. The task of signalling such events, both rewarding and aversive, from the VTA to the NAc has largely been ascribed to dopamine neurons. The VTA also contains GABA (γ-aminobutyric acid)-releasing neurons, which provide local inhibition and also project to the NAc. However, the cellular targets and functional importance of this long-range inhibitory projection have not been ascertained. Here we show that GABA-releasing neurons of the VTA that project to the NAc (VTA GABA projection neurons) inhibit accumbal cholinergic interneurons (CINs) to enhance stimulus-outcome learning. Combining optogenetics with structural imaging and electrophysiology, we found that VTA GABA projection neurons selectively target NAc CINs, forming multiple symmetrical synaptic contacts that generated inhibitory postsynaptic currents. This is remarkable considering that CINs represent a very small population of all accumbal neurons, and provide the primary source of cholinergic tone in the NAc. Brief activation of this projection was sufficient to halt the spontaneous activity of NAc CINs, resembling the pause recorded in animals learning stimulus-outcome associations. Indeed, we found that forcing CINs to pause in behaving mice enhanced discrimination of a motivationally important stimulus that had been associated with an aversive outcome. Our results demonstrate that VTA GABA projection neurons, through their selective targeting of accumbal CINs, provide a novel route through which the VTA communicates saliency to the NAc. VTA GABA projection neurons thus emerge as orchestrators of dopaminergic and cholinergic modulation in the NAc.

  19. In vivo PET imaging of brain nicotinic cholinergic receptors

    Energy Technology Data Exchange (ETDEWEB)

    Bottlaender, M.; Valette, H.; Saba, W.; Schollhorn-Peyronneau, M.A.; Dolle, F.; Syrota, A. [Service Hospitalier Frederic Joliot (CEA/DSV/DRM), 91 - Orsay (France)

    2006-07-01

    Neuronal acetylcholine receptors (nAChRs) are widely distributed throughout the central nervous system where they modulate a number of CNS functions including neurotransmitter release, cognitive function, anxiety, analgesia and control of cerebral blood flow. In the brain, a major subtype is composed of the {alpha}4{beta}2 subunit combination. Density of this subtype has been shown to be decreased in patients with neuro-degenerative disease such as Alzheimer and Parkinson's disease (AD and PD), and mutated receptors has been described in some familial epilepsy. Thus, in vivo mapping of the nicotinic nAChRs by Positron Emission Tomography (PET) are of great interest to monitor the evolution of these pathologies and changes in the neuronal biochemistry induced by therapeutic agents. Recently, a new compound, 3-[2(S)-2-azetidinyl-methoxy]pyridine (A-85380) has been synthesised and labelled with fluorine-18, [{sup 18}F]fluoro-A-85380 (Dolle et al., 1999). The [{sup 18}F]fluoro-A-85380 has been shown to bind with high affinity t o nAChRs in vitro (Saba et al., 2004), and its toxicity was low and compatible with it s use at tracer dose in human PET studies (Valette, 2002). PET studies in baboons showed that, after in vivo administration of [ {sup 18}F]fluoro-A-85380 at a tracer dose, the distribution of the radioactivity in the brain reflect the distribution of the < 4R2 nAChRs. Competition and pre-blocking studies, using nicotinic agonists, confirm that the radiotracer binds specifically to the heteromeric nAChRs in the brain (Valette et al., 1999). The in vivo, characteristics of the [{sup 18}F]fluoro-A-8538 0 combined with its low toxicity make possible the imaging of the nicotinic receptor s in human by PET (Bottlaender 2003). Studies were performed in healthy non-smoker volunteers to evaluate the brain kinetics of [{sup 18}F]fluoro-A-85380 and to assess the quantification of its nAChRs binding in the human brain with PET (Gallezot et a., 2005). The [{sup 18}F