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Sample records for cholinergic neuronal decline

  1. 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

  2. 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.

  3. Cholinergic Neurons Excite Cortically Projecting Basal Forebrain GABAergic Neurons

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    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

  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. 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...

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

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    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

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

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    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

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

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    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.

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

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

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    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.

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

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    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.

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

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    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.

  13. 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.

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

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    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.

  15. Orexin Receptor Activation Generates Gamma Band Input to Cholinergic and Serotonergic Arousal System Neurons and Drives an Intrinsic Ca2+-Dependent Resonance in LDT and PPT Cholinergic Neurons

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    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

  16. 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.

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

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    Masaru eIshibashi

    2015-06-01

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

  18. 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.

  19. Striatal cholinergic interneurons and D2 receptor-expressing GABAergic medium spiny neurons regulate tardive dyskinesia.

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    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.

  20. 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.

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

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    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.

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

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    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.

  3. 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

  4. Interaction of basal forebrain cholinergic neurons with the glucocorticoid system in stress regulation and cognitive impairment.

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    Paul, Saswati; Jeon, Won Kyung; Bizon, Jennifer L; Han, Jung-Soo

    2015-01-01

    A substantial number of studies on basal forebrain (BF) cholinergic neurons (BFCN) have provided compelling evidence for their role in the etiology of stress, cognitive aging, Alzheimer's disease (AD), and other neurodegenerative diseases. BFCN project to a broad range of cortical sites and limbic structures, including the hippocampus, and are involved in stress and cognition. In particular, the hippocampus, the primary target tissue of the glucocorticoid stress hormones, is associated with cognitive function in tandem with hypothalamic-pituitary-adrenal (HPA) axis modulation. The present review summarizes glucocorticoid and HPA axis research to date in an effort to establish the manner in which stress affects the release of acetylcholine (ACh), glucocorticoids, and their receptor in the context of cognitive processes. We attempt to provide the molecular interactive link between the glucocorticoids and cholinergic system that contributes to BFCN degeneration in stress-induced acceleration of cognitive decline in aging and AD. We also discuss the importance of animal models in facilitating such studies for pharmacological use, to which could help decipher disease states and propose leads for pharmacological intervention.

  5. Interaction of basal forebrain cholinergic neurons with the glucocorticoid system in stress regulation and cognitive impairment

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    Saswati ePaul

    2015-04-01

    Full Text Available A substantial number of studies on basal forebrain cholinergic neurons (BFCN have provided compelling evidence for their role in the etiology of stress, cognitive aging, Alzheimer’s disease (AD, and other neurodegenerative diseases. BFCN project to a broad range of cortical sites and limbic structures, including the hippocampus, and are involved in stress and cognition. In particular, the hippocampus, the primary target tissue of the glucocorticoid stress hormones, is associated with cognitive function in tandem with hypothalamic-pituitary-adrenal (HPA axis modulation. The present review summarizes glucocorticoid and HPA axis research to date in an effort to establish the manner in which stress affects the release of acetylcholine, glucocorticoids, and their receptor in the context of cognitive processes. We attempt to provide the molecular interactive link between the glucocorticoids and cholinergic system that contributes to BFCN degeneration in stress-induced acceleration of cognitive decline in aging and AD. We also discuss the importance of animal models in facilitating such studies for pharmacological use, which could help decipher disease states and propose leads for pharmacological intervention.

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

    Directory of Open Access Journals (Sweden)

    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.

  7. 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

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

    Science.gov (United States)

    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.

  9. 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

  10. 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...

  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. 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

  13. 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.

  14. 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

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. Effects of amyotrophic lateral sclerosis sera on cultured cholinergic neurons

    Energy Technology Data Exchange (ETDEWEB)

    Touzeau, G.; Kato, A.C.

    1983-03-01

    Dissociated monolayer cultures of chick ciliary ganglion neurons have been used to study the effects of control and ALS sera. The cultured neurons survive and extend neurites for a minimum of 2 weeks in a standard tissue culture medium that contains 10% heat-inactivated human serum. Three parameters of the neurons have been examined when cultured in control and ALS sera for 8 to 12 days: (1) neuronal survival, (2) activity of the enzyme choline acetyltransferase, and (3) synthesis of /sup 3/H-acetylcholine using /sup 3/H-choline as precursor. ALS sera cause a small decrease in these three parameters, but this difference is not significant.

  20. 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.

  1. Reciprocal cholinergic and GABAergic modulation of the small ventrolateral pacemaker neurons of Drosophila's circadian clock neuron network.

    Science.gov (United States)

    Lelito, Katherine R; Shafer, Orie T

    2012-04-01

    The relatively simple clock neuron network of Drosophila is a valuable model system for the neuronal basis of circadian timekeeping. Unfortunately, many key neuronal classes of this network are inaccessible to electrophysiological analysis. We have therefore adopted the use of genetically encoded sensors to address the physiology of the fly's circadian clock network. Using genetically encoded Ca(2+) and cAMP sensors, we have investigated the physiological responses of two specific classes of clock neuron, the large and small ventrolateral neurons (l- and s-LN(v)s), to two neurotransmitters implicated in their modulation: acetylcholine (ACh) and γ-aminobutyric acid (GABA). Live imaging of l-LN(v) cAMP and Ca(2+) dynamics in response to cholinergic agonist and GABA application were well aligned with published electrophysiological data, indicating that our sensors were capable of faithfully reporting acute physiological responses to these transmitters within single adult clock neuron soma. We extended these live imaging methods to s-LN(v)s, critical neuronal pacemakers whose physiological properties in the adult brain are largely unknown. Our s-LN(v) experiments revealed the predicted excitatory responses to bath-applied cholinergic agonists and the predicted inhibitory effects of GABA and established that the antagonism of ACh and GABA extends to their effects on cAMP signaling. These data support recently published but physiologically untested models of s-LN(v) modulation and lead to the prediction that cholinergic and GABAergic inputs to s-LN(v)s will have opposing effects on the phase and/or period of the molecular clock within these critical pacemaker neurons.

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

    Directory of Open Access Journals (Sweden)

    Meaghan C Creed

    2014-01-01

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

  3. 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.

  4. Cholinergic neuronal differentiation of bone marrow mesenchymal stem cells in rhesus monkeys

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    The purpose of the present study was to determine the best cholinergic neuronal differentiation method of rhesus monkey bone marrow mesenchymal stem cells(BMSCs).Four methods were used to induce differentiation,and the groups were assigned accordingly:basal inducing group(culture media,bFGF,and forskolin);SHH inducing group(SHH,inducing group);RA inducing group(RA,basal inducing group);and SHH+RA inducing group(SHH,RA,and basal inducing group).All groups displayed neuronal morphology and increased expression of nestin and neuron-specific enolase.The basal inducing group did not express synapsin,and cells from the SHH inducing group did not exhibit neuronal resting membrane potential.In contrast,results demonstrated that BMSCs from the RA and SHH+RA inducing groups exhibited neuronal resting membrane potential,and cells from the SHH+RA inducing group expressed higher levels of synapsin and acetylcholine.In conclusion,the induction of cholinergic differentiation through SHH+RA was determined to be superior to the other methods.

  5. 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.

  6. 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.

  7. Non-neuronal cholinergic system in airways and lung cancer susceptibility.

    Science.gov (United States)

    Saracino, Laura; Zorzetto, Michele; Inghilleri, Simona; Pozzi, Ernesto; Stella, Giulia Maria

    2013-08-01

    In the airway tract acetylcholine (ACh) is known to be the mediator of the parasympathetic nervous system. However ACh is also synthesized by a large variety of non-neuronal cells. Strongest expression is documented in neuroendocrine and in epithelial cells (ciliated, basal and secretory elements). Growing evidence suggests that a cell-type specific Ach expression and release do exist and act with local autoparacrine loop in the non-neuronal airway compartment. Here we review the molecular mechanism by which Ach is involved in regulating various aspects of innate mucosal defense, including mucociliary clearance, regulation of macrophage activation as well as in promoting epithelial cells proliferation and conferring susceptibility to lung carcinoma onset. Importantly this non-neuronal cholinergic machinery is differently regulated than the neuronal one and could be specifically therapeutically targeted.

  8. GRK5 Deficiency Leads to Selective Basal Forebrain Cholinergic Neuronal Vulnerability.

    Science.gov (United States)

    He, Minchao; Singh, Prabhakar; Cheng, Shaowu; Zhang, Qiang; Peng, Wei; Ding, XueFeng; Li, Longxuan; Liu, Jun; Premont, Richard T; Morgan, Dave; Burns, Jeffery M; Swerdlow, Russell H; Suo, William Z

    2016-05-19

    Why certain diseases primarily affect one specific neuronal subtype rather than another is a puzzle whose solution underlies the development of specific therapies. Selective basal forebrain cholinergic (BFC) neurodegeneration participates in cognitive impairment in Alzheimer's disease (AD), yet the underlying mechanism remains elusive. Here, we report the first recapitulation of the selective BFC neuronal loss that is typical of human AD in a mouse model termed GAP. We created GAP mice by crossing Tg2576 mice that over-express the Swedish mutant human β-amyloid precursor protein gene with G protein-coupled receptor kinase-5 (GRK5) knockout mice. This doubly defective mouse displayed significant BFC neuronal loss at 18 months of age, which was not observed in either of the singly defective parent strains or in the wild type. Along with other supporting evidence, we propose that GRK5 deficiency selectively renders BFC neurons more vulnerable to degeneration.

  9. 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.

  10. Cholinergic, Glutamatergic, and GABAergic Neurons of the Pedunculopontine Tegmental Nucleus Have Distinct Effects on Sleep/Wake Behavior in Mice.

    Science.gov (United States)

    Kroeger, Daniel; Ferrari, Loris L; Petit, Gaetan; Mahoney, Carrie E; Fuller, Patrick M; Arrigoni, Elda; Scammell, Thomas E

    2017-02-01

    The pedunculopontine tegmental (PPT) nucleus has long been implicated in the regulation of cortical activity and behavioral states, including rapid eye-movement (REM) sleep. For example, electrical stimulation of the PPT region during sleep leads to rapid awakening, whereas lesions of the PPT in cats reduce REM sleep. Though these effects have been linked with the activity of cholinergic PPT neurons, the PPT also includes intermingled glutamatergic and GABAergic cell populations, and the precise roles of cholinergic, glutamatergic, and GABAergic PPT cell groups in regulating cortical activity and behavioral state remain unknown. Using a chemogenetic approach in three Cre-driver mouse lines, we found that selective activation of glutamatergic PPT neurons induced prolonged cortical activation and behavioral wakefulness, whereas inhibition reduced wakefulness and increased non-REM (NREM) sleep. Activation of cholinergic PPT neurons suppressed lower-frequency electroencephalogram rhythms during NREM sleep. Last, activation of GABAergic PPT neurons slightly reduced REM sleep. These findings reveal that glutamatergic, cholinergic, and GABAergic PPT neurons differentially influence cortical activity and sleep/wake states. More than 40 million Americans suffer from chronic sleep disruption, and the development of effective treatments requires a more detailed understanding of the neuronal mechanisms controlling sleep and arousal. The pedunculopontine tegmental (PPT) nucleus has long been considered a key site for regulating wakefulness and REM sleep. This is mainly because of the cholinergic neurons contained in the PPT nucleus. However, the PPT nucleus also contains glutamatergic and GABAergic neurons that likely contribute to the regulation of cortical activity and sleep-wake states. The chemogenetic experiments in the present study reveal that cholinergic, glutamatergic, and GABAergic PPT neurons each have distinct effects on sleep/wake behavior, improving our

  11. Β-amyloid 1-42 oligomers impair function of human embryonic stem cell-derived forebrain cholinergic neurons.

    Directory of Open Access Journals (Sweden)

    Linn Wicklund

    Full Text Available Cognitive impairment in Alzheimer's disease (AD patients is associated with a decline in the levels of growth factors, impairment of axonal transport and marked degeneration of basal forebrain cholinergic neurons (BFCNs. Neurogenesis persists in the adult human brain, and the stimulation of regenerative processes in the CNS is an attractive prospect for neuroreplacement therapy in neurodegenerative diseases such as AD. Currently, it is still not clear how the pathophysiological environment in the AD brain affects stem cell biology. Previous studies investigating the effects of the β-amyloid (Aβ peptide on neurogenesis have been inconclusive, since both neurogenic and neurotoxic effects on progenitor cell populations have been reported. In this study, we treated pluripotent human embryonic stem (hES cells with nerve growth factor (NGF as well as with fibrillar and oligomeric Aβ1-40 and Aβ1-42 (nM-µM concentrations and thereafter studied the differentiation in vitro during 28-35 days. The process applied real time quantitative PCR, immunocytochemistry as well as functional studies of intracellular calcium signaling. Treatment with NGF promoted the differentiation into functionally mature BFCNs. In comparison to untreated cells, oligomeric Aβ1-40 increased the number of functional neurons, whereas oligomeric Aβ1-42 suppressed the number of functional neurons. Interestingly, oligomeric Aβ exposure did not influence the number of hES cell-derived neurons compared with untreated cells, while in contrast fibrillar Aβ1-40 and Aβ1-42 induced gliogenesis. These findings indicate that Aβ1-42 oligomers may impair the function of stem cell-derived neurons. We propose that it may be possible for future AD therapies to promote the maturation of functional stem cell-derived neurons by altering the brain microenvironment with trophic support and by targeting different aggregation forms of Aβ.

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

    Science.gov (United States)

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

    1989-06-01

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

  13. 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...

  14. Interleukin-1 Inhibits Putative Cholinergic Neurons in Vitro and REM Sleep when Microinjected into the Rat Laterodorsal Tegmental Nucleus

    Science.gov (United States)

    Brambilla, Dario; Barajon, Isabella; Bianchi, Susanna; Opp, Mark R.; Imeri, Luca

    2010-01-01

    Study Objectives: REM sleep is suppressed during infection, an effect mimicked by the administration of cytokines such as interleukin-1 (IL-1). In spite of this observation, brain sites and neurochemical systems mediating IL-1-induced suppression of REM sleep have not been identified. Cholinergic neurons in the brainstem laterodorsal tegmental nucleus (LDT) are part of the neuronal circuitry responsible for REM sleep generation. Since IL-1 inhibits acetylcholine synthesis and release, the aim of this study was to test the two different, but related hypotheses. We hypothesized that IL-1 inhibits LDT cholinergic neurons, and that, as a result of this inhibition, IL-1 suppresses REM sleep. Design, Measurement, and Results: To test these hypotheses, the electrophysiological activity of putative cholinergic LDT neurons was recorded in a rat brainstem slice preparation. Interleukin-1 significantly inhibited the firing rate of 76% of recorded putative cholinergic LDT neurons and reduced the amplitude of glutamatergic evoked potentials in 60% of recorded neurons. When IL-1 (1 ng) was microinjected into the LDT of freely behaving rats, REM sleep was reduced by about 50% (from 12.7% ± 1.5% of recording time [after vehicle] to 6.1% ± 1.4% following IL-1 administration) during post-injection hours 3-4. Conclusions: Results of this study support the hypothesis that IL-1 can suppress REM sleep by acting at the level of the LDT nucleus. Furthermore this effect may result from the inhibition of evoked glutamatergic responses and of spontaneous firing of putative cholinergic LDT neurons. Citation: Brambilla D; Barajon I; Bianchi S; Opp MR; Imeri L. Interleukin-1 inhibits putative cholinergic neurons in vitro and REM sleep when microinjected into the rat laterodorsal tegmental nucleus. SLEEP 2010;33(7):919-929. PMID:20614852

  15. The response of GABAergic and cholinergic neurons to transient cerebral ischemia.

    Science.gov (United States)

    Francis, A; Pulsinelli, W

    1982-07-15

    The vulnerability of striatal and hippocampal neurons to ischemia was studied by measuring the activity of neurotransmitter-related enzymes after transient forebrain ischemia in rats. Activities of glutamic acid decarboxylase (GAD) and choline acetyltransferase (CAT) were measured 6 h to 8 days after 20, 30 or 40 min of forebrain ischemia, as markers for GABAergic and cholinergic neurons respectively. Transient forebrain ischemia resulted in depression of striatal GAD activity while striatal CAT and hippocampal GAD activities were unaffected. Striatal GAD activity progressively decreased during the first 24 h postischemia and remained depressed 5--8 days later, suggesting irreversible damage to this population of neurons. The stability of striatal CAT and hippocampal GAD activity indicates that these cells were resistant to the present ischemic conditions.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

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

    2014-08-18

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

  18. 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...

  19. Colonic mucosal mediators from patients with irritable bowel syndrome excite enteric cholinergic motor neurons.

    Science.gov (United States)

    Balestra, B; Vicini, R; Cremon, C; Zecchi, L; Dothel, G; Vasina, V; De Giorgio, R; Paccapelo, A; Pastoris, O; Stanghellini, V; Corinaldesi, R; De Ponti, F; Tonini, M; Barbara, G

    2012-12-01

    Mediators released in the mucosal milieu have been suggested to be involved in visceral hypersensitivity and abdominal pain in patients with irritable bowel syndrome (IBS). However, their impact on myenteric neurons remains unsettled. Mucosal biopsies were obtained from the descending colon of patients with IBS and controls. Mucosal mast cells were identified immunohistochemically. The impact of spontaneously released mucosal mediators on guinea pig electrically stimulated longitudinal muscle myenteric plexus (LMMP) preparations was assessed in vitro by means of selective receptor antagonists and inhibitors. Patients with IBS showed an increased mast cell count compared with controls. Application of mucosal mediators of IBS to LMMPs potentiated cholinergic twitch contractions, an effect directly correlated with mast cell counts. Enhanced contractions were inhibited by 50.3% with the prostaglandin D2 antagonist BW A868C, by 31.3% and 39% with the TRPV1 antagonists capsazepine and HC-030031, respectively, and by 60.5% with purinergic P2X antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid. Conversely, the serotonin1-4, histamine1-3, tachykinin1-3 receptor blockade, and serine protease inhibition had no significant effect. Colonic mucosal mediators from patients with IBS excite myenteric cholinergic motor neurons. These effects were correlated with mast cell counts and mediated by activation of prostanoid receptors, TRPV1, and P2X receptors. These results support the role of mucosal inflammatory mediators and mast cell activation in altered motor function of IBS. © 2012 Blackwell Publishing Ltd.

  20. 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.

  1. 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.

  2. 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.

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

    Science.gov (United States)

    Yang, C; Brown, R E

    2014-01-31

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

  4. 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.

  5. 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.

  6. Effect of bilobalide B on cholinergic hippocampal neurons exposed to cholesterol and apoliprotein E4

    Institute of Scientific and Technical Information of China (English)

    Xijuan Jiang; Bin Lu; Yingchang Fan

    2008-01-01

    BACKGROUND: Extracts of ginkgo biloba leaves have been reported to improve nerve function and activity in Alzheimer's disease, which is associated with reduced secretion of cholinergic neurotransmitter in hippocampal neurons.OBJECTIVE: To validate the protective effect of bilobalide B against in vitro injury of cholinergic neurons of the hippocampus induced by combined cholesterol and apoE4DESIGN, TIME AND SETTING: This randomized, controlled animal experiment was performed in the Pathology Laboratory, Tianjin University of Traditional Chinese Medicine from July 2003 to July 2006.MATERIALS: Neonatal Wistar rats, 1-day-old, both male and female, and mean body mass of 5g were selected for this study. Cholesterol and apolipoprotein E4 (apoE4) were purchased from Sigma Company (USA), bilobalide B was purchased from Tianjin Zhongyi Pharmaceutical Factory, batch number 20050312.METHODS: Hippocampal neurons were divided into three groups; a normal control group (routinely added media), a model group (exposed to media containing 40mg/L cholesterol and 30mg/L apoE4 for 24 hours) and a bilobalide B group (exposed to media containing 160mg/L bilobalide B for 16 hours, and then with addition of 40mg/L cholesterol and 30mg/L apoE4 for an additional 24 hours).MAIN OUTCOME MEASURES: Levels of acetylcholine (ACh) and activity of acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) in hippocampal neurons were determined by microdosage hydroxylamine colorimetry, hydroxylamine colorimetry and radiological chemistry, respectively.RESULTS: The ACh level was significantly lower in the model group than that in the normal control group (P0.05). Activity of ChAT was significantly lower in the model group than in the normal control group (P<0.01), while the activity was significantly higher in the bilobalide B group than in the model group (P<0.05).CONCLUSION: Bilobalide B can enhance the ACh level of hippocampal neurons damaged by combined cholesterol and apoE4, by promoting

  7. Influence of interferon-gamma on the differentiation of cholinergic neurons in rat embryonic basal forebrain and septal nuclei

    Institute of Scientific and Technical Information of China (English)

    Yanhong Luo; Lin An

    2006-01-01

    BACKGROUND: Interferon-gamma (IFN-γ) can make neurons in basal forebrain and septal nuclei differentiate into cholinergic neurons by treating the cells in cerebral cortex of newborn rats, without the inhibition from IFN-γ antibody. The important effect of IFN-γ on the development and differentiation of neurons has been found by some scholars.OBJ ECTIVE:To investigate whether IFN-γ has differentiational effect on cholinergic neurons in basal forebrain and septal nuclei, and make clear that the increased number of cholinergic neurons is resulted by cell differentiation or cell proliferation.DESIGN: Controlled observation trial.SETTING: Department of Cell Biology, Medical School, Beijing University.MATERIALS: Sixty-eight female Wistar rats at embryonic 16 days, weighing 250 to 350 g, were enrolled in this study, and they were provided by the Experimental Animal Center, Medical School, Beijing University.IFN-γ was the product of Gibco Company.METHODS: This study was carried out in the Department of Cell Biology, Medical School, Beijing University and Daheng Image Company of Chinese Academy of Sciences during September 1995 to December 2002.The female Wistar rats at embryonic 16 days were sacrificed, and their fetuses were taken out. Primary culture of the isolated basal forebrain and septal nuclei was performed. The cultured nerve cells were assigned into 3 groups: control group (nothing added), IFN-γ group(1×105 U/L interferon), IFN-γ+ IFN-γ antibody group (1 ×105 U/L IFN-γ± IFN-γ antibody). The specific marker enzyme (choline acetyl transferase) of cholinergic neuron was stained with immunohistochemical method. Choline acetyl transferase positive cells were counted, and 14C-acetyl CoA was used as substrate to detect the activity of choline acetyl transferase, so as to reflect the differentiational effect of IFN-γ on cholinergic neuron in basal forebrain and septal nuclei. Flow cytometry was used to analyze cell circle and detect the proliferation of

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

    Directory of Open Access Journals (Sweden)

    Avital eAdler

    2013-09-01

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

  9. GABAergic inputs from direct and indirect striatal projection neurons onto cholinergic interneurons in the primate putamen.

    Science.gov (United States)

    Gonzales, Kalynda Kari; Pare, Jean-Francois; Wichmann, Thomas; Smith, Yoland

    2013-08-01

    Striatal cholinergic interneurons (ChIs) are involved in reward-dependent learning and the regulation of attention. The activity of these neurons is modulated by intrinsic and extrinsic γ-aminobutyric acid (GABA)ergic and glutamatergic afferents, but the source and relative prevalence of these diverse regulatory inputs remain to be characterized. To address this issue, we performed a quantitative ultrastructural analysis of the GABAergic and glutamatergic innervation of ChIs in the postcommissural putamen of rhesus monkeys. Postembedding immunogold localization of GABA combined with peroxidase immunostaining for choline acetyltransferase showed that 60% of all synaptic inputs to ChIs originate from GABAergic terminals, whereas 21% are from putatively glutamatergic terminals that establish asymmetric synapses, and 19% from other (non-GABAergic) sources of symmetric synapses. Double pre-embedding immunoelectron microscopy using substance P and Met-/Leu-enkephalin antibodies to label GABAergic terminals from collaterals of "direct" and "indirect" striatal projection neurons, respectively, revealed that 47% of the indirect pathway terminals and 36% of the direct pathway terminals target ChIs. Together, substance P- and enkephalin-positive terminals represent 24% of all synapses onto ChIs in the monkey putamen. These findings show that ChIs receive prominent GABAergic inputs from multiple origins, including a significant contingent from axon collaterals of direct and indirect pathway projection neurons. Copyright © 2013 Wiley Periodicals, Inc.

  10. Cholinergic neurons of the pelvic autonomic ganglia and uterus of the female rat: distribution of axons and presence of muscarinic receptors.

    Science.gov (United States)

    Papka, R E; Traurig, H H; Schemann, M; Collins, J; Copelin, T; Wilson, K

    1999-05-01

    Acetylcholine (ACh) stimulates contraction of the uterus and dilates the uterine arterial supply. Uterine cholinergic nerves arise from the paracervical ganglia and were, in the past, characterized based on acetylcholinesterase (AChE) histochemistry. However, the histochemical reaction for acetylcholinesterase provides only indirect evidence of acetylcholine location and is a nonspecific marker for cholinergic nerves. The present study: (1) reevaluated cholinergic neurons of the paracervical ganglia, (2) examined the cholinergic innervation of the uterus by using retrograde axonal tracing and antibodies against molecules specific to cholinergic neurons, choline acetyltransferase and the vesicular acetylcholine transporter, and (3) examined muscarinic receptors in the paracervical ganglia using autoradiography and a radiolabeled agonist. Most ganglionic neurons were choline acetyltransferase- and vesicular acetylcholine transporter-immunoreactive and were apposed by choline acetyltransferase/vesicular acetylcholine transporter-immunoreactive terminals. Retrograde tracing showed that some cholinergic neurons projected axons to the uterus. These nerves formed moderately dense plexuses in the myometrium, cervical smooth muscle and microarterial system of the uterine horns and cervix. Finally, the paracervical ganglia contain muscarinic receptors. These results clearly reveal the cholinergic innervation of the uterus and cervix, a source of these nerves, and demonstrate the muscarinic receptor content of the paracervical ganglia. Cholinergic nerves could play significant roles in the control of uterine myometrium and vasculature.

  11. Ethanol affects striatal interneurons directly and projection neurons through a reduction in cholinergic tone.

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    Blomeley, Craig P; Cains, Sarah; Smith, Richard; Bracci, Enrico

    2011-04-01

    The acute effects of ethanol on the neurons of the striatum, a basal ganglia nucleus crucially involved in motor control and action selection, were investigated using whole-cell recordings. An intoxicating concentration of ethanol (50 mM) produced inhibitory effects on striatal large aspiny cholinergic interneurons (LAIs) and low-threshold spike interneurons (LTSIs). These effects persisted in the presence of tetrodotoxin and were because of an increase in potassium currents, including those responsible for medium and slow afterhyperpolarizations. In contrast, fast-spiking interneurons (FSIs) were directly excited by ethanol, which depolarized these neurons through the suppression of potassium currents. Medium spiny neurons (MSNs) became hyperpolarized in the presence of ethanol, but this effect did not persist in the presence of tetrodotoxin and was mimicked and occluded by application of the M1 muscarinic receptor antagonist telenzepine. Ethanol effects on MSNs were also abolished by 100 μM barium. This showed that the hyperpolarizations observed in MSNs were because of decreased tonic activation of M1 muscarinic receptors, resulting in an increase in Kir2 conductances. Evoked GABAergic responses of MSNs were reversibly decreased by ethanol with no change in paired-pulse ratio. Furthermore, ethanol impaired the ability of thalamostriatal inputs to inhibit a subsequent corticostriatal glutamatergic response in MSNs. These results offer the first comprehensive description of the highly cell type-specific effects of ethanol on striatal neurons and provide a cellular basis for the interpretation of ethanol influence on a brain area crucially involved in the motor and decisional impairment caused by this drug.

  12. Nitric oxide activates leak K+ currents in the presumed cholinergic neuron of basal forebrain.

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    Kang, Youngnam; Dempo, Yoshie; Ohashi, Atsuko; Saito, Mitsuru; Toyoda, Hiroki; Sato, Hajime; Koshino, Hisashi; Maeda, Yoshinobu; Hirai, Toshihiro

    2007-12-01

    Learning and memory are critically dependent on basal forebrain cholinergic (BFC) neuron excitability, which is modulated profoundly by leak K(+) channels. Many neuromodulators closing leak K(+) channels have been reported, whereas their endogenous opener remained unknown. We here demonstrate that nitric oxide (NO) can be the endogenous opener of leak K(+) channels in the presumed BFC neurons. Bath application of 1 mM S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, induced a long-lasting hyperpolarization, which was often interrupted by a transient depolarization. Soluble guanylyl cyclase inhibitors prevented SNAP from inducing hyperpolarization but allowed SNAP to cause depolarization, whereas bath application of 0.2 mM 8-bromoguanosine-3',5'-cyclomonophosphate (8-Br-cGMP) induced a similar long-lasting hyperpolarization alone. These observations indicate that the SNAP-induced hyperpolarization and depolarization are mediated by the cGMP-dependent and -independent processes, respectively. When examined with the ramp command pulse applied at -70 mV under the voltage-clamp condition, 8-Br-cGMP application induced the outward current that reversed at K(+) equilibrium potential (E(K)) and displayed Goldman-Hodgkin-Katz rectification, indicating the involvement of voltage-independent K(+) current. By contrast, SNAP application in the presumed BFC neurons either dialyzed with the GTP-free internal solution or in the presence of 10 muM Rp-8-bromo-beta-phenyl-1,N(2)-ethenoguanosine 3',5'-cyclic monophosphorothioate sodium salt, a protein kinase G (PKG) inhibitor, induced the inward current that reversed at potentials much more negative than E(K) and close to the reversal potential of Na(+)-K(+) pump current. These observations strongly suggest that NO activates leak K(+) channels through cGMP-PKG-dependent pathway to markedly decrease the excitability in BFC neurons, while NO simultaneously causes depolarization by the inhibition of Na(+)-K(+) pump through ATP

  13. 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.

  14. Cholinergic modulation of primary afferent glutamatergic transmission in rat medullary dorsal horn neurons.

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    Jeong, Seok-Gwon; Choi, In-Sun; Cho, Jin-Hwa; Jang, Il-Sung

    2013-12-01

    Although muscarinic acetylcholine (mACh) receptors are expressed in trigeminal ganglia, it is still unknown whether mACh receptors modulate glutamatergic transmission from primary afferents onto medullary dorsal horn neurons. In this study, we have addressed the cholinergic modulation of primary afferent glutamatergic transmission using a conventional whole cell patch clamp technique. Glutamatergic excitatory postsynaptic currents (EPSCs) were evoked from primary afferents by electrical stimulation of trigeminal tract and monosynaptic EPSCs were recorded from medullary dorsal horn neurons of rat horizontal brain stem slices. Muscarine and ACh reversibly and concentration-dependently decreased the amplitude of glutamatergic EPSCs and increased the paired-pulse ratio. In addition, muscarine reduced the frequency of miniature EPSCs without affecting the current amplitude, suggesting that muscarine acts presynaptically to decrease the probability of glutamate release onto medullary dorsal horn neurons. The muscarine-induced decrease of glutamatergic EPSCs was significantly occluded by methoctramine or AF-DX116, M2 receptor antagonists, but not pirenzepine, J104129 and MT-3, selective M1, M3 and M4 receptor antagonists. The muscarine-induced decrease of glutamatergic EPSCs was highly dependent on the extracellular Ca2+ concentration. Physostigmine and clinically available acetylcholinesterase inhibitors, such as rivastigmine and donepezil, significantly shifted the concentration-inhibition relationship of ACh for glutamatergic EPSCs. These results suggest that muscarine acts on presynaptic M2 receptors to inhibit glutamatergic transmission by reducing the Ca2+ influx into primary afferent terminals, and that M2 receptor agonists and acetylcholinesterase inhibitors could be, at least, potential targets to reduce nociceptive transmission from orofacial tissues.

  15. Targeting the non-neuronal cholinergic system in macrophages for the management of infectious diseases and cancer: challenge and promise

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    Reichrath, Sandra; Reichrath, Jörg; Moussa, Amira-Talaat; Meier, Carola; Tschernig, Thomas

    2016-01-01

    Macrophages represent key players of the immune system exerting highly effective defense mechanisms against microbial infections and cancer that include phagocytosis and programmed cell removal. Recent findings highlight the relevance of the non-neuronal cholinergic system for the regulation of macrophage function that opens promising new concepts for the treatment of infectious diseases and cancer. This mini review summarizes our present knowledge on this topic and gives an outlook on future developments.

  16. 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.

  17. 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.

  18. Discharge Profiles across the Sleep–Waking Cycle of Identified Cholinergic, GABAergic, and Glutamatergic Neurons in the Pontomesencephalic Tegmentum of the Rat

    Science.gov (United States)

    Boucetta, Soufiane; Cissé, Youssouf; Mainville, Lynda; Morales, Marisela

    2014-01-01

    Distributed within the laterodorsal tegmental and pedunculopontine tegmental nuclei (LDT and PPT), cholinergic neurons in the pontomesencephalic tegmentum have long been thought to play a critical role in stimulating cortical activation during waking (W) and paradoxical sleep (PS, also called REM sleep), yet also in promoting PS with muscle atonia. However, the discharge profile and thus precise roles of the cholinergic neurons have remained uncertain because they lie intermingled with GABAergic and glutamatergic neurons, which might also assume these roles. By applying juxtacellular recording and labeling in naturally sleeping–waking, head-fixed rats, we investigated the discharge profiles of histochemically identified cholinergic, GABAergic, and glutamatergic neurons in the LDT, SubLDT, and adjoining medial part of the PPT (MPPT) in relation to sleep–wake states, cortical activity, and muscle tone. We found that all cholinergic neurons were maximally active during W and PS in positive correlation with fast (γ) cortical activity, as “W/PS-max active neurons.” Like cholinergic neurons, many GABAergic and glutamatergic neurons were also “W/PS-max active.” Other GABAergic and glutamatergic neurons were “PS-max active,” being minimally active during W and maximally active during PS in negative correlation with muscle tone. Conversely, some glutamatergic neurons were “W-max active,” being maximally active during W and minimally active during PS in positive correlation with muscle tone. Through different discharge profiles, the cholinergic, GABAergic, and glutamatergic neurons of the LDT, SubLDT, and MPPT thus appear to play distinct roles in promoting W and PS with cortical activation, PS with muscle atonia, or W with muscle tone. PMID:24672016

  19. Modulation of specific sensory cortical areas by segregated basal forebrain cholinergic neurons demonstrated by neuronal tracing and optogenetic stimulation in mice

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    Irene eChaves-Coira

    2016-04-01

    Full Text Available Neocortical cholinergic activity plays a fundamental role in sensory processing and cognitive functions. Previous results have suggested a refined anatomical and functional topographical organization of basal forebrain (BF projections that may control cortical sensory processing in a specific manner. We have used retrograde anatomical procedures to demonstrate the existence of specific neuronal groups in the BF involved in the control of specific sensory cortices. Fluoro-gold and Fast Blue fluorescent retrograde tracers were deposited into the primary somatosensory (S1 and primary auditory (A1 cortices in mice. Our results revealed that the BF is a heterogeneous area in which neurons projecting to different cortical areas are segregated into different neuronal groups. Most of the neurons located in the horizontal limb of the diagonal band of Broca (HDB projected to the S1 cortex, indicating that this area is specialized in the sensory processing of tactile stimuli. However, the nucleus basalis magnocellularis (B nucleus shows a similar number of cells projecting to the S1 as to the A1 cortices. In addition, we analyzed the cholinergic effects on the S1 and A1 cortical sensory responses by optogenetic stimulation of the BF neurons in urethane-anesthetized transgenic mice. We used transgenic mice expressing the light-activated cation channel, channelrhodopsin-2, tagged with a fluorescent protein (ChR2-YFP under the control of the choline-acetyl transferase promoter (ChAT. Cortical evoked potentials were induced by whisker deflections or by auditory clicks. According to the anatomical results, optogenetic HDB stimulation induced more extensive facilitation of tactile evoked potentials in S1 than auditory evoked potentials in A1, while optogenetic stimulation of the B nucleus facilitated either tactile or auditory evoked potentials equally. Consequently, our results suggest that cholinergic projections to the cortex are organized into segregated

  20. Modulation of Specific Sensory Cortical Areas by Segregated Basal Forebrain Cholinergic Neurons Demonstrated by Neuronal Tracing and Optogenetic Stimulation in Mice

    Science.gov (United States)

    Chaves-Coira, Irene; Barros-Zulaica, Natali; Rodrigo-Angulo, Margarita; Núñez, Ángel

    2016-01-01

    Neocortical cholinergic activity plays a fundamental role in sensory processing and cognitive functions. Previous results have suggested a refined anatomical and functional topographical organization of basal forebrain (BF) projections that may control cortical sensory processing in a specific manner. We have used retrograde anatomical procedures to demonstrate the existence of specific neuronal groups in the BF involved in the control of specific sensory cortices. Fluoro-Gold (FlGo) and Fast Blue (FB) fluorescent retrograde tracers were deposited into the primary somatosensory (S1) and primary auditory (A1) cortices in mice. Our results revealed that the BF is a heterogeneous area in which neurons projecting to different cortical areas are segregated into different neuronal groups. Most of the neurons located in the horizontal limb of the diagonal band of Broca (HDB) projected to the S1 cortex, indicating that this area is specialized in the sensory processing of tactile stimuli. However, the nucleus basalis magnocellularis (B) nucleus shows a similar number of cells projecting to the S1 as to the A1 cortices. In addition, we analyzed the cholinergic effects on the S1 and A1 cortical sensory responses by optogenetic stimulation of the BF neurons in urethane-anesthetized transgenic mice. We used transgenic mice expressing the light-activated cation channel, channelrhodopsin-2, tagged with a fluorescent protein (ChR2-YFP) under the control of the choline-acetyl transferase promoter (ChAT). Cortical evoked potentials were induced by whisker deflections or by auditory clicks. According to the anatomical results, optogenetic HDB stimulation induced more extensive facilitation of tactile evoked potentials in S1 than auditory evoked potentials in A1, while optogenetic stimulation of the B nucleus facilitated either tactile or auditory evoked potentials equally. Consequently, our results suggest that cholinergic projections to the cortex are organized into segregated

  1. Inositol 1,4,5-triphosphate drives glutamatergic and cholinergic inhibition selectively in spiny projection neurons in the striatum.

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    Clements, Michael A; Swapna, Immani; Morikawa, Hitoshi

    2013-02-06

    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 study, using mouse striatal slices, we show that glutamatergic and cholinergic inputs exert direct inhibitory regulation of SPN activity via activation of metabotropic glutamate receptors (mGluRs) and muscarinic acetylcholine receptors. While pressure ejection of the group I mGluR (mGluR1/5) agonist DHPG [(S)-3,5-dihydroxyphenylglycine] equally engages both mGluR1 and mGluR5 subtypes, the mGluR-dependent component of IPSCs elicited by intrastriatal electrical stimulation is almost exclusively mediated by the mGluR1 subtype. Ca(2+) release from intracellular stores specifically through inositol 1,4,5-triphospahte receptors (IP(3)Rs) and not ryanodine receptors (RyRs) mediates this form of inhibition by gating two types of Ca(2+)-activated K(+) channels (i.e., small-conductance SK channels and large-conductance BK channels). Conversely, spike-evoked Ca(2+) influx triggers Ca(2+) release solely through RyRs to generate SK-dependent slow afterhyperpolarizations, demonstrating functional segregation of IP(3)Rs and RyRs. Finally, IP(3)-induced Ca(2+) release is uniquely observed in SPNs and not in different types of interneurons in the striatum. These results demonstrate that IP(3)-mediated activation of SK and BK channels provides a robust mechanism for glutamatergic and cholinergic inputs to selectively suppress striatal output neuron activity.

  2. CHOLINERGIC NEURONS OF THE BASAL FOREBRAIN MEDIATE BIOCHEMICAL AND ELECTROPHYSIOLOGICAL MECHANISMS UNDERLYING SLEEP HOMEOSTASIS

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    Kalinchuk, Anna V.; Porkka-Heiskanen, Tarja; McCarley, Robert W.; Basheer, Radhika

    2015-01-01

    The tight coordination of biochemical and electrophysiological mechanisms underlies the homeostatic sleep pressure (HSP) produced by sleep deprivation (SD). We have reported that during SD the levels of inducible nitric oxide synthase (iNOS), extracellular nitric oxide (NO), adenosine [AD]ex, lactate [Lac]ex and pyruvate [Pyr]ex increase in the basal forebrain (BF). However, it is not clear whether all of them contribute to HSP leading to increased electroencephalogram (EEG) delta activity during non-rapid eye movement (NREM) recovery sleep (RS) following SD. Previously, we showed that NREM delta increase evident during RS depends on the presence of BF cholinergic (ChBF) neurons. Here, we investigated the role of ChBF cells in coordination of biochemical and EEG changes seen during SD and RS in the rat. Increases in low theta power (5–7Hz), but not high theta (7–9Hz), during SD correlated with the increase in NREM delta power during RS, and with the changes in nitrate/nitrite [NOx]ex and [AD]ex. Lesions of ChBF cells using IgG 192-saporin prevented increases in [NOx]ex, [AD]ex and low theta activity, during SD, but did not prevent increases in [Lac]ex and [Pyr]ex. Infusion of NO donor DETA NONOate into the saporin-treated BF failed to increase NREM RS and delta power, suggesting ChBF cells are important for mediating NO homeostatic effects. Finally, SD-induced iNOS was mostly expressed in ChBF cells, and the intensity of iNOS induction correlated with the increase in low theta activity. Together, our data indicate ChBF cells are important in regulating the biochemical and EEG mechanisms that contribute to HSP. PMID:25369989

  3. Distribution of secretagogin-containing neurons in the basal forebrain of mice, with special reference to the cholinergic corticopetal system.

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    Gyengesi, Erika; Andrews, Zane B; Paxinos, George; Zaborszky, Laszlo

    2013-05-01

    Cholinergic and GABAergic corticopetal neurons in the basal forebrain play important roles in cortical activation, sensory processing, and attention. Cholinergic neurons are intermingled with peptidergic, and various calcium binding protein-containing cells, however, the functional role of these neurons is not well understood. In this study we examined the expression pattern of secretagogin (Scgn), a newly described calcium-binding protein, in neurons of the basal forebrain. We also assessed some of the corticopetal projections of Scgn neurons and their co-localization with choline acetyltransferase (ChAT), neuropeptide-Y, and other calcium-binding proteins (i.e., calbindin, calretinin, and parvalbumin). Scgn is expressed in cell bodies of the medial and lateral septum, vertical and horizontal diagonal band nuclei, and of the extension of the amygdala but it is almost absent in the ventral pallidum. Scgn is co-localized with ChAT in neurons of the bed nucleus of the stria terminalis, extension of the amygdala, and interstitial nucleus of the posterior limb of the anterior commissure. Scgn was co-localized with calretinin in the accumbens nucleus, medial division of the bed nucleus of stria terminalis, the extension of the amygdala, and interstitial nucleus of the posterior limb of the anterior commissure. We have not found co-expression of Scgn with parvalbumin, calbindin, or neuropeptide-Y. Retrograde tracing studies using Fluoro Gold in combination with Scgn-specific immunohistochemistry revealed that Scgn neurons situated in the nucleus of the horizontal limb of the diagonal band project to retrosplenial and cingulate cortical areas.

  4. The Role of Cholinergic Basal Forebrain Neurons in Adenosine-Mediated Homeostatic Control of Sleep: Lessons from 192 IgG-Saporin Lesions

    Science.gov (United States)

    Kalinchuk, Anna V.; McCarley, Robert W.; Stenberg, Dag; Porkka-Heiskanen, Tarja; Basheer, Radhika

    2013-01-01

    A topic of high current interest and controversy is the basis of the homeostatic sleep response, the increase in non-rapid-eye-movement (NREM) sleep and NREM-delta activity following sleep deprivation (SD). Adenosine, which accumulates in the cholinergic basal forebrain (BF) during SD, has been proposed as one of the important homeostatic sleep factors. It is suggested that sleep-inducing effects of adenosine are mediated by inhibiting the wake-active neurons of the BF, including cholinergic neurons. Here we examined the association between SD-induced adenosine release, the homeostatic sleep response and the survival of cholinergic neurons in the BF after injections of the immunotoxin 192 IgG-saporin (saporin) in rodents. We correlated SD-induced adenosine level in the BF and the homeostatic sleep response with the cholinergic cell loss 2 weeks after local saporin injections into the BF, as well as 2 and 3 weeks after intracerebroventricular (ICV) saporin injections. Two weeks after local saporin injection there was an 88% cholinergic cell loss, coupled with nearly complete abolition of the SD-induced adenosine increase in the BF, the homeostatic sleep response, and the sleep-inducing effects of BF adenosine infusion. Two weeks after ICV saporin injection there was a 59% cholinergic cell loss, correlated with significant increase in SD-induced adenosine level in the BF and an intact sleep response. Three weeks after ICV saporin injection there was an 87% cholinergic cell loss, nearly complete abolition of the SD-induced adenosine increase in the BF and the homeostatic response, implying that the time course of ICV saporin lesions is a key variable in interpreting experimental results. Taken together, these results strongly suggest that cholinergic neurons in the BF are important for the SD-induced increase in adenosine as well as for its sleep-inducing effects and play a major, although not exclusive, role in sleep homeostasis. PMID:18805464

  5. BETA-AMYLOID((1-42)) AFFECTS CHOLINERGIC BUT NOT PARVALBUMIN-CONTAINING NEURONS IN THE SEPTAL COMPLEX OF THE RAT

    NARCIS (Netherlands)

    HARKANY, T; DEJONG, GI; SOOS, K; PENKE, B; LUITEN, PGM; GULYA, K

    1995-01-01

    beta-Amyloid((1-42)) peptide (beta AP((1-42))) was injected into the medial septum of rats. After a 14-day survival time, neuronal alterations in the septal cholinergic and GABAergic systems were visualized by means of histo- and immunocytochemical methods. Neurons insulted by the peptide were prima

  6. β-Amyloid(1-42) affects cholinergic but not parvalbumin-containing neurons in the septal complex of the rat

    NARCIS (Netherlands)

    Harkany, T.; Jong, G.I. de; Soós, K.; Penke, B.; Luiten, P.G.M.; Gulya, K.

    1995-01-01

    β-Amyloid(1-42) peptide (βAP(1-42)) was injected into the medial septum of rats. After a 14-day survival time, neuronal alterations in the septal cholinergic and GABAergic systems were visualized by means of histo- and immunocytochemical methods. Neurons insulted by the peptide were primarily cholin

  7. Role of cholinergic neurons in the motor effects of glucagon-like peptide-2 in mouse colon.

    Science.gov (United States)

    Amato, Antonella; Rotondo, Alessandra; Cinci, Lorenzo; Baldassano, Sara; Vannucchi, Maria Giuliana; Mulè, Flavia

    2010-11-01

    Glucagon-like peptide-2 (GLP-2) reduces mouse gastric tone and small intestine transit, but its action on large intestine motility is still unknown. The purposes of the present study were 1) to examine the influence of GLP-2 on spontaneous mechanical activity and on neurally evoked responses, by recording intraluminal pressure from mouse isolated colonic segments; 2) to characterize GLP-2 mechanism of action; and 3) to determine the distribution of GLP-2 receptor (GLP-2R) in the mouse colonic muscle coat by immunohistochemistry. Exogenous GLP-2 (0.1-300 nM) induced a concentration-dependent reduction of the spontaneous mechanical activity, which was abolished by the desensitization of GLP-2 receptor or by tetrodotoxin, a voltage-dependent Na(+)-channel blocker. GLP-2 inhibitory effect was not affected by N(ω)-nitro-l-arginine methyl ester (a nitric oxide synthase inhibitor), apamin (a blocker of small conductance Ca(2+)-dependent K(+) channels), or [Lys1,Pro2,5,Arg3,4,Tyr6]VIP(7-28) (a VIP receptor antagonist), but it was prevented by atropine or pertussis toxin (PTX), a G(i/o) protein inhibitor. Proximal colon responses to electrical field stimulation were characterized by nitrergic relaxation, which was followed by cholinergic contraction. GLP-2 reduced only the cholinergic evoked contractions. This effect was almost abolished by GLP-2 receptor desensitization or PTX. GLP-2 failed to affect the contractile responses to exogenous carbachol. GLP-2R immunoreactivity (IR) was detected only in the neuronal cells of both plexuses of the colonic muscle coat. More than 50% of myenteric GLP-2R-IR neurons shared the choline acetyltransferase IR. In conclusion, the activation of GLP-2R located on cholinergic neurons may modulate negatively the colonic spontaneous and electrically evoked contractions through inhibition of acetylcholine release. The effect is mediated by G(i) protein.

  8. 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.

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Directory of Open Access Journals (Sweden)

    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.

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

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    Craig Peter Blomeley

    2015-11-01

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

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

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    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.

  13. Stem cell derived basal forebrain cholinergic neurons from Alzheimer's disease patients are more susceptible to cell death.

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    Duan, Lishu; Bhattacharyya, Bula J; Belmadani, Abdelhak; Pan, Liuliu; Miller, Richard J; Kessler, John A

    2014-01-08

    An early substantial loss of basal forebrain cholinergic neurons (BFCNs) is a constant feature of Alzheimer's disease (AD) and is associated with deficits in spatial learning and memory. Induced pluripotent stem cells (iPSCs) derived from patients with AD as well as from normal controls could be efficiently differentiated into neurons with characteristics of BFCNs. We used BFCNs derived from iPSCs to model sporadic AD with a focus on patients with ApoE3/E4 genotypes (AD-E3/E4). BFCNs derived from AD-E3/E4 patients showed typical AD biochemical features evidenced by increased Aβ42/Aβ40 ratios. AD-E3/E4 neurons also exhibited altered responses to treatment with γ-secretase inhibitors compared to control BFCNs or neurons derived from patients with familial AD. BFCNs from patients with AD-E3/E4 also exhibited increased vulnerability to glutamate-mediated cell death which correlated with increased intracellular free calcium upon glutamate exposure. The ability to generate BFCNs with an AD phenotype is a significant step both for understanding disease mechanisms and for facilitating screening for agents that promote synaptic integrity and neuronal survival.

  14. Pallial origin of basal forebrain cholinergic neurons in the nucleus basalis of Meynert and horizontal limb of the diagonal band nucleus.

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    Pombero, Ana; Bueno, Carlos; Saglietti, Laura; Rodenas, Monica; Guimera, Jordi; Bulfone, Alexandro; Martinez, Salvador

    2011-10-01

    The majority of the cortical cholinergic innervation implicated in attention and memory originates in the nucleus basalis of Meynert and in the horizontal limb of the diagonal band nucleus of the basal prosencephalon. Functional alterations in this system give rise to neuropsychiatric disorders as well as to the cognitive alterations described in Parkinson and Alzheimer's diseases. Despite the functional importance of these basal forebrain cholinergic neurons very little is known about their origin and development. Previous studies suggest that they originate in the medial ganglionic eminence of the telencephalic subpallium; however, our results identified Tbr1-expressing, reelin-positive neurons migrating from the ventral pallium to the subpallium that differentiate into cholinergic neurons in the basal forebrain nuclei projecting to the cortex. Experiments with Tbr1 knockout mice, which lack ventropallial structures, confirmed the pallial origin of cholinergic neurons in Meynert and horizontal diagonal band nuclei. Also, we demonstrate that Fgf8 signaling in the telencephalic midline attracts these neurons from the pallium to follow a tangential migratory route towards the basal forebrain.

  15. The Evolutionarily Conserved LIM Homeodomain Protein LIM-4/LHX6 Specifies the Terminal Identity of a Cholinergic and Peptidergic C. elegans Sensory/Inter/Motor Neuron-Type

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    Choi, Seong-Kyoon; Huh, Yang Hoon; Fang, Zi; Park, Seo Jin; Kim, Myoung Ok; Ryoo, Zae Young; Kang, Kyeongjin; Kweon, Hee-Seok; Jeon, Won Bae; Li, Chris; Kim, Kyuhyung

    2015-01-01

    The expression of specific transcription factors determines the differentiated features of postmitotic neurons. However, the mechanism by which specific molecules determine neuronal cell fate and the extent to which the functions of transcription factors are conserved in evolution are not fully understood. In C. elegans, the cholinergic and peptidergic SMB sensory/inter/motor neurons innervate muscle quadrants in the head and control the amplitude of sinusoidal movement. Here we show that the LIM homeobox protein LIM-4 determines neuronal characteristics of the SMB neurons. In lim-4 mutant animals, expression of terminal differentiation genes, such as the cholinergic gene battery and the flp-12 neuropeptide gene, is completely abolished and thus the function of the SMB neurons is compromised. LIM-4 activity promotes SMB identity by directly regulating the expression of the SMB marker genes via a distinct cis-regulatory motif. Two human LIM-4 orthologs, LHX6 and LHX8, functionally substitute for LIM-4 in C. elegans. Furthermore, C. elegans LIM-4 or human LHX6 can induce cholinergic and peptidergic characteristics in the human neuronal cell lines. Our results indicate that the evolutionarily conserved LIM-4/LHX6 homeodomain proteins function in generation of precise neuronal subtypes. PMID:26305787

  16. Cholinergic and glutamatergic transmission at synapses between pedunculopotine tegmental nucleus axonal terminals and A7 catecholamine cell group noradrenergic neurons in the rat.

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    Li, Meng-Jiyuan; Chang, Tien-Wei; Hung, Wei-Chen; Wu, Chieh-Yi; Luo, Yu-Cheng; Chang, Ting-Hsuan; Lin, Chingju; Yang, Chi-Sheng; Yang, Hsiu-Wen; Min, Ming-Yuan

    2016-11-01

    We characterized transmission from the pedunculopotine tegmental nucleus (PPTg), which contains cholinergic and glutamatergic neurons, at synapses with noradrenergic (NAergic) A7 neurons. Injection of an anterograde neuronal tracer, biotinylated-dextran amine, into the PPTg resulted in labeling of axonal terminals making synaptic connection with NAergic A7 neurons. Consistent with this, extracellular stimulation using a train of 10 pulses at 100 Hz evoked both fast and slow excitatory synaptic currents (EPSCs) that were blocked, respectively, by DNQX, a non-N-methyl-d-aspartate receptor blocker, or atropine, a cholinergic muscarinic receptor (mAChR) blocker. Interestingly, many spontaneous-like, but stimulation-dependent, EPSCs, were seen for up to one second after the end of stimulation and were blocked by DNQX and decreased by EGTA-AM, a membrane permeable form of EGTA, showing they are glutamatergic EPSCs causing by asynchronous release of vesicular quanta. Moreover, application of atropine or carbachol, an mAChR agonist, caused, respectively, an increase in the number of asynchronous EPSCs or a decrease in the frequency of miniature EPSCs, showing that mAChRs mediated presynaptic inhibition of glutamatergic transmission of the PPTg onto NAergic A7 neurons. In conclusion, our data show direct synaptic transmission of PPTg afferents onto pontine NAergic neurons that involves cooperation of cholinergic and glutamatergic transmission. This dual-transmitter transmission drives the firing rate of NAergic neurons, which may correlate with axonal and somatic/dendritic release of NA.

  17. Cholinergic neurons regulate secretion of glial cell line-derived neurotrophic factor by skeletal muscle cells in culture.

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    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.

  18. Preferential entry of botulinum neurotoxin A Hc domain through intestinal crypt cells and targeting to cholinergic neurons of the mouse intestine.

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    Aurélie Couesnon

    Full Text Available Botulism, characterized by flaccid paralysis, commonly results from botulinum neurotoxin (BoNT absorption across the epithelial barrier from the digestive tract and then dissemination through the blood circulation to target autonomic and motor nerve terminals. The trafficking pathway of BoNT/A passage through the intestinal barrier is not yet fully understood. We report that intralumenal administration of purified BoNT/A into mouse ileum segment impaired spontaneous muscle contractions and abolished the smooth muscle contractions evoked by electric field stimulation. Entry of BoNT/A into the mouse upper small intestine was monitored with fluorescent HcA (half C-terminal domain of heavy chain which interacts with cell surface receptor(s. We show that HcA preferentially recognizes a subset of neuroendocrine intestinal crypt cells, which probably represent the entry site of the toxin through the intestinal barrier, then targets specific neurons in the submucosa and later (90-120 min in the musculosa. HcA mainly binds to certain cholinergic neurons of both submucosal and myenteric plexuses, but also recognizes, although to a lower extent, other neuronal cells including glutamatergic and serotoninergic neurons in the submucosa. Intestinal cholinergic neuron targeting by HcA could account for the inhibition of intestinal peristaltism and secretion observed in botulism, but the consequences of the targeting to non-cholinergic neurons remains to be determined.

  19. Pathway for interferon-gamma to promote the differentiation of cholinergic neurons in rat embryonic basal forebrain/septal nuclei

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    BACKGROUND: The supernatant of interferon-gamma (IFN γ ) co-cultured with neonatal rat cortical glia can promote the cells in embryonic basal forebrain/septal nuclei to differentiate into cholinergic neurons, but the mechanism is still unclear.OBJECTIVE: To analyze the pathways for IFN γ to promote the differentiation of primarily cultured cholinergic neurons in rat embryonic basal forebrain/septal nuclei through culture in different conditioned medium.DESIGN: A controlled experiment taking cells as the observational target.SETTINGS: Department of Biochemistry and Molecular Biology, Youjiang Medical College for Nationalities; Department of Cell Biology, Beijing University Health Science Center.MATERIALS: Sixty-four pregnant Wistar rats for 16 days (250 - 350 g) and 84 Wistar rats (either male or female, 5 - 7 g) of 0 - 1 day after birth were provided by the experimental animal department of Beijing University Health Science Center. Rat IFN γ were provided by Gibco Company; Glial fibrillary acidic protein by Huamei Company.METHODS: The experiments were carried out in the Department of Cell Biology, Beijing University Health Science Center and Daheng Image Company of Chinese Academy of Science from July 1995 to December 2002. ① Interventions: The nerve cells in the basal forebrain/septal nuclei of the pregnant Wistar rats for 16 days were primarily cultured, and then divided into four groups: Blank control group (not any supernatant and medium was added); Control group (added by mixed glial cell or astrocyte conditioned medium); IFN γ group (added by mixed glial cell or astrocyte conditioned medium+IFN γ ). Antibody group (added by mixed glial cell or astrocyte conditioned medium+IFN γ +Ab-IFN γ ). Mixed glial cell or astrocyte conditioned medium was prepared using cerebral cortex of Wistar rats of 0 - 1 day after birth. ② Evaluation: The immunohistochemical method was used to perform the choline acetyltransferase (ChAT) staining of cholinergic neurons

  20. 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.

  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. cGMP activates a pH-sensitive leak K+ current in the presumed cholinergic neuron of basal forebrain.

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    Toyoda, Hiroki; Saito, Mitsuru; Sato, Hajime; Dempo, Yoshie; Ohashi, Atsuko; Hirai, Toshihiro; Maeda, Yoshinobu; Kaneko, Takeshi; Kang, Youngnam

    2008-05-01

    In an earlier study, we demonstrated that nitric oxide (NO) causes the long-lasting membrane hyperpolarization in the presumed basal forebrain cholinergic (BFC) neurons by cGMP-PKG-dependent activation of leak K+ currents in slice preparations. In the present study, we investigated the ionic mechanisms underlying the long-lasting membrane hyperpolarization with special interest in the pH sensitivity because 8-Br-cGMP-induced K+ current displayed Goldman-Hodgkin-Katz rectification characteristic of TWIK-related acid-sensitive K+ (TASK) channels. When examined with the ramp command pulse depolarizing from -130 to -40 mV, the presumed BFC neurons displayed a pH-sensitive leak K+ current that was larger in response to pH decrease from 8.3 to 7.3 than in response to pH decrease from 7.3 to 6.3. This K+ current was similar to TASK1 current in its pH sensitivity, whereas it was highly sensitive to Ba(2+), unlike TASK1 current. The 8-Br-cGMP-induced K+ currents in the presumed BFC neurons were almost completely inhibited by lowering external pH to 6.3 as well as by bath application of 100 microM Ba(2+), consistent with the nature of the leak K+ current expressed in the presumed BFC neurons. After 8-Br-cGMP application, the K+ current obtained by pH decrease from 7.3 to 6.3 was larger than that obtained by pH decrease from pH 8.3 to 7.3, contrary to the case seen in the control condition. These observations strongly suggest that 8-Br-cGMP activates a pH- and Ba(2+)-sensitive leak K+ current expressed in the presumed BFC neurons by modulating its pH sensitivity.

  3. Attenuation of cadmium-induced decline in spatial, habituation and recognition memory by long-term administration of almond and walnut supplementation: Role of cholinergic function.

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    Batool, Zehra; Agha, Faiza; Ahmad, Saara; Liaquat, Laraib; Tabassum, Saiqa; Khaliq, Saima; Anis, Lubna; Sajid, Irfan; Emad, Shaista; Perveen, Tahira; Haider, Saida

    2017-01-01

    Excessive exposure of cadmium which is regarded as a neurotoxin can stimulate aging process by inducing abnormality in neuronal function. It has been reported that supplementation of almond and walnut attenuate age-related memory loss. Present study was designed to investigate the weekly administration of cadmium for one month on learning and memory function with relation to cholinergic activity. Cadmium was administered at the dose of 50 mg/kg/week. Whereas, almond and walnut was supplemented at the dose of 400 mg/kg/day along with cadmium administration to separate set of rats. At the end of experiment, memory function was assessed by Morris water maze, open field test and novel object recognition test. Results of the present study showed that cadmium administration significantly reduced memory retention. Reduced acetylcholine levels and elevated acetyl cholinesterase activity were also observed in frontal cortex and hippocampus of cadmium treated rats. Malondialdehyde levels were also significantly increased following the administration of cadmium. Daily supplementation of almond and walnut for 28 days significantly attenuated cadmium-induced memory impairment in rats. Results of the present study are discussed in term of cholinergic activity in cadmium-induced memory loss and its attenuation by nuts supplementation in rats.

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

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    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.

  5. Identification of cholinergic and non-cholinergic neurons in the pons expressing phosphorylated cyclic adenosine monophosphate response element-binding protein as a function of rapid eye movement sleep.

    Science.gov (United States)

    Datta, S; Siwek, D F; Stack, E C

    2009-09-29

    Recent studies have shown that in the pedunculopontine tegmental nucleus (PPT), increased neuronal activity and kainate receptor-mediated activation of intracellular protein kinase A (PKA) are important physiological and molecular steps for the generation of rapid eye movement (REM) sleep. In the present study performed on rats, phosphorylated cyclic AMP response element-binding protein (pCREB) immunostaining was used as a marker for increased intracellular PKA activation and as a reflection of increased neuronal activity. To identify whether activated cells were either cholinergic or noncholinergic, the PPT and laterodorsal tegmental nucleus (LDT) cells were immunostained for choline acetyltransferase (ChAT) in combination with pCREB or c-Fos. The results demonstrated that during high rapid eye movement sleep (HR, approximately 27%), significantly higher numbers of cells expressed pCREB and c-Fos in the PPT, of which 95% of pCREB-expressing cells were ChAT-positive. With HR, the numbers of pCREB-positive cells were also significantly higher in the medial pontine reticular formation (mPRF), pontine reticular nucleus oral (PnO), and dorsal subcoeruleus nucleus (SubCD) but very few in the locus coeruleus (LC) and dorsal raphe nucleus (DRN). Conversely, with low rapid eye movement sleep (LR, approximately 2%), the numbers of pCREB expressing cells were very few in the PPT, mPRF, PnO, and SubCD but significantly higher in the LC and DRN. The results of regression analyses revealed significant positive relationships between the total percentages of REM sleep and numbers of ChAT+/pCREB+ (Rsqr=0.98) cells in the PPT and pCREB+ cells in the mPRF (Rsqr=0.88), PnO (Rsqr=0.87), and SubCD (Rsqr=0.84); whereas significantly negative relationships were associated with the pCREB+ cells in the LC (Rsqr=0.70) and DRN (Rsqr=0.60). These results provide evidence supporting the hypothesis that during REM sleep, the PPT cholinergic neurons are active, whereas the LC and DRN neurons are

  6. The KRUPPEL-like transcription factor DATILOGRAFO is required in specific cholinergic neurons for sexual receptivity in Drosophila females.

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    Joseph Moeller Schinaman

    2014-10-01

    Full Text Available Courtship is a widespread behavior in which one gender conveys to the other a series of cues about their species identity, gender, and suitability as mates. In many species, females decode these male displays and either accept or reject them. Despite the fact that courtship has been investigated for a long time, the genes and circuits that allow females to generate these mutually exclusive responses remain largely unknown. Here, we provide evidence that the Krüppel-like transcription factor datilógrafo (dati is required for proper locomotion and courtship acceptance in adult Drosophila females. dati mutant females are completely unable to decode male courtship and almost invariably reject males. Molecular analyses reveal that dati is broadly expressed in the brain and its specific removal in excitatory cholinergic neurons recapitulates the female courtship behavioral phenotype but not the locomotor deficits, indicating that these are two separable functions. Clonal analyses in female brains identified three discrete foci where dati is required to generate acceptance. These include neurons around the antennal lobe, the lateral horn, and the posterior superior lateral protocerebrum. Together, these results show that dati is required to organize and maintain a relatively simple excitatory circuit in the brain that allows females to either accept or reject courting males.

  7. Low-Affinity Neurotrophin Receptor p75 Promotes the Transduction of Targeted Lentiviral Vectors to Cholinergic Neurons of Rat Basal Forebrain.

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    Antyborzec, Inga; O'Leary, Valerie B; Dolly, James O; Ovsepian, Saak V

    2016-10-01

    Basal forebrain cholinergic neurons (BFCNs) are one of the most affected neuronal types in Alzheimer's disease (AD), with their extensive loss documented at late stages of the pathology. While discriminatory provision of neuroprotective agents and trophic factors to these cells is thought to be of substantial therapeutic potential, the intricate topography and structure of the forebrain cholinergic system imposes a major challenge. To overcome this, we took advantage of the physiological enrichment of BFCNs with a low-affinity p75 neurotrophin receptor (p75(NTR)) for their targeting by lentiviral vectors within the intact brain of adult rat. Herein, a method is described that affords selective and effective transduction of BFCNs with a green fluorescence protein (GFP) reporter, which combines streptavidin-biotin technology with anti-p75(NTR) antibody-coated lentiviral vectors. Specific GFP expression in cholinergic neurons was attained in the medial septum and nuclei of the diagonal band Broca after a single intraventricular administration of such targeted vectors. Bioelectrical activity of GFP-labeled neurons was proven to be unchanged. Thus, proof of principle is obtained for the utility of the low-affinity p75(NTR) for targeted transduction of vectors to BFCNs in vivo.

  8. Acute effects of alcohol on sleep are mediated by components of homeostatic sleep regulatory system: An Editorial Highlight for 'Lesions of the basal forebrain cholinergic neurons attenuates sleepiness and adenosine after alcohol consumption' on page 710.

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    Alam, Md Noor; McGinty, Dennis

    2017-09-01

    Alcohol causes adenosine buildup, which inhibits wake-active neurons via adenosine A1 receptors thus disinhibiting sleep active neurons and also stimulates sleep-active neurons via A2A receptors, causing sleep. This editorial highlights the study entitled, "Lesions of the basal forebrain cholinergic neurons attenuates sleepiness and adenosine after alcohol consumption" by Sharma and colleagues. They report that the wake-promoting basal forebrain (BF) cholinergic neurons play a crucial role in mediating acute alcohol-induced sleep via adenosinergic signaling. © 2017 International Society for Neurochemistry.

  9. The failure in NGF maturation and its increased degradation as the probable cause for the vulnerability of cholinergic neurons in Alzheimer's disease.

    Science.gov (United States)

    Cuello, A Claudio; Bruno, Martin A

    2007-06-01

    This short review discusses the arguments to consider the dismetabolism of the pathway responsible for both the maturation and degradation of NGF as the culprit of vulnerability of the forebrain cholinergic system to the Alzheimer's disease neuropathology. This summary includes information regarding a novel metabolic cascade converting Pro-NGF to mature NGF in the extracellular space and its ultimate degradation by a metalloprotease. It also describes how this pathway is altered in Alzheimer's disease with the consequential CNS accumulation of proNGF and impairment in the formation of NGF along with increased degradation of this key trophic factor. This metabolic scenario in Alzheimer's disease should result in the failure of NGF trophic support to forebrain cholinergic neurons and thus explaining the vulnerability of these neurons in this neurodegenerative condition.

  10. Alterations in the cholinergic system of brain stem neurons in a mouse model of Rett syndrome.

    Science.gov (United States)

    Oginsky, Max F; Cui, Ningren; Zhong, Weiwei; Johnson, Christopher M; Jiang, Chun

    2014-09-15

    Rett syndrome is an autism-spectrum disorder resulting from mutations to the X-linked gene, methyl-CpG binding protein 2 (MeCP2), which causes abnormalities in many systems. It is possible that the body may develop certain compensatory mechanisms to alleviate the abnormalities. The norepinephrine system originating mainly in the locus coeruleus (LC) is defective in Rett syndrome and Mecp2-null mice. LC neurons are subject to modulation by GABA, glutamate, and acetylcholine (ACh), providing an ideal system to test the compensatory hypothesis. Here we show evidence for potential compensatory modulation of LC neurons by post- and presynaptic ACh inputs. We found that the postsynaptic currents of nicotinic ACh receptors (nAChR) were smaller in amplitude and longer in decay time in the Mecp2-null mice than in the wild type. Single-cell PCR analysis showed a decrease in the expression of α3-, α4-, α7-, and β3-subunits and an increase in the α5- and α6-subunits in the mutant mice. The α5-subunit was present in many of the LC neurons with slow-decay nAChR currents. The nicotinic modulation of spontaneous GABAA-ergic inhibitory postsynaptic currents in LC neurons was enhanced in Mecp2-null mice. In contrast, the nAChR manipulation of glutamatergic input to LC neurons was unaffected in both groups of mice. Our current-clamp studies showed that the modulation of LC neurons by ACh input was reduced moderately in Mecp2-null mice, despite the major decrease in nAChR currents, suggesting possible compensatory processes may take place, thus reducing the defects to a lesser extent in LC neurons.

  11. [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.

  12. 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.

  13. Differential actions of orexin receptors in brainstem cholinergic and monoaminergic neurons revealed by receptor knockouts: implications for orexinergic signaling in arousal and narcolepsy

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    Kristi A Kohlmeier

    2013-12-01

    Full Text Available Orexin neuropeptides influence multiple homeostatic functions and play an essential role in the expression of normal sleep-wake behavior. While their two known receptors (OX1 and OX2 are targets for novel pharmacotherapeutics, the actions mediated by each receptor remain largely unexplored. Using brain slices from mice constitutively lacking either receptor, we used whole-cell and Ca2+ imaging methods to delineate the cellular actions of each receptor within cholinergic (laterodorsal tegmental nucleus; LDT and monoaminergic (dorsal raphe; DR and locus coeruleus; LC brainstem nuclei – where orexins promote arousal and suppress REM sleep. In slices from OX2-/- mice, orexin-A (300 nM elicited wild-type responses in LDT, DR and LC neurons consisting of a depolarizing current and augmented voltage-dependent Ca2+ transients. In slices from OX1-/- mice, the depolarizing current was absent in LDT and LC neurons and was attenuated in DR neurons, although Ca2+-transients were still augmented. Since orexin-A produced neither of these actions in slices lacking both receptors, our findings suggest that orexin-mediated depolarization is mediated by both receptors in DR, but is exclusively mediated by OX1 in LDT and LC neurons, even though OX2 is present and OX2 mRNA appears elevated in brainstems from OX1-/- mice. Considering published behavioral data, these findings support a model in which orexin-mediated excitation of mesopontine cholinergic and monoaminergic neurons contributes little to stabilizing spontaneous waking and sleep bouts, but functions in context-dependent arousal and helps restrict muscle atonia to REM sleep. The augmented Ca2± transients mediated by both receptors appeared mediated by influx via L-type Ca2+ channels, which is often linked to transcriptional signaling. This could provide an adaptive signal to compensate for receptor loss or prolonged antagonism and may contribute to the reduced severity of narcolepsy in single receptor

  14. 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

  15. 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.

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

    Science.gov (United States)

    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.

  17. Laser Acupuncture at HT7 Acupoint Improves Cognitive Deficit, Neuronal Loss, Oxidative Stress, and Functions of Cholinergic and Dopaminergic Systems in Animal Model of Parkinson's Disease.

    Science.gov (United States)

    Wattanathorn, Jintanaporn; Sutalangka, Chatchada

    2014-01-01

    To date, the therapeutic strategy against cognitive impairment in Parkinson's disease (PD) is still not in satisfaction level and requires novel effective intervention. Based the oxidative stress reduction and cognitive enhancement induced by laser acupuncture at HT7, the beneficial effect of laser acupuncture at HT7 against cognitive impairment in PD has been focused. In this study, we aimed to determine the effect of laser acupuncture at HT7 on memory impairment, oxidative stress status, and the functions of both cholinergic and dopaminergic systems in hippocampus of animal model of PD. Male Wistar rats, weighing 180-220 g, were induced unilateral lesion at right substantianigra by 6-OHDA and were treated with laser acupuncture continuously at a period of 14 days. The results showed that laser acupuncture at HT7 enhanced memory and neuron density in CA3 and dentate gyrus. The decreased AChE, MAO-B, and MDA together with increased GSH-Px in hippocampus of a 6-OHDA lesion rats were also observed. In conclusion, laser acupuncture at HT7 can improve neuron degeneration and memory impairment in animal model of PD partly via the decreased oxidative stress and the improved cholinergic and dopaminergic functions. More researches concerning effect of treatment duration are still required.

  18. 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

  19. 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.

  20. Smad-dependent alterations of PPT cholinergic neurons as a pathophysiological mechanism of age-related sleep-dependent memory impairments.

    Science.gov (United States)

    George, O; Parducz, A; Dupret, D; Kharouby, M; Le Moal, M; Piazza, P V; Mayo, W

    2006-12-01

    In humans, memory impairments are highly prevalent in the aged population, but their functional and structural origins are still unknown. We hypothesized that circadian rhythm alterations may predict spatial memory impairment in aged rats. We demonstrate an association between sleep/wake circadian rhythm disturbances (non-REM sleep fragmentation) and spatial memory impairments in aged rats. We show by light and electron microscopy that these age-related disruptions in circadian rhythm and spatial memory are also associated with degeneration of cholinergic neurons of the pedunculopontine nucleus (PPT), a structure known to be involved in sleep and cognitive functions and which is altered during aging. Finally, we demonstrate that a trophic deregulation of the PPT occur in aged impaired rats, involving an over activation of the TGFbeta-Smad cascade, a signalling pathway involved in neurodegeneration. In conclusion these results provide a new pathophysiological mechanism for age-related sleep-dependent memory impairments opening the ground for the development of new therapeutic approaches of these pathologies.

  1. A protein phosphatase is involved in the cholinergic suppression of the Ca(2+)-activated K(+) current sI(AHP) in hippocampal pyramidal neurons.

    Science.gov (United States)

    Krause, M; Pedarzani, P

    2000-04-27

    The slow calcium-activated potassium current sI(AHP) underlies spike-frequency adaptation and has a substantial impact on the excitability of hippocampal CA1 pyramidal neurons. Among other neuromodulatory substances, sI(AHP) is modulated by acetylcholine acting via muscarinic receptors. The second-messenger systems mediating the suppression of sI(AHP) by muscarinic agonists are largely unknown. Both protein kinase C and A do not seem to be involved, whereas calcium calmodulin kinase II has been shown to take part in the muscarinic action on sI(AHP). We re-examined the mechanism of action of muscarinic agonists on sI(AHP) combining whole-cell recordings with the use of specific inhibitors or activators of putative constituents of the muscarinic pathway. Our results suggest that activation of muscarinic receptors reduces sI(AHP) in a G-protein-mediated and phospholipase C-independent manner. Furthermore, we obtained evidence for the involvement of the cGMP-cGK pathway and of a protein phosphatase in the cholinergic suppression of sI(AHP), whereas release of Ca(2+) from IP(3)-sensitive stores seems to be relevant neither for maintenance nor for modulation of sI(AHP).

  2. 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.

    Science.gov (United States)

    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.

  3. Behavioral decline and premature lethality upon pan-neuronal ferritin overexpression in Drosophila infected with a virulent form of Wolbachia.

    Directory of Open Access Journals (Sweden)

    Stylianos eKosmidis

    2014-04-01

    Full Text Available Iron is required for organismal growth. Therefore, limiting iron availability may be a key part of the host’s innate immune response to various pathogens, for example in Drosophila infected with Zygomycetes. One way the host can transiently reduce iron bioavailability is by ferritin overexpression. To study the effects of neuronal-specific ferritin overexpression on survival and neurodegeneration we generated flies simultaneously over-expressing transgenes for both ferritin subunits in all neurons. We used two independent recombinant chromosomes bearing UAS-Fer1HCH, UAS-Fer2LCH transgenes and obtained qualitatively different levels of late-onset behavioral and lifespan declines. We subsequently discovered that one parental strain had been infected with a virulent form of the bacterial endosymbiont Wolbachia, causing widespread neuronal apoptosis and premature death. This phenotype was exacerbated by ferritin overexpression and was curable by antibiotic treatment. Neuronal ferritin overexpression in uninfected flies did not cause evident neurodegeneration but resulted in a late-onset behavioral decline, as previously reported for ferritin overexpression in glia. The results suggest that ferritin overexpression in the central nervous system of flies is tolerated well in young individuals with adverse manifestations appearing only late in life or under unrelated pathophysiological conditions.

  4. 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.

  5. Treatment of beta amyloid 1–42 (Aβ1–42)-induced basal forebrain cholinergic damage by a non-classical estrogen signaling activator in vivo

    Science.gov (United States)

    Kwakowsky, Andrea; Potapov, Kyoko; Kim, SooHyun; Peppercorn, Katie; Tate, Warren P.; Ábrahám, István M.

    2016-01-01

    In Alzheimer’s disease (AD), there is a loss in cholinergic innervation targets of basal forebrain which has been implicated in substantial cognitive decline. Amyloid beta peptide (Aβ1–42) accumulates in AD that is highly toxic for basal forebrain cholinergic (BFC) neurons. Although the gonadal steroid estradiol is neuroprotective, the administration is associated with risk of off-target effects. Previous findings suggested that non-classical estradiol action on intracellular signaling pathways has ameliorative potential without estrogenic side effects. After Aβ1–42 injection into mouse basal forebrain, a single dose of 4-estren-3α, 17β-diol (estren), the non-classical estradiol pathway activator, restored loss of cholinergic cortical projections and also attenuated the Aβ1–42-induced learning deficits. Estren rapidly and directly phosphorylates c-AMP-response–element-binding-protein and extracellular-signal-regulated-kinase-1/2 in BFC neurons and restores the cholinergic fibers via estrogen receptor-α. These findings indicated that selective activation of non-classical intracellular estrogen signaling has a potential to treat the damage of cholinergic neurons in AD. PMID:26879842

  6. Amyloid burden, neuronal function, and cognitive decline in middle-aged adults at risk for Alzheimer's disease.

    Science.gov (United States)

    Okonkwo, Ozioma C; Oh, Jennifer M; Koscik, Rebecca; Jonaitis, Erin; Cleary, Caitlin A; Dowling, N Maritza; Bendlin, Barbara B; Larue, Asenath; Hermann, Bruce P; Barnhart, Todd E; Murali, Dhanabalan; Rowley, Howard A; Carlsson, Cynthia M; Gallagher, Catherine L; Asthana, Sanjay; Sager, Mark A; Christian, Brad T; Johnson, Sterling C

    2014-04-01

    The relative influence of amyloid burden, neuronal structure and function, and prior cognitive performance on prospective memory decline among asymptomatic late middle-aged individuals at risk for Alzheimer's disease (AD) is currently unknown. We investigated this using longitudinal cognitive data from 122 middle-aged adults (21 "Decliners" and 101 "Stables") enrolled in the Wisconsin Registry for Alzheimer's Prevention who underwent multimodality neuroimaging [11C-Pittsburgh Compound B (PiB), 18F-fluorodeoxyglucose (FDG), and structural/functional magnetic resonance imaging (fMRI)] 5.7 ± 1.4 years (range = 2.9-8.9) after their baseline cognitive assessment. Covariate-adjusted regression analyses revealed that the only imaging measure that significantly distinguished Decliners from Stables (p = .027) was a Neuronal Function composite derived from FDG and fMRI. In contrast, several cognitive measures, especially those that tap episodic memory, significantly distinguished the groups (p's<.05). Complementary receiver operating characteristic curve analyses identified the Brief Visuospatial Memory Test-Revised (BVMT-R) Total (.82 ± .05, p < .001), the BVMT-R Delayed Recall (.73 ± .06, p = .001), and the Reading subtest from the Wide-Range Achievement Test-III (.72 ± .06, p = .002) as the top three measures that best discriminated the groups. These findings suggest that early memory test performance might serve a more clinically pivotal role in forecasting future cognitive course than is currently presumed.

  7. Changes in hippocampal volume and neuron number co-occur with memory decline in old homing pigeons (Columba livia).

    Science.gov (United States)

    Coppola, Vincent J; Kanyok, Nate; Schreiber, Austin J; Flaim, Mary E; Bingman, Verner P

    2016-05-01

    The mammalian hippocampus is particularly susceptible to age-related structural changes, which have been used to explain, in part, age-related memory decline. These changes are generally characterized by atrophy (e.g., a decrease in volume and number of synaptic contacts). Recent studies have reported age-related spatial memory deficits in older pigeons similar to those seen in older mammals. However, to date, little is known about any co-occurring changes in the aging avian hippocampal formation (HF). In the current study, it was found that the HF of older pigeons was actually larger and contained more neurons than the HF of younger pigeons, a finding that suggests that the pattern of structural changes during aging in the avian HF is different from that seen in the mammalian hippocampus. A working hypothesis for relating the observed structural changes with spatial-cognitive decline is offered.

  8. Amyloid burden, neuronal function, and cognitive decline in middle-aged adults at risk for Alzheimer’s disease

    Science.gov (United States)

    Okonkwo, Ozioma C.; Oh, Jennifer M.; Koscik, Rebecca; Jonaitis, Erin; Cleary, Caitlin A.; Dowling, N. Maritza; Bendlin, Barbara B.; LaRue, Asenath; Hermann, Bruce P.; Barnhart, Todd E.; Murali, Dhanabalan; Rowley, Howard A.; Carlsson, Cynthia M.; Gallagher, Catherine L.; Asthana, Sanjay; Sager, Mark A.; Christian, Brad T.; Johnson, Sterling C.

    2014-01-01

    The relative influence of amyloid burden, neuronal structure and function, and prior cognitive performance on prospective memory decline among asymptomatic late middle-aged individuals at risk for Alzheimer’s disease (AD) is currently unknown. We investigated this using longitudinal cognitive data from 122 middle-aged adults (21 “Decliners” and 101 “Stables”) enrolled in the Wisconsin Registry for Alzheimer’s Prevention who underwent multimodality neuroimaging (11C-Pittsburgh Compound B (PiB), 18F-fluorodeoxyglucose (FDG), and structural/functional MRI) 5.7±1.4 years (range=2.9–8.9) after their baseline cognitive assessment. Covariate-adjusted regression analyses revealed that the only imaging measure that significantly distinguished Decliners from Stables (p=.027) was a Neuronal Function composite derived from FDG and fMRI. In contrast, several cognitive measures, especially those that tap episodic memory, significantly distinguished the groups (p’s < .05). Complementary receiver operating characteristic curve analyses identified the Brief Visuospatial Memory Test-Revised (BVMT-R) Total (.82±.05, p<.001), the BVMT-R Delayed Recall (.73±.06, p=.001), and the Reading subtest from the Wide-Range Achievement Test-III (.72±.06, p=.002) as the top three measures that best discriminated the groups. These findings suggest that early memory test performance might serve a more clinically-pivotal role in forecasting future cognitive course than is currently presumed. PMID:24621494

  9. Highly efficient generation of glutamatergic/cholinergic NT2-derived postmitotic human neurons by short-term treatment with the nucleoside analogue cytosine β-d-arabinofuranoside

    Directory of Open Access Journals (Sweden)

    Imanol González-Burguera

    2016-03-01

    Taken together, our results further reinforce the notion NT2 cells are a versatile source of neuronal phenotypes and provide a new encouraging platform for studying mechanisms of neuronal differentiation and for exploring neuronal replacement strategies.

  10. 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.

  11. Anti-allergic role of cholinergic neuronal pathway via α7 nicotinic ACh receptors on mucosal mast cells in a murine food allergy model.

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    Takeshi Yamamoto

    Full Text Available The prevalence of food allergy (FA has increased in developed countries over the past few decades. However, no effective drug therapies are currently available. Therefore, we investigated cholinergic anti-inflammatory pathway as a regulatory system to ameliorate disrupted mucosal immune homeostasis in the gut based on the pathophysiological elucidation of mucosal mast cells (MMCs in a murine FA model. BALB/c mice sensitized with ovalbumin received repeated oral ovalbumin for the development of FA. FA mice developed severe allergic diarrhea and exhibited enhanced type 2 helper T (Th2 cell immune responses in both systemic immunity and mucosal immunity, along with MMCs hyperplasia in the colon. MMCs were localized primarily in the strategic position of the mucosal epithelium. Furthermore, the allergic symptoms did not develop in p85α disrupted phosphoinositide-3 kinase-deficient mice that lacked mast cells in the gut. Vagal stimulation by 2-deoxy-D-glucose and drug treatment with nicotinic ACh receptor (nAChR agonists (nicotine and α7 nAChR agonist GTS-21 alleviated the allergic symptoms in the FA mice. Nicotine treatment suppressed MMCs hyperplasia, enhanced MPO and upregulated mRNA expression of Th1 and Th2 cytokines in the FA mice colon. MMCs, which are negatively regulated by α7 nAChRs, were often located in close proximity to cholinergic CGRP-immunoreactive nerve fibers in the FA mice colon. The present results reveal that the cholinergic neuroimmune interaction via α7 nAChRs on MMCs is largely involved in maintaining intestinal immune homeostasis and can be a target for a new therapy against mucosal immune diseases with homeostatic disturbances such as FA.

  12. 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.

  13. Substitution of natural sensory input by artificial neurostimulation of an amputated trigeminal nerve does not prevent the degeneration of basal forebrain cholinergic circuits projecting to the somatosensory cortex

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    Celia eHerrera-Rincon

    2014-11-01

    Full Text Available Peripheral deafferentation downregulates acetylcholine (ACh synthesis in sensory cortices. However the responsible neural circuits and processes are not known. We irreversibly transected the rat infraorbital nerve and implanted neuroprosthetic microdevices for proximal stump stimulation, and assessed cytochrome-oxidase and choline- acetyl-transferase (ChAT in somatosensory, auditory and visual cortices; estimated the number and density of ACh-neurons in the magnocellular basal nucleus (MBN; and localized down-regulated ACh-neurons in basal forebrain using retrograde labeling from deafferented cortices. Here we show that nerve transection, causes down regulation of MBN cholinergic neurons. Stimulation of the cut nerve reverses the metabolic decline but does not affect the decrease in cholinergic fibers in cortex or cholinergic neurons in basal forebrain. Artifical stimulation of the nerve also has no affect of ACh-innervation of other cortices. Cortical ChAT depletion is due to loss of corticopetal MBN ChAT-expressing neurons. MBN ChAT downregulation is not due to decrease neither of afferent activity nor to failure of trophic support. Basalocortical ACh circuits are sensory specific, ACh is provided to each sensory cortex on demand by dedicated circuits. Our data support the existence of a modality-specific cortex-MBN-cortex circuit for cognitive information processing.

  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. Presence of a non-neuronal cholinergic system and occurrence of up- and down-regulation in expression of M2 muscarinic acetylcholine receptors: new aspects of importance regarding Achilles tendon tendinosis (tendinopathy).

    Science.gov (United States)

    Bjur, Dennis; Danielson, Patrik; Alfredson, Håkan; Forsgren, Sture

    2008-02-01

    Limited information is available concerning the existence of a cholinergic system in the human Achilles tendon. We have studied pain-free normal Achilles tendons and chronically painful Achilles tendinosis tendons with regard to immunohistochemical expression patterns of the M(2) muscarinic acetylcholine receptor (M(2)R), choline acetyltransferase (ChAT), and vesicular acetylcholine transporter (VAChT). M(2)R immunoreactivity was detected in the walls of blood vessels. As evidenced via parallel staining for CD31 and alpha-smooth muscle actin, most M(2)R immunoreactivity was present in the endothelium. M(2)R immunoreactivity also occured in tenocytes, which regularly immunoreact for vimentin. The degree of M(2)R immunoreactivity was highly variable, tendinosis tendons that exhibit hypercellularity and hypervascularity showing the highest levels of immunostaining. Immunoreaction for ChAT and VAChT was detected in tenocytes in tendinosis specimens, particularly in aberrant cells. In situ hybridization revealed that mRNA for ChAT is present in tenocytes in tendinosis specimens. Our results suggest that autocrine/paracrine effects occur concerning the tenocytes in tendinosis. Up-regulation/down-regulation in the levels of M(2)R immunoreactivity possibly take place in tenocytes and blood vessel cells during the various stages of tendinosis. The presumed local production of acetylcholine (ACh), as evidenced by immunoreactivity for ChAT and VAChT and the detection of ChAT mRNA, appears to evolve in response to tendinosis. These observations are of importance because of the well-known vasoactive, trophic, and pain-modulating effects that ACh is known to have and do unexpectedly establish the presence of a non-neuronal cholinergic system in the Achilles tendon.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. Central cholinergic regulation of respiration: nicotinic receptors

    Institute of Scientific and Technical Information of China (English)

    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. Decline in Proliferation and Immature Neuron Markers in the Human Subependymal Zone during Aging: Relationship to EGF- and FGF-related Transcripts

    Directory of Open Access Journals (Sweden)

    Christin Weissleder

    2016-11-01

    Full Text Available Neuroblasts exist within the human subependymal zone (SEZ; however, it is debated to what extent neurogenesis changes during normal aging. It is also unknown how precursor proliferation may correlate with the generation of neuronal and glial cells or how expression of growth factors and receptors may change throughout the adult lifespan. We provided evidence of dividing cells in the human SEZ in conjunction with a dramatic age-related decline (n=50; 21-103 years of mRNAs indicative of proliferating cells (Ki67 and immature neurons (doublecortin. Microglia mRNA (ionized calcium-binding adapter molecule 1 increased during aging, whereas transcript levels of stem/precursor cells (glial fibrillary acidic protein delta and achaete-scute homolog 1, astrocytes (vimentin and glial fibrillary acidic protein and oligodendrocytes (oligodendrocyte lineage transcription factor 2 remained stable. Epidermal growth factor receptor (EGFR and fibroblast growth factor 2 (FGF2 mRNAs increased throughout adulthood, while transforming growth factor alpha (TGFα, EGF, Erb-B2 receptor tyrosine kinase 4 (ErbB4 and FGF receptor 1 (FGFR1 mRNAs were unchanged across adulthood. Cell proliferation mRNA positively correlated with FGFR1 transcripts. Immature neuron and oligodendrocyte expression positively correlated with TGFα and ErbB4 mRNAs, whilst astrocyte transcripts positively correlated with EGF, FGF2 and FGFR1 mRNAs. Microglia mRNA positively correlated with EGF and FGF2 expression. Our findings indicate that neurogenesis in the human SEZ continues well into adulthood, although proliferation and neuronal differentiation may decline across adulthood. We suggest that mRNA expression of EGF- and FGF-related family members do not become limited during aging and may modulate neuronal and glial fate determination in the SEZ throughout human life.

  4. 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.

  5. Phospholipase A2 - nexus of aging, oxidative stress, neuronal excitability and functional decline of the aging nervous system? Insights from a snail model system of neuronal aging and age-associated memory impairment.

    Directory of Open Access Journals (Sweden)

    Petra Maria Hermann

    2014-12-01

    Full Text Available TThe aging brain can undergo a range of changes varying from subtle structural and physiological changes causing only minor functional decline under healthy normal aging conditions, to severe cognitive or neurological impairment associated with extensive loss of neurons and circuits due to age-associated neurodegenerative disease conditions. Understanding how biological aging processes affect the brain and how they contribute to the onset and progress of age-associated neurodegenerative diseases is a core research goal in contemporary neuroscience. This review focuses on the idea that changes in intrinsic neuronal electrical excitability associated with (peroxidation of membrane lipids and activation of phospholipase A2 (PLA2 enzymes are an important mechanism of learning and memory failure under normal aging conditions. Specifically, in the context of this special issue on the Biology of cognitive aging we (1 portray the opportunities offered by the identifiable neurons and behaviorally characterized neural circuits of the freshwater snail Lymnaea stagnalis in neuronal aging research and (2 recapitulate recent insights indicating a key role of lipid peroxidation-induced PLA2 as instruments of aging, oxidative stress and inflammation in age-associated neuronal and memory impairment in this model system. The findings are discussed in view of accumulating evidence suggesting involvement of analogous mechanisms in the etiology of age-associated dysfunction and disease of the human and mammalian brain.

  6. PKA and cAMP/CNG Channels Independently Regulate the Cholinergic Ca2+-Response of Drosophila Mushroom Body Neurons1,2,3

    Science.gov (United States)

    Pavot, Pierre; Carbognin, Elena

    2015-01-01

    Abstract The mushroom bodies (MBs), one of the main structures in the adult insect brain, play a critical role in olfactory learning and memory. Though historical genes such as dunce and rutabaga, which regulate the level of cAMP, were identified more than 30 years ago, their in vivo effects on cellular and physiological mechanisms and particularly on the Ca2+-responses still remain largely unknown. In this work, performed in Drosophila, we took advantage of in vivo bioluminescence imaging, which allowed real-time monitoring of the entire MBs (both the calyx/cell-bodies and the lobes) simultaneously. We imaged neuronal Ca2+-activity continuously, over a long time period, and characterized the nicotine-evoked Ca2+-response. Using both genetics and pharmacological approaches to interfere with different components of the cAMP signaling pathway, we first show that the Ca2+-response is proportional to the levels of cAMP. Second, we reveal that an acute change in cAMP levels is sufficient to trigger a Ca2+-response. Third, genetic manipulation of protein kinase A (PKA), a direct effector of cAMP, suggests that cAMP also has PKA-independent effects through the cyclic nucleotide-gated Ca2+-channel (CNG). Finally, the disruption of calmodulin, one of the main regulators of the rutabaga adenylate cyclase (AC), yields different effects in the calyx/cell-bodies and in the lobes, suggesting a differential and regionalized regulation of AC. Our results provide insights into the complex Ca2+-response in the MBs, leading to the conclusion that cAMP modulates the Ca2+-responses through both PKA-dependent and -independent mechanisms, the latter through CNG-channels. PMID:26464971

  7. Protective effects of panax notoginseng saponins on cholinergic neurons in rats with Alzheimer disease%三七总皂苷对阿尔茨海默病大鼠脑胆碱能神经的保护作用

    Institute of Scientific and Technical Information of China (English)

    钟振国; 屈泽强; 王乃平; 王进声; 谢智光; 张凤芬; 张雯艳; 卢忠朋

    2006-01-01

    .④采用单因素方差分析进行计量资料间差异比较.主要观察指标:三七总皂苷对阿尔茨海默病大脑胆碱能神经元分布和胆碱乙酰基转移酶的影响.结果:老年大鼠75只和青年大鼠15只均进入结果分析.①青年对照组胆碱乙酰转移酶免疫阳性神经元最多,免疫阳性物质染色最深;三七总皂苷高剂量组免疫阳性神经元明显多于石杉碱甲组和模型组;模型组免疫阳性神经元较其他各组的神经元小,且数目明显减少,胞体的轴突及树突变短.②基底前脑胆碱乙酰转移酶免疫阳性细胞数:模型组明显少于其他各组(P<0.05),三七总皂苷低剂量组、石杉碱甲组、模型组明显少于老年对照组(P<0.05),石杉碱甲组、模型组明显少于三七总皂苷高、低剂量组(P<0.05),青年对照组明显高于其他各组(P<0.05).基底前脑胆碱乙酰转移酶免疫阳性细胞平均A值:变化与各组免疫阳性细胞数变化基本相同.基底前脑胆碱乙酰转移酶免疫阳性细胞平均截面积:三七总皂苷低剂量组和模型组明显小于青年对照组(P<0.05),其他各组间差异不明显(P>0.05).结论:三七总皂苷对老年性痴呆大鼠动物模型大脑胆碱能神经元具有较强的保护作用,通过改善和修复受损神经元而提高细胞存活的数量和质量、提高胆碱乙酰转移酶的含量和活性,从而保护和改善中枢胆碱能系统的功能,发挥抗老化、抗痴呆的作用.%BACKGROUND: There are no effective methods to cure Alzheimer disease (AD). Now, researches have shown that panax notoginseng saponins (PNS) play an important role in improving AD, but its mechanism is unclear.OBJECTIVE: To observe the protective effect of PNS characterized by removing blood stasis to stop bleeding and promoting blood circulation to relieve pain on pathological lesion of cholinergic neuron in rat with AD.DESIGN: Completely randomized grouping design and controlled study

  8. 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.

  9. 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.

  10. AF64A诱导的大鼠大缝际核胆碱能神经损伤改变吗啡的镇痛作用%Effect of morphine-induced antinociception is altered by AF64A-induced lesions on cholinergic neurons in rat nucleus raphe magnus

    Institute of Scientific and Technical Information of China (English)

    Kenji ABE; Kota ISHIDA; Masatoshi KATO; Toshiro SHIGENAGA; Kyoji TAGUCHI; Tadashi MIYATAKE

    2002-01-01

    AIM: To examine the role of cholinergic neurons in the nucleus raphe magnus (NRM) in noxious heat stimulationand in the effects of morphine-induced antinociception by rats. METHODS: After the cholinergic neuron selectivetoxin, AF64A, was microinjected into the NRM, we examined changes in the antinociceptive threshold and effectsof morphine (5 mg/kg, ip) using the hot-plate (HP) and tail-flick (TF) tests. RESULTS: Systemic administration ofmorphine inhibited HP and TF responses in control rats. Microinjection of AF64A (2 nmol/site) into the NRMsignificantly decreased the threshold of HP response after 14 d, whereas the TF response was not affected. Mor-phine-induced antinociception was significantly attenuated in rats administered AF64A. Extracellular acetylcholinewas attenuated after 14 d to below detectable levels in rats given AF64A. Naloxone (1 μg/site) microinjected intocontrol rat NRM also antagonized the antinociceptive effect of systemic morphine. CONCLUSION: These find-ings suggest that cbolinergic neuron activation in the NRM modulates the antinociceptive effect of morphine simul-taneously with the opiate system.

  11. 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.

  12. [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.

  13. 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.

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

    Science.gov (United States)

    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

  15. 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.

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

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    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.

  17. 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.

  18. Somatic expression of unc-54 and vha-6 mRNAs declines but not pan-neuronal rgef-1 and unc-119 expression in aging Caenorhabditis elegans.

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    Adamla, Frauke; Ignatova, Zoya

    2015-06-02

    Aging is a highly controlled biological process characterized by a progressive deterioration of various cellular activities. One of several hallmarks of aging describes a link to transcriptional alteration, suggesting that it may impact the steady-state mRNA levels. We analyzed the mRNA steady-state levels of polyCAG-encoding transgenes and endogenous genes under the control of well-characterized promoters for intestinal (vha-6), muscular (unc-54, unc-15) and pan-neuronal (rgef-1, unc-119) expression in the nematode Caenorhabditis elegans. We find that there is not a uniform change in transcriptional profile in aging, but rather a tissue-specific difference in the mRNA levels of these genes. While levels of mRNA in the intestine (vha-6) and muscular (unc-54, unc-15) cells decline with age, pan-neuronal tissue shows more stable mRNA expression (rgef-1, unc-119) which even slightly increases with the age of the animals. Our data on the variations in the mRNA abundance from exemplary cases of endogenous and transgenic gene expression contribute to the emerging evidence for tissue-specific variations in the aging process.

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

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    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.

  20. Age-related hearing loss: prevention of threshold declines, cell loss and apoptosis in spiral ganglion neurons

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    Zhu, Xiaoxia; Walton, Joseph P.

    2016-01-01

    Age-related hearing loss (ARHL) -presbycusis - is the most prevalent neurodegenerative disease and number one communication disorder of our aged population; and affects hundreds of millions of people worldwide. Its prevalence is close to that of cardiovascular disease and arthritis, and can be a precursor to dementia. The auditory perceptual dysfunction is well understood, but knowledge of the biological bases of ARHL is still somewhat lacking. Surprisingly, there are no FDA-approved drugs for treatment. Based on our previous studies of human subjects, where we discovered relations between serum aldosterone levels and the severity of ARHL, we treated middle age mice with aldosterone, which normally declines with age in all mammals. We found that hearing thresholds and suprathreshold responses significantly improved in the aldosterone-treated mice compared to the non-treatment group. In terms of cellular and molecular mechanisms underlying this therapeutic effect, additional experiments revealed that spiral ganglion cell survival was significantly improved, mineralocorticoid receptors were upregulated via post-translational protein modifications, and age-related intrinsic and extrinsic apoptotic pathways were blocked by the aldosterone therapy. Taken together, these novel findings pave the way for translational drug development towards the first medication to prevent the progression of ARHL. PMID:27667674

  1. Muscarinic and dopaminergic receptor subtypes on striatal cholinergic interneurons

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    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.

  2. Choline acetyltransferase-containing neurons in the human parietal neocortex

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    V Benagiano

    2009-06-01

    Full Text Available A number of immunocytochemical studies have indicated the presence of cholinergic neurons in the cerebral cortex of various species of mammals. Whether such cholinergic neurons in the human cerebral cortex are exclusively of subcortical origin is still debated. In this immunocytochemical study, the existence of cortical cholinergic neurons was investigated on surgical samples of human parietal association neocortex using a highly specific monoclonal antibody against choline acetyltransferase (ChAT, the acetylcholine biosynthesising enzyme. ChAT immunoreactivity was detected in a subpopulation of neurons located in layers II and III. These were small or medium-sized pyramidal neurons which showed cytoplasmic immunoreactivity in the perikarya and processes, often in close association to blood microvessels. This study, providing demonstration of ChAT neurons in the human parietal neocortex, strongly supports the existence of intrinsic cholinergic innervation of the human neocortex. It is likely that these neurons contribute to the cholinergic innervation of the intracortical microvessels.

  3. 新生大鼠海马源性神经干细胞的分离培养及其向胆碱能神经元定向诱导分化研究%ISOLATION OF NEURAL STEM CELLS FROM NEONATAL RAT HIPPOCAMPUS AND THEIR IN VITRO DIFFERENTIATION INTO CHOLINERGIC NEURONS

    Institute of Scientific and Technical Information of China (English)

    罗湘颖; 杨志敏; 宋晓斌; 刘苏; 赵匡彦; 冯忠堂; 王廷华

    2005-01-01

    The present study aims to isolate neural stem cells from neonatal rat hippocampus and induce them to differentiate into cholinergic neurons. A multipotent cell line derived from the hippocampi of neonatal rats which had the ability to form clones was incubated in serum-free DMEM/F12 medium added with 20ng/ml basic fibroblast growth factor (bFGF) and B27. After differentiation of the neural stem cells, immunocytochemistry was used to detect nestin, the antigen of the cell clone, and β-tubulin (Tuj 1 ), glial fibrillary acidic protein (GFAP) and galactocerebroside (Galc), the markers specific for neurons, astrocytes and oligodendrocytes, respectively. Embryonic chick skeletal muscle extract was used to induce the differentiation of the neural stem cells into cholinergic neurons. The results showed that the cell line isolated from the hippocampi of neonatal rats expressed nestin and had the potential to form clones and differentiate into neurons, astrocytes and oligodendrocytes. Embryonic chick skeletal muscle extract can induce 9.6% of the isolated cell line to differentiate into cholinergic neurons compared with 3.9% in controls. These findings suggested that the cell line, which expressed nestin antigen, was a multipotent cell line capable of self-renewing, and was believed to contain stem cells of the CNS. These neural stem cells can be induced to differentiate into cholinergic neurons by using embryonic chick skeletal muscle extract.%本研究目的是从新生SD大鼠海马分离、培养神经干细胞并诱导其向胆碱能神经元方向分化.利用含b-FGF(20 ng/ml)和B27的无血清DMEM/F12培养基培养新生SD大鼠海马分离的具有自我更新和多向分化能力的细胞群,用免疫细胞化学技术检测巢蛋白(nestin),并于分化后分别检查特异性成熟神经细胞、星形胶质细胞、少突胶质细胞的标记抗原β-微管蛋白(Tuj1)、胶质纤维酸性蛋白(GFAP)和半乳糖脑苷脂(Galc)的表达;用鸡胚骨骼肌提

  4. Neuronal histamine and cognitive symptoms in Alzheimer's disease.

    Science.gov (United States)

    Zlomuzica, Armin; Dere, Dorothea; Binder, Sonja; De Souza Silva, Maria Angelica; Huston, Joseph P; Dere, Ekrem

    2016-07-01

    Alzheimer's disease is a neurodegenerative disorder characterized by extracellular amyloid plaque deposits, mainly composed of amyloid-beta peptide and intracellular neurofibrillary tangles consisting of aggregated hyperphosphorylated tau protein. Amyloid-beta represents a neurotoxic proteolytic cleavage product of amyloid precursor protein. The progressive cognitive decline that is associated with Alzheimer's disease has been mainly attributed to a deficit in cholinergic neurotransmission due to the continuous degeneration of cholinergic neurons e.g. in the basal forebrain. There is evidence suggesting that other neurotransmitter systems including neuronal histamine also contribute to the development and maintenance of Alzheimer's disease-related cognitive deficits. Pathological changes in the neuronal histaminergic system of such patients are highly predictive of ensuing cognitive deficits. Furthermore, histamine-related drugs, including histamine 3 receptor antagonists, have been demonstrated to alleviate cognitive symptoms in Alzheimer's disease. This review summarizes findings from animal and clinical research on the relationship between the neuronal histaminergic system and cognitive deterioration in Alzheimer's disease. The significance of the neuronal histaminergic system as a promising target for the development of more effective drugs for the treatment of cognitive symptoms is discussed. Furthermore, the option to use histamine-related agents as neurogenesis-stimulating therapy that counteracts progressive brain atrophy in Alzheimer's disease is considered. This article is part of a Special Issue entitled 'Histamine Receptors'.

  5. 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.

  6. 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.

  7. 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

  8. Effects of bone morphogenetic proteins 2 on neural stem cells of 14-day-old fetal rat telencephalon differentiating into cholinergic neurons%骨形态发生蛋白2对14d胎鼠端脑神经干细胞分化为胆碱能神经元的影响

    Institute of Scientific and Technical Information of China (English)

    梁军; 李明秋; 赵富生; 董建将; 李月珍

    2011-01-01

    BACKGROUND: Bone morphogenetic protein-2 (BMP2) may be an extracellular regulatory factor involved in cholinergic differentiation of neuronal precursor cells. OBJECTIVE: To explore the effects of BMP2 on neural stem cells of 14-day-old fetus rat telencephalons induced into cholinergic neurons. METHODS: Fetus telencephalons of 14-day-old SD rats were isolated, and tissues were divisively treated with collagenase typeⅠcontained EDTA following trituration. The cells were raised in polylysine culture plates with serum-free medium. Primary culture medium was changed half after 24 hours, and 10 μg/L BMP2 was added. RESULTS AND CONCLUSION: The adherent monoculture neural stem cells could been obtained using collagenase. The Nestin positve cells were obtained, and the purity was over 99%. After induced by BMP2, the ChAT positve cells were obtained, and the purity was over 97%. BMP2 can induce neural stem cells of 14-day-old fetus rat telencephalons into cholinergic neurons.%背景:骨形态发生蛋白2可能是参与胆碱能神经元前体细胞分化的细胞外调控因子.目的:观察骨形态发生蛋白2在孕14 d胎鼠端脑神经干细胞诱导成胆碱能神经元过程中的作用.方法:取孕14 d胎鼠端脑,用含EDTA的胰酶和Ⅰ型胶原酶消化,无血清培养基培养细胞,种植于涂有多聚赖氨酸的培养板,细胞原代培养24 h后半量换液,加入10 μg/L骨形态发生蛋白2继续培养.结果与结论:胶原酶消化得到的神经干细胞呈单层贴壁生长;Nestin免疫荧光鉴定细胞为阳性,获取的神经干细胞纯度大于99%;ChAT免疫荧光鉴定骨形态发生蛋白2可以将孕14 d胎鼠端脑神经干细胞诱导成胆碱能神经元,细胞纯度大于97%.

  9. 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.

  10. 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

  11. 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.

  12. 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.

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

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    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.

  14. Role of metal ions in the cognitive decline of Down syndrome

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    Nakisa eMalakooti

    2014-06-01

    Full Text Available Down syndrome (DS, caused by trisomy of whole or part of chromosome 21 is the most common mental impairment. All Down syndrome (DS individuals suffer from cognitive decline and develop Alzheimer’s disease (AD by the age of forty. The appearance of enlarged early endosomes, followed by Amyloid β peptide deposition, the appearance of tau-containing neurofibrillary tangles and basal forebrain cholinergic neuron (BFCN degeneration are the neuropathological characteristics of this disease. In this review we will examine the role of metal ion dyshomeostasis and the genes which may be involved in these processes, and relate these back to the manifestation of age-dependant cognitive decline in DS.

  15. Alpha7 Nicotinic Acetylcholine Receptors Play a Predominant Role in the Cholinergic Potentiation of N-Methyl-D-Aspartate Evoked Firing Responses of Hippocampal CA1 Pyramidal Cells

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    Zsolt K. Bali

    2017-09-01

    Full Text Available The aim of the present study was to identify in vivo electrophysiological correlates of the interaction between cholinergic and glutamatergic neurotransmission underlying memory. Extracellular spike recordings were performed in the hippocampal CA1 region of anesthetized rats in combination with local microiontophoretic administration of N-methyl-D-aspartate (NMDA and acetylcholine (ACh. Both NMDA and ACh increased the firing rate of the neurons. Furthermore, the simultaneous delivery of NMDA and ACh resulted in a more pronounced excitatory effect that was superadditive over the sum of the two mono-treatment effects and that was explained by cholinergic potentiation of glutamatergic neurotransmission. Next, animals were systemically treated with scopolamine or methyllycaconitine (MLA to assess the contribution of muscarinic ACh receptor (mAChR or α7 nicotinic ACh receptor (nAChR receptor-mediated mechanisms to the observed effects. Scopolamine totally inhibited ACh-evoked firing, and attenuated the firing rate increase evoked by simultaneous application of NMDA and ACh. However, the superadditive nature of the combined effect was preserved. The α7 nAChR antagonist MLA robustly decreased the firing response to simultaneous application of NMDA and ACh, suspending their superadditive effect, without modifying the tonic firing rate increasing effect of ACh. These results provide the first in vivo electrophysiological evidence that, in the hippocampal CA1 region, α7 nAChRs contribute to pyramidal cell activity mainly through potentiation of glutamatergic signaling, while the direct cholinergic modulation of tonic firing is notably mediated by mAChRs. Furthermore, the present findings also reveal cellular physiological correlates of the interplay between cholinergic and glutamatergic agents in behavioral pharmacological models of cognitive decline.

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. 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

  1. 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.

  2. 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.

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

    OpenAIRE

    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...

  4. 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...

  5. Declination Calculator

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Declination is calculated using the current International Geomagnetic Reference Field (IGRF) model. Declination is calculated using the current World Magnetic Model...

  6. 束缚-浸水应激对大鼠迷走背核胆碱能神经元活动的影响%Influence of restraint water-immersion stress on activity of cholinergic neurons in the dorsal motor nucleus of the vagus in the rat

    Institute of Scientific and Technical Information of China (English)

    赵东芹; 艾洪滨

    2011-01-01

    目的 研究束缚-浸水应激(RWIS)大鼠迷走神经背核(DMV)中胆碱能神经元的活动情况.方法 随机将10只雄性Wistar大鼠分为对照组和应激组,采用Fos和胆碱乙酰化酶(ChAT)免疫组织化学双标技术,统计对照组和应激组Fos、ChAT、Fos/ChAT双标阳性神经元数目.结果 与对照组相比,应激组大鼠DMV大量神经元表达Fos,Fos阳性神经元主要集中于DMV尾段和吻段(P<0.01);CHAT 阳性神经元主要分布于DMV中段和尾段,应激组大鼠DMV中单位面积内ChAT阳性神经元数目减少(P<0.01);Fos/ChAT双标阳性神经元的分布与Fos阳性神经元分布情况相似,RWIS组Fos/ChAT双标阳性神经元数目显著增加(P<0.01),Fos/ChAT双标阳性神经元占ChAT 阳性神经元的比例在对照组和RWIS组中分别为7.17%、21.12%(P<0.01).结论 DMV中胆碱能神经元参与RWIS调控过程.%Objective To investigate activity of cholinergic neurons in the dorsal motor nucleus of the vagus (DMV) in response to water-immersion stress (RWIS) in rats. Methods Ten rats were randomly divided into the control group and the RWIS group. Fos-immunoreactive (Fos-IR), choline acetyltransferase immunoreactive (ChAT-IR) and double labeled (Fos/ChAT-IR) neurons were counted using dual Fos and ChAT immunohistochemistry. Results Compared with unstressed rats, Fos-lR neurons dramatically increased in the DMV of RWIS rats ( P <0.01 ), and Fos expression was higher in the caudal portion of the NTS compared with the rostral and intermedial portions. ChAT-IR neurons decreased and were mainly observed in the caudal and intermediate portions of the DMV in RWIS rats(P <0.01 ). Percentages of Fos/ChAT-IR norons in ChAT-IR neurons in unstressed and RWIS rats were 7.17% and 21.12%, respectively( P <0.01 ). Conclusion Cholinergic neurons in DMV are involved in the stress response.

  7. 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.

  8. 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.

  9. 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.

  10. 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…

  11. 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…

  12. 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.

  13. 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.

  14. Injury effects of advanced glycation end products on the cultured primary rat basal forebrain cholinergic neurons%糖基化终末产物对大鼠基底前脑胆碱能神经元的损伤作用

    Institute of Scientific and Technical Information of China (English)

    殷青青; 刘雪平; 董传芳; 董雪丽; 李艳菊; 罗鼎真; 侯训尧

    2012-01-01

    目的 研究糖基化终末产物(AGE-BSA)对原代培养的基底前脑胆碱能神经元形态、生存率、凋亡率、胆碱乙酰转移酶(ChAT)与乙酰胆碱酯酶(AchE)活性的影响.在体外水平研究AGEs在阿尔茨海默病(Alzheimer's disease,AD)神经元缺失发生中的作用及其可能机制.方法 原代培养大鼠基底前脑胆碱能神经元,观察细胞生长变化,进行免疫荧光细胞化学鉴定;用300 μg/mLAGE-BSA以及糖基化终末产物受体(RAGE)中和抗体阻断处理原代培养的基底前脑胆碱能神经元,作用不同时间后置于倒置显微镜下观察细胞形态变化;采用MTT法检测神经元的存活率;采用流式细胞术检测神经元的凋亡率;经比色法检测ChAT和AchE的活性变化.结果 AGEBSA干预胆碱能神经元72 h后,细胞形态发生明显损伤性变化,细胞存活率明显降低,凋亡率增高,ChAT活性明显下降,AchE活性明显升高;RAGE中和抗体阻断组72 h较之AGE-BSA组,细胞形态损伤变化较轻,生存率偏高,凋亡率较低,ChAT活性较高,AchE活性偏低,但比空白对照组生存率降低,凋亡率增高,ChAT活性明显下降,AchE活性明显升高.结论 糖基化终末产物作用72 h可以引起胆碱能神经元的损伤,并造成ChAT活性下降和AchE活性明显升高,部分阻断其与特异性受体RAGE的结合可以减弱其损伤作用,提示糖基化终末产物通过其受体参与了对胆碱能神经元的损伤作用.%Objective To investigate effects of advanced glycation end products (AGEs) on the cell morphology, survival rate, apoptosis rate, choline acetyltransfesterase (ChAT) activity and acetylcholine( AchE) activity of the cultured primary rat basal forebrain cholinergic neurons. To explore the effect and the possible mechanism of AGEs in Alzheimer's disease( AD) at the cell level. Methods Cultured primary rat basal forebrain cholinergic neurons were intervened by AGE-BSA and the RAGE neutralizing antibody, then the cell

  15. 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.

  16. 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.

  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. 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.

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

    Science.gov (United States)

    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.

  20. 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.

  1. Comparative analyses of the cholinergic locus of ChAT and VAChT and its expression in the silkworm Bombyx mori.

    Science.gov (United States)

    Banzai, Kota; Adachi, Takeshi; Izumi, Susumu

    2015-07-01

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

  2. 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.

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. 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.

  8. 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...

  9. Deciphering the molecular profile of plaques, memory decline and neuron loss in two mouse models for Alzheimer's disease by deep sequencing.

    Science.gov (United States)

    Bouter, Yvonne; Kacprowski, Tim; Weissmann, Robert; Dietrich, Katharina; Borgers, Henning; Brauß, Andreas; Sperling, Christian; Wirths, Oliver; Albrecht, Mario; Jensen, Lars R; Kuss, Andreas W; Bayer, Thomas A

    2014-01-01

    One of the central research questions on the etiology of Alzheimer's disease (AD) is the elucidation of the molecular signatures triggered by the amyloid cascade of pathological events. Next-generation sequencing allows the identification of genes involved in disease processes in an unbiased manner. We have combined this technique with the analysis of two AD mouse models: (1) The 5XFAD model develops early plaque formation, intraneuronal Aβ aggregation, neuron loss, and behavioral deficits. (2) The Tg4-42 model expresses N-truncated Aβ4-42 and develops neuron loss and behavioral deficits albeit without plaque formation. Our results show that learning and memory deficits in the Morris water maze and fear conditioning tasks in Tg4-42 mice at 12 months of age are similar to the deficits in 5XFAD animals. This suggested that comparative gene expression analysis between the models would allow the dissection of plaque-related and -unrelated disease relevant factors. Using deep sequencing differentially expressed genes (DEGs) were identified and subsequently verified by quantitative PCR. Nineteen DEGs were identified in pre-symptomatic young 5XFAD mice, and none in young Tg4-42 mice. In the aged cohort, 131 DEGs were found in 5XFAD and 56 DEGs in Tg4-42 mice. Many of the DEGs specific to the 5XFAD model belong to neuroinflammatory processes typically associated with plaques. Interestingly, 36 DEGs were identified in both mouse models indicating common disease pathways associated with behavioral deficits and neuron loss.

  10. 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.

  11. N-palmitoyl serotonin alleviates scopolamine-induced memory impairment via regulation of cholinergic and antioxidant systems, and expression of BDNF and p-CREB in mice.

    Science.gov (United States)

    Min, A Young; Doo, Choon Nan; Son, Eun Jung; Sung, Nak Yun; Lee, Kun Jong; Sok, Dai-Eun; Kim, Mee Ree

    2015-12-05

    N-Palmitoyl-5-hydroxytryptamines (Pal-5HT), a cannabinoid, has recently been reported to express anti-allergic and anti-inflammatory actions in RBL-2H3 cells, and ameliorate glutamate-induced cytotoxicity in HT-22 cells. In this study, we examined the effect of Pal-5HT on deficits of learning and memory induced by scopolamine in mice. Memory performance was evaluated using Morris water maze test and passive avoidance test. Activities of acetylcholinesterase (AChE) and choline acetyltransferase (ChAT), level of oxidative stress markers, and expression of brain-derived neurotrophic factor (BDNF), phosphorylation of cAMP response element-binding protein (p-CREB) were determined. Loss of neuronal cells in hippocampus was evaluated by histological examinations. Pal-5HT significantly improved the amnesia in the behavioral assessment. Pal-5HT regulated cholinergic function by inhibiting scopolamine-induced elevation of AChE activity and decline of ChAT activity. Pal-5HT suppressed oxidative stress by increasing activities of glutathione peroxidase (GPx), glutathione reductase (GR) or NAD(P)H quinine oxidoreductase-1 (NQO-1) and lowering MDA level. Additionally, it prevented against scopolamine-induced expression of iNOS and COX-2. Moreover, Pal-5HT suppressed the death of neuronal cells in CA1 and CA3 regions, while it restored expression of p-CREB and BDNF in hippocampus. Taken together, Pal-5HT is suggested to ameliorate deficits of memory and learning through regulation of cholinergic function, activation of antioxidant systems as well as restoration of BDNF and p-CREB expression. From these, Pal-5HT may be a potential candidate to prevent against neurodegeneration related to the memory deficit.

  12. 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

  13. 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.

  14. 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…

  15. 慢性间断性低氧大鼠认知功能和脑胆碱能神经元的进行性变化%The progressive effects of chronic intermittent hypoxia on cognitive function and the cholinergic neuron in rats

    Institute of Scientific and Technical Information of China (English)

    陈燕; 赵春玲; 张春来; 徐倩

    2011-01-01

    Objective: To investigate the relation between the progressive effects of chronic intermittent hypoxia(CIH) on cognitive function and the change of cholinergic neuron. Methods: Forty adult male Sprague-Dawley rats were randomly averagely divided into four groups: control group, CIH 1 week group, CIH 3 week group and CIH 5 week group. The cognitive function was assessed by the Morris Water Maze. The necrosis neurons in prefrontal cortex and hippocampus were observed and counted. The cholin aeetyltransferase(ChAT) immunostained cells in prefrontal cortex and hippocampus were identified and quantitated. Results: The spatial learning and memory impairments progressed from 1 to 5weeks in rats. Compared with the control group, the cognitive impairments in CIH5w group were significant( P < 0.05). The degeneration or necrosis neurons in prefrontal cortex and hippocampus were significantly increased in CIH rats, and worsen gradually along with the hypoxia. The ChAT immunostained cells in prefrontal cortex and hippocampus were gradually reduced. The ChAT immunostained cells of prefrontal cortex and hippocampus in CIH3w group and CIH5w group were less than that in control group ( P <0.05). Conclusion: Chronic intermittent hypoxia induced slowly progressive spatial learning and memory impairments in rats, which maybe associated with the damage of neurons and the reduction of ChAT in prefrontal cortex and hippocampus.%目的:探讨慢性间断性低氧(CIH)大鼠认知功能的进行性变化及其与脑胆碱能神经元变化的关系.方法:成年雄性SD大鼠40只,随机均分为对照组、慢性间断性低氧1,3,5周组.应用Morris水迷宫检测认知功能的变化:利用HE染色在光镜下计数前额叶皮层和海马坏死神经元数;利用免疫组化方法检测前额叶皮层和海马胆碱乙酰转移酶(ChAT)阳性表达.结果:CIH各组大鼠学习记忆能力呈进行性下降趋势;与对照组比较,CIH5w组出现明显学习记忆功能障碍(P<0

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

    Directory of Open Access Journals (Sweden)

    Fischer Andy J

    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.

  17. 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.

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

    Science.gov (United States)

    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.

  19. 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.

  20. 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.

  1. Chronic caffeine consumption prevents cognitive decline from young to middle age in rats, and is associated with increased length, branching, and spine density of basal dendrites in CA1 hippocampal neurons.

    Science.gov (United States)

    Vila-Luna, S; Cabrera-Isidoro, S; Vila-Luna, L; Juárez-Díaz, I; Bata-García, J L; Alvarez-Cervera, F J; Zapata-Vázquez, R E; Arankowsky-Sandoval, G; Heredia-López, F; Flores, G; Góngora-Alfaro, J L

    2012-01-27

    Chronic caffeine consumption has been inversely associated with the risk of developing dementia and Alzheimer's disease. Here we assessed whether chronic caffeine treatment prevents the behavioral and cognitive decline that male Wistar rats experience from young (≈3 months) to middle age (≈10 months). When animals were young they were evaluated at weekly intervals in three tests: motor activity habituation in the open field (30-min sessions at the same time on consecutive days), continuous spontaneous alternation in the Y-maze (8 min), and elevated plus-maze (5 min). Afterward, rats from the same litter were randomly assigned either to a caffeine-treated group (n=13) or a control group (n=11), which received only tap water. Caffeine treatment (5 mg/kg/day) began when animals were ≈4 months old, and lasted for 6 months. Behavioral tests were repeated from day 14 to day 28 after caffeine withdrawal, a time period that is far in excess for the full excretion of a caffeine dose in this species. Thirty days after caffeine discontinuation brains were processed for Golgi-Cox staining. Compared with controls, we found that middle-aged rats that had chronically consumed low doses of caffeine (1) maintained their locomotor habituation during the second consecutive day exposure to the open field (an index of non-associative learning), (2) maintained their exploratory drive to complete the conventional minimum of nine arm visits required to calculate the alternation performance in the Y-maze in a greater proportion, (3) maintained their alternation percentage above chance level (an index of working memory), and (4) did not increase the anxiety indexes assessed by measuring the time spent in the open arms of the elevated plus maze. In addition, morphometric analysis of hippocampal neurons revealed that dendritic branching (90-140 μm from the soma), length of 4th and 5th order branches, total dendritic length, and spine density in distal dendritic branches were greater in

  2. Nicotinic activation of laterodorsal tegmental neurons

    DEFF Research Database (Denmark)

    Ishibashi, Masaru; Leonard, Christopher S; Kohlmeier, Kristi A

    2009-01-01

    are unknown. We addressed this issue by examining the effects of nicotine on identified cholinergic and non-cholinergic LDT neurons using whole-cell patch clamp and Ca(2+)-imaging methods in brain slices from mice (P12-P45). Nicotine applied by puffer pipette or bath superfusion elicited membrane...... depolarization that often induced firing and TTX-resistant inward currents. Nicotine also enhanced sensitivity to injected current; and, baseline changes in intracellular calcium were elicited in the dendrites of some cholinergic LDT cells. In addition, activity-dependent calcium transients were increased......, suggesting that nicotine exposure sufficient to induce firing may lead to enhancement of levels of intracellular calcium. Nicotine also had strong actions on glutamate and GABA-releasing presynaptic terminals, as it greatly increased the frequency of miniature EPSCs and IPSCs to both cholinergic and non...

  3. 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

  4. 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

  5. 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

  6. 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.

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

    Directory of Open Access Journals (Sweden)

    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

  8. Differentiation of a teratocarcinoma line: preferential development of cholinergic neurons

    OpenAIRE

    1981-01-01

    A line of embryonal carcinoma cells, PCC7-S, established in vitro from a spontaneous testicular teratocarcinoma, has been studied. Upon removing the cells from a low density monolayer culture system and permitting the cells to form aggregates in suspension, we observed a change of several physical and biochemical parameters: (a) reduction in average cell volume, (b) blockage and accumulation of cells in G1, (c) rise in secreted protease activity, (d) rise in acetylcholinesterase and choline a...

  9. 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.

  10. Improvements in Memory after Medial Septum Stimulation Are Associated with Changes in Hippocampal Cholinergic Activity and Neurogenesis

    Directory of Open Access Journals (Sweden)

    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.

  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. 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.

  13. Subpopulations of rat dorsal root ganglion neurons express active vesicular acetylcholine transporter.

    Science.gov (United States)

    Tata, Ada Maria; De Stefano, M Egle; Tomassy, Giulio Srubek; Vilaró, M Teresa; Levey, Allan I; Biagioni, Stefano

    2004-01-15

    The vesicular acetylcholine transporter (VAChT) is a transmembrane protein required, in cholinergic neurons, for selective storage of acetylcholine into synaptic vesicles. Although dorsal root ganglion (DRG) neurons utilize neuropeptides and amino acids for neurotransmission, we have previously demonstrated the presence of a cholinergic system. To investigate whether, in sensory neurons, the vesicular accumulation of acetylcholine relies on the same mechanisms active in classical cholinergic neurons, we investigated VAChT presence, subcellular distribution, and activity. RT-PCR and Western blot analysis demonstrated the presence of VAChT mRNA and protein product in DRG neurons and in the striatum and cortex, used as positive controls. Moreover, in situ hybridization and immunocytochemistry showed VAChT staining located mainly in the medium/large-sized subpopulation of the sensory neurons. A few small neurons were also faintly labeled by immunocytochemistry. In the electron microscope, immunolabeling was associated with vesicle-like elements distributed in the neuronal cytoplasm and in both myelinated and unmyelinated intraganglionic nerve fibers. Finally, [(3)H]acetylcholine active transport, evaluated either in the presence or in the absence of ATP, also demonstrated that, as previously reported, the uptake of acetylcholine by VAChT is ATP dependent. This study suggests that DRG neurons not only are able to synthesize and degrade ACh and to convey cholinergic stimuli but also are capable of accumulating and, possibly, releasing acetylcholine by the same mechanism used by the better known cholinergic neurons.

  14. 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.

  15. Impairment of cognitive function and reduced hippocampal cholinergic activity in a rat model of chronic intermittent hypoxia

    Institute of Scientific and Technical Information of China (English)

    Chunling Zhao; Yan Chen; Chunlai Zhang; Linya Lü; Qian Xu

    2011-01-01

    The present study established a rat model of chronic intermittent hypoxia (CIH) to simulate obstructive sleep apnea syndrome. CIH rats were evaluated for cognitive function using the Morris water maze, and neuronal pathology in the hippocampus was observed using hematoxylin-eosin staining. In addition, hippocampal choline acetyl transferase (ChAT) and nicotinic acetylcholine receptor (nAChR) expression was determined by immunohistochemistry. Our results revealed necrotic hippocampal neurons, decreased ChAT and nAChR expression, as well as cognitive impairment in CIH rats. These results suggest that hippocampal neuronal necrosis and decreased cholinergic activity may be involved in CIH-induced cognitive impairment in rats.

  16. 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.)

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

    Science.gov (United States)

    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. 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.

  19. Satureja bachtiarica ameliorate beta-amyloid induced memory impairment, oxidative stress and cholinergic deficit in animal model of Alzheimer's disease.

    Science.gov (United States)

    Soodi, Maliheh; Saeidnia, Soodabeh; Sharifzadeh, Mohammad; Hajimehdipoor, Homa; Dashti, Abolfazl; Sepand, Mohammad Reza; Moradi, Shahla

    2016-04-01

    Extracellular deposition of Beta-amyloid peptide (Aβ) is the main finding in the pathophysiology of Alzheimer's disease (AD), which damages cholinergic neurons through oxidative stress and reduces the cholinergic neurotransmission. Satureja bachtiarica is a medicinal plant from the Lamiaceae family which was widely used in Iranian traditional medicine. The aim of the present study was to investigate possible protective effects of S. bachtiarica methanolic extract on Aβ induced spatial memory impairment in Morris Water Maze (MWM), oxidative stress and cholinergic neuron degeneration. Pre- aggregated Aβ was injected into the hippocampus of each rat bilaterally (10 μg/rat) and MWM task was performed 14 days later to evaluate learning and memory function. Methanolic extract of S.bachtiarica (10, 50 and 100 mg/Kg) was injected intraperitoneally for 19 consecutive days, after Aβ injection. After the probe test the brain tissue were collected and lipid peroxidation, Acetylcholinesterase (AChE) activity and Cholin Acetyl Transferees (ChAT) immunorectivity were measured in the hippocampus. Intrahipocampal injection of Aβ impaired learning and memory in MWM in training days and probe trail. Methanolic extract of S. bachtiarica (50 and 100 mg/Kg) could attenuate Aβ-induced memory deficit. ChAT immunostaining revealed that cholinergic neurons were loss in Aβ- injected group and S. bachtiarica (100 mg/Kg) could ameliorate Aβ- induced ChAT reduction in the hippocampus. Also S. bachtiarica could ameliorate Aβ-induced lipid peroxidation and AChE activity increase in the hippocampus. In conclusion our study represent that S.bachtiarica methanolic extract can improve Aβ-induced memory impairment and cholinergic loss then we recommended this extract as a candidate for further investigation in treatment of AD.

  20. Dorsal raphe nucleus acetylcholine-mediated neurotransmission modulates post-ictal antinociception: The role of muscarinic and nicotinic cholinergic receptors.

    Science.gov (United States)

    de Oliveira, Rithiele Cristina; de Oliveira, Ricardo; Biagioni, Audrey Francisco; Falconi-Sobrinho, Luiz Luciano; Coimbra, Norberto Cysne

    2016-01-15

    The dorsal raphe nucleus (DRN) is a key structure of the endogenous pain inhibitory system. Although the DRN is rich in serotoninergic neurons, cholinergic neurons are also found in that nucleus. Both ictal and inter-ictal states are followed by post-ictal analgesia. The present study investigated the role of cholinergic mechanisms in postictal antinociceptive processes using microinjections of atropine and mecamylamine, muscarinic and nicotinic cholinergic receptor antagonists, respectively, in the DRN of rats. Intraperitoneal injection of pentylenetetrazole (PTZ) (at 64mg/kg) caused tonic and tonic-clonic seizures. The convulsive motor reactions were followed by an increase in pain thresholds, a phenomenon known as post-ictal analgesia. Pre-treatment of the DRN with atropine or mecamylamine at 1µg, 3µg and 5µg/0.2µL decreased the post-ictal antinociceptive phenomenon. The present results showed that the post-ictal analgesia was mediated by muscarinic and nicotinic cholinergic receptors in the DRN, a structure crucially involved in the neural network that organises post-ictal hypoalgesia.

  1. 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.

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

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    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

  3. Nerve Growth Factor is Primarily Produced by GABAergic Neurons of the Rat Neocortex

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    Jeremy eBiane

    2014-08-01

    Full Text Available Within the cortex, nerve growth factor (NGF mediates the innervation of cholinergic neurons during development, maintains cholinergic corticopetal projections during adulthood and modulates cholinergic function through phenotypic control of the cholinergic gene locus. Recent studies suggest NGF may also play an important role in cortical plasticity in adulthood. Previously, NGF-producing cells have been shown to colocalize with GABAergic cell markers within the hippocampus, striatum, and basal forebrain. Classification of cells producing NGF in the cortex is lacking, however, and cholinergic corticopetal projections have been shown to innervate both pyramidal and GABAergic neurons in the cortex. In order to clarify potential trophic interactions between cortical neurons and cholinergic projections, we used double-fluorescent immunohistochemistry to classify NGF-expressing cells in several cortical regions, including the prefrontal cortex, primary motor cortex, parietal cortex and temporal cortex. Our results show that NGF colocalizes extensively with GABAergic cell markers in all cortical regions examined, with >91% of NGF-labeled cells coexpressing GAD65/67. Conversely, NGF-labeled cells exhibit very little co-localization with the excitatory cell marker CaMKIIα (less than 5% of cells expressing NGF. NGF expression was present in 56% of GAD-labeled cells, suggesting that production is confined to a specific subset of GABAergic neurons. These findings demonstrate that GABAergic cells are the primary source of NGF production in the cortex, and likely support the maintenance and function of basal forebrain cholinergic projections in adulthood.

  4. 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.

  5. Glucocorticoid programming of the mesopontine cholinergic system

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    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.

  6. A cholinergic feedback circuit to regulate striatal population uncertainty and optimize reinforcement learning.

    Science.gov (United States)

    Franklin, Nicholas T; Frank, Michael J

    2015-12-25

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

  7. Effects of infantile/prepubertal chronic estrogen treatment and chemical sympathectomy with guanethidine on developing cholinergic nerves of the rat uterus.

    Science.gov (United States)

    Richeri, Analía; Viettro, Lorena; Chávez-Genaro, Rebeca; Burnstock, Geoffrey; Cowen, Timothy; Brauer, M Mónica

    2002-06-01

    The innervation of the uterus is remarkable in that it exhibits physiological changes in response to altered levels in the circulating levels of sex hormones. Previous studies by our group showed that chronic administration of estrogen to rats during the infantile/prepubertal period provoked, at 28 days of age, an almost complete loss of norepinephrine-labeled sympathetic nerves, similar to that observed in late pregnancy. It is not known, however, whether early exposure to estrogen affects uterine cholinergic nerves. Similarly, it is not known to what extent development and estrogen-induced responses in the uterine cholinergic innervation are affected by the absence of sympathetic nerves. To address this question, in this study we analyzed the effects of infantile/prepubertal chronic estrogen treatment, chronic chemical sympathectomy with guanethidine, and combined sympathectomy and chronic estrogen treatment on developing cholinergic nerves of the rat uterus. Cholinergic nerves were visualized using a combination of acetylcholinesterase histochemistry and the immunohistochemical demonstration of the vesicular acetylcholine transporter (VAChT). After chronic estrogen treatment, a well-developed plexus of cholinergic nerves was observed in the uterus. Quantitative studies showed that chronic exposure to estrogen induced contrasting responses in uterine cholinergic nerves, increasing the density of large and medium-sized nerve bundles and reducing the intercept density of fine fibers providing myometrial and perivascular innervation. Estrogen-induced changes in the uterine cholinergic innervation did not appear to result from the absence/impairment of sympathetic nerves, because sympathectomy did not mimic the effects produced by estrogen. Estrogen-induced responses in parasympathetic nerves are discussed, considering the direct effects of estrogen on neurons and on changes in neuron-target interactions.

  8. Role for calcium/calmodulin-dependent protein kinase II in the p75-mediated regulation of sympathetic cholinergic transmission

    OpenAIRE

    Slonimsky, John D.; Mattaliano, Mark D.; Moon, Jung-Il; Leslie C. Griffith; Birren, Susan J.

    2006-01-01

    Neurotrophins regulate sympathetic neuron cotransmission by modulating the activity-dependent release of norepinephrine and acetylcholine. Nerve growth factor promotes excitatory noradrenergic transmission, whereas brain-derived neurotrophic factor (BDNF), acting through the p75 receptor, increases inhibitory cholinergic transmission. This regulation of corelease by target-derived factors leads to the functional modulation of myocyte beat rate in neuron–myocyte cocultures. Calcium/calmodulin-...

  9. Cholinergic interneurons mediate fast VGluT3-dependent glutamatergic transmission in the striatum.

    Science.gov (United States)

    Higley, Michael J; Gittis, Aryn H; Oldenburg, Ian A; Balthasar, Nina; Seal, Rebecca P; Edwards, Robert H; Lowell, Bradford B; Kreitzer, Anatol C; Sabatini, Bernardo L

    2011-04-22

    The neurotransmitter glutamate is released by excitatory projection neurons throughout the brain. However, non-glutamatergic cells, including cholinergic and monoaminergic neurons, express markers that suggest that they are also capable of vesicular glutamate release. Striatal cholinergic interneurons (CINs) express the Type-3 vesicular glutamate transporter (VGluT3), although whether they form functional glutamatergic synapses is unclear. To examine this possibility, we utilized mice expressing Cre-recombinase under control of the endogenous choline acetyltransferase locus and conditionally expressed light-activated Channelrhodopsin2 in CINs. Optical stimulation evoked action potentials in CINs and produced postsynaptic responses in medium spiny neurons that were blocked by glutamate receptor antagonists. CIN-mediated glutamatergic responses exhibited a large contribution of NMDA-type glutamate receptors, distinguishing them from corticostriatal inputs. CIN-mediated glutamatergic responses were insensitive to antagonists of acetylcholine receptors and were not seen in mice lacking VGluT3. Our results indicate that CINs are capable of mediating fast glutamatergic transmission, suggesting a new role for these cells in regulating striatal activity.

  10. Cholinergic interneurons mediate fast VGluT3-dependent glutamatergic transmission in the striatum.

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    Michael J Higley

    Full Text Available The neurotransmitter glutamate is released by excitatory projection neurons throughout the brain. However, non-glutamatergic cells, including cholinergic and monoaminergic neurons, express markers that suggest that they are also capable of vesicular glutamate release. Striatal cholinergic interneurons (CINs express the Type-3 vesicular glutamate transporter (VGluT3, although whether they form functional glutamatergic synapses is unclear. To examine this possibility, we utilized mice expressing Cre-recombinase under control of the endogenous choline acetyltransferase locus and conditionally expressed light-activated Channelrhodopsin2 in CINs. Optical stimulation evoked action potentials in CINs and produced postsynaptic responses in medium spiny neurons that were blocked by glutamate receptor antagonists. CIN-mediated glutamatergic responses exhibited a large contribution of NMDA-type glutamate receptors, distinguishing them from corticostriatal inputs. CIN-mediated glutamatergic responses were insensitive to antagonists of acetylcholine receptors and were not seen in mice lacking VGluT3. Our results indicate that CINs are capable of mediating fast glutamatergic transmission, suggesting a new role for these cells in regulating striatal activity.

  11. 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.

  12. 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

    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.

  13. 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.

  14. Luteolin enhances cholinergic activities in PC12 cells through ERK1/2 and PI3K/Akt pathways.

    Science.gov (United States)

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

    2012-02-09

    Luteolin, a 3', 4', 5, 7-tetrahydroxyflavone, is an active compound in Rosmarinus officinalis (Lamiacea), and has been reported to exert several benefits in neuronal cells. However cholinergic-induced activities of luteolin still remain unknown. Neuronal differentiation encompasses an elaborate developmental program which plays a key role in the development of the nervous system. The advent of several cell lines, like PC12 cells, able to differentiate in culture proved to be the turning point for gaining and understanding of molecular neuroscience. In this work, we investigated the ability of luteolin to induce PC12 cell differentiation and its effect on cholinergic activities. Our findings showed that luteolin treatment significantly induced neurite outgrowth extension, enhanced acetylcholinesterase (AChE) activity, known as neuronal differentiation marker, and increased the level of total choline and acetylcholine in PC12 cells. In addition, luteolin persistently, activated extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt; while the addition of pharmacological MEK/ERK1/2 inhibitor (U0126) and PI3k/Akt inhibitor (LY294002) attenuated luteolin-induced AChE activity and neurite outgrowth in PC12 cells. The above findings suggest that luteolin induces neurite outgrowth and enhanced cholinergic activities, at least in part, through the activation of ERK1/2 and Akt signaling.

  15. Effects of acetylcholine on neuronal properties in entorhinal cortex

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    James G Heys

    2012-07-01

    Full Text Available The entorhinal cortex receives prominent cholinergic innervation from the medial septum and the vertical limb of the diagonal band of Broca (MSDB. To understand how cholinergic neurotransmission can modulate behavior, research has been directed towards identification of the specific cellular mechanisms in entorhinal cortex that can be modulated through cholinergic activity. This review focuses on intrinsic cellular properties of neurons in entorhinal cortex that may underlie functions such as working memory, spatial processing and episodic memory. In particular, the study of stellate cells in medial entorhinal has resulted in discovery of correlations between physiological properties of these neurons and properties of the unique spatial representation that is demonstrated through unit recordings of neurons in medial entorhinal cortex from awake-behaving animals. A separate line of investigation has demonstrated persistent firing behavior among neurons in entorhinal cortex that is enhanced by cholinergic activity and could underlie working memory. There is also evidence that acetylcholine plays a role in modulation of synaptic transmission that could also enhance mnemonic function in entorhinal cortex. Finally, the local circuits of entorhinal cortex demonstrate a variety of interneuron physiology, which is also subject to cholinergic modulation. Together these effects alter the dynamics of entorhinal cortex to underlie the functional role of acetylcholine in memory.

  16. 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...

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

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    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

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

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    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.

  19. 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.

  20. Nicotinic activation of laterodorsal tegmental neurons: implications for addiction to nicotine.

    Science.gov (United States)

    Ishibashi, Masaru; Leonard, Christopher S; Kohlmeier, Kristi A

    2009-11-01

    Identifying the neurological mechanisms underlying nicotine reinforcement is a healthcare imperative, if society is to effectively combat tobacco addiction. The majority of studies of the neurobiology of addiction have focused on dopamine (DA)-containing neurons of the ventral tegmental area (VTA). However, recent data suggest that neurons of the laterodorsal tegmental (LDT) nucleus, which sends cholinergic, GABAergic, and glutamatergic-containing projections to DA-containing neurons of the VTA, are critical to gating normal functioning of this nucleus. The actions of nicotine on LDT neurons are unknown. We addressed this issue by examining the effects of nicotine on identified cholinergic and non-cholinergic LDT neurons using whole-cell patch clamp and Ca(2+)-imaging methods in brain slices from mice (P12-P45). Nicotine applied by puffer pipette or bath superfusion elicited membrane depolarization that often induced firing and TTX-resistant inward currents. Nicotine also enhanced sensitivity to injected current; and, baseline changes in intracellular calcium were elicited in the dendrites of some cholinergic LDT cells. In addition, activity-dependent calcium transients were increased, suggesting that nicotine exposure sufficient to induce firing may lead to enhancement of levels of intracellular calcium. Nicotine also had strong actions on glutamate and GABA-releasing presynaptic terminals, as it greatly increased the frequency of miniature EPSCs and IPSCs to both cholinergic and non-cholinergic neurons. Utilization of nicotinic acetylcholine receptors (nAChR) subunit antagonists revealed that presynaptic, inhibitory terminals on cholinergic neurons were activated by receptors containing alpha 7, beta2, and non-alpha 7 subunits, whereas, presynaptic glutamatergic terminals were activated by nAChRs that comprised non-alpha 7 subunits. We also found that direct nicotinic actions on cholinergic LDT neurons were mediated by receptors containing alpha 7, beta2, and non

  1. ( sup 3 H)cytisine binding to nicotinic cholinergic receptors in brain

    Energy Technology Data Exchange (ETDEWEB)

    Pabreza, L.A.; Dhawan, S.; Kellar, K.J. (Georgetown Univ. School of Medicine, Washington, DC (USA))

    1991-01-01

    Cytisine, a ganglionic agonist, competes with high affinity for brain nicotinic cholinergic receptors labeled by any of several nicotinic {sup 3}H-agonist ligands. Here we have examined the binding of ({sup 3}H)cytisine in rat brain homogenates. ({sup 3}H)Cytisine binds with high affinity (Kd less than 1 nM), and specific binding represented 60-90% of total binding at all concentrations examined up to 15 nM. The nicotinic cholinergic agonists nicotine, acetylcholine, and carbachol compete with high affinity for ({sup 3}H)cytisine binding sites, whereas among nicotinic receptor antagonists only dihydro-beta-erythroidine competes with high affinity (in the nanomolar range). Comparison of binding in several brain regions showed that ({sup 3}H)cytisine binding is higher in the thalamus, striatum, and cortex than in the hippocampus, cerebellum, or hypothalamus. The pharmacology and brain regional distribution of ({sup 3}H)cytisine binding sites are those predicted for neuronal nicotinic receptor agonist recognition sites. The high affinity and low nonspecific binding of ({sup 3}H)cytisine should make it a very useful ligand for studying neuronal nicotinic receptors.

  2. Distribution of Acetylcholinesterase Positive Neurons in the Oviduct of Laying Hen

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    Jameel Ahmed Gandahi1,2,§, Noor Samad Gandahi2,§, Ping Yang1, Xun Guang Bian1, Muhammad Ghiasuddin Shah2, Moolchand Malhi1,2, Lin Li Zhang1, Qian Zhang1 and Qiusheng Chen1,*

    2013-04-01

    Full Text Available The acetylcholinesterase histochemistry is used to identify the cholinergic nerves in tissue sections. Little is known on localization of cholinergic nerves in the oviduct of laying hens. We have used this technique to localize and compare the acetylcholinergic neurons in different regions through the oviduct in laying hens. The cholinergic neurons were seen as single cells, pairs or three cells arranged together. The cytoplasm and the processes of positive neurons showed strong reaction, with an eccentric nucleus. Morphologically, the neurons were rounded and oval cells of unipolar, bipolar and multipolar shapes. Similar features were seen in the whole mounts. Varicose nerve fibers were present. Cholinergic neurons were commonly seen in the muscularis; the fibers ran along the muscularis, occasionally showed a bifurcation to enter the lamina propria, reaching the secondary and tertiary mucosal folds; the fibers also targeted the blood vessels in the intermuscular region. The regional distribution of cholinergic neurons was highest seen in the infundibulum; medium in the magnum, isthmus and uterus (shell gland, while vagina had significantly lower (P<0.05 number; i.e. 8.00±1.00, 5.33±0.33, 4.67±0.67; 5.67±0.33; and 3.67±0.33, respectively. The local comparison of cholinergic neurons in muscularis and lamina propria showed significantly higher (P<0.05 number in muscularis than lamina propria of the isthmus. It was concluded that acetylcholinesterase positive (cholinergic nerves may have a role in the regulation of the smooth muscle functions and blood supply in the oviduct of chicken.

  3. Catecholaminergic and cholinergic systems of mouse brain are modulated by LMN diet, rich in theobromine, polyphenols and polyunsaturated fatty acids.

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    Fernández-Fernández, Laura; Esteban, Gerard; Giralt, Mercedes; Valente, Tony; Bolea, Irene; Solé, Montse; Sun, Ping; Benítez, Susana; Morelló, José Ramón; Reguant, Jordi; Ramírez, Bartolomé; Hidalgo, Juan; Unzeta, Mercedes

    2015-04-01

    The possible modulatory effect of the functional LMN diet, rich in theobromine, polyphenols and polyunsaturated fatty acids, on the catecholaminergic and cholinergic neurotransmission, affecting cognition decline during aging has been studied. 129S1/SvlmJ mice were fed for 10, 20, 30 and 40 days with either LMN or control diets. The enzymes involved in catecholaminergic and cholinergic metabolism were determined by both immunohistological and western blot analyses. Noradrenalin, dopamine and other metabolites were quantified by HPLC analysis. Theobromine, present in cocoa, the main LMN diet component, was analysed in parallel using SH-SY5Y and PC12 cell lines. An enhanced modulatory effect on both cholinergic and catecholaminergic transmissions was observed on 20 day fed mice. Similar effect was observed with theobromine, besides its antioxidant capacity inducing SOD-1 and GPx expression. The enhancing effect of the LMN diet and theobromine on the levels of acetylcholine-related enzymes, dopamine and specially noradrenalin confirms the beneficial role of this diet on the "cognitive reserve" and hence a possible reducing effect on cognitive decline underlying aging and Alzheimer's disease.

  4. Rapid desensitization with autologous sweat in cholinergic urticaria.

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    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.

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

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    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.

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

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    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.

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

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    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.

  8. Personalized genetics of the cholinergic blockade of neuroinflammation.

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    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.

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

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    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.

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

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    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.

  11. Evidence for the existence of non-GABAergic, cholinergic interneurons in the rodent hippocampus.

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    Frotscher, M; Vida, I; Bender, R

    2000-01-01

    Previous studies have revealed a small number of hippocampal interneurons immunoreactive for choline acetyltransferase, the acetylcholine-synthesizing enzyme. It remained an open question, however, whether these neurons represented a subgroup of inhibitory GABAergic neurons co-localizing acetylcholine. In this study, we have combined immunocytochemistry for choline acetyltransferase and in situ hybridization for glutamate decarboxylase messenger RNA, the GABA-synthesizing enzyme. None of the choline acetyltransferase-immunoreactive neurons in the various layers of the hippocampus proper and fascia dentata were found to co-localize glutamate decarboxylase messenger RNA. The lack of an in situ hybridization signal in these neurons is unlikely to result from the combination of the two labeling techniques. When combining in situ hybridization for glutamate decarboxylase messenger RNA with immunostaining for parvalbumin, a calcium-binding protein expressed by many GABAergic hippocampal interneurons, numerous double-labeled cells were observed. These data provide neurochemical evidence for the existence of non-GABAergic, supposedly cholinergic non-principal cells in the hippocampus.

  12. Descending projections from the basal forebrain to the orexin neurons in mice.

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    Agostinelli, Lindsay J; Ferrari, Loris L; Mahoney, Carrie E; Mochizuki, Takatoshi; Lowell, Bradford B; Arrigoni, Elda; Scammell, Thomas E

    2017-05-01

    The orexin (hypocretin) neurons play an essential role in promoting arousal, and loss of the orexin neurons results in narcolepsy, a condition characterized by chronic sleepiness and cataplexy. The orexin neurons excite wake-promoting neurons in the basal forebrain (BF), and a reciprocal projection from the BF back to the orexin neurons may help promote arousal and motivation. The BF contains at least three different cell types (cholinergic, glutamatergic, and γ-aminobutyric acid (GABA)ergic neurons) across its different regions (medial septum, diagonal band, magnocellular preoptic area, and substantia innominata). Given the neurochemical and anatomical heterogeneity of the BF, we mapped the pattern of BF projections to the orexin neurons across multiple BF regions and neuronal types. We performed conditional anterograde tracing using mice that express Cre recombinase only in neurons producing acetylcholine, glutamate, or GABA. We found that the orexin neurons are heavily apposed by axon terminals of glutamatergic and GABAergic neurons of the substantia innominata (SI) and magnocellular preoptic area, but there was no innervation by the cholinergic neurons. Channelrhodopsin-assisted circuit mapping (CRACM) demonstrated that glutamatergic SI neurons frequently form functional synapses with the orexin neurons, but, surprisingly, functional synapses from SI GABAergic neurons were rare. Considering their strong reciprocal connections, BF and orexin neurons likely work in concert to promote arousal, motivation, and other behaviors. J. Comp. Neurol. 525:1668-1684, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  13. 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.

  14. Deficit in sustained attention following selective cholinergic lesion of the pedunculopontine tegmental nucleus in rat, as measured with both post-mortem immunocytochemistry and in vivo PET imaging with [¹⁸F]fluoroethoxybenzovesamicol.

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    Cyr, Marilyn; Parent, Maxime J; Mechawar, Naguib; Rosa-Neto, Pedro; Soucy, Jean-Paul; Clark, Stewart D; Aghourian, Meghmik; Bedard, Marc-Andre

    2015-02-01

    Cholinergic neurons of the pedunculopontine tegmental nucleus (PPTg) are thought to be involved in cognitive functions such as sustained attention, and lesions of these cells have been documented in patients showing fluctuations of attention such as in Parkinson's disease or dementia with Lewy Body. Animal studies have been conducted to support the role of these cells in attention, but the lesions induced in these animals were not specific to the cholinergic PPTg system, and were assessed by post-mortem methods remotely performed from the in vivo behavioral assessments. Moreover, sustained attention have not been directly assessed in these studies, but rather deduced from indirect measurements. In the present study, rats were assessed on the 5-Choice Serial Reaction Time Task (5-CSRTT), and a specific measure of variability in response latency was created. Animals were observed both before and after selective lesion of the PPTg cholinergic neurons. Brain cholinergic denervation was assessed both in vivo and ex vivo, using PET imaging with [(18)F]fluoroethoxybenzovesamicol ([(18)F]FEOBV) and immunocytochemistry respectively. Results showed that the number of correct responses and variability in response latency in the 5-CSRTT were the only behavioral measures affected following the lesions. These measures were found to correlate significantly with the number of PPTg cholinergic cells, as measured with both [(18)F]FEOBV and immunocytochemistry. This suggests the primary role of the PPTg cholinergic cells in sustained attention. It also allows to reliably use the PET imaging with [(18)F]FEOBV for the purpose of assessing the relationship between behavior and cholinergic innervation in living animals.

  15. Effects of anticholinesterase agents on synaptic transmission in the in vitro and in vivo pontine reticular formation. An electrophysiological characterization of Medical Pontine Reticular Formation (MPRF) neuronal response to cholinergic and serotonergic activation. Annual report, 15 January 1989-30 September 1990

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    McCarley, R.W.; Greene, R.W.

    1990-10-30

    Carbachol treatment of medial pontine reticular formation neurons(mPRF) neurons resulted in depolarization associated with an increase in input resistance. The inward current elicited was dependent on extracellular potassium. Carbachol also elicited a hyperpolarization associated with a conductance increase also dependent on potassium. Muscarinic responses were relatively insensitive to pirenzepine indicating mediation by non-M1 receptors. Nicotinic agonists elicited a depolarization in 77% of neurons with an inward current and conductance increase. This response was sensitive to dihydro-B-ethroidine, an antagonist of neuromuscular type nicotinic responses. Application of soman resulted in depolarization and excitation of mPRF neurons. This action was absent in the presence of tetrodotoxin. Methacholine, responses were enhanced, consistent with mediation of the soman excitation by the blockage of esterase activity. Serotonin excited 62% of the neurons, associated with inward current. These responses had a reversal potential close to that expected for potassium, consistent with a decrease in potassium conductance. The remainder became hyperpolarized.

  16. 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.

  17. Effects of chronic alcohol consumption, withdrawal and nerve growth factor on neuropeptide Y expression and cholinergic innervation of the rat dentate hilus.

    Science.gov (United States)

    Pereira, Pedro A; Rocha, João P; Cardoso, Armando; Vilela, Manuel; Sousa, Sérgio; Madeira, M Dulce

    2016-05-01

    Several studies have demonstrated the vulnerability of the hippocampal formation (HF) to chronic alcohol consumption and withdrawal. Among the brain systems that appear to be particularly vulnerable to the effects of these conditions are the neuropeptide Y (NPY)-ergic and the cholinergic systems. Because these two systems seem to closely interact in the HF, we sought to study the effects of chronic alcohol consumption (6months) and subsequent withdrawal (2months) on the expression of NPY and on the cholinergic innervation of the rat dentate hilus. As such, we have estimated the areal density and the somatic volume of NPY-immunoreactive neurons, and the density of the cholinergic varicosities. In addition, because alcohol consumption and withdrawal are associated with impaired nerve growth factor (NGF) trophic support and the administration of exogenous NGF alters the effects of those conditions on various cholinergic markers, we have also estimated the same morphological parameters in withdrawn rats infused intracerebroventricularly with NGF. NPY expression increased after withdrawal and returned to control values after NGF treatment. Conversely, the somatic volume of these neurons did not differ among all groups. On other hand, the expression of vesicular acetylcholine transporter (VAChT) was reduced by 24% in ethanol-treated rats and by 46% in withdrawn rats. The administration of NGF to withdrawn rats increased the VAChT expression to values above control levels. These results show that the effects of prolonged alcohol intake and protracted withdrawal on the hilar NPY expression differ from those induced by shorter exposures to ethanol and by abrupt withdrawal. They also suggest that the normalizing effect of NGF on NPY expression might rely on the NGF-induced improvement of cholinergic neurotransmission in the dentate hilus.

  18. Subcellular redistribution of m2 muscarinic acetylcholine receptors in striatal interneurons in vivo after acute cholinergic stimulation.

    Science.gov (United States)

    Bernard, V; Laribi, O; Levey, A I; Bloch, B

    1998-12-01

    The purpose of our work was to investigate how the cholinergic environment influences the targeting and the intracellular trafficking of the muscarinic receptor m2 (m2R) in vivo. To address this question, we have used immunohistochemical approaches at light and electron microscopic levels to detect the m2R in control rats and rats treated with muscarinic receptor agonists. In control animals, m2Rs were located mostly at postsynaptic sites at the plasma membrane of perikarya and dendrites of cholinergic and NPY-somatostatin interneurons as autoreceptors and heteroreceptors, respectively. Presynaptic receptors were also detected in boutons. The m2Rs were usually detected at extrasynaptic sites, but they could be found rarely in association with symmetrical synapses, suggesting that the cholinergic transmission mediated by m2R occurs via synaptic and nonsynaptic mechanisms. The stimulation of muscarinic receptors with oxotremorine provoked a dramatic alteration of m2R compartmentalization, including endocytosis with a decrease of the density of m2R at the membrane (-63%) and an increase of those associated with endosomes (+86%) in perikarya. The very strong increase of m2R associated with multivesicular bodies (+732%) suggests that oxotremorine activated degradation. The slight increase in the Golgi apparatus (+26%) suggests that the m2R stimulation had an effect on the maturation of m2R. The substance P receptor located at the membrane of the same neurons was unaffected by oxotremorine. Our data demonstrate that cholinergic stimulation dramatically influences the subcellular distribution of m2R in striatal interneurons in vivo. These events may have key roles in controlling abundance and availability of muscarinic receptors via regulation of receptor endocytosis, degradation, and/or neosynthesis. Further, the control of muscarinic receptor trafficking may influence the activity of striatal interneurons, including neurotransmitter release and/or electric activity.

  19. 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.

  20. 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.

  1. Cholinergic modulation of excitatory synaptic input integration in hippocampal CA1.

    Science.gov (United States)

    McQuiston, A Rory

    2010-10-01

    During theta rhythm, the timing of inputs to hippocampal CA1 from the perforant path (PP) of the entorhinal cortex and the Schaffer collaterals (SCs) from individual CA3 pyramidal neurons can vary within an individual theta period. Importantly, during theta rhythms these interactions occur during elevated acetylcholine concentrations. Thus, I examined the effect that PP inputs have on SC inputs in hippocampal CA1 during cholinergic receptor activation. To do this I measured the impact that a single electrical stimulus of the stratum lacunosum-moleculare (SLM, which contains the PP) had on excitation evoked by stimulation of the stratum radiatum (SR, which contains the SC) using voltage-sensitive dye imaging, field excitatory postsynaptic potentials and whole cell patch clamping in rat hippocampal brain slices. My data showed that SLM stimulation one half a theta cycle or less (25-75 ms) before SR stimulation resulted in the summation of excitatory events in SR and SP of hippocampal CA1. The summation was unaffected by cholinergic receptor activation by carbachol. SLM stimulation one theta cycle (150-225 ms) preceding SR stimulation significantly suppressed excitatory events measured in SR and SP. This SLM stimulus inhibition of SR-driven excitatory events was augmented by carbachol application. The carbachol effect was blocked by atropine and SLM-driven suppression of excitatory events was blocked by the GABA(B) receptor antagonist CGP 54626. SR field EPSP slopes were unaffected by SLM prepulses. Carbachol increased the probability of SR input to drive action potential firing in CA1 pyramidal neurons, which was inhibited by SLM prepulses (150-225 ms). Together these data provide important information regarding the integration of inputs in hippocampal CA1 during theta rhythms. More specifically, SR inputs can be differentially gated by SLM feedforward inhibition at varying temporal intervals within a theta cycle.

  2. Mini-ruby is rapidly taken up by neurons and astrocytes in organotypic brain slices.

    Science.gov (United States)

    Ullrich, Celine; Humpel, Christian

    2011-10-01

    Cholinergic neurons are intensively studied, because they degenerate in Alzheimer's disease. Although neurotracer techniques are widely used to study axonal transport, guidance, regeneration or sprouting it is not clear if cholinergic neurons can be stained by tracer techniques and studied in brain slices. The aim of the present study was to evaluate the characteristics of the neurotracer Mini-ruby in organotypic brain slices of the basal nucleus of Meynert (nBM), focusing on cholinergic neurons. Mini-ruby is a biotinylated dextran amine and is taken up very fast by a variety of cells. When 2-week old nerve growth factor-incubated brain slices of the nBM were treated with Mini-ruby crystals for 1 h, only a few (2-3%) cholinergic neurons were clearly labeled as shown by co-localization with choline acetyltransferase. The staining was found in neuN-positive neurons and microtubule associated protein-2 (MAP-2)-positive nerve fibers. A very rapid dynamic change was observed in these labeled varicosities within seconds. However, Mini-ruby was taken up also by many glutamine synthethase-positive astrocytes. At the site of Mini-ruby application an intense CD11b-positive microglial staining was evident. In conclusion, neurons and astrocytes in organotypic brain slices can be labeled very fast with the fluorescent dye Mini-ruby which undergoes dynamic processes.

  3. Rosmarinus officinalis polyphenols produce anti-depressant like effect through monoaminergic and cholinergic functions modulation.

    Science.gov (United States)

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

    2013-02-01

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

  4. What Makes Clusters Decline?

    DEFF Research Database (Denmark)

    Østergaard, Christian Richter; Park, Eun Kyung

    2015-01-01

    Most studies on regional clusters focus on identifying factors and processes that make clusters grow. However, sometimes technologies and market conditions suddenly shift, and clusters decline. This paper analyses the process of decline of the wireless communication cluster in Denmark....... The longitudinal study on the high-tech cluster reveals that technological lock-in and exit of key firms have contributed to decline. Entrepreneurship has a positive effect on the cluster’s adaptive capabilities, while multinational companies have contradicting effects by bringing in new resources to the cluster...

  5. US Historic Declination Calculator

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — This programs derives a table of secular change in magnetic declination for a specified point in the conterminous United States. It utilizes the USD polynomial and...

  6. ROBUST DECLINE CURVE ANALYSIS

    Directory of Open Access Journals (Sweden)

    Sutawanir Darwis

    2012-05-01

    Full Text Available Empirical decline curve analysis of oil production data gives reasonable answer in hyperbolic type curves situations; however the methodology has limitations in fitting real historical production data in present of unusual observations due to the effect of the treatment to the well in order to increase production capacity. The development ofrobust least squares offers new possibilities in better fitting production data using declinecurve analysis by down weighting the unusual observations. This paper proposes a robustleast squares fitting lmRobMM approach to estimate the decline rate of daily production data and compares the results with reservoir simulation results. For case study, we usethe oil production data at TBA Field West Java. The results demonstrated that theapproach is suitable for decline curve fitting and offers a new insight in decline curve analysis in the present of unusual observations.

  7. 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.

  8. 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.

  9. Cholinergic modulation of local pyramid-interneuron synapses exhibiting divergent short-term dynamics in rat sensory cortex.

    Science.gov (United States)

    Levy, Robert B; Reyes, Alex D; Aoki, Chiye

    2008-06-18

    Acetylcholine (ACh) influences attention, short-term memory, and sleep/waking transitions, through its modulatory influence on cortical neurons. It has been proposed that behavioral state changes mediated by ACh result from its selective effects on the intrinsic membrane properties of diverse cortical inhibitory interneuron classes. ACh has been widely shown to reduce the strength of excitatory (glutamatergic) synapses. But past studies using extracellular stimulation have not been able to examine the effects of ACh on local cortical connections important for shaping sensory processing. Here, using dual intracellular recording in slices of rat somatosensory cortex, we show that reduction of local excitatory input to inhibitory neurons by ACh is coupled to differences in the underlying short-term synaptic plasticity (STP). In synapses with short-term depression, where successive evoked excitatory postsynaptic potentials (EPSPs; >5 Hz) usually diminish in strength (short-term depression), cholinergic agonist (5-10 microM carbachol (CCh)) reduced the amplitude of the first EPSP in an evoked train, but CCh's net effect on subsequent EPSPs rapidly diminished. In synapses where successive EPSPs increased in strength (facilitation), the effect of CCh on later EPSPs in an evoked train became progressively greater. The effect of CCh on both depressing and facilitating synapses was blocked by the muscarinic antagonist, 1-5 microM atropine. It is suggested that selective influence on STP contributes fundamentally to cholinergic "switching" between cortical rhythms that underlie different behavioral states.

  10. C. elegans dopaminergic D2-like receptors delimit recurrent cholinergic-mediated motor programs during a goal-oriented behavior.

    Directory of Open Access Journals (Sweden)

    Paola Correa

    Full Text Available Caenorhabditis elegans male copulation requires coordinated temporal-spatial execution of different motor outputs. During mating, a cloacal circuit consisting of cholinergic sensory-motor neurons and sex muscles maintains the male's position and executes copulatory spicule thrusts at his mate's vulva. However, distinct signaling mechanisms that delimit these behaviors to their proper context are unclear. We found that dopamine (DA signaling directs copulatory spicule insertion attempts to the hermaphrodite vulva by dampening spurious stimulus-independent sex muscle contractions. From pharmacology and genetic analyses, DA antagonizes stimulatory ACh signaling via the D2-like receptors, DOP-2 and DOP-3, and Gα(o/i proteins, GOA-1 and GPA-7. Calcium imaging and optogenetics suggest that heightened DA-expressing ray neuron activities coincide with the cholinergic cloacal ganglia function during spicule insertion attempts. D2-like receptor signaling also attenuates the excitability of additional mating circuits to reduce the duration of mating attempts with unproductive and/or inappropriate partners. This suggests that, during wild-type mating, simultaneous DA-ACh signaling modulates the activity threshold of repetitive motor programs, thus confining the behavior to the proper situational context.

  11. Neuronal nicotinic acetylcholine receptors serve as sensitive targets that mediate β-amyloid neurotoxicity

    Institute of Scientific and Technical Information of China (English)

    Qiang LIU; Jie WU

    2006-01-01

    Alzheimer's disease (AD) is the most common form of brain dementia characterized by the accumulation of β-amyloid peptides (Aβ) and loss of forebrain cholinergic neurons. Aβ accumulation and aggregation are thought to contribute to cholinergic neuronal degeneration, in turn causing learning and memory deficits, but the specific targets that mediate Aβ neurotoxicity remain elusive. Recently, accumlating lines of evidence have demonstrated that Aβ directly modulates the function of neuronal nicotinic acetylcholine receptors (nAChRs), which leads to the new hypothesis that neuronal nAChRs may serve as important targets that mediate Aβ neurotoxicity. In this review, we summarize current studies performed in our laboratory and in others to address the question of how Aβ modulates neuronal nAChRs, especially nAChR subunit function.

  12. 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.

  13. A neuronal acetylcholine receptor regulates the balance of muscle excitation and inhibition in Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    Maelle Jospin

    2009-12-01

    Full Text Available In the nematode Caenorhabditis elegans, cholinergic motor neurons stimulate muscle contraction as well as activate GABAergic motor neurons that inhibit contraction of the contralateral muscles. Here, we describe the composition of an ionotropic acetylcholine receptor that is required to maintain excitation of the cholinergic motor neurons. We identified a gain-of-function mutation that leads to spontaneous muscle convulsions. The mutation is in the pore domain of the ACR-2 acetylcholine receptor subunit and is identical to a hyperactivating mutation in the muscle receptor of patients with myasthenia gravis. Screens for suppressors of the convulsion phenotype led to the identification of other receptor subunits. Cell-specific rescue experiments indicate that these subunits function in the cholinergic motor neurons. Expression of these subunits in Xenopus oocytes demonstrates that the functional receptor is comprised of three alpha-subunits, UNC-38, UNC-63 and ACR-12, and two non-alpha-subunits, ACR-2 and ACR-3. Although this receptor exhibits a partially overlapping subunit composition with the C. elegans muscle acetylcholine receptor, it shows distinct pharmacology. Recordings from intact animals demonstrate that loss-of-function mutations in acr-2 reduce the excitability of the cholinergic motor neurons. By contrast, the acr-2(gf mutation leads to a hyperactivation of cholinergic motor neurons and an inactivation of downstream GABAergic motor neurons in a calcium dependent manner. Presumably, this imbalance between excitatory and inhibitory input into muscles leads to convulsions. These data indicate that the ACR-2 receptor is important for the coordinated excitation and inhibition of body muscles underlying sinusoidal movement.

  14. 可视法脑片膜片钳技术观察大鼠前庭内侧核神经元毒蕈碱样胆碱能受体的电生理特性%Electrophysiological characteristics of muscarinic cholinergic receptor in rat medial vestibular nucleus neurons by visual patch clamp technique

    Institute of Scientific and Technical Information of China (English)

    张宇; 孔维佳; 刘邦华; 郭长凯; 孙大为; 夏交; 朱云; 张建

    2007-01-01

    目的 建立大鼠前庭内侧核脑片可视法膜片钳实验技术,探讨前庭内侧核神经元毒蕈碱样胆碱能受体(muscarinic cholinergic receptor,M受体)介导电流的生物学特性.方法 选用15只Wistar大鼠用于制备前庭内侧核脑片,应用红外微分干涉相差(infrared differential interference contrast,IR-DIC)技术结合电荷耦合式感光成像(charge coupled device-camera,CCD-camera)系统,在可视法膜片钳全细胞记录模式下对20个正常功能状态的前庭内侧核神经元M受体的通道电流性质进行观察和分析.结果 可视法脑片膜片钳技术可对神经元直接进行准确定位和功能状态的筛选.前庭内侧核神经元给予毒蕈碱后电流-电压(I-V)曲线斜率增加,毒蕈碱引发效应电流的反转电位为(-88.4±4.9)mV((-x)±s,下同),表明M受体去极化效应是由钾电导的减少所介导;M受体介导电流的电压敏感性测试显示:毒蕈碱引发的效应曲线呈线性关系,反转电位为(-86.7±3.5)mV,提示毒蕈碱所阻断的钾电流为非电压敏感性的漏钾电流.结论 可视法脑片膜片钳实验技术克服了盲法脑片膜片钳技术的缺陷,提高了神经元封接的成功率.通过对前庭内侧核神经元M受体通道电流性质的分析,进一步揭示毒蕈碱样胆碱能机制的兴奋性调节作用,为临床抗胆碱药物的应用提供新思路.

  15. 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

  16. 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.

  17. 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

  18. 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.

  19. Cluster Decline and Resilience

    DEFF Research Database (Denmark)

    Østergaard, Christian Richter; Park, Eun Kyung

    -2011. Our longitudinal study reveals that technological lock-in and exit of key firms have contributed to impairment of the cluster’s resilience in adapting to disruptions. Entrepreneurship has a positive effect on cluster resilience, while multinational companies have contradicting effects by bringing......Most studies on regional clusters focus on identifying factors and processes that make clusters grow. However, sometimes technologies and market conditions suddenly shift, and clusters decline. This paper analyses the process of decline of the wireless communication cluster in Denmark, 1963...

  20. Well production decline

    Energy Technology Data Exchange (ETDEWEB)

    Cvetkovic, Branimir

    2008-12-15

    Effective rate-time analysis during a declining production in an oil or gas wells is an important tool for establishing a successful management. The reasons behind the production decline include reservoir, fracture and well conditions. A well's decline rate is transient, signifying that the pressure wave propagates freely from the wellbore, leading to depletion when the outer boundary for the well is reached and to the wave propagation coming to a halt. This thesis studies the transient decline, with emphasis on a horizontal well with fracture wellbore responses. It also deals with the depletion decline, investigating the wellbore pressure responses for a vertical well producing under variable rate conditions of Arps decline. The well decline model solutions are analytical, and the modelling itself is carried out in two steps. The first step involves modelling the transient well responses of a multi fractured horizontal well. These responses originate from an infinitive reservoir and are considered as full-time rate-time responses. Multi-fractured horizontal well rate-time responses represent the solutions to a diffusion equation with varying boundary conditions and different fracture options (i.e., with or without fracture, a variety of fracture orientations, various fracture lengths, etc). The transient model calculates individual fracture rates, productivity indexes and an equivalent wellbore radius for the multi-fractured well. For the transient decline of a fractured-horizontal well model, well data is matched and the reservoir diagnosis and production prognosis are improved through the individual fracture production, with a model screening ability, and novel model features that can handle wellbore conditions changing from rate-to-pressure. Screening analyses can generate valuable information for fracture diagnosis in addition to a well and fracture production prognosis. Further model runs are carried out to match the real well data. The model solution is

  1. 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.

  2. 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

  3. Contribution of nitric oxide synthase isoforms to cholinergic vasodilation in murine retinal arterioles.

    Science.gov (United States)

    Gericke, Adrian; Goloborodko, Evgeny; Sniatecki, Jan J; Steege, Andreas; Wojnowski, Leszek; Pfeiffer, Norbert

    2013-04-01

    Nitric oxide synthases (NOSs) are critically involved in regulation of ocular perfusion. However, the contribution of the individual NOS isoforms to vascular responses is unknown in the retina. Because some previous findings suggested an involvement of inducible nitric oxide synthase (iNOS) in the regulation of retinal vascular tone, a major goal of the present study was to examine the hypothesis that iNOS is involved in mediating cholinergic vasodilation responses of murine retinal arterioles. Another subject of this study was to test the contribution of the other two NOS isoforms, neuronal (nNOS) and endothelial NOS (eNOS), to cholinergic retinal arteriole responses. Expression of individual NOS isoforms was determined in murine retinal arterioles using real-time PCR. All three NOS isoforms were expressed in retinal arterioles. However, eNOS mRNA was found to be most, and iNOS mRNA least abundant. To examine the functional relevance of iNOS for mediating vascular responses, retinal vascular preparations from gene-targeted iNOS-deficient mice (iNOS-/-) and wild-type mice were studied in vitro. Changes in luminal vessel diameter in response to the thromboxane mimetic 9,11-dideoxy-9α,11α-methanoepoxy prostaglandin F2α (U-46619), the endothelium-dependent vasodilator acetylcholine, and the nitric oxide donor nitroprusside were measured by video microscopy. To determine the contribution of individual NOS isoforms to cholinergic vasodilation responses, retinas from iNOS-/- and wild-type mice were incubated with Nω-nitro-l-arginine methyl ester (l-NAME), a non-isoform-selective inhibitor of NOS, 7-nitroindazole, a selective nNOS blocker and aminoguanidine, a selective iNOS inhibitor. U-46619 evoked concentration-dependent vasoconstriction that was similar in retinal arterioles from iNOS-/- and wild-type mice. In retinal arterioles preconstricted with U-46619, acetylcholine and nitroprusside produced dose-dependent dilation that did not differ between iNOS-/- and

  4. 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

  5. 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

  6. Intrinsic membrane properties underlying spontaneous tonic firing in neostriatal cholinergic interneurons.

    Science.gov (United States)

    Bennett, B D; Callaway, J C; Wilson, C J

    2000-11-15

    Neostriatal cholinergic interneurons produce spontaneous tonic firing in the absence of synaptic input. Perforated patch recording and whole-cell recording combined with calcium imaging were used in vitro to identify the intrinsic membrane properties underlying endogenous excitability. Spontaneous firing was driven by the combined action of a sodium current and the hyperpolarization-activated cation current (I(h)), which together ensured that there was no zero current point in the subthreshold voltage range. Blockade of sodium channels or I(h) established a stable subthreshold resting membrane potential. A tetrodotoxin-sensitive region of negative slope conductance was observed between approximately -60 mV and threshold (approximately -50 mV) and the h-current was activated at all subthreshold voltages. Calcium imaging experiments revealed that there was minimal calcium influx at subthreshold membrane potentials but that action potentials produced elevations of calcium in both the soma and dendrites. Spike-triggered calcium entry shaped the falling phase of the action potential waveform and activated calcium-dependent potassium channels. Blockade of big-conductance channels caused spike broadening. Application of apamin, which blocks small-conductance channels, abolished the slow spike afterhyperpolarization (AHP) and caused a transition to burst firing. In the absence of synaptic input, a range of tonic firing patterns are observed, suggesting that the characteristic spike sequences described for tonically active cholinergic neurons (TANs) recorded in vivo are intrinsic in origin. The pivotal role of the AHP in regulating spike patterning indicates that burst firing of TANs in vivo could arise from direct or indirect modulation of the AHP without requiring phasic synaptic input.

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

    Directory of Open Access Journals (Sweden)

    Ying Jiang

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

  8. Nicotine-Induced Modulation of the Cholinergic Twitch Response in the Ileum of Guinea Pig.

    Science.gov (United States)

    Donnerer, Josef; Liebmann, Ingrid

    2015-01-01

    In the present study, the direct drug effects of nicotine and its effects on the cholinergic twitch responses of the electrically stimulated longitudinal muscle-myenteric plexus strip from the ileum of guinea pig were investigated. Nicotine dose-dependently (0.3-10 µmol/l) evoked the well-known contractile responses on its own. Whereas the interposed twitch responses remained present without a change in height at 1 µmol/l nicotine, a nicotine concentration of 3 µmol/l slightly and a concentration of 10 µmol/l markedly diminished the twitch during their presence. After the washout of 1-10 µmol/l nicotine, the height of the twitch response was also temporarily and significantly reduced by 30-77%. The P2X purinoceptor agonist αβ-methylene ATP (1-10 µmol/l) dose-dependently induced contractions on its own and reduced the twitch response during its presence in the organ bath; however, it did not diminish the twitch responses after washout of the drug as nicotine did. The P2X antagonist pyridoxalphosphate-6-azophenyl-2'-4'-disulphonic acid, the NMDA channel blocker MK-801 and the inhibitor of small conductance Ca(2+)-activated K(+) (SK) channels apamin reduced the contractile effect of 1 µmol/l nicotine. Apamin also significantly prevented the 'post-nicotine inhibition of the twitch' following the washout of 1-3 µmol/l nicotine. As a conclusion, we provide evidence for a functional interaction between nicotinic receptors and the P2X receptors in the ileum of the guinea pig. The 'post-nicotine inhibition of the twitch' is not due to nicotinic acetylcholine receptor desensitization or transmitter depletion, but most probably the secondary effects of nicotine on SK channels determine the reduced cholinergic motor neuron excitability.

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

    Directory of Open Access Journals (Sweden)

    Jun Il Kang

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

  10. Differential expression of voltage-gated K+ currents in medial septum/diagonal band complex neurons exhibiting distinct firing phenotypes

    OpenAIRE

    Garrido-Sanabria, Emilio R.; Perez-Cordova, Miriam G.; Colom, Luis V.

    2011-01-01

    The medial septum/diagonal band complex (MSDB) controls hippocampal excitability, rhythms and plastic processes. Medial septal neuronal populations display heterogeneous firing patterns. In addition, some of these populations degenerate during age-related disorders (e.g. cholinergic neurons). Thus, it is particularly important to examine the intrinsic properties of theses neurons in order to create new agents that effectively modulate hippocampal excitability and enhance memory processes. Her...

  11. A point mutation in the hair cell nicotinic cholinergic receptor prolongs cochlear inhibition and enhances noise protection.

    Directory of Open Access Journals (Sweden)

    Julian Taranda

    2009-01-01

    Full Text Available The transduction of sound in the auditory periphery, the cochlea, is inhibited by efferent cholinergic neurons projecting from the brainstem and synapsing directly on mechanosensory hair cells. One fundamental question in auditory neuroscience is what role(s this feedback plays in our ability to hear. In the present study, we have engineered a genetically modified mouse model in which the magnitude and duration of efferent cholinergic effects are increased, and we assess the consequences of this manipulation on cochlear function. We generated the Chrna9L9'T line of knockin mice with a threonine for leucine change (L9'T at position 9' of the second transmembrane domain of the alpha9 nicotinic cholinergic subunit, rendering alpha9-containing receptors that were hypersensitive to acetylcholine and had slower desensitization kinetics. The Chrna9L9'T allele produced a 3-fold prolongation of efferent synaptic currents in vitro. In vivo, Chrna9L9'T mice had baseline elevation of cochlear thresholds and efferent-mediated inhibition of cochlear responses was dramatically enhanced and lengthened: both effects were reversed by strychnine blockade of the alpha9alpha10 hair cell nicotinic receptor. Importantly, relative to their wild-type littermates, Chrna9(L9'T/L9'T mice showed less permanent hearing loss following exposure to intense noise. Thus, a point mutation designed to alter alpha9alpha10 receptor gating has provided an animal model in which not only is efferent inhibition more powerful, but also one in which sound-induced hearing loss can be restrained, indicating the ability of efferent feedback to ameliorate sound trauma.

  12. Puerarin partly counteracts the inflammatory response after cerebral ischemia/reperfusion via activating the cholinergic anti-inflammatory pathway

    Institute of Scientific and Technical Information of China (English)

    Xiaojie Liu; Zhigang Mei; Jingping Qian; Yongbao Zeng; Mingzhi Wang

    2013-01-01

    Puerarin, a major isoflavonoid derived from the Chinese medical herb radix puerariae (Gegen), has been reported to inhibit neuronal apoptosis and play an anti-inflammatory role in focal cerebral ischemia model rats. Recent findings regarding stroke pathophysiology have recognized that an-ti-inflammation is an important target for the treatment of ischemic stroke. The cholinergic an-ti-inflammatory pathway is a highly robust neural-immune mechanism for inflammation control. This study was to investigate whether activating the cholinergic anti-inflammatory pathway can be in-volved in the mechanism of inhibiting the inflammatory response during puerarin-induced cerebral ischemia/reperfusion in rats. Results showed that puerarin pretreatment (intravenous injection) re-duced the ischemic infarct volume, improved neurological deficit after cerebral ischemia/reperfusion and decreased the levels of interleukin-1β, interleukin-6 and tumor necrosis factor-αin brain tissue. Pretreatment with puerarin (intravenous injection) attenuated the inflammatory response in rats, which was accompanied by janus-activated kinase 2 (JAK2) and signal transducers and activators of transcription 3 (STAT3) activation and nuclear factor kappa B (NF-κB) inhibition. These observa-tions were inhibited by the alpha7 nicotinic acetylcholine receptor (α7nAchR) antagonistα-bungarotoxin (α-BGT). In addition, puerarin pretreatment increased the expression of α7nAchR mRNA in ischemic cerebral tissue. These data demonstrate that puerarin pretreatment strongly protects the brain against cerebral ischemia/reperfusion injury and inhibits the inflammatory re-sponse. Our results also indicated that the anti-inflammatory effect of puerarin may partly be me-diated through the activation of the cholinergic anti-inflammatory pathway.

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

    Science.gov (United States)

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

    2010-11-01

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

  14. Impact of Altered Cholinergic Tones on the Neurovascular Coupling Response to Whisker Stimulation.

    Science.gov (United States)

    Lecrux, Clotilde; Sandoe, Claire H; Neupane, Sujaya; Kropf, Pascal; Toussay, Xavier; Tong, Xin-Kang; Lacalle-Aurioles, María; Shmuel, Amir; Hamel, Edith

    2017-02-08

    imaging techniques. However, the impact of altered brain states on this relationship is largely unknown. We therefore investigated how acetylcholine (ACh), known to drive brain states of attention and arousal and to be deficient in pathologies such as Alzheimer's disease, would alter neurovascular coupling responses to sensory stimulation. Whereas acutely increased ACh enhanced neuronal responses and the resulting hemodynamic signals, chronic loss of cholinergic input resulted in dramatic impairments in both types of sensory-evoked signals. We conclude that ACh is not only a potent modulator but also a requirement for the full expression of sensory-evoked neurovascular coupling responses. Copyright © 2017 the authors 0270-6474/17/371518-14$15.00/0.

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. 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...

  20. 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...

  1. The involvement of ventral tegmental area cholinergic muscarinic receptors in classically conditioned fear expression as measured with fear-potentiated startle.

    Science.gov (United States)

    Greba, Q; Munro, L J; Kokkinidis, L

    2000-07-01

    Accumulating evidence suggests that dopamine (DA) neurons in the ventral tegmental area (VTA) contribute to the complex amygdala-based neurocircuitry that mediates fear-motivated behaviors. Because of acetylcholine's (ACh) role in DA neuronal activation, the involvement of VTA cholinergic muscarinic receptors in Pavlovian conditioned fear responding was evaluated in the present study. Fear-potentiated startle was used to assess the effects of intraVTA infused methylscopolamine on conditioned fear performance in laboratory rats. Application of this nonspecific muscarinic receptor antagonist to VTA neurons was observed to inhibit the ability of a conditioned stimulus (CS) previously paired with footshock to enhance the amplitude of the acoustic startle reflex. Doses of methylscopolamine that blocked conditioned fear expression did not alter baseline sensorimotor responding. These results identify ACh neurotransmission in the VTA as a potential excitatory mechanism underlying the fear-arousing properties of threatening environmental stimuli.

  2. 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.

  3. 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.

  4. 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.

  5. Special function of nestin+neurons in the medial septum-diagonal band of Broca in adult rats

    Institute of Scientific and Technical Information of China (English)

    Yuhong Zhao; Kaihua Guo; Dongpei Li; Qunfang Yuan; Zhibin Yao

    2014-01-01

    Nestin+neurons have been shown to express choline acetyltransferase (ChAT) in the medial septum-diagonal band of Broca in adult rats. This study explored the projection of nestin+neu-rons to the olfactory bulb and the time course of nestin+neurons in the medial septum-diagonal band of Broca in adult rats during injury recovery after olfactory nerve transection. This study observed that all nestin+neurons were double-labeled with ChAT in the medial septum-diagonal band of Broca. Approximately 53.6%of nestin+neurons were projected to the olfactory bulb and co-labeled with fast blue. A large number of nestin+neurons were not present in each region of the medial septum-diagonal band of Broca. Nestin+neurons in the medial septum and vertical limb of the diagonal band of Broca showed obvious compensatory function. The number of nestin+neurons decreased to a minimum later than nestin-/ChAT+neurons in the medial sep-tum-diagonal band of Broca. The results suggest that nestin+cholinergic neurons may have a closer connection to olfactory bulb neurons. Nestin+cholinergic neurons may have a stronger tolerance to injury than Nestin-/ChAT+neurons. The difference between nestin+and nestin-/ChAT+neurons during the recovery process requires further investigations.

  6. 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....

  7. Fertility decline in Paraguay.

    Science.gov (United States)

    Ishida, Kanako; Stupp, Paul; Melian, Mercedes

    2009-09-01

    Recent reproductive health surveys show that the fertility rate in Paraguay decreased precipitously from 4.3 lifetime births per woman in 1995-98 to 2.9 births in 2001-04. In this study, we establish data consistency between the 1998 and 2004 surveys by comparing a series of cohort-specific period rates and use the Bongaarts framework of proximate determinants of fertility to demonstrate that an increase in the contraceptive prevalence rate (CPR) between 1998 and 2004 fully accounts for the fertility decline. Decomposition of rates shows that changes in group-specific CPRs explain a greater proportion of the change in the overall CPR than do changes in population composition by educational attainment, urban residence, region, and language spoken at home. Finally, we show that younger cohorts of women in 2004 reported ideal completed fertility desires of less than 2.9 births, suggesting that the fertility rate is likely to continue to decrease.

  8. Mangrove forest decline

    DEFF Research Database (Denmark)

    Malik, Abdul; Mertz, Ole; Fensholt, Rasmus

    2017-01-01

    Mangrove forests in the tropics and subtropics grow in saline sediments in coastal and estuarine environments. Preservation of mangrove forests is important for many reasons, including the prevention of coastal erosion and seawater intrusion; the provision of spawning, nursery, and feeding grounds...... and severe mangrove loss with serious consequences. The mangrove forests of the Takalar District, South Sulawesi, are studied here as a case area that has suffered from degradation and declining spatial extent during recent decades. On the basis of a post-classification comparison of change detection from...... satellite imagery and a survey of households, we provide an estimate of the mangrove change in the Takalar District during 1979–2011 and the consequences of those changes. Mangrove forest areas were reduced by 66.05 % (3344 hectares) during the 33-year period of analysis, and the biggest annual negative...

  9. Mobility decline in old age

    DEFF Research Database (Denmark)

    Rantakokko, Merja; Mänty, Minna Regina; Rantanen, Taina

    2013-01-01

    Mobility is important for community independence. With increasing age, underlying pathologies, genetic vulnerabilities, physiological and sensory impairments, and environmental barriers increase the risk for mobility decline. Understanding how mobility declines is paramount to finding ways to pro...... to promote mobility in old age.......Mobility is important for community independence. With increasing age, underlying pathologies, genetic vulnerabilities, physiological and sensory impairments, and environmental barriers increase the risk for mobility decline. Understanding how mobility declines is paramount to finding ways...

  10. Penconazole alters redox status, cholinergic function, and membrane-bound ATPases in the cerebrum and cerebellum of adult rats.

    Science.gov (United States)

    Chaâbane, M; Ghorbel, I; Elwej, A; Mnif, H; Boudawara, T; Chaâbouni, S Ellouze; Zeghal, N; Soudani, N

    2017-08-01

    Pesticides exposure causes usually harmful effects to the environment and human health. The present study aimed to investigate the potential toxic effects of penconazole, a triazole fungicide, on the cerebrum and cerebellum of adult rats. Penconazole was administered intraperitoneally to male Wistar rats at a dose of 67 mg kg(-1) body weight every 2 days during 9 days. Results showed that penconazole induced oxidative stress in rat cerebrum and cerebellum tissues. In fact, we have found a significant increase in malondialdehyde, hydrogen peroxide, and advanced oxidation protein product levels, as well as an alteration of the antioxidant status, enzymatic (superoxide dismutase and catalase) and nonenzymatic (glutathione), the cholinergic function, and membrane-bound ATPases (Na(+)/K(+)-ATPase and Mg(2+)-ATPase). Penconazole also provoked histological alterations marked by pyknotic and vacuolated neurons in the cerebrum and apoptosis and edema in the cerebellum Purkinje cells' layer. Therefore, the use of this neurotoxicant fungicide must be regularly monitored in the environment.

  11. Direction-selective circuitry in rat retina develops independently of GABAergic, cholinergic and action potential activity.

    Directory of Open Access Journals (Sweden)

    Le Sun

    Full Text Available The ON-OFF direction selective ganglion cells (DSGCs in the mammalian retina code image motion by responding much more strongly to movement in one direction. They do so by receiving inhibitory inputs selectively from a particular sector of processes of the overlapping starburst amacrine cells, a type of retinal interneuron. The mechanisms of establishment and regulation of this selective connection are unknown. Here, we report that in the rat retina, the morphology, physiology of the ON-OFF DSGCs and the circuitry for coding motion directions develop normally with pharmacological blockade of GABAergic, cholinergic activity and/or action potentials for over two weeks from birth. With recent results demonstrating light independent formation of the retinal DS circuitry, our results strongly suggest the formation of the circuitry, i.e., the connections between the second and third order neurons in the visual system, can be genetically programmed, although emergence of direction selectivity in the visual cortex appears to require visual experience.

  12. Therapeutic potential and limitations of cholinergic anti-inflammatory pathway in sepsis.

    Science.gov (United States)

    Kanashiro, Alexandre; Sônego, Fabiane; Ferreira, Raphael G; Castanheira, Fernanda V S; Leite, Caio A; Borges, Vanessa F; Nascimento, Daniele C; Cólon, David F; Alves-Filho, José Carlos; Ulloa, Luis; Cunha, Fernando Q

    2017-03-01

    Sepsis is one of the main causes of mortality in hospitalized patients. Despite the recent technical advances and the development of novel generation of antibiotics, severe sepsis remains a major clinical and scientific challenge in modern medicine. Unsuccessful efforts have been dedicated to the search of therapeutic options to treat the deleterious inflammatory components of sepsis. Recent findings on neuronal networks controlling immunity raised expectations for novel therapeutic strategies to promote the regulation of sterile inflammation, such as autoimmune diseases. Interesting studies have dissected the anatomical constituents of the so-called "cholinergic anti-inflammatory pathway", suggesting that electrical vagus nerve stimulation and pharmacological activation of beta-2 adrenergic and alpha-7 nicotinic receptors could be alternative strategies for improving inflammatory conditions. However, the literature on infectious diseases, such as sepsis, is still controversial and, therefore, the real therapeutic potential of this neuroimmune pathway is not well defined. In this review, we will discuss the beneficial and detrimental effects of neural manipulation in sepsis, which depend on the multiple variables of the immune system and the nature of the infection. These observations suggest future critical studies to validate the clinical implications of vagal parasympathetic signaling in sepsis treatment.

  13. Expression of the M3 Muscarinic Receptor on Orexin Neurons that Project to the Rostral Ventrolateral Medulla.

    Science.gov (United States)

    Dai, Yu-Wen E; Lee, Yen-Hsien; Chen, Jennifer Y S; Lin, Yen-Kuang; Hwang, Ling-Ling

    2016-05-01

    Activation of central cholinergic receptors causes a pressor response in rats, and the hypothalamus is important for this response. Projections from hypothalamic orexin neurons to the rostral ventrolateral medulla (RVLM) are involved in sympatho-excitation of the cardiovascular system. A small population of orexin neurons is regulated by cholinergic inputs through M3 muscarinic acetylcholine receptor (M3 R). To elucidate whether the M3 R on orexin neurons is involved in cardiosympathetic regulation through the RVLM, we examined the presence of the M3 R on retrograde-labeled RVLM-projecting orexin neurons. The retrograde tracer was unilaterally injected into the RVLM. Within the hypothalamus, retrograde-labeled neurons were located predominantly ipsilateral to the injection side. In the anterior hypothalamus (-1.5 to -2.3 mm to the bregma), retrograde-labeled neurons were densely distributed in the paraventricular nuclei and scattered in the retrochiasmatic area. At -2.3 to -3.5 mm from the bregma, labeled neurons were located in the regions where orexin neurons were situated, that is, the tuberal lateral hypothalamic area, perifornical area, and dorsomedial nuclei. Very few retrograde-labeled neurons were observed in the hypothalamus at -3.5 to -4.5 mm from the bregma. About 19.5% ± 1.6% of RVLM-projecting neurons in the tuberal hypothalamus were orexinergic. The M3 R was present on 18.7% ± 3.0% of RVLM-projecting orexin neurons. Injection of a muscarinic agonist, oxotremorine, in the perifornical area resulted in a pressor response, which was attenuated by a pretreatment of atropine. We conclude that cholinergic inputs to orexin neurons may be involved in cardiosympathetic regulation through the M3 R on the orexin neurons that directly project to the RVLM.

  14. Ameliorative Effect of Ginsenoside Rg1 on Lipopolysaccharide-Induced Cognitive Impairment: Role of Cholinergic System.

    Science.gov (United States)

    Jin, Yang; Peng, Jian; Wang, Xiaona; Zhang, Dong; Wang, Tianyin

    2017-01-11

    Bacterial endotoxin lipopolysaccharide (LPS) can induce systemic inflammation, and therefore disrupt learning and memory processes. Ginsenoside Rg1, a major bioactive component of ginseng, is shown to greatly improve cognitive function. The present study was designed to further investigate whether administration of ginsenoside Rg1 can ameliorate LPS-induced cognitive impairment in the Y-maze and Morris water maze (MWM) task, and to explore the underlying mechanisms. Results showed that exposure to LPS (500 μg/kg) significantly impaired working and spatial memory and that repeated treatment with ginsenoside Rg1 (200 mg/kg/day, for 30 days) could effectively alleviate the LPS-induced cognitive decline as indicated by increased working and spatial memory in the Y-maze and MWM tests. Furthermore, ginsenoside Rg1 treatment prevented LPS-induced decrease of acetylcholine (ACh) levels and increase of acetylcholinesterase (AChE) activity. Ginsenoside Rg1 treatment also reverted the decrease of alpha7 nicotinic acetylcholine receptor (α7 nAChR) protein expression in the prefrontal cortex (PFC) and hippocampus of LPS-treated rats. These findings suggest that ginsenoside Rg1 has protective effect against LPS-induced cognitive deficit and that prevention of LPS-induced changes in cholinergic system is crucial to this ameliorating effect.

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

    Directory of Open Access Journals (Sweden)

    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

  16. 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.

  17. Midazolam-ketamine dual therapy stops cholinergic status epilepticus and reduces Morris water maze deficits.

    Science.gov (United States)

    Niquet, Jerome; Baldwin, Roger; Norman, Keith; Suchomelova, Lucie; Lumley, Lucille; Wasterlain, Claude G

    2016-09-01

    Pharmacoresistance remains an unsolved therapeutic challenge in status epilepticus (SE) and in cholinergic SE induced by nerve agent intoxication. SE triggers a rapid internalization of synaptic γ-aminobutyric acid A (GABAA ) receptors and externalization of N-methyl-d-aspartate (NMDA) receptors that may explain the loss of potency of standard antiepileptic drugs (AEDs). We hypothesized that a drug combination aimed at correcting the consequences of receptor trafficking would reduce SE severity and its long-term consequences. A severe model of SE was induced in adult Sprague-Dawley rats with a high dose of lithium and pilocarpine. The GABAA receptor agonist midazolam, the NMDA receptor antagonist ketamine, and/or the AED valproate were injected 40 min after SE onset in combination or as monotherapy. Measures of SE severity were the primary outcome. Secondary outcomes were acute neuronal injury, spontaneous recurrent seizures (SRS), and Morris water maze (MWM) deficits. Midazolam-ketamine dual therapy was more efficient than double-dose midazolam or ketamine monotherapy or than valproate-midazolam or valproate-ketamine dual therapy in reducing several parameters of SE severity, suggesting a synergistic mechanism. In addition, midazolam-ketamine dual therapy reduced SE-induced acute neuronal injury, epileptogenesis, and MWM deficits. This study showed that a treatment aimed at correcting maladaptive GABAA receptor and NMDA receptor trafficking can stop SE and reduce its long-term consequences. Early midazolam-ketamine dual therapy may be superior to monotherapy in the treatment of benzodiazepine-refractory SE. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

  18. 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

  19. 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

  20. Central cholinergic control of vasopressin release in conscious rats

    Energy Technology Data Exchange (ETDEWEB)

    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.

  1. 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

  2. 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

  3. Transmitter modulation of spike-evoked calcium transients in arousal related neurons

    DEFF Research Database (Denmark)

    Kohlmeier, Kristi Anne; Leonard, Christopher S

    2006-01-01

    Nitric oxide synthase (NOS)-containing cholinergic neurons in the laterodorsal tegmentum (LDT) influence behavioral and motivational states through their projections to the thalamus, ventral tegmental area and a brainstem 'rapid eye movement (REM)-induction' site. Action potential-evoked intracel......Nitric oxide synthase (NOS)-containing cholinergic neurons in the laterodorsal tegmentum (LDT) influence behavioral and motivational states through their projections to the thalamus, ventral tegmental area and a brainstem 'rapid eye movement (REM)-induction' site. Action potential......-evoked intracellular calcium transients dampen excitability and stimulate NO production in these neurons. In this study, we investigated the action of several arousal-related neurotransmitters and the role of specific calcium channels in these LDT Ca(2+)-transients by simultaneous whole-cell recording and calcium...... of cholinergic LDT neurons and that inhibition of spike-evoked Ca(2+)-transients is a common action of neurotransmitters that also activate GIRK channels in these neurons. Because spike-evoked calcium influx dampens excitability, our findings suggest that these 'inhibitory' transmitters could boost firing rate...

  4. MOLECULAR-BIOLOGY OF CLOSTRIDIAL TOXINS - EXPRESSION OF MESSENGER-RNAS ENCODING TETANUS AND BOTULINUM NEUROTOXINS IN APLYSIA NEURONS

    NARCIS (Netherlands)

    MOCHIDA, S; POULAIN, B; EISEL, U; BINZ, T; KURAZONO, H; NIEMANN, H; TAUC, L

    1990-01-01

    mRNAs encoding the light chain of tetanus and botulinum neurotoxins were transcribed, in vitro, from the cloned and specifically truncated genes of Clostridium tetani and Clostridium botulinum, respectively, and injected into presynaptic identified cholinergic neurons of the buccal ganglia of

  5. MOLECULAR-BIOLOGY OF CLOSTRIDIAL TOXINS - EXPRESSION OF MESSENGER-RNAS ENCODING TETANUS AND BOTULINUM NEUROTOXINS IN APLYSIA NEURONS

    NARCIS (Netherlands)

    MOCHIDA, S; POULAIN, B; EISEL, U; BINZ, T; KURAZONO, H; NIEMANN, H; TAUC, L

    1990-01-01

    mRNAs encoding the light chain of tetanus and botulinum neurotoxins were transcribed, in vitro, from the cloned and specifically truncated genes of Clostridium tetani and Clostridium botulinum, respectively, and injected into presynaptic identified cholinergic neurons of the buccal ganglia of Aplysi

  6. Exposure to multiple cholinergic pesticides impairs olfactory learning and memory in honeybees.

    Science.gov (United States)

    Williamson, Sally M; Wright, Geraldine A

    2013-05-15

    Pesticides are important agricultural tools often used in combination to avoid resistance in target pest species, but there is growing concern that their widespread use contributes to the decline of pollinator populations. Pollinators perform sophisticated behaviours while foraging that require them to learn and remember floral traits associated with food, but we know relatively little about the way that combined exposure to multiple pesticides affects neural function and behaviour. The experiments reported here show that prolonged exposure to field-realistic concentrations of the neonicotinoid imidacloprid and the organophosphate acetylcholinesterase inhibitor coumaphos and their combination impairs olfactory learning and memory formation in the honeybee. Using a method for classical conditioning of proboscis extension, honeybees were trained in either a massed or spaced conditioning protocol to examine how these pesticides affected performance during learning and short- and long-term memory tasks. We found that bees exposed to imidacloprid, coumaphos, or a combination of these compounds, were less likely to express conditioned proboscis extension towards an odor associated with reward. Bees exposed to imidacloprid were less likely to form a long-term memory, whereas bees exposed to coumaphos were only less likely to respond during the short-term memory test after massed conditioning. Imidacloprid, coumaphos and a combination of the two compounds impaired the bees' ability to differentiate the conditioned odour from a novel odour during the memory test. Our results demonstrate that exposure to sublethal doses of combined cholinergic pesticides significantly impairs important behaviours involved in foraging, implying that pollinator population decline could be the result of a failure of neural function of bees exposed to pesticides in agricultural landscapes.

  7. 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.

  8. Pharmacological Mechanisms of Cortical Enhancement Induced by the Repetitive Pairing of Visual/Cholinergic Stimulation.

    Directory of Open Access Journals (Sweden)

    Jun-Il Kang

    Full Text Available Repetitive visual training paired with electrical activation of cholinergic projections to the primary visual cortex (V1 induces long-term enhancement of cortical processing in response to the visual training stimulus. To better determine the receptor subtypes mediating this effect the selective pharmacological blockade of V1 nicotinic (nAChR, M1 and M2 muscarinic (mAChR or GABAergic A (GABAAR receptors was performed during the training session and visual evoked potentials (VEPs were recorded before and after training. The training session consisted of the exposure of awake, adult rats to an orientation-specific 0.12 CPD grating paired with an electrical stimulation of the basal forebrain for a duration of 1 week for 10 minutes per day. Pharmacological agents were infused intracortically during this period. The post-training VEP amplitude was significantly increased compared to the pre-training values for the trained spatial frequency and to adjacent spatial frequencies up to 0.3 CPD, suggesting a long-term increase of V1 sensitivity. This increase was totally blocked by the nAChR antagonist as well as by an M2 mAChR subtype and GABAAR antagonist. Moreover, administration of the M2 mAChR antagonist also significantly decreased the amplitude of the control VEPs, suggesting a suppressive effect on cortical responsiveness. However, the M1 mAChR antagonist blocked the increase of the VEP amplitude only for the high spatial frequency (0.3 CPD, suggesting that M1 role was limited to the spread of the enhancement effect to a higher spatial frequency. More generally, all the drugs used did block the VEP increase at 0.3 CPD. Further, use of each of the aforementioned receptor antagonists blocked training-induced changes in gamma and beta band oscillations. These findings demonstrate that visual training coupled with cholinergic stimulation improved perceptual sensitivity by enhancing cortical responsiveness in V1. This enhancement is mainly mediated by n

  9. 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.

  10. 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.

  11. Calcium Homeostasis in ageing neurons

    Directory of Open Access Journals (Sweden)

    Vassiliki eNikoletopoulou

    2012-10-01

    Full Text Available The nervous system becomes increasingly vulnerable to insults and prone to dysfunction during ageing. Age-related decline of neuronal function is manifested by the late onset of many neurodegenerative disorders, as well as by reduced signalling and processing capacity of individual neuron populations. Recent findings indicate that impairment of Ca2+ homeostasis underlies the increased susceptibility of neurons to damage, associated with the ageing process. However, the impact of ageing on Ca2+ homeostasis in neurons remains largely unknown. Here, we survey the molecular mechanisms that mediate neuronal Ca2+ homeostasis and discuss the impact of ageing on their efficacy. To address the question of how ageing impinges on Ca2+ homeostasis, we consider potential nodes through which mechanisms regulating Ca2+ levels interface with molecular pathways known to influence the process of ageing and senescent decline. Delineation of this crosstalk would facilitate the development of interventions aiming to fortify neurons against age-associated functional deterioration and death by augmenting Ca2+ homeostasis.

  12. 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

  13. Hippocampal long term memory: effect of the cholinergic system on local protein synthesis.

    Science.gov (United States)

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

    2013-11-01

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

  14. The synthetic thyroid hormone, levothyroxine, protects cholinergic neurons in the hippocampus of naturally aged mice

    Institute of Scientific and Technical Information of China (English)

    Ailing Fu; Rumei Zhou; Xingran Xu

    2014-01-01

    The thyroid hormones, triiodothyronine and thyroxine, play important roles in cognitive func-tion during the mammalian lifespan. However, thyroid hormones have not yet been used as a therapeutic agent for normal age-related cognitive deficits. In this study, CD-1 mice (aged 24 months) were intraperitoneally injected with levothyroxine (L-T4;1.6μg/kg per day) for 3 consecutive months. Our findings revealed a significant improvement in hippocampal cyto-skeletal rearrangement of actin and an increase in serum hormone levels of L-T4-treated aged mice. Furthermore, the survival rate of these mice was dramatically increased from 60%to 93.3%. The Morris water maze task indicated that L-T4 restored impaired spatial memory in aged mice. Furthermore, level of choline acetyltransferase, acetylcholine, and superoxide dismutase were in-creased in these mice, thus suggesting that a possible mechanism by which L-T4 reversed cognitive impairment was caused by increased activity of these markers. Overall, supplement of low-dosage L-T4 may be a potential therapeutic strategy for normal age-related cognitive deifcits.

  15. Do sensory calcitonin gene-related peptide nerve fibres in the rat pelvic plexus supply autonomic neurons projecting to the uterus and cervix?

    Science.gov (United States)

    Houdeau, E; Barranger, E; Rossano, B

    2002-10-25

    Sensory nerve fibres containing calcitonin gene-related peptide (CGRP) innervate neurons of the paracervical ganglion (PCG) in the female rat pelvic plexus. We have combined retrograde tracing with immunocytochemistry to investigate whether CGRP-immunoreactive (-IR) fibres supply neurons targeting the genital tract. Of the total neurons projecting to either the uterine horns or the cervix, 38 and 41% received CGRP-IR innervation, respectively. All these neurons displayed choline acetyltransferase-IR, thus are cholinergic. They were found throughout the PCG and other pelvic plexus ganglia, namely accessory ganglia (AG) and hypogastric plexus (HP). Pelvic nerve section showed that afferent fibres in these nerves provided most of the CGRP-IR fibres supplying uterine- or cervical-related neurons in the PCG/AG, none in HP. It is suggested that such sensory-motor network may provide a local pathway for reflex control of genital tract activity, acting through cholinergic nerve projections.

  16. Increased cholinergic contractions of jejunal smooth muscle caused by a high cholesterol diet are prevented by the 5-HT4 agonist – tegaserod

    Directory of Open Access Journals (Sweden)

    Shaffer Eldon

    2006-02-01

    -treatment removed the effects of a high cholesterol diet on neuronal muscarinic receptors, as the potentiating effect of TTX on carbachol-elicited contractions was maintained in these animals. Conclusion A high cholesterol diet causes significant changes to cholinergic neurotransmission in the enteric nerves of the jejunum. The mechanisms by which these effects of cholesterol are reversed by tegaserod are unknown, but relate to removal of an inhibitory effect of cholesterol on enteric nerves.

  17. A small molecule p75NTR ligand, LM11A-31, reverses cholinergic neurite dystrophy in Alzheimer's disease mouse models with mid- to late-stage disease progression.

    Directory of Open Access Journals (Sweden)

    Danielle A Simmons

    Full Text Available Degeneration of basal forebrain cholinergic neurons contributes significantly to the cognitive deficits associated with Alzheimer's disease (AD and has been attributed to aberrant signaling through the neurotrophin receptor p75 (p75NTR. Thus, modulating p75NTR signaling is considered a promising therapeutic strategy for AD. Accordingly, our laboratory has developed small molecule p75NTR ligands that increase survival signaling and inhibit amyloid-β-induced degenerative signaling in in vitro studies. Previous work found that a lead p75NTR ligand, LM11A-31, prevents degeneration of cholinergic neurites when given to an AD mouse model in the early stages of disease pathology. To extend its potential clinical applications, we sought to determine whether LM11A-31 could reverse cholinergic neurite atrophy when treatment begins in AD mouse models having mid- to late stages of pathology. Reversing pathology may have particular clinical relevance as most AD studies involve patients that are at an advanced pathological stage. In this study, LM11A-31 (50 or 75 mg/kg was administered orally to two AD mouse models, Thy-1 hAPPLond/Swe (APPL/S and Tg2576, at age ranges during which marked AD-like pathology manifests. In mid-stage male APPL/S mice, LM11A-31 administered for 3 months starting at 6-8 months of age prevented and/or reversed atrophy of basal forebrain cholinergic neurites and cortical dystrophic neurites. Importantly, a 1 month LM11A-31 treatment given to male APPL/S mice (12-13 months old with late-stage pathology reversed the degeneration of cholinergic neurites in basal forebrain, ameliorated cortical dystrophic neurites, and normalized increased basal forebrain levels of p75NTR. Similar results were seen in female Tg2576 mice. These findings suggest that LM11A-31 can reduce and/or reverse fundamental AD pathologies in late-stage AD mice. Thus, targeting p75NTR is a promising approach to reducing AD-related degenerative processes that have

  18. A parallel cholinergic brainstem pathway for enhancing locomotor drive

    Science.gov (United States)

    Smetana, Roy; Juvin, Laurent; Dubuc, Réjean; Alford, Simon

    2010-01-01

    The brainstem locomotor system is believed to be organized serially from the mesencephalic locomotor region (MLR) to reticulospinal neurons, which in turn, project to locomotor neurons in the spinal cord. In contrast, we now identify in lampreys, brainstem muscarinoceptive neurons receiving parallel inputs from the MLR and projecting back to reticulospinal cells to amplify and extend durations of locomotor output. These cells respond to muscarine with extended periods of excitation, receive direct muscarinic excitation from the MLR, and project glutamatergic excitation to reticulospinal neurons. Targeted block of muscarine receptors over these neurons profoundly reduces MLR-induced excitation of reticulospinal neurons and markedly slows MLR-evoked locomotion. Their presence forces us to rethink the organization of supraspinal locomotor control, to include a sustained feedforward loop that boosts locomotor output. PMID:20473293

  19. Canton Fair: Decline, but Optimistic

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    @@ The Canton Fair, long regarded as an important weather vane for China's foreign trade, this year faced bitter, cold winds. Trade volume of main "export products such as machines and light industrial products all saw a decline, although the degree of decline differed in different sectors. The total trade volume in this Canton Fair dropped 16.9% below the previous one.

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

    Directory of Open Access Journals (Sweden)

    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.

  2. 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.

  3. [Bombesin-mediated non-cholinergic late slow excitatory postsynaptic potentials in guinea pig inferior mesenteric ganglion in vitro].

    Science.gov (United States)

    Kong, De-Hu; Wang, Gang; Wang, Hong-Mei; Ke, Dao-Ping; Hu, Jin-Lan; Zhu, Yan; Huang, Zhen-Xin

    2003-08-25

    The effect of bombesin (BOM) on non-cholinergic excitatory synaptic transmission of the guinea pig inferior mesenteric ganglion (IMG) was investigated by intracellular recording. Repetitive stimulation of the colon nerves (1 ms, 25 Hz, 4 s) elicited a burst of action potentials, which was followed by a long-lasting depolarization in 74.3% (52/70) of the IMG neurons. The depolarization was not blocked by nicotinic (d-tubocurarine, 100 micromol/L) and muscarinic (atropine, 1 micromol/L) antagonists, but was eliminated in a low Ca(2+)/high Mg(2+) Krebs solution, indicating that the depolarization was due to the release of non-cholinergic transmitters. Superfusing the ganglia with BOM (10 micromol/L, 1 min) induced a slow depolarization in 66.5% (109/164) neurons tested. The BOM response was not appreciably changed in low Ca(2+)/high Mg(2+) Krebs solution (n=6, P>0.05), suggesting that BOM depolarized the neurons by acting directly on the postsynaptic membrane rather than via a release of other endogenous depolarizing substances. In a total of 102 cells that exhibited late slow excitatory postsynaptic potential (ls-EPSP), superfusion of the ganglia with BOM produced a membrane depolarization in 82 neurons (80%), while the remaining 20 cells (20%) exhibited no response to BOM. In 18 neurons with ls-EPSP, 4 (22%) neurons were sensitive to both BOM and SP; 6 (33%) and 5 (28%) neurons were only sensitive to BOM and SP, respectively. The remaining 3 (17%) neurons were insensitive to both BOM and SP. Membrane resistance (Rm) had no apparent change in 47.3%, 59.5 % of the neurons tested during the ls-EPSP (n=55) and BOM depolarization (n=84), respectively, but had a marked decrease in 38.2%, 27.4%, and a marked increase in the remaining 14.5%, 13.1% of the neurons. However, when the Rm change accompanying ls-EPSP was compared with that accompanying BOM depolarization (n=20) in the same neuron, the changes in Rm were always parallel. Moreover, ls-EPSP (n=6) and BOM

  4. Neurogenic abnormalities in Alzheimer's disease differ between stages of neurogenesis and are partly related to cholinergic pathology.

    Science.gov (United States)

    Perry, Elaine K; Johnson, Mary; Ekonomou, Antigoni; Perry, Robert H; Ballard, Clive; Attems, Johannes

    2012-08-01

    Neurogenesis occurs in the subventricular zone and the sub-granular layer of the hippocampus and is thought to take place in 5 stages, including proliferation, differentiation, migration, targeting, and integration phases, respectively. In Alzheimer's disease (AD) both increased and decreased neurogenesis has been reported and cholinergic activity is assumed to be involved in neurogenesis. The aim of this study was to systematically assess different phases of neurogenesis and their relation to AD and cholinergic pathology. We investigated post-mortem brain tissue from 20 AD patients and 21 non-demented controls that was neuropathologically characterized according to standardized criteria. Hippocampal sections were stained with antibodies against neurogenic markers Musashi-1, nestin, PSA-NCAM, doublecortin, and β-III-tubulin as well as ChAT (choline-acetyltransferase). Using image analysis immunoreactivity was assessed in the subventricular zone, the sub-granular layer, and the granule cell layer by determining the integrated optical density. In the sub-granular layer and the granule cell layer Musashi-1 and ChAT immunoreactivities were significantly lower in AD and decreased with increasing Braak stages. Conversely, immunorreactivities of both nestin and PSA-NCAM were significantly higher in AD and increased with increasing Braak stages while no changes were seen for doublecortin and β-III-tubulin, except for significantly higher doublecortin levels in the granule cell layer of AD cases. Of note, Musashi-1 immunoreactivity significantly correlated with ChAT immuonoreactivity across different Braak stages. In the subventricular zone only nestin immunoreactivity was significantly higher in AD and significantly increased with increasing Braak stages, while no significant differences were seen for all other markers. Our finding of a reduction of ChAT and Musashi-1 levels in AD is compatible with the assumption that cholinergic pathology per se has a detrimental

  5. Integration of human model neurons (NT2) into embryonic chick nervous system.

    Science.gov (United States)

    Podrygajlo, Grzegorz; Wiegreffe, Christoph; Scaal, Martin; Bicker, Gerd

    2010-02-01

    Postmitotic neurons were generated from the human NT2 teratocarcinoma cell line in a novel cell aggregate differentiation procedure. Approximately a third of the differentiated neurons expressed cell markers related to cholinergic neurotransmission. To examine whether this human cell model system can be directed toward a motoneuronal fate, postmitotic neurons were co-cultured with mouse myotubes. Outgrowing neuronal processes established close contact with the myotubes and formed neuromuscular junction-like structures that bound alpha-bungarotoxin. To determine how grafted precursor cells and neurons respond to embryonic nerve tissue, NT2 cells at different stages of neural development were injected into chick embryo neural tube and brain. Grafted NT2 neurons populated both parts of the nervous system, sometimes migrating away from the site of injection. The neural tube appeared to be more permissive for neurite extensions than the brain. Moreover, extending neurites of spinal grafts were approaching the ventral roots, thus resembling motoneuronal projections.

  6. Locality-dependent descending reflex motor activity in the anal canal-cholinergic and nitrergic contributions in the rat model

    Institute of Scientific and Technical Information of China (English)

    Radomir RADOMIROV; Christina IVANCHEVA; Dimitar ITZEV; Polina PETKOVA-KIROVA

    2009-01-01

    Aim: Since the distal part of the intestine is targeted by a wide range of pathogens, the motility of the recto-anal region has been the object of many experimental and clinical observations. In this study, we investigated descending motor responses in the anal canal as a measure of the activation of autonomic reflex pathways underlying evacuatory recto-anal activity. Methods: The partitioned organ bath method was used to register motor responses of the anal canal as induced by balloon distension of the rectum in isolated rat recto-anal preparations. Results: Distension-induced descending responses of the anal canal comprised contractions (with distension at a distance of 15 mm), initial contractions and secondary relaxations (at 10 mm) and short contractions followed by deep relaxations (at 3-5 mm). Decreas-ing the distance between the distension stimulus and the anal canal resulted in a decreased contraction response and increased relaxation. Tetrodotoxin (0.1 μmol/L) inhibited these responses. Atropine (0.3 μmol/L) decreased contraction and did not change the relaxation response. N~G-nitro-L-arginine (0.5 mmol/L) enhanced contraction in both the absence and presence of atropine. L-arginine (0.5 mmol/L) inhibited contraction and extended relaxation in atropine-pretreated preparations. The actions of N~G-nitro-L-arginine and L-arginine were more pronounced in the aboral direction. ChAT-positive nerve fibers were observed in myenteric ganglia of the rectum and the anal canal. The density of NADPH-diaphorase-positive neurons was higher in the anal canal region. Conclusion: Our results suggest that locality-dependent activation of the descending reflex neuromuscular communications underlie evacuatory activity in the recto-anal region. This activation response involves long excitatory cholinergic and non-cholinergic pathways along the rectum and short inhibitory nitrergic pathways located predominantly in the anal canal region.

  7. Optogenetic identification of an intrinsic cholinergically driven inhibitory oscillator sensitive to cannabinoids and opioids in hippocampal CA1.

    Science.gov (United States)

    Nagode, Daniel A; Tang, Ai-Hui; Yang, Kun; Alger, Bradley E

    2014-01-01

    Neuronal electrical oscillations in the theta (4-14 Hz) and gamma (30-80 Hz) ranges are necessary for the performance of certain animal behaviours and cognitive processes. Perisomatic GABAergic inhibition is prominently involved in cortical oscillations driven by ACh release from septal cholinergic afferents. In neocortex and hippocampal CA3 regions, parvalbumin (PV)-expressing basket cells, activated by ACh and glutamatergic agonists, largely mediate oscillations. However, in CA1 hippocampus in vitro, cholinergic agonists or the optogenetic release of endogenous ACh from septal afferents induces rhythmic, theta-frequency inhibitory postsynaptic currents (IPSCs) in pyramidal cells, even with glutamatergic transmission blocked. The IPSCs are regulated by exogenous and endogenous cannabinoids, suggesting that they arise from type 1 cannabinoid receptor-expressing (CB1R+) interneurons - mainly cholecystokinin (CCK)-expressing cells. Nevertheless, an occult contribution of PV-expressing interneurons to these rhythms remained conceivable. Here, we directly test this hypothesis by selectively silencing CA1 PV-expressing cells optogenetically with halorhodopsin or archaerhodopsin. However, this had no effect on theta-frequency IPSC rhythms induced by carbachol (CCh). In contrast, the silencing of glutamic acid decarboxylase 2-positive interneurons, which include the CCK-expressing basket cells, strongly suppressed inhibitory oscillations; PV-expressing interneurons appear to play no role. The low-frequency IPSC oscillations induced by CCh or optogenetically stimulated ACh release were also inhibited by a μ-opioid receptor (MOR) agonist, which was unexpected because MORs in CA1 are not usually associated with CCK-expressing cells. Our results reveal novel properties of an inhibitory oscillator circuit within CA1 that is activated by muscarinic agonists. The oscillations could contribute to behaviourally relevant, atropine-sensitive, theta rhythms and link cannabinoid and

  8. 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.

  9. Chronic dietary administration of valproic acid protects neurons of the rat nucleus basalis magnocellularis from ibotenic acid neurotoxicity.

    Science.gov (United States)

    Eleuteri, Simona; Monti, Barbara; Brignani, Sara; Contestabile, Antonio

    2009-02-01

    Valproic acid (VPA) has been used for many years as a drug of choice for epilepsy and mood disorders. Recently, evidence has been proposed for a wide spectrum of actions of this drug, including antitumoral and neuroprotective properties. Valproic acid-mediated neuroprotection in vivo has been so far demonstrated in a limited number of experimental models. In this study, we have tested the neuroprotective potential of chronic (4 + 1 weeks) dietary administration of VPA on degeneration of cholinergic and GABAergic neurons of the rat nucleus basalis magnocellularis (NBM), injected with the excitotoxin, ibotenic acid (IBO), an animal models that is relevant for Alzheimer's disease-like neurodegeneration. We show that VPA treatment significantly protects both cholinergic and GABAergic neurons present in the injected area from the excitotoxic insult. A significant level of neuroprotection, in particular, is exerted towards the cholinergic neurons of the NBM projecting to the cortex, as demonstrated by the substantially higher levels of cholinergic markers maintained in the target cortical area of VPA-treated rats after IBO injection in the NBM. We further show that chronic VPA administration results in increased acetylation of histone H3 in brain, consistent with the histone deacetylase inhibitory action of VPA and putatively linked to a neuroprotective action of the drug mediated at the epigenetic level.

  10. Dysfunction of inflammation-resolving pathways is associated with exaggerated postoperative cognitive decline in a rat model of the metabolic syndrome

    OpenAIRE

    Su, X.; Feng, X.; Terrando, N; Yan, Y.; Chawla, A; Koch, LG; Britton, SL; Matthay, MA; Maze, M

    2013-01-01

    The cholinergic antiinflammatory pathway (CAP), which terminates in the spleen, attenuates postoperative cognitive decline (PCD) in rodents. Surgical patients with metabolic syndrome exhibit exaggerated and persistent PCD that is reproduced in postoperative rats selectively bred for easy fatigability and that contain all features of metabolic syndrome (low-capacity runners [LCRs]). We compared the CAP and lipoxin A4 (LXA4), another inflammation-resolving pathway in LCR, with its counterpart h...

  11. 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.

  12. 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.

  13. Mirror neurons

    National Research Council Canada - National Science Library

    Rubia Vila, Francisco José

    2011-01-01

    Mirror neurons were recently discovered in frontal brain areas of the monkey. They are activated when the animal makes a specific movement, but also when the animal observes the same movement in another animal...

  14. Formation and Dynamics of Waves in a Cortical Model of Cholinergic Modulation.

    Directory of Open Access Journals (Sweden)

    James P Roach

    2015-08-01

    Full Text Available Acetylcholine (ACh is a regulator of neural excitability and one of the neurochemical substrates of sleep. Amongst the cellular effects induced by cholinergic modulation are a reduction in spike-frequency adaptation (SFA and a shift in the phase response curve (PRC. We demonstrate in a biophysical model how changes in neural excitability and network structure interact to create three distinct functional regimes: localized asynchronous, traveling asynchronous, and traveling synchronous. Our results qualitatively match those observed experimentally. Cortical activity during slow wave sleep (SWS differs from that during REM sleep or waking states. During SWS there are traveling patterns of activity in the cortex; in other states stationary patterns occur. Our model is a network composed of Hodgkin-Huxley type neurons with a M-current regulated by ACh. Regulation of ACh level can account for dynamical changes between functional regimes. Reduction of the magnitude of this current recreates the reduction in SFA the shift from a type 2 to a type 1 PRC observed in the presence of ACh. When SFA is minimal (in waking or REM sleep state, high ACh patterns of activity are localized and easily pinned by network inhomogeneities. When SFA is present (decreasing ACh, traveling waves of activity naturally arise. A further decrease in ACh leads to a high degree of synchrony within traveling waves. We also show that the level of ACh determines how sensitive network activity is to synaptic heterogeneity. These regimes may have a profound functional significance as stationary patterns may play a role in the proper encoding of external input as memory and traveling waves could lead to synaptic regularization, giving unique insights into the role and significance of ACh in determining patterns of cortical activity and functional differences arising from the patterns.

  15. Cognitive decline affects diabetic women

    Directory of Open Access Journals (Sweden)

    Perzyński Adam

    2016-12-01

    Full Text Available Introduction: DM provokes peripheral complications and changes in central nervous system. Central changes in the course of diabetes mellitus (DM include changes in brain tissue structure, electrophysiological abnormalities but also disturbances in neurotransmission leading to cognitive decline.

  16. Neuronal Networks on Nanocellulose Scaffolds.

    Science.gov (United States)

    Jonsson, Malin; Brackmann, Christian; Puchades, Maja; Brattås, Karoline; Ewing, Andrew; Gatenholm, Paul; Enejder, Annika

    2015-11-01

    Proliferation, integration, and neurite extension of PC12 cells, a widely used culture model for cholinergic neurons, were studied in nanocellulose scaffolds biosynthesized by Gluconacetobacter xylinus to allow a three-dimensional (3D) extension of neurites better mimicking neuronal networks in tissue. The interaction with control scaffolds was compared with cationized nanocellulose (trimethyl ammonium betahydroxy propyl [TMAHP] cellulose) to investigate the impact of surface charges on the cell interaction mechanisms. Furthermore, coatings with extracellular matrix proteins (collagen, fibronectin, and laminin) were investigated to determine the importance of integrin-mediated cell attachment. Cell proliferation was evaluated by a cellular proliferation assay, while cell integration and neurite propagation were studied by simultaneous label-free Coherent anti-Stokes Raman Scattering and second harmonic generation microscopy, providing 3D images of PC12 cells and arrangement of nanocellulose fibrils, respectively. Cell attachment and proliferation were enhanced by TMAHP modification, but not by protein coating. Protein coating instead promoted active interaction between the cells and the scaffold, hence lateral cell migration and integration. Irrespective of surface modification, deepest cell integration measured was one to two cell layers, whereas neurites have a capacity to integrate deeper than the cell bodies in the scaffold due to their fine dimensions and amoeba-like migration pattern. Neurites with lengths of >50 μm were observed, successfully connecting individual cells and cell clusters. In conclusion, TMAHP-modified nanocellulose scaffolds promote initial cellular scaffold adhesion, which combined with additional cell-scaffold treatments enables further formation of 3D neuronal networks.

  17. 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

  18. 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.

  19. 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.

  20. Cytokines and cholinergic signals co-modulate surgical stress-induced changes in mood and memory.

    Science.gov (United States)

    Shapira-Lichter, Irit; Beilin, Benzion; Ofek, Keren; Bessler, Hanna; Gruberger, Michal; Shavit, Yehuda; Seror, Dan; Grinevich, Galina; Posner, Eldad; Reichenberg, Abraham; Soreq, Hermona; Yirmiya, Raz

    2008-03-01

    Inflammatory cytokines and the cholinergic system have been implicated in the effects of stressors on mood and memory; however, the underlying mechanisms involved and the potential interrelationships between these pathways remain unclear. To address these questions, we administered neuropsychological tests to 33 generally healthy surgery patients who donated blood samples several days prior to undergoing moderate surgery (baseline), on the morning of the surgery (i.e., a psychological stressor), and one day after surgery. Eighteen control subjects were similarly tested. Serum levels of inflammatory cytokines, acetylcholinesterase (AChE) activity, and the stressor-inducible AChE-R variant were measured. An elevation in anxiety levels, an increase in depressed mood, and a decline in declarative memory were observed on the morning of the surgery, prior to any medical intervention, and were exacerbated one day after surgery. The surgical stressor-induced elevated IL-1 beta levels, which contributed to the increased depressed mood and to the post-surgery increase in AChE-R expression. The latter increase, which was also predicted by pre-surgery AChE-R and post-surgery mood disturbances, was associated with exacerbated memory impairments induced by surgery. In addition, elevated levels of AChE-R on the morning of the surgery predicted the post-surgery elevation in IL-6 levels, which was associated with amelioration of the memory impairments induced by surgery. Taken together, these findings suggest that exposure to a surgical stressor induces a reciprocal up-regulation of AChE-R and pro-inflammatory cytokines, which are involved in regulating the surgery-induced mood and memory disturbances.

  1. 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....

  2. 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....

  3. Cerebrolysin modulates pronerve growth factor/nerve growth factor ratio and ameliorates the cholinergic deficit in a transgenic model of Alzheimer's disease.

    Science.gov (United States)

    Ubhi, Kiren; Rockenstein, Edward; Vazquez-Roque, Ruben; Mante, Michael; Inglis, Chandra; Patrick, Christina; Adame, Anthony; Fahnestock, Margaret; Doppler, Edith; Novak, Philip; Moessler, Herbert; Masliah, Eliezer

    2013-02-01

    Alzheimer's disease (AD) is characterized by degeneration of neocortex, limbic system, and basal forebrain, accompanied by accumulation of amyloid-β and tangle formation. Cerebrolysin (CBL), a peptide mixture with neurotrophic-like effects, is reported to improve cognition and activities of daily living in patients with AD. Likewise, CBL reduces synaptic and behavioral deficits in transgenic (tg) mice overexpressing the human amyloid precursor protein (hAPP). The neuroprotective effects of CBL may involve multiple mechanisms, including signaling regulation, control of APP metabolism, and expression of neurotrophic factors. We investigate the effects of CBL in the hAPP tg model of AD on levels of neurotrophic factors, including pro-nerve growth factor (NGF), NGF, brain-derived neurotrophic factor (BDNF), neurotropin (NT)-3, NT4, and ciliary neurotrophic factor (CNTF). Immunoblot analysis demonstrated that levels of pro-NGF were increased in saline-treated hAPP tg mice. In contrast, CBL-treated hAPP tg mice showed levels of pro-NGF comparable to control and increased levels of mature NGF. Consistently with these results, immunohistochemical analysis demonstrated increased NGF immunoreactivity in the hippocampus of CBL-treated hAPP tg mice. Protein levels of other neurotrophic factors, including BDNF, NT3, NT4, and CNTF, were unchanged. mRNA levels of NGF and other neurotrophins were also unchanged. Analysis of neurotrophin receptors showed preservation of the levels of TrKA and p75(NTR) immunoreactivity per cell in the nucleus basalis. Cholinergic cells in the nucleus basalis were reduced in the saline-treated hAPP tg mice, and treatment with CBL reduced these cholinergic deficits. These results suggest that the neurotrophic effects of CBL might involve modulation of the pro-NGF/NGF balance and a concomitant protection of cholinergic neurons.

  4. 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.

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

    Science.gov (United States)

    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.

  6. 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.

  7. New tools for targeted disruption of cholinergic synaptic transmission in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Monica Mejia

    Full Text Available Nicotinic acetylcholine receptors (nAChRs are pentameric ligand-gated ion channels. The α7 subtype of nAChRs is involved in neurological pathologies such as Parkinson's disease, Alzheimer's disease, addiction, epilepsy and autism spectrum disorders. The Drosophila melanogaster α7 (Dα7 has the closest sequence homology to the vertebrate α7 subunit and it can form homopentameric receptors just as the vertebrate counterpart. The Dα7 subunits are essential for the function of the Giant Fiber circuit, which mediates the escape response of the fly. To further characterize the receptor function, we generated different missense mutations in the Dα7 nAChR's ligand binding domain. We characterized the effects of targeted expression of two UAS-constructs carrying a single mutation, D197A and Y195T, as well as a UAS-construct carrying a triple D77T, L117Q, I196P mutation in a Dα7 null mutant and in a wild type background. Expression of the triple mutation was able to restore the function of the circuit in Dα7 null mutants and had no disruptive effects when expressed in wild type. In contrast, both single mutations severely disrupted the synaptic transmission of Dα7-dependent but not glutamatergic or gap junction dependent synapses in wild type background, and did not or only partially rescued the synaptic defects of the null mutant. These observations are consistent with the formation of hybrid receptors, consisting of D197A or Y195T subunits and wild type Dα7 subunits, in which the binding of acetylcholine or acetylcholine-induced conformational changes of the Dα7 receptor are altered and causes inhibition of cholinergic responses. Thus targeted expression of D197A or Y195T can be used to selectively disrupt synaptic transmission of Dα7-dependent synapses in neuronal circuits. Hence, these constructs can be used as tools to study learning and memory or addiction associated behaviors by allowing the manipulation of neuronal processing in the

  8. Muscarinic depolarization of layer II neurons of the parasubiculum.

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    Stephen D Glasgow

    Full Text Available The parasubiculum (PaS is a component of the hippocampal formation that sends its major output to layer II of the entorhinal cortex. The PaS receives strong cholinergic innervation from the basal forebrain that is likely to modulate neuronal excitability and contribute to theta-frequency network activity. The present study used whole cell current- and voltage-clamp recordings to determine the effects of cholinergic receptor activation on layer II PaS neurons. Bath application of carbachol (CCh; 10-50 µM resulted in a dose-dependent depolarization of morphologically-identified layer II stellate and pyramidal cells that was not prevented by blockade of excitatory and inhibitory synaptic inputs. Bath application of the M1 receptor antagonist pirenzepine (1 µM, but not the M2-preferring antagonist methoctramine (1 µM, blocked the depolarization, suggesting that it is dependent on M1 receptors. Voltage-clamp experiments using ramped voltage commands showed that CCh resulted in the gradual development of an inward current that was partially blocked by concurrent application of the selective Kv7.2/3 channel antagonist XE-991, which inhibits the muscarine-dependent K(+ current I M. The remaining inward current also reversed near EK and was inhibited by the K(+ channel blocker Ba(2+, suggesting that M1 receptor activation attenuates both I M as well as an additional K(+ current. The additional K(+ current showed rectification at depolarized voltages, similar to K(+ conductances mediated by Kir 2.3 channels. The cholinergic depolarization of layer II PaS neurons therefore appears to occur through M1-mediated effects on I M as well as an additional K(+ conductance.

  9. Muscarinic Depolarization of Layer II Neurons of the Parasubiculum

    Science.gov (United States)

    Glasgow, Stephen D.; Chapman, C. Andrew

    2013-01-01

    The parasubiculum (PaS) is a component of the hippocampal formation that sends its major output to layer II of the entorhinal cortex. The PaS receives strong cholinergic innervation from the basal forebrain that is likely to modulate neuronal excitability and contribute to theta-frequency network activity. The present study used whole cell current- and voltage-clamp recordings to determine the effects of cholinergic receptor activation on layer II PaS neurons. Bath application of carbachol (CCh; 10–50 µM) resulted in a dose-dependent depolarization of morphologically-identified layer II stellate and pyramidal cells that was not prevented by blockade of excitatory and inhibitory synaptic inputs. Bath application of the M1 receptor antagonist pirenzepine (1 µM), but not the M2-preferring antagonist methoctramine (1 µM), blocked the depolarization, suggesting that it is dependent on M1 receptors. Voltage-clamp experiments using ramped voltage commands showed that CCh resulted in the gradual development of an inward current that was partially blocked by concurrent application of the selective Kv7.2/3 channel antagonist XE-991, which inhibits the muscarine-dependent K+ current IM. The remaining inward current also reversed near EK and was inhibited by the K+ channel blocker Ba2+, suggesting that M1 receptor activation attenuates both IM as well as an additional K+ current. The additional K+ current showed rectification at depolarized voltages, similar to K+ conductances mediated by Kir 2.3 channels. The cholinergic depolarization of layer II PaS neurons therefore appears to occur through M1-mediated effects on IM as well as an additional K+ conductance. PMID:23520542

  10. Cholinergic and noradrenergic triggers' in soman induced convulsions

    Energy Technology Data Exchange (ETDEWEB)

    Shipley, M.T.; Zimmer, L.; Ennis, M.; Etri, M.

    1993-05-13

    Considerable evidence suggests that soman induced seizure's are initiated in the piriform cortex (PC). Consistent with this, PC is the most frequent site of neuropathology in soman treated rats and other species. Previous studies in this laboratory have shown that convulsive doses of soman cause the rapid induction of the immediate early gene protein product, Fos, in piriform cortex (PC). Fos is known to be expressed when neurons undergo sustained excitatory activity. Following soman, Fos is selectively expressed by neurons in layers II Ill of PC. These neurons are known to send excitatory projections to the hippocampus and to thalamus and neocortex. Thus, we have suggested that soman may initially cause seizure activity in layer II-III PC neurons; this seizure activity could then spread to the hippocampus and neocortex. Consistent with this hypothesis, we have observed that Fos is expressed in hippocampus, thalamus and neocortex subsequent to its expression in PC.

  11. Astrocytes Mediate In Vivo Cholinergic-Induced Synaptic Plasticity

    OpenAIRE

    2012-01-01

    In vivo and in vitro studies reveal that astrocytes, classically considered supportive cells for neurons, regulate synaptic plasticity in the mouse hippocampus and are directly involved in information storage.

  12. A ganglionic stimulant, 1,1-dimethyl-4-phenylpiperazinium, caused both cholinergic and adrenergic responses in the isolated mouse atrium.

    Science.gov (United States)

    Ochi, Kenta; Teraoka, Hiroki; Unno, Toshihiro; Komori, Sei-Ichi; Yamada, Masahisa; Kitazawa, Takio

    2013-03-15

    An isolated atrial preparation of the mouse is useful for analyzing the actions of drugs on the myocardium, autonomic neurons and endocardial endothelium. The aim of the present study was to examine the functions of intrinsic neurons of the atrium using a ganglionic stimulant, 1,1-dimethyl-4-phenylpiperazinium (DMPP). DMPP (1-100 μM) caused a negative chronotropic action followed by a positive chronotropic action in spontaneously beating right atria and also caused biphasic inotropic actions consisting of initial inhibition followed by potentiation of electrical field stimulation (EFS)-induced contraction in the left atria. Inotropic actions in the left atria induced by DMPP were characterized using some autonomic drugs and M2 and/or M3 muscarinic receptor knockout (M2R-KO, M3R-KO and M2M3R-KO) mice. Atropine and hexamethonium decreased the initial negative inotropic actions of DMPP. In the atria from pertussis toxin-treated, M2R-KO and M2/M3R-KO mice, the negative inotropic actions were abolished. On the other hand, the following positive inotropic actions were decreased by hexamethonium, atropine and atenolol. In the atria from reserpine-treated mice, positive inotropic actions were also decreased. The positive inotropic action induced by DMPP was almost the same in M2R-KO mice but was reduced in both M3R-KO mice and M2/M3R-KO mice. In conclusion, DMPP caused biphasic inotropic/chronotropic actions in the mouse atrium through activation of intrinsic cholinergic and adrenergic neurons. M2 and M3 muscarinic receptors and β1-adrenoceptor are thought to be involved in these actions.

  13. Genetically-directed, cell type-specific sparse labeling for the analysis of neuronal morphology.

    Directory of Open Access Journals (Sweden)

    Thomas Rotolo

    Full Text Available BACKGROUND: In mammals, genetically-directed cell labeling technologies have not yet been applied to the morphologic analysis of neurons with very large and complex arbors, an application that requires extremely sparse labeling and that is only rendered practical by limiting the labeled population to one or a few predetermined neuronal subtypes. METHODS AND FINDINGS: In the present study we have addressed this application by using CreER technology to non-invasively label very small numbers of neurons so that their morphologies can be fully visualized. Four lines of IRES-CreER knock-in mice were constructed to permit labeling selectively in cholinergic or catecholaminergic neurons [choline acetyltransferase (ChAT-IRES-CreER or tyrosine hydroxylase (TH-IRES-CreER], predominantly in projection neurons [neurofilament light chain (NFL-IRES-CreER], or broadly in neurons and some glia [vesicle-associated membrane protein2 (VAMP2-IRES-CreER]. When crossed to the Z/AP reporter and exposed to 4-hydroxytamoxifen in the early postnatal period, the number of neurons expressing the human placental alkaline phosphatase reporter can be reproducibly lowered to fewer than 50 per brain. Sparse Cre-mediated recombination in ChAT-IRES-CreER;Z/AP mice shows the full axonal and dendritic arbors of individual forebrain cholinergic neurons, the first time that the complete morphologies of these very large neurons have been revealed in any species. CONCLUSIONS: Sparse genetically-directed, cell type-specific neuronal labeling with IRES-creER lines should prove useful for studying a wide variety of questions in neuronal development and disease.

  14. Differentiation renders susceptibility to excitotoxicity in HT22 neurons

    Institute of Scientific and Technical Information of China (English)

    Minchao He; Jun Liu; Shaowu Cheng; Yigang Xing; William Z Suo

    2013-01-01

    HT22 is an immortalized mouse hippocampal neuronal cell line that does not express cholinergic and glutamate receptors like mature hippocampal neurons in vivo. This in part prevents its use as a model for mature hippocampal neurons in memory-related studies. We now report that HT22 cells were appropriately induced to differentiate and possess properties similar to those of mature hippocampal neurons in vivo, such as becoming more glutamate-receptive and excitatory. Results showed that sensitivity of HT22 cells to glutamate-induced toxicity changed dramatically when comparing undifferentiated with differentiated cells, with the half-effective concentration for differentiated cells reducing approximately two orders of magnitude. Moreover, glutamate-induced toxicity in differentiated cells, but not undifferentiated cells, was inhibited by the N-methyl-D- aspartate receptor antagonists MK-801 and memantine. Evidently, differentiated HT22 cells expressed N-methyl-D-aspartate receptors, while undifferentiated cells did not. Our experimental findings indicated that differentiation is important for immortalized cell lines to render post-mitotic neuronal properties, and that differentiated HT22 neurons represent a better model of hippocampal neurons than undifferentiated cells.

  15. Multiple functions of precursor BDNF to CNS neurons: negative regulation of neurite growth, spine formation and cell survival

    Directory of Open Access Journals (Sweden)

    Koshimizu Hisatsugu

    2009-08-01

    Full Text Available Abstract Background Proneurotrophins and mature neurotrophins elicit opposite effects via the p75 neurotrophin receptor (p75NTR and Trk tyrosine kinase receptors, respectively; however the molecular roles of proneurotrophins in the CNS are not fully understood. Results Based on two rare single nucleotide polymorphisms (SNPs of the human brain-derived neurotrophic factor (BDNF gene, we generated R125M-, R127L- and R125M/R127L-BDNF, which have amino acid substitution(s near the cleavage site between the pro- and mature-domain of BDNF. Western blot analyses demonstrated that these BDNF variants are poorly cleaved and result in the predominant secretion of proBDNF. Using these cleavage-resistant proBDNF (CR-proBDNF variants, the molecular and cellular roles of proBDNF on the CNS neurons were examined. First, CR-proBDNF showed normal intracellular distribution and secretion in cultured hippocampal neurons, suggesting that inhibition of proBDNF cleavage does not affect intracellular transportation and secretion of BDNF. Second, we purified recombinant CR-proBDNF and tested its biological effects using cultured CNS neurons. Treatment with CR-proBDNF elicited apoptosis of cultured cerebellar granule neurons (CGNs, while treatment with mature BDNF (matBDNF promoted cell survival. Third, we examined the effects of CR-proBDNF on neuronal morphology using more than 2-week cultures of basal forebrain cholinergic neurons (BFCNs and hippocampal neurons. Interestingly, in marked contrast to the action of matBDNF, which increased the number of cholinergic fibers and hippocampal dendritic spines, CR-proBDNF dramatically reduced the number of cholinergic fibers and hippocampal dendritic spines, without affecting the survival of these neurons. Conclusion These results suggest that proBDNF has distinct functions in different populations of CNS neurons and might be responsible for specific physiological cellular processes in the brain.

  16. [Mirror neurons].

    Science.gov (United States)

    Rubia Vila, Francisco José

    2011-01-01

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

  17. Cholinergic Degeneration and Alterations in the TrkA and p75NTR Balance as a Result of Pro-NGF Injection into Aged Rats

    Directory of Open Access Journals (Sweden)

    Ashley M. Fortress

    2011-01-01

    Full Text Available Learning and memory impairments occurring with Alzheimer's disease (AD are associated with degeneration of the basal forebrain cholinergic neurons (BFCNs. BFCNs extend their axons to the hippocampus where they bind nerve growth factor (NGF which is retrogradely transported to the cell body. While NGF is necessary for BFCN survival and function via binding to the high-affinity receptor TrkA, its uncleaved precursor, pro-NGF has been proposed to induce neurodegeneration via binding to the p75NTR and its coreceptor sortilin. Basal forebrain TrkA and NGF are downregulated with aging while pro-NGF is increased. Given these data, the focus of this paper was to determine a mechanism for how pro-NGF accumulation may induce BFCN degeneration. Twenty-four hours after a single injection of pro-NGF into hippocampus, we found increased hippocampal p75NTR levels, decreased hippocampal TrkA levels, and cholinergic degeneration. The data suggest that the increase in p75NTR with AD may be mediated by elevated pro-NGF levels as a result of decreased cleavage, and that pro-NGF may be partially responsible for age-related degenerative changes observed in the basal forebrain. This paper is the first in vivo evidence that pro-NGF can affect BFCNs and may do so by regulating expression of p75NTR neurotrophin receptors.

  18. 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.

  19. Time-scale invariance as an emergent property in a perceptron with realistic, noisy neurons

    Science.gov (United States)

    Buhusi, Catalin V.; Oprisan, Sorinel A.

    2013-01-01

    In most species, interval timing is time-scale invariant: errors in time estimation scale up linearly with the estimated duration. In mammals, time-scale invariance is ubiquitous over behavioral, lesion, and pharmacological manipulations. For example, dopaminergic drugs induce an immediate, whereas cholinergic drugs induce a gradual, scalar change in timing. Behavioral theories posit that time-scale invariance derives from particular computations, rules, or coding schemes. In contrast, we discuss a simple neural circuit, the perceptron, whose output neurons fire in a clockwise fashion (interval timing) based on the pattern of coincidental activation of its input neurons. We show numerically that time-scale invariance emerges spontaneously in a perceptron with realistic neurons, in the presence of noise. Under the assumption that dopaminergic drugs modulate the firing of input neurons, and that cholinergic drugs modulate the memory representation of the criterion time, we show that a perceptron with realistic neurons reproduces the pharmacological clock and memory patterns, and their time-scale invariance, in the presence of noise. These results suggest that rather than being a signature of higher-order cognitive processes or specific computations related to timing, time-scale invariance may spontaneously emerge in a massively-connected brain from the intrinsic noise of neurons and circuits, thus providing the simplest explanation for the ubiquity of scale invariance of interval timing. PMID:23518297

  20. Life and death of neurons in the aging brain

    Science.gov (United States)

    Morrison, J. H.; Hof, P. R.; Bloom, F. E. (Principal Investigator)

    1997-01-01

    Neurodegenerative disorders are characterized by extensive neuron death that leads to functional decline, but the neurobiological correlates of functional decline in normal aging are less well defined. For decades, it has been a commonly held notion that widespread neuron death in the neocortex and hippocampus is an inevitable concomitant of brain aging, but recent quantitative studies suggest that neuron death is restricted in normal aging and unlikely to account for age-related impairment of neocortical and hippocampal functions. In this article, the qualitative and quantitative differences between aging and Alzheimer's disease with respect to neuron loss are discussed, and age-related changes in functional and biochemical attributes of hippocampal circuits that might mediate functional decline in the absence of neuron death are explored. When these data are viewed comprehensively, it appears that the primary neurobiological substrates for functional impairment in aging differ in important ways from those in neurodegenerative disorders such as Alzheimer's disease.

  1. Estrogen intervention in microvascular morphology and choline acetyltransferase expression in rat hippocampal neurons in chronic cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Zhenjun Yang; Hongwei Yan; Guomin Zhang; Zhihong Chen; Jingfeng Xue

    2011-01-01

    We observed dynamic changes in microvessels and a protective effect of estrogen on chronic cerebral ischemia ovariectomized rat models established through permanent occlusion of bilateral carotid arteries at 7, 14 and 21 days. The results revealed that estrogen improved microvasculature in the hippocampus of chronic cerebral ischemic rats, upregulated Bcl-2 protein expression, downregulated Bax protein expression, increased choline acetyltransferase expression in hippocampal cholinergic neurons, and suppressed hippocampal neuronal apoptosis. These findings indicate that estrogen can protect hippocampal neurons in rats with chronic cerebral ischemia.

  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

    hippocampal pyramidal layer thickness and live neurons in IBO induced rats, with slight pathological changes in the entorhinal cortex (EC of rat brain, which was prevented on RSV administration. Our study thus concludes that RSV administration significantly ameliorated the deleterious effects in the IBO lesioned rat model for AD by alleviating cholinergic pathways, reducing oxidative stress and thereby improving spatial memory.

  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

    pyramidal layer thickness and live neurons in IBO induced rats, with slight pathological changes in the entorhinal cortex (EC) of rat brain, which was prevented on RSV administration. Our study thus concludes that RSV administration significantly ameliorated the deleterious effects in the IBO lesioned rat model for AD by alleviating cholinergic pathways, reducing oxidative stress and thereby improving spatial memory.

  4. Research progress of muscarinic cholinergic receptors in tumors%毒蕈碱胆碱受体与肿瘤关系的研究进展

    Institute of Scientific and Technical Information of China (English)

    何花; 张淑香

    2015-01-01

    非神经元性胆碱能信号通路与肿瘤关系密切,许多肿瘤细胞表达胆碱能自分泌环。肿瘤细胞自分泌及旁分泌乙酰胆碱,作用于自身或邻近细胞的烟碱胆碱受体及毒蕈碱胆碱受体,调节肿瘤细胞的增殖、血管发生及凋亡。毒蕈碱胆碱受体是 G 蛋白耦联受体,主要有 M1R-M5R 共5个亚型。研究发现毒蕈碱胆碱受体在肺癌、结肠癌、黑色素瘤、乳腺癌、卵巢癌、前列腺癌、胃癌和脑星形细胞瘤等多种恶性肿瘤中均有表达,与肿瘤细胞的增殖、迁移、血管发生、凋亡有密切关系,其中尤以毒蕈碱胆碱受体3最为重要,这为肿瘤的治疗提供了一个新的研究方向。%Non-neuronal cholinergic system is closely related with tumor.Many tumor cells express a cholinergic autocrine loop.Acetylcholine secreted by the tumor or neighboring cells interacts with nicotinic cholinergic receptors and muscarinic cholinergic receptors (MRs)expressed on the tumor cells to stimulate tumor cells proliferation,angiogenesis,and apoptosis.MRs are G-protein-coupled receptors and five subtypes have been identified.Researches have found that MRs are expressed in a variety of tumors, such as lung cancer,colon cancer,melanoma,breast cancer,ovarian cancer,prostate cancer,gastric cancer, and brain cancer.M3R is the most important one.This may provide a new direction for the treatment of cancer.

  5. Replicated Risk Nicotinic Cholinergic Receptor Genes for Nicotine Dependence

    Directory of Open Access Journals (Sweden)

    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.

  6. 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

    2016-01-01

    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

  7. Photocolorimetric Biosensor for Detection of Cholinergic Organophosphorus Compounds

    Directory of Open Access Journals (Sweden)

    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

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  9. 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.

  10. Recovery of network-driven glutamatergic activity in rat hippocampal neurons during chronic glutamate receptor blockade.

    Science.gov (United States)

    Leininger, Eric; Belousov, Andrei B

    2009-01-28

    Previous studies indicated that a long-term decrease in the activity of ionotropic glutamate receptors induces cholinergic activity in rat and mouse hypothalamic neuronal cultures. Here we studied whether a prolonged inactivation of ionotropic glutamate receptors also induces cholinergic activity in hippocampal neurons. Receptor activity was chronically suppressed in rat hippocampal primary neuronal cultures with two proportionally increasing sets of concentrations of NMDA plus non-NMDA receptor antagonists: 100 microM/10 microM AP5/CNQX (1X cultures) and 200 microM/20 microM AP5/CNQX (2X cultures). Using calcium imaging we demonstrate that cholinergic activity does not develop in these cultures. Instead, network-driven glutamate-dependent activity, that normally is detected in hyper-excitable conditions, reappears in each culture group in the presence of these antagonists and can be reversibly suppressed by higher concentrations of AP5/CNQX. This activity is mediated by non-NMDA receptors and is modulated by NMDA receptors. Further, non-NMDA receptors, the general level of glutamate receptor activity and CaMK-dependent signaling are critical for development of this network-driven glutamatergic activity in the presence of receptor antagonists. Using electrophysiology, western blotting and calcium imaging we show that some neuronal parameters are either reduced or not affected by chronic glutamate receptor blockade. However, other parameters (including neuronal excitability, mEPSC frequency, and expression of GluR1, NR1 and betaCaMKII) become up-regulated and, in some cases, proportionally between the non-treated, 1X and 2X cultures. Our data suggest recovery of the network-driven glutamatergic activity after chronic glutamate receptor blockade. This recovery may represent a form of neuronal plasticity that compensates for the prolonged suppression of the activity of glutamate receptors.

  11. Bibliography on Decline and Retrenchment.

    Science.gov (United States)

    National Center for Higher Education Management Systems, Boulder, CO.

    A bibliography on decline and retrenchment in higher education is presented that includes publications from the fields of higher education, the organization sciences, and public administration. The objective is to make available the reference tools that have been useful in conducting the National Center for Higher Education Management Systems'…

  12. Declining Enrollment--A Blessing.

    Science.gov (United States)

    Imhof, Howard E.

    This report describes how a New York school district took advantage of a decline in elementary school enrollment to restructure the district's educational program, reduce staff requirements, and eliminate double shifting at the district's junior high and high school. The district's plan involved closing one of the three elementary schools and…

  13. Strong families and declining fertility

    NARCIS (Netherlands)

    Hilevych, Yuliya

    2016-01-01

    This dissertation focuses on the role of family and social relationships in individuals’ reproductive careers during the fertility decline in Soviet Ukraine from around 1950 to 1975. These three decades after the Second World War signified the end of the First Demographic Transition in Ukraine

  14. Declining Efficiency in the Economy

    DEFF Research Database (Denmark)

    Nørgaard, Jørgen

    1995-01-01

    The paper discusses the concept of resource efficiency in the economy as a whole. This implies some unfoldings of the simple definition of efficiency as human satisfaction over throughput of resources. It is suggested, that the efficiency of the economic systems is declining in the countries...

  15. French Wines on the Decline?:

    DEFF Research Database (Denmark)

    Steiner, Bodo

    2004-01-01

    French wines, differentiated by geographic origin, served for many decades as a basis for the French success in the British wine market. However in the early 1990s, market share began to decline. This article explores the values that market participants placed on labelling information on French...

  16. Chinese culture and fertility decline.

    Science.gov (United States)

    Wu, C; Jia, S

    1992-01-01

    Coale has suggested that cultural factors exert a significant influence on fertility reduction; countries in the "Chinese cultural circle" would be the first to show fertility decline. In China, the view was that traditional Chinese culture contributed to increased population. This paper examines the nature of the relationship between Chinese culture and fertility. Attention was directed to a comparison of fertility rates of developing countries with strong Chinese cultural influence and of fertility within different regions of China. Discussion was followed by an explanation of the theoretical impact of Chinese culture on fertility and direct and indirect beliefs and practices that might either enhance or hinder fertility decline. Emigration to neighboring countries occurred after the Qing dynasty. Fertility after the 1950s declined markedly in Japan, Singapore, Hong Kong, South Korea, Taiwan, and mainland China: all countries within the Chinese cultural circle. Other countries within the Chinese circle which have higher fertility, yet lower fertility than other non-Chinese cultural countries, are Malaysia, Thailand, and Indonesia. Within China, regions with similar fertility patterns are identified as coastal regions, central plains, and mountainous and plateau regions. The Han ethnic group has lower fertility than that of ethnic minorities; regions with large Han populations have lower fertility. Overseas Chinese in East Asian countries also tend to have lower fertility than their host populations. Chinese culture consisted of the assimilation of other cultures over 5000 years. Fertility decline was dependent on the population's desire to limit reproduction, favorable social mechanisms, and availability of contraception: all factors related to economic development. Chinese culture affects fertility reduction by affecting reproductive views and social mechanisms directly, and indirectly through economics. Confucianism emphasizes collectivism, self

  17. 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.

  18. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  20. Motor Neurons

    DEFF Research Database (Denmark)

    Hounsgaard, Jorn

    2017-01-01

    Motor neurons translate synaptic input from widely distributed premotor networks into patterns of action potentials that orchestrate motor unit force and motor behavior. Intercalated between the CNS and muscles, motor neurons add to and adjust the final motor command. The identity and functional...... properties of this facility in the path from synaptic sites to the motor axon is reviewed with emphasis on voltage sensitive ion channels and regulatory metabotropic transmitter pathways. The catalog of the intrinsic response properties, their underlying mechanisms, and regulation obtained from motoneurons...... in in vitro preparations is far from complete. Nevertheless, a foundation has been provided for pursuing functional significance of intrinsic response properties in motoneurons in vivo during motor behavior at levels from molecules to systems....

  1. Influence of the Cholinergic System on the Immune Response of Teleost Fishes: Potential Model in Biomedical Research

    Directory of Open Access Journals (Sweden)

    G. A. Toledo-Ibarra

    2013-01-01

    Full Text Available Fishes are the phylogenetically oldest vertebrate group, which includes more than one-half of the vertebrates on the planet; additionally, many species have ecological and economic importance. Fish are the first evolved group of organisms with adaptive immune mechanisms; consequently, they are an important link in the evolution of the immune system, thus a potential model for understanding the mechanisms of immunoregulation. Currently, the influence of the neurotransmitter acetylcholine (ACh on the cells of the immune system is widely studied in mammalian models, which have provided evidence on ACh production by immune cells (the noncholinergic neuronal system; however, these neuroimmunomodulation mechanisms in fish and lower vertebrates are poorly studied. Therefore, the objective of this review paper was to analyze the influence of the cholinergic system on the immune response of teleost fish, which could provide information concerning the possibility of bidirectional communication between the nervous and immune systems in these organisms and provide data for a better understanding of basic issues in neuroimmunology in lower vertebrates, such as bony fishes. Thus, the use of fish as a model in biomedical research may contribute to a better understanding of human diseases and diseases in other animals.

  2. Cross-talk between oxidative stress and modifications of cholinergic and glutaminergic receptors in the pathogenesis of Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    Zhi-zhong GUAN

    2008-01-01

    Alzheimer's disease (AD) is the most common neurodegenerative disorder, and its pathogenesis is likely to be associated with multiple etiologies and mechanisms in which oxidative stress and deficits of neurotransmitter receptors may play impor-tant roles. It has been indicated that a high level of free radicals can influence the expressions of nicotinic receptors (nAChRs), muscarinic receptors (mAChRs), and N-methyl-D-aspartate (NMDA) receptors, exhibiting disturbances of cellular mem-brane by lipid peroxidation, damages of the protein receptors by protein oxidation, and possible modified gene expressions of these receptors by DNA oxidation. nAChRs have shown an antioxidative effect by a direct or an indirect pathway; mAChR stimulation may generate reactive oxygen species, which might be a physi-ological compensative reaction, or improve oxidative stress; and high stimulation to NMDA receptors can increase the sensitivity of oxidative stress of neurons. This review may provide complemental information" for understanding the correla-tion between oxidative stress and changed cholinergic and glutaminergic recep-tors in AD processing, and for revealing the underlying molecular mechanisms of these factors in the multiple etiologies and pathophysiology of the disorder.

  3. The quantitative evaluation of cholinergic markers in spatial memory improvement induced by nicotine-bucladesine combination in rats.

    Science.gov (United States)

    Azami, Kian; Etminani, Maryam; Tabrizian, Kaveh; Salar, Fatemeh; Belaran, Maryam; Hosseini, Asieh; Hosseini-Sharifabad, Ali; Sharifzadeh, Mohammad

    2010-06-25

    We previously showed that post-training intra-hippocampal infusion of nicotine-bucladesine combination enhanced spatial memory retention in the Morris water maze. Here we investigated the role of cholinergic markers in nicotine-bucladesine combination-induced memory improvement. We assessed the expression of choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) in CA1 region of the hippocampus and medial septal area (MSA) of the brain. Post-training bilateral infusion of a low concentration of either nicotine or bucladesine into the CA1 region of the hippocampus did not affect spatial memory significantly. Quantitative immunostaining analysis of optical density in CA1 regions and evaluation of immunopositive neurons in medial septal area of brain sections from all combination groups revealed a significant increase (Pnicotine and in a concentration dependent manner. Also, increase in the optical density and amount of ChAT and VAChT immunostaining correlated with the decrease in escape latency and traveled distance in rats treated with nicotine and low dose of bucladesine. Taken together, these results suggest that significant increases of ChAT and VAChT protein expressions in the CA1 region and medial septal area are the possible mechanisms of spatial memory improvement induced by nicotine-bucladesine combination.

  4. 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

  5. Cardiovascular Prevention of Cognitive Decline

    Directory of Open Access Journals (Sweden)

    Jean-Jacques Monsuez

    2011-01-01

    Full Text Available Midlife cardiovascular risk factors, including diabetes, hypertension, dyslipemia, and an unhealthy lifestyle, have been linked to subsequent incidence, delay of onset, and progression rate of Alzheimer disease and vascular dementia. Conversely, optimal treatment of cardiovascular risk factors prevents and slows down age-related cognitive disorders. The impact of antihypertensive therapy on cognitive outcome in patients with hypertension was assessed in large trials which demonstrated a reduction in progression of MRI white matter hyperintensities, in cognitive decline and in incidence of dementia. Large-scale database correlated statin use and reduction in the incidence of dementia, mainly in patients with documented atherosclerosis, but clinical trials failed to reach similar conclusions. Whether a multitargeted intervention would substantially improve protection, quality of life, and reduce medical cost expenditures in patients with lower risk profile has not been ascertained. This would require appropriately designed trials targeting large populations and focusing on cognitive decline as a primary outcome endpoint.

  6. A cholinergic-regulated circuit coordinates the maintenance and bi-stable states of a sensory-motor behavior during Caenorhabditis elegans male copulation.

    Directory of Open Access Journals (Sweden)

    Yishi Liu

    2011-03-01

    Full Text Available Penetration of a male copulatory organ into a suitable mate is a conserved and necessary behavioral step for most terrestrial matings; however, the detailed molecular and cellular mechanisms for this distinct social interaction have not been elucidated in any animal. During mating, the Caenorhabditis elegans male cloaca is maintained over the hermaphrodite's vulva as he attempts to insert his copulatory spicules. Rhythmic spicule thrusts cease when insertion is sensed. Circuit components consisting of sensory/motor neurons and sex muscles for these steps have been previously identified, but it was unclear how their outputs are integrated to generate a coordinated behavior pattern. Here, we show that cholinergic signaling between the cloacal sensory/motor neurons and the posterior sex muscles sustains genital contact between the sexes. Simultaneously, via gap junctions, signaling from these muscles is transmitted to the spicule muscles, thus coupling repeated spicule thrusts with vulval contact. To transit from rhythmic to sustained muscle contraction during penetration, the SPC sensory-motor neurons integrate the signal of spicule's position in the vulva with inputs from the hook and cloacal sensilla. The UNC-103 K(+ channel maintains a high excitability threshold in the circuit, so that sustained spicule muscle contraction is not stimulated by fewer inputs. We demonstrate that coordination of sensory inputs and motor outputs used to initiate, maintain, self-monitor, and complete an innate behavior is accomplished via the coupling of a few circuit components.

  7. 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.

  8. A cholinergic-regulated circuit coordinates the maintenance and bi-stable states of a sensory-motor behavior during Caenorhabditis elegans male copulation.

    Directory of Open Access Journals (Sweden)

    Yishi Liu

    2011-03-01

    Full Text Available Penetration of a male copulatory organ into a suitable mate is a conserved and necessary behavioral step for most terrestrial matings; however, the detailed molecular and cellular mechanisms for this distinct social interaction have not been elucidated in any animal. During mating, the Caenorhabditis elegans male cloaca is maintained over the hermaphrodite's vulva as he attempts to insert his copulatory spicules. Rhythmic spicule thrusts cease when insertion is sensed. Circuit components consisting of sensory/motor neurons and sex muscles for these steps have been previously identified, but it was unclear how their outputs are integrated to generate a coordinated behavior pattern. Here, we show that cholinergic signaling between the cloacal sensory/motor neurons and the posterior sex muscles sustains genital contact between the sexes. Simultaneously, via gap junctions, signaling from these muscles is transmitted to the spicule muscles, thus coupling repeated spicule thrusts with vulval contact. To transit from rhythmic to sustained muscle contraction during penetration, the SPC sensory-motor neurons integrate the signal of spicule's position in the vulva with inputs from the hook and cloacal sensilla. The UNC-103 K(+ channel maintains a high excitability threshold in the circuit, so that sustained spicule muscle contraction is not stimulated by fewer inputs. We demonstrate that coordination of sensory inputs and motor outputs used to initiate, maintain, self-monitor, and complete an innate behavior is accomplished via the coupling of a few circuit components.

  9. Cholinergic modulation of non-N-methyl-D-aspartic acid glutamatergic transmission in the chick ventral lateral geniculate nucleus.

    Science.gov (United States)

    Guo, J-Z; Sorenson, E M; Chiappinelli, V A

    2010-03-17

    Neurotransmission between glutamatergic terminals of retinal ganglion cells and principal neurons of the ventral lateral geniculate nucleus (LGNv) was examined with patch clamp recordings in chick brain slices during electrical stimulation of the optic tract. Since muscarinic and nicotinic receptors are present in high densities in LGNv, the present study examined possible roles of both receptors in modulating retinogeniculate transmission. During whole-cell recordings from LGNv neurons, acetylcholine (ACh, 100 microM) caused an initial increase in amplitudes of optic tract-evoked non-N-methyl-D-aspartic acid (NMDA) glutamatergic postsynaptic currents (PSCs). This increase was unchanged when 1 microM atropine was present, indicating that this initial enhancement of PSCs was due entirely to activation of nicotinic receptors. However, during washout of ACh the amplitudes of evoked PSCs became significantly decreased by 40.4+/-5.0% for several minutes before recovering to their original amplitudes, an effect blocked by 1 microM atropine. Exogenously applied muscarine (10 microM) markedly depressed optic tract-evoked PSCs, and this decrease in amplitude was blocked by atropine. In a second set of experiments, we examined effects of releasing endogenous ACh prior to optic tract stimulation. This was accomplished by stimulation of the lateral portion of LGNv via a separate conditioning electrode. Following a brief train of low intensity conditioning stimuli, non-NMDA glutamatergic PSCs evoked by optic tract stimulation were potentiated. However, at higher conditioning stimulus intensities the PSCs were markedly decreased compared with control, and this decrease was partially blocked by atropine (1 microM). Neither ACh nor muscarine altered amplitudes of PSCs elicited by exogenously applied glutamate. Muscarine significantly reduced the frequency but not the amplitudes of miniature PSCs, consistent with a presynaptic location for muscarinic receptors mediating these

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

    Science.gov (United States)

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

    2008-01-01

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

  11. 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.

  12. 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.

  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. 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

    BACKGROUND: Previous experiments have confirmed bone morphogenetic proteins (BMPs) upregulate cholinergic expression in neurons isolated from the embryonic rat hippocampus and cerebral cortex. Therefore, BMPs could be useful for treating Alzheimer's disease and other neurodegenerative diseases. OBJECTIVE: BMP-4 was infused into the hippocampal dentate gyrus of fornix-fimbria transected rats to test the effects of BMP-4 on cholinergic expression in dentate gyrus neurons, and to observe changes in spatial memory behavior. DESIGN: A randomized controlled animal experiment. SETTING: Department of Neurosurgery and Laboratory for Cell Biology, Institute of Geriatrics, General Hospital of Chinese PLA.MATERIALS: Twenty-seven healthy adult male Sprague Dawley (SD) rats, weighing 250-300 g, were provided by the Laboratory Animal Center of the General Hospital of Chinese PLA. Reagents: BMP-4 (B-2680, Sigma Company) and choline acetyl transferase (ChAT) antibody (AB5042, Chemicon Company) were used in this study. Equipments: a rat stereotaxic instrument (type: SN-2N, Narushige Group, Japan) and Image-prog-plus image analysis software (Media Cybernetics company, USA) were used in this study. The protocol was carried out in accordance with ethical guidelines for the use and care of animals.METHODS: This experiment was performed in the Institute of Geriatrics, General Hospital of Chinese PLA between July 2004 and March 2005. Rats were randomly divided into 4 groups: Alzheimer's disease group (n = 7), normal control group (n = 5), BMP-4-Alzheimer's disease group (n = 8), and model group (n = 7). In the Alzheimer's disease group, the left hippocampal fornix-fimbria of rats was transected to mimic Alzheimer's disease symptoms. In the BMP-4-Alzheimer's disease group, 1 μL BMP-4 (10 mg/L) was perfused into the left dentate gyrus with a microinjector at 1 μL/min. In the model group, 1 μL saline was perfused into the same position by the same method. Twenty-eight days after injection

  15. 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

  16. Proprioceptive coupling within motor neurons drives C. elegans forward locomotion

    Science.gov (United States)

    Wen, Quan; Po, Michelle; Hulme, Elizabeth; Chen, Sway; Liu, Xinyu; Kwok, Sen Wai; Gershow, Marc; Leifer, Andrew M; Butler, Victoria; Fang-Yen, Christopher; Kawano, Taizo; Schafer, William R; Whitesides, George

    2012-01-01

    Summary Locomotion requires coordinated motor activity throughout an animal’s body. In both vertebrates and invertebrates, chains of coupled Central Pattern Generators (CPGs) are commonly evoked to explain local rhythmic behaviors. In C. elegans, we report that proprioception within the motor circuit is responsible for propagating and coordinating rhythmic undulatory waves from head to tail during forward movement. Proprioceptive coupling between adjacent body regions transduces rhythmic movement initiated near the head into bending waves driven along the body by a chain of reflexes. Using optogenetics and calcium imaging to manipulate and monitor motor circuit activity of moving C. elegans held in microfluidic devices, we found that the B-type cholinergic motor neurons transduce the proprioceptive signal. In C. elegans, a sensorimotor feedback loop operating within a specific type of motor neuron both drives and organizes body movement. PMID:23177960

  17. The fertility decline in Kenya.

    Science.gov (United States)

    Robinson, W C; Harbison, S F

    1995-01-01

    In Sub-Saharan Africa Kenya is a prime example of a country experiencing a rapid decline in fertility and greater contraceptive prevalence. These changes have occurred since 1980 when fertility was high at 8.0 children per woman. In 1993 the total fertility rate (TFR) was 5.4, and the growth rate declined to about 2.0%. This transition is swifter than any country in contemporary Asia or historical Europe. The likely projection for Kenya is attainment of replacement level fertility during the 2020s and a leveling of population at about 100 million persons. Fertility has declined the most in urban areas and central and eastern regions. Bongaarts' proximate determinants (TFR, total marital fertility rate, total natural marital fertility rate, and total fecundity) are reduced to the proportion of currently married women using contraception, the proportion in lactational nonfecund status, and the proportion currently married. Actual fertility change is accounted for by total fertility change of 3.0 children. Lactational infecundability accounts for 0.5 potential births, and changes in marital fertility account for 1.0 reduced births per woman. About 70% of fertility reduction is accounted for by contraception and abortion. During 1977-78 80% of fertility control was due to lactational nonfecundity, 10% to nonmarriage, and 10% to contraception. In 1993 lactational nonfecundity accounted for 50% of the reduction, nonmarriage for 20%, and abortion about 30%. Future fertility is expected to be dependent on contraceptive prevalence. Kenya has experienced the Coale paradigm of preconditions necessary for demographic transition (willing, ready, and able). High fertility in Africa is not intractable. Creating the change in attitudes that leads to readiness is linked to education, health, and exposure to modernizing media and urban lifestyles. The public sector family planning program in Kenya has created the opportunity for access and availability of contraception. The key

  18. Declining Efficiency in the Economy

    DEFF Research Database (Denmark)

    Nørgaard, Jørgen

    1995-01-01

    The paper discusses the concept of resource efficiency in the economy as a whole. This implies some unfoldings of the simple definition of efficiency as human satisfaction over throughput of resources. It is suggested, that the efficiency of the economic systems is declining in the countries...... with a high material standard of living. Examples are presented as are suggestions for how to improve the efficiency. These improvements, however, have a tendency to reduce the gross domestic product and hence are conflicting with the conventional political goals of growing GDP....

  19. Nicotine inhibits potassium currents in Aplysia bag cell neurons.

    Science.gov (United States)

    White, Sean H; Sturgeon, Raymond M; Magoski, Neil S

    2016-06-01

    Acetylcholine and the archetypal cholinergic agonist, nicotine, are typically associated with the opening of ionotropic receptors. In the bag cell neurons, which govern the reproductive behavior of the marine snail, Aplysia californica, there are two cholinergic responses: a relatively large acetylcholine-induced current and a relatively small nicotine-induced current. Both currents are readily apparent at resting membrane potential and result from the opening of distinct ionotropic receptors. We now report a separate current response elicited by applying nicotine to cultured bag cell neurons under whole cell voltage-clamp. This current was ostensibly inward, best resolved at depolarized voltages, presented a noncooperative dose-response with a half-maximal concentration near 1.5 mM, and associated with a decrease in membrane conductance. The unique nicotine-evoked response was not altered by intracellular perfusion with the G protein blocker GDPβS or exposure to classical nicotinic antagonists but was occluded by replacing intracellular K(+) with Cs(+) Consistent with an underlying mechanism of direct inhibition of one or more K(+) channels, nicotine was found to rapidly reduce the fast-inactivating A-type K(+) current as well as both components of the delayed-rectifier K(+) current. Finally, nicotine increased bag cell neuron excitability, which manifested as reduction in spike threshold, greater action potential height and width, and markedly more spiking to continuous depolarizing current injection. In contrast to conventional transient activation of nicotinic ionotropic receptors, block of K(+) channels could represent a nonstandard means for nicotine to profoundly alter the electrical properties of neurons over prolonged periods of time.

  20. 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

  1. Dopamine receptor gene expression by enkephalin neurons in rat forebrain

    Energy Technology Data Exchange (ETDEWEB)

    Le Moine, C.; Normand, E.; Guitteny, A.F.; Fouque, B.; Teoule, R.; Bloch, B. (Universite de Bordeaux II (France))

    1990-01-01

    In situ hybridization experiments were performed with brain sections from normal, control and haloperidol-treated rats to identify and map the cells expressing the D2 dopamine receptor gene. D2 receptor mRNA was detected with radioactive or biotinylated oligonucleotide probes. D2 receptor mRNA was present in glandular cells of the pituitary intermediate lobe and in neurons of the substantia nigra, ventral tegmental area, and forebrain, especially in caudate putamen, nucleus accumbens, olfactory tubercle, and piriform cortex. Hybridization with D2 and preproenkephalin A probes in adjacent sections, as well as combined hybridization with the two probes in the same sections, demonstrated that all detectable enkephalin neurons in the striatum contained the D2 receptor mRNA. Large neurons in caudate putamen, which were unlabeled with the preproenkephalin A probe and which may have been cholinergic, also expressed the D2 receptor gene. Haloperidol treatment (14 or 21 days) provoked an increase in mRNA content for D2 receptor and preproenkephalin A in the striatum. This suggests that the increase in D2 receptor number observed after haloperidol treatment is due to increased activity of the D2 gene. These results indicate that in the striatum, the enkephalin neurons are direct targets for dopamine liberated from mesostriatal neurons.

  2. REST and CoREST modulate neuronal subtype specification, maturation and maintenance.

    Directory of Open Access Journals (Sweden)

    Joseph J Abrajano

    Full Text Available BACKGROUND: The repressor element-1 silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF is a master regulator of neuronal gene expression. REST functions as a modular scaffold for dynamic recruitment of epigenetic regulatory factors including its primary cofactor, the corepressor for element-1-silencing transcription factor (CoREST, to genomic loci that contain the repressor element-1 (RE1 binding motif. While REST was initially believed to silence RE1 containing neuronal genes in neural stem cells (NSCs and non-neuronal cells, emerging evidence shows an increasingly complex cell type- and developmental stage-specific repertoire of REST target genes and functions that include regulation of neuronal lineage maturation and plasticity. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we utilized chromatin immunoprecipitation on chip (ChIP-chip analysis to examine REST and CoREST functions during NSC-mediated specification of cholinergic neurons (CHOLNs, GABAergic neurons (GABANs, glutamatergic neurons (GLUTNs, and medium spiny projection neurons (MSNs. We identified largely distinct but overlapping profiles of REST and CoREST target genes during neuronal subtype specification including a disproportionately high percentage that are exclusive to each neuronal subtype. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate that the differential deployment of REST and CoREST is an important regulatory mechanism that mediates neuronal subtype specification by modulating specific gene networks responsible for inducing and maintaining neuronal subtype identity. Our observations also implicate a broad array of factors in the generation of neuronal diversity including but not limited to those that mediate homeostasis, cell cycle dynamics, cell viability, stress responses and epigenetic regulation.

  3. 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…

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

    Science.gov (United States)

    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…

  5. 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.

  6. 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.

  7. 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.

  8. 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

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  11. 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

  12. 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...

  13. 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.

  14. Can Occupational Therapy Slow Alzheimer's Decline?

    Science.gov (United States)

    ... news/fullstory_162135.html Can Occupational Therapy Slow Alzheimer's Decline? Patients, caregivers may reap some benefits, but ... slow down the physical decline that comes with Alzheimer's disease, a new clinical trial suggests. The study ...

  15. Who fears and who welcomes population decline?

    Directory of Open Access Journals (Sweden)

    Hendrik P. Van Dalen

    2011-08-01

    Full Text Available European countries are experiencing population decline and the tacit assumption in most analyses is that the decline may have detrimental welfare effects. In this paper we use a survey among the population in the Netherlands to discover whether population decline is always met with fear. A number of results stand out: population size preferences differ by geographic proximity: at a global level the majority of respondents favors a (global population decline, but closer to home one supports a stationary population. Population decline is clearly not always met with fear: 31 percent would like the population to decline at the national level and they generally perceive decline to be accompanied by immaterial welfare gains (improvement environment as well as material welfare losses (tax increases, economic stagnation. In addition to these driving forces it appears that the attitude towards immigrants is a very strong determinant at all geographical levels: immigrants seem to be a stronger fear factor than population decline.

  16. Soman increases