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Sample records for cholinergic neuromodulation controls

  1. Muscarinic cholinergic neuromodulation reduces proactive interference between stored odor memories during associative learning in rats.

    Science.gov (United States)

    De Rosa, E; Hasselmo, M E

    2000-02-01

    Previous electrophysiological studies and computational modeling suggest the hypothesis that cholinergic neuromodulation may reduce olfactory associative interference during learning (M. E. Hasselmo, B. P. Anderson, & J. M. Bower, 1992; M. E. Hasselmo & J. M. Bower, 1993). These results provide behavioral evidence supporting this hypothesis. A simultaneous discrimination task required learning a baseline odor pair (A+B-) and then, under the influence of scopolamine, a novel odor pair (A-C+) with an overlapping component (A) versus a novel odor pair (D+E-) with no overlapping component. As predicted by the model, rats that received scopolamine (0.50 and 0.25 mg/kg) were more impaired at acquiring overlapping than nonoverlapping odor pairs relative to their performance under normal saline or methylscopolamine. These results support the prediction that the physiological effects of acetylcholine can reduce interference between stored odor memories during associative learning.

  2. Functional and laminar dissociations between muscarinic and nicotinic cholinergic neuromodulation in the tree shrew primary visual cortex.

    Science.gov (United States)

    Bhattacharyya, Anwesha; Bießmann, Felix; Veit, Julia; Kretz, Robert; Rainer, Gregor

    2012-04-01

    Acetylcholine is an important neuromodulator involved in cognitive function. The impact of cholinergic neuromodulation on computations within the cortical microcircuit is not well understood. Here we investigate the effects of layer-specific cholinergic drug application in the tree shrew primary visual cortex during visual stimulation with drifting grating stimuli of varying contrast and orientation. We describe differences between muscarinic and nicotinic cholinergic effects in terms of both the layer of cortex and the attribute of visual representation. Nicotinic receptor activation enhanced the contrast response in the granular input layer of the cortex, while tending to reduce neural selectivity for orientation across all cortical layers. Muscarinic activation modestly enhanced the contrast response across cortical layers, and tended to improve orientation tuning. This resulted in highest orientation selectivity in the supra- and infragranular layers, where orientation selectivity was already greatest in the absence of pharmacological stimulation. Our results indicate that laminar position plays a crucial part in functional consequences of cholinergic stimulation, consistent with the differential distribution of cholinergic receptors. Nicotinic receptors function to enhance sensory representations arriving in the cortex, whereas muscarinic receptors act to boost the cortical computation of orientation tuning. Our findings suggest close homology between cholinergic mechanisms in tree shrew and primate visual cortices.

  3. Control Networks and Neuromodulators of Early Development

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    Posner, Michael I.; Rothbart, Mary K.; Sheese, Brad E.; Voelker, Pascale

    2012-01-01

    In adults, most cognitive and emotional self-regulation is carried out by a network of brain regions, including the anterior cingulate, insula, and areas of the basal ganglia, related to executive attention. We propose that during infancy, control systems depend primarily upon a brain network involved in orienting to sensory events that includes…

  4. Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury

    NARCIS (Netherlands)

    Wenger, N.; Moraud, E.M.; Gandar, J; Musienko, P.; Capogrosso, M.; Baud, L.; Le Goff, C.G.; Barraud, Q.; Pavlova, N.; Dominici, N.; Minev, I.R.; Asboth, L.; Hirsch, A.; Duis, S.; Kreider, J.; Mortera, A.; Haverbeck, O.; Kraus, S.; Schmitz, F.; DiGiovanna, J.; den Brand, van R.; Bloch, J; Detemple, P.; Lacour, S.P.; Bézard, E.; Micera, S.; Courtine, G.

    2016-01-01

    Electrical neuromodulation of lumbar segments improves motor control after spinal cord injury in animal models and humans. However, the physiological principles underlying the effect of this intervention remain poorly understood, which has limitedthe therapeutic approach to continuous stimulation ap

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

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    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.

  6. Neurotransmitters and neuromodulators controlling the anterior byssus retractor muscle of Mytilus edulis.

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    Muneoka, Y; Fujisawa, Y; Matsuura, M; Ikeda, T

    1991-01-01

    1. The anterior byssus retractor muscle (ABRM) of Mytilus edulis is innervated by at least two kinds of nerves, excitatory and relaxing nerves. The principal neurotransmitters released from these nerves have been shown to be acetylcholine and serotonin, respectively. 2. Some other monoamines, such as dopamine and octopamine, and various peptides, such as FMRFamide-related peptides, Mytilus inhibitory peptides, SCP-related peptides and a catch-relaxing peptide, may also be involved in the regulation of the muscle as neurotransmitters or neuromodulators. 3. The ABRM seems to be typical of invertebrate muscles controlled by multiple neurotransmitters and neuromodulators.

  7. Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury

    Science.gov (United States)

    Wenger, Nikolaus; Moraud, Eduardo Martin; Gandar, Jerome; Musienko, Pavel; Capogrosso, Marco; Baud, Laetitia; Le Goff, Camille G.; Barraud, Quentin; Pavlova, Natalia; Dominici, Nadia; Minev, Ivan R.; Asboth, Leonie; Hirsch, Arthur; Duis, Simone; Kreider, Julie; Mortera, Andrea; Haverbeck, Oliver; Kraus, Silvio; Schmitz, Felix; DiGiovanna, Jack; van den Brand, Rubia; Bloch, Jocelyne; Detemple, Peter; Lacour, Stéphanie P.; Bézard, Erwan; Micera, Silvestro; Courtine, Grégoire

    2016-01-01

    Electrical neuromodulation of lumbar segments improves motor control after spinal cord injury in animal models and humans. However, the physiological principles underlying the effect of this intervention remain poorly understood, which has limited this therapeutic approach to continuous stimulation applied to restricted spinal cord locations. Here, we developed novel stimulation protocols that reproduce the natural dynamics of motoneuron activation during locomotion. For this, we computed the spatiotemporal activation pattern of muscle synergies during locomotion in healthy rats. Computer simulations identified optimal electrode locations to target each synergy through the recruitment of proprioceptive feedback circuits. This framework steered the design of spatially selective spinal implants and real–time control software that modulate extensor versus flexor synergies with precise temporal resolution. Spatiotemporal neuromodulation therapies improved gait quality, weight–bearing capacities, endurance and skilled locomotion in multiple rodent models of spinal cord injury. These new concepts are directly translatable to strategies to improve motor control in humans. PMID:26779815

  8. Ultrasonic neuromodulation

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    Naor, Omer; Krupa, Steve; Shoham, Shy

    2016-06-01

    Ultrasonic waves can be non-invasively steered and focused into mm-scale regions across the human body and brain, and their application in generating controlled artificial modulation of neuronal activity could therefore potentially have profound implications for neural science and engineering. Ultrasonic neuro-modulation phenomena were experimentally observed and studied for nearly a century, with recent discoveries on direct neural excitation and suppression sparking a new wave of investigations in models ranging from rodents to humans. In this paper we review the physics, engineering and scientific aspects of ultrasonic fields, their control in both space and time, and their effect on neuronal activity, including a survey of both the field’s foundational history and of recent findings. We describe key constraints encountered in this field, as well as key engineering systems developed to surmount them. In closing, the state of the art is discussed, with an emphasis on emerging research and clinical directions.

  9. Cholinergic control of visual categorisation in macaques

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    Nikolaos C. Aggelopoulos

    2011-11-01

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

  10. 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.

  11. Neuromodulation as a Robot Controller: A Brain Inspired Strategy for Controlling Autonomous Robots

    Science.gov (United States)

    2009-09-01

    risks, rewards, novelty , effort, and social cooperation. Moreover, the neuromodulatory systems provide a foundation for cognitive function in...brain areas such as the amygdala, frontal cortex, and hippocampus . Therefore, understanding neuromodulatory function may provide control and action...of the brain such as the amygdala, frontal cortex and the hippocampus [2]. 3. The effect of each of these neuromodulatory systems on downstream

  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. Neuromodulation and Synaptic Plasticity for the Control of Fast Periodic Movement:Energy Efficiency in Coupled Compliant Joints via PCA

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    Philipp eStratmann

    2016-03-01

    Full Text Available There are multiple indications that the nervous system of animals tunes muscle output to exploit natural dynamics of the elastic locomotor system and the environment. This is an advantageous strategy especially in fast periodic movements, since the elastic elements store energy and increase energy efficiency and movement speed.Experimental evidence suggests that coordination among joints involves proprioceptive input and neuromodulatory influence originating in the brain stem. However, the neural strategies underlying the coordination of fast periodic movements remain poorly understood.Based on robotics control theory, we suggest that the nervous system implements a mechanism to accomplish coordination between joints by a linear coordinate transformation from the multi-dimensional space representing proprioceptive input at the joint level into a one-dimensional controller space. In this one-dimensional subspace, the movements of a whole limb can be driven by a single oscillating unit as simple as a reflex interneuron. The output of the oscillating unit is transformed back to joint space via the same transformation. The transformation weights correspond to the dominant principal component of the movement.In this study, we propose a biologically plausible neural network to exemplify that the central nervous system may encode our controller design. Using theoretical considerations and computer simulations, we demonstrate that spike-timing-dependent plasticity for the input mapping and serotonergic neuromodulation for the output mapping can extract the dominant principal component of sensory signals. Our simulations show that our network can reliably control mechanical systems of different complexity and increase the energy efficiency of ongoing cyclic movements.The proposed network is simple and consistent with previous biologic experiments. Thus, our controller could serve as a candidate to describe the neural control of fast, energy

  14. Neuromodulation and Synaptic Plasticity for the Control of Fast Periodic Movement: Energy Efficiency in Coupled Compliant Joints via PCA.

    Science.gov (United States)

    Stratmann, Philipp; Lakatos, Dominic; Albu-Schäffer, Alin

    2016-01-01

    There are multiple indications that the nervous system of animals tunes muscle output to exploit natural dynamics of the elastic locomotor system and the environment. This is an advantageous strategy especially in fast periodic movements, since the elastic elements store energy and increase energy efficiency and movement speed. Experimental evidence suggests that coordination among joints involves proprioceptive input and neuromodulatory influence originating in the brain stem. However, the neural strategies underlying the coordination of fast periodic movements remain poorly understood. Based on robotics control theory, we suggest that the nervous system implements a mechanism to accomplish coordination between joints by a linear coordinate transformation from the multi-dimensional space representing proprioceptive input at the joint level into a one-dimensional controller space. In this one-dimensional subspace, the movements of a whole limb can be driven by a single oscillating unit as simple as a reflex interneuron. The output of the oscillating unit is transformed back to joint space via the same transformation. The transformation weights correspond to the dominant principal component of the movement. In this study, we propose a biologically plausible neural network to exemplify that the central nervous system (CNS) may encode our controller design. Using theoretical considerations and computer simulations, we demonstrate that spike-timing-dependent plasticity (STDP) for the input mapping and serotonergic neuromodulation for the output mapping can extract the dominant principal component of sensory signals. Our simulations show that our network can reliably control mechanical systems of different complexity and increase the energy efficiency of ongoing cyclic movements. The proposed network is simple and consistent with previous biologic experiments. Thus, our controller could serve as a candidate to describe the neural control of fast, energy

  15. Neuromodulation of Attentional Control in Major Depression: A Pilot DeepTMS Study

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    Jodie Naim-Feil

    2016-01-01

    Full Text Available While Major Depressive Disorder (MDD is primarily characterized by mood disturbances, impaired attentional control is increasingly identified as a critical feature of depression. Deep transcranial magnetic stimulation (deepTMS, a noninvasive neuromodulatory technique, can modulate neural activity and induce neuroplasticity changes in brain regions recruited by attentional processes. This study examined whether acute and long-term high-frequency repetitive deepTMS to the dorsolateral prefrontal cortex (DLPFC can attenuate attentional deficits associated with MDD. Twenty-one MDD patients and 26 matched control subjects (CS were administered the Beck Depression Inventory and the Sustained Attention to Response Task (SART at baseline. MDD patients were readministered the SART and depressive assessments following a single session (n=21 and after 4 weeks (n=13 of high-frequency (20 Hz repetitive deepTMS applied to the DLPFC. To control for the practice effect, CS (n=26 were readministered the SART a further two times. The MDD group exhibited deficits in sustained attention and cognitive inhibition. Both acute and long-term high-frequency repetitive frontal deepTMS ameliorated sustained attention deficits in the MDD group. Improvement after acute deepTMS was related to attentional recovery after long-term deepTMS. Longer-term improvement in sustained attention was not related to antidepressant effects of deepTMS treatment.

  16. GABAA receptors are located in cholinergic terminals in the nucleus pontis oralis of the rat: implications for REM sleep control.

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    Liang, Chang-Lin; Marks, Gerald A

    2014-01-16

    The oral pontine reticular formation (PnO) of rat is one region identified in the brainstem as a rapid eye movement (REM) sleep induction zone. Microinjection of GABA(A) receptor antagonists into PnO induces a long lasting increase in REM sleep, which is similar to that produced by cholinergic agonists. We previously showed that this REM sleep-induction can be completely blocked by a muscarinic antagonist, indicating that the REM sleep-inducing effect of GABA(A) receptor antagonism is dependent upon the local cholinergic system. Consistent with these findings, it has been reported that GABA(A) receptor antagonists microdialyzed into PnO resulted in increased levels of acetylcholine. We hypothesize that GABA(A) receptors located on cholinergic boutons in the PnO are responsible for the REM sleep induction by GABA(A) receptor antagonists through blocking GABA inhibition of acetylcholine release. Cholinergic, varicose axon fibers were studied in the PnO by immunofluorescence and confocal, laser scanning microscopy. Immunoreactive cholinergic boutons were found to be colocalized with GABA(A) receptor subunit protein γ2. This finding implicates a specific subtype and location of GABA(A) receptors in PnO of rat in the control of REM sleep.

  17. Is zinc a neuromodulator?

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    Kay, Alan R; Tóth, Katalin

    2008-01-01

    The vesicles of certain glutamatergic terminals in the mammalian forebrain are replete with ionic zinc. It is believed that during synaptic transmission zinc is released, binds to receptors on the pre- or postsynaptic membranes, and hence acts as a neuromodulator. Although exogenous zinc modulates a wide variety of channels, whether synaptic zinc transits across the synaptic cleft and alters the response of channels has been difficult to establish. We will review the evidence for zinc as a neuromodulator and propose diagnostic criteria for establishing whether it is indeed one. Moreover, we will delineate alternative ways in which zinc might act at synapses.

  18. Regional and muscle layer variations in cholinergic nerve control of the rat myometrium during the oestrous cycle.

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    Houdeau, Eric; Rossano, Bernadette; Prud'homme, Marie-Jeanne

    2003-02-28

    To determine regional and muscle layer differences in the cholinergic nerve control of uterine activity, functional and immunohistochemical experiments were carried out on the cervix, and circular and longitudinal muscle from the caudal and rostral uterine horn in cyclic rats. During oestrus, in vitro electrical field stimulation evoked contractions in the cervix and myometrium of the caudal horn, predominantly in circular muscle layer. All evoked responses were tetrodotoxin-sensitive and completely abolished by atropine, thus were cholinergic nerve-mediated. In contrast, no electrical field stimulation-induced contraction occurred in either the circular or longitudinal muscle from the rostral uterus. Concentration-response curves for carbachol showed that muscarinic receptor-mediated contractions occurred in all uterine regions and muscle layers during oestrus. Immunohistochemistry for the cholinergic nerve marker, vesicular acetylcholine transporter showed that the predominance of the acetylcholine-dependent contractions in circular muscle preparations were related to a layer-specific distribution of cholinergic nerve fibres, abundant in the circular muscle but scarce in the longitudinal muscle layer. In addition, the absence of electrical field stimulation-evoked acetylcholine-dependent contractions in the rostral uterus was correlated to a marked decrease in the density of cholinergic fibres along the caudo-rostral axis of the organ. In the uterus from diestrus rats, contractions were not elicited in response to electrical field stimulation in the cervix and circular or longitudinal muscle from the caudal as well as rostral uterine horn. Addition of cumulative doses of carbachol failed to increase in a concentration-dependent manner the frequency and amplitude of contractions in the cervix and myometrial layers from either the caudal and rostral uterine horn. The distribution and density of cholinergic nerve fibres along the uterus and between the muscle layers

  19. Neuromodulation of intestinal inflammation

    NARCIS (Netherlands)

    Costes, L.M.M.

    2015-01-01

    Interactions between the central nervous system and the immune system have been shown to exert a crucial role in the tight regulation of the immune response in the intestine. In particular, the vagus nerve was recently unraveled as an important player in this neuromodulation of intestinal inflammati

  20. Cholinergic dermographism.

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    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.

  1. The level of cholinergic nucleus basalis activation controls the specificity of auditory associative memory.

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    Weinberger, Norman M; Miasnikov, Alexandre A; Chen, Jemmy C

    2006-11-01

    Learning involves not only the establishment of memory per se, but also the specific details of its contents. In classical conditioning, the former concerns whether an association was learned while the latter discloses what was learned. The neural bases of associativity have been studied extensively while neural mechanisms of memory specificity have been neglected. Stimulation of the cholinergic nucleus basalis (NBs) paired with a preceding tone induces CS-specific associative memory. As different levels of acetylcholine may be released naturally during different learning situations, we asked whether the level of activation of the cholinergic neuromodulatory system can control the degree of detail that is encoded and retrieved. Adult male rats were tested pre- and post-training for behavioral responses (interruption of ongoing respiration) to tones of various frequencies (1-15 kHz, 70 dB, 2 s). Training consisted of 200 trials/day of tone (8.0 kHz, 70 dB, 2 s) either paired or unpaired with NBs (CS-NBs = 1.8 s) at moderate (65.7+/-9.0 microA, one day) or weak (46.7+/-12.1 microA, three training days) levels of stimulation, under conditions of controlled behavioral state (pre-trial stable respiration rate). Post-training (24 h) responses to tones revealed that moderate activation induced both associative and CS-specific behavioral memory, whereas weak activation produced associative memory lacking frequency specificity. The degree of memory specificity 24 h after training was positively correlated with the magnitude of CS-elicited increase in gamma activity within the EEG during training, but only in the moderate NBs group. Thus, a low level of acetylcholine released by the nucleus basalis during learning is sufficient to induce associativity whereas a higher level of release enables the storage of greater experiential detail. gamma waves, which are thought to reflect the coordinated activity of cortical cells, appear to index the encoding of CS detail. The findings

  2. An integrated modelling framework for neural circuits with multiple neuromodulators

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    Vemana, Vinith

    2017-01-01

    Neuromodulators are endogenous neurochemicals that regulate biophysical and biochemical processes, which control brain function and behaviour, and are often the targets of neuropharmacological drugs. Neuromodulator effects are generally complex partly owing to the involvement of broad innervation, co-release of neuromodulators, complex intra- and extrasynaptic mechanism, existence of multiple receptor subtypes and high interconnectivity within the brain. In this work, we propose an efficient yet sufficiently realistic computational neural modelling framework to study some of these complex behaviours. Specifically, we propose a novel dynamical neural circuit model that integrates the effective neuromodulator-induced currents based on various experimental data (e.g. electrophysiology, neuropharmacology and voltammetry). The model can incorporate multiple interacting brain regions, including neuromodulator sources, simulate efficiently and easily extendable to large-scale brain models, e.g. for neuroimaging purposes. As an example, we model a network of mutually interacting neural populations in the lateral hypothalamus, dorsal raphe nucleus and locus coeruleus, which are major sources of neuromodulator orexin/hypocretin, serotonin and norepinephrine/noradrenaline, respectively, and which play significant roles in regulating many physiological functions. We demonstrate that such a model can provide predictions of systemic drug effects of the popular antidepressants (e.g. reuptake inhibitors), neuromodulator antagonists or their combinations. Finally, we developed user-friendly graphical user interface software for model simulation and visualization for both fundamental sciences and pharmacological studies. PMID:28100828

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

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

    2014-10-01

    Previous studies have shown that dexmedetomidine exerted anti-inflammatory effect on several animal models with inflammation, but the mechanism is not clear. This study intends to elucidate the anti-inflammatory mechanism of dexmedetomidine through the cholinergic anti-inflammatory pathway. To investigate this therapeutic potential of dexmedetomidine, a murine model of endotoxemia was established induced by lipopolysaccharide (LPS). Animals were assigned to one of four protocols. Protocol one: animals were randomly assigned to control group, dexmedetomidine group, and sterile saline group (n=20 each), and these animals were used for survival analysis. The survival rate was assessed up to 120 h after endotoxin injection. Protocol two: animals were randomly assigned to one of four groups (n=16 each): group 1 (group Saline), treated with sterile saline 15 min prior to endotoxin treatment (10 mg kg(-1) over 2 min); group 2 (group Dex), treated with dexmedetomidine 15 min prior to endotoxin treatment; group 3 (group αBGT+Dex), treated with alpha-7 nicotinic acetylcholine receptors (α7nAChR) antagonist alpha-bungarotoxin (αBGT, 1 μg/kg) 15 min prior to dexmedetomidine treatment; group 4 (group saline+Dex), treated with equivalent sterile saline 15 min prior to dexmedetomidine treatment. Protocol three: animals were randomly assigned to one of two groups (n=16 each): vagotomy group (group VNX+Dex), right cervical vagus nerve was exposed and transected; sham-operated group (group SHAM+Dex), the cervical vagus nerve was visualized, but was neither isolated from the surrounding tissues nor transected. Protocol four: animals were treated with dexmedetomidine (40 μg/kg) and sterile saline to observe the discharge activity of cervical vagus nerves by using BL-420F data acquisition and analysis system (n=16 each). In the survival analysis groups, the survival rate of dexmedetomidine group was significantly higher than that of the endotoxemia group (65 versus 25

  4. 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

  5. Neuromodulation of cancer pain.

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    Prinsloo, Sarah; Gabel, Stephanie; Lyle, Randall; Cohen, Lorenzo

    2014-01-01

    Managing cancer-related chronic pain is challenging to health care professionals as well as cancer patients and survivors. The management of cancer-related pain has largely consisted of pharmacological treatments, which has caused researchers to focus on neurotransmitter activity as a mediator of patients' perception of pain rather than the electrical activity during neurobiological processes of cancer-related pain. Consequently, brain-based pain treatment has focused mainly on neurotransmitters and not electrical neuromodulation. Neuroimaging research has revealed that brain activity is associated with patients' perceptions of symptoms across various diagnoses. The brain modulates internally generated neural activity and adjusts perceptions according to sensory input from the peripheral nervous system. Cancer-related pain may result not only from changes in the peripheral nervous system but also from changes in cortical activity over time. Thus, cortical reorganization by way of the brain's natural, plastic ability (neuroplasticity) may be used to manage pain symptoms. Physical and psychological distress could be modulated by giving patients tools to regulate neural activity in symptom-specific regions of interest. Initial research in nononcology populations suggests that encouraging neuroplasticity through a learning paradigm can be a useful technique to help treat chronic pain. Here we review evidence that indicates a measurable link between brain activity and patient-reported psychological and physical distress. We also summarize findings regarding both the neuroelectrical and neuroanatomical experience of symptoms, review research examining the mechanisms of the brain's ability to modify its own activity, and propose a brain-computer interface as a learning paradigm to augment neuroplasticity for pain management.

  6. Neuromodulators: available agents, physiology, and anatomy.

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    Nettar, Kartik; Maas, Corey

    2011-12-01

    Neuromodulators have risen to the forefront of aesthetic medicine. By reversibly relaxing target muscles, neuromodulators exhibit their effect by softening hyperfunctional lines. An understanding of their physiology, relevant facial anatomy, and current agents is imperative for a successful aesthetic practice.

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

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    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.

  8. Nosce te ipsum--Socrates revisited? Controlling momentary ruminative self-referent thoughts by neuromodulation of emotional working memory.

    Science.gov (United States)

    Vanderhasselt, Marie-Anne; Brunoni, Andre R; Loeys, Tom; Boggio, Paulo S; De Raedt, Rudi

    2013-11-01

    It becomes ever more evident that cognitive operations serve as fundamental mechanisms underlying higher order ruminative thoughts. In this sham controlled within subjects study, we performed anodal transcranial Direct Current Stimulation (tDCS) over the left dorsolateral prefrontal cortex (DLPFC) in 32 healthy participants. We tested the causal hypothesis that the relationship between DLPFC activity and ruminative thinking is mediated by working memory operations. We used the Internal Shift Task, a paradigm in which participants have to update and shift between specific (non)emotional representations in working memory. Subsequently, during an unguided rest period approximately 20 min after the stimulation, we explored the occurrence of momentary ruminative self-referent thought. The results demonstrated that the influence of anodal tDCS of the left DLPFC (and not of sham stimulation) on momentary ruminative self-referent thinking is mediated by the enhancement of WM operations for angry faces. Moreover, the more individuals ruminate in everyday life (as measured using the Ruminative Response Style), the larger this mediation effect was. These findings suggest that enhancing cognitive self-regulation, by increasing the ability to update and shift away from negative representations in working memory, might help individuals to control unintentional streams of self-referent thoughts that are self-critical and self-evaluative, a thinking style known as rumination.

  9. Frequency-dependent signal transmission and modulation by neuromodulators

    Directory of Open Access Journals (Sweden)

    Hiroshi T Ito

    2008-12-01

    Full Text Available The brain uses a strategy of labor division, which may allow it to accomplish more elaborate and complicated tasks, but in turn, imposes a requirement for central control to integrate information among different brain areas. Anatomically, the divergence of long-range neuromodulator projections appears well-suited to coordinate communication between brain areas. Oscillatory brain activity is a prominent feature of neural transmission. Thus, the ability of neuromodulators to modulate signal transmission in a frequency-dependent manner adds an additional level of regulation. Here, we review the significance of frequency-dependent signal modulation in brain function and how a neuronal network can possess such properties. We also describe how a neuromodulator, dopamine, changes frequency-dependent signal transmission, controlling information flow from the entorhinal cortex to the hippocampus.

  10. 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.

  11. 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...

  12. Noradrenergic and cholinergic modulation of late ERP responses to deviant stimuli.

    Science.gov (United States)

    Brown, Stephen B R E; van der Wee, Nic J A; van Noorden, Martijn S; Giltay, Erik J; Nieuwenhuis, Sander

    2015-12-01

    Researchers have proposed several hypotheses about the neuromodulator systems involved in generating P3 components of the ERP. To test some of these hypotheses, we conducted a randomized placebo-controlled crossover study in which we investigated how the late positive ERP response to deviant stimuli is modulated by (a) clonidine, an α2 agonist that attenuates baseline noradrenergic activity; and (b) scopolamine, a muscarinic antagonist of acetylcholine receptors. We collected EEG data from 18 healthy volunteers during the performance of an auditory oddball task with several active and passive task conditions. We then used temporospatial principal component analysis (PCA) to decompose the ERP waveforms. The PCA revealed two distinct late positive ERP components: the classic parietal P300 and the frontal novelty P3. Statistical analysis of the temporospatial factor scores indicated that in most conditions the amplitude of the classic P300 was increased by clonidine and scopolamine. In contrast, the amplitude of the novelty P3 was decreased by both drugs. The similar pattern of results for clonidine and scopolamine probably reflects the strong interactions between the noradrenergic and cholinergic systems. The results, in combination with previous pharmacological studies, suggest a critical role for both neuromodulator systems in the generation of the P300 and the novelty P3.

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

    Directory of Open Access Journals (Sweden)

    Maya Kaufman

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

  14. Noninvasive neuromodulation in cluster headache

    DEFF Research Database (Denmark)

    Láinez, Miguel J A; Jensen, Rigmor

    2015-01-01

    using this approach. RECENT FINDINGS: Techniques as occipital nerve stimulation or sphenopalatine ganglion stimulation are recommended as first-line therapy in refractory cluster patients, but they are invasive and maybe associated with complications. Noninvasive vagal nerve stimulation with an external......: In the last decade, invasive neuromodulation treatments have demonstrated good efficacy in cluster refractory patients. Noninvasive approaches such as the noninvasive vagal nerve stimulation have shown efficacy in one trial and could be an easier alternative in the management of this debilitating headache. We...

  15. Neuromodulation, Emotional Feelings and Affective Disorders

    Directory of Open Access Journals (Sweden)

    Fushun Wang

    2016-01-01

    Full Text Available Affective disorders such as anxiety, phobia and depression are a leading cause of disabilities worldwide. Monoamine neuromodulators are used to treat most of them, with variable degrees of efficacy. Here, we review and interpret experimental findings about the relation of neuromodulation and emotional feelings, in pursuit of two goals: (a to improve the conceptualisation of affective/emotional states, and (b to develop a descriptive model of basic emotional feelings related to the actions of neuromodulators. In this model, we hypothesize that specific neuromodulators are effective for basic emotions. The model can be helpful for mental health professionals to better understand the affective dynamics of persons and the actions of neuromodulators - and respective psychoactive drugs - on this dynamics.

  16. Addressing neurological disorders with neuromodulation.

    Science.gov (United States)

    Oluigbo, Chima O; Rezai, Ali R

    2011-07-01

    Neurological disorders are becoming increasingly common in developed countries as a result of the aging population. In spite of medications, these disorders can result in progressive loss of function as well as chronic physical, cognitive, and emotional disability that ultimately places enormous emotional and economic on the patient, caretakers, and the society in general. Neuromodulation is emerging as a therapeutic option in these patients. Neuromodulation is a field, which involves implantable devices that allow for the reversible adjustable application of electrical, chemical, or biological agents to the central or peripheral nervous system with the objective of altering its functioning with the objective of achieving a therapeutic or clinically beneficial effect. It is a rapidly evolving field that brings together many different specialties in the fields of medicine, materials science, computer science and technology, biomedical, and neural engineering as well as the surgical or interventional specialties. It has multiple current and emerging indications, and an enormous potential for growth. The main challenges before it are in the need for effective collaboration between engineers, basic scientists, and clinicians to develop innovations that address specific problems resulting in new devices and clinical applications.

  17. 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…

  18. Peripheral neuromodulation in chronic migraine.

    Science.gov (United States)

    Perini, F; De Boni, A

    2012-05-01

    Patients with chronic migraines are often refractory to medical treatment. Therefore, they might need other strategies to modulate their pain, according to their level of disability. Neuromodulation can be achieved with several tools: meditation, biofeedback, physical therapy, drugs and electric neurostimulation (ENS). ENS can be applied to the central nervous system (brain and spinal cord), either invasively (cortical or deep brain) or non-invasively [cranial electrotherapy stimulation, transcranial direct current stimulation and transcranial magnetic stimulation]. Among chronic primary headaches, cluster headaches are most often treated either through deep brain stimulation or occipital nerve stimulation because there is a high level of disability related to this condition. ENS, employed through several modalities such as transcutaneous electrical nerve stimulation, interferential currents and pulsed radiofrequency, has been applied to the peripheral nervous system at several sites. We briefly review the indications for the use of peripheral ENS at the site of the occipital nerves for the treatment of chronic migraine.

  19. [Neuromodulation in severe neuropathic pain].

    Science.gov (United States)

    van Dongen, Robert T M; Samwel, Han; Arnts, Inge J J; Steegers, Monique A H; Joosten, Elbert A; van Kleef, Maarten

    2015-01-01

    Pain relief in patients with chronic neuropathic pain can be difficult to accomplish. If pharmacological treatment combined with a form of physical therapy and psychological support does not lead to improvement, nerve blocks and rehabilitation can be considered. Appropriately screened patients with persistent incapacitating pain may respond to neuromodulation. A specific form of this technique - spinal cord stimulation - delivers electric pulses via an implanted electrode connected to a battery in the epidural space around the spinal cord. We describe three patients, two of whom had persistent leg pain after disc surgery. The third patient suffered from diabetic neuropathy. Despite thorough pre-procedural screening by an anaesthetist-pain specialist, psychologist, physical therapist and specialised nurse, spinal cord stimulation failed in one patient. Psycho-social factors, inadequate coping skills and depression may lead to inadequate improvement and failure of this therapy.

  20. Cholinergic control of gamma power in the midbrain spatial attention network.

    Science.gov (United States)

    Bryant, Astra S; Goddard, C Alex; Huguenard, John R; Knudsen, Eric I

    2015-01-14

    The modulation of gamma power (25-90 Hz) is associated with attention and has been observed across species and brain areas. However, mechanisms that control these modulations are poorly understood. The midbrain spatial attention network in birds generates high-amplitude gamma oscillations in the local field potential that are thought to represent the highest priority location for attention. Here we explore, in midbrain slices from chickens, mechanisms that regulate the power of these oscillations, using high-resolution techniques including intracellular recordings from neurons targeted by calcium imaging. The results identify a specific subtype of neuron, expressing non-α7 nicotinic acetylcholine receptors, that directly drives inhibition in the gamma-generating circuit and switches the network into a primed state capable of producing high-amplitude oscillations. The special properties of this mechanism enable rapid, persistent changes in gamma power. The brain may employ this mechanism wherever rapid modulations of gamma power are critical to information processing.

  1. A kinetic model for the frequency dependence of cholinergic modulation at hippocampal GABAergic synapses.

    Science.gov (United States)

    Stone, Emily; Haario, Heikki; Lawrence, J Josh

    2014-12-01

    In this paper we use a simple model of presynaptic neuromodulation of GABA signaling to decipher paired whole-cell recordings of frequency dependent cholinergic neuromodulation at CA1 parvalbumin-containing basket cell (PV BC)-pyramidal cell synapses. Variance-mean analysis is employed to normalize the data, which is then used to estimate parameters in the mathematical model. Various parameterizations and hidden parameter dependencies are investigated using Markov Chain Monte Carlo (MCMC) parameter estimation techniques. This analysis reveals that frequency dependence of cholinergic modulation requires both calcium-dependent recovery from depression and mAChR-induced inhibition of presynaptic calcium entry. A reduction in calcium entry into the presynaptic terminal in the kinetic model accounted for the frequency-dependent effects of mAChR activation.

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

    Directory of Open Access Journals (Sweden)

    L M Jordan

    2014-11-01

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

  3. [Sacral neuromodulation for neurogenic bladder dysfunction].

    Science.gov (United States)

    Kessler, T M; Wöllner, J; Kozomara, M; Mordasini, L; Mehnert, U

    2012-02-01

    Sacral neuromodulation (SNM) represents a promising option for managing treatment-refractory neurogenic bladder dysfunction. It remains to be seen, however, which types of neurogenic bladder dysfunction and which underlying neurological disorders best respond to SNM. Constant improvements in SNM have been achieved and it is now a minimally invasive approach performed under local anesthesia which should be considered before undertaking larger reconstructive procedures. An electrode is implanted in the S3 or S4 sacral foramen and during a test phase lasting for days to weeks the patient keeps a bladder diary to determine whether SNM has provided a relevant benefit. If the results of the test phase are positive, a neuromodulator is implanted in the gluteal area (or more rarely in the abdominal wall).The mechanism of action of SNM has not been completely clarified, but the afferent nerves most likely play a key role. It appears that SNM produces a modulation of medullary reflexes and brain centers by peripheral afferents. The implanted neuromodulation system does not lead to limitation of the patient's activities. However, it should be noted that high-frequency diathermy and unipolar electrocauterization are contraindicated in patients with neuromodulators, that during extracorporeal shock wave lithotripsy the focal point should not be in the direct vicinity of the neuromodulator or the electrode, that ultrasound and radiotherapy in the region of the implanted components should be avoided, that the neuromodulation should be discontinued in pregnancy, and that MRI examinations should only be conducted when urgently indicated and the neuromodulator is turned off.

  4. Neuromodulation and antenatal depression: a review

    Science.gov (United States)

    Kim, Deborah R; Snell, Jessica L; Ewing, Grace C; O’Reardon, John

    2015-01-01

    Background Depression during pregnancy affects 5%–8% of women. While the percentage of women in the US taking serotonin reuptake inhibitors during pregnancy has risen over the last decade, pregnant women continue to report that they prefer non-pharmacologic interventions. Objective We review the literature regarding neuromodulation techniques for major depressive disorder during pregnancy. The rationale for their use in this population, new developments, and future directions are discussed. Methods A literature search was conducted in PubMed Plus, Ovid Medline, and Embase to collect all articles on neuromodulation for the treatment of depression during pregnancy. Key search words included electroconvulsive therapy, transcranial magnetic stimulation, deep brain stimulation, transcranial direct current stimulation, neuromodulation, depression, and pregnancy. Given the sparse literature, all articles from 1960 to 2014 that addressed the use of neuromodulation in pregnancy were included. Conclusion The data support the use of electroconvulsive therapy in all trimesters of pregnancy for major depressive disorder. New data are emerging for the use of transcranial magnetic stimulation in pregnancy, which is likely safe, but more data are needed before it can be recommended as a primary treatment modality during pregnancy. Other neuromodulation techniques have not been well studied in this population. PMID:25897234

  5. Tonic neuromodulation of the inspiratory rhythm generator

    Directory of Open Access Journals (Sweden)

    Fernando ePeña-Ortega

    2012-07-01

    Full Text Available The generation of neural network dynamics relies on the interactions between the intrinsic and synaptic properties of their neural components. Moreover, neuromodulators allow networks to change these properties and adjust their activity to specific challenges. Endogenous continuous (tonic neuromodulation can regulate and sometimes be indispensible for networks to produce basal activity. This seems to be the case for the inspiratory rhythm generator located in the pre-Bötzinger complex (preBötC. This neural network is necessary and sufficient for generating inspiratory rhythms. The preBötC produces normal respiratory activity (eupnea as well as sighs under normoxic conditions, and it generates gasping under hypoxic conditions after a reconfiguration process. The reconfiguration leading to gasping generation involves changes of synaptic and intrinsic properties that can be mediated by several neuromodulators. Over the past years, it has been shown that endogenous continuous neuromodulation of the preBötC may involve the continuous action of amines and peptides on extrasynaptic receptors. I will summarize the findings supporting the role of endogenous continuous neuromodulation in the generation and regulation of different inspiratory rhythms, exploring the possibility that these neuromodulatory actions involve extrasynaptic receptors along with evidence of glial modulation of preBötC activity.

  6. Cyborg psychiatry to ensure agency and autonomy in mental disorders. A proposal for neuromodulation therapeutics.

    Directory of Open Access Journals (Sweden)

    Jean-Arthur eMicoulaud Franchi

    2013-09-01

    Full Text Available Neuromodulation therapeutics—as repeated Transcranial Magnetic Stimulation (rTMS and neurofeedback—are valuable tools for psychiatry. Nevertheless, they currently face some limitations: rTMS has confounding effects on neural activation patterns, and neurofeedback fails to change neural dynamics in some cases. Here we propose how coupling rTMS and neurofeedback can tackle both issues by adapting neural activations during rTMS and actively guiding individuals during neurofeedback. An algorithmic challenge then consists in designing the proper recording, processing, feedback, and control of unwanted effects. But this new neuromodulation technique also poses an ethical challenge: ensuring treatment occurs within a biopsychosocial model of medicine, while considering both the interaction between the patients and the psychiatrist, and the maintenance of individuals’ autonomy. Our solution is the concept of Cyborg psychiatry, which embodies the technique and includes a self-engaged interaction between patients and the neuromodulation device.

  7. 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.

  8. 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.

  9. Desynchronizing Electrical and Sensory Coordinated Reset Neuromodulation

    Directory of Open Access Journals (Sweden)

    Oleksandr V. Popovych

    2012-03-01

    Full Text Available Coordinated reset (CR stimulation is a desynchronizing stimulation technique based on timely coordinated phase resets of sub-populations of a synchronized neuronal ensemble. It has initially been computationally developed for electrical deep brain stimulation (DBS,to enable an effective desynchronization and unlearning of pathological synchrony and connectivity (anti-kindling. Here we computationally show for ensembles of spiking and bursting model neurons interacting via excitatory and inhibitory adaptive synapses that a phase reset of neuronal populations as well as a desynchronization and an anti-kindling can robustly be achieved by direct electrical stimulation or indirect (synaptically-mediated excitatory and inhibitory stimulation.Our findings are relevant for DBS as well as for sensory stimulation in neurological disorders characterized by pathological neuronalsynchrony. Based on the obtained results, we may expect that the local effects in the vicinity of a depth electrode (realized by direct stimulation of the neurons' somata or stimulation of axon terminals and the non-local CR effects (realized by stimulation of excitatory or inhibitory efferent fibers of deep brain CR neuromodulation may be similar or even identical. Furthermore, ourresults indicate that an effective desynchronization and anti-kindlingcan even be achieved by non-invasive, sensory CR neuromodulation. We discuss the concept of sensory CR neuromodulation in the context of neurological disorders.

  10. 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.

  11. 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.

  12. Update on Neuromodulation for Treatment-Resistant Depression

    Science.gov (United States)

    Bewernick, Bettina; Schlaepfer, Thomas E

    2015-01-01

    About 30% of patients suffering from a major depressive disorder do not respond sufficiently to established pharmacological, psychotherapeutic, or somatic treatments. Advances in technology and emerging knowledge about the dysfunctional brain circuits underlying depression have led to the development of different neuromodulation techniques. The aim of the present review is to give an update on noninvasive techniques, such as electroconvulsive therapy (ECT), magnetic seizure therapy (MST), transcranial magnetic stimulation (TMS), and invasive techniques requiring brain surgery, such as vagus nerve stimulation (VNS) and deep brain stimulation (DBS). First, the clinical relevance for therapy-resistant depression, including the current level of evidence, are presented. Neuroethics is concerned with the ethical, legal and social policy implications of neuroscience. A second focus of the review is the application of fundamental ethical principles, such as patient autonomy, patient well-being and justice to neuromodulation therapies. Due to reduced availability and lacking long-term efficacy data, most patients with treatment-resistant depression face a trial-and-error approach to therapeutics. This contravenes the ethical criteria of patient autonomy and justice. In order to raise the level of evidence, financial support of long-term studies, including large samples and randomized control trials, are necessary. PMID:26918135

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

    Directory of Open Access Journals (Sweden)

    Jolien Schaeverbeke

    2017-01-01

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

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

    Science.gov (United States)

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

    2014-04-01

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

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

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    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.

  16. Control of spontaneous firing patterns by the selective coupling of calcium currents to calcium-activated potassium currents in striatal cholinergic interneurons.

    Science.gov (United States)

    Goldberg, Joshua A; Wilson, Charles J

    2005-11-02

    The spontaneous firing patterns of striatal cholinergic interneurons are sculpted by potassium currents that give rise to prominent afterhyperpolarizations (AHPs). Large-conductance calcium-activated potassium (BK) channel currents contribute to action potential (AP) repolarization; small-conductance calcium-activated potassium channel currents generate an apamin-sensitive medium AHP (mAHP) after each AP; and bursts of APs generate long-lasting slow AHPs (sAHPs) attributable to apamin-insensitive currents. Because all these currents are calcium dependent, we conducted voltage- and current-clamp whole-cell recordings while pharmacologically manipulating calcium channels of the plasma membrane and intracellular stores to determine what sources of calcium activate the currents underlying AP repolarization and the AHPs. The Cav2.2 (N-type) blocker omega-conotoxin GVIA (1 microM) was the only blocker that significantly reduced the mAHP, and it induced a transition to rhythmic bursting in one-third of the cells tested. Cav1 (L-type) blockers (10 microM dihydropyridines) were the only ones that significantly reduced the sAHP. When applied to cells induced to burst with apamin, dihydropyridines reduced the sAHPs and abolished bursting. Depletion of intracellular stores with 10 mM caffeine also significantly reduced the sAHP current and reversibly regularized firing. Application of 1 microM omega-conotoxin MVIIC (a Cav2.1/2.2 blocker) broadened APs but had a negligible effect on APs in cells in which BK channels were already blocked by submillimolar tetraethylammonium chloride, indicating that Cav2.1 (Q-type) channels provide the calcium to activate BK channels that repolarize the AP. Thus, calcium currents are selectively coupled to the calcium-dependent potassium currents underlying the AHPs, thereby creating mechanisms for control of the spontaneous firing patterns of these neurons.

  17. 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.

  18. Neuromodulation therapies and treatment-resistant depression

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    Al-Harbi KS

    2012-07-01

    Full Text Available Khalid Saad Al-Harbi,1 Naseem Akhtar Qureshi21National Guard Hospital, King Abdulaziz Medical City, Riyadh, Saudi Arabia; 2General Administration for Research and Studies and Mental Health and Social Services, Riyadh, Saudi ArabiaBackground: Patients with treatment-resistant depression (TRD who showed partial response to pharmacological and psychotherapeutic interventions need a trial of neuromodulation therapies (NTs.Objective: This paper aims to review evidence-based data on the use of NTs in TRD.Method: Using keywords and combined-word strategy, multiple computer searches of PubMed, Google Scholar, Quertle(R, and Medline were conducted for retrieving relevant articles published in English-language peer-reviewed journals (2000–2012. Those papers that addressed NTs in TRD were retained for extensive review.Results: Despite methodological challenges, a range of 30%–93% of TRD patients showed substantial improvement to one of the NTs. One hundred–percent improvement was reported in two single-case studies on deep brain stimulation. Some studies reported no benefits from transcranial direct current stimulation. NTs were reported to have good clinical efficacy, better safety margin, and benign side-effect profile. Data are limited regarding randomized clinical trials, long-term efficacy, and cost-effectiveness of these approaches. Both modified electroconvulsive therapy and magnetic seizure therapy were associated with reversible but disturbing neurocognitive adverse effects. Besides clinical utility, NTs including approaches on the horizon may unlock the biological basis underlying mood disorders including TRD.Conclusion: NTs are promising in patients with TRD, as the majority of them show good clinical response measured by standardized depression scales. NTs need further technological refinements and optimization together with continuing well-designed studies that recruit larger numbers of participants with TRD.Keywords: treatment

  19. 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.

  20. [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.

  1. Control of Spontaneous Firing Patterns by the Selective Coupling of Calcium Currents to Calcium Activated Potassium Currents in Striatal Cholinergic Interneurons

    OpenAIRE

    Goldberg, Joshua A.; Wilson, Charles J.

    2005-01-01

    The spontaneous firing patterns of striatal cholinergic interneurons are sculpted by potassium currents that give rise to prominent afterhyperpolarizations (AHPs): BK currents contribute to action potential (AP) repolarization; SK currents generate an apamin-sensitive medium AHP (mAHP) following each AP; and bursts of APs generate long-lasting slow AHPs (sAHPs) due to apamin-insensitive currents. As all these currents are calcium-dependent, we conducted voltage- and current-clamp whole-cell r...

  2. Functional differentiation of cholinergic and noradrenergic modulation in a biophysical model of olfactory bulb granule cells.

    Science.gov (United States)

    Li, Guoshi; Linster, Christiane; Cleland, Thomas A

    2015-12-01

    Olfactory bulb granule cells are modulated by both acetylcholine (ACh) and norepinephrine (NE), but the effects of these neuromodulators have not been clearly distinguished. We used detailed biophysical simulations of granule cells, both alone and embedded in a microcircuit with mitral cells, to measure and distinguish the effects of ACh and NE on cellular and microcircuit function. Cholinergic and noradrenergic modulatory effects on granule cells were based on data obtained from slice experiments; specifically, ACh reduced the conductance densities of the potassium M current and the calcium-dependent potassium current, whereas NE nonmonotonically regulated the conductance density of an ohmic potassium current. We report that the effects of ACh and NE on granule cell physiology are distinct and functionally complementary to one another. ACh strongly regulates granule cell firing rates and afterpotentials, whereas NE bidirectionally regulates subthreshold membrane potentials. When combined, NE can regulate the ACh-induced expression of afterdepolarizing potentials and persistent firing. In a microcircuit simulation developed to investigate the effects of granule cell neuromodulation on mitral cell firing properties, ACh increased spike synchronization among mitral cells, whereas NE modulated the signal-to-noise ratio. Coapplication of ACh and NE both functionally improved the signal-to-noise ratio and enhanced spike synchronization among mitral cells. In summary, our computational results support distinct and complementary roles for ACh and NE in modulating olfactory bulb circuitry and suggest that NE may play a role in the regulation of cholinergic function.

  3. Functional differentiation of cholinergic and noradrenergic modulation in a biophysical model of olfactory bulb granule cells

    Science.gov (United States)

    Linster, Christiane

    2015-01-01

    Olfactory bulb granule cells are modulated by both acetylcholine (ACh) and norepinephrine (NE), but the effects of these neuromodulators have not been clearly distinguished. We used detailed biophysical simulations of granule cells, both alone and embedded in a microcircuit with mitral cells, to measure and distinguish the effects of ACh and NE on cellular and microcircuit function. Cholinergic and noradrenergic modulatory effects on granule cells were based on data obtained from slice experiments; specifically, ACh reduced the conductance densities of the potassium M current and the calcium-dependent potassium current, whereas NE nonmonotonically regulated the conductance density of an ohmic potassium current. We report that the effects of ACh and NE on granule cell physiology are distinct and functionally complementary to one another. ACh strongly regulates granule cell firing rates and afterpotentials, whereas NE bidirectionally regulates subthreshold membrane potentials. When combined, NE can regulate the ACh-induced expression of afterdepolarizing potentials and persistent firing. In a microcircuit simulation developed to investigate the effects of granule cell neuromodulation on mitral cell firing properties, ACh increased spike synchronization among mitral cells, whereas NE modulated the signal-to-noise ratio. Coapplication of ACh and NE both functionally improved the signal-to-noise ratio and enhanced spike synchronization among mitral cells. In summary, our computational results support distinct and complementary roles for ACh and NE in modulating olfactory bulb circuitry and suggest that NE may play a role in the regulation of cholinergic function. PMID:26334007

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

    Directory of Open Access Journals (Sweden)

    Jan Krzysztof Blusztajn

    2016-03-01

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

  5. The dopamine metabolite 3-methoxytyramine is a neuromodulator.

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    Tatyana D Sotnikova

    Full Text Available Dopamine (3-hydroxytyramine is a well-known catecholamine neurotransmitter involved in multiple physiological functions including movement control. Here we report that the major extracellular metabolite of dopamine, 3-methoxytyramine (3-MT, can induce behavioral effects in a dopamine-independent manner and these effects are partially mediated by the trace amine associated receptor 1 (TAAR1. Unbiased in vivo screening of putative trace amine receptor ligands for potential effects on the movement control revealed that 3-MT infused in the brain is able to induce a complex set of abnormal involuntary movements in mice acutely depleted of dopamine. In normal mice, the central administration of 3-MT caused a temporary mild hyperactivity with a concomitant set of abnormal movements. Furthermore, 3-MT induced significant ERK and CREB phosphorylation in the mouse striatum, signaling events generally related to PKA-mediated cAMP accumulation. In mice lacking TAAR1, both behavioral and signaling effects of 3-MT were partially attenuated, consistent with the ability of 3-MT to activate TAAR1 receptors and cause cAMP accumulation as well as ERK and CREB phosphorylation in cellular assays. Thus, 3-MT is not just an inactive metabolite of DA, but a novel neuromodulator that in certain situations may be involved in movement control. Further characterization of the physiological functions mediated by 3-MT may advance understanding of the pathophysiology and pharmacology of brain disorders involving abnormal dopaminergic transmission, such as Parkinson's disease, dyskinesia and schizophrenia.

  6. Neuromodulation of group prejudice and religious belief.

    Science.gov (United States)

    Holbrook, Colin; Izuma, Keise; Deblieck, Choi; Fessler, Daniel M T; Iacoboni, Marco

    2016-03-01

    People cleave to ideological convictions with greater intensity in the aftermath of threat. The posterior medial frontal cortex (pMFC) plays a key role in both detecting discrepancies between desired and current conditions and adjusting subsequent behavior to resolve such conflicts. Building on prior literature examining the role of the pMFC in shifts in relatively low-level decision processes, we demonstrate that the pMFC mediates adjustments in adherence to political and religious ideologies. We presented participants with a reminder of death and a critique of their in-group ostensibly written by a member of an out-group, then experimentally decreased both avowed belief in God and out-group derogation by downregulating pMFC activity via transcranial magnetic stimulation. The results provide the first evidence that group prejudice and religious belief are susceptible to targeted neuromodulation, and point to a shared cognitive mechanism underlying concrete and abstract decision processes. We discuss the implications of these findings for further research characterizing the cognitive and affective mechanisms at play.

  7. Modeling nicotinic neuromodulation from global functional and network levels to nAChR based mechanisms

    Institute of Scientific and Technical Information of China (English)

    Michael GRAUPNER; Boris GUTKIN

    2009-01-01

    Neuromodulator action has received increasing attention in theoretical neuroscience. Yet models involving both neuronal populations dynamics at the circuit level and detailed receptor properties are only now being developed. Here we review recent computational approaches to neuromodulation, focusing specifically on acetylcholine (ACh) and nicotine. We dis-cuss illustrative examples of models ranging from functional top-down to neurodynamical bottom-up. In the top-down approach, a computational theory views ACh as encoding the uncertainty expected in an environment. A different line of models accounts for neural population dynamics treating ACh as toggling neuronal networks between read-in of informa-tion and recall of memory. Building on the neurodynamics idea we discuss two models of nicotine's action with increasing degree of biological realism. Both consider explicitly receptor-level mechanisms but with different scales of detail. The first is a large-scale model of nicotine-dependent modulation of dopaminergic signaling that is capable of simulating nicotine self-administration. The second is a novel approach where circuit-level neurodynamics of the ventral tegmental area (VTA) are combined with explicit models of the dynamics of specific nicotinic ACh receptor subtypes. We show how the model is constructed based on local anatomy, electrophysiology and receptor properties and provide an illustration of its potential. In particular, we show how the model can shed light on the specific mechanisms by which nicotine controls dopaminergic neurotransmission in the VTA. This model serves us to conclude that detailed accounts for neuromodulator action at the basis of behavioral and cognitive models are crucial to understand how neuromodulators mediate their functional proper-ties.

  8. 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.

  9. Neuromodulation of reward-based learning and decision making in human aging.

    Science.gov (United States)

    Eppinger, Ben; Hämmerer, Dorothea; Li, Shu-Chen

    2011-10-01

    In this paper, we review the current literature to highlight relations between age-associated declines in dopaminergic and serotonergic neuromodulation and adult age differences in adaptive goal-directed behavior. Specifically, we focus on evidence suggesting that deficits in neuromodulation contribute to older adults' behavioral disadvantages in learning and decision making. These deficits are particularly pronounced when reward information is uncertain or the task context requires flexible adaptations to changing stimulus-reward contingencies. Moreover, emerging evidence points to age-related differences in the sensitivity to rewarding and aversive outcomes during learning and decision making if the acquisition of behavior critically depends on outcome processing. These age-related asymmetries in outcome valuation may be explained by age differences in the interplay of dopaminergic and serotonergic neuromodulation. This hypothesis is based on recent neurocomputational and psychopharmacological approaches, which suggest that dopamine and serotonin serve opponent roles in regulating the balance between approach behavior and inhibitory control. Studying adaptive regulation of behavior across the adult life span may shed new light on how the aging brain changes functionally in response to its diminishing resources.

  10. Cell-Type-Selective Effects of Intramembrane Cavitation as a Unifying Theoretical Framework for Ultrasonic Neuromodulation.

    Science.gov (United States)

    Plaksin, Michael; Kimmel, Eitan; Shoham, Shy

    2016-01-01

    Diverse translational and research applications could benefit from the noninvasive ability to reversibly modulate (excite or suppress) CNS activity using ultrasound pulses, however, without clarifying the underlying mechanism, advanced design-based ultrasonic neuromodulation remains elusive. Recently, intramembrane cavitation within the bilayer membrane was proposed to underlie both the biomechanics and the biophysics of acoustic bio-effects, potentially explaining cortical stimulation results through a neuronal intramembrane cavitation excitation (NICE) model. Here, NICE theory is shown to provide a detailed predictive explanation for the ability of ultrasonic (US) pulses to also suppress neural circuits through cell-type-selective mechanisms: according to the predicted mechanism T-type calcium channels boost charge accumulation between short US pulses selectively in low threshold spiking interneurons, promoting net cortical network inhibition. The theoretical results fit and clarify a wide array of earlier empirical observations in both the cortex and thalamus regarding the dependence of ultrasonic neuromodulation outcomes (excitation-suppression) on stimulation and network parameters. These results further support a unifying hypothesis for ultrasonic neuromodulation, highlighting the potential of advanced waveform design for obtaining cell-type-selective network control.

  11. 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.

  12. 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.

  13. Technical Considerations for Filler and Neuromodulator Refinements

    Science.gov (United States)

    Wilson, Anthony J.; Chang, Brian L.; Percec, Ivona

    2016-01-01

    Background: The toolbox for cosmetic practitioners is growing at an unprecedented rate. There are novel products every year and expanding off-label indications for neurotoxin and soft-tissue filler applications. Consequently, aesthetic physicians are increasingly challenged by the task of selecting the most appropriate products and techniques to achieve optimal patient outcomes. Methods: We employed a PubMed literature search of facial injectables from the past 10 years (2005–2015), with emphasis on those articles embracing evidence-based medicine. We evaluated the scientific background of every product and the physicochemical properties that make each one ideal for specific indications. The 2 senior authors provide commentary regarding their clinical experience with specific technical refinements of neuromodulators and soft-tissue fillers. Results: Neurotoxins and fillers are characterized by unique physical characteristics that distinguish each product. This results in subtle but important differences in their clinical applications. Specific indications and recommendations for the use of the various neurotoxins and soft-tissue fillers are reviewed. The discussion highlights refinements in combination treatments and product physical modifications, according to specific treatment zones. Conclusions: The field of facial aesthetics has evolved dramatically, mostly secondary to our increased understanding of 3-dimensional structural volume restoration. Our work reviews Food and Drug Administration–approved injectables. In addition, we describe how to modify products to fulfill specific indications such as treatment of the mid face, décolletage, hands, and periorbital regions. Although we cannot directly evaluate the duration or exact physical properties of blended products, we argue that “product customization” is safe and provides natural results with excellent patient outcomes. PMID:28018778

  14. 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.

  15. 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.

  16. Neuromodulation for Lower Urinary Tract Dysfunction – An Update

    Directory of Open Access Journals (Sweden)

    Zahid Hussain

    2007-01-01

    Full Text Available The aim of this review is to provide an update on the use of neuromodulation using sacral nerve stimulation for the treatment of disorders of the lower urinary tract. Neuromodulation using the InterStim® system (Medtronic Inc. is now accepted as an established therapeutic option for patients with detrusor overactivity, and for women with retention or severe voiding difficulties. However, the use of nerve stimulation in modulating lower urinary tract function has to be regarded as a technique that is in its infancy. Much has yet to be learned about the mechanism by which neuromodulation exerts its effects and there is a need to better define the clinical indications for the treatment. There is also work to be done in terms of optimising stimulation delivery, both in anatomical and electronic terms.

  17. Sacral Neuromodulation for Bladder Atony – A Case Report

    Directory of Open Access Journals (Sweden)

    Joseph Sujka

    2014-01-01

    Full Text Available In most cases, sacral neuromodulation is used as a treatment for urge incontinence and symptoms of urgency and frequency. It is most used in those who are refractory to traditional management. It is much less common to be used for bladder atony. In this report, we present a case of a 24-year-old woman with a history of urinary retention and bladder atony who failed medical management and subsequently had an InterStim sacral neuromodulator implanted. After implantation, she was able to discontinue intermittent catheterization and had a decrease in her postvoid residual from 848 to 72 mL.

  18. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  20. Neuromodulation of Behavioral and Cognitive Development across the Life Span

    Science.gov (United States)

    Li, Shu-Chen

    2012-01-01

    Among other mechanisms, behavioral and cognitive development entail, on the one hand, contextual scaffolding and, on the other hand, neuromodulation of adaptive neurocognitive representations across the life span. Key brain networks underlying cognition, emotion, and motivation are innervated by major transmitter systems (e.g., the catecholamines…

  1. Bionic autonomic neuromodulation revolutionizes cardiology in the 21st century.

    Science.gov (United States)

    Sunagawa, Kenji

    2009-01-01

    In this invited session, we would like to address the impact of bionic neuromodulation on cardiovascular diseases. It has been well established that cardiovascular dysregulation plays major roles in the pathogenesis of cardiovascular diseases. This is the reason why most drugs currently used in cardiology have significant pharmacological effects on the cardiovascular regulatory system. Since the ultimate center for cardiovascular regulation is the brainstem, it is conceivable that autonomic neuromodulation would have significant impacts on cardiovascular diseases. On the basis of this framework, we first developed a bionic, neurally regulated artificial pacemaker. We then substituted the brainstem by CPU and developed a bionic artificial baroreflex system. We further developed a bionic brain that achieved better regulatory conditions than the native brainstem in order to improve survival in animal model with heart failure. We recently developed a bionic neuromodulation system to reduce infarction size following acute myocardial infarction. We believe that the bionic neuromodulation will inspire even more intricate applications in cardiology in the 21(st) century.

  2. Neuromodulation and antenatal depression: a review

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    Kim DR

    2015-04-01

    Full Text Available Deborah R Kim,1 Jessica L Snell,1 Grace C Ewing,1 John O’Reardon2 1Department of Psychiatry, Penn Center for Women’s Behavioral Health, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 2Department of Psychiatry, Rowan University, Rowan School of Medicine, Cherry Hill, NJ, USA Background: Depression during pregnancy affects 5%–8% of women. While the percentage of women in the US taking serotonin reuptake inhibitors during pregnancy has risen over the last decade, pregnant women continue to report that they prefer non-pharmacologic interventions. Objective: We review the literature regarding neuromodulation techniques for major depressive disorder during pregnancy. The rationale for their use in this population, new developments, and future directions are discussed. Methods: A literature search was conducted in PubMed Plus, Ovid Medline, and Embase to collect all articles on neuromodulation for the treatment of depression during pregnancy. Key search words included electroconvulsive therapy, transcranial magnetic stimulation, deep brain stimulation, transcranial direct current stimulation, neuromodulation, depression, and pregnancy. Given the sparse literature, all articles from 1960 to 2014 that addressed the use of neuromodulation in pregnancy were included. Conclusion: The data support the use of electroconvulsive therapy in all trimesters of pregnancy for major depressive disorder. New data are emerging for the use of transcranial magnetic stimulation in pregnancy, which is likely safe, but more data are needed before it can be recommended as a primary treatment modality during pregnancy. Other neuromodulation techniques have not been well studied in this population. Keywords: electroconvulsive therapy, transcranial magnetic stimulation, pregnancy, depression, antenatal depression, perinatal

  3. Brain plasticity effects of neuromodulation against multiple sclerosis fatigue

    Directory of Open Access Journals (Sweden)

    Franca eTecchio

    2015-07-01

    Full Text Available RationaleWe recently reported on the efficacy of a personalized transcranial direct current stimulation (tDCS treatment in reducing MS fatigue. That result supports the notion that interventions targeted at modifying unbalanced interactions within the sensorimotor network could represent valid non-pharmacological treatments. ObjectiveThe present work aimed at assessing whether the mentioned intervention also induces changes in the excitability of cortical areas. MethodTwo separate groups of fatigued MS patients were given a 5-day tDCS treatments targeting respectively the whole body somatosensory areas (S1wb and the hand sensorimotor areas (SM1hand. The study had a double blind, sham-controlled, randomized, cross-over (Real vs. Sham design. Before and after each treatment, we measured fatigue levels (by the modified Fatigue Impact Scale, mFIS, motor evoked potentials (MEPs in response to transcranial magnetic stimulation (TMS and somatosensory evoked potentials (SEP in response to median nerve stimulation. We took MEPs and SEPs as measures of the excitability of the primary motor area (M1 and the primary somatosensory area (S1 respectively.ResultsThe Real S1wb treatment produced a 27% reduction of the mFIS baseline level, while the SM1hand treatment showed no difference between Real and Sham stimulations. M1 excitability increased on average 6 % of the baseline in the S1wb group and 40% in the SM1hand group. Observed SEP changes were not significant and we found no association between M1 excitability changes and mFIS decrease.ConclusionsThe tDCS treatment was more effective against MS fatigue when the electrode was focused on the bilateral whole body somatosensory area. Changes in S1 and M1 excitability did not correlate with symptoms amelioration.SignificanceThe neuromodulation treatment that proved effective against MS fatigue induced only minor variations of the motor cortex excitability, not enough to explain the beneficial effects of

  4. Muscarinic and dopaminergic receptor subtypes on striatal cholinergic interneurons

    Energy Technology Data Exchange (ETDEWEB)

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

    1990-12-01

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

  5. 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.

  6. 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.

  7. Network burst dynamics under heterogeneous cholinergic modulation of neural firing properties and heterogeneous synaptic connectivity.

    Science.gov (United States)

    Knudstrup, Scott; Zochowski, Michal; Booth, Victoria

    2016-05-01

    The characteristics of neural network activity depend on intrinsic neural properties and synaptic connectivity in the network. In brain networks, both of these properties are critically affected by the type and levels of neuromodulators present. The expression of many of the most powerful neuromodulators, including acetylcholine (ACh), varies tonically and phasically with behavioural state, leading to dynamic, heterogeneous changes in intrinsic neural properties and synaptic connectivity properties. Namely, ACh significantly alters neural firing properties as measured by the phase response curve in a manner that has been shown to alter the propensity for network synchronization. The aim of this simulation study was to build an understanding of how heterogeneity in cholinergic modulation of neural firing properties and heterogeneity in synaptic connectivity affect the initiation and maintenance of synchronous network bursting in excitatory networks. We show that cells that display different levels of ACh modulation have differential roles in generating network activity: weakly modulated cells are necessary for burst initiation and provide synchronizing drive to the rest of the network, whereas strongly modulated cells provide the overall activity level necessary to sustain burst firing. By applying several quantitative measures of network activity, we further show that the existence of network bursting and its characteristics, such as burst duration and intraburst synchrony, are dependent on the fraction of cell types providing the synaptic connections in the network. These results suggest mechanisms underlying ACh modulation of brain oscillations and the modulation of seizure activity during sleep states.

  8. 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.

  9. 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.

  10. Non-Invasive Neuromodulation Using Time-Varying Caloric Vestibular Stimulation

    Science.gov (United States)

    Rogers, Lesco L.; Ade, Kristen K.; Nicoletto, Heather A.; Adkins, Heather D.; Laskowitz, Daniel T.

    2016-01-01

    Caloric vestibular stimulation (CVS) to elicit the vestibulo-ocular reflex has long been used in clinical settings to aid in the diagnosis of balance disorders and to confirm the absence of brainstem function. While a number of studies have hinted at the potential therapeutic applications of CVS, the limitations of existing devices have frustrated that potential. Current CVS irrigators use water or air during short-duration applications; however, this approach is not tenable for longer duration therapeutic protocols or home use. Here, we describe a solid-state CVS device we developed in order to address these limitations. This device delivers tightly controlled time-varying thermal waveforms, which can be programmed through an external control unit. It contains several safety features, which limit patients to the prescribed waveform and prevent the potential for temperature extremes. In this paper, we provide evidence that CVS treatment with time-varying, but not constant temperature waveforms, elicits changes in cerebral blood flow physiology consistent with the neuromodulation of brainstem centers, and we present results from a small pilot study, which demonstrate that the CVS can safely and feasibly be used longitudinally in the home setting to treat episodic migraine. Together, these results indicate that this solid-state CVS device may be a viable tool for non-invasive neuromodulation. PMID:27777829

  11. Migraine generator network and spreading depression dynamics as neuromodulation targets in episodic migraine

    Science.gov (United States)

    Dahlem, Markus A.

    2013-12-01

    Migraine is a common disabling headache disorder characterized by recurrent episodes sometimes preceded or accompanied by focal neurological symptoms called aura. The relation between two subtypes, migraine without aura (MWoA) and migraine with aura (MWA), is explored with the aim to identify targets for neuromodulation techniques. To this end, a dynamically regulated control system is schematically reduced to a network of the trigeminal nerve, which innervates the cranial circulation, an associated descending modulatory network of brainstem nuclei, and parasympathetic vasomotor efferents. This extends the idea of a migraine generator region in the brainstem to a larger network and is still simple and explicit enough to open up possibilities for mathematical modeling in the future. In this study, it is suggested that the migraine generator network (MGN) is driven and may therefore respond differently to different spatio-temporal noxious input in the migraine subtypes MWA and MWoA. The noxious input is caused by a cortical perturbation of homeostasis, known as spreading depression (SD). The MGN might even trigger SD in the first place by a failure in vasomotor control. As a consequence, migraine is considered as an inherently dynamical disease to which a linear course from upstream to downstream events would not do justice. Minimally invasive and noninvasive neuromodulation techniques are briefly reviewed and their rational is discussed in the context of the proposed mechanism.

  12. Neuromodulation of chronic headaches: position statement from the European Headache Federation.

    Science.gov (United States)

    Martelletti, Paolo; Jensen, Rigmor H; Antal, Andrea; Arcioni, Roberto; Brighina, Filippo; de Tommaso, Marina; Franzini, Angelo; Fontaine, Denys; Heiland, Max; Jürgens, Tim P; Leone, Massimo; Magis, Delphine; Paemeleire, Koen; Palmisani, Stefano; Paulus, Walter; May, Arne

    2013-10-21

    The medical treatment of patients with chronic primary headache syndromes (chronic migraine, chronic tension-type headache, chronic cluster headache, hemicrania continua) is challenging as serious side effects frequently complicate the course of medical treatment and some patients may be even medically intractable. When a definitive lack of responsiveness to conservative treatments is ascertained and medication overuse headache is excluded, neuromodulation options can be considered in selected cases. Here, the various invasive and non-invasive approaches, such as hypothalamic deep brain stimulation, occipital nerve stimulation, stimulation of sphenopalatine ganglion, cervical spinal cord stimulation, vagus nerve stimulation, transcranial direct current stimulation, repetitive transcranial magnetic stimulation, and transcutaneous electrical nerve stimulation are extensively published although proper RCT-based evidence is limited. The European Headache Federation herewith provides a consensus statement on the clinical use of neuromodulation in headache, based on theoretical background, clinical data, and side effect of each method. This international consensus further gives recommendations for future studies on these new approaches. In spite of a growing field of stimulation devices in headaches treatment, further controlled studies to validate, strengthen and disseminate the use of neurostimulation are clearly warranted. Consequently, until these data are available any neurostimulation device should only be used in patients with medically intractable syndromes from tertiary headache centers either as part of a valid study or have shown to be effective in such controlled studies with an acceptable side effect profile.

  13. Neuromodulation of the conscious state following severe brain injuries.

    Science.gov (United States)

    Fridman, Esteban A; Schiff, Nicholas D

    2014-12-01

    Disorders of consciousness (DOC) following severe structural brain injuries globally affect the conscious state and the expression of goal-directed behaviors. In some subjects, neuromodulation with medications or electrical stimulation can markedly improve the impaired conscious state present in DOC. We briefly review recent studies and provide an organizing framework for considering the apparently widely disparate collection of medications and approaches that may modulate the conscious state in subjects with DOC. We focus on neuromodulation of the anterior forebrain mesocircuit in DOC and briefly compare mechanisms supporting recovery from structural brain injuries to those underlying facilitated emergence from unconsciousness produced by anesthesia. We derive some general principles for approaching the problem of restoration of consciousness after severe structural brain injuries, and suggest directions for future research.

  14. Specific Tips for General Controversies in Sacral Neuromodulation.

    Science.gov (United States)

    El-Azab, Ahmed S; Siegel, Steven W

    2016-11-01

    The field of Sacral Neuromodulation is continually evolving and still in its infancy. Common dilemmas experienced with this therapy will be discussed in this article, including ways to avoid and manage them. The focus will be on test evaluations performed with either peripheral nerve evaluation (PNE) or staged procedure, the clinical effectiveness and safety of unilateral versus bilateral test stimulation for both the PNE and staged procedures, and best methods to determine the success of the trial phase. We will also discuss how to deal with the problem of declining efficacy of the device over time. The article presents a discussion on future technological innovations to enhance techniques and mode of positioning and use of leads, which along with a refined understanding of how neuromodulation is effective for different problems, will lead to better outcomes.

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

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    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.

  16. Neuromodulation of the Feedforward Dentate Gyrus-CA3 Microcircuit

    Science.gov (United States)

    Prince, Luke Y.; Bacon, Travis J.; Tigaret, Cezar M.; Mellor, Jack R.

    2016-01-01

    The feedforward dentate gyrus-CA3 microcircuit in the hippocampus is thought to activate ensembles of CA3 pyramidal cells and interneurons to encode and retrieve episodic memories. The creation of these CA3 ensembles depends on neuromodulatory input and synaptic plasticity within this microcircuit. Here we review the mechanisms by which the neuromodulators aceylcholine, noradrenaline, dopamine, and serotonin reconfigure this microcircuit and thereby infer the net effect of these modulators on the processes of episodic memory encoding and retrieval. PMID:27799909

  17. Neuromodulation of the feedforward dentate gyrus-CA3 microcircuit

    OpenAIRE

    Luke Yuri Prince; Travis J Bacon; Tigaret, Cezar M.; Mellor, Jack R.

    2016-01-01

    The feedforward dentate gyrus-CA3 microcircuit in the hippocampus is thought to activate ensembles of CA3 pyramidal cells and interneurons to encode and retrieve episodic memories. The creation of these CA3 ensembles depends on neuromodulatory input and synaptic plasticity within this microcircuit. Here we review the mechanisms by which the neuromodulators aceylcholine, noradrenaline, dopamine, and serotonin reconfigure this microcircuit and thereby infer the net effect of these modulators on...

  18. Neuromodulation of the Feedforward Dentate Gyrus-CA3 Microcircuit

    OpenAIRE

    Prince, Luke; Travis J Bacon; Tigaret, Cezar; Mellor, Jack

    2016-01-01

    The feedforward dentate gyrus-CA3 microcircuit in the hippocampus is thought to activate ensembles of CA3 pyramidal cells and interneurons to encode and retrieve episodic memories. The creation of these CA3 ensembles depends on neuromodulatory input and synaptic plasticity within this microcircuit. Here we review the mechanisms by which the neuromodulators aceylcholine, noradrenaline, dopamine, and serotonin reconfigure this microcircuit and thereby infer the net effect of these modulators on...

  19. Neuromodulation of the Feedforward Dentate Gyrus-CA3 Microcircuit.

    Science.gov (United States)

    Prince, Luke Y; Bacon, Travis J; Tigaret, Cezar M; Mellor, Jack R

    2016-01-01

    The feedforward dentate gyrus-CA3 microcircuit in the hippocampus is thought to activate ensembles of CA3 pyramidal cells and interneurons to encode and retrieve episodic memories. The creation of these CA3 ensembles depends on neuromodulatory input and synaptic plasticity within this microcircuit. Here we review the mechanisms by which the neuromodulators aceylcholine, noradrenaline, dopamine, and serotonin reconfigure this microcircuit and thereby infer the net effect of these modulators on the processes of episodic memory encoding and retrieval.

  20. Development of neuromodulation and localization research on implantable device

    Directory of Open Access Journals (Sweden)

    Hong-wei HAO

    2015-09-01

    Full Text Available After over twenty years of clinical research and application, neuromodulation technology has significant efficacy and broad prospect in movement disorders, pain, epilepsy and psychiatric diseases. In this paper, localization process and future trends of typical neurostimulation systems such as deep brain stimulator and vagus nerve stimulator were introduced. DOI: 10.3969/j.issn.1672-6731.2015.09.004

  1. Timing is not everything: neuromodulation opens the STDP gate

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    Verena Pawlak

    2010-10-01

    Full Text Available Spike timing dependent plasticity (STDP is a temporally specific extension of Hebbian associative plasticity that has tied together the timing of presynaptic inputs relative to the postsynaptic single spike. However, it is difficult to translate this mechanism to in vivo conditions where there is an abundance of presynaptic activity constantly impinging upon the dendritic tree as well as ongoing postsynaptic spiking activity that backpropagates along the dendrite. Theoretical studies have proposed that, in addition to this pre- and postsynaptic activity, a ‘third factor’ would enable the association of specific inputs to specific outputs. Experimentally, the picture that is beginning to emerge, is that in addition to the precise timing of pre- and postsynaptic spikes, this third factor involves neuromodulators that have a distinctive influence on STDP rules. Specifically, neuromodulatory systems can influence STDP rules by acting via dopaminergic, noradrenergic, muscarinic and nicotinic receptors. Neuromodulator actions can enable STDP induction or - by increasing or decreasing the threshold - can change the conditions for plasticity induction. Because some of the neuromodulators are also involved in reward, a link between STDP and reward-mediated learning is emerging. However, many outstanding questions concerning the relationship between neuromodulatory systems and STDP rules remain, that once solved, will help make the crucial link from timing-based synaptic plasticity rules to behaviorally-based learning.

  2. Sacral neuromodulation in overactive bladder: a review and current perspectives

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    Sukhu T

    2016-10-01

    Full Text Available Troy Sukhu,1 Michael J Kennelly,2 Raj Kurpad1 1Department of Urology, University of North Carolina, Chapel Hill, 2Department of Urology, Carolinas Medical Center, Charlotte, NC, USA Abstract: Overactive bladder (OAB symptoms of urgency, frequency, and urge incontinence currently affect a substantial portion of the population, especially as age increases. Sacral neuromodulation has become a popular option for refractory OAB symptoms over the past 2 decades. Studies have demonstrated that it is an effective treatment for OAB and urge incontinence as indicated by decreased number of voids, increased bladder capacity, and fewer leakage events. In addition, the effects have proved to be durable to multiple years following implantation. These benefits come at the expense of a high rate of adverse events, although with comparable long-term cost-effectiveness to botulinum toxin A. We aimed to review the literature that demonstrates that sacral neuromodulation continues to be an efficacious treatment for refractory OAB wet and dry patients, with continuously expanding indications. Keywords: urge incontinence, sacral neuromodulation, overactive bladder, refractory, voiding dysfunction

  3. Cross-entropy optimization for neuromodulation.

    Science.gov (United States)

    Brar, Harleen K; Yunpeng Pan; Mahmoudi, Babak; Theodorou, Evangelos A

    2016-08-01

    This study presents a reinforcement learning approach for the optimization of the proportional-integral gains of the feedback controller represented in a computational model of epilepsy. The chaotic oscillator model provides a feedback control systems view of the dynamics of an epileptic brain with an internal feedback controller representative of the natural seizure suppression mechanism within the brain circuitry. Normal and pathological brain activity is simulated in this model by adjusting the feedback gain values of the internal controller. With insufficient gains, the internal controller cannot provide enough feedback to the brain dynamics causing an increase in correlation between different brain sites. This increase in synchronization results in the destabilization of the brain dynamics, which is representative of an epileptic seizure. To provide compensation for an insufficient internal controller an external controller is designed using proportional-integral feedback control strategy. A cross-entropy optimization algorithm is applied to the chaotic oscillator network model to learn the optimal feedback gains for the external controller instead of hand-tuning the gains to provide sufficient control to the pathological brain and prevent seizure generation. The correlation between the dynamics of neural activity within different brain sites is calculated for experimental data to show similar dynamics of epileptic neural activity as simulated by the network of chaotic oscillators.

  4. Update on Neuromodulation for Treatment-Resistant Depression [version 1; referees: 3 approved

    Directory of Open Access Journals (Sweden)

    Bettina Bewernick

    2015-12-01

    Full Text Available About 30% of patients suffering from a major depressive disorder do not respond sufficiently to established pharmacological, psychotherapeutic, or somatic treatments. Advances in technology and emerging knowledge about the dysfunctional brain circuits underlying depression have led to the development of different neuromodulation techniques. The aim of the present review is to give an update on noninvasive techniques, such as electroconvulsive therapy (ECT, magnetic seizure therapy (MST, transcranial magnetic stimulation (TMS, and invasive techniques requiring brain surgery, such as vagus nerve stimulation (VNS and deep brain stimulation (DBS. First, the clinical relevance for therapy-resistant depression, including the current level of evidence, are presented.   Neuroethics is concerned with the ethical, legal and social policy implications of neuroscience. A second focus of the review is the application of fundamental ethical principles, such as patient autonomy, patient well-being and justice to neuromodulation therapies. Due to reduced availability and lacking long-term efficacy data, most patients with treatment-resistant depression face a trial-and-error approach to therapeutics. This contravenes the ethical criteria of patient autonomy and justice. In order to raise the level of evidence, financial support of long-term studies, including large samples and randomized control trials, are necessary.

  5. 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.

  6. Neuroprotection trek--the next generation: neuromodulation I. Techniques--deep brain stimulation, vagus nerve stimulation, and transcranial magnetic stimulation

    Science.gov (United States)

    Andrews, Russell J.

    2003-01-01

    Neuromodulation denotes controlled electrical stimulation of the central or peripheral nervous system. The three forms of neuromodulation described in this paper-deep brain stimulation, vagus nerve stimulation, and transcranial magnetic stimulation-were chosen primarily for their demonstrated or potential clinical usefulness. Deep brain stimulation is a completely implanted technique for improving movement disorders, such as Parkinson's disease, by very focal electrical stimulation of the brain-a technique that employs well-established hardware (electrode and pulse generator/battery). Vagus nerve stimulation is similar to deep brain stimulation in being well-established (for the treatment of refractory epilepsy), completely implanted, and having hardware that can be considered standard at the present time. Vagus nerve stimulation differs from deep brain stimulation, however, in that afferent stimulation of the vagus nerve results in diffuse effects on many regions throughout the brain. Although use of deep brain stimulation for applications beyond movement disorders will no doubt involve placing the stimulating electrode(s) in regions other than the thalamus, subthalamus, or globus pallidus, the use of vagus nerve stimulation for applications beyond epilepsy-for example, depression and eating disorders-is unlikely to require altering the hardware significantly (although stimulation protocols may differ). Transcranial magnetic stimulation is an example of an external or non-implanted, intermittent (at least given the current state of the hardware) stimulation technique, the clinical value of which for neuromodulation and neuroprotection remains to be determined.

  7. Brainjacking: Implant Security Issues in Invasive Neuromodulation.

    Science.gov (United States)

    Pycroft, Laurie; Boccard, Sandra G; Owen, Sarah L F; Stein, John F; Fitzgerald, James J; Green, Alexander L; Aziz, Tipu Z

    2016-08-01

    The security of medical devices is critical to good patient care, especially when the devices are implanted. In light of recent developments in information security, there is reason to be concerned that medical implants are vulnerable to attack. The ability of attackers to exert malicious control over brain implants ("brainjacking") has unique challenges that we address in this review, with particular focus on deep brain stimulation implants. To illustrate the potential severity of this risk, we identify several mechanisms through which attackers could manipulate patients if unauthorized access to an implant can be achieved. These include blind attacks in which the attacker requires no patient-specific knowledge and targeted attacks that require patient-specific information. Blind attacks include cessation of stimulation, draining implant batteries, inducing tissue damage, and information theft. Targeted attacks include impairment of motor function, alteration of impulse control, modification of emotions or affect, induction of pain, and modulation of the reward system. We also discuss the limitations inherent in designing implants and the trade-offs that must be made to balance device security with battery life and practicality. We conclude that researchers, clinicians, manufacturers, and regulatory bodies should cooperate to minimize the risk posed by brainjacking.

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

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    Susan D Motts

    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.

  9. Neuromodulation of the feedforward dentate gyrus-CA3 microcircuit

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    Luke Yuri Prince

    2016-10-01

    Full Text Available The feedforward dentate gyrus-CA3 microcircuit in the hippocampus is thought to activate ensembles of CA3 pyramidal cells and interneurons to encode and retrieve episodic memories. The creation of these CA3 ensembles depends on neuromodulatory input and synaptic plasticity within this microcircuit. Here we review the mechanisms by which the neuromodulators aceylcholine, noradrenaline, dopamine, and serotonin reconfigure this microcircuit and thereby infer the net effect of these modulators on the processes of episodic memory encoding and retrieval.

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

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    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.

  11. 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.

  12. Optimal number of stimulation contacts for coordinated reset neuromodulation

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    Borys eLysyansky

    2013-07-01

    Full Text Available In this computational study we investigatecoordinated reset (CR neuromodulation designed for an effective controlof synchronization by multi-site stimulation of neuronal target populations. This method was suggested to effectively counteract pathological neuronal synchronycharacteristic for several neurological disorders. We studyhow many stimulation sites are required for optimal CR-induced desynchronization. We found that a moderate increase of the number of stimulation sitesmay significantly prolong the post-stimulation desynchronized transientafter the stimulation is completely switched off. This can, in turn,reduce the amount of the administered stimulation current for theintermittent ON-OFF CR stimulation protocol, where time intervalswith stimulation ON are recurrently followed by time intervals withstimulation OFF. In addition, we found that the optimal number ofstimulation sites essentially depends on how strongly the administeredcurrent decays within the neuronal tissue with increasing distancefrom the stimulation site. In particular, for a broad spatial stimulationprofile, i.e., for a weak spatial decay rate of the stimulation current,CR stimulation can optimally be delivered via a small number of stimulationsites. Our findings may contribute to an optimization of therapeutic applications of CR neuromodulation.

  13. Striatal cholinergic interneuron regulation and circuit effects

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    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.

  14. Non-additive modulation of synaptic transmission by serotonin, adenosine, and cholinergic modulators in the sensory thalamus

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    Ya-Chin eYang

    2015-03-01

    Full Text Available The thalamus relays sensory information to the cortex. Oscillatory activities of the thalamocortical network are modulated by monoamines, acetylcholine, and adenosine, and could be the key features characteristic of different vigilance states. Although the thalamus is almost always subjective to the actions of more than just one neuromodulator, reports on the modulatory effect of coexisting neuromodulators on thalamic synaptic transmission are unexpectedly scarce. We found that either monoamine or adenosine decreases retinothalamic synaptic strength and short-term depression, whereas cholinergic modulators generally enhance postsynaptic response to presynaptic activity. However, combinations of different modulators tend to produce non-additive effect, not predictable based on the action of one single modulator. Acetylcholine, acting via nicotinic receptors, can interact with either serotonin or adenosine to abolish most short-term synaptic depression. Moreover, the coexistence of adenosine and monoamine, with or without acetylcholine, results in robustly decreased synaptic strength and transforms short-term synaptic depression to facilitation. These findings are consistent with a view that acetylcholine is essential for an enriched sensory flow through the thalamus, and the flow is trimmed down by concomitant monoamine or adenosine (presumably for the wakefulness and rapid-eye movement, or REM, sleep state, respectively. In contrast, concomitant adenosine and monoamine would lead to a markedly deprived (and high-pass filtered sensory flow, and thus the dramatic decrease of monoamine may constitute the essential demarcation between non-REM and REM sleep. The collective actions of different neuromodulators on thalamic synaptic transmission thus could be essential for the understanding of network responsiveness in different vigilance states.

  15. 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.

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

    NARCIS (Netherlands)

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

    2003-01-01

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

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

    NARCIS (Netherlands)

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

    2011-01-01

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

  18. Structural dichotomy of the mind; the role of sexual neuromodulators

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    Ion G. Motofei

    2016-10-01

    Full Text Available The mind (mental function and sexuality represent two distinct environmental functions, but which are supported within the brain by a common (somatic-autonomic neurobiological substrate. As a consequence, mental function takes on autonomic characteristics from the sexual-autonomic system (like autonomy, duality, while sexual function takes on features from mental functioning (such as lateralization. In this paper we discuss the lateralized action of two classes of sexual neuromodulators: hormones and pheromones. This process of lateralization is assimilated with the structural dichotomy of the mind. A relatively similar process but related to informational dichotomy of the mind will be presented in a forthcoming paper. Structural and informational dichotomies of the mind represent essential aspects that need clarification in order to continue the solving of the mind-body process, a work in progress articulated through a succession of papers.

  19. 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.

  20. S100b Counteracts Neurodegeneration of Rat Cholinergic Neurons in Brain Slices after Oxygen-Glucose Deprivation

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    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. 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

  2. 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.

  3. 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.

  4. Neuromodulation for Addiction by Transcranial Direct Current Stimulation: Opportunities and Challenges

    Science.gov (United States)

    Bashir, Shahid; Yoo, Woo-Kyoung

    2016-01-01

    The field of neuromodulation encompasses a wide spectrum of interventional technologies that modify the pathological activity within the nervous system to achieve a therapeutic effect. Therapy, including transcranial direct current stimulation, has shown promising results across a range of neurological and neuropsychiatric disorders. This article reviews the state-of-the-art of neuromodulation for addiction and discusses the opportunities and challenges available for clinicians and researchers interested in advancing the neuromodulation therapy. A neuromodulation-based approach for addiction has the advantage that the effects might be immediate and selective to the dysfunction. If an alteration in the mechanisms of brain plasticity indeed represents the proximal cause for nicotine-associated cognitive decline and is a critical contributor to the early pathogenesis of addiction, novel interventions that forestall the development of symptoms might be possible.

  5. Cholinergic imaging in dementia spectrum disorders

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    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.)

  6. Emerging horizons in neuromodulation new frontiers in brain and spine stimulation

    CERN Document Server

    Hamani, Clement

    2012-01-01

    This issue of International Review of Neurobiology brings together cutting-edge research on neuromodulation. It reviews current knowledge and understanding, provides a starting point for researchers and practitioners entering the field, and builds a platform for further research and discovery.This issue of International Review of Neurobiology brings together cutting-edge research on neuromodulation. It reviews current knowledge and understanding, provides a starting point for researchers and practitioners entering the field, and builds a platform for further research and

  7. 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.

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

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    Fischer Andy J

    2008-02-01

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

  9. 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.

  10. 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.

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

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    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

  12. Neuromodulator and Emotion Biomarker for Stress Induced Mental Disorders

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    Simeng Gu

    2016-01-01

    Full Text Available Affective disorders are a leading cause of disabilities worldwide, and the etiology of these many affective disorders such as depression and posttraumatic stress disorder is due to hormone changes, which includes hypothalamus-pituitary-adrenal axis in the peripheral nervous system and neuromodulators in the central nervous system. Consistent with pharmacological studies indicating that medical treatment acts by increasing the concentration of catecholamine, the locus coeruleus (LC/norepinephrine (NE system is regarded as a critical part of the central “stress circuitry,” whose major function is to induce “fight or flight” behavior and fear and anger emotion. Despite the intensive studies, there is still controversy about NE with fear and anger. For example, the rats with LC ablation were more reluctant to leave a familiar place and took longer to consume the food pellets in an unfamiliar place (neophobia, i.e., fear in response to novelty. The reason for this discrepancy might be that NE is not only for flight (fear, but also for fight (anger. Here, we try to review recent literatures about NE with stress induced emotions and their relations with mental disorders. We propose that stress induced NE release can induce both fear and anger. “Adrenaline rush or norepinephrine rush” and fear and anger emotion might act as biomarkers for mental disorders.

  13. Peripheral neuromodulation for the treatment of refractory trigeminal neuralgia.

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    Shaparin, Naum; Gritsenko, Karina; Garcia-Roves, Diego Fernandez; Shah, Ushma; Schultz, Todd; DeLeon-Casasola, Oscar

    2015-01-01

    Trigeminal neuralgia is a type of orofacial pain that is diagnosed in 150,000 individuals each year, with an incidence of 12.6 per 100,000 person-years and a prevalence of 155 cases per 1,000,000 in the United States. Trigeminal neuralgia pain is characterized by sudden, severe, brief, stabbing or lancinating, recurrent episodes of pain in the distribution of one or more branches of the trigeminal nerve, which can cause significant suffering for the affected patient population. In many patients, a combination of medication and interventional treatments can be therapeutic, but is not always successful. Peripheral nerve stimulation has gained popularity as a simple and effective neuromodulation technique for the treatment of many pain conditions, including chronic headache disorders. Specifically in trigeminal neuralgia, neurostimulation of the supraorbital and infraorbital nerves may serve to provide relief of neuropathic pain by targeting the distal nerves that supply sensation to the areas of the face where the pain attacks occur, producing a field of paresthesia within the peripheral distribution of pain through the creation of an electric field in the vicinity of the leads. The purpose of the present case report is to introduce a new, less-invasive interventional technique, and to describe the authors' first experience with supraorbital and infraorbital neurostimulation therapy for the treatment of trigeminal neuralgia in a patient who had failed previous conservative management.

  14. Physiological Importance of Hydrogen Sulfide: Emerging Potent Neuroprotector and Neuromodulator

    Science.gov (United States)

    Chung, Hyung-Joo

    2016-01-01

    Hydrogen sulfide (H2S) is an emerging neuromodulator that is considered to be a gasotransmitter similar to nitrogen oxide (NO) and carbon monoxide (CO). H2S exerts universal cytoprotective effects and acts as a defense mechanism in organisms ranging from bacteria to mammals. It is produced by the enzymes cystathionine β-synthase (CBS), cystathionine ϒ-lyase (CSE), 3-mercaptopyruvate sulfurtransferase (MST), and D-amino acid oxidase (DAO), which are also involved in tissue-specific biochemical pathways for H2S production in the human body. H2S exerts a wide range of pathological and physiological functions in the human body, from endocrine system and cellular longevity to hepatic protection and kidney function. Previous studies have shown that H2S plays important roles in peripheral nerve regeneration and degeneration and has significant value during Schwann cell dedifferentiation and proliferation but it is also associated with axonal degradation and the remyelination of Schwann cells. To date, physiological and toxic levels of H2S in the human body remain unclear and most of the mechanisms of action underlying the effects of H2S have yet to be fully elucidated. The primary purpose of this review was to provide an overview of the role of H2S in the human body and to describe its beneficial effects. PMID:27413423

  15. Short neuropeptide F acts as a functional neuromodulator for olfactory memory in Kenyon cells of Drosophila mushroom bodies.

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    Knapek, Stephan; Kahsai, Lily; Winther, Asa M E; Tanimoto, Hiromu; Nässel, Dick R

    2013-03-20

    In insects, many complex behaviors, including olfactory memory, are controlled by a paired brain structure, the so-called mushroom bodies (MB). In Drosophila, the development, neuroanatomy, and function of intrinsic neurons of the MB, the Kenyon cells, have been well characterized. Until now, several potential neurotransmitters or neuromodulators of Kenyon cells have been anatomically identified. However, whether these neuroactive substances of the Kenyon cells are functional has not been clarified yet. Here we show that a neuropeptide precursor gene encoding four types of short neuropeptide F (sNPF) is required in the Kenyon cells for appetitive olfactory memory. We found that activation of Kenyon cells by expressing a thermosensitive cation channel (dTrpA1) leads to a decrease in sNPF immunoreactivity in the MB lobes. Targeted expression of RNA interference against the sNPF precursor in Kenyon cells results in a highly significant knockdown of sNPF levels. This knockdown of sNPF in the Kenyon cells impairs sugar-rewarded olfactory memory. This impairment is not due to a defect in the reflexive sugar preference or odor response. Consistently, knockdown of sNPF receptors outside the MB causes deficits in appetitive memory. Altogether, these results suggest that sNPF is a functional neuromodulator released by Kenyon cells.

  16. 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

  17. 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...

  18. Acoustic Coordinated Reset Neuromodulation in a Real Life Patient Population with Chronic Tonal Tinnitus

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    Christian Hauptmann

    2015-01-01

    Full Text Available Purpose. Primary tinnitus has a severe negative influence on the quality of life of a significant portion of the general population. Acoustic coordinated reset neuromodulation is designed to induce a long-lasting reduction of tinnitus symptoms. To test acoustic coordinated reset neuromodulation as a treatment for chronic, tonal tinnitus under real life conditions, an outpatient study “RESET Real Life” was commissioned by ANM GmbH. Herein we present the results of this study. Methods. In a prospective, open-label, nonrandomized, noncontrolled multicenter clinical study with 200 chronic tinnitus patients, tinnitus questionnaire TBF-12 and Global Clinical Improvement-Impression Scale (CGI-I7 are used to study the safety and efficacy of acoustic coordinated reset neuromodulation. 189 patients completed the last 12-month visit, 11 patients dropped out (8 because of nontreatment related reasons; 2 because tinnitus did not change; and 1 because tinnitus got louder. Results. Acoustic coordinated reset neuromodulation caused a statistically and clinically significant decrease in TBF-12 scores as well as in CGI-I7 after 12 months of therapy under real life conditions. There were no persistent adverse events reported that were related to the therapy. Conclusion. The field study “RESET Real Life” provides evidence for safety and efficacy of acoustic coordinated reset neuromodulation in a prospective, open-label, real life setting.

  19. 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.

  20. Cost-effectiveness evaluations of spinal neuromodulation with ziconotide continuous infusion in cancer pain in a real clinical practice

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    Orietta Zaniolo

    2011-06-01

    Full Text Available Introduction and objective: ziconotide is the first-in-class drug of selective N-type voltage-sensitive calcium-channel blockers used to control severe chronic pain. The present study is developed in order to analyze clinical and economical outcomes of spinal neuromodulation with ziconotide continuous infusion in cancer pain in a real clinical practice.Methods: costs and effects of ziconotide are compared with those of traditional neuromodulation with morphine and adjuvant drugs, administered by intrathecal infusion.Effectiveness and resources consumption data were retrospectively collected in 22 patients with severe complex cancer pain followed by one Italian centre from the day of port implantation to drop-out , due to death or consent withdrawal. 11 patients received morphine regimens and the other 11 were treated with ziconotide. The evaluation of the number of days with controlled pain (i.e., with an at least 30% reduction on the Numeric Rating Scale-Pain Intensity, NRSPI is the primary outcome of the analysis. The evaluated consumed health resources include drugs, visits, port maintenance, and pump recharge and amortization. Current Italian prices, real practice acquisition and remuneration costs borne by the third payer are applied.Results: patients receiving ziconotide lived significantly more days with controlled pain (78% vs 40%; p < 0.05. Average weekly cost is about 232 € for ziconotide and 120 € for morphine; the main driver being the pharmaceutical cost (respectively 81% and 65% of the total. Higher ziconotide acquisition costs are partially offset by minor expenses for adjuvant therapies, as ziconotide-treated patients on average receive a lower number of drugs than those receiving a traditional regimen. The incremental cost for one further day with controlled pain resulted of 42,30 €.Conclusions: ziconotide permits effective treatment of extremely difficult-to-manage pain, with a mild increment of cost, as compared to

  1. The Appropriate Use of Neurostimulation of the Spinal Cord and Peripheral Nervous System for the Treatment of Chronic Pain and Ischemic Diseases : The Neuromodulation Appropriateness Consensus Committee

    NARCIS (Netherlands)

    Deer, Timothy R.; Mekhail, Nagy; Provenzano, David; Pope, Jason; Krames, Elliot; Leong, Michael; Levy, Robert M.; Abejon, David; Buchser, Eric; Burton, Allen; Buvanendran, Asokumar; Candido, Kenneth; Caraway, David; Cousins, Michael; de Jongste, Micheal; Diwan, Sudhir; Eldabe, Sam; Gatzinsky, Kliment; Foreman, Robert D.; Hayek, Salim; Kim, Philip; Kinfe, Thomas; Kloth, David; Kumar, Krishna; Rizvi, Syed; Lad, Shivanand P.; Liem, Liong; Linderoth, Bengt; Mackey, Sean; McDowell, Gladstone; McRoberts, Porter; Poree, Lawrence; Prager, Joshua; Raso, Lou; Rauck, Richard; Russo, Marc; Simpson, Brian; Slavin, Konstantin; Staats, Peter; Stanton-Hicks, Michael; Verrills, Paul; Wellington, Joshua; Williams, Kayode; North, Richard

    2014-01-01

    Introduction: The Neuromodulation Appropriateness Consensus Committee (NACC) of the International Neuromodulation Society (INS) evaluated evidence regarding the safety and efficacy of neurostimulation to treat chronic pain, chronic critical limb ischemia, and refractory angina and recommended approp

  2. Enabling functional neural circuit simulations with distributed computing of neuromodulated plasticity.

    Science.gov (United States)

    Potjans, Wiebke; Morrison, Abigail; Diesmann, Markus

    2010-01-01

    A major puzzle in the field of computational neuroscience is how to relate system-level learning in higher organisms to synaptic plasticity. Recently, plasticity rules depending not only on pre- and post-synaptic activity but also on a third, non-local neuromodulatory signal have emerged as key candidates to bridge the gap between the macroscopic and the microscopic level of learning. Crucial insights into this topic are expected to be gained from simulations of neural systems, as these allow the simultaneous study of the multiple spatial and temporal scales that are involved in the problem. In particular, synaptic plasticity can be studied during the whole learning process, i.e., on a time scale of minutes to hours and across multiple brain areas. Implementing neuromodulated plasticity in large-scale network simulations where the neuromodulatory signal is dynamically generated by the network itself is challenging, because the network structure is commonly defined purely by the connectivity graph without explicit reference to the embedding of the nodes in physical space. Furthermore, the simulation of networks with realistic connectivity entails the use of distributed computing. A neuromodulated synapse must therefore be informed in an efficient way about the neuromodulatory signal, which is typically generated by a population of neurons located on different machines than either the pre- or post-synaptic neuron. Here, we develop a general framework to solve the problem of implementing neuromodulated plasticity in a time-driven distributed simulation, without reference to a particular implementation language, neuromodulator, or neuromodulated plasticity mechanism. We implement our framework in the simulator NEST and demonstrate excellent scaling up to 1024 processors for simulations of a recurrent network incorporating neuromodulated spike-timing dependent plasticity.

  3. Enabling functional neural circuit simulations with distributed computing of neuromodulated plasticity

    Directory of Open Access Journals (Sweden)

    Wiebke ePotjans

    2010-11-01

    Full Text Available A major puzzle in the field of computational neuroscience is how to relate system-level learning in higher organisms to synaptic plasticity. Recently, plasticity rules depending not only on pre- and post-synaptic activity but also on a third, non-local neuromodulatory signal have emerged as key candidates to bridge the gap between the macroscopic and the microscopic level of learning. Crucial insights into this topic are expected to be gained from simulations of neural systems, as these allow the simultaneous study of the multiple spatial and temporal scales that are involved in the problem. In particular, synaptic plasticity can be studied during the whole learning process, i.e. on a time scale of minutes to hours and across multiple brain areas. Implementing neuromodulated plasticity in large-scale network simulations where the neuromodulatory signal is dynamically generated by the network itself is challenging, because the network structure is commonly defined purely by the connectivity graph without explicit reference to the embedding of the nodes in physical space. Furthermore, the simulation of networks with realistic connectivity entails the use of distributed computing. A neuromodulated synapse must therefore be informed in an efficient way about the neuromodulatory signal, which is typically generated by a population of neurons located on different machines than either the pre- or post-synaptic neuron. Here, we develop a general framework to solve the problem of implementing neuromodulated plasticity in a time-driven distributed simulation, without reference to a particular implementation language, neuromodulator or neuromodulated plasticity mechanism. We implement our framework in the simulator NEST and demonstrate excellent scaling up to 1024 processors for simulations of a recurrent network incorporating neuromodulated spike-timing dependent plasticity.

  4. Mechanisms Underlying the Neuromodulation of Spinal Circuits for Correcting Gait and Balance Deficits after Spinal Cord Injury.

    Science.gov (United States)

    Moraud, Eduardo Martin; Capogrosso, Marco; Formento, Emanuele; Wenger, Nikolaus; DiGiovanna, Jack; Courtine, Grégoire; Micera, Silvestro

    2016-02-17

    Epidural electrical stimulation of lumbar segments facilitates standing and walking in animal models and humans with spinal cord injury. However, the mechanisms through which this neuromodulation therapy engages spinal circuits remain enigmatic. Using computer simulations and behavioral experiments, we provide evidence that epidural electrical stimulation interacts with muscle spindle feedback circuits to modulate muscle activity during locomotion. Hypothesis-driven strategies emerging from simulations steered the design of stimulation protocols that adjust bilateral hindlimb kinematics throughout gait execution. These stimulation strategies corrected subject-specific gait and balance deficits in rats with incomplete and complete spinal cord injury. The conservation of muscle spindle feedback circuits across mammals suggests that the same mechanisms may facilitate motor control in humans. These results provide a conceptual framework to improve stimulation protocols for clinical applications.

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

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    Cecilia Tubert

    2016-09-01

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

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

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    Da Un Jeong

    2014-01-01

    Full Text Available Deep brain stimulation (DBS has been found to have therapeutic effects in patients with dementia, but DBS mechanisms remain elusive. To provide evidence for the effectiveness of DBS as a treatment for dementia, we performed DBS in a rat model of dementia with intracerebroventricular administration of 192 IgG-saporins. We utilized four groups of rats, group 1, unlesioned control; group 2, cholinergic lesion; group 3, cholinergic lesion plus medial septum (MS electrode implantation (sham stimulation; group 4, cholinergic lesions plus MS electrode implantation and stimulation. During the probe test in the water maze, performance of the lesion group decreased for measures of time spent and the number of swim crossings over the previous platform location. Interestingly, the stimulation group showed an equivalent performance to the normal group on all measures. And these are partially reversed by the electrode implantation. Acetylcholinesterase activity in the hippocampus was decreased in lesion and implantation groups, whereas activity in the stimulation group was not different from the normal group. Hippocampal neurogenesis was increased in the stimulation group. Our results revealed that DBS of MS restores spatial memory after damage to cholinergic neurons. This effect is associated with an increase in hippocampal cholinergic activity and neurogenesis.

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

    NARCIS (Netherlands)

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

    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

  8. [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.

  9. Microstructural effects of a neuro-modulating drug evaluated by diffusion tensor imaging.

    Science.gov (United States)

    Egger, K; Janz, P; Döbrössy, M D; Bienert, T; Reisert, M; Obmann, M; Glauche, V; Haas, C; Harsan, L A; Urbach, H; von Elverfeldt, D

    2016-02-15

    In a longitudinal mouse study we evaluated whether diffusion tensor imaging (DTI) can monitor microstructural changes after administration of the neuromodulating drug EPO and whether erythropoietin (EPO) has an effect on cognitive performance. Twelve mice (2 groups with 6 mice each) were scanned in a 7T Bruker Biospin animal scanner with a highly resolved DTI sequence before and 16 days after intraperitoneal injections of EPO or saline. All mice underwent behavioral testing (Morris water maze) and histologic evaluation of hippocampal and corpus callosum cell proliferation and oligodendrogenesis. Whole brain DTI analysis showed significant Trace, RD and AD decrease within the dentate gyrus, subiculum, primary motor, somatosensory, and supplementary somatosensory areas and FA increase in the hippocampus, corpus callosum, and fimbria fornix in EPO treated mice only. ROI-based DTI analysis showed significant Trace and RD decrease and FA increase only in the corpus callosum of EPO treated mice, whereas in the dentate gyrus significant Trace, RD, and AD decrease occurred in both, EPO- and control-group. Behavioral tests showed that EPO treated mice performed better and learned faster than controls. Histologically, the number of BrdU-positive nuclei and optical density of DCX-labeled juvenile neurons significantly increased within the dentate gyrus, corpus callosum and fimbria fornix and the number of NG2-positive oligodendrocyte progenitors in corpus callosum and fimbria fornix, respectively. In conclusion we were able to monitor microstructural changes with DTI and showed EPO treatment-related alterations correlating with enhanced dentate gyrus and corpus callosum cell proliferation and better learning capabilities.

  10. Results of sacral neuromodulation therapy for urinary voiding dysfunction: outcomes of a prospective, worldwide clinical study.

    NARCIS (Netherlands)

    Kerrebroeck, P.E.V.A. van; Voskuilen, A.C. van; Heesakkers, J.P.; Lycklama à Nijeholt, A.A.B.; Siegel, S.; Jonas, U.; Fowler, C.J.; Fall, M.; Gajewski, J.B.; Hassouna, M.M.; Cappellano, F.; Elhilali, M.M.; Milam, D.F.; Das, A.K.; Dijkema, H.E.; Hombergh, U. van den

    2007-01-01

    PURPOSE: This 5-year, prospective, multicenter trial evaluated the long-term safety and efficacy of sacral neuromodulation in patients with refractory urge incontinence, urgency frequency and retention. MATERIALS AND METHODS: A total of 17 centers worldwide enrolled 163 patients (87% female). Follow

  11. Non-Traditional Management of the Neurogenic Bladder: Tissue Engineering and Neuromodulation

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    Jane M. Lewis

    2007-01-01

    Full Text Available Patients with spina bifida and a neurogenic bladder have traditionally been managed with clean intermittent catheterization and pharmacotherapy in order to treat abnormal bladder wall dynamics, protect the upper urinary tract from damage, and achieve urinary continence. However, some patients will fail this therapy and require surgical reconstruction in the form of bladder augmentation surgery using reconfigured intestine or stomach to increase the bladder capacity while reducing the internal storage pressure. Despite functional success of bladder augmentation in achieving a low pressure reservoir, there are several associated complications of this operation and patients do not have the ability to volitionally void. For these reasons, alternative treatments have been sought. Two exciting alternative approaches that are currently being investigated are tissue engineering and neuromodulation. Tissue engineering aims to create new bladder tissue for replacement purposes with both “seeded” and “unseeded” technology. Advances in the fields of nanotechnology and stem cell biology have further enhanced these tissue engineering technologies. Neuromodulation therapies directly address the root of the problem in patients with spina bifida and a neurogenic bladder, namely the abnormal relationship between the nerves and the bladder wall. These therapies include transurethral bladder electrostimulation, sacral neuromodulation, and neurosurgical techniques such as selective sacral rhizotomy and artificial somatic-autonomic reflex pathway construction. This review will discuss both tissue engineering techniques and neuromodulation therapies in more detail including rationale, experimental data, current status of clinical application, and future direction.

  12. 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.

  13. The role of multiple neuromodulators in reinforcement learning that is based on competition between eligibility traces

    Directory of Open Access Journals (Sweden)

    Marco A Huertas

    2016-12-01

    Full Text Available The ability to maximize reward and avoid punishment is essential for animal survival. Reinforcement learning (RL refers to the algorithms used by biological or artificial systems to learn how to maximize reward or avoid negative outcomes based on past experiences. While RL is also important in machine learning, the types of mechanistic constraints encountered by biological machinery might be different than those for artificial systems. Two major problems encountered by RL are how to relate a stimulus with a reinforcing signal that is delayed in time (temporal credit assignment, and how to stop learning once the target behaviors are attained (stopping rule. To address the first problem, synaptic eligibility traces were introduced, bridging the temporal gap between a stimulus and its reward. Although these were mere theoretical constructs, recent experiements have provided evidence of their existence. These experiments also reveal that the presence of specific neuromodulators converts the traces into changes in synaptic efficacy. A mechanistic implementation of the stopping rule usually assumes the inhibition of the reward nucleus; however, recent experimental results have shown that learning terminates at the appropriate network state even in setups where the reward cannot be inhibited. In an effort to describe a learning rule that solves the temporal credit assignment problem and implements a biologically plausible stopping rule, we proposed a model based on two separate synaptic eligibility traces, one for long-term potentiation (LTP and one for long-term depression (LTD, each obeying different dynamics and having different effective magnitudes. The model has been shown to successfully generate stable learning in recurrent networks. Although the model assumes the presence of a single neuromodulator, evidence indicates that there are different neuromodulators for expressing the different traces. What could be the role of different

  14. Computational exploration of wave propagation and heating from transcranial focused ultrasound for neuromodulation

    Science.gov (United States)

    Mueller, Jerel K.; Ai, Leo; Bansal, Priya; Legon, Wynn

    2016-10-01

    Objective. While ultrasound is largely established for use in diagnostic imaging, its application for neuromodulation is relatively new and crudely understood. The objective of the present study was to investigate the effects of tissue properties and geometry on the wave propagation and heating in the context of transcranial neuromodulation. Approach. A computational model of transcranial-focused ultrasound was constructed and validated against empirical data. The models were then incrementally extended to investigate a number of issues related to the use of ultrasound for neuromodulation, including the effect on wave propagation of variations in geometry of skull and gyral anatomy as well as the effect of multiple tissue and media layers, including scalp, skull, CSF, and gray/white matter. In addition, a sensitivity analysis was run to characterize the influence of acoustic properties of intracranial tissues. Finally, the heating associated with ultrasonic stimulation waveforms designed for neuromodulation was modeled. Main results. The wave propagation of a transcranially focused ultrasound beam is significantly influenced by the cranial domain. The half maximum acoustic beam intensity profiles are insensitive overall to small changes in material properties, though the inclusion of sulci in models results in greater peak intensity values compared to a model without sulci (1%-30% greater). Finally, heating using currently employed stimulation parameters in humans is highest in bone (0.16 °C) and is negligible in brain (4.27 × 10-3 °C) for a 0.5 s exposure. Significance. Ultrasound for noninvasive neuromodulation holds great promise and appeal for its non-invasiveness, high spatial resolution and deep focal lengths. Here we show gross brain anatomy and biological material properties to have limited effect on ultrasound wave propagation and to result in safe heating levels in the skull and brain.

  15. 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.

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

    Science.gov (United States)

    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

  17. GABAergic actions on cholinergic laterodorsal tegmental neurons

    DEFF Research Database (Denmark)

    Kohlmeier, K A; Kristiansen, Uffe

    2010-01-01

    (IRK) mediated this effect. Further, outward currents were never additive with those induced by application of carbachol, suggesting that they were mediated by activation of GABA(B) receptors linked to the same G(IRK) activated in these cells by muscarinic receptor stimulation. Activation of GABA(B) receptors....... 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...... neurons. Post-synaptic location of GABA(A) receptors was demonstrated by persistence of muscimol-induced inward currents in TTX and low Ca(2+) solutions. THIP, a selective GABA(A) receptor agonist with a preference for d-subunit containing GABA(A) receptors, induced inward currents, suggesting...

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

    DEFF Research Database (Denmark)

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

    2015-01-01

    A cholinergic (muscarinic) contribution to the initial circulatory response to exercise in humans remains controversial. Herein, we posit that this may be due to exercise mode with a cholinergic contribution being important during isometric handgrip exercise, where the hyperemic response...... of the muscle is relatively small compared with the onset of leg cycling, where a marked increase in muscle blood flow rapidly occurs as a consequence of multiple redundant mechanisms. We recorded blood pressure (BP; brachial artery), stroke volume (pulse contour analysis), cardiac output, and systemic vascular...... resistance (SVR) in young healthy males, while performing either 20 s of isometric handgrip contraction at 40% maximum voluntary contraction (protocol 1; n = 9) or 20 s of low-intensity leg cycling exercise (protocol 2; n = 8, 42 ± 8 W). Exercise trials were conducted under control (no drug) conditions...

  19. Nicotine increases impulsivity and decreases willingness to exert cognitive effort despite improving attention in "slacker" rats: insights into cholinergic regulation of cost/benefit decision making.

    Directory of Open Access Journals (Sweden)

    Jay G Hosking

    Full Text Available Successful decision making in our daily lives requires weighing an option's costs against its associated benefits. The neuromodulator acetylcholine underlies both the etiology and treatment of a number of illnesses in which decision making is perturbed, including Alzheimer's disease, attention-deficit/hyperactivity disorder, and schizophrenia. Nicotine acts on the cholinergic system and has been touted as a cognitive enhancer by both smokers and some researchers for its attention-boosting effects; however, it is unclear whether treatments that have a beneficial effect on attention would also have a beneficial effect on decision making. Here we utilize the rodent Cognitive Effort Task (rCET, wherein animals can choose to allocate greater visuospatial attention for a greater reward, to examine cholinergic contributions to both attentional performance and choice based on attentional demand. Following the establishment of baseline behavior, four drug challenges were administered: nicotine, mecamylamine, scopolamine, and oxotremorine (saline plus three doses for each. As per previous rCET studies, animals were divided by their baseline preferences, with "worker" rats choosing high-effort/high-reward options more than their "slacker" counterparts. Nicotine caused slackers to choose even fewer high-effort trials than at baseline, but had no effect on workers' choice. Despite slackers' decreased willingness to expend effort, nicotine improved their attentional performance on the task. Nicotine also increased measures of motor impulsivity in all animals. In contrast, scopolamine decreased animals' choice of high-effort trials, especially for workers, while oxotremorine decreased motor impulsivity for all animals. In sum, the cholinergic system appears to contribute to decision making, and in part these contributions can be understood as a function of individual differences. While nicotine has been considered as a cognitive enhancer, these data suggest

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

    Science.gov (United States)

    Vianna, Lauro C; Fadel, Paul J; Secher, Niels H; Fisher, James P

    2015-04-01

    A cholinergic (muscarinic) contribution to the initial circulatory response to exercise in humans remains controversial. Herein, we posit that this may be due to exercise mode with a cholinergic contribution being important during isometric handgrip exercise, where the hyperemic response of the muscle is relatively small compared with the onset of leg cycling, where a marked increase in muscle blood flow rapidly occurs as a consequence of multiple redundant mechanisms. We recorded blood pressure (BP; brachial artery), stroke volume (pulse contour analysis), cardiac output, and systemic vascular resistance (SVR) in young healthy males, while performing either 20 s of isometric handgrip contraction at 40% maximum voluntary contraction (protocol 1; n = 9) or 20 s of low-intensity leg cycling exercise (protocol 2; n = 8, 42 ± 8 W). Exercise trials were conducted under control (no drug) conditions and following cholinergic blockade (glycopyrrolate). Under control conditions, isometric handgrip elicited an initial increase in BP (+5 ± 2 mmHg at 3 s and +3 ± 1 mmHg at 10 s, P mechanism is important for the BP and SVR responses at the onset of isometric handgrip exercise in humans.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-09-15

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

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

    Science.gov (United States)

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

    2008-08-15

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

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

    Science.gov (United States)

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

    2017-01-01

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

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

    Science.gov (United States)

    Berger, M; Riemann, D; Krieg, C

    1991-01-01

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

  5. Endomorphins 1 and 2 reduce relaxant non-adrenergic, non-cholinergic neurotransmission in rat gastric fundus.

    Science.gov (United States)

    Storr, M; Gaffal, E; Schusdziarra, V; Allescher, H-D

    2002-06-14

    It is now well established that opioids modulate cholinergic excitatory neurotransmission in the gastrointestinal tract. The aim of the present study was to characterize a possible effect of endomorphins on nonadrenergic, noncholinergic (NANC) relaxant neurotransmission in the rat gastric fundus in vitro. The drugs used in the experiments were the endogenous mu-opioid receptors (MORs) endomorphin 1 and 2 and the mu-opioid receptor antagonist CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2). CTAP left the basal tonus and the spontaneous activity of the preparation unchanged. Electrical field stimulation (EFS) under NANC conditions at frequencies ranging from 0.5 to 16 Hz caused a frequency-dependent relaxant response on the 5-hydoxytryptamine (5-HT) (10(-7) M) precontracted smooth-muscle strip. Both endomorphin 1 and endomorphin 2 significantly reduced this relaxation in a concentration-dependent manner. Endomorphin 1 proved to be more potent in reducing the relaxant responses. The endomorphin effects were significantly reversed by the MOR antagonist CTAP. CTAP itself did not influence the EFS-induced relaxation. In summary, these data provide evidence that the endogenous MOR agonists endomorphin 1 and 2 can reduce nonadrenergic, noncholinergic neurotransmission in the rat gastric fundus smooth muscle via a pathway involving MORs. The physiological relevance of these findings remains to be established, since the data presented suggest that the endomorphins act as neuromodulators within NANC relaxant neurotransmission.

  6. 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.

  7. Personalized genetics of the cholinergic blockade of neuroinflammation.

    Science.gov (United States)

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

    2017-03-21

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

  8. The Role of Multiple Neuromodulators in Reinforcement Learning That Is Based on Competition between Eligibility Traces

    Science.gov (United States)

    Huertas, Marco A.; Schwettmann, Sarah E.; Shouval, Harel Z.

    2016-01-01

    The ability to maximize reward and avoid punishment is essential for animal survival. Reinforcement learning (RL) refers to the algorithms used by biological or artificial systems to learn how to maximize reward or avoid negative outcomes based on past experiences. While RL is also important in machine learning, the types of mechanistic constraints encountered by biological machinery might be different than those for artificial systems. Two major problems encountered by RL are how to relate a stimulus with a reinforcing signal that is delayed in time (temporal credit assignment), and how to stop learning once the target behaviors are attained (stopping rule). To address the first problem synaptic eligibility traces were introduced, bridging the temporal gap between a stimulus and its reward. Although, these were mere theoretical constructs, recent experiments have provided evidence of their existence. These experiments also reveal that the presence of specific neuromodulators converts the traces into changes in synaptic efficacy. A mechanistic implementation of the stopping rule usually assumes the inhibition of the reward nucleus; however, recent experimental results have shown that learning terminates at the appropriate network state even in setups where the reward nucleus cannot be inhibited. In an effort to describe a learning rule that solves the temporal credit assignment problem and implements a biologically plausible stopping rule, we proposed a model based on two separate synaptic eligibility traces, one for long-term potentiation (LTP) and one for long-term depression (LTD), each obeying different dynamics and having different effective magnitudes. The model has been shown to successfully generate stable learning in recurrent networks. Although, the model assumes the presence of a single neuromodulator, evidence indicates that there are different neuromodulators for expressing the different traces. What could be the role of different neuromodulators for

  9. 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.

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

    Directory of Open Access Journals (Sweden)

    Yehudit eGnatek

    2012-05-01

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

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

    Science.gov (United States)

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

    2017-01-01

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

  12. THE ROLE OF VENTRAL MIDLINE THALAMUS IN CHOLINERGIC-BASED RECOVERY IN THE AMNESTIC RAT

    Science.gov (United States)

    Bobal, Michael G.; Savage, Lisa M.

    2014-01-01

    The thalamus is a critical node for several pathways involved in learning and memory. Damage to the thalamus by trauma, disease or malnourishment can impact the effectiveness of the prefrontal cortex (PFC) and hippocampus (HPC) and lead to a profound amnesia state. Using the pyrithiamine-induced thiamine deficiency (PTD) rat model of human Wernicke-Korsakoff syndrome, we tested the hypothesis that co-infusion of the acetylcholinesterase inhibitor physostigmine across the PFC and HPC would recover spatial alternation performance in PTD rats. When cholinergic tone was increased by dual injections across the PFC-HPC, spontaneous alternation performance in PTD rats was recovered. In addition, we tested a second hypothesis that two ventral midline thalamic nuclei, the rhomboid nucleus and nucleus reuniens (Rh-Re), form a critical node needed for the recovery of function observed when cholinergic tone was increased across the PFC and HPC. By using the GABAA agonist muscimol to temporarily deactivate the Rh-Re the recovery of alternation behavior obtained in the PTD model by cholinergic stimulation across the PFC-HPC was blocked. In control pair-fed (PF) rats, inactivation of the Rh-Re impaired spontaneous alternation. However, when inactivation of the Rh-Re co-occurred with physostigmine infusions across the PFC-HPC, PF rats had normal performance. These results further demonstrate that the Rh-Re is critical in facilitating interactions between the HPC and PFC, but other redundant pathways also exist. PMID:25446352

  13. Impact of acoustic coordinated reset neuromodulation on effective connectivity in a neural network of phantom sound.

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    Silchenko, Alexander N; Adamchic, Ilya; Hauptmann, Christian; Tass, Peter A

    2013-08-15

    Chronic subjective tinnitus is an auditory phantom phenomenon characterized by abnormal neuronal synchrony in the central auditory system. As recently shown in a proof of concept clinical trial, acoustic coordinated reset (CR) neuromodulation causes a significant relief of tinnitus symptoms combined with a significant decrease of pathological oscillatory activity in a network comprising auditory and non-auditory brain areas. The objective of the present study was to analyze whether CR therapy caused an alteration of the effective connectivity in a tinnitus related network of localized EEG brain sources. To determine which connections matter, in a first step, we considered a larger network of brain sources previously associated with tinnitus. To that network we applied a data-driven approach, combining empirical mode decomposition and partial directed coherence analysis, in patients with bilateral tinnitus before and after 12 weeks of CR therapy as well as in healthy controls. To increase the signal-to-noise ratio, we focused on the good responders, classified by a reliable-change-index (RCI). Prior to CR therapy and compared to the healthy controls, the good responders showed a significantly increased connectivity between the left primary cortex auditory cortex and the posterior cingulate cortex in the gamma and delta bands together with a significantly decreased effective connectivity between the right primary auditory cortex and the dorsolateral prefrontal cortex in the alpha band. Intriguingly, after 12 weeks of CR therapy most of the pathological interactions were gone, so that the connectivity patterns of good responders and healthy controls became statistically indistinguishable. In addition, we used dynamic causal modeling (DCM) to examine the types of interactions which were altered by CR therapy. Our DCM results show that CR therapy specifically counteracted the imbalance of excitation and inhibition. CR significantly weakened the excitatory connection

  14. Hot spots and labyrinths: Why cortical neuromodulation for episodic migraine with aura should be personalized

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    Markus A Dahlem

    2015-03-01

    Full Text Available Stimulation protocols for medical devices should be rationally designed. For episodic migraine with aura we outline model-based design strategies towards preventive and acute therapies using stereotactic cortical neuromodulation. To this end, we regard a localized spreading depression (SD wave segment as a central element in migraine pathophysiology. To describe nucleation and propagation features of the SD wave segment, we define the new concepts of cortical hot spots and labyrinths, respectively. In particular, we firstly focus exclusively on curvature-induced dynamical properties by studying a generic reaction-diffusion model of SD on the folded cortical surface. This surface is described with increasing level of details, including finally personalized simulations using patient's magnetic resonance imaging (MRI scanner readings. At this stage, the only relevant factor that can modulate nucleation and propagation paths is the Gaussian curvature, which has the advantage of being rather readily accessible by MRI. We conclude with discussing further anatomical factors, such as areal, laminar, and cellular heterogeneity, that in addition to and in relation to Gaussian curvature determine the generalized concept of cortical hot spots and labyrinths as target structures for neuromodulation. Our numerical simulations suggest that these target structures are like fingerprints, they are individual features of each migraine sufferer. The goal in the future will be to provide individualized neural tissue simulations. These simulations should predict the clinical data and therefore can also serve as a test bed for exploring stereotactic cortical neuromodulation.

  15. The ethics of neuromodulation for anorexia nervosa: a focus on rTMS

    Science.gov (United States)

    2014-01-01

    Objective Recently there has been emerging clinical and research interest in the application of deep brain stimulation (DBS) and repetitive transcranial magnetic stimulation (rTMS) to the treatment of anorexia nervosa (AN). To our knowledge, few studies have discussed ethical aspects associated with the increased use of neuromodulation in AN, some of which are quite specific to AN, despite the rapid development and dissemination of these new technologies. Method We provide a brief overview of three published rTMS studies for AN and discuss ethical issues involved in the use of neuromodulation for AN. Results In contrast to neurosurgery or DBS, rTMS is a less invasive technique, with less associated risk, and thus has greater potential to become a more widespread augmentation or add-on therapy for AN. New therapeutic procedures are promising, yet they raise ethical questions regarding informed consent and patient selection. Illness-specific issues surrounding authenticity and autonomy are important to consider, ensuring an ethical approach to treatment for patients with AN. Discussion We argue that ethical investigations for neuromodulation techniques are timely and important, and discussions should go beyond the immediate goals of patient safety, consent, and risk and benefit, to consider broader ethical concepts such as authenticity and autonomy. PMID:24690315

  16. Permanente sakrale Neuromodulation mittels InterStim®: Ergebnisse einer Anwendungsbefragung zu aktuellen technischen Entwicklungen

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    Sievert KD

    2007-01-01

    Full Text Available In den vergangenen über 20 Jahren wurde die sakrale Neuromodulation als klinische Therapie etabliert. Die anfängliche Indikation wurde ständig erweitert und umfaßt heute verschiedene Formen der Blasen- und Stuhlentleerungsstörung sowie eingeschränkt die Schmerztherapie im kleinen Becken. Fortwährend wurde die Technik der Implantation verbessert und die zur Verfügung stehende Hardware verkleinert. Als Resultat der konsequenten Weiterentwicklung wurde im letzten Jahr der miniaturisierte InterStim® II vorgestellt und dessen klinischer Einsatz durch versierte Operateure der unterschiedlichsten Disziplinen mittels einer internetbasierten Befragung beurteilt. Durch die Verwendung des InterStim® II werden im Vergleich zum InterStim® die operative Invasivität mit der Operationszeit und daraus resultierend der postoperative Schmerz gesenkt. Die neue Fernbedienung läßt einen weiteren Anstieg der Akzeptanz erwarten, da durch das Display der Fernbedienung der Patient die Einstellungen kontrollieren kann. Die weitere Miniaturisierung mit gleichzeitig erweiterter Programmierbarkeit des Implantates, der direkten Verbindung von Elektrode und Impulsgeber mit einer einzelnen Schraube verbessert die Option der Neuromodulation weiter. Die Entwicklungen unterstützen den minimal-invasiven Aspekt der InterStim®-Therapie, wodurch die Möglichkeit der ambulanten Therapieoption gegeben sein könnte. Es bleibt abzuwarten, ob die Therapie der Neuromodulation durch die erweiterten Programmiermöglichkeiten für den einzelnen Patienten in Zukunft noch individueller im chronischen Einsatz optimiert werden kann.

  17. Feed-Forward Inhibition of CD73 and Upregulation of Adenosine Deaminase Contribute to the Loss of Adenosine Neuromodulation in Postinflammatory Ileitis

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    Cátia Vieira

    2014-01-01

    Full Text Available Purinergic signalling is remarkably plastic during gastrointestinal inflammation. Thus, selective drugs targeting the “purinome” may be helpful for inflammatory gastrointestinal diseases. The myenteric neuromuscular transmission of healthy individuals is fine-tuned and controlled by adenosine acting on A2A excitatory receptors. Here, we investigated the neuromodulatory role of adenosine in TNBS-inflamed longitudinal muscle-myenteric plexus of the rat ileum. Seven-day postinflammation ileitis lacks adenosine neuromodulation, which may contribute to acceleration of gastrointestinal transit. The loss of adenosine neuromodulation results from deficient accumulation of the nucleoside at the myenteric synapse despite the fact that the increases in ATP release were observed. Disparity between ATP outflow and adenosine deficit in postinflammatory ileitis is ascribed to feed-forward inhibition of ecto-5′-nucleotidase/CD73 by high extracellular ATP and/or ADP. Redistribution of NTPDase2, but not of NTPDase3, from ganglion cell bodies to myenteric nerve terminals leads to preferential ADP accumulation from released ATP, thus contributing to the prolonged inhibition of muscle-bound ecto-5′-nucleotidase/CD73 and to the delay of adenosine formation at the inflamed neuromuscular synapse. On the other hand, depression of endogenous adenosine accumulation may also occur due to enhancement of adenosine deaminase activity. Both membrane-bound and soluble forms of ecto-5′-nucleotidase/CD73 and adenosine deaminase were detected in the inflamed myenteric plexus. These findings provide novel therapeutic targets for inflammatory gut motility disorders.

  18. Loss of catecholaminergic neuromodulation of persistent forms of hippocampal synaptic plasticity with increasing age

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    Hannah Twarkowski

    2016-09-01

    Full Text Available Neuromodulation by means of the catecholaminergic system is a key component of motivation-driven learning and behaviorally modulated hippocampal synaptic plasticity. In particular, dopamine acting on D1/D5 receptors and noradrenaline acting on beta-adrenergic receptors exert a very potent regulation of forms of hippocampal synaptic plasticity that last for very long-periods of time (>24h, and occur in conjunction with novel spatial learning. Antagonism of these receptors not only prevents long-term potentiation (LTP and long-term depression (LTD, but prevents the memory of the spatial event that, under normal circumstances, leads to the perpetuation of these plasticity forms. Spatial learning behavior that normally comes easily to rats, such as object-place learning and spatial reference learning, becomes increasingly impaired with aging. Middle-aged animals display aging-related deficits of specific, but not all, components of spatial learning, and one possibility is that this initial manifestation of decrements in learning ability that become manifest in middle-age relate to changes in motivation, attention and/or the regulation by neuromodulatory systems of these behavioral states.Here, we compared the regulation by dopaminergic D1/D5 and beta-adrenergic receptors of persistent LTP in young (2-4 month old and middle-aged (8-14 month old rats. We observed in young rats, that weak potentiation that typically lasts for ca. 2h could be strengthened into persistent (>24h LTP by pharmacological activation of either D1/D5 or beta-adrenergic receptors. By contrast, no such facilitation occurred in middle-aged rats. This difference was not related to an ostensible learning deficit: a facilitation of weak potentiation into LTP by spatial learning was possible both in young and middle-aged rats. It was also not directly linked to deficits in LTP: strong afferent stimulation resulted in equivalent LTP in both age groups. We postulate that this change in

  19. Loss of Catecholaminergic Neuromodulation of Persistent Forms of Hippocampal Synaptic Plasticity with Increasing Age

    Science.gov (United States)

    Twarkowski, Hannah; Manahan-Vaughan, Denise

    2016-01-01

    Neuromodulation by means of the catecholaminergic system is a key component of motivation-driven learning and behaviorally modulated hippocampal synaptic plasticity. In particular, dopamine acting on D1/D5 receptors and noradrenaline acting on beta-adrenergic receptors exert a very potent regulation of forms of hippocampal synaptic plasticity that last for very long-periods of time (>24 h), and occur in conjunction with novel spatial learning. Antagonism of these receptors not only prevents long-term potentiation (LTP) and long-term depression (LTD), but prevents the memory of the spatial event that, under normal circumstances, leads to the perpetuation of these plasticity forms. Spatial learning behavior that normally comes easily to rats, such as object-place learning and spatial reference learning, becomes increasingly impaired with aging. Middle-aged animals display aging-related deficits of specific, but not all, components of spatial learning, and one possibility is that this initial manifestation of decrements in learning ability that become apparent in middle-age relate to changes in motivation, attention and/or the regulation by neuromodulatory systems of these behavioral states. Here, we compared the regulation by dopaminergic D1/D5 and beta-adrenergic receptors of persistent LTP in young (2–4 month old) and middle-aged (8–14 month old) rats. We observed in young rats, that weak potentiation that typically lasts for ca. 2 h could be strengthened into persistent (>24 h) LTP by pharmacological activation of either D1/D5 or beta-adrenergic receptors. By contrast, no such facilitation occurred in middle-aged rats. This difference was not related to an ostensible learning deficit: a facilitation of weak potentiation into LTP by spatial learning was possible both in young and middle-aged rats. It was also not directly linked to deficits in LTP: strong afferent stimulation resulted in equivalent LTP in both age groups. We postulate that this change in

  20. Morphine dependence and withdrawal induced changes in cholinergic signaling

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    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

  1. Effects of septal cholinergic lesion on rat exploratory behavior in an open-field

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    M.R. Lamprea

    2003-02-01

    Full Text Available The medial septum participates in the modulation of exploratory behavior triggered by novelty. Also, selective lesions of the cholinergic component of the septohippocampal system alter the habituation of rats to an elevated plus-maze without modifying anxiety indices. We investigated the effects of the intraseptal injection of the cholinergic immunotoxin 192 IgG-saporin (SAP on the behavior of rats in an open-field. Thirty-nine male Wistar rats (weight: 194-230 g were divided into three groups, non-injected controls and rats injected with either saline (0.5 µl or SAP (237.5 ng/0.5 µl. Twelve days after surgery, the animals were placed in a square open-field (120 cm and allowed to freely explore for 5 min. After the test, the rats were killed by decapitation and the septum, hippocampus and frontal cortex were removed and assayed for acetylcholinesterase activity. SAP increased acetylcholinesterase activity in the septum, hippocampus and frontal cortex and decreased the total distance run (9.15 ± 1.51 m in comparison to controls (13.49 ± 0.91 m. The time spent in the center and at the periphery was not altered by SAP but the distance run was reduced during the first and second minutes (2.43 ± 0.36 and 1.75 ± 0.34 m compared to controls (4.18 ± 0.26 and 3.14 ± 0.25 m. SAP-treated rats showed decreased but persistent exploration throughout the session. These results suggest that septohippocampal cholinergic mechanisms contribute to at least two critical processes, one related to the motivation to explore new environments and the other to the acquisition and storage of spatial information (i.e., spatial memory.

  2. 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.

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

    Science.gov (United States)

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

    2017-01-01

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

  4. Historical development of epistemology and the study of pain: Place of neuromodulation of electroacupuncture in the experimental pain research

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    Bárbara B. Garrido-Suárez

    2013-10-01

    Full Text Available Despite the diffusion of acupuncture and its related techniques in Cuba and the World, its mechanism of action is still controversial, being considered by the most sceptics as placebo or some kind oriental myth, and it only should by related to this subjects as a matter of cultural-historical elements and not to science. The purpose of this revision is to characterize the pain sensation, after a critical analysis of the different philosophical streams related to the human knowledge and its expression in the historical evolution of the algology. On the other hand, to emphasize the importance of electroacupuncture-induced neuro-modulation in the field of experimental pain researches. In this content will be analyzed the concept of Khun paradigm and his ideas about the structure of scientific revolution in the theory of gates control and the explosion of pain researches in the last decades. It will related the introduction to acupuncture and its techniques in pain clinics, with scientific context of the historical moment. In addition, a space will be dedicated to the topic of complementary and alternative medicine on the century of evidence based medicine, given its scientific needs of validation in ours times.

  5. Pacemaker neuron and network oscillations depend on a neuromodulator-regulated linear current

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    Shunbing Zhao

    2010-05-01

    Full Text Available Linear leak currents have been implicated in the regulation of neuronal excitability, generation of neuronal and network oscillations, and network state transitions. Yet, few studies have directly tested the dependence of network oscillations on leak currents or explored the role of leak currents on network activity. In the oscillatory pyloric network of decapod crustaceans neuromodulatory inputs are necessary for pacemaker activity. A large subset of neuromodulators is known to activate a single voltage-gated inward current IMI, which has been shown to regulate the rhythmic activity of the network and its pacemaker neurons. Using the dynamic clamp technique, we show that the crucial component of IMI for the generation of oscillatory activity is only a close-to-linear portion of the current-voltage relationship. The nature of this conductance is such that the presence or the absence of neuromodulators effectively regulates the amount of leak current and the input resistance in the pacemaker neurons. When deprived of neuromodulatory inputs, pyloric oscillations are disrupted; yet, a linear reduction of the total conductance in a single neuron within the pacemaker group recovers not only the pacemaker activity in that neuron, but also leads to a recovery of oscillations in the entire pyloric network. The recovered activity produces proper frequency and phasing that is similar to that induced by neuromodulators. These results show that the passive properties of pacemaker neurons can significantly affect their capacity to generate and regulate the oscillatory activity of an entire network, and that this feature is exploited by neuromodulatory inputs.

  6. Novel Neuromodulation Techniques to Assess Interhemispheric Communication in Neural Injury and Neurodegenerative Diseases

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    Shin, Samuel S.; Pelled, Galit

    2017-01-01

    Interhemispheric interaction has a major role in various neurobehavioral functions. Its disruption is a major contributor to the pathological changes in the setting of brain injury such as traumatic brain injury, peripheral nerve injury, and stroke, as well as neurodegenerative diseases. Because interhemispheric interaction has a crucial role in functional consequence in these neuropathological states, a review of noninvasive and state-of-the-art molecular based neuromodulation methods that focus on or have the potential to elucidate interhemispheric interaction have been performed. This yielded approximately 170 relevant articles on human subjects or animal models. There has been a recent surge of reports on noninvasive methods such as transcranial magnetic stimulation and transcranial direct current stimulation. Since these are noninvasive techniques with little to no side effects, their widespread use in clinical studies can be easily justified. The overview of novel neuromodulation methods and how they can be applied to study the role of interhemispheric communication in neural injury and neurodegenerative disease is provided. Additionally, the potential of each method in therapeutic use as well as investigating the pathophysiology of interhemispheric interaction in neurodegenerative diseases and brain injury is discussed. New technologies such as transcranial magnetic stimulation or transcranial direct current stimulation could have a great impact in understanding interhemispheric pathophysiology associated with acquired injury and neurodegenerative diseases, as well as designing improved rehabilitation therapies. Also, advances in molecular based neuromodulation techniques such as optogenetics and other chemical, thermal, and magnetic based methods provide new capabilities to stimulate or inhibit a specific brain location and a specific neuronal population. PMID:28337129

  7. Thalamocortical dynamics of sleep: roles of purinergic neuromodulation.

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    Halassa, Michael M

    2011-04-01

    Thalamocortical dynamics, the millisecond to second changes in activity of thalamocortical circuits, are central to perception, action and cognition. Generated by local circuitry and sculpted by neuromodulatory systems, these dynamics reflect the expression of vigilance states. In sleep, thalamocortical dynamics are thought to mediate "offline" functions including memory consolidation and synaptic scaling. Here, I discuss thalamocortical sleep dynamics and their modulation by the ascending arousal system and locally released neurochemicals. I focus on modulation of these dynamics by electrically silent astrocytes, highlighting the role of purinergic signaling in this glial form of communication. Astrocytes modulate cortical slow oscillations, sleep behavior, and sleep-dependent cognitive function. The discovery that astrocytes can modulate sleep dynamics and sleep-related behaviors suggests a new way of thinking about the brain, in which integrated circuits of neurons and glia control information processing and behavioral output.

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

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    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.

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

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    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.

  10. 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

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

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    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.

  12. Selective optogenetic stimulation of cholinergic axons in neocortex.

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    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.

  13. 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

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

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    Claude Sadis

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

  15. Linking Neuromodulated Spike-Timing Dependent Plasticity with the Free-Energy Principle.

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    Isomura, Takuya; Sakai, Koji; Kotani, Kiyoshi; Jimbo, Yasuhiko

    2016-09-01

    The free-energy principle is a candidate unified theory for learning and memory in the brain that predicts that neurons, synapses, and neuromodulators work in a manner that minimizes free energy. However, electrophysiological data elucidating the neural and synaptic bases for this theory are lacking. Here, we propose a novel theory bridging the information-theoretical principle with the biological phenomenon of spike-timing dependent plasticity (STDP) regulated by neuromodulators, which we term mSTDP. We propose that by integrating an mSTDP equation, we can obtain a form of Friston's free energy (an information-theoretical function). Then we analytically and numerically show that dopamine (DA) and noradrenaline (NA) influence the accuracy of a principal component analysis (PCA) performed using the mSTDP algorithm. From the perspective of free-energy minimization, these neuromodulatory changes alter the relative weighting or precision of accuracy and prior terms, which induces a switch from pattern completion to separation. These results are consistent with electrophysiological findings and validate the free-energy principle and mSTDP. Moreover, our scheme can potentially be applied in computational psychiatry to build models of the faulty neural networks that underlie the positive symptoms of schizophrenia, which involve abnormal DA levels, as well as models of the NA contribution to memory triage and posttraumatic stress disorder.

  16. New approach to neurorehabilitation: cranial nerve noninvasive neuromodulation (CN-NINM) technology

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    Danilov, Yuri P.; Tyler, Mitchel E.; Kaczmarek, Kurt A.; Skinner, Kimberley L.

    2014-06-01

    Cranial Nerve NonInvasive NeuroModulation (CN-NINM) is a primary and complementary multi-targeted rehabilitation therapy that appears to initiate the recovery of multiple damaged or suppressed brain functions affected by neurological disorders. It is deployable as a simple, home-based device (portable neuromodulation stimulator, or PoNSTM) and training regimen following initial patient training in an outpatient clinic. It may be easily combined with many existing rehabilitation therapies, and may reduce or eliminate the need for more aggressive invasive procedures or possibly decrease total medication intake. CN-NINM uses sequenced patterns of electrical stimulation on the tongue. Our hypothesis is that CN-NINM induces neuroplasticity by noninvasive stimulation of two major cranial nerves: trigeminal (CN-V), and facial (CN-VII). This stimulation excites a natural flow of neural impulses to the brainstem (pons varolli and medulla), and cerebellum, to effect changes in the function of these targeted brain structures, extending to corresponding nuclei of the brainstem. CN-NINM represents a synthesis of a new noninvasive brain stimulation technique with applications in physical medicine, cognitive, and affective neurosciences. Our new stimulation method appears promising for treatment of a full spectrum of movement disorders, and for both attention and memory dysfunction associated with traumatic brain injury.

  17. Neuroimaging and neuromodulation approaches to study eating behavior and prevent and treat eating disorders and obesity

    Directory of Open Access Journals (Sweden)

    D. Val-Laillet

    2015-01-01

    Full Text Available Functional, molecular and genetic neuroimaging has highlighted the existence of brain anomalies and neural vulnerability factors related to obesity and eating disorders such as binge eating or anorexia nervosa. In particular, decreased basal metabolism in the prefrontal cortex and striatum as well as dopaminergic alterations have been described in obese subjects, in parallel with increased activation of reward brain areas in response to palatable food cues. Elevated reward region responsivity may trigger food craving and predict future weight gain. This opens the way to prevention studies using functional and molecular neuroimaging to perform early diagnostics and to phenotype subjects at risk by exploring different neurobehavioral dimensions of the food choices and motivation processes. In the first part of this review, advantages and limitations of neuroimaging techniques, such as functional magnetic resonance imaging (fMRI, positron emission tomography (PET, single photon emission computed tomography (SPECT, pharmacogenetic fMRI and functional near-infrared spectroscopy (fNIRS will be discussed in the context of recent work dealing with eating behavior, with a particular focus on obesity. In the second part of the review, non-invasive strategies to modulate food-related brain processes and functions will be presented. At the leading edge of non-invasive brain-based technologies is real-time fMRI (rtfMRI neurofeedback, which is a powerful tool to better understand the complexity of human brain–behavior relationships. rtfMRI, alone or when combined with other techniques and tools such as EEG and cognitive therapy, could be used to alter neural plasticity and learned behavior to optimize and/or restore healthy cognition and eating behavior. Other promising non-invasive neuromodulation approaches being explored are repetitive transcranial magnetic stimulation (rTMS and transcranial direct-current stimulation (tDCS. Converging evidence points at

  18. Neuroimaging and neuromodulation approaches to study eating behavior and prevent and treat eating disorders and obesity.

    Science.gov (United States)

    Val-Laillet, D; Aarts, E; Weber, B; Ferrari, M; Quaresima, V; Stoeckel, L E; Alonso-Alonso, M; Audette, M; Malbert, C H; Stice, E

    2015-01-01

    Functional, molecular and genetic neuroimaging has highlighted the existence of brain anomalies and neural vulnerability factors related to obesity and eating disorders such as binge eating or anorexia nervosa. In particular, decreased basal metabolism in the prefrontal cortex and striatum as well as dopaminergic alterations have been described in obese subjects, in parallel with increased activation of reward brain areas in response to palatable food cues. Elevated reward region responsivity may trigger food craving and predict future weight gain. This opens the way to prevention studies using functional and molecular neuroimaging to perform early diagnostics and to phenotype subjects at risk by exploring different neurobehavioral dimensions of the food choices and motivation processes. In the first part of this review, advantages and limitations of neuroimaging techniques, such as functional magnetic resonance imaging (fMRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), pharmacogenetic fMRI and functional near-infrared spectroscopy (fNIRS) will be discussed in the context of recent work dealing with eating behavior, with a particular focus on obesity. In the second part of the review, non-invasive strategies to modulate food-related brain processes and functions will be presented. At the leading edge of non-invasive brain-based technologies is real-time fMRI (rtfMRI) neurofeedback, which is a powerful tool to better understand the complexity of human brain-behavior relationships. rtfMRI, alone or when combined with other techniques and tools such as EEG and cognitive therapy, could be used to alter neural plasticity and learned behavior to optimize and/or restore healthy cognition and eating behavior. Other promising non-invasive neuromodulation approaches being explored are repetitive transcranial magnetic stimulation (rTMS) and transcranial direct-current stimulation (tDCS). Converging evidence points at the value of

  19. 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.

  20. Sleep in depression: the influence of age, gender and diagnostic subtype on baseline sleep and the cholinergic REM induction test with RS 86.

    Science.gov (United States)

    Riemann, D; Hohagen, F; Bahro, M; Berger, M

    1994-01-01

    One hundred and eight healthy controls and 178 patients with a major depressive disorder according to DSM-III were investigated in the sleep laboratory after a 7-day drug wash-out period. Subsamples of 36 healthy controls and 56 patients additionally took part in the cholinergic rapid eye movement (REM) sleep induction test with RS 86. Data analysis revealed that age exerted powerful influences on sleep in control subjects and depressed patients. Sleep efficiency and amount of slow wave sleep (SWS) decreased with age, whereas the number of awakenings, early morning awakening, and amounts of wake time and stage 1 increased with age. REM latency was negatively correlated with age only in the group of patients with a major depression. Statistical analysis revealed group differences for almost all parameters of sleep continuity with disturbed indices in the depressed group. Differences in SWS were not detected. REM latency and REM density were altered in depression compared to healthy subjects. Sex differences existed for the amounts of stage 1 and SWS. The cholinergic REM induction test resulted in a significantly more pronounced induction of REM sleep in depressed patients compared with healthy controls, provoking sleep onset REM periods as well in those depressed patients showing baseline REM latencies in the normal range. Depressed patients with or without melancholia (according to DSM-III) did not differ from each other, either concerning baseline sleep or with respect to the results of the cholinergic REM induction test. The results stress the importance of age when comparing sleep patterns of healthy controls with those of depressed patients. Furthermore they underline the usefulness of the cholinergic REM induction test for differentiating depressed patients from healthy controls and support the reciprocal interaction model of nonREM-REM regulation and the cholinergic-aminergic imbalance hypothesis of affective disorders.

  1. Diabetic plasticity of non-adrenergic non-cholinergic and P2X-mediated rat bladder contractions.

    Science.gov (United States)

    Munoz, Alvaro; Boone, Timothy B; Smith, Christopher P; Somogyi, George T

    2013-06-01

    We investigated the plasticity effects of diabetes mellitus and diuresis on the non-adrenergic non-cholinergic (NANC) and purinergic (P2X-type) contractile responses in longitudinal rat bladder strips. Female Sprague-Dawley rats received streptozotocin to induce diabetes, or sucrose in water to induce diuresis as a control condition for polyuria. Experiments were carried out at four weeks after treatments, using bladders from non-treated rats as control. Urinary bladder strips were electrically stimulated throughout the experiments to generate neurally evoked contractions (NEC). In all cases, P2X-mediated purinergic contractions were evaluated at the beginning and end of the stimulations with α,β-methylene-adenosine triphosphate (α,βMeATP). The NANC responses were assessed by using two independent protocols. First, cholinergic receptors were activated with carbachol (CCh), followed by inhibition of the muscarinic component with atropine. In the second protocol, the application order for CCh and atropine was reversed. The NANC response, unmasked with the application of atropine, and the P2X purinergic contractions were analyzed. NANC contractions in diabetic bladder strips are more resistant to the desensitizing effects caused by activation of cholinergic receptors. In early stages of experimental diabetes, NANC responses in diabetic strips are less sensitive to functional inhibition mediated by the cholinergic activation. However, P2X-mediated purinergic contractions are more sensitive to desensitization in diabetic or diuretic bladders. For instance preventing muscarinic receptor activation with atropine does not counteract the desensitization of purinergic contractions in either diabetic or diuretic strips. We suggest that diabetes may induce a plasticity of the NANC and P2X-mediated bladder contractile responses. The first one may be associated with diabetic neuropathic damage to bladder nerves, while impaired P2X purinergic contractions might be associated

  2. Electrical neuromodulation improves myocardial perfusion and ameliorates refractory angina pectoris in patients with syndrome X : fad or future?

    NARCIS (Netherlands)

    Jessurun, G; Hautvast, RWM; Tio, RA; DeJongste, M

    2003-01-01

    At present, there is no reliable antianginal drug therapy for patients with cardiac syndrome X. Therefore, the effect of electrical neuromodulation on refractory angina pectoris and myocardial perfusion in cardiac syndrome X was assessed. Eight patients (aged 55 +/- 7 years) with heterogeneous myoca

  3. Consciousness in waking and dreaming: the roles of neuronal oscillation and neuromodulation in determining similarities and differences.

    Science.gov (United States)

    Kahn, D; Pace-Schott, E F; Hobson, J A

    1997-05-01

    State-dependent aspects of consciousness are explored with particular attention to waking and dreaming. First, those phenomenological differences between waking and dreaming that have been established through subjective reports are reviewed. These differences are robustly expressed in most aspects of consciousness including perception, attention, memory, emotion, orientation, and thought. Next, the roles of high frequency neuronal oscillation and neuromodulation are explored in waking and rapid eye movement sleep, the stage of sleep with which the most intense dreaming is associated. The high frequency neuronal oscillations serve similar functions in the wake and rapid eye movement states sleep but neuromodulation is very different in the two states. The collective high frequency oscillatory activity gives coherence to spatially separate neurons but, because of the different neuromodulation, the binding of sensory input in the wake state is very different from the binding of internally perceived input during rapid eye movement sleep. An explanatory model is presented which states that neuromodulation, as well as input source and brain activation level differentiate states of the brain, while the self-organized collective neuronal oscillations unify consciousness via long range correlations.

  4. Neuromodulation of the cervical spinal cord in the treatment of chronic intractable neck and upper extremity pain: a case series and review of the literature.

    Science.gov (United States)

    Vallejo, Ricardo; Kramer, Jeffery; Benyamin, Ramsin

    2007-03-01

    Electrical spinal neuromodulation in the form of spinal cord stimulation is currently used for treating chronic painful conditions such as complex regional pain syndrome, diabetic neuropathy, postherpetic neuralgia, peripheral ischemia, low back pain, and other conditions refractory to more conservative treatments. To date, there are very few published reports documenting the use of spinal cord stimulation in the treatment of head/neck and upper limb pain. This paper reports a case series of 5 consecutive patients outlining the use of spinal cord stimulation to treat upper extremity pain. All subjects had previously undergone cervical fusion surgery to treat chronic neck and upper limb pain. Patients were referred following failure of the surgery to manage their painful conditions. Spinal cord stimulators were placed in the cervical epidural space through a thoracic needle placement. Stimulation parameters were adjusted to capture as much of the painful area(s) as possible. In total, 4 out of 5 patients moved to implantation. In all cases, patients reported significant (70-90%) reductions in pain, including axial neck pain and upper extremity pain. Interestingly, 2 patients with associated headache and lower extremity pain obtained relief after paresthesia-steering reportedly covered those areas. Moreover, 2 patients reported that cervical spinal cord stimulation significantly improved axial low back pain. Patients continue to report excellent pain relief up to 9 months following implantation. This case series documents the successful treatment of neck and upper extremity pain following unsuccessful cervical spine fusion surgery. Given this initial success, prospective, controlled studies are warranted to more adequately assess the long term utility and cost effectiveness of electrical neuromodulation treatment of chronic neck and upper extremity pain.

  5. Altitude acclimatization improves submaximal cognitive performance in mice and involves an imbalance of the cholinergic system.

    Science.gov (United States)

    Guerra-Narbona, R; Delgado-García, J M; López-Ramos, J C

    2013-06-15

    The aim of this work was to reveal a hypothetical improvement of cognitive abilities in animals acclimatized to altitude and performing under ground level conditions, when looking at submaximal performance, once seen that it was not possible when looking at maximal scores. We modified contrasted cognitive tasks (object recognition, operant conditioning, eight-arm radial maze, and classical conditioning of the eyeblink reflex), increasing their complexity in an attempt to find performance differences in acclimatized animals vs. untrained controls. In addition, we studied, through immunohistochemical quantification, the expression of choline acetyltransferase and acetyl cholinesterase, enzymes involved in the synthesis and degradation of acetylcholine, in the septal area, piriform and visual cortexes, and the hippocampal CA1 area of animals submitted to acute hypobaric hypoxia, or acclimatized to this simulated altitude, to find a relationship between the cholinergic system and a cognitive improvement due to altitude acclimatization. Results showed subtle improvements of the cognitive capabilities of acclimatized animals in all of the tasks when performed under ground-level conditions (although not before 24 h), in the three tasks used to test explicit memory (object recognition, operant conditioning in the Skinner box, and eight-arm radial maze) and (from the first conditioning session) in the classical conditioning task used to evaluate implicit memory. An imbalance of choline acetyltransferase/acetyl cholinesterase expression was found in acclimatized animals, mainly 24 h after the acclimatization period. In conclusion, altitude acclimatization improves cognitive capabilities, in a process parallel to an imbalance of the cholinergic system.

  6. Acetylcholine released from cholinergic nerves contributes to cutaneous vasodilation during heat stress

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    Shibasaki, Manabu; Wilson, Thad E.; Cui, Jian; Crandall, Craig G.

    2002-01-01

    Nitric oxide (NO) contributes to active cutaneous vasodilation during a heat stress in humans. Given that acetylcholine is released from cholinergic nerves during whole body heating, coupled with evidence that acetylcholine causes vasodilation via NO mechanisms, it is possible that release of acetylcholine in the dermal space contributes to cutaneous vasodilation during a heat stress. To test this hypothesis, in seven subjects skin blood flow (SkBF) and sweat rate were simultaneously monitored over three microdialysis membranes placed in the dermal space of dorsal forearm skin. One membrane was perfused with the acetylcholinesterase inhibitor neostigmine (10 microM), the second membrane was perfused with the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME; 10 mM) dissolved in the aforementioned neostigmine solution (l-NAME(Neo)), and the third membrane was perfused with Ringer solution as a control site. Each subject was exposed to approximately 20 min of whole body heating via a water-perfused suit, which increased mean body temperature from 36.4 +/- 0.1 to 37.5 +/- 0.1 degrees C (P acetylcholine released from cholinergic nerves is capable of modulating cutaneous vasodilation via NO synthase mechanisms early in the heat stress but not after substantial cutaneous vasodilation.

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

    Directory of Open Access Journals (Sweden)

    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.

  8. Longitudinal measures of cholinergic forebrain atrophy in the transition from healthy aging to Alzheimer's disease.

    Science.gov (United States)

    Grothe, Michel; Heinsen, Helmut; Teipel, Stefan

    2013-04-01

    Recent evidence from cross-sectional in vivo imaging studies suggests that atrophy of the cholinergic basal forebrain (BF) in Alzheimer's disease (AD) can be distinguished from normal age-related degeneration even at predementia stages of the disease. Longitudinal study designs are needed to specify the dynamics of BF degeneration in the transition from normal aging to AD. We applied recently developed techniques for in vivo volumetry of the BF to serial magnetic resonance imaging scans of 82 initially healthy elderly individuals (60-93 years) and 50 patients with very mild AD (Clinical Dementia Rating score = 0.5) that were clinically followed over an average of 3 ± 1.5 years. BF atrophy rates were found to be significantly higher than rates of global brain shrinkage even in cognitively stable healthy elderly individuals. Compared with healthy control subjects, very mild AD patients showed reduced BF volumes at baseline and increased volume loss over time. Atrophy of the BF was more pronounced in progressive patients compared with those that remained stable. The cholinergic BF undergoes disproportionate degeneration in the aging process, which is further increased by the presence of AD.

  9. Administration of MPTP to the common marmoset does not alter cortical cholinergic function

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    Garvey, J.; Petersen, M.; Waters, C.M.; Rose, S.P.; Hunt, S.; Briggs, R.; Jenner, P.; Marsden, C.D.

    1986-01-01

    The administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to common marmosets induced persistent motor deficits and decreased concentrations of dopamine, homovanillic acid, and 3,4-dihydroxy-phenylacetic acid (DOPAC) and (TH)dopamine uptake in the caudate-putamen. There was an 80% reduction in tyrosine hydroxylase immunoreactive cells in substantia nigra. At 10 days following the start of MPTP administration, the activity of choline acetyltransferase in the thalamus and frontal cortex was unchanged compared with control animals. Similarly, specific (TH)QNB binding was unaltered. At 4-6 weeks following the start of MPTP treatment, choline acetyltransferase activity and (TH)QNB binding in the frontal cortex and thalamus remained unaffected. There was no evidence for cell loss in the nucleus basalis of Meynert or alteration in the intensity of staining for acetylcholinesterase. MPTP treatment of the common marmoset produces a nigrostriatal lesion. In contrast, MPTP did not alter cortical cholinergic function and was not neurotoxic to the cholinergic cells in the nucleus basalis of Meynert.

  10. 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.

  11. 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.

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

    Science.gov (United States)

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

    2011-12-30

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

  13. Cholinergic signals in mouse barrel cortex during active whisker sensing.

    Science.gov (United States)

    Eggermann, Emmanuel; Kremer, Yves; Crochet, Sylvain; Petersen, Carl C H

    2014-12-11

    Internal brain states affect sensory perception, cognition, and learning. Many neocortical areas exhibit changes in the pattern and synchrony of neuronal activity during quiet versus active behaviors. Active behaviors are typically associated with desynchronized cortical dynamics. Increased thalamic firing contributes importantly to desynchronize mouse barrel cortex during active whisker sensing. However, a whisking-related cortical state change persists after thalamic inactivation, which is mediated at least in part by acetylcholine, as we show here by using whole-cell recordings, local pharmacology, axonal calcium imaging, and optogenetic stimulation. During whisking, we find prominent cholinergic signals in the barrel cortex, which suppress spontaneous cortical activity. The desynchronized state of barrel cortex during whisking is therefore driven by at least two distinct signals with opposing functions: increased thalamic activity driving glutamatergic excitation of the cortex and increased cholinergic input suppressing spontaneous cortical activity.

  14. Cholinergic Signals in Mouse Barrel Cortex during Active Whisker Sensing

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    Emmanuel Eggermann

    2014-12-01

    Full Text Available Internal brain states affect sensory perception, cognition, and learning. Many neocortical areas exhibit changes in the pattern and synchrony of neuronal activity during quiet versus active behaviors. Active behaviors are typically associated with desynchronized cortical dynamics. Increased thalamic firing contributes importantly to desynchronize mouse barrel cortex during active whisker sensing. However, a whisking-related cortical state change persists after thalamic inactivation, which is mediated at least in part by acetylcholine, as we show here by using whole-cell recordings, local pharmacology, axonal calcium imaging, and optogenetic stimulation. During whisking, we find prominent cholinergic signals in the barrel cortex, which suppress spontaneous cortical activity. The desynchronized state of barrel cortex during whisking is therefore driven by at least two distinct signals with opposing functions: increased thalamic activity driving glutamatergic excitation of the cortex and increased cholinergic input suppressing spontaneous cortical activity.

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

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    Cabeza Carolina

    2012-03-01

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

  16. 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.

  17. 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...

  18. 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

  19. 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...

  20. 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.

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

    Science.gov (United States)

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

    2016-08-01

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

  2. An Ethics Perspective on Transcranial Magnetic Stimulation (TMS and Human Neuromodulation

    Directory of Open Access Journals (Sweden)

    Judy Illes

    2006-01-01

    Full Text Available This paper concerns the ethics of human neuromodulation using transcranial magnetic stimulation (TMS. We examine the challenges of modulating the brain with TMS through the research ethics lens and in clinical medicine for treating frank pathology, primarily in psychiatric diseases. We also consider contemporary issues raised in the neuroethics literature about managing unexpected findings, and relate these to TMS and to other frontier neurotechnology that is becoming openly available in the public domain. We argue that safety and informed consent are of paramount importance for TMS, but that personal values and sociocultural factors must also be considered when examining the promise of this technology and applications that ought to be highlighted for extra precautions.

  3. Neuromodulation for mood and memory: from the engineering bench to the patient bedside.

    Science.gov (United States)

    Deng, Zhi-De; McClintock, Shawn M; Oey, Nicodemus E; Luber, Bruce; Lisanby, Sarah H

    2015-02-01

    Brain stimulation, in the form of electroconvulsive therapy (ECT), has long been a gold standard treatment for depression, but today, the field of neuromodulation is rapidly changing with the advent of newer and more precise tools to alter neuroplasticity and to treat brain-based disorders. Now there are new means to induce focal seizures, as with magnetic seizure therapy (MST), or modifications to ECT. There are also surgical approaches to target brain circuits via implanted stimulators placed in the brain or on cranial nerves. Finally, there are noninvasive subconvulsive approaches for the transcranial application of either electric or magnetic fields. Collectively, these tools have transformed the face of neurotherapeutics and informed our understanding of the brain basis of complex neurobehavioral conditions.

  4. 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.

  5. Neurostimulation for primary headache disorders: Part 2, review of central neurostimulators for primary headache, overall therapeutic efficacy, safety, cost, patient selection, and future research in headache neuromodulation.

    Science.gov (United States)

    Jenkins, Brian; Tepper, Stewart J

    2011-10-01

    This article is the second of 2 articles reviewing neurostimulation for primary headaches. In Part 1, we described methods, pathophysiology and anatomy, and history of neuromodulation in the treatment of headache, as well as reviewing the literature on peripheral neuromodulation for primary headaches. Peripheral targets for stimulation include percutaneous nerves, transcranial holocephalic, occipital nerves, auriculotemporal nerves, supraorbital nerves, cervical epidural, and sphenopalatine ganglia. In Part 2, we describe available literature on central neuromodulation in primary headaches. Central stimulation targets include vagus nerve and deep brain structures. Part 2 also analyzes overall therapeutic efficacy, safety, cost, patient selection, and recommendations for further research of neurostimulation modalities based on available data.

  6. 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.

  7. 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

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

    Science.gov (United States)

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

    2015-01-01

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

  9. Acetylcholine released from cholinergic nerves contributes to cutaneous vasodilation during heat stress

    Science.gov (United States)

    Shibasaki, Manabu; Wilson, Thad E.; Cui, Jian; Crandall, Craig G.

    2002-01-01

    Nitric oxide (NO) contributes to active cutaneous vasodilation during a heat stress in humans. Given that acetylcholine is released from cholinergic nerves during whole body heating, coupled with evidence that acetylcholine causes vasodilation via NO mechanisms, it is possible that release of acetylcholine in the dermal space contributes to cutaneous vasodilation during a heat stress. To test this hypothesis, in seven subjects skin blood flow (SkBF) and sweat rate were simultaneously monitored over three microdialysis membranes placed in the dermal space of dorsal forearm skin. One membrane was perfused with the acetylcholinesterase inhibitor neostigmine (10 microM), the second membrane was perfused with the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME; 10 mM) dissolved in the aforementioned neostigmine solution (l-NAME(Neo)), and the third membrane was perfused with Ringer solution as a control site. Each subject was exposed to approximately 20 min of whole body heating via a water-perfused suit, which increased mean body temperature from 36.4 +/- 0.1 to 37.5 +/- 0.1 degrees C (P vasodilation was significantly lower at the neostigmine-treated site relative to the other sites (neostigmine: 36.6 +/- 0.1 degrees C, l-NAME(Neo): 37.1 +/- 0.1 degrees C, control: 36.9 +/- 0.1 degrees C), whereas no significant threshold difference was observed between the l-NAME(Neo)-treated and control sites. At the end of the heat stress, SkBF was not different between the neostigmine-treated and control sites, whereas SkBF at the l-NAME(Neo)-treated site was significantly lower than the other sites. These results suggest that acetylcholine released from cholinergic nerves is capable of modulating cutaneous vasodilation via NO synthase mechanisms early in the heat stress but not after substantial cutaneous vasodilation.

  10. 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.

  11. 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.

  12. 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.

  13. 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

  14. 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

  15. Involvement of M3 Cholinergic Receptor Signal Transduction Pathway in Regulation of the Expression of Chemokine MOB-1, MCP-1 Genes in Pancreatic Acinar Cells

    Institute of Scientific and Technical Information of China (English)

    郑海; 陈道达; 张景輝; 田原

    2004-01-01

    Whether M3 cholinergic receptor signal transduction pathway is involved in regulation of the activation of NF-κB and the expression of chemokine MOB-1, MCP-1genes in pancreatic acinar cells was investigated. Rat pancreatic acinar cells were isolated, cultured and treated with carbachol, atropine and PDTC in vitro. The MOB-1 and MCP-1 mRNA expression was detected by using RT-PCR. The activation of NF-κB was monitored by using electrophoretic mobility shift assay.The results showed that as compared with control group, M3 cholinergic receptor agonist (103mol/L, 104-4ol/L carbachol) could induce a concentration-dependent and time-dependent increase in the expression of MOB-1, MCP-1 mRNA in pancreatic acinar cells. After treatment with 10 -3mol/L carbachol for 2 h, the expression of MOB-1, MCP-1 mRNA was strongest. The activity of NF-κB in pancreatic acinar cells was significantly increased (P<0.01) after treated with M3 cholinergic receptor agonist (10-3 mol/L carbachol) in vitro for 30 min. Either M3 cholinergic receptor antagonist (10-5 mol/L atropine) or NF-κB inhibitor (10-2 mol/L PDTC) could obviously inhibit the activation of NF-κB and the chemokine MOB-1, MCP-1 mRNA expression induced by carbachol (P <0.05). This inhibitory effect was significantly increased by atropine plus PDTC (P<0.01). The results of these studies indicated that M3 cholinergic receptor signal transduction pathway was likely involved in regulation of the expression of chemokine MOB-1 and MCP-1genes in pancreatic acinar cells in vitro through the activation of NF-κB.

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

    Directory of Open Access Journals (Sweden)

    Jae Hoon Jeong

    2015-06-01

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

  17. 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

  18. Changing the brain, changing the society: clinical and ethical implications of neuromodulation techniques in neurology and psychiatry.

    Science.gov (United States)

    Vuilleumier, Patrik; Sander, David; Baertschi, Bernard

    2014-01-01

    New neurotechnologies for modulating brain functions are becoming increasingly powerful and applicable to diverse diseases, but raise new questions for clinicians, ethicists, policy makers, and laymen. This issue of Brain Topography gathers several papers exploring the clinical and ethical implications of several invasive and noninvasive neuromodulation approaches. The opportunities and challenges associated with the emergence of neuro-engineering solutions to brain research and brain repair require a close dialogue between multiple disciplines, as well as open discussion with the general public.

  19. 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

  20. Hydrogen sulfide functions as a neuromodulator to regulate striatal neurotransmission in a mouse model of Parkinson's disease.

    Science.gov (United States)

    Wang, Min; Zhu, Jun; Pan, Yang; Dong, Jingde; Zhang, Lili; Zhang, Xiangrong; Zhang, Li

    2015-03-01

    Hydrogen sulfide (H2S), a novel endogenous gasotransmitter, has been considered a neuromodulator to enhance hippocampal long-term potentiation and exerts neuroprotective effects against neurotoxin-induced neurodegeneration in rodent models of Parkinson's disease (PD). However, whether H2S can function as a neuromodulator to regulate the levels of nigrostriatal neurotransmitters and then impact the vulnerability of dopaminergic (DA) neurons in response to neurotoxins remains unknown. For this study, we prepared a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine plus probenecid (MPTP/p)-induced mouse subacute model of PD to explore the modulatory effect of H2S on monoamine and amino acid neurotransmitters in the striatum of MPTP-treated mice. This study shows that NaHS (an H2S donor, 5.6 mg/kg/day, i.p.) administration improves the survival rate and significantly ameliorates the weight loss of MPTP-treated mice. NaHS treatment attenuated MPTP-induced neuronal damage, restored the diminution of DA neurons, and suppressed the overactivation of astrocytes in the mouse striatum. Additionally, NaHS upregulated striatal serotonin levels and modulated the balance of excitatory glutamate and the inhibitory γ-aminobutyric acid system in response to MPTP challenge. The current study indicates that H2S may function as an effective neuromodulator to regulate striatal neurotransmission and provides insight into the potential of H2S for PD therapy.

  1. Distinct forms of synaptic inhibition and neuromodulation regulate calretinin-positive neuron excitability in the spinal cord dorsal horn.

    Science.gov (United States)

    Smith, K M; Boyle, K A; Mustapa, M; Jobling, P; Callister, R J; Hughes, D I; Graham, B A

    2016-06-21

    The dorsal horn (DH) of the spinal cord contains a heterogenous population of neurons that process incoming sensory signals before information ascends to the brain. We have recently characterized calretinin-expressing (CR+) neurons in the DH and shown that they can be divided into excitatory and inhibitory subpopulations. The excitatory population receives high-frequency excitatory synaptic input and expresses delayed firing action potential discharge, whereas the inhibitory population receives weak excitatory drive and exhibits tonic or initial bursting discharge. Here, we characterize inhibitory synaptic input and neuromodulation in the two CR+ populations, in order to determine how each is regulated. We show that excitatory CR+ neurons receive mixed inhibition from GABAergic and glycinergic sources, whereas inhibitory CR+ neurons receive inhibition, which is dominated by glycine. Noradrenaline and serotonin produced robust outward currents in excitatory CR+ neurons, predicting an inhibitory action on these neurons, but neither neuromodulator produced a response in CR+ inhibitory neurons. In contrast, enkephalin (along with selective mu and delta opioid receptor agonists) produced outward currents in inhibitory CR+ neurons, consistent with an inhibitory action but did not affect the excitatory CR+ population. Our findings show that the pharmacology of inhibitory inputs and neuromodulator actions on CR+ cells, along with their excitatory inputs can define these two subpopulations further, and this could be exploited to modulate discrete aspects of sensory processing selectively in the DH.

  2. Sacral-neuromodulation CT-guided; Nuova tecnica di centraggio TC-assistista nella neuromodulazione sacrale

    Energy Technology Data Exchange (ETDEWEB)

    Amoroso, Lamberto; Ricci, Stefano [INRCA, Ancona (Italy). Dipartimento di radiologia e medicina nucleare; Pelliccioni, Giuseppe; Scarpino, Osvaldo [INRCA, Ancona (Italy). Unita' operativa di radiologia; Ghiselli, Roberto; Saba, Vittorio [INRCA, Ancona (Italy). Dipartimento di chirurgia

    2005-04-01

    Purpose: Sacral neuromodulation is a new treatment for refractory voiding disorders such as urge incontinence, urinary retention, frequency-urgency syndromes and faecal incontinence. The current approach to sacral nerve stimulation consists of a two-stage procedure. The first is a PNE test (Percutaneous Nerve Evaluation) by a provisional electrically stimulated spinal needle, placed percutaneously in the S3 foramina for four of ten days. If successful, the second stage, permanent implantation, is carried out. The PNE test is performed under fluoroscopic control using the palpable bony sacral foramina as referral points. This technique can show some limitations, such as operator Rx exposure, poor visualization of sacral foramina because of bowel gas artefacts or sacral malformation. In order to reduce these inconveniences and to improve efficiency of the test we tried an alternative technique. The purpose of our study was to test the use of CT as an alternative technique in order to evaluate its advantages and possible routine use. Materials and methods: We tested 30 patients with the PNE test under CT guidance (16 males and 14 females) suffering from serious pelvic disorders and not responding to the normal therapeutic regime. Twenty-seven patient showed relative anatomical integrity of the pelvis and the sacrum, the remaining 3 patients presented morphological anormalities of the sacral foramina. With the patient in the prone position the sacral foramina were identified with CT volumetric scanning using a spiral CT scanner equipped with a second console for the three-dimensional reconstructions. Having identified the location of the S3 foramina, a sterile field was prepared and the spiral needle introduced checking correct positioning with a CT control scan. An electrode was inserted after having checked correct muscular contractile response and the precise position with a further CT scan. Results: Thirty patients were subjected to PNE under CT guidance for a

  3. 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.

  4. 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.

  5. 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.

  6. Dysfunction of cortical dendritic integration in neuropathic pain reversed by serotoninergic neuromodulation.

    Science.gov (United States)

    Santello, Mirko; Nevian, Thomas

    2015-04-08

    Neuropathic pain is caused by long-term modifications of neuronal function in the peripheral nervous system, the spinal cord, and supraspinal areas. Although functional changes in the forebrain are thought to contribute to the development of persistent pain, their significance and precise subcellular nature remain unexplored. Using somatic and dendritic whole-cell patch-clamp recordings from neurons in the anterior cingulate cortex, we discovered that sciatic nerve injury caused an activity-dependent dysfunction of hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels in the dendrites of layer 5 pyramidal neurons resulting in enhanced integration of excitatory postsynaptic inputs and increased neuronal firing. Specific activation of the serotonin receptor type 7 (5-HT7R) alleviated the lesion-induced pathology by increasing HCN channel function, restoring normal dendritic integration, and reducing mechanical pain hypersensitivity in nerve-injured animals in vivo. Thus, serotoninergic neuromodulation at the forebrain level can reverse the dendritic dysfunction induced by neuropathic pain and may represent a potential therapeutical target.

  7. Soft implantable microelectrodes for future medicine: prosthetics, neural signal recording and neuromodulation.

    Science.gov (United States)

    Lee, Joong Hoon; Kim, Hanseop; Kim, Jeong Hun; Lee, Sang-Hoon

    2016-03-21

    Implantable devices have provided various potential diagnostic options and therapeutic methods in diverse medical fields. A variety of hard-material-based implantable electrodes have been developed. However, several limitations for their chronic implantation remain, including mechanical mismatches at the interface between the electrode and the soft tissue, and biocompatibility. Soft-material-based implantable devices are suitable candidates for complementing the limitations of hard electrodes. Advances in microtechnology and materials science have largely solved many challenges, such as optimization of shape, minimization of infection, enhancement of biocompatibility and integration with components for diverse functions. Significant strides have also been made in mechanical matching of electrodes to soft tissue. In this review, we provide an overview of recent advances in soft-material-based implantable electrodes for medical applications, categorized according to their implantation site and material composition. We then review specific applications in three categories: neuroprosthetics, neural signal recording, and neuromodulation. Finally, we describe various strategies for the future development and application of implantable, soft-material-based devices.

  8. Role of functional imaging in the development and refinement of invasive neuromodulation for psychiatric disorders

    Institute of Scientific and Technical Information of China (English)

    Nolan; R; Williams; Joseph; J; Taylor; Kayla; Lamb; Colleen; A; Hanlon; E; Baron; Short; Mark; S; George

    2014-01-01

    Deep brain stimulation(DBS) is emerging as a pow-erful tool for the alleviation of targeted symptoms in treatment-resistant neuropsychiatric disorders. Despite the expanding use of neuropsychiatric DBS, the mecha-nisms responsible for its effects are only starting to be elucidated. Several modalities such as quantitative elec-troencephalography as well a intraoperative recordings have been utilized to attempt to understand the under-pinnings of this new treatment modality, but functional imaging appears to offer several unique advantages. Functional imaging techniques like positron emission tomography, single photon emission computed tomog-raphy and functional magnetic resonance imaging have been used to examine the effects of focal DBS on activ-ity in a distributed neural network. These investigations are critical for advancing the field of invasive neuro-modulation in a safe and effective manner, particularly in terms of defining the neuroanatomical targets and refining the stimulation protocols. The purpose of this review is to summarize the current functional neuroim-aging findings from neuropsychiatric DBS implantation for three disorders: treatment-resistant depression, obsessive-compulsive disorder, and Tourette syndrome. All of the major targets will be discussed(Nucleus ac-cumbens, anterior limb of internal capsule, subcallosal cingulate, Subthalamic nucleus, Centromedial nucleus of the thalamus-Parafasicular complex, frontal pole, and dorsolateral prefrontal cortex). We will also address some apparent inconsistencies within this literature, and suggest potential future directions for this promis-ing area.

  9. Neuromodulation of thought: flexibilities and vulnerabilities in prefrontal cortical network synapses.

    Science.gov (United States)

    Arnsten, Amy F T; Wang, Min J; Paspalas, Constantinos D

    2012-10-04

    This review describes unique neuromodulatory influences on working memory prefrontal cortical (PFC) circuits that coordinate cognitive strength with arousal state. Working memory arises from recurrent excitation within layer III PFC pyramidal cell NMDA circuits, which are afflicted in aging and schizophrenia. Neuromodulators rapidly and flexibly alter the efficacy of these synaptic connections, while leaving the synaptic architecture unchanged, a process called dynamic network connectivity (DNC). Increases in calcium-cAMP signaling open ion channels in long, thin spines, gating network connections. Inhibition of calcium-cAMP signaling by stimulating α2A-adrenoceptors on spines strengthens synaptic efficacy and increases network firing, whereas optimal stimulation of dopamine D1 receptors sculpts network inputs to refine mental representation. Generalized increases in calcium-cAMP signaling during fatigue or stress disengage dlPFC recurrent circuits, reduce firing and impair top-down cognition. Impaired DNC regulation contributes to age-related cognitive decline, while genetic insults to DNC proteins are commonly linked to schizophrenia.

  10. The Neuromodulator of Exploration: A Unifying Theory of the Role of Dopamine in Personality

    Directory of Open Access Journals (Sweden)

    Colin G DeYoung

    2013-11-01

    Full Text Available The neuromodulator dopamine is centrally involved in reward, approach behavior, exploration, and various aspects of cognition. Variations in dopaminergic function are assumed to be associated with variations in personality, but exactly which traits are influenced by dopamine remains an open question. This paper proposes a theory of the role of dopamine in personality that organizes and explains the diversity of findings, utilizing the division of the dopaminergic system into value coding and salience coding neurons (Bromberg-Martin, Matsumoto, and Hikosaka, 2010. The value coding system is proposed to be related primarily to Extraversion and the salience coding system to Openness/Intellect. Global levels of dopamine influence the higher order personality factor, Plasticity, which comprises the shared variance of Extraversion and Openness/Intellect. All other traits related to dopamine are linked to Plasticity or its subtraits. The general function of dopamine is to promote exploration, by facilitating engagement with cues of specific reward (value and cues of the reward value of information (salience. This theory constitutes an extension of the entropy model of uncertainty (EMU; Hirsh, Mar, & Peterson, 2012, enabling EMU to account for the fact that uncertainty is an innate incentive reward as well as an innate threat. The theory accounts for the association of dopamine with traits ranging from sensation and novelty seeking, to impulsivity and aggression, to achievement striving, creativity, and cognitive abilities, to the overinclusive thinking characteristic of schizotypy.

  11. Male/female differences in neuroprotection and neuromodulation of brain dopamine.

    Directory of Open Access Journals (Sweden)

    Mélanie eBourque

    2011-09-01

    Full Text Available The existence of a sex difference in Parkinson’s disease is observed in several variables, including susceptibility of the disease, age at onset and symptoms. These differences between men and women represent a significant characteristic of Parkinson’s disease which suggests that estrogens may exert beneficial effects against the development and the progression of the disease. This paper reviews the neuroprotective and neuromodulator effect of 17β-estradiol and progesterone as compared to androgens in the nigrostriatal dopaminergic system of both female and male rodents. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP mice model of Parkinson’s disease and methamphetamine toxicity faithfully reproduce the sex differences of Parkinson’s disease in that endogenous estrogen levels appear to influence the vulnerability to toxins targeting the nigrostriatal dopaminergic system. Exogenous 17β-estradiol and/or progesterone treatments show neuroprotective properties against nigrostriatal dopaminergic toxins while androgens fail to induce beneficial effect. Sex steroids treatments show males and females difference in their neuroprotective action against methamphetamine toxicity. Nigrostriatal dopaminergic structure and function, as well as the distribution of estrogen receptors, show sex difference and may influence the susceptibility to the toxins and the response to sex steroids. Genomic and non-genomic actions of 17β-estradiol converge to promote survival factors and the presence of both estrogen receptors α and β are critical to 17β-estradiol neuroprotective action against MPTP toxicity.

  12. 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

  13. 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

  14. Does a Combination of Virtual Reality, Neuromodulation and Neuroimaging Provide a Comprehensive Platform for Neurorehabilitation? – A Narrative Review of the Literature

    Science.gov (United States)

    Teo, Wei-Peng; Muthalib, Makii; Yamin, Sami; Hendy, Ashlee M.; Bramstedt, Kelly; Kotsopoulos, Eleftheria; Perrey, Stephane; Ayaz, Hasan

    2016-01-01

    In the last decade, virtual reality (VR) training has been used extensively in video games and military training to provide a sense of realism and environmental interaction to its users. More recently, VR training has been explored as a possible adjunct therapy for people with motor and mental health dysfunctions. The concept underlying VR therapy as a treatment for motor and cognitive dysfunction is to improve neuroplasticity of the brain by engaging users in multisensory training. In this review, we discuss the theoretical framework underlying the use of VR as a therapeutic intervention for neurorehabilitation and provide evidence for its use in treating motor and mental disorders such as cerebral palsy, Parkinson’s disease, stroke, schizophrenia, anxiety disorders, and other related clinical areas. While this review provides some insights into the efficacy of VR in clinical rehabilitation and its complimentary use with neuroimaging (e.g., fNIRS and EEG) and neuromodulation (e.g., tDCS and rTMS), more research is needed to understand how different clinical conditions are affected by VR therapies (e.g., stimulus presentation, interactivity, control and types of VR). Future studies should consider large, longitudinal randomized controlled trials to determine the true potential of VR therapies in various clinical populations. PMID:27445739

  15. Does a Combination of Virtual Reality, Neuromodulation and Neuroimaging Provide a Comprehensive Platform for Neurorehabilitation? - A Narrative Review of the Literature.

    Science.gov (United States)

    Teo, Wei-Peng; Muthalib, Makii; Yamin, Sami; Hendy, Ashlee M; Bramstedt, Kelly; Kotsopoulos, Eleftheria; Perrey, Stephane; Ayaz, Hasan

    2016-01-01

    In the last decade, virtual reality (VR) training has been used extensively in video games and military training to provide a sense of realism and environmental interaction to its users. More recently, VR training has been explored as a possible adjunct therapy for people with motor and mental health dysfunctions. The concept underlying VR therapy as a treatment for motor and cognitive dysfunction is to improve neuroplasticity of the brain by engaging users in multisensory training. In this review, we discuss the theoretical framework underlying the use of VR as a therapeutic intervention for neurorehabilitation and provide evidence for its use in treating motor and mental disorders such as cerebral palsy, Parkinson's disease, stroke, schizophrenia, anxiety disorders, and other related clinical areas. While this review provides some insights into the efficacy of VR in clinical rehabilitation and its complimentary use with neuroimaging (e.g., fNIRS and EEG) and neuromodulation (e.g., tDCS and rTMS), more research is needed to understand how different clinical conditions are affected by VR therapies (e.g., stimulus presentation, interactivity, control and types of VR). Future studies should consider large, longitudinal randomized controlled trials to determine the true potential of VR therapies in various clinical populations.

  16. 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.

  17. 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.

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

    Directory of Open Access Journals (Sweden)

    Masaru eIshibashi

    2015-06-01

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

  19. 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

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

    Science.gov (United States)

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

    2015-02-01

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

  1. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  3. 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.

  4. rTMS neuromodulation improves electrocortical functional measures of information processing and behavioral responses in autism

    Directory of Open Access Journals (Sweden)

    Estate M Sokhadze

    2014-08-01

    Full Text Available Objectives: Reports in autism spectrum disorders (ASD of a minicolumnopathy with consequent deficits of lateral inhibition help explain observed behavioral and executive dysfunctions. We propose that neuromodulation based on rTMS will enhance lateral inhibition through activation of inhibitory double bouquet interneurons and will be accompanied by improvements in the prefrontal executive functions. Methods: The current study used ERPs in a visual oddball task with illusory figures. We compared clinical, behavioral and electrocortical outcomes in 2 groups of children with autism (TMS, wait-list group [WTL]. We predicted that 18 session long course in autistic patients will have better behavioral and ERP outcomes as compared to age- and IQ-matched wait-list group. We used 18 sessions of 1Hz rTMS applied over the dorso-lateral prefrontal cortex in 27 individuals with ASD diagnosis. The WTL group was comprised of 27 age-matched ASD subjects. Results: Post-TMS evaluations showed decreased irritability and hyperactivity and decreased stereotypic behaviors. Following rTMS we found decreased amplitude and prolonged latency in the fronto-central ERPs to non-targets in the TMS group. These ERP changes along with increased centro-parietal ERPs to targets are indicative of more efficient processing of information post-TMS. Another finding was increased magnitude of error-related negativity (ERN during commission errors. We calculated normative post-error reaction time (RT slowing response in both groups and found that rTMS was accompanied by post-error RT slowing and higher accuracy of responses, whereas the WTL group kept on showing typical for ASD post-error RT speeding and had higher error rate. Conclusion: Results from our study indicate that rTMS improves executive functioning in ASD as evidenced by normalization of ERP responses and behavioral reactions during executive function test, and also by improvements in clinical behavioral evaluations.

  5. Detecting a cortical fingerprint of Parkinson’s disease for closed-loop neuromodulation

    Directory of Open Access Journals (Sweden)

    Kevin eKern

    2016-03-01

    Full Text Available Recent evidence suggests that deep brain stimulation (DBS of the subthalamic nucleus (STN in Parkinson’s disease (PD mediates its clinical effects by modulating cortical oscillatory activity, presumably via a direct cortico-subthalamic connection. This observation might pave the way for novel closed-loop approaches comprising a cortical sensor. Enhanced beta oscillations (13-35 Hz have been linked to the pathophysiology of PD and may serve as such a candidate marker to localize a cortical area reliably modulated by DBS. However, beta-oscillations are widely distributed over the cortical surface, necessitating an additional signal source for spotting the cortical area linked to the pathologically synchronized cortico-subcortical motor network.In this context, both cortico-subthalamic coherence and cortico-muscular coherence (CMC have been studied in PD patients. Whereas the former requires invasive recordings, the latter allows for non-invasive detection, but displays a rather distributed cortical synchronization pattern in motor tasks. This distributed cortical representation may conflict with the goal of detecting a cortical localization with robust biomarker properties which is detectable on a single subject basis. We propose that this limitation could be overcome when recording CMC at rest. We hypothesized that – unlike healthy subjects – PD would show CMC at rest owing to the enhanced beta oscillations observed in PD. By performing source space analysis of beta CMC recorded during resting-state magnetoencephalography, we provide preliminary evidence in one patient for a cortical hot spot that is modulated most strongly by subthalamic DBS. Such a spot would provide a prominent target region either for direct neuromodulation or for placing a potential sensor in closed-loop DBS approaches, a proposal that requires investigation in a larger cohort of PD patients.

  6. Neuromodulation for treatment resistant depression: state of the art and recommendations for clinical and scientific conduct.

    Science.gov (United States)

    Schlaepfer, Thomas E; Bewernick, Bettina H

    2014-01-01

    Research of Deep Brain Stimulation as a putative treatment for resistant psychiatric disorders might very well lead to the most significant development in clinical psychiatry of the last 40 years-possibly offering a rise of hope for patients to whom medicine had hitherto little to offer. Furthermore, translational research on neuromodulation will allow us to glean something about the underlying cause of patient's illnesses before figuring out a treatment that addresses the source of the problem. Major depression offers perhaps the best example of the rapid progress being made in understanding the biology of mental illness. Studies on the underlying neurobiology of major depression have typically focused on the description of biological differences between patients and healthy subjects such as alterations of monoaminergic or endocrine systems. Psychotropic drugs work by altering neurochemistry to a large extent in widespread regions of the brain, many of which may be unrelated to depression. We believe that more focused, targeted treatment approaches that modulate specific networks in the brain will prove a more effective approach to help treatment-resistant patients. In other words, whereas existing depression treatments approach this disease as a general brain dysfunction, a more complete and appropriate treatment will arise from thinking of depression as a dysfunction of specific brain networks that mediate mood and reward signals (Berton and Nestler, Nat Rev Neurosci 7 (2):137-151, 2006; Krishnan and Nestler, Nature 455(7215):894-902, 2008). A better understanding of defined dysfunctions in these networks will invariably lead to a better understanding of patients afflicted with depression and perhaps contribute to a de-stigmatization of psychiatric patients and the medical specialty treating them.

  7. Re: Effect of Sacral Neuromodulation on Female Sexual Function and Quality of Life: Are They Correlated?

    Directory of Open Access Journals (Sweden)

    Mai Banakhar

    2015-06-01

    Full Text Available Sacral neuromodulation (SNM has become an established therapy for voiding dysfunction (VD. There have been published papers that documented improvement in bowel functions and bladder pain via SNM. However, improvement in female sexual function (FSF after SNM treatment remains unclear. Recently, Banakhar et al. evaluated the effects of SNM on FSF and its impact on quality of life (QoL and analyzed any correlation. They evaluated 33 female patients who were treated with SNM for VD. All patients completed the Female Sexual Function Index (FSFI, the 36-Item Short-Form Health Survey (SF-36, and incontinence questionnaires (the Urinary Distress Inventory [UDI-6] preoperatively and 4 months postoperatively. Ten patients were excluded from the study because they were not sexually active. The indications were: refractory overactive bladder in 19, frequency urgency syndrome in 2, and non-obstructive urinary retention in another 2 patients. SNM therapy significantly improved the total FSFI score (p=0.011. When the SF-36 and UDI-6 scores were compared, QoL showed significant improvement after SNM treatment. However, improvement in FSFI scores was not correlated with improvement in QoL. SNM therapy is an effective treatment modality in selected patient groups. In our country, SNM therapy has become a new option in the treatment of lower urinary tract problems. According to the results of this study, it is too early to conclude that SNM certainly improve FSF and QoL. The study just evaluated 23 cases. In order to have a more discrete conclusion, we need prospective trials with larger series

  8. Reconsidering the role of neuronal intrinsic properties and neuromodulation in vestibular homeostasis

    Directory of Open Access Journals (Sweden)

    Mathieu eBeraneck

    2012-02-01

    Full Text Available The sensorimotor transformations performed by central vestibular neurons (2°VN constantly adapt as the animal faces conflicting sensory information or sustains injuries. In order to ensure the homeostasis of vestibular-related functions, neural changes could in part rely on the regulation of 2°VN intrinsic properties. Here, we review evidence which demonstrates modulation and plasticity of 2°VN intrinsic properties. We first present partition of rodents 2°VN into distinct subtypes, namely type A and type B. Then, we focus on the respective properties of each type and their putative roles in vestibular functions. The intrinsic properties of 2°VN can be swiftly modulated by a wealth of neuromodulators, to adapt rapidly, for example, to temporary changes of the ecophysiological surroundings. To illustrate how intrinsic excitability can rapidly be modified in physiological conditions and therefore be targeted in the clinic, we present the modulation of vestibular reflexes in relation to the neuromodulatory fluctuation of the sleep/wake cycle. On the other hand, intrinsic properties can also be slowly yet deeply modified in response to major perturbations as is the case following a unilateral labyrinthectomy (UL. We revisit the experimental evidence which demonstrate that drastic alterations of the 2°VN intrinsic properties occur following UL, however with a slow dynamic, more on par with the compensation of dynamic deficits than static ones. Data are interpreted in the framework of a distributed process which progress from the global, large scale coping mechanisms (e.g. changes in behavioural strategies to the local, small scale ones (e.g. changes in intrinsic properties. Within this framework, the compensation of dynamic deficits improves with time as deeper modifications are engraved within the finer parts of the vestibular-related networks. Finally, we propose perspectives and working hypotheses to pave the way for future research aiming at

  9. Can Neuromodulation also Enhance Social Inequality? Some Possible Indirect Interventions of the State

    Science.gov (United States)

    Lavazza, Andrea

    2017-01-01

    There is evidence that noninvasive brain stimulation (NIBS), and especially transcranial direct current stimulation (tDCS), can improve some cognitive functions, at least temporarily. However, as the improvement only applies to some “lucky” people, it may raise ethical, social and legal issues related to fairness in selective contexts (exams, competitions, job interviews). In this regard, an important element tends to be overlooked: the variability in individual response to tDCS in particular. If intensive study or practice and massive doses of chemical enhancers can have slightly different effects over different people, tDCS can sometimes be completely ineffective. The variability in individual response, if tDCS were widely used, could add to the already present natural inequalities between people, or even create new ones, leaving some in a disadvantaged condition. The discussion of the various ethical, social and legal consequences of different individual responses to tDCS might also address a potential indirect intervention by the State. In fact, if NIBS were to be widespread in competitive contexts, those who do not benefit from tDCS would be disadvantaged compared to those able to enhance their skills thanks to neuromodulation technologies. The most disadvantaged people for their lower response to tDCS could then acquire the right to receive and use free and safe cognitive enhancing drugs or other forms of bettering cognitive skills and functions, so as to reduce the gap between them and those who respond well to tDCS, in the light of the principle of equal opportunity. PMID:28326031

  10. A novel treatment modality in patients with premature ejaculation resistant to conventional methods: the neuromodulation of dorsal penile nerves by pulsed radiofrequency.

    Science.gov (United States)

    Basal, Seref; Goktas, Serdar; Ergin, Atilla; Yildirim, Ibrahim; Atim, Abdulkadir; Tahmaz, Lutfi; Dayanc, Murat

    2010-01-01

    Premature ejaculation (PE) is the most common sexual problem experienced by men, and it affects 20%-30% of them. Pulsed radiofrequency (PRF) neuromodulation has been shown to be an effective treatment for a wide range of pain conditions. We used PRF to treat PE by desensitizing dorsal penile nerves in patients resistant to conventional treatments. Fifteen patients with a lifelong history of PE, defined as an intravaginal ejaculatory latency time (IELT) of IELT and sexual satisfaction score (SSS; for patients and their partners) were obtained. The mean IELTs before and 3 weeks after procedure were 18.5 +/- 17.9 and 139.9 +/- 55.1 seconds, respectively. Side effects did not occur. Mean SSSs of patients before and after treatment were 1.3 +/- 0.3 and 4.6 +/- 0.5, and mean SSSs of partners before and after treatment were 1.3 +/- 0.4 and 4.4 +/- 0.5, respectively. In all cases, IELT and SSS were significantly increased (P < .05). None of the patients or their wives reported any treatment failure during the follow-up period. The mean follow-up time was 8.3 +/- 1.9 months. It is early to conclude that this new treatment modality might be used widely for the treatment of PE; however, because it is an innovative modality, placebo-controlled studies (eg, sham procedure), with larger numbers of patients and including assessment of penile sensitivity (eg, biothesiometry), are needed.

  11. Research on Autoantibodies Against Myocardial β1-adrenergic and M2 Cholinergic Receptors in Patients With Chronic Keshan Disease

    Institute of Scientific and Technical Information of China (English)

    Han Zhenhua; Niu Xiaolin; Ren Fuxian

    2006-01-01

    Objectives To explore the relationship between serum autoantibodies against myocardial β1-adrenergic, M2-cholinergic receptors and chronic Keshan disease (CKD). Methods The second extracellular loops of β1 and M2 receptors on human cardiomyocytes were used as the antigens.Enzyme linked immunosorbent assay (ELISA) was applied to determine serum autoantibodies against myocardial β1 and M2 receptors in 32 CKD patients. 31 healthy subjects from endemic area were selected as the control. Results Positive rate of autoantibodies against myocardial β1 adrenergic (51.3%, 17/32) and M2cholinergic (56.3% , 18/32) receptors weresignificantly higher than those in the control (9.7%, 3/31; 12.9%, 4/31) (both P < 0.01). Both positive rate and titers of above autoantibodies in NYHA Ⅱ~Ⅲ CKD patients were significantly higher than those in NYHA Ⅳ , demonstrating an apparently positive correlation between serum antibodies against myocardial β1 and M2 receptors (r=0.95). Conclusions Autoantibodies against myocardial β1 and M2 receptors were found in sera of CKD patients; distribution of positive rate and titers of the autoantibodies in CKD patients in various NYHA classes of cardiac function are significantly different.

  12. The Regulatory Action of Radix Astragali on M-Cholinergic Receptor of the Brain of Senile Rats

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    @@The changes in density of M-cholinergic receptors in different areas of senile rats and the regulatory action of Huang Qi (黄芪Radix Astragali, a drug for warming yang and replenishing qi) were observed by autoradiography. The results showed that the gray scale displayed in brain sections was clear and mainly distributed in the cortex, hippocampus and striate body, while that due to nonspecific combination was negligible. The gray scale in the cortex, hippocampus and striate body of the experimental group was markedly lower than that in the young control rats, decreased respectively by 24.87%, 14.12% and 12.76% (all P<0.05); but it was obviously higher than those in the senile control rats, increased respectively by 24.15%, 14.38% and 13.47% (P<0.05). The data indicate that Huang Qi (黄芪Radix Astragali) may up-regulate the decreased density of M-cholinergic receptors in the brain of senile rats.

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

    Science.gov (United States)

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

    2015-01-14

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

  14. 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.

  15. 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

  16. Acetylcholine released from cholinergic nerves contributes to cutaneous vasodilation during heat stress

    Science.gov (United States)

    Shibasaki, Manabu; Wilson, Thad E.; Cui, Jian; Crandall, Craig G.

    2002-01-01

    Nitric oxide (NO) contributes to active cutaneous vasodilation during a heat stress in humans. Given that acetylcholine is released from cholinergic nerves during whole body heating, coupled with evidence that acetylcholine causes vasodilation via NO mechanisms, it is possible that release of acetylcholine in the dermal space contributes to cutaneous vasodilation during a heat stress. To test this hypothesis, in seven subjects skin blood flow (SkBF) and sweat rate were simultaneously monitored over three microdialysis membranes placed in the dermal space of dorsal forearm skin. One membrane was perfused with the acetylcholinesterase inhibitor neostigmine (10 microM), the second membrane was perfused with the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME; 10 mM) dissolved in the aforementioned neostigmine solution (l-NAME(Neo)), and the third membrane was perfused with Ringer solution as a control site. Each subject was exposed to approximately 20 min of whole body heating via a water-perfused suit, which increased mean body temperature from 36.4 +/- 0.1 to 37.5 +/- 0.1 degrees C (P heat stress, SkBF at each site was normalized to its maximum value, identified by administration of 28 mM sodium nitroprusside. Mean body temperature threshold for cutaneous vasodilation was significantly lower at the neostigmine-treated site relative to the other sites (neostigmine: 36.6 +/- 0.1 degrees C, l-NAME(Neo): 37.1 +/- 0.1 degrees C, control: 36.9 +/- 0.1 degrees C), whereas no significant threshold difference was observed between the l-NAME(Neo)-treated and control sites. At the end of the heat stress, SkBF was not different between the neostigmine-treated and control sites, whereas SkBF at the l-NAME(Neo)-treated site was significantly lower than the other sites. These results suggest that acetylcholine released from cholinergic nerves is capable of modulating cutaneous vasodilation via NO synthase mechanisms early in the heat stress but not after

  17. 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.

  18. Vagus nerve stimulation: state of the art of stimulation and recording strategies to address autonomic function neuromodulation

    Science.gov (United States)

    Guiraud, David; Andreu, David; Bonnet, Stéphane; Carrault, Guy; Couderc, Pascal; Hagège, Albert; Henry, Christine; Hernandez, Alfredo; Karam, Nicole; Le Rolle, Virginie; Mabo, Philippe; Maciejasz, Paweł; Malbert, Charles-Henri; Marijon, Eloi; Maubert, Sandrine; Picq, Chloé; Rossel, Olivier; Bonnet, Jean-Luc

    2016-08-01

    Objective. Neural signals along the vagus nerve (VN) drive many somatic and autonomic functions. The clinical interest of VN stimulation (VNS) is thus potentially huge and has already been demonstrated in epilepsy. However, side effects are often elicited, in addition to the targeted neuromodulation. Approach. This review examines the state of the art of VNS applied to two emerging modulations of autonomic function: heart failure and obesity, especially morbid obesity. Main results. We report that VNS may benefit from improved stimulation delivery using very advanced technologies. However, most of the results from fundamental animal studies still need to be demonstrated in humans.

  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. 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.

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

    Science.gov (United States)

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

    2015-01-13

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

  2. Cholinergic Interneurons Amplify Corticostriatal Synaptic Responses in the Q175 Model of Huntington’s Disease

    Directory of Open Access Journals (Sweden)

    Asami Tanimura

    2016-12-01

    Full Text Available Huntington’s disease (HD is a neurodegenerative disorder characterized by deficits in movement control that are widely viewed as stemming from pathophysiological changes in the striatum. Giant, aspiny cholinergic interneurons (ChIs are key elements in the striatal circuitry controlling movement, but whether their physiological properties are intact in the HD brain is unclear. To address this issue, the synaptic properties of ChIs were examined using optogenetic approaches in the Q175 mouse model of HD. In ex vivo brain slices, synaptic facilitation at thalamostriatal synapses onto ChIs was reduced in Q175 mice. The alteration in thalamostriatal transmission was paralleled by an increased response to optogenetic stimulation of cortical axons, enabling these inputs to more readily induce burst-pause patterns of activity in ChIs. This adaptation was dependent upon amplification of cortically evoked responses by a post-synaptic upregulation of voltage-dependent Na+ channels. This upregulation also led to an increased ability of somatic spikes to invade ChI dendrites. However, there was not an alteration in the basal pacemaking rate of ChIs, possibly due to increased availability of Kv4 channels. Thus, there is a functional ‘re-wiring’ of the striatal networks in Q175 mice, which results in greater cortical control of phasic ChI activity, which is widely thought to shape the impact of salient stimuli on striatal action selection.

  3. 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....

  4. 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.

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

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    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.

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

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    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.

  7. 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.

  8. 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.

  9. EEG sleep in depression and in remission and the REM sleep response to the cholinergic agonist RS 86.

    Science.gov (United States)

    Riemann, D; Berger, M

    1989-06-01

    A comparison of the sleep EEG patterns of patients with a major depressive disorder intraindividually between remitted and depressed state revealed an improvement of parameters of sleep continuity and a tendency for normalization of rapid eye movement (REM) latency and REM density in the former. Additional application of the cholinergic agonist RS 86 prior to sleep did not reveal a heightened sensitivity of the REM sleep system in the remitted sample. Whereas a group of presently ill depressives displayed a drastic reduction of REM latency, results of the remitted patients were comparable to healthy controls. Furthermore, RS 86 significantly reduced slow-wave sleep in all groups investigated and had a differential impact on the density of the first REM period and early morning awakening in actively ill patients as compared to remitted patients. The results do not favor the hypothesis of a trait specificity of REM sleep abnormalities for depressive disorders. Furthermore they support the model of a cholinergic supersensitivity, as measured by REM induction after RS 86, as a state but not a trait marker of affective illness. Generalization of the present study may, however, be limited by the fact that the remitted patients were free of symptomatology and psychoactive medication for a long period (mean 3 years), therefore constituting an untypical group of formerly depressed patients with a seemingly low risk of relapse.

  10. 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...

  11. 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...

  12. Dose-dependent effect of donepezil administration on long-term enhancement of visually evoked potentials and cholinergic receptor overexpression in rat visual cortex.

    Science.gov (United States)

    Chamoun, Mira; Groleau, Marianne; Bhat, Menakshi; Vaucher, Elvire

    2016-09-01

    Stimulation of the cholinergic system tightly coupled with periods of visual stimulation boosts the processing of specific visual stimuli via muscarinic and nicotinic receptors in terms of intensity, priority and long-term effect. However, it is not known whether more diffuse pharmacological stimulation with donepezil, a cholinesterase inhibitor, is an efficient tool for enhancing visual processing and perception. The goal of the present study was to potentiate cholinergic transmission with donepezil treatment (0.5 and 1mg/kg) during a 2-week visual training to examine the effect on visually evoked potentials and to profile the expression of cholinergic receptor subtypes. The visual training was performed daily, 10min a day, for 2weeks. One week after the last training session, visual evoked potentials were recorded, or the mRNA expression level of muscarinic (M1-5) and nicotinic (α/β) receptors subunits was determined by quantitative RT-PCR. The visual stimulation coupled with any of the two doses of donepezil produced significant amplitude enhancement of cortical evoked potentials compared to pre-training values. The enhancement induced by the 1mg/kg dose of donepezil was spread to neighboring spatial frequencies, suggesting a better sensitivity near the visual detection threshold. The M3, M4, M5 and α7 receptors mRNA were upregulated in the visual cortex for the higher dose of donepezil but not the lower one, and the receptors expression was stable in the somatosensory (non-visual control) cortex. Therefore, higher levels of acetylcholine within the cortex sustain the increased intensity of the cortical response and trigger the upregulation of cholinergic receptors.

  13. Developing a Deep Brain Stimulation Neuromodulation Network for Parkinson Disease, Essential Tremor, and Dystonia: Report of a Quality Improvement Project

    Science.gov (United States)

    O’Suilleabhain, Padraig E.; Sanghera, Manjit; Patel, Neepa; Khemani, Pravin; Lacritz, Laura H.; Chitnis, Shilpa; Whitworth, Louis A.; Dewey, Richard B.

    2016-01-01

    Objective To develop a process to improve patient outcomes from deep brain stimulation (DBS) surgery for Parkinson disease (PD), essential tremor (ET), and dystonia. Methods We employed standard quality improvement methodology using the Plan-Do-Study-Act process to improve patient selection, surgical DBS lead implantation, postoperative programming, and ongoing assessment of patient outcomes. Results The result of this quality improvement process was the development of a neuromodulation network. The key aspect of this program is rigorous patient assessment of both motor and non-motor outcomes tracked longitudinally using a REDCap database. We describe how this information is used to identify problems and to initiate Plan-Do-Study-Act cycles to address them. Preliminary outcomes data is presented for the cohort of PD and ET patients who have received surgery since the creation of the neuromodulation network. Conclusions Careful outcomes tracking is essential to ensure quality in a complex therapeutic endeavor like DBS surgery for movement disorders. The REDCap database system is well suited to store outcomes data for the purpose of ongoing quality assurance monitoring. PMID:27711133

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

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    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

  15. Replicated Risk Nicotinic Cholinergic Receptor Genes for Nicotine Dependence

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    Lingjun Zuo

    2016-11-01

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

  16. Photocolorimetric Biosensor for Detection of Cholinergic Organophosphorus Compounds

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    Kamila Vymazalová

    2012-11-01

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

  17. 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.

  18. Replicated Risk Nicotinic Cholinergic Receptor Genes for Nicotine Dependence

    Science.gov (United States)

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

    2016-01-01

    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

  19. 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.

  20. Development of a CT-guided standard approach for tined lead implantation at the sacral nerve root S3 in minipigs for chronic neuromodulation

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    Foditsch EE

    2016-09-01

    Full Text Available Elena Esra Foditsch,1 Reinhold Zimmermann2 1Urology, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, 2University Clinic of Urology and Andrology, Salzburg General Hospital, Paracelsus Medical University, Salzburg, Austria Purpose: The aim of this study was to develop a controlled approach for sacral neuromodulation (SNM to improve both nerve targeting and tined lead placement, for which a new computed tomography (CT-guided implantation technique was analyzed in minipigs.Materials and methods: This study included five female, adult Göttingen minipigs. In deep sedoanalgesia, the minipigs were placed in an extended prone position. Commercially available SNM materials were used (needle, introduction sheath, and quadripolar tined lead electrode. Gross anatomy was displayed by CT, and the nerves were bilaterally identified. The optimal angles to puncture the S3 foramen, the resulting access path, and the site for the skin incision were defined subsequently. The needle puncture and the tined lead placement were followed by successive CT scans/3D-reconstruction images. Once proper CT-guided placement of the needle and electrode was established, response to functional stimuli was intraoperatively checked to verify correct positioning.Results: Successful bilateral tined lead implantation was performed in four out of five minipigs. Implantation was different from the clinical situation because the puncture was done from the contralateral side at a 30° angle to the midline and 60° horizontal angle to ensure both passage through the foramen and nerve access. Surgery time was 50–150 minutes. Stimulation response comprised a twitch of the perianal musculature and tail rotation to the contralateral side.Conclusion: We have established a new, minimally invasive, highly standardized, CT-guided SNM electrode implantation technique. Functional outcomes are clearly defined and reproducible. All procedures can be

  1. 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.

  2. 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

  3. rTMS neuromodulation improves electrocortical functional measures of information processing and behavioral responses in autism

    Science.gov (United States)

    Sokhadze, Estate M.; El-Baz, Ayman S.; Sears, Lonnie L.; Opris, Ioan; Casanova, Manuel F.

    2014-01-01

    Objectives: Reports in autism spectrum disorders (ASD) of a minicolumnopathy with consequent deficits of lateral inhibition help explain observed behavioral and executive dysfunctions. We propose that neuromodulation based on low frequency repetitive Transcranial Magnetic Stimulation (rTMS) will enhance lateral inhibition through activation of inhibitory double bouquet interneurons and will be accompanied by improvements in the prefrontal executive functions. In addition we proposed that rTMS will improve cortical excitation/inhibition ratio and result in changes manifested in event-related potential (ERP) recorded during cognitive tests. Materials and Methods: Along with traditional clinical behavioral evaluations the current study used ERPs in a visual oddball task with illusory figures. We compared clinical, behavioral and electrocortical outcomes in two groups of children with autism (TMS, wait-list group). We predicted that 18 session long course in autistic patients will have better behavioral and ERP outcomes as compared to age- and IQ-matched WTL group. We used 18 sessions of 1 Hz rTMS applied over the dorso-lateral prefrontal cortex in 27 individuals with ASD diagnosis. The WTL group was comprised of 27 age-matched subjects with ASD tested twice. Both TMS and WTL groups were assessed at the baseline and after completion of 18 weekly sessions of rTMS (or wait period) using clinical behavioral questionnaires and during performance on visual oddball task with Kanizsa illusory figures. Results: Post-TMS evaluations showed decreased irritability and hyperactivity on the Aberrant Behavior Checklist (ABC), and decreased stereotypic behaviors on the Repetitive Behavior Scale (RBS-R). Following rTMS course we found decreased amplitude and prolonged latency in the frontal and fronto-central N100, N200 and P300 (P3a) ERPs to non-targets in active TMS treatment group. TMS resulted in increase of P2d (P2a to targets minus P2a to non-targets) amplitude. These ERP

  4. 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.

  5. Fade of the responses of the isolated, blood-perfused dog atrium to cholinergic interventions.

    Science.gov (United States)

    Furukawa, Y; Martin, P; Levy, M N

    1984-05-01

    In the isolated, blood-perfused, canine right atrium, intramural parasympathetic nerve stimulation and intra-arterial infusions of acetylcholine induced substantial negative chronotropic and inotropic responses. The responses to parasympathetic stimulation reached their maximum values quickly, and then usually faded back toward control levels over the next 1 or 2 min of stimulation. The fade of the responses at high stimulation frequencies (greater than or equal to 30 Hz) was significantly greater than that at lower frequencies. The inotropic responses to acetylcholine infusion (1 microgram/min) faded slightly but significantly, whereas the chronotropic responses did not fade at all. These results suggest that the fade of the cardiac responses to parasympathetic stimulation is mainly ascribable to a progressive reduction in the rate of acetylcholine release from the nerve endings, especially at higher stimulation frequencies. The fade of the inotropic responses was more pronounced and had a longer time course than that of the chronotropic responses. Furthermore, the fade of the inotropic responses diminished significantly as the response magnitude was augmented by an increase in stimulation voltage. Conversely, the fade of chronotropic responses was not significantly affected by this intervention. These differences in the inotropic and chronotropic responses to neural stimulation, and the occurrence of a slight fade of the inotropic response to acetylcholine infusion, suggest that in addition to the predominant prejunctional mechanism, a postjunctional phenomenon may also be partly responsible for the fade of the inotropic response to cholinergic interventions.

  6. Amphetamine sensitization and amygdala kindling: pharmacological evaluation of catecholaminergic and cholinergic mechanisms.

    Science.gov (United States)

    Kirkby, R D; Kokkinidis, L

    1991-03-01

    Chronic pharmacological experiments were conducted to evaluate the relationship between sensitization induced by repeated administration of amphetamine (AMPH) and electrical stimulation of the amygdala. While AMPH withdrawal did not influence the kindling process, AMPH administered during the kindling procedure increased the rate at which seizures evolved, and under these conditions withdrawal from chronic AMPH further facilitated the propensity to kindle. Haloperidol (HAL) treatment failed to block the stimulant-induced increase in kindling acquisition indicating that changes in dopamine (DA) are not necessary for the AMPH/kindling synergism to develop. Scopolamine dose-dependently retarded kindling evolution irrespective of prior AMPH pretreatment also ruling out a cholinergic mechanism in the kindling sensitization. Subsequent experiments assessed the interactive effects of AMPH and desipramine (DMI) on the kindling process. Animals chronically exposed to AMPH and switched to DMI treatment during the kindling procedure kindled faster than control subjects. In addition, withdrawal from DMI preexposure advanced the AMPH-induced increase in kindling rate. These results were discussed in terms of the role of norepinephrine-mediated inhibition of the kindling process, and were related to drug-elicited alterations in beta-adrenergic receptor functioning. Taken together, these findings implicate the amygdala as an important structure in the development of non-DA forms of AMPH sensitization.

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

    Science.gov (United States)

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

    2016-01-01

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

  8. Nonequilibrium calcium dynamics regulate the autonomous firing pattern of rat striatal cholinergic interneurons.

    Science.gov (United States)

    Goldberg, Joshua A; Teagarden, Mark A; Foehring, Robert C; Wilson, Charles J

    2009-07-01

    Striatal cholinergic interneurons discharge rhythmically in two patterns associated with different afterhyperpolarization timescales, each dictated by a different calcium-dependent potassium current. Single spiking depends on a medium-duration afterhyperpolarization (mAHP) generated by rapid SK currents that are associated with N-type calcium channels. Periodic bursting is driven by a delayed and slowly decaying afterhyperpolarization (sAHP) current associated with L-type channels. Using calcium imaging we show that the calcium transients underlying these currents exhibit two corresponding timescales throughout the somatodendritic tree. This result is not consistent with spatial compartmentalization of calcium entering through the two calcium channels and acting on the two potassium currents, or with differences in channel gating kinetics of the calcium dependent potassium currents. Instead, we show that nonequilibrium dynamics of calcium redistribution among cytoplasmic binding sites with different calcium binding kinetics can give rise to multiple timescales within the same cytoplasmic volume. The resulting independence of mAHP and sAHP currents allows cytoplasmic calcium to control two different and incompatible firing patterns (single spiking or bursting and pausing), depending on whether calcium influx is pulsatile or sustained. During irregular firing, calcium entry at both timescales can be detected, suggesting that an interaction between the medium and slow calcium-dependent afterhyperpolarizations may underlie this firing pattern.

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

    Science.gov (United States)

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

    2016-01-01

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

  10. Positive effects of cholinergic stimulation favor young APOE epsilon4 carriers.

    Science.gov (United States)

    Marchant, Natalie L; King, Sarah L; Tabet, Naji; Rusted, Jennifer M

    2010-04-01

    The potential of putative cognitive-enhancing compounds to improve mental processing both in healthy and vulnerable populations is an area of growing interest to scientific and clinical communities. The possible influence of individual genetic differences on efficacy of these compounds has yet to be considered. We sought to investigate the profile of young-adult apolipoprotein E (APOE) varepsilon4 carriers across cognitive domains given that possession of this gene variant increases risk of developing dementia in later life. We also explored whether APOE genotype interacts with the cognitive enhancer, nicotine. A total of 1 mg of the cholinergic agonist nicotine was administered through nasal spray to healthy non-smoking young adults (aged 18-30) with either varepsilon3/varepsilon3 (N=29) or varepsilon4 (at least one varepsilon4 allele, N=27) genotype. Participants were matched on age, sex, and IQ in a placebo-controlled, double-blind 2 (drug: placebo, nicotine) x 2 (genotype: varepsilon3, varepsilon4) between subjects design. Here, we show that, paradoxically, possession of the varepsilon4 allele confers a cognitive advantage on tasks mediated by the frontal lobe, and that young carriers of the varepsilon4 allele show larger cognitive benefit from procholinergic nicotinic stimulation. These results are the first to show that genetic differences influence the efficacy of a cognitive enhancer.

  11. 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

  12. TITERS OF ANTIBODIES TO Β1-ADRENOCEPTOR AND M2 CHOLINERGIC RECEPTORS IN PATIENTS WITH VENTRICULAR ARRHYTHMIAS WITHOUT AN ORGANIC CARDIOVASCULAR DISEASE AND THEIR POSSIBLE CLINICAL SIGNIFICANCE

    Directory of Open Access Journals (Sweden)

    M. M. Rogova

    2012-01-01

    Full Text Available Aim. To identify the most promising epitopes that simulate various sites β1-adrenergic and M2-cholinergic receptors, and to evaluate their possible contribution to the development and maintenance of cardiac arrhythmias, particularly idiopathic ventricular arrhythmia. Material and methods. Patients with ventricular arrhythmias without organic cardiovascular disease (the study group; n=70 were included in the study. The control group consisted of 20 healthy volunteers. Evaluation of levels of antibodies to antigenic determinants, modeling various sites β1-adrenergic and M2-cholinergic performed in all patients. Causal treatment with clarithromycin and valacyclovir performed in part of patients. Results. Antibodies to different peptide sequences of β1-adrenergic and M2-cholinergic receptors have been identified in 25% of main group patients. A direct correlation between the frequency of episodes of ventricular tachycardia and IgG levels to MRI-MRIV (p=0.02 revealed. Increase in titre of antibodies to β1-adrenoceptors, to a peptide sequence β8 (p=0.02, and lower titers of antibodies to the M2 acetylcholine receptor — chimera MRI-MRIV IgM (p=0.06 and ARI-MRIV IgM (p=0.07 were observed when assessing the efficacy of the therapy in the causal dynamics in the group of "untreated" patients. IgG titer reduction of ARI-MRIV (p=0.02, which is 4 times out of 10 with reduction of ventricular ectopic activity , recorded after valacyclovir therapy. Clarithromycin therapy on the level of antibodies exerted no significant effect. Conclusion. Possible involvement of antibodies to β1-adrenoceptor and M2-cholinergic receptors in the development of idiopathic ventricular arrhythmias demonstrated. The relationship between the frequency of episodes of ventricular tachycardia and levels of antibody titers to M2-cholinergic receptors found. Attempt of causal treatment, depending on the possible mechanisms of the autoimmune process is executed. Further studies to

  13. Effect of growth hormone-releasing peptide on ardiac cholinergic nerve fiber density distribution in a rat model of heart failure

    Institute of Scientific and Technical Information of China (English)

    Guozhong Tian; Xiuqin Ni; Yong Zhao; Jia Feng; Yanjun Li; Zhenya Zhong; Shuling Bai

    2009-01-01

    BACKGROUND: Changes in the cardiac autonomic nerve are considered to be important factors in the mechanisms of heart failure. It is possible to reduce or slow down nerve degeneration and necrosis, provided that patients take effective neuroprotectants during the early stages of heart failure. Moreover, it is possible to relieve the pathological process and reduce the risk of death.OBJECTIVE: To study the effect of growth hormone releasing peptide (GHRP) on cardiac cholinergic nerve fiber density distribution in a rat model of heart failure, and verify whether GHRP can ameliorate denervation.DESIGN, TIME AND SETTING: A randomized controlled study was performed at the Key Laboratory of Anatomy, Harbin Medical University, between June and October 2009.MATERIALS: Fifty adult, healthy, female, Wistar rats, weighing (200±20) g, were randomly divided into GHRP (n=30), model (n=10), and sham operation (n=10) groups. GHRP-2 was made in Shanghai, China (batch No. z071212-03).METHODS: Acute myocardial infarction was established by ligating the left anterior descending coronary artery in the GHRP and model groups. Five weeks later, myocardial function was detected using color ultrasound electrocardiograph. Ejection fraction < 60% was considered to be a successful marker of chronic heart failure models. However, the left anterior descending coronary artery was not ligated in the sham operation group. The GHRP group was injected with 100μg/kg GHRP-2, and the other two groups were injected with the same volume of physiological saline, once per day.MAIN OUTCOME MEASURES: After 4 weeks, pathological changes in cardiac cholinergic nerve fibers were detected under optic microscopy following hematoxylin/eosin staining. In addition, density distribution was measured using a multi-function color pathological image system.RESULTS: In the sham operation group, myocardial cells were regular, uniformly stained, and no inflammatory cells were present. In the model group, myocardial cells

  14. 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.

  15. 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.

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

    Science.gov (United States)

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

    2009-12-09

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

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

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    E. I. Zakharova

    2010-01-01

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

  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. 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

  20. Resonant cholinergic dynamics in cognitive and motor decision-making:Attention, category learning, and choice in neocortex, superior colliculus, and optic tectum

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    Stephen eGrossberg

    2016-01-01

    Full Text Available Freely behaving organisms need to rapidly calibrate their perceptual, cognitive, and motor decisions based on continuously changing environmental conditions. These plastic changes include sharpening or broadening of cognitive and motor attention and learning to match the behavioral demands that are imposed by changing environmental statistics. This article proposes that a shared circuit design for such flexible decision-making is used in specific cognitive and motor circuits, and that both types of circuits use acetylcholine to modulate choice selectivity. Such task-sensitive control is proposed to control thalamocortical choice of the critical features that are cognitively attended and that are incorporated through learning into prototypes of visual recognition categories. A cholinergically-modulated process of vigilance control determines if a recognition category and its attended features are abstract (low vigilance or concrete (high vigilance. Homologous neural mechanisms of cholinergic modulation are proposed to focus attention and learn a multimodal map within the deeper layers of superior colliculus. This map enables visual, auditory, and planned movement commands to compete for attention, leading to selection of a winning position that controls where the next saccadic eye movement will go. Such map learning may be viewed as a kind of attentive motor category learning. The article hereby explicates a link between attention, learning, and cholinergic modulation during decision making within both cognitive and motor systems. Homologs between the mammalian superior colliculus and the avian optic tectum lead to predictions about how multimodal map learning may occur in the avian brain and how such learning may be modulated by acetycholine.

  1. Resonant Cholinergic Dynamics in Cognitive and Motor Decision-Making: Attention, Category Learning, and Choice in Neocortex, Superior Colliculus, and Optic Tectum.

    Science.gov (United States)

    Grossberg, Stephen; Palma, Jesse; Versace, Massimiliano

    2015-01-01

    Freely behaving organisms need to rapidly calibrate their perceptual, cognitive, and motor decisions based on continuously changing environmental conditions. These plastic changes include sharpening or broadening of cognitive and motor attention and learning to match the behavioral demands that are imposed by changing environmental statistics. This article proposes that a shared circuit design for such flexible decision-making is used in specific cognitive and motor circuits, and that both types of circuits use acetylcholine to modulate choice selectivity. Such task-sensitive control is proposed to control thalamocortical choice of the critical features that are cognitively attended and that are incorporated through learning into prototypes of visual recognition categories. A cholinergically-modulated process of vigilance control determines if a recognition category and its attended features are abstract (low vigilance) or concrete (high vigilance). Homologous neural mechanisms of cholinergic modulation are proposed to focus attention and learn a multimodal map within the deeper layers of superior colliculus. This map enables visual, auditory, and planned movement commands to compete for attention, leading to selection of a winning position that controls where the next saccadic eye movement will go. Such map learning may be viewed as a kind of attentive motor category learning. The article hereby explicates a link between attention, learning, and cholinergic modulation during decision making within both cognitive and motor systems. Homologs between the mammalian superior colliculus and the avian optic tectum lead to predictions about how multimodal map learning may occur in the mammalian and avian brain and how such learning may be modulated by acetycholine.

  2. 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.

  3. 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.

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

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    Saak V. Ovsepian

    2013-12-01

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

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

    Science.gov (United States)

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

    2016-04-15

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

  6. 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

  7. 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

  8. 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

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

    Directory of Open Access Journals (Sweden)

    Irene eChaves-Coira

    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

  10. 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

  11. Mechanisms determining cholinergic neural responses in airways of young and mature rabbits.

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    Larsen, Gary L; Loader, Joan; Nguyen, Dee Dee; Fratelli, Cori; Dakhama, Azzeddine; Colasurdo, Giuseppe N

    2004-08-01

    Neural pathways help control airway caliber and responsiveness. Yet little is known of how neural control changes as a function of development. In rabbits, we found electrical field stimulation (EFS) of airway nerves led to more marked contractile responses in 2- vs. 13-week-old animals. This enhanced response to EFS may be due to prejunctional, junctional, and/or postjunctional neural mechanisms. We assessed these mechanisms in airways of 2- and 13-week-old rabbits. The contractile responses to methacholine did not differ in the groups, suggesting postjunctional neural events are not primarily responsible for differing responses to EFS. To address junctional events, acetylcholinesterase (AChE) was measured (spectrophotometry). AChE was elevated in 2-week-olds. However, this should lead to less and not greater responses. Prejunctionally, EFS-induced acetylcholine (ACh) release was assessed by HPLC. Airways of 2-week-old rabbits released significantly more ACh than airways from mature rabbits. Choline acetyltransferase, a marker of cholinergic nerves, was not different between groups, suggesting that more ACh release in young rabbits was not due to increased nerve density. ACh release in the presence of polyarginine increased significantly in both groups, supporting the presence of functional muscarinic autoreceptors (M2) at both ages. Because substance P (SP) increases release of ACh, SP was measured by ELISA. This neuropeptide was significantly elevated in airways of younger rabbits. Nerve growth factor (NGF) increased SP and was also significantly increased in airways from younger rabbits. This work suggests that increases in EFS-induced responsiveness in young rabbits are likely due to prejunctional events with enhanced release of ACh. Increases in NGF and SP early in life may contribute to this increased responsiveness.

  12. Neurostimulation for primary headache disorders, part 1: pathophysiology and anatomy, history of neuromodulation in headache treatment, and review of peripheral neuromodulation in primary headaches.

    Science.gov (United States)

    Jenkins, Brian; Tepper, Stewart J

    2011-09-01

    Neurostimulation for primary headaches is being increasingly utilized as a treatment modality. Use of neuromoduation has generated multiple case reports as well as some controlled studies. This article is the first of 2 systematic reviews of available data regarding neurostimulation for primary headache conditions. The pathophysiology, relative anatomy, theoretical mechanisms, and history of neurostimulation for primary headache are covered in this section, Part 1 of 2. The literature regarding peripheral neurostimulatory targets is also reviewed in Part 1. These peripheral targets include: percutaneous nerves, transcranial holocephalic, occipital nerves, auriculotemporal nerves, supraorbital nerves, cervical epidural, and sphenopalatine ganglia. Part 2 will focus on central stimulation, covering vagus nerve, and deep brain stimulation. Part 2 also contains an overall analysis of efficacy, safety, cost, patient selection, and suggestions for further study based on available evidence.

  13. Evidence for activation of both adrenergic and cholinergic nervous pathways by yohimbine, an alpha 2-adrenoceptor antagonist.

    Science.gov (United States)

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

    1995-01-01

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

  14. 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.

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

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    Antonia Kaltsatou

    2015-06-01

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

  16. 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

  17. 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.

  18. Effects of Chemical Agents on the Cholinergic Neurotransmitter System: Mechanisms of Adaptation.

    Science.gov (United States)

    1984-06-20

    changes in cholinergic neurochemistry (31). The former was observed in such symptoms as salivation, lacrimation and tremor and in measures of hypothermia...to the belladonna drugs occurs in man to a limited extent, e.g., patients with Parkinsonism may eventually receive daily doses of atropine or

  19. 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.

  20. 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

  1. 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.

  2. 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.

  3. 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…

  4. 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…

  5. 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…

  6. Cholinergic involvement in vascular and glucoregulatory actions of insulin in rats.

    Science.gov (United States)

    Lévesque, Martin; Santuré, Marta; Pitre, Maryse; Nadeau, André; Bachelard, Hélène

    2006-02-01

    This study was designed to test the glucose metabolic and vasodilator actions of insulin in rats and its relation to cholinergic system-dependent mechanisms. The first group of rats had pulsed Doppler flow probes and intravascular catheters implanted to determine blood pressure, heart rate, and regional blood flows. Insulin sensitivity was assessed by the euglycemic-hyperinsulinemic clamp technique carried out in the absence or presence of atropine. The second group of rats was used to determine the cholinergic contribution to in vivo insulin-mediated glucose utilization in individual muscles. Glucose uptake was examined by using [(3)H]2-deoxy-D-glucose. Muscarinic cholinergic blockade was found to significantly (P = 0.002) reduce insulin sensitivity and to completely abrogate the renal (P = 0.008) and hindquarter (P = 0.02) vasodilator responses to euglycemic infusion of insulin. A significant reduction in insulin-stimulated in vivo glucose uptake was also noted in soleus (P = 0.006), quadriceps (P = 0.03), gastrocnemius (P = 0.02), and extensor digitorum longus (EDL) (P = 0.001) muscles, when insulin was infused at a rate of 4 mU . kg(-1) . min(-1), whereas at the rate of 16 mU . kg(-1) . min(-1), a significant reduction in glucose uptake was only observed in EDL (P = 0.03) and quadriceps (P = 0.01) muscles. Together, these results demonstrate a potential role for cholinergic involvement with physiological insulin actions in glucose clearance and blood flow regulation in rats.

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

    Directory of Open Access Journals (Sweden)

    Feng eYi

    2015-03-01

    Full Text Available Release of acetylcholine (ACh in the hippocampus (HC occurs during exploration, arousal, and learning. Although the medial septum-diagonal band of Broca (MS-DBB is the major extrinsic source of cholinergic input to the HC, cholinergic neurons intrinsic to the HC also exist but remain poorly understood. Here, ChAT-tauGFP and ChAT-CRE/Rosa26YFP (ChAT-Rosa mice were examined in HC. The HC of ChAT-tauGFP mice was densely innervated with GFP-positive axons, often accompanied by large GFP-positive structures, some of which were Neurotrace/DAPI-negative and likely represent large axon terminals. In the HC of ChAT-Rosa mice, ChAT-YFP cells were Neurotrace-positive and more abundant in CA3 and dentate gyrus than CA1 with partial overlapping with calretinin/VIP. Moreover, an anti-ChAT antibody consistently showed ChAT immunoreactivity in ChAT-YFP cells from MS-DBB but rarely from HC. Furthermore, ChAT-YFP cells from CA1 stratum radiatum/stratum lacunosum moleculare (SR/SLM exhibited a stuttering firing phenotype but a delayed firing phenotype in stratum pyramidale (SP of CA3. Input resistance and capacitance were also different between CA1 SR/LM and CA3 SP ChAT-YFP cells. Bath application of ACh increased firing frequency in all ChAT-YFP cells; however, cholinergic modulation was larger in CA1 SR/SLM than CA3 SP ChAT-YFP cells. Finally, CA3 SP ChAT-YFP cells exhibited a wider AP half-width and weaker cholinergic modulation than YFP-negative CA3 pyramidal cells. Consistent with CRE expression in a subpopulation of principal cells, optogenetic stimulation evoked glutamatergic postsynaptic currents in CA1 SR/SLM interneurons. In conclusion, the presence of fluorescently labeled hippocampal cells common to both ChAT-Rosa and ChAT-tauGFP mice are in good agreement with previous reports on the existence of cholinergic interneurons, but both transgenic mouse lines exhibited unexpected anatomical features that departed considerably from earlier observations.

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

    Science.gov (United States)

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

    2015-01-01

    Release of acetylcholine (ACh) in the hippocampus (HC) occurs during exploration, arousal, and learning. Although the medial septum-diagonal band of Broca (MS-DBB) is the major extrinsic source of cholinergic input to the HC, cholinergic neurons intrinsic to the HC also exist but remain poorly understood. Here, ChAT-tauGFP and ChAT-CRE/Rosa26YFP (ChAT-Rosa) mice were examined in HC. The HC of ChAT-tauGFP mice was densely innervated with GFP-positive axons, often accompanied by large GFP-positive structures, some of which were Neurotrace/DAPI-negative and likely represent large axon terminals. In the HC of ChAT-Rosa mice, ChAT-YFP cells were Neurotrace-positive and more abundant in CA3 and dentate gyrus than CA1 with partial overlap with calretinin/VIP. Moreover, an anti-ChAT antibody consistently showed ChAT immunoreactivity in ChAT-YFP cells from MS-DBB but rarely from HC. Furthermore, ChAT-YFP cells from CA1 stratum radiatum/stratum lacunosum moleculare (SR/SLM) exhibited a stuttering firing phenotype but a delayed firing phenotype in stratum pyramidale (SP) of CA3. Input resistance and capacitance were also different between CA1 SR/LM and CA3 SP ChAT-YFP cells. Bath application of ACh increased firing frequency in all ChAT-YFP cells; however, cholinergic modulation was larger in CA1 SR/SLM than CA3 SP ChAT-YFP cells. Finally, CA3 SP ChAT-YFP cells exhibited a wider AP half-width and weaker cholinergic modulation than YFP-negative CA3 pyramidal cells. Consistent with CRE expression in a subpopulation of principal cells, optogenetic stimulation evoked glutamatergic postsynaptic currents in CA1 SR/SLM interneurons. In conclusion, the presence of fluorescently labeled hippocampal cells common to both ChAT-tauGFP and ChAT-Rosa mice are in good agreement with previous reports on the existence of cholinergic interneurons, but both transgenic mouse lines exhibited unexpected anatomical features that departed considerably from earlier observations.

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

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    Shannon L Risacher

    2013-09-01

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

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

    Science.gov (United States)

    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.

  11. 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.

  12. Blockade of GABA, type A, receptors in the rat pontine reticular formation induces rapid eye movement sleep that is dependent upon the cholinergic system.

    Science.gov (United States)

    Marks, G A; Sachs, O W; Birabil, C G

    2008-09-22

    The brainstem reticular formation is an area important to the control of rapid eye movement (REM) sleep. The antagonist of GABA-type A (GABA(A)) receptors, bicuculline methiodide (BMI), injected into the rat nucleus pontis oralis (PnO) of the reticular formation resulted in a long-lasting increase in REM sleep. Thus, one factor controlling REM sleep appears to be the number of functional GABA(A) receptors in the PnO. The long-lasting effect produced by BMI may result from secondary influences on other neurotransmitter systems known to have long-lasting effects. To study this question, rats were surgically prepared for chronic sleep recording and additionally implanted with guide cannulas aimed at sites in the PnO. Multiple, 60 nl, unilateral injections were made either singly or in combination. GABA(A) receptor antagonists, BMI and gabazine (GBZ), produced dose-dependent increases in REM sleep with GBZ being approximately 35 times more potent than BMI. GBZ and the cholinergic agonist, carbachol, produced very similar results, both increasing REM sleep for about 8 h, mainly through increased period frequency, with little reduction in REM latency. Pre-injection of the muscarinic antagonist, atropine, completely blocked the REM sleep-increase by GBZ. GABAergic control of REM sleep in the PnO requires the cholinergic system and may be acting through presynaptic modulation of acetylcholine release.

  13. 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.

  14. 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.

  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. 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.

  17. Brain region-specific alterations in the gene expression of cytokines, immune cell markers and cholinergic system components during peripheral endotoxin-induced inflammation.

    Science.gov (United States)

    Silverman, Harold A; Dancho, Meghan; Regnier-Golanov, Angelique; Nasim, Mansoor; Ochani, Mahendar; Olofsson, Peder S; Ahmed, Mohamed; Miller, Edmund J; Chavan, Sangeeta S; Golanov, Eugene; Metz, Christine N; Tracey, Kevin J; Pavlov, Valentin A

    2015-03-11

    Inflammatory conditions characterized by excessive peripheral immune responses are associated with diverse alterations in brain function, and brain-derived neural pathways regulate peripheral inflammation. Important aspects of this bidirectional peripheral immune-brain communication, including the impact of peripheral inflammation on brain region-specific cytokine responses, and brain cholinergic signaling (which plays a role in controlling peripheral cytokine levels), remain unclear. To provide insight, we studied gene expression of cytokines, immune cell markers and brain cholinergic system components in the cortex, cerebellum, brainstem, hippocampus, hypothalamus, striatum and thalamus in mice after an intraperitoneal lipopolysaccharide injection. Endotoxemia was accompanied by elevated serum levels of interleukin (IL)-1β, IL-6 and other cytokines and brain region-specific increases in Il1b (the highest increase, relative to basal level, was in cortex; the lowest increase was in cerebellum) and Il6 (highest increase in cerebellum; lowest increase in striatum) mRNA expression. Gene expression of brain Gfap (astrocyte marker) was also differentially increased. However, Iba1 (microglia marker) mRNA expression was decreased in the cortex, hippocampus and other brain regions in parallel with morphological changes, indicating microglia activation. Brain choline acetyltransferase (Chat ) mRNA expression was decreased in the striatum, acetylcholinesterase (Ache) mRNA expression was decreased in the cortex and increased in the hippocampus, and M1 muscarinic acetylcholine receptor (Chrm1) mRNA expression was decreased in the cortex and the brainstem. These results reveal a previously unrecognized regional specificity in brain immunoregulatory and cholinergic system gene expression in the context of peripheral inflammation and are of interest for designing future antiinflammatory approaches.

  18. Distinct synaptic properties of perisomatic inhibitory cell types and their different modulation by cholinergic receptor activation in the CA3 region of the mouse hippocampus.

    Science.gov (United States)

    Szabó, Gergely G; Holderith, Noémi; Gulyás, Attila I; Freund, Tamás F; Hájos, Norbert

    2010-06-01

    Perisomatic inhibition originates from three types of GABAergic interneurons in cortical structures, including parvalbumin-containing fast-spiking basket cells (FSBCs) and axo-axonic cells (AACs), as well as cholecystokinin-expressing regular-spiking basket cells (RSBCs). These interneurons may have significant impact in various cognitive processes, and are subjects of cholinergic modulation. However, it is largely unknown how cholinergic receptor activation modulates the function of perisomatic inhibitory cells. Therefore, we performed paired recordings from anatomically identified perisomatic interneurons and pyramidal cells in the CA3 region of the mouse hippocampus. We determined the basic properties of unitary inhibitory postsynaptic currents (uIPSCs) and found that they differed among cell types, e.g. GABA released from axon endings of AACs evoked uIPSCs with the largest amplitude and with the longest decay measured at room temperature. RSBCs could also release GABA asynchronously, the magnitude of the release increasing with the discharge frequency of the presynaptic interneuron. Cholinergic receptor activation by carbachol significantly decreased the uIPSC amplitude in all three types of cell pairs, but to different extents. M2-type muscarinic receptors were responsible for the reduction in uIPSC amplitudes in FSBC- and AAC-pyramidal cell pairs, while an antagonist of CB(1) cannabinoid receptors recovered the suppression in RSBC-pyramidal cell pairs. In addition, carbachol suppressed or even eliminated the short-term depression of uIPSCs in FSBC- and AAC-pyramidal cell pairs in a frequency-dependent manner. These findings suggest that not only are the basic synaptic properties of perisomatic inhibitory cells distinct, but acetylcholine can differentially control the impact of perisomatic inhibition from different sources.

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

    Science.gov (United States)

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

    2007-06-01

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

  20. Targeting the affective and cognitive aspects of chronic neuropathic pain using basal forebrain neuromodulation: rationale, review and proposal.

    Science.gov (United States)

    Oluigbo, Chima O; Salma, Asem; Rezai, Ali R

    2012-09-01

    Chronic pain is a major health problem in developed countries where it may affect as much as 20% of the adult population. There have been no significant clinical breakthroughs in therapeutic options for persons with chronic neuropathic pain. These limitations underscore the importance of developing new therapies for this disabling pain syndrome. We have reviewed the limitations of the present treatment strategies for chronic pain, neurophysiology of somatosensory transmission and nociception, mechanisms of neuropathic pain, the concept of a "pain matrix" and the "top-down" modulation of pain, and the cognitive affective role in processing of the pain experience. We found that affective and cognitive aspects of pain constitute important considerations in achieving improvements in the outcomes of pain neuromodulation in patients with chronic neuropathic pain. Based on our review, we propose that future novel neuromodulatory therapeutic strategies should be directed at areas in the brain that are involved in the neural mechanisms of reward valuation and appetitive motivation such as nucleus accumbens, ventral tegmental area, and prefrontal cortex.

  1. Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs.

    Science.gov (United States)

    Saccone, Scott F; Hinrichs, Anthony L; Saccone, Nancy L; Chase, Gary A; Konvicka, Karel; Madden, Pamela A F; Breslau, Naomi; Johnson, Eric O; Hatsukami, Dorothy; Pomerleau, Ovide; Swan, Gary E; Goate, Alison M; Rutter, Joni; Bertelsen, Sarah; Fox, Louis; Fugman, Douglas; Martin, Nicholas G; Montgomery, Grant W; Wang, Jen C; Ballinger, Dennis G; Rice, John P; Bierut, Laura Jean

    2007-01-01

    Nicotine dependence is one of the world's leading causes of preventable death. To discover genetic variants that influence risk for nicotine dependence, we targeted over 300 candidate genes and analyzed 3713 single nucleotide polymorphisms (SNPs) in 1050 cases and 879 controls. The Fagerström test for nicotine dependence (FTND) was used to assess dependence, in which cases were required to have an FTND of 4 or more. The control criterion was strict: control subjects must have smoked at least 100 cigarettes in their lifetimes and had an FTND of 0 during the heaviest period of smoking. After correcting for multiple testing by controlling the false discovery rate, several cholinergic nicotinic receptor genes dominated the top signals. The strongest association was from an SNP representing CHRNB3, the beta3 nicotinic receptor subunit gene (P = 9.4 x 10(-5)). Biologically, the most compelling evidence for a risk variant came from a non-synonymous SNP in the alpha5 nicotinic receptor subunit gene CHRNA5 (P = 6.4 x 10(-4)). This SNP exhibited evidence of a recessive mode of inheritance, resulting in individuals having a 2-fold increase in risk of developing nicotine dependence once exposed to cigarette smoking. Other genes among the top signals were KCNJ6 and GABRA4. This study represents one of the most powerful and extensive studies of nicotine dependence to date and has found novel risk loci that require confirmation by replication studies.

  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 subcellular distribution of [3H]-CGS 21680 binding sites in the rat striatum: copurification with cholinergic nerve terminals.

    Science.gov (United States)

    James, S; Richardson, P J

    1993-08-01

    The subcellular distribution of the adenosine A2a receptor in rat striatum has been investigated using specific binding of the A2a-selective ligand [3H]-CGS 21680. After subcellular fractionation, the distribution of [3H]-CGS 21680 binding was similar to that of the cholinergic nerve terminal marker acetylcholinesterase rather than the more general membrane marker 5'-nucleotidase, with 42% of binding associated with the synaptosomal sub-fraction and 19% with a light membrane fraction. Binding of [3H]-CGS 21680 was also found to co-purify with the cholinergic nerve terminal marker choline acetyltransferase during immunoaffinity purification of striatal cholinergic nerve terminals. These results demonstrate that some adenosine A2a receptors are present on cholinergic nerve terminals in rat striatum.

  4. 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.

  5. Antidepressant-like properties of sildenafil in a genetic rat model of depression: Role of cholinergic cGMP-interactions

    DEFF Research Database (Denmark)

    Liebenberg, Nico; Brink, Christiaan; Brand, Linda

    2008-01-01

    a strategy for the treatment of depression, using a PDE5 inhibitor in the presence of cholinergic inhibition. Sildenafil-induced augmentation of imipramine, an antidepressant with inherent anticholinergic properties, concurs with this suggestion, and highlights the potential clinical value...

  6. 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.

  7. Lifespan Development of Neuromodulation of Adaptive Control and Motivation as an Ontogenetic Mechanism for Developmental Niche Construction

    Science.gov (United States)

    Li, Shu-Chen

    2013-01-01

    Instead of viewing organisms and individuals as passive recipients of their biological, ecological, and cultural inheritances, the developmental niche construction theory and the biocultural co-construction framework both emphasize that the individual's agency plays a key role in regulating how environmental and sociocontextual influences may…

  8. 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...

  9. 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...

  10. 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.

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

    Science.gov (United States)

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

    2017-01-01

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

  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. The role of efferent cholinergic transmission for the insulinotropic and glucagonostatic effects of GLP-1

    DEFF Research Database (Denmark)

    Plamboeck, Astrid; Veedfald, Simon; Deacon, Carolyn F

    2015-01-01

    The importance of vagal efferent signaling for the insulinotropic and glucagonostatic effects of glucagon-like peptide-1 (GLP-1) was investigated in a randomized single-blinded study. Healthy male participants (n = 10) received atropine to block vagal cholinergic transmission or saline infusions...... on separate occasions. At t = 15 min, plasma glucose was clamped at 6 mmol/l. GLP-1 was infused at a low dose (0.3 pmol·kg(-1)·min(-1)) from t = 45-95 min and at a higher dose (1 pmol·kg(-1)·min(-1)) from t = 95-145 min. Atropine blocked muscarinic, cholinergic transmission, as evidenced by an increase...... in heart rate [peak: 70 ± 2 (saline) vs. 90 ± 2 (atropine) beats/min, P atropine) pmol/l × min, P

  14. A cholinergic receptor gene (CHRM2) affects event-related oscillations.

    Science.gov (United States)

    Jones, Kevin A; Porjesz, Bernice; Almasy, Laura; Bierut, Laura; Dick, Danielle; Goate, Alison; Hinrichs, Anthony; Rice, John P; Wang, Jen C; Bauer, Lance O; Crowe, Raymond; Foroud, Tatiana; Hesselbrock, Victor; Kuperman, Samuel; Nurnberger, John; O'Connor, Sean J; Rohrbaugh, John; Schuckit, Marc A; Tischfield, Jay; Edenberg, Howard J; Begleiter, Henri

    2006-09-01

    We report genetic linkage and association findings which implicate the gene encoding the muscarinic acetylcholine receptor M2 (CHRM2) in the modulation of a scalp-recorded electrophysiological phenotype. The P3 (P300) response was evoked using a three-stimulus visual oddball paradigm and a phenotype that relates to the energy in the theta band (4-5 Hz) was analyzed. Studies have shown that similar electrophysiological measures represent cognitive correlates of attention, working memory, and response selection; a role has been suggested for the ascending cholinergic pathway in the same functions. The results of our genetic association tests, combined with knowledge regarding the presence of presynaptic cholinergic M2 autoreceptors in the basal forebrain, indicate that the cognitive processes required by the experiment may in part be mediated by inhibitory neural networks. These findings underscore the utility of electrophysiology and neurogenetics in the understanding of cognitive function and the study of brain-related disorders.

  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. 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.

  17. 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.

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

    Directory of Open Access Journals (Sweden)

    C.M. Queiroz

    2013-01-01

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

  19. Modulation of Cholinergic Pathways and Inflammatory Mediators in Blast-Induced Traumatic Brain Injury

    Science.gov (United States)

    2013-01-01

    Neuroinflammation including cross-talk between central and peripheral immune systems is considered to be a primary event after blast exposure...cholinergic anti-inflammatory pathway has been proposed as a link in neuroimmunomodulation, especially during stress con- ditions [8–11]. Neuroinflammation is...BINT) elicits early complement activation and tumor necrosis factor alpha (TNFalpha) release in a rat brain, J. Neurol. Sci. 318 (2012) 146–154. [8

  20. A bio-behavioural investigation into the role of the cholinergic system in stress / Ilse Groenewald

    OpenAIRE

    Groenewald, Ilse

    2006-01-01

    Posttraumatic stress disorder (PTSD) is an anxiety disorder that may follow exposure to severe emotional trauma and presents with various symptoms of anxiety, hyperarousal and cognitive anomalies. Interestingly, only 10-30% of an exposed population will go on to develop full-blown PTSD. Cholinergic neurotransmission is implicated in anxiety as well as other typical manifestations of PTSD, particularly cognitive changes. The frontal cortex and hippocampus regulate and in turn ar...

  1. Neurostimulation of the cholinergic anti-inflammatory pathway ameliorates disease in rat collagen-induced arthritis.

    Directory of Open Access Journals (Sweden)

    Yaakov A Levine

    Full Text Available INTRODUCTION: The inflammatory reflex is a physiological mechanism through which the nervous system maintains immunologic homeostasis by modulating innate and adaptive immunity. We postulated that the reflex might be harnessed therapeutically to reduce pathological levels of inflammation in rheumatoid arthritis by activating its prototypical efferent arm, termed the cholinergic anti-inflammatory pathway. To explore this, we determined whether electrical neurostimulation of the cholinergic anti-inflammatory pathway reduced disease severity in the collagen-induced arthritis model. METHODS: Rats implanted with vagus nerve cuff electrodes had collagen-induced arthritis induced and were followed for 15 days. Animals underwent active or sham electrical stimulation once daily from day 9 through the conclusion of the study. Joint swelling, histology, and levels of cytokines and bone metabolism mediators were assessed. RESULTS: Compared with sham treatment, active neurostimulation of the cholinergic anti-inflammatory pathway resulted in a 52% reduction in ankle diameter (p = 0.02, a 57% reduction in ankle diameter (area under curve; p = 0.02 and 46% reduction overall histological arthritis score (p = 0.01 with significant improvements in inflammation, pannus formation, cartilage destruction, and bone erosion (p = 0.02, accompanied by numerical reductions in systemic cytokine levels, not reaching statistical significance. Bone erosion improvement was associated with a decrease in serum levels of receptor activator of NF-κB ligand (RANKL from 132±13 to 6±2 pg/mL (mean±SEM, p = 0.01. CONCLUSIONS: The severity of collagen-induced arthritis is reduced by neurostimulation of the cholinergic anti-inflammatory pathway delivered using an implanted electrical vagus nerve stimulation cuff electrode, and supports the rationale for testing this approach in human inflammatory disorders.

  2. Novel GABAergic circuits mediate the reinforcement-related signals of striatal cholinergic interneurons

    OpenAIRE

    English, Daniel F.; Ibanez-Sandoval, Osvaldo; Stark, Eran; Tecuapetla, Fatuel; Buzsaki, Gyorgy; Deisseroth, Karl; Tepper, James M.; Koos, Tibor

    2011-01-01

    Neostriatal cholinergic interneurons are believed to play an important role in reinforcement mediated learning and response selection by signaling the occurrence and motivational value of behaviorally relevant stimuli through precisely timed multiphasic population responses. An important problem is to understand how these signals regulate the functioning of the neostriatum. Here we describe the synaptic organization of a novel circuit that involves direct nicotinic excitation of GABAergic int...

  3. 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.

  4. Nonequilibrium Calcium Dynamics Regulate the Autonomous Firing Pattern of Rat Striatal Cholinergic Interneurons

    OpenAIRE

    Goldberg, Joshua A.; Teagarden, Mark A.; Foehring, Robert C.; Wilson, Charles J.

    2009-01-01

    Striatal cholinergic interneurons discharge rhythmically in two patterns associated with different afterhyperpolarization timescales, each dictated by a different calcium-dependent potassium current. Single spiking depends on a medium-duration afterhyperpolarization (mAHP) generated by rapid SK currents that are associated with N-type calcium channels. Periodic bursting is driven by a delayed and slowly decaying afterhyperpolarization (sAHP) current associated with L-type channels. Using calc...

  5. Do we need to establish guidelines for patients with neuromodulation implantable devices, including spinal cord stimulators undergoing nonspinal surgeries?

    Directory of Open Access Journals (Sweden)

    Ramsis F Ghaly

    2016-01-01

    Full Text Available Background: Spinal cord stimulation is currently approved to treat chronic intractable pain of the trunk and limbs. However, such implantable electronic devices are vulnerable to external electrical currents and magnetic fields. Within the hospitals and modern operating rooms (ORs, there is an abundance of electrical devices and other types of equipment that could interfere with such devices. Despite the increasing number of patients with neuromodulation implantable devices, there are no written guidelines available or consensus of cautions for such patients undergoing unrelated surgery. Case Descriptions: A 60-year-old female with a permanent St. Jude′s spinal cord stimulator (SCS presented for open total abdominal hysterectomy. Both the anesthesia and gynecology staffs were aware of the device presence, but were unaware of any precautions regarding intraoperative management. The device was found to be nonmagnetic resonance imaging compatible, and bipolar cautery was used instead of monopolar cautery. A 59-year-old female with a 9-year-old permanent Medtronic SCS, presented for right total hip arthroplasty. The device was switched off prior to entering the OR, bipolar cautery was used, and grounding pads were placed away from her battery site. In each case, the manufacturer′s representative was contacted preoperative. Both surgeries proceeded uneventfully. Conclusions: The Food and Drug Administration safety information manual warns about the use of diathermy, concomitant implanted stimulation devices, lithotripsy, external defibrillation, radiation therapy, ultrasonic scanning, and high-output ultrasound, all of which can lead to permanent implant damage if not turned off prior to undertaking procedures. Lack of uniform guidelines makes intraoperative management, as well as remote anesthesia care of patients with previously implanted SCSs unsafe.

  6. Bladder response to acute sacral neuromodulation while treating rats in different phases of complete spinal cord injury: a preliminary study

    Directory of Open Access Journals (Sweden)

    Ping Shi

    2015-12-01

    Full Text Available Background: Compared to conventional therapies, sacral neuromodulation (SNM may offer an alternative, non-destructive treatment for SCI patients with bladder dysfunction. Understanding bladder response to SNM treatment for SCI in different phases may yield new insights for innovative use of this promising technique. Materials and Methods: Female Sprague-Dawley rats were used in this study to examine the effects of acute SNM on bladder reflex in complete SCI rats. All rats were anesthetized and set up for continuous saline infusion. Acute SNM treatment was implemented for about 6 hours for each rat. Cystometric parameters, including time between contractions, contraction duration, bladder peak pressure, and number of uninhibited contractions, were analyzed and compared within rats before and after SNM treatment. Results: For the spinally transected rats during early phase (less than two weeks post spinalization, the time between contractions and contraction duration both increased after SNM treatments, yet the increased amplitude was about or less than 20%. For the spinally transected rats with a longer days survival (about two to four weeks post spinalization, the time between contractions and contraction duration substantially increased after SNM treatment and the changes for their average values were more than 90%. For the spinally transected rats with a much longer days survival (more than five weeks post spinalization, the time between contractions and contraction duration increased after SNM treatments, yet the magnitude of changes were less than 30%. Conclusion: The present study suggested that the significant effectiveness of SNM for complete SCI played its role after the spinal shock phase and prior to the development of detrusor overactivity. It indicated that the time point of SNM treatment is necessary to be paid attention.

  7. Lesions of cholinergic pedunculopontine tegmental nucleus neurons fail to affect cocaine or heroin self-administration or conditioned place preference in rats.

    Directory of Open Access Journals (Sweden)

    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.

  8. 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.

  9. Effects of histamine and cholinergic systems on memory retention of passive avoidance learning in rats.

    Science.gov (United States)

    Eidi, Maryam; Zarrindast, Mohammad-Reza; Eidi, Akram; Oryan, Shahrbanoo; Parivar, Kazem

    2003-03-28

    In the present study, the effects of the histamine and cholinergic systems on memory retention in adult male rats were investigated. Post-training intracerebroventricular injections were carried out in all the experiments. Cholinoceptor agonist, acetylcholine (1-10 microg/rat) or nicotine (1-10 microg/rat), increased, while a cholinoceptor antagonist, scopolamine (5-20 microg/rat), decreased memory retention. The response to acetylcholine was attenuated by scopolamine. Administration of histamine (5-20 microg/rat) reduced, but the histamine H(1) receptor antagonist, pyrilamine (10-50 microg/rat), and the histamine H(2) receptor antagonist, cimetidine (1-50 microg/rat), increased memory retention in rats. The histamine receptor antagonists attenuated the response to histamine. Histamine reduced the acetylcholine- or nicotine-induced enhancement. The histamine receptor antagonists enhanced the nicotine- or acetylcholine-induced response. Histamine potentiated the inhibitory effect induced by scopolamine. It is concluded that histaminergic and cholinergic systems have opposing effects on memory retention. Also, the histaminergic system elicits an interaction with the cholinergic system in memory retention.

  10. 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.

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

    Directory of Open Access Journals (Sweden)

    Ignacio Alejandro Pérez-Legaspi

    2014-05-01

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

  12. Targeted ablation of cholinergic interneurons in the dorsolateral striatum produces behavioral manifestations of Tourette syndrome.

    Science.gov (United States)

    Xu, Meiyu; Kobets, Andrew; Du, Jung-Chieh; Lennington, Jessica; Li, Lina; Banasr, Mounira; Duman, Ronald S; Vaccarino, Flora M; DiLeone, Ralph J; Pittenger, Christopher

    2015-01-20

    Gilles de la Tourette syndrome (TS) is characterized by tics, which are transiently worsened by stress, acute administration of dopaminergic drugs, and by subtle deficits in motor coordination and sensorimotor gating. It represents the most severe end of a spectrum of tic disorders that, in aggregate, affect ∼ 5% of the population. Available treatments are frequently inadequate, and the pathophysiology is poorly understood. Postmortem studies have revealed a reduction in specific striatal interneurons, including the large cholinergic interneurons, in severe disease. We tested the hypothesis that this deficit is sufficient to produce aspects of the phenomenology of TS, using a strategy for targeted, specific cell ablation in mice. We achieved ∼ 50% ablation of the cholinergic interneurons of the striatum, recapitulating the deficit observed in patients postmortem, without any effect on GABAergic markers or on parvalbumin-expressing fast-spiking interneurons. Interneuron ablation in the dorsolateral striatum (DLS), corresponding roughly to the human putamen, led to tic-like stereotypies after either acute stress or d-amphetamine challenge; ablation in the dorsomedial striatum, in contrast, did not. DLS interneuron ablation also led to a deficit in coordination on the rotorod, but not to any abnormalities in prepulse inhibition, a measure of sensorimotor gating. These results support the causal sufficiency of cholinergic interneuron deficits in the DLS to produce some, but not all, of the characteristic symptoms of TS.

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

    Directory of Open Access Journals (Sweden)

    F. Z. Zangeneh

    2006-07-01

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

  14. Developmental Neurotoxicity of Tobacco Smoke Directed Toward Cholinergic and Serotonergic Systems: More Than Just Nicotine.

    Science.gov (United States)

    Slotkin, Theodore A; Skavicus, Samantha; Card, Jennifer; Stadler, Ashley; Levin, Edward D; Seidler, Frederic J

    2015-09-01

    Tobacco smoke contains thousands of compounds in addition to nicotine, a known neuroteratogen. We evaluated the developmental neurotoxicity of tobacco smoke extract (TSE) administered to pregnant rats starting preconception and continued through the second postnatal week. We simulated nicotine concentrations encountered with second-hand smoke, an order of magnitude below those seen in active smokers, and compared TSE with an equivalent dose of nicotine alone, and to a 10-fold higher nicotine dose. We conducted longitudinal evaluations in multiple brain regions, starting in adolescence (postnatal day 30) and continued to full adulthood (day 150). TSE exposure impaired presynaptic cholinergic activity, exacerbated by a decrement in nicotinic cholinergic receptor concentrations. Although both nicotine doses produced presynaptic cholinergic deficits, these were partially compensated by hyperinnervation and receptor upregulation, effects that were absent with TSE. TSE also produced deficits in serotonin receptors in females that were not seen with nicotine. Regression analysis showed a profound sex difference in the degree to which nicotine could account for overall TSE effects: whereas the 2 nicotine doses accounted for 36%-46% of TSE effects in males, it accounted for only 7%-13% in females. Our results show that the adverse effects of TSE on neurodevelopment exceed those that can be attributed to just the nicotine present in the mixture, and further, that the sensitivity extends down to levels commensurate with second-hand smoke exposure. Because nicotine itself evoked deficits at low exposures, "harm reduction" nicotine products do not eliminate the potential for neurodevelopmental damage.

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

    Indian Academy of Sciences (India)

    Monika Sadananda

    2004-06-01

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

  16. Comparison of neural targets for neuromodulation of bladder micturition reflex in the rat.

    Science.gov (United States)

    Su, Xin; Nickles, Angela; Nelson, Dwight E

    2012-10-15

    Spinal nerve (SN) stimulation inhibits the bladder rhythmic contraction (BRC) in anesthetized rats. This preparation was used to study the effects of electrical stimulation of the tibial nerve (TN) and the dorsal nerve of the clitoris (DNC) on BRC. Stimulation of the TN and DNC for 10 min produced a frequency- and intensity-dependent attenuation of the frequency of bladder contractions. As observed with the SN, 10-Hz stimulation of either TN or DNC produced the greatest degree of inhibition, with lower or higher frequencies being either less efficacious or inactive. In contrast to the prolonged inhibition produced by SN stimulation, both TN and DNC stimulation produced "short" lasting inhibition of bladder contractions and the maximal inhibition occurred during stimulation. TN stimulation was effective over only a narrow range of current intensities [3-4 × motor threshold current for inducing a toe twitch (T(mot))] and only at a frequency of 10 Hz. Stimulation of TN at 10 Hz, 3 × T(mot) inhibited BRC to 23% of control. Ten-hertz DNC stimulation at 2 × T(EAS), the threshold current for evoking a reflex anal sphincter contraction, decreased the frequency of contractions to 4% of control. Although compared with the respective threshold current the BRC response was more sensitive to DNC compared with TN stimulation, the absolute current required to reduce BRC using DNC stimulation appeared to be higher. Comparing the effects of TN and DNC stimulation to our previous results with SN stimulation, SN stimulation produces the largest duration and efficacy of bladder inhibition.

  17. Neuromodulation of motor-evoked potentials during stepping in spinal rats.

    Science.gov (United States)

    Gad, Parag; Lavrov, Igor; Shah, Prithvi; Zhong, Hui; Roy, Roland R; Edgerton, V Reggie; Gerasimenko, Yury

    2013-09-01

    The rat spinal cord isolated from supraspinal control via a complete low- to midthoracic spinal cord transection produces locomotor-like patterns in the hindlimbs when facilitated pharmacologically and/or by epidural electrical stimulation. To evaluate the role of epidural electrical stimulation in enabling motor control (eEmc) for locomotion and posture, we recorded potentials evoked by epidural spinal cord stimulation in selected hindlimb muscles during stepping and standing in adult spinal rats. We hypothesized that the temporal details of the phase-dependent modulation of these evoked potentials in selected hindlimb muscles while performing a motor task in the unanesthetized state would be predictive of the potential of the spinal circuitries to generate stepping. To test this hypothesis, we characterized soleus and tibialis anterior (TA) muscle responses as middle response (MR; 4-6 ms) or late responses (LRs; >7 ms) during stepping with eEmc. We then compared these responses to the stepping parameters with and without a serotoninergic agonist (quipazine) or a glycinergic blocker (strychnine). Quipazine inhibited the MRs induced by eEmc during nonweight-bearing standing but facilitated locomotion and increased the amplitude and number of LRs induced by eEmc during stepping. Strychnine facilitated stepping and reorganized the LRs pattern in the soleus. The LRs in the TA remained relatively stable at varying loads and speeds during locomotion, whereas the LRs in the soleus were strongly modulated by both of these variables. These data suggest that LRs facilitated electrically and/or pharmacologically are not time-locked to the stimulation pulse but are highly correlated to the stepping patterns of spinal rats.

  18. The role of muscarinic cholinergic signaling in cost-benefit decision making

    Science.gov (United States)

    Fobbs, Wambura

    Animals regularly face decisions that affect both their immediate success and long term survival. Such decisions typically involve some form of cost-benefit analysis and engage a number of high level cognitive processes, including learning, memory and motivational influences. While decision making has been a focus of study for over a century, it's only in the last 20 years that researchers have begun to identify functional neural circuits that subserve different forms of cost-benefit decision making. Even though the cholinergic system is both functionally and anatomically positioned to modulate cost-benefit decision circuits, the contribution of the cholinergic system to decision making has been little studied. In this thesis, I investigated the cognitive and neural contribution of muscarinic cholinergic signaling to cost-benefit decision making. I, first, re-examined the effects of systemic administration of 0.3 mg/kg atropine on delay and probability discounting tasks and found that blockade of muscarinic acetylcholine receptors by atropine induced suboptimal choices (impulsive and risky) in both tasks. Since the effect on delay discounting was restricted to the No Cue version of the delay discounting task, I concluded that muscarinic cholinergic signaling mediates both forms of cost-benefit decision making and is selectively engaged when decisions require valuation of reward options whose costs are not externally signified. Second, I assessed the impact of inactivating the nucleus basalis (NBM) on both forms decision making and the effect of injecting atropine locally into the orbitofrontal cortex (OFC), basolateral amygdala (BLA), or nucleus accumbens (NAc) core during the No Cue version of the delay discounting task. I discovered that although NBM inactivation failed to affect delay discounting, it induced risk aversion in the probability discounting task; and blockade of intra- NAc core, but not intra-OFC or intra-BLA, muscarinic cholinergic signaling lead to

  19. Low-dose pterostilbene, but not resveratrol, is a potent neuromodulator in aging and Alzheimer's disease.

    Science.gov (United States)

    Chang, Jaewon; Rimando, Agnes; Pallas, Merce; Camins, Antoni; Porquet, David; Reeves, Jennifer; Shukitt-Hale, Barbara; Smith, Mark A; Joseph, James A; Casadesus, Gemma

    2012-09-01

    Recent studies have implicated resveratrol and pterostilbene, a resveratrol derivative, in the protection against age-related diseases including Alzheimer's disease (AD). However, the mechanism for the favorable effects of resveratrol in the brain remains unclear and information about direct cross-comparisons between these analogs is rare. As such, the purpose of this study was to compare the effectiveness of diet-achievable supplementation of resveratrol to that of pterostilbene at improving functional deficits and AD pathology in the SAMP8 mouse, a model of accelerated aging that is increasingly being validated as a model of sporadic and age-related AD. Furthermore we sought to determine the mechanism of action responsible for functional improvements observed by studying cellular stress, inflammation, and pathology markers known to be altered in AD. Two months of pterostilbene diet but not resveratrol significantly improved radial arm water maze function in SAMP8 compared with control-fed animals. Neither resveratrol nor pterostilbene increased sirtuin 1 (SIRT1) expression or downstream markers of sirtuin 1 activation. Importantly, markers of cellular stress, inflammation, and AD pathology were positively modulated by pterostilbene but not resveratrol and were associated with upregulation of peroxisome proliferator-activated receptor (PPAR) alpha expression. Taken together our findings indicate that at equivalent and diet-achievable doses pterostilbene is a more potent modulator of cognition and cellular stress than resveratrol, likely driven by increased peroxisome proliferator-activated receptor alpha expression and increased lipophilicity due to substitution of hydroxy with methoxy group in pterostilbene.

  20. The Neuromodulation of the Intestinal Immune System and Its Relevance in Inflammatory Bowel Disease.

    Science.gov (United States)

    Di Giovangiulio, Martina; Verheijden, Simon; Bosmans, Goele; Stakenborg, Nathalie; Boeckxstaens, Guy E; Matteoli, Gianluca

    2015-01-01

    One of the main tasks of the immune system is to discriminate and appropriately react to "danger" or "non-danger" signals. This is crucial in the gastrointestinal tract, where the immune system is confronted with a myriad of food antigens and symbiotic microflora that are in constant contact with the mucosa, in addition to any potential pathogens. This large number of antigens and commensal microflora, which are essential for providing vital nutrients, must be tolerated by the intestinal immune system to prevent aberrant inflammation. Hence, the balance between immune activation versus tolerance should be tightly regulated to maintain intestinal homeostasis and to prevent immune activation indiscriminately against all luminal antigens. Loss of this delicate equilibrium can lead to chronic activation of the intestinal immune response resulting in intestinal disorders, such as inflammatory bowel diseases (IBD). In order to maintain homeostasis, the immune system has evolved diverse regulatory strategies including additional non-immunological actors able to control the immune response. Accumulating evidence strongly indicates a bidirectional link between the two systems in which the brain modulates the immune response via the detection of circulating cytokines and via direct afferent input from sensory fibers and from enteric neurons. In the current review, we will highlight the most recent findings regarding the cross-talk between the nervous system and the mucosal immune system and will discuss the potential use of these neuronal circuits and neuromediators as novel therapeutic tools to reestablish immune tolerance and treat intestinal chronic inflammation.

  1. Neuromodulation of Limb Proprioceptive Afferents Decreases Apnea of Prematurity and Accompanying Intermittent Hypoxia and Bradycardia.

    Directory of Open Access Journals (Sweden)

    Kalpashri Kesavan

    Full Text Available Apnea of Prematurity (AOP is common, affecting the majority of infants born at <34 weeks gestational age. Apnea and periodic breathing are accompanied by intermittent hypoxia (IH. Animal and human studies demonstrate that IH exposure contributes to multiple pathologies, including retinopathy of prematurity (ROP, injury to sympathetic ganglia regulating cardiovascular action, impaired pancreatic islet cell and bone development, cerebellar injury, and neurodevelopmental disabilities. Current standard of care for AOP/IH includes prone positioning, positive pressure ventilation, and methylxanthine therapy; these interventions are inadequate, and not optimal for early development.The objective is to support breathing in premature infants by using a simple, non-invasive vibratory device placed over limb proprioceptor fibers, an intervention using the principle that limb movements trigger reflexive facilitation of breathing.Premature infants (23-34 wks gestational age, with clinical evidence of AOP/IH episodes were enrolled 1 week after birth. Caffeine treatment was not a reason for exclusion. Small vibration devices were placed on one hand and one foot and activated in 6 hour ON/OFF sequences for a total of 24 hours. Heart rate, respiratory rate, oxygen saturation (SpO2, and breathing pauses were continuously collected.Fewer respiratory pauses occurred during vibration periods, relative to baseline (p<0.005. Significantly fewer SpO2 declines occurred with vibration (p<0.05, relative to control periods. Significantly fewer bradycardic events occurred during vibration periods, relative to no vibration periods (p<0.05.In premature neonates, limb proprioceptive stimulation, simulating limb movement, reduces breathing pauses and IH episodes, and lowers the number of bradycardic events that accompany aberrant breathing episodes. This low-cost neuromodulatory procedure has the potential to provide a non-invasive intervention to reduce apnea, bradycardia and

  2. The brain of the archerfish Toxotes chatareus: A Nissl-based neuroanatomical atlas and catecholaminergic/cholinergic systems

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    Naomi Karoubi

    2016-11-01

    Full Text Available Over recent years, the seven-spot archerfish (Toxotes chatareus has emerged as a new model for studies in visual and behavioral neuroscience thanks to its unique hunting strategy. Its natural ability to spit at insects outside of water can be used in the lab for well controlled behavioral experiments where the fish is trained to aim at targets on a screen. The need for a documentation of the neuroanatomy of this animal became critical as more research groups use it as a model. Here we present an atlas of adult T. chatareus specimens caught in the wild in South East Asia. The atlas shows representative sections of the brain and specific structures revealed by a classic Nissl staining as well as corresponding schematic drawings. Additional immunostainings for catecholaminergic and cholinergic systems were conducted to corroborate the identification of certain nuclei and the data of a whole brain scanner is available online. We describe the general features of the archerfish brain as well as its specificities, especially for the visual system and compare the neuroanatomy of the archerfish with other teleosts. This atlas of the archerfish brain shows all levels of the neuraxis and intends to provide a solid basis for further neuroscientific research on T. chatareus, in particular electrophysiological studies.

  3. Mangiferin, a natural xanthone, accelerates gastrointestinal transit in mice involving cholinergic mechanism

    Institute of Scientific and Technical Information of China (English)

    Talita Cavalcante Morais; Synara Cavalcante Lopes; Karine Maria Martins Bezerra Carvalho; Bruno Rodrigues Arruda; Francisco Thiago Correia de Souza; Maria Teresa Salles Trevisan; Vietla Satyanarayana Rao; Flávia Almeida Santos

    2012-01-01

    vehicle-treated control,P < 0.05).Unlike tegaserod,which showed an enhanced water content in fecal pellets (59.20% ± 1.09% vs 51.44% ± 1.19% of control,P < 0.05),mangiferin evidenced no such effect,indicating that it has only a motor and not a secretomotor effect.CONCLUSION:Our data indicate the prokinetic action of mangiferin.It can stimulate the normal GIT and also overcome the drug-induced transit delay,via a cholinergic physiological mechanism.

  4. Mangiferin, a natural xanthone, accelerates gastrointestinal transit in mice involving cholinergic mechanism

    Science.gov (United States)

    Morais, Talita Cavalcante; Lopes, Synara Cavalcante; Carvalho, Karine Maria Martins Bezerra; Arruda, Bruno Rodrigues; de Souza, Francisco Thiago Correia; Trevisan, Maria Teresa Salles; Rao, Vietla Satyanarayana; Santos, Flávia Almeida

    2012-01-01

    vs 161.9 ± 10.82 mg of vehicle-treated control, P < 0.05). Unlike tegaserod, which showed an enhanced water content in fecal pellets (59.20% ± 1.09% vs 51.44% ± 1.19% of control, P < 0.05), mangiferin evidenced no such effect, indicating that it has only a motor and not a secretomotor effect. CONCLUSION: Our data indicate the prokinetic action of mangiferin. It can stimulate the normal GIT and also overcome the drug-induced transit delay, via a cholinergic physiological mechanism. PMID:22783044

  5. Histaminergic modulation of cholinergic release from the nucleus basalis magnocellularis into insular cortex during taste aversive memory formation.

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    Liliana Purón-Sierra

    Full Text Available The ability of acetylcholine (ACh to alter specific functional properties of the cortex endows the cholinergic system with an important modulatory role in memory formation. For example, an increase in ACh release occurs during novel stimulus processing, indicating that ACh activity is critical during early stages of memory processing. During novel taste presentation, there is an increase in ACh release in the insular cortex (IC, a major structure for taste memory recognition. There is extensive evidence implicating the cholinergic efferents of the nucleus basalis magnocellularis (NBM in cortical activity changes during learning processes, and new evidence suggests that the histaminergic system may interact with the cholinergic system in important ways. However, there is little information as to whether changes in cholinergic activity in the IC are modulated during taste memory formation. Therefore, in the present study, we evaluated the influence of two histamine receptor subtypes, H1 in the NBM and H3 in the IC, on ACh release in the IC during conditioned taste aversion (CTA. Injection of the H3 receptor agonist R-α-methylhistamine (RAMH into the IC or of the H1 receptor antagonist pyrilamine into the NBM during CTA training impaired subsequent CTA memory, and simultaneously resulted in a reduction of ACh release in the IC. This study demonstrated that basal and cortical cholinergic pathways are finely tuned by histaminergic activity during CTA, since dual actions of histamine receptor subtypes on ACh modulation release each have a significant impact during taste memory formation.

  6. 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.

  7. 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

  8. Neurotransmitters and putative neuromodulators in the gut of Anguilla anguilla (L.. Localizations in the enteric nervous and endocrine systems

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    A Veggetti

    2009-12-01

    Full Text Available The gut of silver eels (Anguilla anguilla L. was investigated in order to describe both the cholinergic and adrenergic intramural innervations, and the localization of possible accessory neuromediators. Histochemical reactions for the demonstration of nicotinamide adenine dinucleotide phosphate, reduced form-(NADPH-diaphorase and acetylcholinesterese (AChEase were performed, as well as the immunohistochemical testing of tyrosine hydroxylase, met-enkephalin, substance P, calcitonin gene-related peptide (CGRP, bombesin, vasoactive intestinal peptide (VIP, neuropeptide Y (NPY, somatostatin, cholecystokinin-octapeptide (CCK-8, serotonin, cholineacetyltransferase. The results evidenced a different pattern in comparison with other vertebrates, namely mammals, and with other fish. Both NADPH-diaphorase and AChEase activities were histochemically detected all along the gut in the myenteric plexus, the inner musculature and the propria-submucosa. Tyrosine hydroxylase immunoreactivity was observed in the intestinal tract only, both in the myenteric plexus and in the inner musculature. Several neuropeptides (metenkephalin, CGRP, bombesin, substance P, VIP, NPY, somatostatin were, in addition, detected in the intramural innervation; some of them also in epithelial cells of the diffuse endocrine system (met-enkephalin, substance P, NPY, somatostatin. Serotonin was only present in endocrine cells. Tyrosine hydroxylase immunoreactivity was present in localizations to those of similar NADPHdiaphorase- reactivity, and in the same nerve bundles in which substance P- and CGRP-likeimmunoreactivities were detectable in the intestinal tract. In addition, NADPH-diaphorase-reactive neurons showed an anatomical relationship with AChEase-reactive nerve terminals, and a similar relationship existed between the latter and substance P-like immunoreactivity.

  9. Muscarinic and nicotinic cholinergic receptor antagonists differentially mediate acquisition of fructose-conditioned flavor preference and quinine-conditioned flavor avoidance in rats.

    Science.gov (United States)

    Rotella, Francis M; Olsson, Kerstin; Vig, Vishal; Yenko, Ira; Pagirsky, Jeremy; Kohen, Ilanna; Aminov, Alon; Dindyal, Trisha; Bodnar, Richard J

    2015-09-01

    Rats display both conditioned flavor preference (CFP) for fructose, and conditioned flavor avoidance (CFA) following sweet adulteration with quinine. Previous pharmacological analyses revealed that fructose-CFP expression was significantly reduced by dopamine (DA) D1 or D2 antagonists, but not NMDA or opioid antagonists. Fructose-CFP acquisition was significantly reduced by DA D1, DA D2 or NMDA antagonists, but not opioid antagonists. Quinine-CFA acquisition was significantly enhanced and prolonged by DA D1, NMDA or opioid, but not DA D2 antagonists. Cholinergic interneurons and projections interact with DA systems in the nucleus accumbens and ventral tegmental area. Further, both muscarinic and nicotinic cholinergic receptor signaling have been implicated in sweet intake and development of food-related preferences. Therefore, the present study examined whether systemic administration of muscarinic (scopolamine: SCOP) or nicotinic (mecamylamine: MEC) cholinergic receptor antagonists mediated fructose-CFP expression, fructose-CFP acquisition and quinine-CFA acquisition. For fructose-CFP expression, rats were trained over 10 sessions with a CS+ flavor in 8% fructose and 0.2% saccharin and a CS- flavor in 0.2% saccharin. Two-bottle choice tests with CS+ and CS- flavors mixed in 0.2% saccharin occurred following vehicle, SCOP (0.1-10mg/kg) and MEC (1-8mg/kg). For fructose-CFP acquisition, six groups of rats received vehicle, SCOP (1 or 2.5mg/kg), MEC (4 or 6mg/kg) or a limited intake vehicle control 0.5h prior to 10 CS+ and CS- training sessions followed by six 2-bottle CS+ and CS- choice tests in 0.2% saccharin. For quinine-CFA acquisition, five groups of rats received vehicle, SCOP (1 or 2.5mg/kg) or MEC (4 or 6mg/kg) 0.5h prior to 8 one-bottle CS- (8% fructose+0.2% saccharin: FS) and CS+ (fructose+saccharin+quinine (0.030%: FSQ) training sessions followed by six 2-bottle CS- and CS+ choice tests in fructose-saccharin solutions. Fructose-CFP expression was

  10. The cholinergic system is involved in regulation of the development of the hematopoietic system.

    Science.gov (United States)

    Serobyan, Naira; Jagannathan, Suchitra; Orlovskaya, Irina; Schraufstatter, Ingrid; Skok, Marina; Loring, Jeanne; Khaldoyanidi, Sophia

    2007-05-30

    Gene expression profiling demonstrated that components of the cholinergic system, including choline acetyltransferase, acetylcholinesterase and nicotinic acetylcholine receptors (nAChRs), are expressed in embryonic stem cells and differentiating embryoid bodies (EBs). Triggering of nAChRs expressed in EBs by nicotine resulted in activation of MAPK and shifts of spontaneous differentiation toward hemangioblast. In vivo, non-neural nAChRs are detected early during development in fetal sites of hematopoiesis. Similarly, in vivo exposure of the developing embryo to nicotine resulted in higher numbers of hematopoietic progenitors in fetal liver. However postpartum, the number of hematopoietic stem/progenitor cells (HSPC) was decreased, suggesting an impaired colonization of the fetal bone marrow with HSPCs. This correlated with increased number of circulating HSPC and decreased expression of CXCR4 that mediates migration of circulating cells into the bone marrow regulatory niche. In addition, protein microarrays demonstrated that nicotine changed the profile of cytokines produced in the niche. While the levels of IL1alpha, IL1beta, IL2, IL9 and IL10 were not changed, the production of hematopoiesis-supportive cytokines including G-CSF, GM-CSF, IL3, IL6 and IGFBP-3 was decreased. This correlated with the decreased repopulating ability of HSPC in vivo and diminished hematopoietic activity in bone marrow cultures treated with nicotine. Interestingly, nicotine stimulated the production of IL4 and IL5, implying a possible role of the cholinergic system in pathogenesis of allergic diseases. Our data provide evidence that the nicotine-induced imbalance of the cholinergic system during gestation interferes with normal development and provides the basis for negative health outcomes postpartum in active and passive smokers.

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

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    Leite-Panissi C.R.A.

    2004-01-01

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

  12. Intricate paths of cells and networks becoming "Cholinergic" in the embryonic chicken retina.

    Science.gov (United States)

    Thangaraj, Gopenath; Greif, Alexander; Bachmann, Gesine; Layer, Paul G

    2012-10-01

    Choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) are the decisive enzymatic activities regulating the availability of acetylcholine (ACh) at a given synaptic or nonsynaptic locus. The only cholinergic cells of the mature inner retina are the so-called starburst amacrine cells (SACs). A type-I SAC, found at the outer border of the inner plexiform layer (IPL), forms a synaptic subband "a" within the IPL, while a type-II SAC located at the inner IPL border projects into subband "d." Applying immunohistochemistry for ChAT and AChE on sections of the chicken retina, we here have revealed intricate relationships of how retinal networks became dominated by AChE or by ChAT reactivities. AChE+ cells were first detectable in an embryonic day (E)4 retina, while ChAT appeared 1 day later in the very same cells; at this stage all are Brn3a+, a marker for ganglion cells (GCs). On either side of a faint AChE+ band, indicating the future IPL, pairs of ChAT+ /AChE- /Brn3a- cells appeared between E7/8. Type-I cells had increased ChAT and lost AChE; type-II cells presented less ChAT, but some AChE on their surfaces. Direct neighbors of SACs tended to express much AChE. Along with maturation, subband "a" presented more ChAT but less AChE; in subband "d" this pattern was reversed. In conclusion, the two retinal cholinergic networks segregate out from one cell pool, become locally opposed to each other, and become dominated by either synthesis or degradation of ACh. These "cholinergic developmental divergences" may also have significant physiologic consequences.

  13. Protection of early phase hepatic ischemia-reperfusion injury by cholinergic agonists

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    Roth Robert

    2006-02-01

    Full Text Available Abstract Background Cytokine production is critical in ischemia/reperfusion (IR injury. Acetylcholine binds to macrophages and inhibits cytokine synthesis, through the cholinergic anti-inflammatory pathway. This study examined the role of the cholinergic pathway in cytokine production and hepatic IR- injury. Methods Adult male mice underwent 90-min of partial liver ischemia followed by reperfusion. The AChR agonists (1,1-dimethyl-4-phenyl-L-pioperazinium-iodide [DMPP], and nicotine or saline-vehicle were administered i.p. before ischemia. Plasma cytokine tumor necrosis factor (TNF-α, macrophage inflammatory protein-2, and Interleukin-6 were measured. Liver injury was assessed by plasma alanine transaminase (ALT and liver histopathology. Results A reperfusion time-dependent hepatocellular injury occurred as was indicated by increased plasma-ALT and histopathology. The injury was associated with marked elevation of plasma cytokines/chemokines. Pre-ischemic treatment of mice with DMPP or nicotine significantly decreased plasma-ALT and cytokines after 3 h of reperfusion. After 6 h of reperfusion, the protective effect of DMPP decreased and reached a negligible level by 24 h of reperfusion, despite significantly low levels of plasma cytokines. Histopathology showed markedly diminished hepatocellular injury in DMPP- and nicotine-pretreated mice during the early-phase of hepatic-IR, which reached a level comparable to saline-treated mice at late-phase of IR. Conclusion Pharmacological modulation of the cholinergic pathway provides a means to modulate cytokine production and to delay IR-induced heaptocellular injury.

  14. 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.

  15. Neuromodulators for Aging Skin

    Science.gov (United States)

    ... Dermatologic Surgery Expertise for the life of your skin (TM) Public Resources Dermatologic Surgery Conditions Treatments and ... learn-more"> 3 million Americans are diagnosed with skin cancer every year Any suspicious new growths or ...

  16. Neuromodulation of chronic headaches

    DEFF Research Database (Denmark)

    Martelletti, Paolo; Jensen, Rigmor H; Antal, Andrea

    2013-01-01

    stimulation, occipital nerve stimulation, stimulation of sphenopalatine ganglion, cervical spinal cord stimulation, vagus nerve stimulation, transcranial direct current stimulation, repetitive transcranial magnetic stimulation, and transcutaneous electrical nerve stimulation are extensively published although...

  17. Cholinergic stimulation with pyridostigmine improves autonomic function in infarcted rats.

    Science.gov (United States)

    de La Fuente, Raquel N; Rodrigues, Bruno; Moraes-Silva, Ivana C; Souza, Leandro E; Sirvente, Raquel; Mostarda, Cristiano; De Angelis, Kátia; Soares, Pedro P; Lacchini, Silvia; Consolim-Colombo, Fernanda; Irigoyen, Maria-Cláudia

    2013-09-01

    In the present study we evaluated the effects of short-term pyridostigmine bromide (0.14 mg/mL) treatment started early after myocardial infarction (MI) on left ventricular (LV) and autonomic functions in rats. Male Wistar rats were divided into control, pyridostigmine, infarcted and infarcted + pyridostigmine-treated groups. Pyridostigmine was administered in the drinking water, starting immediately after MI or sham operation, for 11 days. Left ventricular function was evaluated indirectly by echocardiography and directly by LV catheterization. Cardiovascular autonomic control was evaluated by baroreflex sensitivity (BRS), heart rate variability (HRV) and pharmacological blockade. All evaluations started after 7 days pyridostigmine treatment and were finalized after 11 days treatment. Pyridostigmine prevented the impairment of +dP/dT and reduced the MI area in infarcted + pyridostigmine compared with infarcted rats (7 ± 3% vs 17 ± 4%, respectively). Mean blood pressure was restored in infarcted + pyridostigmine compared with infarcted rats (103 ± 3 vs 94 ± 3 mmHg, respectively). In addition, compared with the infarcted group, pyridostigmine improved BRS, as evaluated by tachycardic (1.6 ± 0.2 vs 2.5 ± 0.2 b.p.m./mmHg, respectively) and bradycardic (-0.42 ± 0.01 vs -1.9 ± 0.1 b.p.m./mmHg) responses, and reduced the low frequency/high frequency ratio of HRV (0.81 ± 0.11 vs 0.24 ± 0.14, respectively). These improvements are probably associated with increased vagal tone and reduced sympathetic tone in infarcted + pyridostigmine compared with infarcted rats. In conclusion, the data suggest that short-term pyridostigmine treatment started early after MI can improve BRS, HRV and parasympathetic and sympathetic tone in experimental rats. These data may have potential clinical implications because autonomic markers have prognostic significance after MI.

  18. Regulated Extracellular Choline Acetyltransferase Activity- The Plausible Missing Link of the Distant Action of Acetylcholine in the Cholinergic Anti-Inflammatory Pathway.

    Directory of Open Access Journals (Sweden)

    Swetha Vijayaraghavan

    Full Text Available Acetylcholine (ACh, the classical neurotransmitter, also affects a variety of nonexcitable cells, such as endothelia, microglia, astrocytes and lymphocytes in both the nervous system and secondary lymphoid organs. Most of these cells are very distant from cholinergic synapses. The action of ACh on these distant cells is unlikely to occur through diffusion, given that ACh is very short-lived in the presence of acetylcholinesterase (AChE and butyrylcholinesterase (BuChE, two extremely efficient ACh-degrading enzymes abundantly present in extracellular fluids. In this study, we show compelling evidence for presence of a high concentration and activity of the ACh-synthesizing enzyme, choline-acetyltransferase (ChAT in human cerebrospinal fluid (CSF and plasma. We show that ChAT levels are physiologically balanced to the levels of its counteracting enzymes, AChE and BuChE in the human plasma and CSF. Equilibrium analyses show that soluble ChAT maintains a steady-state ACh level in the presence of physiological levels of fully active ACh-degrading enzymes. We show that ChAT is secreted by cultured human-brain astrocytes, and that activated spleen lymphocytes release ChAT itself rather than ACh. We further report differential CSF levels of ChAT in relation to Alzheimer's disease risk genotypes, as well as in patients with multiple sclerosis, a chronic neuroinflammatory disease, compared to controls. Interestingly, soluble CSF ChAT levels show strong correlation with soluble complement factor levels, supporting a role in inflammatory regulation. This study provides a plausible explanation for the long-distance action of ACh through continuous renewal of ACh in extracellular fluids by the soluble ChAT and thereby maintenance of steady-state equilibrium between hydrolysis and synthesis of this ubiquitous cholinergic signal substance in the brain and peripheral compartments. These findings may have important implications for the role of cholinergic

  19. Electrical Stimulation of Low-Threshold Proprioceptive Fibers in the Adult Rat Increases Density of Glutamatergic and Cholinergic Terminals on Ankle Extensor α-Motoneurons.

    Science.gov (United States)

    Gajewska-Woźniak, Olga; Grycz, Kamil; Czarkowska-Bauch, Julita; Skup, Małgorzata

    2016-01-01

    The effects of stimulation of low-threshold proprioceptive afferents in the tibial nerve on two types of excitatory inputs to α-motoneurons were tested. The first input is formed by glutamatergic Ia sensory afferents contacting monosynaptically α-motoneurons. The second one is the cholinergic input originating from V0c-interneurons, located in lamina X of the spinal cord, modulating activity of α-motoneurons via C-terminals. Our aim was to clarify whether enhancement of signaling to ankle extensor α-motoneurons, via direct electrical stimulation addressed predominantly to low-threshold proprioceptive fibers in the tibial nerve of awake rats, will affect Ia glutamatergic and cholinergic innervation of α-motoneurons of lateral gastrocnemius (LG). LG motoneurons were identified with True Blue tracer injected intramuscularly. Tibial nerve was stimulated for 7 days with continuous bursts of three pulses applied in four 20 min sessions daily. The Hoffmann reflex and motor responses recorded from the soleus muscle, LG synergist, allowed controlling stimulation. Ia terminals and C-terminals abutting on LG-labeled α-motoneurons were detected by immunofluorescence (IF) using input-specific anti- VGLUT1 and anti-VAChT antibodies, respectively. Quantitative analysis of confocal images revealed that the number of VGLUT1 IF and VAChT IF terminals contacting the soma of LG α-motoneurons increased after stimulation by 35% and by 26%, respectively, comparing to the sham-stimulated side. The aggregate volume of VGLUT1 IF and VAChT IF terminals increased by 35% and by 30%, respectively. Labeling intensity of boutons was also increased, suggesting an increase of signaling to LG α-motoneurons after stimulation. To conclude, one week of continuous burst stimulation of proprioceptive input to LG α-motoneurons is effective in enrichment of their direct glutamatergic but also indirect cholinergic inputs. The effectiveness of such and longer stimulation in models of injury is a

  20. Cholinergic cells in the nucleus basalis of mice express the N-methyl-D-aspartate-receptor subunit NR2C and its replacement by the NR2B subunit enhances frontal and amygdaloid acetylcholine levels

    NARCIS (Netherlands)

    De Souza Silva, M. A.; Dolga, Amalia; Pieri, I.; Marchetti, L.; Eisel, U. L. M.; Huston, J. P.; Dere, E.

    2006-01-01

    It is known that glutamatergic and cholinergic systems interact functionally at the level of the cholinergic basal forebrain. The N-methyl-D-aspartate receptor (NMDA-R) is a multiprotein complex composed of NR1, NR2 and/or NR3 subunits. The subunit composition of NMDA-R of cholinergic cells in the n

  1. The Protective Effect of Electroacupuncturing Zusanli Points on Hemorrhagic Shock Rats through Cholinergic Anti-inflammatory Pathway

    Institute of Scientific and Technical Information of China (English)

    Zhao-Hui DU; Jian-Guo LI; Yan-Lin WANG; Zhou-Quan PENG; Xiao-Feng YE

    2005-01-01

    @@ 1 Introduction In conditions of circulatory shock, systemic inflammatory response (SIRS) plays a funda mental pathogenetic role, with activation of transcription nuclear factors(mainly NF- kB) and markedly increased production of cytokines (mainly TNF-a), which trigger the inflammatory cascade active ation. Recent research have identified a basic neural pathway that reflexively monitors and adjusts such response. It is through the rapid activation (in "real-time") of efferent vagus nerve fibres(the recentlyrecognized "brain cholinergic antiinflammatory pathway" ) [1].There are show that the rapid activation cholinergic antiinflammatory pathway can protect against the hemorrhagic shock[2,3].

  2. Short-term plasticity and modulation of synaptic transmission at mammalian inhibitory cholinergic olivocochlear synapses

    Directory of Open Access Journals (Sweden)

    Eleonora eKatz

    2014-12-01

    Full Text Available The organ of Corti, the mammalian sensory epithelium of the inner ear, has two types of mechanoreceptor cells, inner hair cells (IHCs and outer hair cells (OHCs. In this sensory epithelium, vibrations produced by sound waves are transformed into electrical signals. When depolarized by incoming sounds, IHCs release glutamate and activate auditory nerve fibers innervating them and OHCs, by virtue of their electromotile property, increase the amplification and fine tuning of sound signals. The medial olivocochlear (MOC system, an efferent feedback system, inhibits OHC activity and thereby reduces the sensitivity and sharp tuning of cochlear afferent fibers. During neonatal development, IHCs fire Ca2+ action potentials which evoke glutamate release promoting activity in the immature auditory system in the absence of sensory stimuli. During this period, MOC fibers also innervate IHCs and are thought to modulate their firing rate. Both the MOC-OHC and the MOC-IHC synapses are cholinergic, fast and inhibitory and mediated by the alpha9alpha10 nicotinic cholinergic receptor (nAChR coupled to the activation of calcium-activated potassium channels that hyperpolarize the hair cells.In this review we discuss the biophysical, functional and molecular data which demonstrate that at the synapses between MOC efferent fibers and cochlear hair cells, modulation of transmitter release as well as short-term synaptic plasticity mechanisms, operating both at the presynaptic terminal and at the postsynaptic hair-cell, determine the efficacy of these synapses and shape the hair cell response pattern.

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

    Directory of Open Access Journals (Sweden)

    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.

  4. Outcomes from two forms of training for first-responder competency in cholinergic crisis management.

    Science.gov (United States)

    Andreatta, Pamela; Klotz, Jessica J; Madsen, James M; Hurst, Charles G; Talbot, Thomas B

    2015-04-01

    Military and civilian first responders must be able to recognize and effectively manage mass disaster casualties. Clinical management of injuries resulting from nerve agents provides different challenges for first responders than those of conventional weapons. We evaluated the impact of a mixed-methods training program on competency acquisition in cholinergic crisis clinical management using multimedia with either live animal or patient actor examples, and hands-on practice using SimMan3G mannequin simulators. A purposively selected sample of 204 civilian and military first responders who had not previously completed nerve agent training were assessed pre- and post-training for knowledge, performance, self-efficacy, and affective state. We conducted analysis of variance with repeated measures; statistical significance p 20%, performance > 50%, self-efficacy > 34%, and affective state > 15%. There were no significant differences between the live animal and patient actor groups. These findings could aid in the specification of training for first-responder personnel in military and civilian service. Although less comprehensive than U.S. Army Medical Research Institute of Chemical Defense courses, the training outcomes associated with this easily distributed program demonstrate its value in increasing the competency of first responders in recognizing and managing a mass casualty cholinergic event.

  5. Repetitive measurements of pulmonary mechanics to inhaled cholinergic challenge in spontaneously breathing mice.

    Science.gov (United States)

    Glaab, Thomas; Mitzner, Wayne; Braun, Armin; Ernst, Heinrich; Korolewitz, Regina; Hohlfeld, Jens M; Krug, Norbert; Hoymann, Heinz G

    2004-09-01

    Precise and repeatable measurements of pulmonary function in intact mice are becoming increasingly important for experimental investigations on various respiratory disorders including asthma. Here, we present validation of a novel in vivo method that, for the first time, combines direct and repetitive recordings of standard pulmonary mechanics with cholinergic aerosol challenges in anesthetized, orotracheally intubated, spontaneously breathing mice. We demonstrate that, in several groups of nonsensitized BALB/c mice, dose-related increases in pulmonary resistance and dynamic compliance to aerosolized methacholine are reproducible over short and extended intervals without causing detectable cytological alterations in the bronchoalveolar lavage or relevant histological changes in the proximal trachea and larynx regardless of the number of orotracheal intubations. Moreover, as further validation, we confirm that allergic mice, sensitized and challenged with Aspergillus fumigatus, were significantly more responsive to cholinergic challenge (P mechanics in studies of various respiratory disorders in mice, including experimental models of asthma and chronic obstructive pulmonary disorder, investigations of pulmonary pharmacology, or more general investigations of the genetic determinants of lung function.

  6. ( 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.

  7. Cholinergic modulation differs between basal and apical dendritic excitation of hippocampal CA1 pyramidal cells.

    Science.gov (United States)

    Leung, L Stan; Péloquin, Pascal

    2010-08-01

    We hypothesize that endogenous cholinergic modulation of dendritic processing of hippocampal CA1 is layer specific, and it specifically enhances spike output resulting from basal as compared with the apical dendritic excitation. Laminar profiles of evoked field potentials were recorded in the CA1 area of urethane-anesthetized rats using multichannel silicon probes and analyzed as current source density. High-frequency stimulation of the pontis oralis (PnO) attenuated the midapical more than the basal or distal apical dendritic excitatory sink. Population spike (PS) and excitatory sink-PS potentiation resulting from basal dendritic excitation were facilitated, while the PS evoked by apical dendritic stimulation was attenuated by PnO stimulation. Perfusion of cholinergic agonist carbachol onto hippocampal slices in vitro also attenuated the apical more than the basal dendritic excitatory postsynaptic potentials. Excitatory sink attenuation and PS changes after PnO stimulation were blocked by systemic or local scopolamine and by intracerebroventricular (icv) M1 receptor antagonist pirenzepine but not by icv M2 receptor antagonist AFDX-116 or nicotinic antagonists. However, a hippocampal theta rhythm activated by PnO stimulation was blocked by systemic but not by local scopolamine. We conclude that endogenous acetylcholine mediates a stronger presynaptic inhibition of the midapical than basal and distal apical excitation mainly through M1 receptors.

  8. Hypothesis for synergistic toxicity of organophosphorus poisoning-induced cholinergic crisis and anaphylactoid reactions

    Energy Technology Data Exchange (ETDEWEB)

    Cowan, F.M.; Shih, T.M.; Lenz, D.E.; Madsen, J.M.; Broomfield, C.A.

    1996-08-01

    The neurotoxicity of organophosphorus (OP) compounds Involves the Inhibition of acetylchollnesterase (AChE), causing accumulation of acetyicholine (ACh) at synapses. However, cholinergic crisis may not be the sole mechanism of OP toxicity. Adverse drug reactions caused by synergistic toxicity between drugs with distinct pharmacological mechanisms are a common problem. Likewise, the multiple pharmacological activities of a single molecule might also contribute to either toxicity or efficacy. For example, certain OP compounds (e.g. soman) exhibit anti-AChE activity and also act as secretagogues by inducing mast cell degranulation with associated autacoid release and anaphylactoid reactions. Anaphylactoid shock can produce a lethal syndrome with symptoms of respiratory failure and circulatory collapse similar to the physiological sequelae observed for OP poisoning. Moreover, the major classes of drugs used as antidotes for OP intoxication can affect anaphylaxis. Acetylcholine can act as an agonist of autacoid release, and autacoids such as histamine can augment soman-Induced bronchial spasm. In concert with the demonstrably critical role of cholinergic crisis In OP toxicity, the precepts of neuroimmunology indicate that secondary adverse reactions encompassing anaphylactold reactions may complicate OP toxicity.

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

    Science.gov (United States)

    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.

  10. Invasive versus noninvasive measurement of allergic and cholinergic airway responsiveness in mice

    Directory of Open Access Journals (Sweden)

    Hohlfeld Jens M

    2005-11-01

    Full Text Available Abstract Background This study seeks to compare the ability of repeatable invasive and noninvasive lung function methods to assess allergen-specific and cholinergic airway responsiveness (AR in intact, spontaneously breathing BALB/c mice. Methods Using noninvasive head-out body plethysmography and the decrease in tidal midexpiratory flow (EF50, we determined early AR (EAR to inhaled Aspergillus fumigatus antigens in conscious mice. These measurements were paralleled by invasive determination of pulmonary conductance (GL, dynamic compliance (Cdyn and EF50 in another group of anesthetized, orotracheally intubated mice. Results With both methods, allergic mice, sensitized and boosted with A. fumigatus, elicited allergen-specific EAR to A. fumigatus (p Conclusion We conclude that invasive and noninvasive pulmonary function tests are capable of detecting both allergen-specific and cholinergic AR in intact, allergic mice. The invasive determination of GL and Cdyn is superior in sensitivity, whereas the noninvasive EF50 method is particularly appropriate for quick and repeatable screening of respiratory function in large numbers of conscious mice.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1990-10-12

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

  12. 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.

  13. Excitatory and inhibitory cholinergic effects of yohimbine on isolated guinea-pig small intestine.

    Science.gov (United States)

    Del Tacca, M; Tadini, P; Blandizzi, C; Bernardini, M C

    1988-08-01

    The interaction of yohimbine with the cholinergic intestinal system was investigated in the isolated guinea-pig ileum using a wide range of drug concentrations from 3 x 10(-13) to 2 x 10(-4) g/ml. Low concentrations of yohimbine (3 x 10(-13) to 3 x 10(-11) g/ml) caused dose-dependent contractions of the ileal longitudinal muscle, which were potentiated by eserine 1 x 10(-8) g/ml and prevented by tetrodotoxin 1 x 10(-6) g/ml or by atropine 1 x 10(-12) g/ml; methysergide and diphenydramine were ineffective up to 3 x 10(-7) g/ml dose. Submaximal stimulatory responses evoked by twitch stimulation or by acetylcholine were significantly potentiated by the same concentrations of yohimbine (3 x 10(-13) to 3 x 10(-11) g/ml) and blocked by atropine 1 x 10(-12) g/ml. By contrast, high concentrations of yohimbine (1 x 10(-6) to 2 x 10(-4) g/ml) displayed dose-dependent inhibitory effects on cholinergic responses. The stimulant effect of yohimbine seems to be indirect and mediated by the increase in the release of acetylcholine, while the inhibitory action may be due to a molecular interaction with the muscarinic receptors allowing non-specific receptor blockade.

  14. In vivo PET imaging of brain nicotinic cholinergic receptors

    Energy Technology Data Exchange (ETDEWEB)

    Bottlaender, M.; Valette, H.; Saba, W.; Schollhorn-Peyronneau, M.A.; Dolle, F.; Syrota, A. [Service Hospitalier Frederic Joliot (CEA/DSV/DRM), 91 - Orsay (France)

    2006-07-01

    Neuronal acetylcholine receptors (nAChRs) are widely distributed throughout the central nervous system where they modulate a number of CNS functions including neurotransmitter release, cognitive function, anxiety, analgesia and control of cerebral blood flow. In the brain, a major subtype is composed of the {alpha}4{beta}2 subunit combination. Density of this subtype has been shown to be decreased in patients with neuro-degenerative disease such as Alzheimer and Parkinson's disease (AD and PD), and mutated receptors has been described in some familial epilepsy. Thus, in vivo mapping of the nicotinic nAChRs by Positron Emission Tomography (PET) are of great interest to monitor the evolution of these pathologies and changes in the neuronal biochemistry induced by therapeutic agents. Recently, a new compound, 3-[2(S)-2-azetidinyl-methoxy]pyridine (A-85380) has been synthesised and labelled with fluorine-18, [{sup 18}F]fluoro-A-85380 (Dolle et al., 1999). The [{sup 18}F]fluoro-A-85380 has been shown to bind with high affinity t o nAChRs in vitro (Saba et al., 2004), and its toxicity was low and compatible with it s use at tracer dose in human PET studies (Valette, 2002). PET studies in baboons showed that, after in vivo administration of [ {sup 18}F]fluoro-A-85380 at a tracer dose, the distribution of the radioactivity in the brain reflect the distribution of the < 4R2 nAChRs. Competition and pre-blocking studies, using nicotinic agonists, confirm that the radiotracer binds specifically to the heteromeric nAChRs in the brain (Valette et al., 1999). The in vivo, characteristics of the [{sup 18}F]fluoro-A-8538 0 combined with its low toxicity make possible the imaging of the nicotinic receptor s in human by PET (Bottlaender 2003). Studies were performed in healthy non-smoker volunteers to evaluate the brain kinetics of [{sup 18}F]fluoro-A-85380 and to assess the quantification of its nAChRs binding in the human brain with PET (Gallezot et a., 2005). The [{sup 18}F

  15. Cholinergic Stimulation Prevents the Development of Autoimmune Diabetes: Evidence for the Modulation of Th17 Effector Cells via an IFNγ-Dependent Mechanism

    Science.gov (United States)

    George, Junu A.; Bashir, Ghada; Qureshi, Mohammed M.; Mohamed, Yassir A.; Azzi, Jamil; al-Ramadi, Basel K.; Fernández-Cabezudo, Maria J.

    2016-01-01

    Type I diabetes (T1D) results from T cell-mediated damage of pancreatic β-cells and loss of insulin production. The cholinergic anti-inflammatory pathway represents a physiological link connecting the central nervous and immune systems via vagus nerve, and functions to control the release of proinflammatory cytokines. Using the multiple low-dose streptozotocin (MLD-STZ) model to induce experimental autoimmune diabetes, we investigated the potential of regulating the development of hyperglycemia through administration of paraoxon, a highly specific acetylcholinesterase inhibitor (AChEI). We demonstrate that pretreatment with paraoxon prevented hyperglycemia in STZ-treated C57BL/6 mice. This correlated with a reduction in T cell infiltration into pancreatic islets and preservation of the structure and functionality of β-cells. Gene expression analysis of pancreatic tissue revealed that increased peripheral cholinergic activity prevented STZ-mediated loss of insulin production, this being associated with a reduction in IL-1β, IL-6, and IL-17 proinflammatory cytokines. Intracellular cytokine analysis in splenic T cells demonstrated that inhibition of AChE led to a shift in STZ-induced immune response from a predominantly disease-causing IL-17-expressing Th17 cells to IFNγ-positive Th1 cells. Consistent with this conclusion, inhibition of AChE failed to prevent STZ-induced hyperglycemia in IFNγ-deficient mice. Our results provide mechanistic evidence for the prevention of murine T1D by inhibition of AChE and suggest a promising strategy for modulating disease severity. PMID:27790217

  16. Maternal exposure to hexachlorophene targets intermediate-stage progenitor cells in the hippocampal neurogenesis involving myelin vacuolation of cholinergic and glutamatergic inputs in mice.

    Science.gov (United States)

    Kato, Mizuho; Abe, Hajime; Itahashi, Megu; Kikuchihara, Yoh; Kimura, Masayuki; Mizukami, Sayaka; Yoshida, Toshinori; Shibutani, Makoto

    2016-02-01

    Hexachlorophene (HCP) has been shown to induce myelin vacuolation due to intramyelinic edema of the nerve fibers in animal neural tissue. We investigated the maternal exposure effect of HCP on hippocampal neurogenesis in the offspring of pregnant mice supplemented with 0 (control), 33 or 100 ppm HCP in diet from gestational day 6 to day 21 after delivery. On postnatal day (PND) 21, offspring as examined in males exhibited decreased granule cell lineage populations expressing paired box 6, sex-determining region Y-box 2 and eomesodermin in the hippocampal subgranular zone (SGZ) accompanied by myelin vacuolation involving white matter tracts of the hippocampal fimbria at ≥ 33 ppm. However, SGZ cellular populations expressing brain lipid binding protein and doublecortin were unchanged at any dose. Transcript expression of cholinergic receptor genes, Chrna4 and Chrnb2, and glutamate receptor genes, Grm1 and Grin2d, examined at 100 ppm, decreased in the dentate gyrus. HCP exposure did not alter the number of proliferating or apoptotic cells in the SGZ, or reelin- or calcium-binding protein-expressing γ-aminobutyric acid (GABA)ergic interneurons in the dentate hilus, on PND 21 and PND 77. All neurogenesis-related changes observed in HCP-exposed offspring on PND 21 disappeared on PND 77, suggesting that maternal HCP exposure at ≥ 33 ppm reversibly decreased type 2 intermediate-stage progenitor cells in the hippocampal neurogenesis. Myelin vacuolation might be responsible for changes in neurogenesis possibly by reducing nerve conduction velocity of cholinergic inputs from the septal-hippocampal pathway to granule cell lineages and/or GABAergic interneurons, and of glutamatergic inputs to granule cell lineages.

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

    Directory of Open Access Journals (Sweden)

    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.

  18. 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.

  19. Role of cholinergic anti-inflammatory pathway in regulating host response and its interventional strategy for inflammatory diseases

    Institute of Scientific and Technical Information of China (English)

    WANG Da-wei; ZHOU Rong-bin; YAO Yong-ming

    2009-01-01

    @@ The cholinergic anti-inflammatory pathway (CAP) is a neurophysiological mechanism that regulates the immune system. The CAP inhibits inflammation by suppressing cytokine synthesis via release of acetylcholine in organs of the reticuloendothelial system, including the lungs, spleen, liver, kidneys and gastrointestinal tract.

  20. The Role of Muscarinic and Nicotinic Cholinergic Neurotransmission in Aversive Conditioning: Comparing Pavlovian Fear Conditioning and Inhibitory Avoidance

    Science.gov (United States)

    Tinsley, Matthew R.; Quinn, Jennifer J.; Fanselow, Michael S.

    2004-01-01

    Aversive conditioning is an ideal model for studying cholinergic effects on the processes of learning and memory for several reasons. First, deficits produced by selective lesions of the anatomical structures shown to be critical for Pavlovian fear conditioning and inhibitory avoidance (such as the amygdala and hippocampus) resemble those deficits…

  1. Learning to Ignore: A Modeling Study of a Decremental Cholinergic Pathway and Its Influence on Attention and Learning

    Science.gov (United States)

    Oros, Nicolas; Chiba, Andrea A.; Nitz, Douglas A.; Krichmar, Jeffrey L.

    2014-01-01

    Learning to ignore irrelevant stimuli is essential to achieving efficient and fluid attention, and serves as the complement to increasing attention to relevant stimuli. The different cholinergic (ACh) subsystems within the basal forebrain regulate attention in distinct but complementary ways. ACh projections from the substantia innominata/nucleus…

  2. The organization of the brainstem and spinal cord of the mouse : Relationships between monoaminergic, cholinergic, and spinal projection systems

    NARCIS (Netherlands)

    VanderHorst, VGJM; Ulfhake, B

    2006-01-01

    Information regarding the organization of the CNS in terms of neurotransmitter systems and spinal connections in the mouse is sparse, especially at the level of the brainstem. An overview is presented of monoaminergic and cholinergic systems in the brainstem and spinal cord that were visualized immu

  3. Long-term effects of cholinergic basal forebrain lesions on neuropeptide Y and somatostatin immunoreactivity in rat neocortex

    NARCIS (Netherlands)

    Gaykema, R.P.A.; Compaan, J.C.; Nyakas, C.; Horvath, E.; Luiten, P.G.M.

    1989-01-01

    The effect of cholinergic basal forebrain lesions on immunoreactivity to somatostatin (SOM-i) and neuropeptide-Y (NPY-i) was investigated in the rat parietal cortex, 16-18 months after multiple bilateral ibotenic acid injections in the nucleus basalis complex. As a result of the lesion, the choliner

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

    Science.gov (United States)

    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.

  5. Fetal cholinergic anti-inflammatory pathway and necrotizing enterocolitis: the brain-gut connection begins in utero

    Directory of Open Access Journals (Sweden)

    Luca eGarzoni

    2013-08-01

    Full Text Available Necrotizing enterocolitis (NEC is an acute neonatal inflammatory disease that affects the intestine and may result in necrosis, systemic sepsis and multisystem organ failure. NEC affects 5-10% of all infants with birth weight ≤ 1500 g or gestational age less than 30 weeks. Chorioamnionitis (CA is the main manifestation of pathological inflammation in the fetus and is strongly associated with NEC. CA affects 20% of full-term pregnancies and up to 60% of preterm pregnancies and, notably, is often an occult finding. Intrauterine exposure to inflammatory stimuli may switch innate immunity cells such as macrophages to a reactive phenotype (‘priming’. Confronted with renewed inflammatory stimuli during labour or postnatally, such sensitized cells can sustain a chronic or exaggerated production of proinflammatory cytokines associated with NEC (two-hit hypothesis. Via the cholinergic anti-inflammatory pathway, a neurally mediated innate anti-inflammatory mechanism, higher levels of vagal activity are associated with lower systemic levels of proinflammatory cytokines. This effect is mediated by the α7 subunit nicotinic acetylcholine receptor (α7nAChR on macrophages. The gut is the most extensive organ innervated by the vagus nerve; it is also the primary site of innate immunity in the newborn. Here we review the mechanisms of possible neuroimmunological brain-gut interactions involved in the induction and control of antenatal intestinal inflammatory response and priming. We propose a neuroimmunological framework to 1 study the long-term effects of perinatal intestinal response to infection and 2 to uncover new targets for preventive and therapeutic intervention.

  6. 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

  7. Alteration of cholinergic and peptidergic neurotransmitters in rat ileum induced by acute stress following transient intestinal infection is mast cell dependent

    Institute of Scientific and Technical Information of China (English)

    LENG Yu-xin; WEI Yan-yu; CHEN Hong; ZHOU Shu-pei; YANG Yan-lin; DUAN Li-ping

    2010-01-01

    Background Mast cells are implicated in the development of irritable bowel syndrome (IBS), which is associated with the activation of the "neural-immune" system. The aim of this study was to investigate the role of mast cells in the remodeling of cholinergic and peptidergic neurotransmitters induced by acute cold restriction stress (ACRS) post infection (PI) using mast cell deficient rats (Ws/Ws) and their wild-type controls (+/+).Methods Transient intestinal infection was initiated by giving 1500 Trichinella spiralis (T.S.) larvae by gavage. ACRS was induced for 2 hours at day 100 PI. Samples of terminal ilea were prepared for H&E staining, mast cell counting and activation and assessment of IL-1β and IL-10.Results When infected, both strains of rats experienced an acute infectious stage followed by a recovery. Histological scores were significantly higher in infected rats compared with those of the non-infected controls at day 10 PI (10 day-PI vs. control: +/+: 2.75±0.17 vs. 0.42±0.09; Ws/Ws: 2.67±0.67 vs. 0.50±0.34; P0.05), accompanied by hyperplasia and activation of mast cells (PI+ACRS vs. control: 58.8±19.2 vs. 28.0±7.6; P <0.01). The balance between acetylcholine (ACh) and substance P (SP) was also disturbed (ACh: PI+ACRS vs. control: (743.94±238.72) vs. (1065.68±256.46) pg/g, P<0.05; SP: PI+ACRS vs. control: (892.60±231.12) vs. (696.61 ±148.61) pg/g, P<0.05). Nevertheless, similar changes of IL-1β/IL-10 and ACh/SP were not detected in Ws/Ws rats. Conclusion The imbalance of ACh/SP, together with the activation of mucosal immunity induced by post-infection ACRS were lacking in mast cell deficient rats, which supports the premise that mast cells play an important role in cholinergic and peptidergic remodeling in the ileum of rats.

  8. Alteration of hepatic cells glucose metabolism as a non-cholinergic detoxication mechanism in counteracting diazinon-induced oxidative stress.

    Science.gov (United States)

    Teimouri, Fatemeh; Amirkabirian, Nasim; Esmaily, Hadi; Mohammadirad, Azadeh; Aliahmadi, Atousa; Abdollahi, Mohammad

    2006-12-01

    The aim of this study was to evaluate effects of acute exposure to various doses of diazinon, a widely used synthetic organophosphorus (OP) insecticide on plasma glucose, hepatic cells key enzymes of glycogenolysis and gluconeogenesis, and oxidative stress in rats. Diazinon was administered by gavage at doses of 15, 30 and 60 mg/ kg. The liver was perfused and removed under anaesthesia. The activities of glycogen phosphorylase (GP), phosphoenolpyruvate carboxykinase (PEPCK), thiobarbituric acid reactive substances (TBARS) and total antioxidant capacity (TAC) were analysed in liver homogenate. Administration of diazinon (15, 30 and 60 mg/kg) increased plasma glucose concentrations by 101.43% (P = 0.001), 103.68% (P = 0.000) and 160.65% (P = 0.000) of control, respectively. Diazinon (15, 30 and 60 mg/kg) increased hepatic GP activity by 43.5% (P = 0.05), 70.3% (P = 0.00) and 117.2% (P = 0.02) of control, respectively. In addition, diazinon (30 and 60 mg/kg) increased hepatic PEPCK by 77.3% (P = 0.000) and 93.5% (P = 0.000) of control, respectively. Diazinon (30 and 60 mg/kg) decreased liver TAC by 38% (P = 0.046) and 48% (P = 0.000) of control, respectively. Also diazinon (30 and 60 mg/kg) increased hepatic cell liver lipid peroxidation by 77% (P = 0.05) and 280% (P = 0.000) of control. The correlations between plasma glucose and hepatic cells TBARS (r2 = 0.537, P = 0.02), between plasma glucose and ChE activity (r2 = 0.81, P = 0.049) and between plasma glucose and hepatic cells GP activity (r2 = 0.833, P = 0.04) were significant. It is concluded that the liver cells are a site of toxic action of diazinon. Diazinon increases glucose release from liver into blood through activation of glycogenolysis and gluconeogenesis as a detoxication non-cholinergic mechanism to overwhelm diazinon-induced toxic stress. The results are in accordance with the hypothesis that OPs are a predisposing factor of diabetes.

  9. 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.

  10. 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

  11. 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.

  12. 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.

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

    Science.gov (United States)

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

    2017-01-01

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

  14. 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.

  15. Effects of mescaline and some of its analogs on cholinergic neuromuscular transmission.

    Science.gov (United States)

    Ghansah, E; Kopsombut, P; Malleque, M A; Brossi, A

    1993-02-01

    Mescaline (3,4,5-trimethoxyphenylethylamine; MES) and its analogs, anhalinine (ANH) and methylenemescaline trimer (MMT) were investigated, using sciatic-sartorius preparations of the frog and cortical tissue from the rat. The effects of MES and its analogs were examined with respect to muscle twitch, resting membrane potential and nicotinic receptor binding. Mescaline and its analogs (10-100 microM) blocked both directly and neurally evoked twitches but their effects on neurally evoked twitches were greater than those on directly evoked twitches. Mescaline, ANH and MMT decreased amplitude of the miniature endplate and endplate potentials, decreased acetylcholine (ACh) quantal content, hyperpolarized the resting membrane potential and prolonged duration of the action potential. They did not significantly displace the binding of [125I]-alpha-bungarotoxin (alpha-BTX) to nicotinic receptors, at concentrations which blocked neuromuscular transmission. These results suggest that MES and its analogs inhibit cholinergic neuromuscular transmission by blocking release of ACh; they also affect K+ conductance.

  16. 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...... the hypothesis that the non-inflammatory antinociception of aspirin and paracetamol could be mediated by an increase of intraspinal acetylcholine release. Microdialysis probes were placed intraspinally in anesthetized rats for acetylcholine sampling. Subcutaneously administered aspirin 100 and 300 mg....../kg increased, while paracetamol 300 mg/kg decreased intraspinal acetylcholine release. Intraspinal drug administration did not affect acetylcholine release. Our results suggest that an increased intraspinal acetylcholine release could be involved in part of the non-inflammatory pain suppression by aspirin...

  17. 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.

  18. 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.

  19. A review study on medicinal plants affecting amnesia through cholinergic system

    Directory of Open Access Journals (Sweden)

    Baradaran Azar

    2012-01-01

    Full Text Available Neurotransmitter modification is an important method for the treatment of memory loss or amnesia. Cholinomimetic drugs, particularly, acetylcholine esterase inhibitors are the mainstream in pharmacotherapy of amnesia. Donepezil, tacrine, galantamine, and rivastigmine are cholinesterase inhibitors which are widely used in the treatment of amnesia, however, their therapeutic effects are not significant. Therefore, other possibilities including herbal medicine sources have been considered for memory loss therapy. There are some Medicinal plants with cholinomimetic property which mostly possess antioxidant activity, too. These plants may not only ameliorate amnesia but also can be a good source for drug discovery. In this paper other than introducing the medicinal plants and their components affective on cholinergic system and effective on memory loss, their probable advantages over synthetic drugs are discussed.

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

    Science.gov (United States)

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

    2016-01-01

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

  1. Human beta-defensin-2 increases cholinergic response in colon epithelium.

    Science.gov (United States)

    Himmerkus, Nina; Vassen, Veit; Sievers, Birte; Goerke, Boeren; Shan, Qixian; Harder, Jürgen; Schröder, Jens-Michael; Bleich, Markus

    2010-06-01

    The human beta-defensin-2 (hBD-2) is expressed in epithelial cells of skin and respiratory and gastrointestinal tracts. Defensins are arginine-rich small cationic peptides with six intramolecular disulfide bonds and are antimicrobially active against a broad spectrum of pathogens. In addition, they have cytokine-like immunomodulatory properties. We hypothesized that hBD-2 also might influence epithelial cells themselves, thereby altering fluid composition in the gastrointestinal tract. We therefore tested its impact on electrogenic ion transport properties of distal colon in Ussing chamber experiments. Application of hBD-2 did not affect transepithelial voltage or resistance in cAMP-stimulated distal colon. However, it increased cholinergic Ca(2+)-dependent Cl(-) secretion. After 20 min of incubation with hBD-2, the effect of carbachol (CCh) on the equivalent short circuit current (I'(sc)) was enhanced twofold compared to vehicle-treated colon. Modulation of Ca(2+) signaling by hBD-2 was validated by Fura-2 measurements in human colon carcinoma HT29 cells. Twenty-minute incubation with hBD-2 increased the CCh-induced Ca(2+) transient by 20-30% compared to either vehicle-treated cells or cells treated with the defensins hBD-1, hBD-3, or HD-5. This effect was concentration-dependent, with an EC(50) of 0.043 microg/ml, and still present in the absence of extracellular Ca(2+). Also, the ionomycin-induced Ca(2+) transient was increased by hBD-2 treatment. We conclude that hBD-2 facilitates cholinergic Ca(2+)-regulated epithelial Cl(-) secretion. These findings contribute to the concept of a specific interaction of antimicrobial peptides with epithelial function.

  2. Alleviating effects of Bushen-Yizhi formula on ibotenic acid-induced cholinergic impairments in rat.

    Science.gov (United States)

    Hou, Xue-Qin; Zhang, Lei; Yang, Cong; Rong, Cui-Ping; He, Wen-Qing; Zhang, Chun-Xia; Li, Shi; Su, Ru-Yu; Chang, Xiang; Qin, Ji-Huan; Chen, Yun-Bo; Xian, Shao-Xiang; Wang, Qi

    2015-04-01

    This study explored the curative effect and underlying mechanisms of a traditional Chinese medicine compound prescription, Bushen-Yizhi formula (BSYZ), in ibotenic acid (IBO)-induced rats. Morris water maze and novel object recognition tests showed that BSYZ significantly improved spatial and object memory. Brain immunohistochemistry staining showed that BSYZ significantly up-regulated expression of choline acetyltransferase (ChAT) and nerve growth factor (NGF) in the hippocampus and cortex. The protein tyrosine kinase high-affinity receptor TrkA was slightly increased in the hippocampus and cortex, and significantly enhanced in the nucleus basalis of Meynert (NBM) after BSYZ intervention. The immunoreactivity of the p75 low-affinity receptor in BSYZ-treated rats was significantly strengthened in the cortex. Similar expression trends of nerve growth factor (NGF), TrkA, and p75 mRNA were observed in the hippocampus and cortex. Additionally, BSYZ reversed IBO-induced disorders of acetylcholine (ACh) levels, ChAT, and cholinesterase (ChE) in the cortex, which was consistent with the changes in mRNA levels of ChAT and acetylcholinesterase (AChE). Expression of ChAT and AChE proteins and mRNA in the hippocampus was up-regulated, whereas the apoptosis-relative protein cleaved caspase-3 was decreased after administration of BSYZ. Moreover, changes in cell death were confirmed by histological morphology. Thus, the results indicated that the BSYZ formula could ameliorate memory impairments in IBO-induced rats, and it exerted its therapeutic action probably by modulating cholinergic pathways, NGF signaling, and anti-apoptosis. Overall, it is suggested that the BSYZ formula might be a potential therapeutic approach for the treatment of Alzheimer's disease (AD) and other cholinergic impairment-related diseases.

  3. 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 activa