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Sample records for cholinergic neuromodulation controls

  1. Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior

    OpenAIRE

    Picciotto, Marina R.; Higley, Michael J.; Mineur, Yann S.

    2012-01-01

    Acetylcholine in the brain alters neuronal excitability, influences synaptic transmission, induces synaptic plasticity and coordinates the firing of groups of neurons. As a result, it changes the state of neuronal networks throughout the brain and modifies their response to internal and external inputs: the classical role of a neuromodulator. Here we identify actions of cholinergic signaling on cellular and synaptic properties of neurons in several brain areas and discuss the consequences of ...

  2. Cholinergic Circuit Control of Postnatal Neurogenesis

    Science.gov (United States)

    Asrican, Brent; Paez-Gonzalez, Patricia; Erb, Joshua; Kuo, Chay T.

    2016-01-01

    New neuron addition via continued neurogenesis in the postnatal/adult mammalian brain presents a distinct form of nervous system plasticity. During embryonic development, precise temporal and spatial patterns of neurogenesis are necessary to create the nervous system architecture. Similar between embryonic and postnatal stages, neurogenic proliferation is regulated by neural stem cell (NSC)-intrinsic mechanisms layered upon cues from their local microenvironmental niche. Following developmental assembly, it remains relatively unclear what may be the key driving forces that sustain continued production of neurons in the postnatal/adult brain. Recent experimental evidence suggests that patterned activity from specific neural circuits can also directly govern postnatal/adult neurogenesis. Here, we review experimental findings that revealed cholinergic modulation, and how patterns of neuronal activity and acetylcholine release may differentially or synergistically activate downstream signaling in NSCs. Higher-order excitatory and inhibitory inputs regulating cholinergic neuron firing, and their implications in neurogenesis control are also considered.

  3. TIMING IS EVERYTHING, EVEN FOR CHOLINERGIC CONTROL

    OpenAIRE

    Berg, Darwin K.

    2011-01-01

    Synaptic plasticity is widely considered to be a cellular mechanism underlying learning and memory. In this issue of Neuron, Gu and Yakel show that the precise timing of a single cholinergic pulse of activity can determine whether plasticity will occur at a glutamatergic synapse and confer long-term potentiation versus depression.

  4. Ultrasonic neuromodulation

    Science.gov (United States)

    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.

  5. Neuromodulation of lower limb motor control in restorative neurology

    OpenAIRE

    Minassian, Karen; Hofstoetter, Ursula; Tansey, Keith; Mayr, Winfried

    2012-01-01

    One consequence of central nervous system injury or disease is the impairment of neural control of movement, resulting in spasticity and paralysis. To enhance recovery, restorative neurology procedures modify altered, yet preserved nervous system function. This review focuses on functional electrical stimulation (FES) and spinal cord stimulation (SCS) that utilize remaining capabilities of the distal apparatus of spinal cord, peripheral nerves and muscles in upper motor neuron dysfunctions. F...

  6. Cholinergic control of visual categorization in macaques.

    Science.gov (United States)

    Aggelopoulos, Nikolaos C; Liebe, Stefanie; Logothetis, Nikos K; Rainer, Gregor

    2011-01-01

    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 behavior needs to be adapted to new situations and to novel sensory events. Categorization, the process of assigning stimuli to a category, is a cognitive function that also involves information acquisition. The role of ACh on categorization has not been previously studied. We have examined the effects of scopolamine, an antagonist of muscarinic ACh receptors, on visual categorization in macaque monkeys using familiar and novel stimuli. When the peripheral effects of scopolamine on the parasympathetic nervous system were controlled for, categorization performance was disrupted following systemic injections of scopolamine. This impairment was observed only when the stimuli that needed to be categorized had not been seen before. In other words, the monkeys were not impaired by the central action of scopolamine in categorizing a set of familiar stimuli (stimuli which they had categorized successfully in previous sessions). Categorization 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 categorization judgments 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 categorization 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 categorization task. PMID:22110428

  7. Cholinergic control of visual categorisation in macaques

    Directory of Open Access Journals (Sweden)

    Nikolaos C. Aggelopoulos

    2011-11-01

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

  8. Neuromodulators for Aging Skin

    Science.gov (United States)

    ... Skin Rejuvenation Soft-tissue Fillers Combination: Soft-tissue Fillers and Neuromodulators Neuromodulators – wrinkle-relaxing injections of botulinum toxin commercially known as Botox, Dysport ...

  9. A neurochemical closed-loop controller for deep brain stimulation: toward individualized smart neuromodulation therapies.

    Science.gov (United States)

    Grahn, Peter J; Mallory, Grant W; Khurram, Obaid U; Berry, B Michael; Hachmann, Jan T; Bieber, Allan J; Bennet, Kevin E; Min, Hoon-Ki; Chang, Su-Youne; Lee, Kendall H; Lujan, J L

    2014-01-01

    Current strategies for optimizing deep brain stimulation (DBS) therapy involve multiple postoperative visits. During each visit, stimulation parameters are adjusted until desired therapeutic effects are achieved and adverse effects are minimized. However, the efficacy of these therapeutic parameters may decline with time due at least in part to disease progression, interactions between the host environment and the electrode, and lead migration. As such, development of closed-loop control systems that can respond to changing neurochemical environments, tailoring DBS therapy to individual patients, is paramount for improving the therapeutic efficacy of DBS. Evidence obtained using electrophysiology and imaging techniques in both animals and humans suggests that DBS works by modulating neural network activity. Recently, animal studies have shown that stimulation-evoked changes in neurotransmitter release that mirror normal physiology are associated with the therapeutic benefits of DBS. Therefore, to fully understand the neurophysiology of DBS and optimize its efficacy, it may be necessary to look beyond conventional electrophysiological analyses and characterize the neurochemical effects of therapeutic and non-therapeutic stimulation. By combining electrochemical monitoring and mathematical modeling techniques, we can potentially replace the trial-and-error process used in clinical programming with deterministic approaches that help attain optimal and stable neurochemical profiles. In this manuscript, we summarize the current understanding of electrophysiological and electrochemical processing for control of neuromodulation therapies. Additionally, we describe a proof-of-principle closed-loop controller that characterizes DBS-evoked dopamine changes to adjust stimulation parameters in a rodent model of DBS. The work described herein represents the initial steps toward achieving a "smart" neuroprosthetic system for treatment of neurologic and psychiatric disorders

  10. A neurochemical closed-loop controller for deep brain stimulation: toward individualized smart neuromodulation therapies.

    Directory of Open Access Journals (Sweden)

    Peter Jonas Grahn

    2014-06-01

    Full Text Available Current strategies for optimizing deep brain stimulation (DBS therapy involve multiple postoperative visits. During each visit, stimulation parameters are adjusted until desired therapeutic effects are achieved and adverse effects are minimized. However, the efficacy of these therapeutic parameters may decline with time due at least in part to disease progression, interactions between the host environment and the electrode, and lead migration. As such, development of closed-loop control systems that can respond to changing neurochemical environments, tailoring DBS therapy to individual patients, is paramount for improving the therapeutic efficacy of DBS.Evidence obtained using electrophysiology and imaging techniques in both animals and humans suggests that DBS works by modulating neural network activity. Recently, animal studies have shown that stimulation-evoked changes in neurotransmitter release that mirror normal physiology are associated with the therapeutic benefits of DBS. Therefore, to fully understand the neurophysiology of DBS and optimize its efficacy, it may be necessary to look beyond conventional electrophysiological analyses and characterize the neurochemical effects of therapeutic and non-therapeutic stimulation. By combining electrochemical monitoring and mathematical modeling techniques, we can potentially replace the trial-and-error process used in clinical programming with deterministic approaches that help attain optimal and stable neurochemical profiles. In this manuscript, we summarize the current understanding of electrophysiological and electrochemical processing for control of neuromodulation therapies. Additionally, we describe a proof-of-principle closed-loop controller that characterizes DBS-evoked dopamine changes to adjust stimulation parameters in a rodent model of DBS. The work described herein represents the initial steps toward achieving a smart neuroprosthetic system for treatment of neurologic and

  11. Ascending control of arousal and motivation: role of nucleus incertus and its peptide neuromodulators in behavioural responses to stress.

    Science.gov (United States)

    Ma, S; Gundlach, A L

    2015-06-01

    Arousal is a process that involves the activation of ascending neural pathways originating in the rostral pons that project to the forebrain through the midbrain reticular formation to promote the activation of key cortical, thalamic, hypothalamic and limbic centres. Established modulators of arousal include the cholinergic, serotonergic, noradrenergic and dopaminergic networks originating in the pons and midbrain. Recent data indicate that a population of largely GABAergic projection neurones located in the nucleus incertus (NI) are also involved in arousal and motivational processes. The NI has prominent efferent connections with distinct hypothalamic, amygdalar and thalamic nuclei, in addition to dense projections to key brain regions associated with the generation and pacing of hippocampal activity. The NI receives strong inputs from the prefrontal cortex, lateral habenula and the interpeduncular and median raphe nuclei, suggesting it is highly integrated in circuits regulating higher cognitive behaviours (hippocampal theta rhythm) and emotion. Anatomical and functional studies have revealed that the NI is a rich source of multiple peptide neuromodulators, including relaxin-3, and may mediate extra-hypothalamic effects of the stress hormone corticotrophin-releasing factor, as well as other key modulators such as orexins and oxytocin. This review provides an overview of earlier studies and highlights more recent research that implicates this neural network in the integration of arousal and motivated behaviours and has begun to identify the associated mechanisms. Future research that should help to better clarify the connectivity and function of the NI in major experimental species and humans is also discussed. PMID:25612218

  12. Central cholinergic control of vasopressin release in conscious rats

    International Nuclear Information System (INIS)

    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 μg icv), but not by the nicotinic blocker, hexamethonium (10 μg 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 μg 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

  13. Neuromodulation: present and emerging methods

    Directory of Open Access Journals (Sweden)

    Song Luan

    2014-07-01

    Full Text Available Neuromodulation has wide ranging potential applications in replacing impaired neural function (prosthetics, as a novel form of medical treatment (therapy, and as a tool for investigating neurons and neural function (research. Voltage and current controlled electrical neural stimulation (ENS are methods that have already been widely applied in both neuroscience and clinical practice for neuroprosthetics. However, there are numerous alternative methods of stimulating or inhibiting neurons. This paper reviews the state-of-the-art in ENS as well as alternative neuromodulation techniques - presenting the operational concepts, technical implementation and limitations - in order to inform system design choices.

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

    Directory of Open Access Journals (Sweden)

    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.

  15. 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

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

    Directory of Open Access Journals (Sweden)

    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

  17. 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

  18. Control of heart rate during thermoregulation in the heliothermic lizard Pogona barbata: importance of cholinergic and adrenergic mechanisms.

    Science.gov (United States)

    Seebacher, F; Franklin, C E

    2001-12-01

    During thermoregulation in the bearded dragon Pogona barbata, heart rate when heating is significantly faster than when cooling at any given body temperature (heart rate hysteresis), resulting in faster rates of heating than cooling. However, the mechanisms that control heart rate during heating and cooling are unknown. The aim of this study was to test the hypothesis that changes in cholinergic and adrenergic tone on the heart are responsible for the heart rate hysteresis during heating and cooling in P. barbata. Heating and cooling trials were conducted before and after the administration of atropine, a muscarinic antagonist, and sotalol, a beta-adrenergic antagonist. Cholinergic and beta-adrenergic blockade did not abolish the heart rate hysteresis, as the heart rate during heating was significantly faster than during cooling in all cases. Adrenergic tone was extremely high (92.3 %) at the commencement of heating, and decreased to 30.7 % at the end of the cooling period. Moreover, in four lizards there was an instantaneous drop in heart rate (up to 15 beats min(-1)) as the heat source was switched off, and this drop in heart rate coincided with either a drop in beta-adrenergic tone or an increase in cholinergic tone. Rates of heating were significantly faster during the cholinergic blockade, and least with a combined cholinergic and beta-adrenergic blockade. The results showed that cholinergic and beta-adrenergic systems are not the only control mechanisms acting on the heart during heating and cooling, but they do have a significant effect on heart rate and on rates of heating and cooling. PMID:11815660

  19. Deletion of neurturin impairs development of cholinergic nerves and heart rate control in postnatal mouse hearts.

    Science.gov (United States)

    Downs, Anthony M; Jalloh, Hawa B; Prater, Kayla J; Fregoso, Santiago P; Bond, Cherie E; Hampton, Thomas G; Hoover, Donald B

    2016-05-01

    The neurotrophic factor neurturin is required for normal cholinergic innervation of adult mouse heart and bradycardic responses to vagal stimulation. Our goals were to determine effects of neurturin deletion on development of cardiac chronotropic and dromotropic functions, vagal baroreflex response, and cholinergic nerve density in nodal regions of postnatal mice. Experiments were performed on postnatal C57BL/6 wild-type (WT) and neurturin knockout (KO) mice. Serial electrocardiograms were recorded noninvasively from conscious pups using an ECGenie apparatus. Mice were treated with atenolol to evaluate and block sympathetic effects on heart rate (HR) and phenylephrine (PE) to stimulate the baroreflex. Immunohistochemistry was used to label cholinergic nerves in paraffin sections. WT and KO mice showed similar age-dependent increases in HR and decreases in PR interval between postnatal days (P) 2.5 and 21. Treatment with atenolol reduced HR significantly in WT and KO pups at P7.5. PE caused a reflex bradycardia that was significantly smaller in KO pups. Cholinergic nerve density was significantly less in nodal regions of P7.5 KO mice. We conclude that cholinergic nerves have minimal influence on developmental changes in HR and PR, QRS, and QTc intervals in mouse pups. However, cholinergic nerves mediate reflex bradycardia by 1 week postnatally. Deletion of neurturin impairs cholinergic innervation of the heart and the vagal efferent component of the baroreflex early during postnatal development. PMID:27162260

  20. Neuromodulation of chronic headaches

    DEFF Research Database (Denmark)

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

    2013-01-01

    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...... 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...

  1. Neuromodulation for restoring memory.

    Science.gov (United States)

    Bick, Sarah K B; Eskandar, Emad N

    2016-05-01

    Disorders of learning and memory have a large social and economic impact in today's society. Unfortunately, existing medical treatments have shown limited clinical efficacy or potential for modification of the disease course. Deep brain stimulation is a successful treatment for movement disorders and has shown promise in a variety of other diseases including psychiatric disorders. The authors review the potential of neuromodulation for the treatment of disorders of learning and memory. They briefly discuss learning circuitry and its involvement in Alzheimer disease and traumatic brain injury. They then review the literature supporting various targets for neuromodulation to improve memory in animals and humans. Multiple targets including entorhinal cortex, fornix, nucleus basalis of Meynert, basal ganglia, and pedunculopontine nucleus have shown a promising potential for improving dysfunctional memory by mechanisms such as altering firing patterns in neuronal networks underlying memory and increasing synaptic plasticity and neurogenesis. Significant work remains to be done to translate these findings into durable clinical therapies. PMID:27132526

  2. Beyond traditional approaches to understand the functional role of neuromodulators in sensory cortices

    Directory of Open Access Journals (Sweden)

    Jean-Marc Edeline

    2012-07-01

    Full Text Available Over the last two decades, a vast literature has described the influence of neuromodulatory systems on the responses of sensory cortex neurons (review in Gu 2002; Edeline 2003; Weinberger 2003; Metherate 2004, 2011. At the single cell level, facilitation of evoked responses, increases in signal-to-noise ratio, and improved functional properties of sensory cortex neurons have been reported in the visual, auditory and somatosensory modality. At the map level, massive cortical reorganizations have been described when repeated activation of a neuromodulatory system are associated with a particular sensory stimulus. In reviewing our knowledge concerning the way the noradrenergic and cholinergic system control sensory cortices, I will point out that the differences between the protocols used to reveal these effects most likely reflect different assumptions concerning the role of the neuromodulators. More importantly, a gap still exists between the descriptions of neuromodulatory effects and the concepts that are currently applied to decipher the neural code operating in sensory cortices. Key examples that bring this gap into focus are the concept of cell assemblies and the role played by the spike timing precision (i.e., by the temporal organization of spike trains at the millisecond time-scale which are now recognized as essential in sensory physiology but are rarely considered in experiments describing the role of neuromodulators in sensory cortices. Thus, I will suggest that several lines of research, particularly in the field of computational neurosciences, should help us to go beyond traditional approaches and, ultimately, to understand how neuromodulators impact on the cortical mechanisms underlying our perceptual abilities.

  3. Neuromodulation for epilepsy

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    Pranshu Bhargava

    2008-01-01

    Full Text Available Epilepsy is a common disease. WHO data suggests that 1 in 20 people may have an epileptic seizure in their lifetime and at least 1 in 200 go on to develop epilepsy. Anticonvulsant drug therapy using one or more drugs works as an effective tool to suppress seizures in only 70% of the patients, the remaining 30% are either not responsive or suffer major side effects. Surgical resection then forms the next line of management in selected patients. However in some cases surgical resection may not be possible, hence arises the need for alternative therapies. Neuromodulation of the Central Nervous system is a novel technique under evaluation for Medically Intractable epilepsy. CNS stimulation for epilepsy has been a matter of extensive research. We review the Neurophysiological basis of Neuromodulation in Epilepsy and various modalities viz Vagal nerve stimulation (VNS, Transcranial magnetic stimulation (TMS and Direct cortical stimulation (DCS. Deep brain stimulation (Hippocampal, Anterior thalamic and STN and RNS are newer modalities and are also reviewed.

  4. Presynaptic transmitter content controls the number of quanta released at a neuro-neuronal cholinergic synapse.

    OpenAIRE

    Poulain, B; Baux, G; Tauc, L

    1986-01-01

    In the buccal ganglion of Aplysia the overloading of the cholinergic presynaptic neuron by exogenous acetylcholine (AcCho) led to an enhancement of the postsynaptic response. The deprivation of choline in the presynaptic neuron by extra- and/or intracellularly applied choline oxidase to prevent AcCho synthesis resulted in a decrease of the postsynaptic response. In both cases, the size of the calculated miniature postsynaptic current (i.e., the size of the quantum) remained unchanged. It was ...

  5. Striatal Cholinergic Interneurons Control Motor Behavior and Basal Ganglia Function in Experimental Parkinsonism

    OpenAIRE

    Nicolas Maurice; Martine Liberge; Florence Jaouen; Samira Ztaou; Marwa Hanini; Jeremy Camon; Karl Deisseroth; Marianne Amalric; Lydia Kerkerian-Le Goff; Corinne Beurrier

    2015-01-01

    Despite evidence showing that anticholinergic drugs are of clinical relevance in Parkinson’s disease (PD), the causal role of striatal cholinergic interneurons (CINs) in PD pathophysiology remains elusive. Here, we show that optogenetic inhibition of CINs alleviates motor deficits in PD mouse models, providing direct demonstration for their implication in parkinsonian motor dysfunctions. As neural correlates, CIN inhibition in parkinsonian mice differentially impacts the excitability of stria...

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

    OpenAIRE

    M. Bauer; C. Kluge; Bach, D.; Bradbury, D.; Heinze, H. J.; Dolan, R J; Driver, J.

    2012-01-01

    Summary Cognitive processes such as visual perception and selective attention induce specific patterns of brain oscillations [1–6]. The neurochemical bases of these spectral changes in neural activity are largely unknown, but neuromodulators are thought to regulate processing [7–9]. The cholinergic system is linked to attentional function in vivo [10–13], whereas separate in vitro studies show that cholinergic agonists induce high-frequency oscillations in slice preparations [14–16]. This has...

  7. Striatal Cholinergic Interneurons Control Motor Behavior and Basal Ganglia Function in Experimental Parkinsonism.

    Science.gov (United States)

    Maurice, Nicolas; Liberge, Martine; Jaouen, Florence; Ztaou, Samira; Hanini, Marwa; Camon, Jeremy; Deisseroth, Karl; Amalric, Marianne; Kerkerian-Le Goff, Lydia; Beurrier, Corinne

    2015-10-27

    Despite evidence showing that anticholinergic drugs are of clinical relevance in Parkinson's disease (PD), the causal role of striatal cholinergic interneurons (CINs) in PD pathophysiology remains elusive. Here, we show that optogenetic inhibition of CINs alleviates motor deficits in PD mouse models, providing direct demonstration for their implication in parkinsonian motor dysfunctions. As neural correlates, CIN inhibition in parkinsonian mice differentially impacts the excitability of striatal D1 and D2 medium spiny neurons, normalizes pathological bursting activity in the main basal ganglia output structure, and increases the functional weight of the direct striatonigral pathway in cortical information processing. By contrast, CIN inhibition in non-lesioned mice does not affect locomotor activity, equally modulates medium spiny neuron excitability, and does not modify spontaneous or cortically driven activity in the basal ganglia output, suggesting that the role of these interneurons in motor function is highly dependent on dopamine tone. PMID:26489458

  8. Striatal Cholinergic Interneurons Control Motor Behavior and Basal Ganglia Function in Experimental Parkinsonism

    Directory of Open Access Journals (Sweden)

    Nicolas Maurice

    2015-10-01

    Full Text Available Despite evidence showing that anticholinergic drugs are of clinical relevance in Parkinson’s disease (PD, the causal role of striatal cholinergic interneurons (CINs in PD pathophysiology remains elusive. Here, we show that optogenetic inhibition of CINs alleviates motor deficits in PD mouse models, providing direct demonstration for their implication in parkinsonian motor dysfunctions. As neural correlates, CIN inhibition in parkinsonian mice differentially impacts the excitability of striatal D1 and D2 medium spiny neurons, normalizes pathological bursting activity in the main basal ganglia output structure, and increases the functional weight of the direct striatonigral pathway in cortical information processing. By contrast, CIN inhibition in non-lesioned mice does not affect locomotor activity, equally modulates medium spiny neuron excitability, and does not modify spontaneous or cortically driven activity in the basal ganglia output, suggesting that the role of these interneurons in motor function is highly dependent on dopamine tone.

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

    Directory of Open Access Journals (Sweden)

    Meaghan C Creed

    2014-01-01

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

  10. 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. PMID:26352794

  11. Evidence for cholinergic participation in the control of bird song; acetylcholinesterase distribution and muscarinic receptor autoradiography in the zebra finch brain

    International Nuclear Information System (INIS)

    Brain regions thought to be involved in the control of song in the zebra finch (Poephila guttata), were examined histochemically using the Karnovsky and Roots direct-coloring method for the detection of acetylcholinesterase (AChE) and the autoradiographic method for the localization of muscarinic cholinergic receptors following injection of tritiated quinuclidinyl benzilate (3H QNB). All presently identified vocal control nuclei in both males and females contain AChE. These nuclei include Area X, magnocellular nucleus of the anterior neostriatum (MAN), nucleus interface (NIF), caudal nucleus of the hyperstriatum ventrale (HVc), intercollicular nucleus (ICo), nucleus uva, robust nucleus of the archistriatum (RA), and tracheosyringeal portion of the hypoglossal nerve nucleus (nXIIts). All nuclei except Area X contain mostly AChE-synthesizing cell bodies. All of these nuclei contain some AChE in the neuropil, with particularly intense staining in Area X, the surrounding LPO, and the dorsomedial portion of ICo. In agreement with this description are very high concentrations of 3H QNB in both Area X and the dorsomedial ICo. HVc also appears specifically labeled. Evidence from these two histological technique suggests that efferent projections of most vocal control area may utilize acetylcholine, and that several of the vocal control nuclei may themselves receive muscarinic cholinergic projection. In Area X, there are sex differences of AChE neuropil staining. This evidence suggesting that sexually dimorphic projections to or within Area X are cholinergic or cholinoceptive

  12. The progressive onset of cholinergic and adrenergic control of heart rate during development in the green iguana, Iguana iguana.

    Science.gov (United States)

    Sartori, Marina R; Leite, Cleo A C; Abe, Augusto S; Crossley, Dane A; Taylor, Edwin W

    2015-10-01

    The autonomic control of heart rate was studied throughout development in embryos of the green iguana, Iguana iguana by applying receptor agonists and antagonists of the parasympathetic and sympathetic systems. Acetylcholine (Ach) slowed or stopped the heart and atropine antagonized the response to Ach indicating the presence of muscarinic cholinoceptors on the heart of early embryos. However, atropine injections had no impact on heart rate until immediately before hatching, when it increased heart rate by 15%. This cholinergic tonus increased to 34% in hatchlings and dropped to 24% in adult iguanas. Although epinephrine was without effect, injection of propranolol slowed the heart throughout development, indicating the presence of β-adrenergic receptors on the heart of early embryos, possibly stimulated by high levels of circulating catecholamines. The calculated excitatory tonus varied between 33% and 68% until immediately before hatching when it fell to 25% and 29%, a level retained in hatchlings and adults. Hypoxia caused a bradycardia in early embryos that was unaffected by injection of atropine indicating that hypoxia has a direct effect upon the heart. In later embryos and hatchlings hypoxia caused a tachycardia that was unaffected by injection of atropine. Subsequent injection of propranolol reduced heart rate both uncovering a hypoxic bradycardia in late embryos and abolishing tachycardia in hatchlings. Hypercapnia was without effect on heart rate in late stage embryos and in hatchlings. PMID:26071949

  13. Attentional Control of Gait and Falls: Is Cholinergic Dysfunction a Common Substrate in the Elderly and Parkinson’s Disease?

    Science.gov (United States)

    Pelosin, Elisa; Ogliastro, Carla; Lagravinese, Giovanna; Bonassi, Gaia; Mirelman, Anat; Hausdorff, Jeffrey M.; Abbruzzese, Giovanni; Avanzino, Laura

    2016-01-01

    The aim of this study was to address whether deficits in the central cholinergic activity may contribute to the increased difficulty to allocate attention during gait in the elderly with heightened risk of falls. We recruited 50 participants with a history of two or more falls (33 patients with Parkinson’s Disease and 17 older adults) and 14 non-fallers age-matched adults. Cholinergic activity was estimated by means of short latency afferent inhibition (SAI), a transcranial magnetic stimulation (TMS) technique that assesses an inhibitory circuit in the sensorimotor cortex and is regarded as a global marker of cholinergic function in the brain. Increased difficulty to allocate attention during gait was evaluated by measuring gait performance under single and dual-task conditions. Global cognition was also assessed. Results showed that SAI was reduced in patients with PD than in the older adults (fallers and non-fallers) and in older adults fallers with respect to non-fallers. Reduction in SAI indicates less inhibition i.e., less cholinergic activity. Gait speed was reduced in the dual task gait compared to normal gait only in our faller population and changes in gait speed under dual task significantly correlated with the mean value of SAI. This association remained significant after adjusting for cognitive status. These findings suggest that central cholinergic activity may be a predictor of change in gait characteristics under dual tasking in older adults and PD fallers independently of cognitive status.

  14. Neuromodulation in obsessive-compulsive disorder.

    Science.gov (United States)

    Bais, Melisse; Figee, Martijn; Denys, Damiaan

    2014-09-01

    Neuromodulation techniques in obsessive-compulsive disorder (OCD) involve electroconvulsive therapy (ECT), transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS), and deep brain stimulation (DBS). This article reviews the available literature on the efficacy and applicability of these techniques in OCD. ECT is used for the treatment of comorbid depression or psychosis. One case report on tDCS showed no effects in OCD. Low-frequency TMS provides significant but mostly transient improvement of obsessive-compulsive symptoms. DBS shows a response rate of 60% in open and sham-controlled studies. In OCD, it can be concluded that DBS, although more invasive, is the most efficacious technique. PMID:25150569

  15. Noninvasive neuromodulation in cluster headache

    DEFF Research Database (Denmark)

    Láinez, Miguel J A; Jensen, Rigmor

    2015-01-01

    PURPOSE OF REVIEW: Neuromodulation is an alternative in the management of medically intractable cluster headache patients. Most of the techniques are invasive, but in the last 2 years, some studies using a noninvasive device have been presented. The objective of this article is to review the data...... 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...... device has been tried in cluster patients. Results from clinical practice and a single randomized clinical trial have been presented showing a reduction of the number of cluster attacks/week in the patients treated with the device. The rate of adverse events was low and most of them were mild. SUMMARY...

  16. 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

  17. Neuromodulation in obsessive-compulsive disorder

    NARCIS (Netherlands)

    Bais, Melisse; Figee, Martijn; Denys, D.

    2014-01-01

    Neuromodulation techniques in obsessive-compulsive disorder (OCD) involve electroconvulsive therapy (ECT), transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS), and deep brain stimulation (DBS). This article reviews the available literature on the efficacy and appl

  18. 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. PMID:25445738

  19. Cholinergic plasticity in the hippocampus

    OpenAIRE

    Colgin, Laura Lee; Kubota, Don; Lynch, Gary

    2003-01-01

    Tests were made for use-dependent plasticity in the cholinergic projections to hippocampus. Transient infusion of the cholinergic agonist carbachol into hippocampal slices induced rhythmic activity that persisted for hours after washout. Comparable effects were obtained with physostigmine, a drug that blocks acetylcholine breakdown and thereby enhances cholinergic transmission. It thus seems that activation of cholinergic synapses induces lasting changes in hippocampal physiology. Two lines o...

  20. The heart side of brain neuromodulation.

    Science.gov (United States)

    Rossi, Simone; Santarnecchi, Emiliano; Valenza, Gaetano; Ulivelli, Monica

    2016-05-13

    Neuromodulation refers to invasive, minimally invasive or non-invasive techniques to stimulate discrete cortical or subcortical brain regions with therapeutic purposes in otherwise intractable patients: for example, thousands of advanced Parkinsonian patients, as well as patients with tremor or dystonia, benefited by deep brain stimulation (DBS) procedures (neural targets: basal ganglia nuclei). A new era for DBS is currently opening for patients with drug-resistant depression, obsessive-compulsive disorders, severe epilepsy, migraine and chronic pain (neural targets: basal ganglia and other subcortical nuclei or associative fibres). Vagal nerve stimulation (VNS) has shown clinical benefits in patients with pharmacoresistant epilepsy and depression. Non-invasive brain stimulation neuromodulatory techniques such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are also being increasingly investigated for their therapeutic potential in several neurological and psychiatric disorders. In this review, we first address the most common neural targets of each of the mentioned brain stimulation techniques, and the known mechanisms of their neuromodulatory action on stimulated brain networks. Then, we discuss how DBS, VNS, rTMS and tDCS could impact on the function of brainstem centres controlling vital functions, critically reviewing their acute and long-term effects on brain sympathetic outflow controlling heart function and blood pressure. Finally, as there is clear experimental evidence in animals that brain stimulation can affect autonomic and heart functions, we will try to give a critical perspective on how it may enhance our understanding of the cortical/subcortical mechanisms of autonomic cardiovascular regulation, and also if it might find a place among therapeutic opportunities in patients with otherwise intractable autonomic dysfunctions. PMID:27044999

  1. Cholinergic dysfunction in Parkinson's disease.

    Science.gov (United States)

    Müller, Martijn L T M; Bohnen, Nicolaas I

    2013-09-01

    There is increasing interest in the clinical effects of cholinergic basal forebrain and tegmental pedunculopontine complex (PPN) projection degeneration in Parkinson's disease (PD). Recent evidence supports an expanded role beyond cognitive impairment, including effects on olfaction, mood, REM sleep behavior disorder, and motor functions. Cholinergic denervation is variable in PD without dementia and may contribute to clinical symptom heterogeneity. Early in vivo imaging evidence that impaired cholinergic integrity of the PPN associates with frequent falling in PD is now confirmed by human post-mortem evidence. Brainstem cholinergic lesioning studies in primates confirm the role of the PPN in mobility impairment. Degeneration of basal forebrain cholinergic projections correlates with decreased walking speed. Cumulatively, these findings provide evidence for a new paradigm to explain dopamine-resistant features of mobility impairments in PD. Recognition of the increased clinical role of cholinergic system degeneration may motivate new research to expand indications for cholinergic therapy in PD. PMID:23943367

  2. Cholinergic Mechanisms in the Cerebral Cortex: Beyond Synaptic Transmission.

    Science.gov (United States)

    Ovsepian, Saak V; O'Leary, Valerie B; Zaborszky, Laszlo

    2016-06-01

    Functional overviews of cholinergic mechanisms in the cerebral cortex have traditionally focused on the release of acetylcholine with modulator and transmitter effects. Recently, however, data have emerged that extend the role of acetylcholine and cholinergic innervations to a range of housekeeping and metabolic functions. These include regulation of amyloid precursor protein (APP) processing with production of amyloid β (Aβ) and other APP fragments and control of the phosphorylation of microtubule-associated protein (MAP) tau. Evidence has been also presented for receptor-ligand like interactions of cholinergic receptors with soluble Aβ peptide and MAP tau, with modulator and signaling effects. Moreover, high-affinity binding of Aβ to the neurotrophin receptor p75 (p75NTR) enriched in basalo-cortical cholinergic projections has been implicated in clearance of Aβ and nucleation of amyloid plaques. Here, we critically evaluate these unorthodox cholinergic mechanisms and discuss their role in neuronal physiology and the biology of Alzheimer's disease. PMID:26002948

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

    OpenAIRE

    Orietta Zaniolo; Sergio Iannazzo; Gian Piero Patrucco; Roberto Bellini

    2011-01-01

    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...

  4. Acoustic CR Neuromodulation Therapy for Subjective Tonal Tinnitus: A Review of Clinical Outcomes in an Independent Audiology Practice Setting

    OpenAIRE

    Williams, Mark; Hauptmann, Christian; Patel, Nitesh

    2015-01-01

    Objective: To describe the quantitative treatment outcomes of patients undergoing acoustic coordinated reset (CR) neuromodulation at a single independent audiology practice over a 22- to 26-week period as part of an open label, non-randomized, non-controlled observational study. Methods: Sixty-six patients with subjective tonal tinnitus were treated with acoustic CR neuromodulation with a retrospective review of patient records being performed in order to identify changes of visual analog ...

  5. 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.

  6. Nematode cholinergic pharmacology

    International Nuclear Information System (INIS)

    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 [3H]N-methylscopolamine ([3H]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

  7. 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.

  8. Neurostimulation, neuromodulation, and the treatment of epilepsies

    OpenAIRE

    Bolden Lauren B.; Pati Sandipan; Szaflarski Jerzy P

    2015-01-01

    Introduction. Neurostimulation and neuromodulation are techniques that may be able to affect the course of epilepsy. In the last 20 years, since the approval of VNS, we have observed a surge of studies assessing the potential of other devices and techniques for the treatment of pharmacoresistant epilepsies including deep brain stimulation (DBS), responsive neurostimulation (RNS), trigeminal nerve stimulation (TNS), transcranial direct current stimulation (tDCS), and repetitive transcranial ma...

  9. Neuromodulation therapies and treatment-resistant depression

    OpenAIRE

    Al-Harbi KS; Qureshi NA

    2012-01-01

    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 NT...

  10. Neuromodulation for treatment-resistant depression

    OpenAIRE

    Holtzheimer, Paul E.; Mayberg, Helen S

    2012-01-01

    Treatment-resistant depression affects at least 1-3% of the US population. This article reviews the current state of focal neuromodulation therapies for treatment-resistant depression, focusing on those treatments published clinical data. These include transcranial magnetic stimulation, transcranial direct current stimulation, magnetic seizure therapy, vagus nerve stimulation, direct cortical stimulation, and deep brain stimulation among others. Of these, only two (transcranial magnetic stimu...

  11. Neuromodulation and antenatal depression: a review

    OpenAIRE

    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. M...

  12. Astroglial networks and implications for therapeutic neuromodulation of epilepsy

    Directory of Open Access Journals (Sweden)

    Mark R Witcher

    2012-08-01

    Full Text Available Epilepsy is a common chronic neurologic disorder affecting approximately 1 percent of the world population. More than one-third of all epilepsy patients have incompletely controlled seizures or debilitating medication side effects in spite of optimal medical management. Medically refractory epilepsy is associated with excess injury and mortality, psychosocial dysfunction, and significant cognitive impairment. Effective treatment options for these patients can be limited. The cellular mechanisms underlying seizure activity are incompletely understood, though we here describe multiple lines of evidence supporting the likely contribution of astroglia to epilepsy, with focus on individual astrocytes and their network functions. Of the emerging therapeutic modalities for epilepsy, one of the most intriguing is the field of neuromodulation. Neuromodulatory treatment, which consists of administering electrical pulses to neural tissue to modulate its activity leading to a beneficial effect, may be an option for these patients. Current modalities consist of vagal nerve stimulation, open and closed loop stimulation, and transcranial magnetic stimulation. Due to their unique properties, we here present astrocytes as likely important targets for the developing field of neuromodulation in the treatment of epilepsy.

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

    OpenAIRE

    Jordan, L M; Noga, B. R.; Cabaj, A. M.; J Provencher

    2014-01-01

    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. Test...

  14. Neurostimulation, neuromodulation, and the treatment of epilepsies

    Directory of Open Access Journals (Sweden)

    Bolden Lauren B.

    2015-06-01

    Full Text Available Introduction. Neurostimulation and neuromodulation are techniques that may be able to affect the course of epilepsy. In the last 20 years, since the approval of VNS, we have observed a surge of studies assessing the potential of other devices and techniques for the treatment of pharmacoresistant epilepsies including deep brain stimulation (DBS, responsive neurostimulation (RNS, trigeminal nerve stimulation (TNS, transcranial direct current stimulation (tDCS, and repetitive transcranial magnetic stimulation (rTMS. Are these devices and techniques simply another treatment option that can be offered to patients with epilepsy or do they offer specific advantages when compared to the standard antiepileptic drugs (AEDs?

  15. Sacral-neuromodulation CT-guided

    International Nuclear Information System (INIS)

    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

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

    OpenAIRE

    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.; Emery N Brown

    2014-01-01

    Rapid eye movement (REM) sleep is a critical component of restful sleep, yet the mechanisms that control REM sleep are incompletely understood. Brainstem cholinergic neurons have been implicated in REM sleep regulation, but heterogeneous cell types in the area have made it difficult to determine the specific role of each population, leading to a debate about the importance of cholinergic neurons. Therefore, we selectively activated brainstem cholinergic neurons to determine their role in REM ...

  17. Cholinergic signal activated renin angiotensin system associated with cardiovascular changes in the ovine fetus

    OpenAIRE

    Geng, Chunsong; Mao, Caiping; Wu, Lei; Cheng, Yu; Liu, Rulu; Chen, Bingxin; Chen, Ling; Zhang, Lubo; Xu, Zhice

    2010-01-01

    Aim: Cholinergic regulation is important in the control of cardiovascular and endocrine responses. The mechanisms behind cardiovascular responses induced by cholinergic activation are explored by studying hormonal systems, including renin-angiotensin and vasopressin (VP). Results: In chronically prepared fetal sheep, intravenous infusion of the cholinergic agonist carbachol increased fetal systolic, diastolic, and mean arterial pressure accompanied with bradycardia at near-term. Although int...

  18. [Invasive neuromodulation in the treatment of drug-resistant epilepsies].

    Science.gov (United States)

    Erőss, Loránd; Entz, László; Fabó, Dániel

    2015-12-27

    Neuromodulation is one of the most developing new disciplines of medical science, which examines how electrical, chemical and mechanical interventions can modulate or change the functioning of the central and peripheral nervous system. Neuromodulation is a reversible form of therapy which uses electrical or mechanical stimulation or centrally-delivered drugs to modulate the abnormal function of the central nervous system in pain, spasticity, epilepsy, movement and psychiatric disorders, and certain cardiac, incontinency, visual and auditory diseases. Neuromodulation therapy has two major branches. Non-invasive neuromodulation includes transcranial magnetic simulation, direct current stimulation and transcutaneous electric nerve stimulation. Invasive neuromodulation includes deep brain stimulation, cortical stimulation, spinal cord stimulation, peripheral nerve stimulation, sacral nerve simulation, and subcutan stimulation. In this article the authors overview the apparently available neural interface technologies in epilepsy surgery. PMID:26686746

  19. Neuromodulation for Refractory Failed Back Surgery Syndrome Patients

    Directory of Open Access Journals (Sweden)

    I.N. Morozov

    2015-09-01

    Full Text Available The aim of the investigation was to assess the capabilities of spinal cord stimulation, and compare it with conventional nonsurgical treatment in failed back syndrome. Materials and Methods. The study involved the patients with at least one anatomically successful lumber disc hernia excision, post-traumatic spinal deformity in their past history, the patients keeping suffering from neuropathic pain. Group 1 patients (n=45 in addition to traditional therapy underwent spinal cord stimulation. Group 2 control patients (n=35 were given medicines, therapeutic blocks, physiotherapy, and psychotherapy. Results. Epidural spinal cord stimulation in chronic pain syndrome treatment enables to improve significantly the patients' condition: it lowers pain level, increases the functionality and improves the quality of life. Conclusion. Being minimally invasive and highly safe, neuromodulation enables to achieve good treatment results in failed back syndrome.

  20. Synthesis of high-complexity rhythmic signals for closed-loop electrical neuromodulation.

    Science.gov (United States)

    Zalay, Osbert C; Bardakjian, Berj L

    2013-06-01

    We propose an approach to synthesizing high-complexity rhythmic signals for closed-loop electrical neuromodulation using cognitive rhythm generator (CRG) networks, wherein the CRG is a hybrid oscillator comprised of (1) a bank of neuronal modes, (2) a ring device (clock), and (3) a static output nonlinearity (mapper). Networks of coupled CRGs have been previously implemented to simulate the electrical activity of biological neural networks, including in silico models of epilepsy, producing outputs of similar waveform and complexity to the biological system. This has enabled CRG network models to be used as platforms for testing seizure control strategies. Presently, we take the application one step further, envisioning therapeutic CRG networks as rhythmic signal generators creating neuromimetic signals for stimulation purposes, motivated by recent research indicating that stimulus complexity and waveform characteristics influence neuromodulation efficacy. To demonstrate this concept, an epileptiform CRG network generating spontaneous seizure-like events (SLEs) was coupled to a therapeutic CRG network, forming a closed-loop neuromodulation system. SLEs are associated with low-complexity dynamics and high phase coherence in the network. The tuned therapeutic network generated a high-complexity, multi-banded rhythmic stimulation signal with prominent theta and gamma-frequency power that suppressed SLEs and increased dynamic complexity in the epileptiform network, as measured by a relative increase in the maximum Lyapunov exponent and decrease in phase coherence. CRG-based neuromodulation outperformed both low and high-frequency periodic pulse stimulation, suggesting that neuromodulation using complex, biomimetic signals may provide an improvement over conventional electrical stimulation techniques for treating neurological disorders such as epilepsy. PMID:23501170

  1. Glucocorticoid programming of the mesopontine cholinergic system

    Directory of Open Access Journals (Sweden)

    Sónia eBorges

    2013-12-01

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

  2. Neuromodulation therapies and treatment-resistant depression

    Directory of Open Access Journals (Sweden)

    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

  3. Integrative neurocomputational perspectives on cognitive aging, neuromodulation, and representation.

    Science.gov (United States)

    Li, Shu-Chen; Sikström, Sverker

    2002-11-01

    Besides neuroanatomical changes, neuromodulatory mechanisms are also compromised during aging. Neural network models are suitable tools for exploring the relatively broad and homogenous neuromodulatory influences on cortical function. Computational approaches for understanding neuromodulation of the dynamic properties of cortical function and recent neurocomputational theories relating different aspects of cognitive aging with declines in neuromodulation are reviewed. Considered within an integrative cross-level neurocomputational framework, aging-related decline in dopaminergic neuromodulation reduces the fidelity of neural information and gives rise to less distinctive neural pattern representations that may underlie various facets of aging cognitive and, possibly also, sensorimotor phenomena. PMID:12470691

  4. Brain cholinergic impairment in liver failure.

    Science.gov (United States)

    García-Ayllón, María-Salud; Cauli, Omar; Silveyra, María-Ximena; Rodrigo, Regina; Candela, Asunción; Compañ, Antonio; Jover, Rodrigo; Pérez-Mateo, Miguel; Martínez, Salvador; Felipo, Vicente; Sáez-Valero, Javier

    2008-11-01

    The cholinergic system is involved in specific behavioural responses and cognitive processes. Here, we examined potential alterations in the brain levels of key cholinergic enzymes in cirrhotic patients and animal models with liver failure. An increase (~30%) in the activity of the acetylcholine-hydrolyzing enzyme, acetylcholinesterase (AChE) is observed in the brain cortex from patients deceased from hepatic coma, while the activity of the acetylcholine-synthesizing enzyme, choline acetyltransferase, remains unaffected. In agreement with the human data, AChE activity in brain cortical extracts of bile duct ligated (BDL) rats was increased (~20%) compared to controls. A hyperammonemic diet did not result in any further increase of AChE levels in the BDL model, and no change was observed in hyperammonemic diet rats without liver disease. Portacaval shunted rats which display increased levels of cerebral ammonia did not show any brain cholinergic abnormalities, confirming that high ammonia levels do not play a role in brain AChE changes. A selective increase of tetrameric AChE, the major AChE species involved in hydrolysis of acetylcholine in the brain, was detected in both cirrhotic humans and BDL rats. Histological examination of BDL and non-ligated rat brains shows that the subcellular localization of both AChE and choline acetyltransferase, and thus the accessibility to their substrates, appears unaltered by the pathological condition. The BDL-induced increase in AChE activity was not parallelled by an increase in mRNA levels. Increased AChE in BDL cirrhotic rats leads to a pronounced decrease (~50-60%) in the levels of acetylcholine. Finally, we demonstrate that the AChE inhibitor rivastigmine is able to improve memory deficits in BDL rats. One week treatment with rivastigmine (0.6 mg/kg; once a day, orally, for a week) resulted in a 25% of inhibition in the enzymatic activity of AChE with no change in protein composition, as assessed by sucrose density gradient

  5. Properties of cholinergic and non-cholinergic submucosal neurons along the mouse colon.

    Science.gov (United States)

    Foong, Jaime Pei Pei; Tough, Iain R; Cox, Helen M; Bornstein, Joel C

    2014-02-15

    Submucosal neurons are vital regulators of water and electrolyte secretion and local blood flow in the gut. Due to the availability of transgenic models for enteric neuropathies, the mouse has emerged as the research model of choice, but much is still unknown about the murine submucosal plexus. The progeny of choline acetyltransferase (ChAT)-Cre × ROSA26(YFP) reporter mice, ChAT-Cre;R26R-yellow fluorescent protein (YFP) mice, express YFP in every neuron that has ever expressed ChAT. With the aid of the robust YFP staining in these mice, we correlated the neurochemistry, morphology and electrophysiology of submucosal neurons in distal colon. We also examined whether there are differences in neurochemistry along the colon and in neurally mediated vectorial ion transport between the proximal and distal colon. All YFP(+) submucosal neurons also contained ChAT. Two main neurochemical but not electrophysiological groups of neurons were identified: cholinergic (containing ChAT) or non-cholinergic. The vast majority of neurons in the middle and distal colon were non-cholinergic but contained vasoactive intestinal peptide. In the distal colon, non-cholinergic neurons had one or two axons, whereas the cholinergic neurons examined had only one axon. All submucosal neurons exhibited S-type electrophysiology, shown by the lack of long after-hyperpolarizing potentials following their action potentials and fast excitatory postsynaptic potentials (EPSPs). Fast EPSPs were predominantly nicotinic, and somatic action potentials were mediated by tetrodotoxin-resistant voltage-gated channels. The size of submucosal ganglia decreased but the proportion of cholinergic neurons increased distally along the colon. The distal colon had a significantly larger nicotinic ion transport response than the proximal colon. This work shows that the properties of murine submucosal neurons and their control of epithelial ion transport differ between colonic regions. There are several key differences

  6. 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.

  7. Regulation of neuronal chloride homeostasis by neuromodulators.

    Science.gov (United States)

    Mahadevan, Vivek; Woodin, Melanie A

    2016-05-15

    KCC2 is the central regulator of neuronal Cl(-) homeostasis, and is critical for enabling strong hyperpolarizing synaptic inhibition in the mature brain. KCC2 hypofunction results in decreased inhibition and increased network hyperexcitability that underlies numerous disease states including epilepsy, neuropathic pain and neuropsychiatric disorders. The current holy grail of KCC2 biology is to identify how we can rescue KCC2 hypofunction in order to restore physiological levels of synaptic inhibition and neuronal network activity. It is becoming increasingly clear that diverse cellular signals regulate KCC2 surface expression and function including neurotransmitters and neuromodulators. In the present review we explore the existing evidence that G-protein-coupled receptor (GPCR) signalling can regulate KCC2 activity in numerous regions of the nervous system including the hypothalamus, hippocampus and spinal cord. We present key evidence from the literature suggesting that GPCR signalling is a conserved mechanism for regulating chloride homeostasis. This evidence includes: (1) the activation of group 1 metabotropic glutamate receptors and metabotropic Zn(2+) receptors strengthens GABAergic inhibition in CA3 pyramidal neurons through a regulation of KCC2; (2) activation of the 5-hydroxytryptamine type 2A serotonin receptors upregulates KCC2 cell surface expression and function, restores endogenous inhibition in motoneurons, and reduces spasticity in rats; and (3) activation of A3A-type adenosine receptors rescues KCC2 dysfunction and reverses allodynia in a model of neuropathic pain. We propose that GPCR-signals are novel endogenous Cl(-) extrusion enhancers that may regulate KCC2 function. PMID:26876607

  8. 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.

  9. Basal ganglia cholinergic and dopaminergic function in progressive supranuclear palsy.

    Science.gov (United States)

    Warren, Naomi M; Piggott, Margaret A; Greally, Elizabeth; Lake, Michelle; Lees, Andrew J; Burn, David J

    2007-08-15

    Progressive Supranuclear Palsy (PSP) is a progressive neurodegenerative disorder. In contrast to Parkinson's disease (PD) and dementia with Lewy bodies (DLB), replacement therapy with dopaminergic and cholinergic agents in PSP has been disappointing. The neurochemical basis for this is unclear. Our objective was to measure dopaminergic and cholinergic receptors in the basal ganglia of PSP and control brains. We measured, autoradiographically, dopaminergic (dopamine transporter, 125I PE2I and dopamine D2 receptors, 125I epidepride) and cholinergic (nicotinic alpha4beta2 receptors, 125I 5IA85380 and muscarinic M1 receptors, 3H pirenzepine) parameters in the striatum and pallidum of pathologically confirmed PSP cases (n=15) and controls (n=32). In PSP, there was a marked loss of dopamine transporter and nicotinic alpha4beta2 binding in the striatum and pallidum, consistent with loss of nigrostriatal neurones. Striatal D2 receptors were increased in the caudate and muscarinic M1 receptors were unchanged compared with controls. These results do not account for the poor response to dopaminergic and cholinergic replacement therapies in PSP, and suggest relative preservation of postsynaptic striatal projection neurones bearing D2/M1 receptors. PMID:17534953

  10. Aging neuromodulation impairs associative binding: a neurocomputational account.

    Science.gov (United States)

    Li, Shu-Chen; Naveh-Benjamin, Moshe; Lindenberger, Ulman

    2005-06-01

    Relative to young adults, older adults are particularly impaired in episodic memory tasks requiring associative binding of separate components into compound episodes, such as tasks requiring item-context and item-item binding. This associative-binding deficit has been attributed to senescent changes in frontal-hippocampal circuitry but has not been formally linked to impaired neuromodulation involving this circuitry. Previous neurocomputational work showed that impaired neuromodulation could result in less distinct neurocognitive representations. Here we extend this computational principle to simulate aging-related deficits in associative binding. As expected, networks with simulated deficiency in neuromodulation resulted in less distinct internal representations than did networks simulating the processing and performance of young adults, and were also more impaired under task conditions that required associative binding. The findings suggest that senescent changes in neuromodulatory mechanisms may play a basic role in aging-related impairment in associative binding by reducing the efficacy of distributed conjunctive coding. PMID:15943670

  11. A Danish survey of spinal cord stimulation baseline data: First results from a national neuromodulation database

    DEFF Research Database (Denmark)

    Meier, Kaare; Scherer, Christian; Rosenlund, Christina; Gulisano, Helga Angela; Enggaard, Thomas Peter; Willumsen, Lisette; Knudsen, Anne Lene Høst; Rasmusson, Mattias; Sørensen, Jens Christian Hedemann

    A Danish survey of spinal cord stimulation baseline data: First results from a national neuromodulation database......A Danish survey of spinal cord stimulation baseline data: First results from a national neuromodulation database...

  12. Megakaryocytopoiesis in culture: modulation by cholinergic mechanisms.

    Science.gov (United States)

    Burstein, S A; Adamson, J W; Harker, L A

    1980-05-01

    Treatment of murine bone marrow cultures with the cholinergic agonist carbamylcholine enhanced megakaryocytic colony growth by as much as 65%. In contrast, adrenergic agonists had no such effect. Addition to cultures of dibutyryl cyclic GMP (db-cGMP) also enhanced megakaryocytic colonies up to 50%, whereas dibutyryl cyclic AMP (db-cAMP) had no effect. Sodium nitroprusside and sodium nitrite, putative guanyl cyclase activators, also enhanced colony numbers, as did imidazole, a postulated cGMP phosphodiesterase inhibitor. Preincubation of marrow for two hours with carbamylcholine resulted both an increase in colony numbers (58%) and percent of progenitors in DNA synthesis (48%, compared to 14% for controls) as determined by tritiated thymidine suicide studies. Treatment of mice with the acetylcholinesterase inhibitor neostigmine resulted in an increase in CFU-M/humerus (62%) and percent in DNA synthesis (45%). These data indicate that 1) cholinergic, but not adrenergic, agonists modulate megakaryocytopoiesis in culture; 2) this effect may be mediated by cyclic GMP; and 3) only a brief period of exposure of marrow cells to agonist results in enhancement of megakaryocytic colonies. PMID:6108328

  13. 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.

  14. Eosinophil-Mediated Cholinergic Nerve Remodeling

    OpenAIRE

    Durcan, Niamh; Costello, Richard W; McLean, W. Graham; Blusztajn, Jan; Madziar, Beata; Fenech, Anthony G; Hall, Ian P; Gleich, Gerard J.; McGarvey, Lorcan; Walsh, Marie-Therese

    2006-01-01

    Eosinophils are observed to localize to cholinergic nerves in a variety of inflammatory conditions such as asthma, rhinitis, eosinophilic gastroenteritis, and inflammatory bowel disease, where they are also responsible for the induction of cell signaling.Wehypothesized that a consequence of eosinophil localization to cholinergic nerves would involve a neural remodeling process. Eosinophil co-culture with cholinergic IMR32 cells led to increased expression of the M2 muscar...

  15. Mental stress in atopic dermatitis--neuronal plasticity and the cholinergic system are affected in atopic dermatitis and in response to acute experimental mental stress in a randomized controlled pilot study.

    Directory of Open Access Journals (Sweden)

    Eva Milena Johanne Peters

    Full Text Available RATIONALE: In mouse models for atopic dermatitis (AD hypothalamus pituitary adrenal axis (HPA dysfunction and neuropeptide-dependent neurogenic inflammation explain stress-aggravated flares to some extent. Lately, cholinergic signaling has emerged as a link between innate and adaptive immunity as well as stress responses in chronic inflammatory diseases. Here we aim to determine in humans the impact of acute stress on neuro-immune interaction as well as on the non-neuronal cholinergic system (NNCS. METHODS: Skin biopsies were obtained from 22 individuals (AD patients and matched healthy control subjects before and after the Trier social stress test (TSST. To assess neuro-immune interaction, nerve fiber (NF-density, NF-mast cell contacts and mast cell activation were determined by immunohistomorphometry. To evaluate NNCS effects, expression of secreted mammal Ly-6/urokinase-type plasminogen activator receptor-related protein (SLURP 1 and 2 (endogenous nicotinic acetylcholine receptor ligands and their main corresponding receptors were assessed by quantitative RT-PCR. RESULTS: With respect to neuro-immune interaction we found higher numbers of NGF+ dermal NF in lesional compared to non-lesional AD but lower numbers of Gap43+ growing NF at baseline. Mast cell-NF contacts correlated with SCORAD and itch in lesional skin. With respect to the NNCS, nicotinic acetylcholine receptor α7 (α7nAChR mRNA was significantly lower in lesional AD skin at baseline. After TSST, PGP 9.5+ NF numbers dropped in lesional AD as did their contacts with mast cells. NGF+ NF now correlated with SCORAD and mast cell-NF contacts with itch in non-lesional skin. At the same time, SLURP-2 levels increased in lesional AD skin. CONCLUSIONS: In humans chronic inflammatory and highly acute psycho-emotional stress interact to modulate cutaneous neuro-immune communication and NNCS marker expression. These findings may have consequences for understanding and treatment of chronic

  16. Development of neuromodulation and localization research on implantable device

    OpenAIRE

    Hao, Hong-Wei; Yuan, Yuan; Lu-ming LI

    2015-01-01

    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

  17. 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…

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

    Directory of Open Access Journals (Sweden)

    Dawe Gavin S

    2009-06-01

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

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

    Directory of Open Access Journals (Sweden)

    Florian Groessl

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

  20. 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

  1. GABAergic actions on cholinergic laterodorsal tegmental neurons

    DEFF Research Database (Denmark)

    Kohlmeier, K A; Kristiansen, Uffe

    2010-01-01

    Cholinergic neurons of the pontine laterodorsal tegmentum (LDT) play a critical role in regulation of behavioral state. Therefore, elucidation of mechanisms that control their activity is vital for understanding of how switching between wakefulness, sleep and anesthetic states is effectuated. In...... vivo studies suggest that GABAergic mechanisms within the pons play a critical role in behavioral state switching. However, the postsynaptic, electrophysiological actions of GABA on LDT neurons, as well as the identity of GABA receptors present in the LDT mediating these actions is virtually unexplored...... 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 the...

  2. Cholinergic and perfusion brain networks in Parkinson disease dementia

    Science.gov (United States)

    McKeith, Ian G.; Burn, David J.; Wyper, David J.; O'Brien, John T.; Taylor, John-Paul

    2016-01-01

    Objective: To investigate muscarinic M1/M4 cholinergic networks in Parkinson disease dementia (PDD) and their association with changes in Mini-Mental State Examination (MMSE) after 12 weeks of treatment with donepezil. Methods: Forty-nine participants (25 PDD and 24 elderly controls) underwent 123I-QNB and 99mTc-exametazime SPECT scanning. We implemented voxel principal components (PC) analysis, producing a series of PC images of patterns of interrelated voxels across individuals. Linear regression analyses derived specific M1/M4 and perfusion spatial covariance patterns (SCPs). Results: We found an M1/M4 SCP of relative decreased binding in basal forebrain, temporal, striatum, insula, and anterior cingulate (F1,47 = 31.9, p < 0.001) in cholinesterase inhibitor–naive patients with PDD, implicating limbic-paralimbic and salience cholinergic networks. The corresponding regional cerebral blood flow SCP showed relative decreased uptake in temporoparietal and prefrontal areas (F1,47 = 177.5, p < 0.001) and nodes of the frontoparietal and default mode networks (DMN). The M1/M4 pattern that correlated with an improvement in MMSE (r = 0.58, p = 0.005) revealed relatively preserved/increased pre/medial/orbitofrontal, parietal, and posterior cingulate areas coinciding with the DMN and frontoparietal networks. Conclusion: Dysfunctional limbic-paralimbic and salience cholinergic networks were associated with PDD. Established cholinergic maintenance of the DMN and frontoparietal networks may be prerequisite for cognitive remediation following cholinergic treatment in this condition. PMID:27306636

  3. 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. PMID:26869313

  4. Cholinergic receptor binding in the frontal cortex of suicide victims

    International Nuclear Information System (INIS)

    Because there is a high incidence of individuals diagnosed as having an affective disorder who subsequently commit suicide, the author thought it would be of interest to determine QNB binding in the brains of a large sample of suicide victims, and to compare the findings with a well-matched control group. Brain samples were obtained at autopsy from 22 suicide victims and 22 controls. Frontal cortex samples were diseected, frozen, and stored until assayed. Samples of tissue homogenate were incubated in duplicate with 10 concentrations of tritium-QNB. Specific binding was determined with and without atropine. The results confirmed previous studies in which no changes were noted in suicide versus control brains. While the findings neither disprove nor support the cholinergic hypothesis of depression, they do suggest that the neurochemical basis for the in vivo observations of increased responsivity of depressed individuals to muscarinic cholinergic agents might not involve changes in receptors estimated by QNB binding

  5. EEG sleep and the cholinergic REM induction test in anorexic and bulimic patients

    OpenAIRE

    Lauer, C.; Zulley, Jürgen; Krieg, J. C.; Riemann, D.; Berger, M

    1988-01-01

    The electroencephalographic (EEG) sleep of 20 anorexic patients, 10 bulimic patients, and 10 age-matched healthy controls was studied. In addition, six anorexic patients and six bulimic patients had a cholinergic rapid eye movement (REM) sleep induction test (RIT) performed with the cholinergic agent RS 86. The three samples showed no major differences in sleep patterns. The same held true when attention was focused on patients who additionally met DSM-III criteria for major depression. The R...

  6. Coordinated regulation of cholinergic motor neuron traits through a conserved terminal selector gene

    OpenAIRE

    Kratsios, Paschalis; Stolfi, Alberto; Levine, Michael; Hobert, Oliver

    2011-01-01

    Cholinergic motor neurons are defined by the co-expression of a battery of genes which encode proteins that act sequentially to synthesize, package and degrade acetylcholine and reuptake its breakdown product, choline. How expression of these critical motor neuron identity determinants is controlled and coordinated is not understood. We show here that in the nematode Caenorhabditis elegans all members of the cholinergic gene battery, as well as many other markers of terminal motor neuron fate...

  7. Effects of cholinergic deafferentation of the rhinal cortex on visual recognition memory in monkeys

    Science.gov (United States)

    Turchi, Janita; Saunders, Richard C.; Mishkin, Mortimer

    2005-01-01

    Excitotoxic lesion studies have confirmed that the rhinal cortex is essential for visual recognition ability in monkeys. To evaluate the mnemonic role of cholinergic inputs to this cortical region, we compared the visual recognition performance of monkeys given rhinal cortex infusions of a selective cholinergic immunotoxin, ME20.4-SAP, with the performance of monkeys given control infusions into this same tissue. The immunotoxin, which leads to selective cholinergic deafferentation of the infused cortex, yielded recognition deficits of the same magnitude as those produced by excitotoxic lesions of this region, providing the most direct demonstration to date that cholinergic activation of the rhinal cortex is essential for storing the representations of new visual stimuli and thereby enabling their later recognition. PMID:15684066

  8. 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.

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

    Directory of Open Access Journals (Sweden)

    Adam S Hamlin

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

  10. 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

  11. Update on Neuromodulation for Treatment-Resistant Depression

    OpenAIRE

    Bettina Bewernick; 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), tra...

  12. Reversing pathologically increased EEG power by acoustic coordinated reset neuromodulation.

    OpenAIRE

    Adamchic, Ilya; Toth, Timea; Hauptmann, Christian; Tass, Peter A.

    2014-01-01

    Acoustic Coordinated Reset (CR) neuromodulation is a patterned stimulation with tones adjusted to the patient's dominant tinnitus frequency, which aims at desynchronizing pathological neuronal synchronization. In a recent proof-of-concept study, CR therapy, delivered 4–6 h/day more than 12 weeks, induced a significant clinical improvement along with a significant long-lasting decrease of pathological oscillatory power in the low frequency as well as γ band and an increase of the α power in a ...

  13. Noninvasive Facial Rejuvenation. Part 2: Physician-Directed-Neuromodulators and Fillers.

    Science.gov (United States)

    Dickey, Ryan M; Louis, Matthew R; Cox, Joshua A; Mohan, Kriti; Lee, Edward I; Nigro, Marjory G

    2016-08-01

    A proper knowledge of noninvasive facial rejuvenation is integral to the practice of a cosmetic surgeon. Noninvasive facial rejuvenation can be divided into patient- versus physician-directed modalities. Patient-directed facial rejuvenation combines the use of facial products such as sunscreen, moisturizers, retinoids, α-hydroxy acids, and various antioxidants to both maintain youthful skin as well as rejuvenate damaged skin. Physicians may recommend and often prescribe certain products, but patients are in control with this type of facial rejuvenation. On the other hand, physician-directed facial rejuvenation entails modalities that require direct physician involvement, such as neuromodulators, filler injections, laser resurfacing, microdermabrasion, and chemical peels. With the successful integration of each of these modalities, a complete facial regimen can be established and patient satisfaction can be maximized. This article is the second in a three-part series describing noninvasive facial rejuvenation. Here the authors discuss neuromodulators and fillers in detail, focusing on indications for use, techniques, and common side effects. PMID:27478422

  14. Striatal Cholinergic Neurotransmission Requires VGLUT3

    OpenAIRE

    Nelson, Alexandra B.; Bussert, Timothy G.; Kreitzer, Anatol C.; Seal, Rebecca P.

    2014-01-01

    It is now clear that many neuronal populations release more than one classical neurotransmitter, yet in most cases the functional role of corelease is unknown. Striatal cholinergic interneurons release both glutamate and acetylcholine, and vesicular loading of glutamate has been shown to enhance acetylcholine content. Using a combination of optogenetics and whole-cell recordings in mice, we now provide physiological evidence that optogenetic stimulation of cholinergic interneurons triggers mo...

  15. Brain cholinergic impairment in liver failure

    OpenAIRE

    García Ayllón, María Salud; Cauli, Omar; Silveyra, María Ximena; Rodrigo, Regina; Candela, Asunción; Compañ, Antonio; Jover, Rodrigo; Pérez-Mateo, Miguel; Martínez, Salvador; Felipo, Vicente; Sáez-Valero, Javier

    2008-01-01

    The cholinergic system is involved in specific behavioural responses and cognitive processes. Here, we examined potential alterations in the brain levels of key cholinergic enzymes in cirrhotic patients and animal models with liver failure. An increase (∼30%) in the activity of the acetylcholine-hydrolyzing enzyme, acetylcholinesterase (AChE) is observed in the brain cortex from patients deceased from hepatic coma, while the activity of the acetylcholine-synthesizing enzyme, choline acetyltra...

  16. A case of postganglionic cholinergic dysautonomia.

    OpenAIRE

    Takayama, H; Kazahaya, Y; Kashihara, N.; Kuroda, H.; Miyawaki, S; Ota, Z; Ogawa, N.

    1987-01-01

    A 24 year old female presented with signs and symptoms of postganglionic cholinergic autonomic dysfunction manifested by impaired lachrymation and salivation, mydriasis of the pupil, decreased gastrointestinal motility, atony of the bladder, and sweating and taste disturbance. Clinical and pharmacological studies confirmed that the abnormalities were restricted mainly to the postganglionic cholinergic autonomic systems. The titre of serum complement was low, antinuclear antibodies revealed a ...

  17. 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.

  18. Striatal cholinergic neurotransmission requires VGLUT3.

    Science.gov (United States)

    Nelson, Alexandra B; Bussert, Timothy G; Kreitzer, Anatol C; Seal, Rebecca P

    2014-06-25

    It is now clear that many neuronal populations release more than one classical neurotransmitter, yet in most cases the functional role of corelease is unknown. Striatal cholinergic interneurons release both glutamate and acetylcholine, and vesicular loading of glutamate has been shown to enhance acetylcholine content. Using a combination of optogenetics and whole-cell recordings in mice, we now provide physiological evidence that optogenetic stimulation of cholinergic interneurons triggers monosynaptic glutamate- and acetylcholine-mediated currents in striatal fast-spiking interneurons (FSIs), both of which depend on the expression of the vesicular glutamate transporter 3 (VGLUT3). In contrast to corticostriatal glutamatergic inputs onto FSIs, which are mediated primarily by AMPA-type glutamate receptors, glutamate release by cholinergic interneurons activates both AMPA- and NMDA-type glutamate receptors, suggesting a unique role for these inputs in the modulation of FSI activity. Importantly, we find that the loss of VGLUT3 not only markedly attenuates glutamatergic and cholinergic inputs on FSIs, but also significantly decreases disynaptic GABAergic input onto medium spiny neurons (MSNs), the major output neurons of the striatum. Our data demonstrate that VGLUT3 is required for normal cholinergic signaling onto FSIs, as well as for acetylcholine-dependent disynaptic inhibition of MSNs. Thus, by supporting fast glutamatergic transmission as well as by modulating the strength of cholinergic signaling, VGLUT3 has the capacity to exert widespread influence on the striatal network. PMID:24966377

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

    Directory of Open Access Journals (Sweden)

    Susan D Motts

    2010-10-01

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

  20. 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.

  1. 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. PMID:27184896

  2. Striatal cholinergic interneuron regulation and circuit effects

    Directory of Open Access Journals (Sweden)

    Sean Austin Lim

    2014-10-01

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

  3. Influence of exercise on serotonergic neuromodulation in the brain.

    Science.gov (United States)

    Weicker, H; Strüder, H K

    2001-01-01

    Implications of exercise on serotonergic neuromodulation in the brain have been investigated in two studies. Acute paroxetine (selective serotonin (5-HT) reuptake inhibitor) administration to endurance athletes, who performed a cycle ergometer test to exhaustion at moderate intensity, reduced time to exhaustion and post exercise cognitive performance in comparison to trials with placebo or BCAA administration. Furthermore, during a 3-week moderate endurance training of sedentary males basaline values of Bmax of 5-HT transporters (5-HTT) and 5-HT2A receptors (5-HT(2A)R) on isolated platelet membranes increased while plasma prolactin (PRL) concentrations decreased as well as mood and physical efficiency improved. In contrast, after an excessive training program over four weeks, well-trained endurance athletes showed no change of Bmax of 5-HTT, but a decline of 5-HT(2A)R density and an increase in basal plasma PRL concentration. Mood was impaired and central fatigue increased. Thus, the impact of exercise on 5-HT neurotransmission may depend on training state of athletes and extent of exertion. The theoretical background of the implication of exercise and the effect of long lasting exhaustive exercise in athletes on mental and physical efficiency or central fatigue are evaluated. The significance of the primary disturbance of central neuromodulation and dysfunction of 5-HTT, 5-HT receptor subtypes and the phosphoinositol signal transduction as well as the limited modulation capacity of the 5-HT system in overstrain are also addressed. PMID:11310929

  4. Aging of cholinergic synapses: fiction or reality?

    International Nuclear Information System (INIS)

    The authors make use of the ciliary ganglion iris preparation of the aging chicken as a model of senescent peripheral cholinergic synapses. Based on the studies performed on the iris, an hypothesis of aging of the cholinergic synapse has been suggested. In order to establish the nature of a deficit, the authors examine the ability of chloinergic synapses in the iris at various ages to take up the precursor tritium-choline and release the formed tritium-ACh in response to high K+ (115 mM) depolarization. A summary of preliminary results of morphometric analysis of nerve endings and synaptic components in the iris of young adult and aged chickens is shown. The experiments suggest that severe changes may occur at later stages of life. A specific functional defect in the cholinergic synapse during aging is found

  5. 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.

  6. Disposed to distraction: Genetic variation in the cholinergic system influences distractibility but not time-on-task effects

    OpenAIRE

    Berry, Anne S.; Demeter, Elise; Sabhapathy, Surya; English, Brett A.; Blakely, Randy D.; Sarter, Martin; Lustig, Cindy

    2014-01-01

    Both the passage of time and external distraction make it difficult to keep attention on the task at hand. We tested the hypothesis that time-on-task and external distraction pose independent challenges to attention, and that the brain’s cholinergic system selectively modulates our ability to resist distraction. Participants with a polymorphism limiting cholinergic capacity (Ile89Val variant (rs1013940) of the choline transporter gene SLC5A7) and matched controls completed self-report measure...

  7. Adult Mouse Basal Forebrain Harbors Two Distinct Cholinergic Populations Defined By Their Electrophysiology

    Directory of Open Access Journals (Sweden)

    Jorge P Golowasch

    2012-05-01

    Full Text Available We performed whole-cell recordings from basal forebrain cholinergic neurons in transgenic mice expressing enhanced green fluorescent protein under the control of choline acetyltransferase promoter. Basal forebrain cholinergic neurons can be differentiated into two electrophysiologically identifiable subtypes: early and late firing neurons. Early firing neurons (70% are more excitable, show prominent spike frequency adaptation and more susceptible to depolarization blockade, a phenomenon characterized by complete silencing of the neuron following initial action potentials. Late firing neurons (30%, albeit being less excitable, could maintain a tonic discharge at low frequencies. In voltage clamp analysis, we have shown that early firing neurons have a higher density of low voltage activated calcium currents. These two cholinergic cell populations might be involved in distinct functions: the early firing group being more suitable for phasic changes in cortical acetylcholine release associated with attention while the late firing neurons could support general arousal by maintaining tonic acetylcholine level.

  8. Multiple cholinergic differentiation factors are present in footpad extracts: comparison with known cholinergic factors

    OpenAIRE

    Rao, M S; Patterson, Paul H.; Landis, S C

    1992-01-01

    Sweat glands in rat footpads contain a neuronal differentiation activity that switches the phenotype of sympathetic neurons from noradrenergic to cholinergic during normal development in vivo. Extracts of developing and adult sweat glands induce changes in neurotransmitter properties in cultured sympathetic neurons that mimic those observed in vivo. We have characterized further the factors present in the extract and compared their properties to those of known cholinergic factors. When assaye...

  9. Cholinergic imaging in dementia spectrum disorders.

    Science.gov (United States)

    Roy, Roman; Niccolini, Flavia; Pagano, Gennaro; Politis, Marios

    2016-07-01

    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 [(11)C]MP4A and [(11)C]PMP PET for acetylcholinesterase (AChE), [(123)I]5IA SPECT for the α4β2 nicotinic acetylcholine receptor and [(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. PMID:26984612

  10. Cholinergic imaging in dementia spectrum disorders

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-07-15

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

  11. Biological targets of cholinergic pesticides and possible use of alternative models for toxicity testing

    OpenAIRE

    C Falugi; Z. Rakonczay; M.G. Aluigi

    2011-01-01

    The use of protection plant products for the control of pests in agriculture should be accompanied by a clear understanding of possible damages to human and environmental health. The mechanisms of action and the affects on developing organisms exerted by acute and chronic exposure to the main classes of cholinergic pesticides are reviewed.

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

    Directory of Open Access Journals (Sweden)

    Fischer Andy J

    2008-02-01

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

  13. 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

  14. Parallel evolution of serotonergic neuromodulation underlies independent evolution of rhythmic motor behavior.

    Science.gov (United States)

    Lillvis, Joshua L; Katz, Paul S

    2013-02-01

    Neuromodulation can dynamically alter neuronal and synaptic properties, thereby changing the behavioral output of a neural circuit. It is therefore conceivable that natural selection might act upon neuromodulation as a mechanism for sculpting the behavioral repertoire of a species. Here we report that the presence of neuromodulation is correlated with the production of a behavior that most likely evolved independently in two species: Tritonia diomedea and Pleurobranchaea californica (Mollusca, Gastropoda, Opisthobranchia, Nudipleura). Individuals of both species exhibit escape swimming behaviors consisting of repeated dorsal-ventral whole-body flexions. The central pattern generator (CPG) circuits underlying these behaviors contain homologous identified neurons: DSI and C2 in Tritonia and As and A1 in Pleurobranchaea. Homologs of these neurons also can be found in Hermissenda crassicornis where they are named CPT and C2, respectively. However, members of this species do not exhibit an analogous swimming behavior. In Tritonia and Pleurobranchaea, but not in Hermissenda, the serotonergic DSI homologs modulated the strength of synapses made by C2 homologs. Furthermore, the serotonin receptor antagonist methysergide blocked this neuromodulation and the swimming behavior. Additionally, in Pleurobranchaea, the robustness of swimming correlated with the extent of the synaptic modulation. Finally, injection of serotonin induced the swimming behavior in Tritonia and Pleurobranchaea, but not in Hermissenda. This suggests that the analogous swimming behaviors of Tritonia and Pleurobranchaea share a common dependence on serotonergic neuromodulation. Thus, neuromodulation may provide a mechanism that enables species to acquire analogous behaviors independently using homologous neural circuit components. PMID:23392697

  15. Pharmakologische Charakterisierung zentraler cholinerger Dysfunktionen in transgenen Mausmodellen

    OpenAIRE

    Mohr, Franziska

    2014-01-01

    Die cholinerge Dysfunktion steht in Zusammenhang mit der Ätiologie der Alzheimer-Krankheit (AD). Das Absterben cholinerger Neurone führt zu einer verminderten cholinergen Neurotransmission im Gehirn. Die Abnahme der Acetylcholinesterase-(AChE)-Aktivität und eine leichte Zunahme der Butyrylcholinesterase-(BChE)-Aktivität zählen zu den charakteristischen Merkmalen der AD. Acetylcholinesterase-Inhibitoren (AChEI) sollen Acetylcholin (ACh)-Konzentrationen im Gehirn steigern, um cholinerge Defizit...

  16. Neuromodulator and Emotion Biomarker for Stress Induced Mental Disorders

    Directory of Open Access Journals (Sweden)

    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.

  17. 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

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

    Science.gov (United States)

    Panthi, Sandesh; Chung, Hyung-Joo; Jung, Junyang; Jeong, Na Young

    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

  19. Evidence of heterosynaptic LTD in the human nociceptive system: superficial skin neuromodulation using a matrix electrode reduces deep pain sensitivity.

    Directory of Open Access Journals (Sweden)

    Martin Mücke

    Full Text Available Long term depression (LTD is a neuronal learning mechanism after low frequency stimulation (LFS. This study compares two types of electrodes (concentric vs. matrix and stimulation frequencies (4 and 30 Hz to examine homo- and heterosynaptic effects indirectly depicted from the somatosensory profile of healthy subjects. Both electrodes were compared in a prospective, randomized, controlled cross-over study using 4 Hz as the conditioning LFS compared to 30 Hz (intended sham condition. Quantitative sensory testing (QST was used to examine 13 thermal and mechanical detection and pain thresholds. Sixteen healthy volunteers (10 women, age 31.0 ± 12.7 years were examined. Depending on the electrodes and frequencies used a divergent pattern of sensory minus signs occurred. Using LFS the concentric electrode increased thermal thresholds, while the matrix electrode rather increased mechanical including deep pain thresholds. Findings after cutaneous neuromodulation using LFS and a matrix electrode are consistent with the concept of heterosynaptic LTD in the human nociceptive system, where deep pain sensitivity was reduced after superficial stimulation of intraepidermal nerve fibres. Cutaneous neuromodulation using LFS and a matrix electrode may be a useful tool to influence deep pain sensitivity in a variety of chronic pain syndromes.

  20. Basal Forebrain Cholinergic Deficits Reduce Glucose Metabolism and Function of Cholinergic and GABAergic Systems in the Cingulate Cortex

    OpenAIRE

    Jeong, Da Un; Oh, Jin Hwan; Lee, Ji Eun; Lee, Jihyeon; Cho, Zang Hee; Chang, Jin Woo; Chang, Won Seok

    2015-01-01

    Purpose Reduced brain glucose metabolism and basal forebrain cholinergic neuron degeneration are common features of Alzheimer's disease and have been correlated with memory function. Although regions representing glucose hypometabolism in patients with Alzheimer's disease are targets of cholinergic basal forebrain neurons, the interaction between cholinergic denervation and glucose hypometabolism is still unclear. The aim of the present study was to evaluate glucose metabolism changes caused ...

  1. What saccadic eye movements tell us about TMS-induced neuromodulation of the DLPFC and mood changes: a pilot study in bipolar disorders.

    Science.gov (United States)

    Beynel, Lysianne; Chauvin, Alan; Guyader, Nathalie; Harquel, Sylvain; Szekely, David; Bougerol, Thierry; Marendaz, Christian

    2014-01-01

    The study assumed that the antisaccade (AS) task is a relevant psychophysical tool to assess (i) short-term neuromodulation of the dorsolateral prefrontal cortex (DLPFC) induced by intermittent theta burst stimulation (iTBS); and (ii) mood change occurring during the course of the treatment. Saccadic inhibition is known to strongly involve the DLPFC, whose neuromodulation with iTBS requires less stimulation time and lower stimulation intensity, as well as results in longer aftereffects than the conventional repetitive transcranial magnetic stimulation (rTMS). Active or sham iTBS was applied every day for 3 weeks over the left DLPFC of 12 drug-resistant bipolar depressed patients. To assess the iTBS-induced short-term neuromodulation, the saccadic task was performed just before (S1) and just after (S2) the iTBS session, the first day of each week. Mood was evaluated through Montgomery and Asberg Depression Rating Scale (MADRS) scores and the difference in scores between the beginning and the end of treatment was correlated with AS performance change between these two periods. As expected, only patients from the active group improved their performance from S1 to S2 and mood improvement was significantly correlated with AS performance improvement. In addition, the AS task also discriminated depressive bipolar patients from healthy control subjects. Therefore, the AS task could be a relevant and useful tool for clinicians to assess if the Transcranial magnetic stimulation (TMS)-induced short-term neuromodulation of the DLPFC occurs as well as a "trait vs. state" objective marker of depressive mood disorder. PMID:25191234

  2. What saccadic eye movements tell us about TMS-induced neuromodulation of the DLPFC and mood changes: a pilot study in bipolar disorders

    Directory of Open Access Journals (Sweden)

    Lysianne Beynel

    2014-08-01

    Full Text Available The study assumed that the antisaccade (AS task is a relevant psychophysical tool to assess (i short-term neuromodulation of the dorsolateral prefrontal cortex (DLPFC induced by intermittent theta burst stimulation (iTBS and (ii mood change occurring during the course of the treatment. Saccadic inhibition is known to strongly involve the DLPFC, whose neuromodulation with iTBS requires less stimulation time and lower stimulation intensity, as well as results in longer aftereffects than the conventional repetitive transcranial magnetic stimulation (rTMS. Active or sham iTBS was applied every day for three weeks over the left DLPFC of 12 drug-resistant bipolar depressed patients. To assess the iTBS-induced short-term neuromodulation, the saccadic task was performed just before (S1 and just after (S2 the iTBS session, the first day of each week. Mood was evaluated through MADRS scores and the difference in scores between the beginning and the end of treatment was correlated with AS performance change between these two periods. As expected, only patients from the active group improved their performance from S1 to S2 and mood improvement was significantly correlated with AS performance improvement. In addition, the AS task also discriminated depressive bipolar patients from healthy control subjects. Therefore, the AS task could be a relevant and useful tool for clinicians to assess if the TMS-induced short-term neuromodulation of the DLPFC occurs as well as a ‘trait vs. state’ objective marker of depressive mood disorder.

  3. Long-Term Effects of Maternal Deprivation on Cholinergic System in Rat Brain

    Directory of Open Access Journals (Sweden)

    Branka Marković

    2014-01-01

    Full Text Available Numerous clinical studies have demonstrated an association between early stressful life events and adult life psychiatric disorders including schizophrenia. In rodents, early life exposure to stressors such as maternal deprivation (MD produces numerous hormonal, neurochemical, and behavioral changes and is accepted as one of the animal models of schizophrenia. The stress induces acetylcholine (Ach release in the forebrain and the alterations in cholinergic neurotransmitter system are reported in schizophrenia. The aim of this study was to examine long-term effects of maternal separation on acetylcholinesterase (AChE activity in different brain structures and the density of cholinergic fibers in hippocampus and retrosplenial (RS cortex. Wistar rats were separated from their mothers on the postnatal day (P 9 for 24 h and sacrificed on P60. Control group of rats was bred under the same conditions, but without MD. Brain regions were collected for AChE activity measurements and morphometric analysis. Obtained results showed significant decrease of the AChE activity in cortex and increase in the hippocampus of MD rats. Density of cholinergic fibers was significantly increased in CA1 region of hippocampus and decreased in RS cortex. Our results indicate that MD causes long-term structure specific changes in the cholinergic system.

  4. Neuro-immune interactions via the cholinergic anti-inflammatory pathway

    OpenAIRE

    Gallowitsch-Puerta, Margot; Pavlov, Valentin A.

    2007-01-01

    The overproduction of TNF and other cytokines can cause the pathophysiology of numerous diseases. Controlling cytokine synthesis and release is critical for preventing unrestrained inflammation and maintaining health. Recent studies identified an efferent vagus nerve-based mechanism termed “the cholinergic anti-inflammatory pathway” that controls cytokine production and inflammation. Here we review current advances related to the role of this pathway in neuro-immune interactions that prevent ...

  5. Novel Fast Adapting Interneurons Mediate Cholinergic-Induced Fast GABAA IPSCs In Striatal Spiny Neurons

    OpenAIRE

    Faust, Thomas W.; Assous, Maxime; Shah, Fulva; Tepper, James M.; Koós, Tibor

    2015-01-01

    Previous work suggests that neostriatal cholinergic interneurons control the activity of several classes of GABAergic interneurons through fast nicotinic receptor mediated synaptic inputs. Although indirect evidence has suggested the existence of several classes of interneurons controlled by this mechanism only one such cell type, the neuropeptide-Y expressing neurogliaform neuron, has been identified to date. Here we tested the hypothesis that in addition to the neurogliaform neurons that el...

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

    Directory of Open Access Journals (Sweden)

    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.

  7. Altering risky decision-making: Influence of impulsivity on the neuromodulation of prefrontal cortex.

    Science.gov (United States)

    Cheng, Gordon L F; Lee, Tatia M C

    2016-08-01

    The prefrontal cortex (PFC) subserves complex cognitive abilities, including risky decision-making; the modulation of this brain area is shown to alter the way people take risks. Yet, neuromodulation of the PFC in relation to risk-taking behavior remains relatively less well-studied. Moreover, the psychological variables that influence such neuromodulation remain poorly understood. To address these issues, 16 participants took part in 3 experimental sessions on separate days. They received: (i) left anodal-right cathodal transcranial direct current stimulation (tDCS); (ii) left cathodal-right anodal stimulation; or (iii) sham stimulation while they completed two risk-taking tasks. They also measured on several cognitive-affective abilities and personality traits. It was revealed that left cathodal-right anodal stimulation led to significantly reduced risk-taking under a context of haste. The reduction of risk-taking (relative to sham) correlated with state and trait impulsivity, such that the effect was larger in more impulsive individuals. For these individuals, the tDCS effect size was considered to be large (generalized partial η(2) > .17). The effect of prefrontal-neuromodulation in reducing risk-taking was influenced by baseline impulsivity, reflecting a state-dependent effect of neuromodulation on the PFC. The results of this study carry important insights into the use of neuromodulation to alter higher cognition. PMID:26343527

  8. Lipid modulation of neuronal cholinergic activity

    International Nuclear Information System (INIS)

    Phospholipids are the major lipids in the plasma membrane, and it is now evident that the function of phospholipids exceeds that of the role of barrier between different aqueous compartments. Several lines of evidence suggest that a major plasma membrane lipids, phosphatidylcholine, may be a useful compound for modulating presynaptic cholinergic transmission. In order to investigate the effects of PC on cholinergic terminals, rat cortical synaptosomes were preloaded with [3H]-ACh and then treated with small unilamellar vesicles (SUV) composed of dipalmitoylphosphatidylcholine (DPPC) at concentrations (0.8-1.5 mg/ml) similar to those found circulating in plasma. The effects of DPPC on levels, hydrolysis, release, and synthesis of [3H]-ACh were then examined. Dipalmitoylphosphatidylcholine decreased the levels of [3H]-ACh. This decrease does not result from a dilution of the radioactive [3H]-choline by nonradioactive choline derived from PC. Specifically, it is the S3 (cytoplasmic) level of [3H]-ACh that is decreased by DPPC treatment. This decrease appears to be partially due to lipid activation of an intraterminal cholinesterase which results in hydrolysis of nonvesicular [3H]-ACh. The ability of the lipid to interfere with exocytosis may account for the blockade of the K+ induced [3H]-ACh release from the P3 (vesicular) fraction. The high affinity choline transporter was competitively inhibited by DPPC treatment when synaptosomes were treated with DPPC prior to [3H]-choline loading; the ubiquitous low affinity transport was not affected. These effects were specific for cholinergic neurons since the uptake and release of dopamine and norepinephrine from the substantia nigra and the cortex, respectively, were not affected

  9. Stress-induced altered cholinergic-glutamatergic interactions in the mouse hippocampus.

    Science.gov (United States)

    Pavlovsky, Lev; Bitan, Yifat; Shalev, Hadar; Serlin, Yonatan; Friedman, Alon

    2012-09-01

    Psychological stress may lead to long-lasting brain dysfunction, specifically altered emotional and cognitive capabilities. Previous studies have demonstrated persistent changes in the expression of key cholinergic genes in the neocortex and hippocampus following stress with muscarinic receptor-mediated enhanced excitability. In the present study we examined cholinergic-mediated glutamatergic transmission in the hippocampus of mice after exposure to stress and its potential role in synaptic plasticity and altered behavior. Adult male mice were tested one month after repeated forced swimming test. Non-treated age-matched animals served as controls. Electrophysiological recordings were performed in the acute in-vitro slice preparation. CA1 pyramidal neurons were recorded using whole cell patch configuration. Extracellular recordings were done in response to Shaffer collaterals (SC) or stratum orien (SO) stimulation. Animal behavior in response to inhibition of acetylcholinesterase (AChE) was tested in open field paradigms. In whole cell patch recordings the frequency of excitatory post-synaptic currents (EPSCs) was significantly increased in response to muscarinic activation in stress-exposed animals. This enhanced cholinergic-modulated excitatory transmission is associated with facilitation of long-term potentiation (LTP) in response to tetanic stimulation at the SO but not at the SC. Stress-related behavioral modulation via central cholinergic pathways was enhanced by the central AChE inhibitor, physostigmine, thus further supporting the notion that stress is associated with long lasting hypersensitivity to acetylcholine. Our results revealed a pathway-specific enhancement of cholinergic-dependent glutamatergic transmission in the hippocampus after stress. These changes may underlie specific hippocampal malfunction, including cognitive and emotional disturbances, as observed in patients with post-traumatic stress disorder (PTSD). PMID:22796599

  10. Cholinergic pesticides cause mushroom body neuronal inactivation in honeybees

    OpenAIRE

    Palmer, Mary J; Moffat, Christopher; Saranzewa, Nastja; Harvey, Jenni; Wright, Geraldine A.; Connolly, Christopher N.

    2013-01-01

    Pesticides that target cholinergic neurotransmission are highly effective, but their use has been implicated in insect pollinator population decline. Honeybees are exposed to two widely used classes of cholinergic pesticide: neonicotinoids (nicotinic receptor agonists) and organophosphate miticides (acetylcholinesterase inhibitors). Although sublethal levels of neonicotinoids are known to disrupt honeybee learning and behaviour, the neurophysiological basis of these effects has not been shown...

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

    Directory of Open Access Journals (Sweden)

    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

  12. Current Approaches to Neuromodulation in Primary Headaches: Focus on Vagal Nerve and Sphenopalatine Ganglion Stimulation.

    Science.gov (United States)

    Puledda, Francesca; Goadsby, Peter J

    2016-07-01

    Neuromodulation is a promising, novel approach for the treatment of primary headache disorders. Neuromodulation offers a new dimension in the treatment that is both easily reversible and tends to be very well tolerated. The autonomic nervous system is a logical target given the neurobiology of common primary headache disorders, such as migraine and the trigeminal autonomic cephalalgias (TACs). This article will review new encouraging results of studies from the most recent literature on neuromodulation as acute and preventive treatment in primary headache disorders, and cover some possible underlying mechanisms. We will especially focus on vagus nerve stimulation (VNS) and sphenopalatine ganglion (SPG) since they have targeted autonomic pathways that are cranial and can modulate relevant pathophysiological mechanisms. The initial data suggests these approaches will find an important role in headache disorder management going forward. PMID:27278441

  13. 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

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

    Directory of Open Access Journals (Sweden)

    Wiebke Potjans

    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.

  15. 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. PMID:21151370

  16. Cholinergic vasodilator mechanism in human fingers

    International Nuclear Information System (INIS)

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

  17. Cholinergic vasodilator mechanism in human fingers

    Energy Technology Data Exchange (ETDEWEB)

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

    1987-03-01

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

  18. Impaired Cholinergic Excitation of Prefrontal Attention Circuitry in the TgCRND8 Model of Alzheimer’s Disease

    Science.gov (United States)

    Proulx, Éliane; Fraser, Paul; McLaurin, JoAnne; Lambe, Evelyn K.

    2015-01-01

    Attention deficits in Alzheimer’s disease can exacerbate its other cognitive symptoms, yet relevant disruptions of key prefrontal circuitry are not well understood. Here, in the TgCRND8 mouse model of this neurological disorder, we demonstrate and characterize a disruption of cholinergic excitation in the major corticothalamic layer of the prefrontal cortex, in which modulation by acetylcholine is essential for optimal attentional function. Using electrophysiology with concurrent multiphoton imaging, we show that layer 6 pyramidal cells are unable to sustain cholinergic excitation to the same extent as their nontransgenic littermate controls, as a result of the excessive activation of calcium-activated hyperpolarizing conductances. We report that cholinergic excitation can be improved in TgCRND8 cortex by pharmacological blockade of SK channels, suggesting a novel target for the treatment of cognitive dysfunction in Alzheimer’s disease. PMID:26377466

  19. Carbachol can be released at a cholinergic ganglionic synapse as a false transmitter.

    OpenAIRE

    Baux, G; Tauc, L

    1983-01-01

    Carbachol was injected into a presynaptic cholinergic neuron in the buccal ganglion of Aplysia and the quantal aspects of the Cl- -dependent postsynaptic response to a prolonged stimulation were analyzed by a statistical fluctuation method. The calculated amplitude of the miniature postsynaptic current was increased with respect to control. Statistical fluctuation analysis was also used to analyze the postsynaptic response obtained during ionophoretic application of acetylcholine and carbacho...

  20. Cholinergic Dysfunction in Fragile X Syndrome and Potential Intervention: A Preliminary 1H MRS Study

    OpenAIRE

    Kesler, Shelli R.; Lightbody, Amy A.; Reiss, Allan L.

    2009-01-01

    Males with fragile X syndrome are at risk for significant cognitive and behavioral deficits, particularly those involving executive prefrontal systems. Disruption of the cholinergic system secondary to fragile X mental retardation protein deficiency may contribute to the cognitive-behavioral impairments associated with fragile X. We measured choline in the dorsolateral prefrontal cortex of 9 males with fragile X syndrome and 9 age-matched typically developing controls using 1H magnetic resona...

  1. Involvement of nicotinic and muscarinic receptors in the endogenous cholinergic modulation of the balance between excitation and inhibition in the young rat visual cortex.

    Science.gov (United States)

    Lucas-Meunier, Estelle; Monier, Cyril; Amar, Muriel; Baux, Gérard; Frégnac, Yves; Fossier, Philippe

    2009-10-01

    This study aims to clarify how endogenous release of cortical acetylcholine (ACh) modulates the balance between excitation and inhibition evoked in visual cortex. We show that electrical stimulation in layer 1 produced a significant release of ACh measured intracortically by chemoluminescence and evoked a composite synaptic response recorded intracellularly in layer 5 pyramidal neurons of rat visual cortex. The pharmacological specificity of the ACh neuromodulation was determined from the continuous whole-cell voltage clamp measurement of stimulation-locked changes of the input conductance during the application of cholinergic agonists and antagonists. Blockade of glutamatergic and gamma-aminobutyric acid (GABAergic) receptors suppressed the evoked response, indicating that stimulation-induced release of ACh does not directly activate a cholinergic synaptic conductance in recorded neurons. Comparison of cytisine and mecamylamine effects on nicotinic receptors showed that excitation is enhanced by endogenous evoked release of ACh through the presynaptic activation of alpha(*)beta4 receptors located on glutamatergic fibers. DHbetaE, the selective alpha4beta2 nicotinic receptor antagonist, induced a depression of inhibition. Endogenous ACh could also enhance inhibition by acting directly on GABAergic interneurons, presynaptic to the recorded cell. We conclude that endogenous-released ACh amplifies the dominance of the inhibitory drive and thus decreases the excitability and sensory responsiveness of layer 5 pyramidal neurons. PMID:19176636

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

    International Nuclear Information System (INIS)

    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

  3. Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias.

    Science.gov (United States)

    Bordia, Tanuja; Perez, Xiomara A; Heiss, Jaime E; Zhang, Danhui; Quik, Maryka

    2016-07-01

    L-dopa-induced dyskinesias (LIDs) are a serious complication of L-dopa therapy for Parkinson's disease. Emerging evidence indicates that the nicotinic cholinergic system plays a role in LIDs, although the pathways and mechanisms are poorly understood. Here we used optogenetics to investigate the role of striatal cholinergic interneurons in LIDs. Mice expressing cre-recombinase under the control of the choline acetyltransferase promoter (ChAT-Cre) were lesioned by unilateral injection of 6-hydroxydopamine. AAV5-ChR2-eYFP or AAV5-control-eYFP was injected into the dorsolateral striatum, and optical fibers implanted. After stable virus expression, mice were treated with L-dopa. They were then subjected to various stimulation protocols for 2h and LIDs rated. Continuous stimulation with a short duration optical pulse (1-5ms) enhanced LIDs. This effect was blocked by the general muscarinic acetylcholine receptor (mAChR) antagonist atropine indicating it was mAChR-mediated. By contrast, continuous stimulation with a longer duration optical pulse (20ms to 1s) reduced LIDs to a similar extent as nicotine treatment (~50%). The general nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine blocked the decline in LIDs with longer optical pulses showing it was nAChR-mediated. None of the stimulation regimens altered LIDs in control-eYFP mice. Lesion-induced motor impairment was not affected by optical stimulation indicating that cholinergic transmission selectively regulates LIDs. Longer pulse stimulation increased the number of c-Fos expressing ChAT neurons, suggesting that changes in this immediate early gene may be involved. These results demonstrate that striatal cholinergic interneurons play a critical role in LIDs and support the idea that nicotine treatment reduces LIDs via nAChR desensitization. PMID:26921469

  4. 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

  5. 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

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

    International Nuclear Information System (INIS)

    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

  7. ACTH neuromodulation of the developing motor system and neonatal learning in the rat.

    Science.gov (United States)

    Acker, G R; Berran, J; Strand, F L

    1985-01-01

    ACTH peptides influence the developing nervous system during the first three weeks of life in the rat. ACTH 4-10 and Org 2766 (10.0 micrograms/kg) accelerate the expression of motor hyperactivity usually exhibited in 15-day old normal animals, with ACTH 4-10 increasing the force of extensor digitorum longus muscle contraction amplitude. Following cold stress and peptide treatment, rate changes in motor activity from one age to the next are dramatically enhanced, with vertical activity being exhibited at an earlier age than controls. Grasping ability is similarly enhanced in 13-day old ACTH 4-10-treated animals. The retention of a T-maze learning paradigm is significantly enhanced in 16-day old ACTH 4-10 (10.0 micrograms/kg)-treated and Org 2766 (0.01 micrograms/kg)-treated animals, with these animals running the maze significantly faster than controls. Peptide treatment appears to reverse the apparent turning preference in the maze during extinction. It is suggested that ACTH peptides modulate the organization of the nervous system and facilitate neurotransmission, and may act on dopaminergic and cholinergic neurotransmitter systems. Motor behavior seems to reflect underlying neural substrates that are integrated to produce the overt behavior of the organism. PMID:2867532

  8. Effect of augmenting cholinergic function on gait and balance

    OpenAIRE

    Mancini, Martina; Fling, Brett W.; Gendreau, Anne; Lapidus, Jodi; Fay B. Horak; Chung, Kathy; Nutt, John G.

    2015-01-01

    Background Impaired mobility and falls are clinically important complications of Parkinson’s disease (PD) and a major detractor from quality of life for which there are limited therapies. Pathological, neuroimaging and clinical evidence suggest that degeneration of cholinergic systems may contribute to impairments of balance and gait in PD. The proposed trial will examine the effects of augmentation of the cholinergic system on balance and gait. Design The study is a single-site, proof of con...

  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. The role of ventral midline thalamus in cholinergic-based recovery in the amnestic rat.

    Science.gov (United States)

    Bobal, M G; Savage, L M

    2015-01-29

    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

  11. Chronic administration of sulbutiamine improves long term memory formation in mice: possible cholinergic mediation.

    Science.gov (United States)

    Micheau, J; Durkin, T P; Destrade, C; Rolland, Y; Jaffard, R

    1985-08-01

    Thiamine deficiency in both man and animals is known to produce memory dysfunction and cognitive disorders which have been related to an impairment of cholinergic activity. The present experiment was aimed at testing whether, inversely, chronic administration of large doses of sulbutiamine would have a facilitative effect on memory and would induce changes in central cholinergic activity. Accordingly mice received 300 mg/kg of sulbutiamine daily for 10 days. They were then submitted to an appetitive operant level press conditioning test. When compared to control subjects, sulbutiamine treated mice learned the task at the same rate in a single session but showed greatly improved performance when tested 24 hr after partial acquisition of the same task. Parallel neurochemical investigations showed that the treatment induced a slight (+ 10%) but significant increase in hippocampal sodium-dependent high affinity choline uptake. The present findings and previous results suggest that sulbutiamine improves memory formation and that this behavioral effect could be mediated by an increase in hippocampal cholinergic activity. PMID:4059305

  12. Transient and sustained afterdepolarizations in accessory olfactory bulb mitral cells are mediated by distinct mechanisms that are differentially regulated by neuromodulators

    Directory of Open Access Journals (Sweden)

    Guy eShpak

    2015-01-01

    Full Text Available Social interactions between mammalian conspecifics rely heavily on molecular communication via the main and accessory olfactory systems. These two chemosensory systems show high similarity in the organization of information flow along their early stages: social chemical cues are detected by the sensory neurons of the main olfactory epithelium and the vomeronasal organ. These neurons then convey sensory information to the main (MOB and accessory (AOB olfactory bulbs, respectively, where they synapse upon mitral cells that project to higher brain areas. Yet, the functional difference between these two chemosensory systems remains unclear. We have previously shown that MOB and AOB mitral cells exhibit very distinct intrinsic biophysical properties leading to different types of information processing. Specifically, we found that unlike MOB mitral cells, AOB neurons display persistent firing responses to strong stimuli. These prolonged responses are mediated by long-lasting calcium-activated non-selective cationic current (Ican. In the current study we further examined the firing characteristics of these cells and their modulation by several neuromodulators. We found that AOB mitral cells display transient depolarizing afterpotentials (DAPs following moderate firing. These DAPs are not found in MOB mitral cells that show instead robust hyperpolarizing afterpotentials. Unlike Ican, the DAPs of AOB mitral cells are activated by low levels of intracellular calcium and are relatively insensitive to flufenamic acid. Moreover, the cholinergic agonist carbachol exerts opposite effects on the persistent firing and DAPs of AOB mitral cells. We conclude that these phenomena are mediated by distinct biophysical mechanisms that may serve to mediate different types of information processing in the AOB at distinct brain states.

  13. Transient and sustained afterdepolarizations in accessory olfactory bulb mitral cells are mediated by distinct mechanisms that are differentially regulated by neuromodulators.

    Science.gov (United States)

    Shpak, Guy; Zylbertal, Asaph; Wagner, Shlomo

    2014-01-01

    Social interactions between mammalian conspecifics rely heavily on molecular communication via the main and accessory olfactory systems. These two chemosensory systems show high similarity in the organization of information flow along their early stages: social chemical cues are detected by the sensory neurons of the main olfactory epithelium and the vomeronasal organ. These neurons then convey sensory information to the main (MOB) and accessory (AOB) olfactory bulbs, respectively, where they synapse upon mitral cells that project to higher brain areas. Yet, the functional difference between these two chemosensory systems remains unclear. We have previously shown that MOB and AOB mitral cells exhibit very distinct intrinsic biophysical properties leading to different types of information processing. Specifically, we found that unlike MOB mitral cells, AOB neurons display persistent firing responses to strong stimuli. These prolonged responses are mediated by long-lasting calcium-activated non-selective cationic current (Ican). In the current study we further examined the firing characteristics of these cells and their modulation by several neuromodulators. We found that AOB mitral cells display transient depolarizing afterpotentials (DAPs) following moderate firing. These DAPs are not found in MOB mitral cells that show instead robust hyperpolarizing afterpotentials. Unlike Ican, the DAPs of AOB mitral cells are activated by low levels of intracellular calcium and are relatively insensitive to flufenamic acid. Moreover, the cholinergic agonist carbachol exerts opposite effects on the persistent firing and DAPs of AOB mitral cells. We conclude that these phenomena are mediated by distinct biophysical mechanisms that may serve to mediate different types of information processing in the AOB at distinct brain states. PMID:25642164

  14. Change of cholinergic transmission and memory deficiency induced by injection of b-amyloid protein into NBM of rats

    Institute of Scientific and Technical Information of China (English)

    马晓峰; 叶惟泠; 梅镇彤

    2001-01-01

    The change of cholinergic transmission of b-amyloid protein (b-AP) treated rats was studied by intracerebral microdialysis sampling combined with HPLC analysis. b-AP1-40 was injected into nucleus basalis magnocellularis (NBM). Passive avoidance response test (step-down test) and delayed alternation task were used for memory testing. The impairment of memory after injection of b-AP1-40 into NBM exhibited mainly the deficiency of short-term working memory. One week after injection of b-AP1-40 the release of acetylcholine (ACh) from frontal cortex of freely-moving rats decreased significantly, and the response of cholinergic nerve ending to the action of high [K+] solution was rather weak. In control animals the percentage of increase of ACh- release during behavioral performance was 57%, while in b-AP1-40 - treated rats it was 34%. The temporary in-crease of the ACh-release of the rat put into a new place was also significantly diminished in b-AP1-40 -treated rats. The results show that the injection of b-AP1-40 into NBM impairs the cholinergic transmission in frontal cortex, and the impairment of cholinergic transmission may be the main cause of the deficit of working memory.

  15. Applications of neuromodulation of the lower urinary tract in female urology

    Directory of Open Access Journals (Sweden)

    Firouz Daneshgari

    2006-06-01

    Full Text Available Neuromodulation is becoming part of clinical armamentarium for treatment of a variety of lower urinary tract conditions in female urology. Its increased usage stems from need of patients who have exhausted all other therapeutic options for their complex and poorly understood lower urinary tract disorders. Currently neuromodulation may consist of the use of sacral nerve stimulation (SNS and injectable therapies. Herein, we will discuss the background and development of SNS, its current indications, methods of patient selection and will review the results of the recent published literature on SNS. In addition, we will discuss some of the newer developments in SNS such as Bion device and the future direction in integration of SNS in female urology.

  16. Failure of cholinergic stimulation to induce a secretory response from the rectal mucosa in cystic fibrosis.

    OpenAIRE

    Hardcastle, J; Hardcastle, P T; Taylor, C J; Goldhill, J

    1991-01-01

    The secretory response to cholinergic stimulation was investigated in rectal biopsy specimens from children with cystic fibrosis and a control group using a modified Ussing chamber technique. Acetylcholine (10(-3) mol/l) increased the short circuit current in 12 control specimens by mean (SEM) 83.0 (16.4) microA/cm2, but samples from five children with cystic fibrosis failed to exhibit such a response (-1.4 (3.2) microA/cm2). Amiloride (10(-4) mol/l), which will inhibit electrogenic sodium ab...

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

    OpenAIRE

    DeYoung, Colin. G.

    2013-01-01

    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 ...

  18. Male/Female Differences in Neuroprotection and Neuromodulation of Brain Dopamine

    OpenAIRE

    Bourque, Mélanie; Dean E Dluzen; Di Paolo, Thérèse

    2011-01-01

    The existence of a sex difference in Parkinson’s disease (PD) is observed as related to several variables, including susceptibility of the disease, age at onset, and symptoms. These differences between men and women represent a significant characteristic of PD, which suggest that estrogens may exert beneficial effects against the development and the progression of the disease. This paper reviews the neuroprotective and neuromodulator effects of 17β-estradiol and progesterone as compared to an...

  19. The neuromodulator of exploration: A unifying theory of the role of dopamine in personality

    OpenAIRE

    DeYoung, Colin. G.

    2013-01-01

    The neuromodulator dopamine is centrally involved in reward, approach behavior, exploration, and various aspects of cognition. Variations in dopaminergic function appear 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 salie...

  20. Modeling Neuromodulation as a Framework to Integrate Uncertainty in General Cognitive Architectures

    OpenAIRE

    Alexandre, Frédéric; Carrere, Maxime

    2016-01-01

    International audience One of the most critical properties of a versatile intelligent agent is its capacity to adapt autonomously to any change in the environment without overly complexifying its cognitive architecture. In this paper, we propose that understanding the role of neuromodulation in the brain is of central interest for this purpose. More precisely, we propose that an accurate estimation of the nature of uncertainty present in the environment is performed by specific brain regio...

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

    Directory of Open Access Journals (Sweden)

    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.

  2. Paying attention to smell: Cholinergic signaling in the olfactory bulb.

    Directory of Open Access Journals (Sweden)

    Rinaldo David D'Souza

    2014-09-01

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

  3. Heavy metal uranium affects the brain cholinergic system in rat following sub-chronic and chronic exposure

    International Nuclear Information System (INIS)

    Uranium is a heavy metal naturally present in the environment that may be chronically ingested by the population. Previous studies have shown that uranium is present in the brain and alters behaviour, notably locomotor activity, sensorimotor ability, sleep/wake cycle and the memory process, but also metabolism of neurotransmitters. The cholinergic system mediates many cognitive systems, including those disturbed after chronic exposure to uranium i.e., spatial memory, sleep/wake cycle and locomotor activity. The objective of this study was to assess whether these disorders follow uranium-induced alteration of the cholinergic system. In comparison with 40 control rats, 40 rats drank 40 mg/L uranyl nitrate for 1.5 or 9 months. Cortex and hippocampus were removed and gene expression and protein level were analysed to determine potential changes in cholinergic receptors and acetylcholine levels. The expression of genes showed various alterations in the two brain areas after short- and long-term exposure. Nevertheless, protein levels of the choline acetyltransferase enzyme (ChAT), the vesicular transporter of acetylcholine (VAChT) and the nicotinic receptor β2 sub-unit (nAChRβ2) were unmodified in all cases of the experiment and muscarinic receptor type 1 (m1AChR) protein level was disturbed only after 9 months of exposure in the cortex (-30%). Acetylcholine levels were unchanged in the hippocampus after 1.5 and 9 months, but were decreased in the cortex after 1.5 months only (-22%). Acetylcholinesterase (AChE) activity was also unchanged in the hippocampus but decreased in the cortex after 1.5 and 9 months (-16% and -18%, respectively). Taken together, these data indicate that the cholinergic system is a target of uranium exposure in a structure-dependent and time-dependent manner. These cholinergic alterations could participate in behavioural impairments.

  4. Cortical cholinergic innervation: Distribution and source in monkeys

    International Nuclear Information System (INIS)

    In Alzheimer's disease (AD) and its late-life variant, senile dementia of the Alzheimer's type (SDAT), the predominant neurochemical abnormalities are marked decrements in the activities of ChAT and AChE, the high affinity uptake of tritium-choline, and synthesis of acetylcholine. Two studies are undertaken to delineate more clearly the variability of cortical cholinergic innervation and the contribution of the Ch system, particularly the Ch4, to this cholinergic innervation. In the first study, ChAT activity was assessed in multiple samples of neocortex from seven normal cynomolgus monkeys. In the second study, the nbM was lesioned in order to determine the contribution of the Ch system to cortical cholinergic innervation

  5. The cholinergic ligand binding material of axonal membranes

    International Nuclear Information System (INIS)

    Choline acetyltransferase and acetylcholinesterase, the enzymes responsible for the synthesis and hydrolysis of ACh, are present in nerve fibers. In crustacean peripheral nerves, release of ACh from cut nerve fibers has been demonstrated. Previously closed membrane vesicles have been prepared from lobster walking leg nerve plasma membrane and saturable binding of cholinergic agonsist and antagonists to such membranes have been demonstrated. This paper studies this axonal cholinergic binding material, and elucidates its functions. The binding of tritium-nicotine to lobster nerve plasma membranes was antagonized by a series of cholinergic ligands as well as by a series of local anesthetics. This preparation was capable of binding I 125-alpha-bungarotoxin, a ligand widely believed to be a specific label for nicotinic ACh receptor. The labelling of 50 K petide band with tritium-MBTA following disulfide reduction is illustrated

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

    International Nuclear Information System (INIS)

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

  7. A novel excitatory network for the control of breathing.

    Science.gov (United States)

    Anderson, Tatiana M; Garcia, Alfredo J; Baertsch, Nathan A; Pollak, Julia; Bloom, Jacob C; Wei, Aguan D; Rai, Karan G; Ramirez, Jan-Marino

    2016-08-01

    Breathing must be tightly coordinated with other behaviours such as vocalization, swallowing, and coughing. These behaviours occur after inspiration, during a respiratory phase termed postinspiration. Failure to coordinate postinspiration with inspiration can result in aspiration pneumonia, the leading cause of death in Alzheimer's disease, Parkinson's disease, dementia, and other neurodegenerative diseases. Here we describe an excitatory network that generates the neuronal correlate of postinspiratory activity in mice. Glutamatergic-cholinergic neurons form the basis of this network, and GABA (γ-aminobutyric acid)-mediated inhibition establishes the timing and coordination relative to inspiration. We refer to this network as the postinspiratory complex (PiCo). The PiCo has autonomous rhythm-generating properties and is necessary and sufficient for postinspiratory activity in vivo.The PiCo also shows distinct responses to neuromodulators when compared to other excitatory brainstem networks. On the basis of the discovery of the PiCo, we propose that each of the three phases of breathing is generated by a distinct excitatory network: the pre-Bötzinger complex, which has been linked to inspiration; the PiCo, as described here for the neuronal control of postinspiration; and the lateral parafacial region (pF(L)), which has been associated with active expiration, a respiratory phase that is recruited during high metabolic demand. PMID:27462817

  8. Cholinergic modulation of event-related oscillations (ERO).

    Science.gov (United States)

    Sanchez-Alavez, Manuel; Robledo, Patricia; Wills, Derek N; Havstad, James; Ehlers, Cindy L

    2014-04-22

    The cholinergic system in the brain modulates patterns of activity involved in general arousal, attention processing, memory and consciousness. In the present study we determined the effects of selective cholinergic lesions of the medial septum area (MS) or nucleus basalis magnocellularis (NBM) on amplitude and phase characteristics of event related oscillations (EROs). A time-frequency based representation was used to determine ERO energy, phase synchronization across trials, recorded within a structure (phase lock index, PLI), and phase synchronization across trials, recorded between brain structures (phase difference lock index, PDLI), in the frontal cortex (Fctx), dorsal hippocampus (DHPC) and central amygdala (Amyg). Lesions in MS produced: (1) decreases in ERO energy in delta, theta, alpha, beta and gamma frequencies in Amyg, (2) reductions in gamma ERO energy and PLI in Fctx, (3) decreases in PDLI between the Fctx-Amyg in the theta, alpha, beta and gamma frequencies, and (4) decreases in PDLI between the DHPC-Amyg and Fctx-DHPC in the theta frequency bands. Lesions in NBM resulted in: (1) increased ERO energy in delta and theta frequency bands in Fctx, (2) reduced gamma ERO energy in Fctx and Amyg, (3) reductions in PLI in the theta, beta and gamma frequency ranges in Fctx, (4) reductions in gamma PLI in DHPC and (5) reduced beta PLI in Amyg. These studies suggest that the MS cholinergic system can alter phase synchronization between brain areas whereas the NBM cholinergic system modifies phase synchronization/phase resetting within a brain area. PMID:24594019

  9. *118494 CHOLINERGIC RECEPTOR, MUSCARINIC, 3; CHRM3 [OMIM

    Lifescience Database Archive (English)

    Full Text Available FIELD NO 118494 FIELD TI 118494 CHOLINERGIC RECEPTOR, MUSCARINIC, 3; CHRM3 ;;ACETYLCHOLINE RECEP ... tones, and unilateral kidney dysfunction. He had a lean ... habitus since childhood. Urologic testing revealed ... scarinic acetylcholine receptor are hypophagic and lean . Nature 410: 207-212, 2001. FIELD CN Ada Hamosh - ...

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

    Directory of Open Access Journals (Sweden)

    Dr Sudip Parajuli

    2006-07-01

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

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

    Directory of Open Access Journals (Sweden)

    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.

  12. Neural stem cells was induced to differentiate into cholinergic neurons in vitro

    International Nuclear Information System (INIS)

    The cholinergic-inducing effect of BMP4 on isolated and cultivated rat's cerebral neural stem cells (NSCs) was examined. NSCs which were isolated from two month's old rat's brain region like hippocampus and striatum were cultivated in a medium containing EGF and bFGF, and were identified with morphological character by microscope and nestin immunocytochemistry test. After 24 hours, half NSCs were cultivated with a BMP4-added medium as a experimental group instead of the primary medium, while the an other half NSCs being cultivated with the primary medium as a control group. After 8 days the expression of choline acetyltransferase (ChAT) of the cultivated cells was observated by indirect immunofluorescence test. Results showed that more positive cells were found in the experimental group, and the fluorescence intensity were stronger; while less positive cells were found in the control group, and the fluorescence intensity was weaker. The differentiational efficiency of the NSCs was examined by FITC-labelled Flow Cytometry. The results showed that about 16% cells of the experimental group appeared ChAT-positive, while that of control group only 7%. So BMP4 may have the function of inducing NSCs to differentiate into neurons with cholinergic characteristic. (authors)

  13. c-fos Expression in mesopontine noradrenergic and cholinergic neurons of the cat during carbachol-induced active sleep: a double-labeling study.

    Science.gov (United States)

    Yamuy, J; Sampogna, S; Morales, F R; Chase, M H

    1998-01-01

    The interaction of cholinergic and catecholaminergic mechanisms in the mesopontine region has been hypothesized as being critical for the generation and maintenance of active (REM) sleep. To further examine this hypothesis, we sought to determine the pattern of neuronal activation (via c-fos expression) of catecholaminergic and cholinergic neurons in this region during active sleep induced by the pontine microapplication of carbachol (designated as active sleep-carbachol). Accordingly, we used two sets of double-labeling techniques; the first to identify tyrosine hydroxylase-containing neurons (putative catecholaminergic cells) which also express the c-fos protein product Fos, and the second to reveal choline acetyltransferase-containing neurons (putative cholinergic cells) which also express Fos. Compared to control cats, active sleep-carbachol cats exhibited a significantly greater number of Fos-expressing neurons in the dorsolateral region of the pons, which encompasses the locus coeruleus, the lateral pontine reticular formation, the peribrachial nuclei and the latero-dorsal and pedunculo-pontine tegmental nuclei. However, both control and active sleep-carbachol cats exhibited a similar number of catecholaminergic and cholinergic neurons in those regions that expressed Fos (i.e., double-labeled cells). A large number of c-fos-expressing neurons in the active sleep-carbachol cats whose neurotransmitter phenotype was not identified suggests that non-catecholaminergic, non-cholinergic neuronal populations in mesopontine regions are involved in the generation and maintenance of active sleep. The lack of increased c-fos expression in catecholaminergic neurons during active sleep-carbachol confirms and extends previous data that indicate that these cells are silent during active sleep-carbachol and naturally-occurring active sleep. The finding that cholinergic neurons of the dorsolateral pons were not activated either during wakefulness or active sleep

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

    Directory of Open Access Journals (Sweden)

    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.

  15. Identification of SLURP-1 as an epidermal neuromodulator explains the clinical phenotype of Mal de Meleda

    DEFF Research Database (Denmark)

    Chimienti, Fabrice; Hogg, Ronald C; Plantard, Laure;

    2003-01-01

    in signal transduction, immune cell activation or cellular adhesion. The high degree of structural similarity between SLURP-1 and the three fingers motif of snake neurotoxins and Lynx1 suggests that this protein interacts with the neuronal acetylcholine receptors. We found that SLURP-1 potentiates...... the human alpha 7 nicotinic acetylcholine receptors that are present in keratinocytes. These results identify SLURP-1 as a secreted epidermal neuromodulator which is likely to be essential for both epidermal homeostasis and inhibition of TNF-alpha release by macrophages during wound healing. This...

  16. 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

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

    Science.gov (United States)

    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. PMID:27391680

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

    Science.gov (United States)

    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.

  19. 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

  20. 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

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

    International Nuclear Information System (INIS)

    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 [3H]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 [3H]QNB binding was unaltered. At 4-6 weeks following the start of MPTP treatment, choline acetyltransferase activity and [3H]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

  2. Adaptive processes of the central and autonomic cholinergic neurotransmitter system: Age-related differences

    Energy Technology Data Exchange (ETDEWEB)

    Fortuna, S.; Pintor, A.; Michalek, H. (Istituto Superiore di Sanita, Rome (Italy))

    1991-01-01

    Potential age-related differences in the response of the ileum strip longitudinal and circular muscle to repeated treatment with diisopropyl fluorophosphate (DFP) were evaluated in Sprague-Dawley rats. The response was measured in terms of both biochemical parameters (acetylcholinesterase-AChE inhibition, muscarinic acetylcholine receptor binding sites-mAChRs, choline acetyltransferase-ChAT) and functional responsiveness (contractility of the isolated ileum stimulated by cholinergic agonists). The biochemical data were compared with those obtained for the cerebral cortex. In the ileum strip of control rats there was a significant age-related decline of AChE, maximal density of {sup 3}H-QNB binding sites (Bmax) and ChAT. During the first week of DFP treatment the cholinergic syndrome was more pronounced in aged than in young rats, resulting in 35% and 10% mortality, respectively; subsequently the syndrome attenuated. At the end of DFP treatment ileal AChE were inhibited by about 30%; the down-regulation of mAChRs was about 50% in young and 35% in aged rats. No significant differences in the recovery rate of AChE were noted between young and aged rats. On the contrary, mAChRs normalized within 5 weeks in young and 3 weeks in aged rats.

  3. Regulation of drugs affecting striatal cholinergic activity by corticostriatal projections

    International Nuclear Information System (INIS)

    Research demonstrates that the chronic degeneration of the corticostriatal excitatory pathway makes the cholinergic neurons of the striatum insensitive to the neuropharmacological action of a number of different drugs. Female rats were used; they were killed and after the i.v. infusion of tritium-choline precursor, choline acetyltransferase activity was measured. Striatal noradrenaline, dopamine and serotonin content was measured by electrochemical detection coupled with high pressure liquid chromatography. Uptake of tritium-glutamic acid was estimated. The data were analyzed statistically. It is shown that there is evidence that the effects of a number of drugs capable of depressing cholinergic activity through receptor-mediated responses are operative only if the corticostriatal pathway is integral. Neuropharmacological responses in the brain appear to be the result of an interaction between several major neurotransmitter systems

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

    Directory of Open Access Journals (Sweden)

    Cabeza Carolina

    2012-03-01

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

  5. Inhibition of airway surface fluid absorption by cholinergic stimulation

    OpenAIRE

    Nam Soo Joo; Krouse, Mauri E.; Jae Young Choi; Hyung-Ju Cho; Wine, Jeffrey J.

    2016-01-01

    In upper airways airway surface liquid (ASL) depth and clearance rates are both increased by fluid secretion. Secretion is opposed by fluid absorption, mainly via the epithelial sodium channel, ENaC. In static systems, increased fluid depth activates ENaC and decreased depth inhibits it, suggesting that secretion indirectly activates ENaC to reduce ASL depth. We propose an alternate mechanism in which cholinergic input, which causes copious airway gland secretion, also inhibits ENaC-mediated ...

  6. Hypertension favors the endothelial non-neuronal cholinergic system

    OpenAIRE

    Zou, Qian; 鄒倩

    2013-01-01

    This thesis investigates the involvement of the non-neuronal cholinergic system in endothelium-dependent relaxations and the impact of hypertension on the function of this system. In Study1 the contribution of nicotinic receptors (nAChRs) to endothelium-dependent relaxations evoked by acetylcholine was examined. Both muscarinic (mAChRs) and nAChR were expressed in the aortic endothelium of spontaneously hypertensive (SHR)and Wistar-Kyoto rats (WKY). However, isometric tension measurements sho...

  7. 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.

  8. PET study of cholinergic system in the brain

    Energy Technology Data Exchange (ETDEWEB)

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

    1999-01-01

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

  9. Dysfunctional penile cholinergic nerves in diabetic impotent men

    International Nuclear Information System (INIS)

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

  10. Dysfunctional penile cholinergic nerves in diabetic impotent men

    Energy Technology Data Exchange (ETDEWEB)

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

    1990-08-01

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

  11. Cholinergic mediation of small intestinal transit in the rat

    International Nuclear Information System (INIS)

    It has been reported that small intestinal transit (SIT) in the rat is not cholinergically mediated. The geometric mean of a marker may be a more powerful method for SIT studies. Therefore, it was their goal to evaluate the effect of muscarinic blockade in normal and prostaglandin E2 (PGE2)-enhanced SIT using this method. Male, food-fasted rats (190 to 240 g) were first dosed subcutaneously with atropine. 30 min after the atropine the rats received an oral dose of PGE2 at 5.0 mg/kg. 5 min after PGE2, a 51Cr-labeled marker was dosed intraduodenally, and a 25 min transit period followed. The results are: (1) 5.0 mg/kg of PGE2 significantly stimulates the geometric mean of the marker in agreement with previous findings and (2) atropine is inhibitory at doses as low as 0.20 mg/kg for basal SIT and 0.10 mg/kg for PGE2-stimulated SIT. This indicates (1) the rat has cholinergically mediated SIT, and (2) cholinergic activation may be important for PGE2 effects on SIT in the rat

  12. PET study of cholinergic system in the brain

    International Nuclear Information System (INIS)

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

  13. Aging-related deficits in orexin/hypocretin modulation of the septo-hippocampal cholinergic system

    OpenAIRE

    Stanley, Emily M.; Fadel, Jim

    2012-01-01

    The medial septum (MS) of the basal forebrain contains cholinergic neurons that project to the hippocampus, support cognitive function, and are implicated in age-related cognitive decline. Hypothalamic orexin/hypocretin neurons innervate and modulate basal forebrain cholinergic neurons and provide direct inputs to the hippocampus. However, the precise role of orexin in modulating hippocampal cholinergic transmission—and how these interactions are altered in aging—is unknown. Here, orexin A wa...

  14. TASK Channels on Basal Forebrain Cholinergic Neurons Modulate Electrocortical Signatures of Arousal by Histamine

    OpenAIRE

    Vu, Michael T.; Du, Guizhi; Bayliss, Douglas A.; Horner, Richard L.

    2015-01-01

    Basal forebrain cholinergic neurons are the main source of cortical acetylcholine, and their activation by histamine elicits cortical arousal. TWIK-like acid-sensitive K+ (TASK) channels modulate neuronal excitability and are expressed on basal forebrain cholinergic neurons, but the role of TASK channels in the histamine-basal forebrain cholinergic arousal circuit is unknown. We first expressed TASK channel subunits and histamine Type 1 receptors in HEK cells. Application of histamine in vitr...

  15. The role of the Cholinergic System on Plasticity in the Basolateral Nucleus of the Amygdala

    OpenAIRE

    Cline, Brandon H.

    2010-01-01

    The amygdala and the cholinergic system play important roles in learning and memory. The amygdala receives substantial cholinergic innervation and in itself ex-presses differences in this innervation. p75NTR is one of the primary receptors of cho-linergic neurons and transgenic mice that are missing exon IV of the p75 neurotro-phin receptor locus, display a change in cholinergic innervation. The loss of p75NTR can induce changes in learning and memory so it was hypothesized p75EXIV animals wo...

  16. Changes of oscillatory activity in pitch processing network and related tinnitus relief induced by acoustic CR neuromodulation

    Directory of Open Access Journals (Sweden)

    Ilya Adamchic

    2012-04-01

    Full Text Available Chronic subjective tinnitus is characterized by abnormal neuronal synchronization in the central auditory system. As shown in a controlled clinical trial, acoustic coordinated reset (CR neuromodulation causes a significant relief of tinnitus symptoms along with a significant decrease of pathological oscillatory activity in a network comprising auditory and non-auditory brain areas, which is often accompanied with a significant tinnitus pitch change. Here, we studied if the tinnitus pitch change correlates with a reduction of tinnitus loudness and/or annoyance as assessed by visual analogue scale (VAS scores. Furthermore, we studied if the changes of the pattern of brain synchrony in tinnitus patients induced by 12 weeks of CR-therapy depend on whether or not the patients undergo a pronounced tinnitus pitch change. For this, we applied standardized low-resolution brain electromagnetic tomography (sLORETA to EEG recordings from two groups of patients with a sustained CR-induced relief of tinnitus symptoms with and without tinnitus pitch change. We found that absolute changes of VAS loudness and VAS annoyance scores significantly correlate with the modulus of the tinnitus pitch change. Moreover, as opposed to patients with weak or no pitch change we found a significantly stronger decrease in gamma power in patients with pronounced tinnitus pitch change in right parietal cortex (BA 1, 40, right frontal cortex (BA 8, 9, 46, and left frontal cortex (BA 4, 6, combined with a significantly stronger increase of alpha (10-12 Hz activity in the right anterior cingulate cortex (BA 32, 24. In addition, we revealed a significantly lower functional connectivity in the gamma band between the right dorsolateral prefrontal cortex (BA 9 and the right anterior cingulate cortex (BA 32 after 12 weeks of CR-therapy in patients with pronounced pitch change. Our results indicate a substantial, CR-induced reduction of tinnitus-related auditory binding in a pitch

  17. Neuromodulation of associative and organizational plasticity across the life span: empirical evidence and neurocomputational modeling.

    Science.gov (United States)

    Li, Shu-Chen; Brehmer, Yvonne; Shing, Yee Lee; Werkle-Bergner, Markus; Lindenberger, Ulman

    2006-01-01

    Developmental plasticity is the key mechanism that allows humans and other organisms to modify and adapt to contextual and experiential influences. Thus, reciprocal co-constructive interactions between behavioral and neuronal plasticity play important roles in regulating neurobehavioral development across the life span. This review focuses on behavioral and neuronal evidence of lifespan differences in associative memory plasticity and plasticity of the functional organization of cognitive and cortical processes, as well as the role of the dopaminergic system in modulating such plasticity. Special attention is given to neurocomputational models that help exploring lifespan differences in neuromodulation of neuronal and behavioral plasticity. Simulation results from these models suggest that lifespan changes in the efficacy of neuromodulatory mechanisms may shape associative memory plasticity and the functional organization of neurocognitive processes by affecting the fidelity of neuronal signal transmission, which has consequences for the distinctiveness of neurocognitive representations and the efficacy of distributed neural coding. PMID:16930705

  18. Brain stimulation: Neuromodulation as a potential treatment for motor recovery following traumatic brain injury.

    Science.gov (United States)

    Clayton, E; Kinley-Cooper, S K; Weber, R A; Adkins, D L

    2016-06-01

    There is growing evidence that electrical and magnetic brain stimulation can improve motor function and motor learning following brain damage. Rodent and primate studies have strongly demonstrated that combining cortical stimulation (CS) with skilled motor rehabilitative training enhances functional motor recovery following stroke. Brain stimulation following traumatic brain injury (TBI) is less well studied, but early pre-clinical and human pilot studies suggest that it is a promising treatment for TBI-induced motor impairments as well. This review will first discuss the evidence supporting brain stimulation efficacy derived from the stroke research field as proof of principle and then will review the few studies exploring neuromodulation in experimental TBI studies. This article is part of a Special Issue entitled SI:Brain injury and recovery. PMID:26855256

  19. Cholinergic, noradrenergic and GABAergic control of sexual behaviour

    DEFF Research Database (Denmark)

    Nedergaard, Per

    acethylcholine, noradrenalin, GABA, sexual dysfunction, erectile dysfunction, rat, human, male, female......acethylcholine, noradrenalin, GABA, sexual dysfunction, erectile dysfunction, rat, human, male, female...

  20. Cholinergic receptors as target for cancer therapy in a systems medicine perspective.

    Science.gov (United States)

    Russo, P; Del Bufalo, A; Milic, M; Salinaro, G; Fini, M; Cesario, A

    2014-01-01

    Epithelial cells not innervated by cholinergic neurons express nicotinic and muscarinic acetylcholine (ACh) receptors (nAChR, mAChR). nAChR and mAChR are components of the auto-/paracrine-regulatory loop of non-neuronal ACh release. The cholinergic control of non-neuronal cells may be mediated by different effects (synergistic, additive, or reciprocal) triggered by these receptors. The ionic events (Ca(+2) influx) are generated by the ACh-opening of nAChR channels, while the metabolic events by ACh-binding to G-proteincoupled mAChR. Effective inter- and intracellular signaling is crucial for valuable cancer cells proliferation and survival. Depending on cancer cell type, different AChR have been identified. The proliferation of airways epithelial cancer cells and pancreatic cancer cells may be under the control of α7-nAChR and M3-mAChR, while breast cancer cells and colon cancer cells are regulated by α9-nAChR, and M3-mAChR, respectively. In turn, these receptors may activate different pathways (Ras-Raf-1-Erk-AKT) as well as other receptors (β- adrenergicR). nAChR or mAChR antagonists may inhibit cancer growth. Inhibition of M3 by antisense or antagonists (Darifenacin, Tiotropium) reduces lung or colon cancer proliferation, as well as inhibition of α9- nAChR [polyphenol (-)-epigallocatechin-3-gallate] diminishes breast cancer cells growth. α7-nAChR silencing inhibits lung cancer proliferation. Moreover, inhibition of the nAChR-β-adrenergicR pathway (β-blockers) could be also useful. This review will describe the future translational perspectives of cholinergic receptors druginhibition in a complex disease such as cancer that poses compelling treatment challenges. Cancer happens as consequence of disease-perturbed molecular networks in relevant organ cells that change during progression. The framework for approaching these challenges is a systems approach. PMID:25324001

  1. Cholinergic interneurons are differentially distributed in the human striatum.

    Directory of Open Access Journals (Sweden)

    Javier Bernácer

    Full Text Available BACKGROUND: The striatum (caudate nucleus, CN, and putamen, Put is a group of subcortical nuclei involved in planning and executing voluntary movements as well as in cognitive processes. Its neuronal composition includes projection neurons, which connect the striatum with other structures, and interneurons, whose main roles are maintaining the striatal organization and the regulation of the projection neurons. The unique electrophysiological and functional properties of the cholinergic interneurons give them a crucial modulating function on the overall striatal response. METHODOLOGY/PRINCIPLE FINDINGS: This study was carried out using stereological methods to examine the volume and density (cells/mm(3 of these interneurons, as visualized by choline acetyltransferase (ChAT immunoreactivity, in the following territories of the CN and Put of nine normal human brains: 1 precommissural head; 2 postcommissural head; 3 body; 4 gyrus and 5 tail of the CN; 6 precommissural and 7 postcommissural Put. The distribution of ChAT interneurons was analyzed with respect to the topographical, functional and chemical territories of the dorsal striatum. The CN was more densely populated by cholinergic neurons than the Put, and their density increased along the anteroposterior axis of the striatum with the CN body having the highest neuronal density. The associative territory of the dorsal striatum was by far the most densely populated. The striosomes of the CN precommissural head and the postcommissural Put contained the greatest number of ChAT-ir interneurons. The intrastriosomal ChAT-ir neurons were abundant on the periphery of the striosomes throughout the striatum. CONCLUSIONS/SIGNIFICANCE: All these data reveal that cholinergic interneurons are differentially distributed in the distinct topographical and functional territories of the human dorsal striatum, as well as in its chemical compartments. This heterogeneity may indicate that the posterior aspects of

  2. Novel aspects of cholinergic regulation of colonic ion transport.

    Science.gov (United States)

    Bader, Sandra; Diener, Martin

    2015-06-01

    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 (I sc) 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 I sc was examined. Choline induced a concentration-dependent, tetrodotoxin-resistant chloride secretion which was, however, resistant against hexamethonium, but was inhibited by atropine. Experiments with inhibitors of muscarinic M1 and M3 receptors revealed that choline-evoked secretion was mainly due to a stimulation of epithelial M3 receptors. Although choline proved to be only a partial agonist, it concentration-dependently desensitized the response to acetylcholine, suggesting that it might act as a modulator of cholinergically induced anion secretion. Thus the cholinergic regulation of colonic ion transport - up to now solely explained by cholinergic submucosal neurons stimulating epithelial muscarinic receptors - is more complex than previously assumed. PMID:26236483

  3. 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.

  4. 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

  5. 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.

  6. 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

  7. Interleukin-6-type cytokines in neuroprotection and neuromodulation: Oncostatin M, but not leukemia inhibitory factor, requires neuronal Adenosine A1 receptor function

    NARCIS (Netherlands)

    Moidunny, S.; Dias, R.; Van Calker, D.; Boddeke, H.; Sebastiao, A.; Biber, K.

    2010-01-01

    Objective: Adenosine is a neuromodulator in the central nervous system exhibiting anticonvulsive, neuroprotective and sedating/sleep regulating properties. A pathophysiological importance of adenosine in various neuropsychiatric diseases (e.g. epilepsy, neurodegenerative disorders, apoplexia and moo

  8. Linking Cholinergic Interneurons, Synaptic Plasticity, and Behavior during the Extinction of a Cocaine-Context Association.

    Science.gov (United States)

    Lee, Junuk; Finkelstein, Joel; Choi, Jung Yoon; Witten, Ilana B

    2016-06-01

    Despite the fact that cholinergic interneurons are a key cell type within the nucleus accumbens, a relationship between synaptic plasticity and the in vivo activity of cholinergic interneurons remains to be established. Here, we identify a three-way link between the activity of cholinergic interneurons, synaptic plasticity, and learning in mice undergoing the extinction of a cocaine-context association. We found that activity of cholinergic interneurons regulates extinction learning for a cocaine-context association and generates a sustained reduction in glutamatergic presynaptic strength onto medium spiny neurons. Interestingly, activation of cholinergic interneurons does not support reinforcement learning or plasticity by itself, suggesting that these neurons have a modulatory rather than a reinforcing function. PMID:27210555

  9. Vitamin D₃ improves decline in cognitive function and cholinergic transmission in prefrontal cortex of streptozotocin-induced diabetic rats.

    Science.gov (United States)

    Alrefaie, Zienab; Alhayani, Abdulmone'em

    2015-01-01

    Complications of diabetes mellitus include cognitive impairments and functional changes in the brain. The present study aimed to investigate the possible beneficial effect of vitamin D3 on episodic memory and cholinergic transmission in the prefrontal cortex of streptozotocin-induced diabetic rats. Thirty male Wistar rats (150-200 g) were included into control, diabetic and diabetic supplemented with vitamin D3 groups. Diabetes was induced by single intraperitoneal injection of streptozotocin 45 mg/kg in citrate buffer. Vitamin D3 was administered orally in a dose of 500 IU/kg/day in corn oil for 10 weeks. Then rats were subjected to novel object recognition test to examine for episodic memory. Animals were sacrificed under diethyl ether anesthesia and prefrontal cortices were dissected to measure the activity of choline acetyl transferase (CAT) and acetyle choline esterase (ACE) enzymes to assess for cholinergic transmission. Diabetic rats spent significantly less time exploring the novel object compared to control animals. Vitamin D3 significantly attenuated the diabetes-induced impairment so that animals again spent significantly more time exploring the novel object. The CAT activity was significantly decreased in diabetic animals while the ACE activity was significantly increased compared to control non-diabetic animals. Diabetes-induced alterations in enzyme activity in the prefrontal cortex were mitigated by vitamin D3 supplementation. The present findings demonstrate the potential effect of vitamin D3 supplementation on cognitive function in diabetic animals. It is possible that this effect is mediated through enhancing the prefrontal cortex cholinergic transmission. PMID:25835318

  10. Combined site-specific sacral neuromodulation and pudendal nerve release surgery in a patient with interstitial cystitis and persistent arousal.

    Science.gov (United States)

    Armstrong, Georgina Louise; Vancaillie, Thierry Georges

    2016-01-01

    A variety of neuromodulation approaches have been described for the management of pelvic neuropathies, including interstitial cystitis, pudendal neuralgia and persistent genital arousal disorder. The benefits of a combined sacral and pudendal nerve neuromodulator has yet to be explored for these patients. In this report, we describe the case of a 35-year-old woman with a complex pelvic neuropathy resulting in urinary, sexual and gastro-intestinal dysfunction. She presented with an established diagnosis of interstitial cystitis; however, she also fulfilled diagnostic criteria for pudendal neuralgia and persistent genital arousal disorder. The patient underwent implantation of a combined sacral and pudendal nerve neuoromodulation device at the time of surgical decompression of the pudendal nerves. An impressive clinical response followed. This case demonstrates a unique clinical presentation and highlights the value of a combined surgical and neuromodulatory approach in the management of patients with complex pelvic neuropathies. PMID:27284095

  11. The role of NO-mediated mechanisms in postradiation measurements of cholinergic regulation of coronal flow and heart contractive function

    International Nuclear Information System (INIS)

    White female rats were exposed to acute gamma-irradiation with dose rate 9*10-4 Gy/s (cumulative dose 1 Gy). Experiments were made on 3, 10 and 30th days after irradiation. Hearts were isolated under thiopental anaesthetic (60 mg/kg) and made perfusion by oxygenic solution with NO-synthase blocker. It were registered intraventricular pressure, coronal volumetric flow rate and frequency of cardiac beat. The result of investigation is conclusion that gamma-radiation exposure in dose 1 Gy modifies cholinergic control mechanisms of functional heart condition

  12. Evaluationof efficiency of methods of neuromodulation in the treatment of spastic syndromes in patients with spinal cord injury

    OpenAIRE

    Smolkin А.А.; Ninel V.G.; Korshunova G.A.

    2014-01-01

    Objective: to evaluate the efficiency of the neuromodulation methods and to determine their role in complex rehabilitation of patients with spastic syndromes after spinal cord injury. Material and methods: Based on the study and treatment of 105 patients with spastic syndromes after injury of the spinal cord, electrical stimulation of the spinal cord, epidural drug therapy in combination with electrical nerve stimulation and local hypothermia spinal cord have been consistently applied for the...

  13. Posterior parietal cortex dynamically ranks topographic signals via cholinergic influence

    Directory of Open Access Journals (Sweden)

    John Broussard

    2012-06-01

    Full Text Available The hypothesis to be discussed in this review is that posterior parietal cortex is directly involved in selecting relevant stimuli and filtering irrelevant distractors. The posterior parietal cortex receives input from several sensory modalities and integrates them in part to direct the allocation of resources to optimize gains. In conjunction with prefrontal cortex, nucleus accumbens, and basal forebrain cholinergic nuclei, it comprises a network mediating sustained attentional performance. Numerous anatomical, neurophysiological, and lesion studies have substantiated the notion that the basic functions of the posterior parietal cortex are conserved from rodents to humans. One such function is the detection and selection of relevant stimuli necessary for making optimal choices or responses. The issues to be addressed here are how behaviorally relevant targets recruit oscillatory potentials and spiking activity of posterior parietal neurons compared to similar yet irrelevant stimuli. Further, the influence of cortical cholinergic input to posterior parietal cortex in learning and decision-making is also discussed. I propose that these neurophysiological correlates of attention are transmitted to frontal cortical areas contributing to the top down selection of stimuli in a timely manner.

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

    International Nuclear Information System (INIS)

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

  15. Somatostatin modulates cholinergic neurotransmission in canine antral muscle

    International Nuclear Information System (INIS)

    Somatostatin has been shown to inhibit antral motility in vivo. To examine the effect of somatostatin on cholinergic neurotransmission in the canine antrum, we studied the mechanical response of and the release of [3H]acetylcholine from canine longitudinal antral muscle in response to substance P, gastrin 17, and electrical stimulation. In unstimulated tissues, somatostatin had a positive inotropic effect on spontaneous phasic contractions. In tissues stimulated with substance P and gastrin 17, but not with electrical stimulation, somatostatin inhibited the phasic inotropic response dose dependently. This inhibitory effect was abolished by indomethacin. Somatostatin stimulated the release of prostaglandin E2 radioimmunoreactivity, and prostaglandin E2 inhibited the release of [3H]acetylcholine induced by substance P and electrical stimulation. Somatostatin increased the release of [3H]acetylcholine from unstimulated tissues by a tetrodotoxin-sensitive mechanism but inhibited the release induced by substance P and electrical stimulation. These results suggest that somatostatin has a dual modulatory effect on cholinergic neutrotransmission in canine longitudinal antral muscle. This effect is excitatory in unstimulated tissues and inhibitory in stimulated tissues. The inhibitory effect is partially mediated by prostaglandins

  16. 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. PMID:25388401

  17. 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

  18. Increased dopamine D1 receptor binding in the human mesocortical system following central cholinergic activation

    International Nuclear Information System (INIS)

    Full text: The interaction between the cholinergic and dopaminergic system has been implicated in many pathological processes including, Alzheimer's disease, schizophrenia and drug addiction. Little is known about the control of dopamine (DA) release following central cholinergic activation in humans, but experimental studies suggest that endogenously released Acetylcholine (ACh) achieved by the administration of cholinesterase inhibitors, can increase dopamine efflux in different regions of the brain. This leads to the activation of different types of post-synaptic dopaminergic receptors which belong to the family of G-protein coupled receptors (GPCRs). A common paradigm of the GPCRs desensitization is that agonist-induced receptor signaling is rapidly attenuated by receptor internalisation. Several experiments have shown that the activation of Dl receptors in acute conditions leads, within minutes, to translocation of the receptor from the surface of the neurons to the endosomal compartment in the cytoplasm and increased receptor turnover. To assess changes in Dl receptor density following an intravenous infusion of the selective cholinesterase inhibitor physostigmine salicylate (PHY), we studied eleven normal subjects (10 male and 1 female, mean age 36.1 and 61617; 9.9) using [11C]-SCH23390 and PET The binding potential (BP) for SCH23390 was significantly (p0.05). There was no statistically significant difference between baseline and physostigmine Kl ratio (p>0.05) suggesting that BP changes observed were not secondary to regional blood flow changes or to an order effect of the scans. Copyright (2002) The Australian and New Zealand Society of Nuclear Medicine Inc

  19. Adolescent Intermittent Alcohol Exposure: Deficits in Object Recognition Memory and Forebrain Cholinergic Markers.

    Directory of Open Access Journals (Sweden)

    H Scott Swartzwelder

    Full Text Available The long-term effects of intermittent ethanol exposure during adolescence (AIE are of intensive interest and investigation. The effects of AIE on learning and memory and the neural functions that drive them are of particular interest as clinical findings suggest enduring deficits in those cognitive domains in humans after ethanol abuse during adolescence. Although studies of such deficits after AIE hold much promise for identifying mechanisms and therapeutic interventions, the findings are sparse and inconclusive. The present results identify a specific deficit in memory function after AIE and establish a possible neural mechanism of that deficit that may be of translational significance. Male rats (starting at PND-30 received exposure to AIE (5g/kg, i.g. or vehicle and were allowed to mature into adulthood. At PND-71, one group of animals was assessed using the spatial-temporal object recognition (stOR test to evaluate memory function. A separate group of animals was used to assess the density of cholinergic neurons in forebrain areas Ch1-4 using immunohistochemistry. AIE exposed animals manifested deficits in the temporal component of the stOR task relative to controls, and a significant decrease in the number of ChAT labeled neurons in forebrain areas Ch1-4. These findings add to the growing literature indicating long-lasting neural and behavioral effects of AIE that persist into adulthood and indicate that memory-related deficits after AIE depend upon the tasks employed, and possibly their degree of complexity. Finally, the parallel finding of diminished cholinergic neuron density suggests a possible mechanism underlying the effects of AIE on memory and hippocampal function as well as possible therapeutic or preventive strategies for AIE.

  20. 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.

  1. 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.

  2. Transcutaneous Neuromodulation at Posterior Tibial Nerve and ST36 for Chronic Constipation

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    Nina Zhang

    2014-01-01

    Full Text Available The aims of this study were to investigate the effects and possible mechanisms of transcutaneous neuromodulation (TN in patients with chronic constipation. Twelve patients were recruited. The treatment consisted of 2-week TN and 2-week sham-TN which was performed in a crossover design. Bowel habit diary, Patient Assessment of Constipation Symptom (PAC-SYM, Patient Assessment of Constipation Quality of Life (PAC-QOL, and anorectal motility were evaluated. Electrocardiogram was recorded for the assessment of autonomic function during acute TN therapy. It was found that (1 TN improved the frequency of spontaneous defecation. After 2-week TN therapy, 83% patients had more than 3 times bowel movements per week which was significantly different from sham-TN (P=0.01. (2 TN improved PAC-SYM and PAC-QOL scores (P<0.001, resp.. (3 TN significantly decreased the threshold volume to elicit RAIR (P<0.05, ameliorated rectal sensory threshold (P=0.04, and maximum tolerance (P=0.04. (4 TN, but not sham-TN, increased the vagal activity (P=0.01 versus baseline and decreased the sympathetic activity (P=0.01, versus baseline. It was concluded that needleless TN at posterior tibial nerve and ST36 using a watch-size stimulator is effective in chronic constipation, and the effect was possibly mediated via the autonomic mechanism.

  3. 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.

  4. Effects of Maternal Choline Supplementation on the Septohippocampal Cholinergic System in the Ts65Dn Mouse Model of Down Syndrome.

    Science.gov (United States)

    Kelley, Christy M; Ash, Jessica A; Powers, Brian E; Velazquez, Ramon; Alldred, Melissa J; Ikonomovic, Milos D; Ginsberg, Stephen D; Strupp, Barbara J; Mufson, Elliott J

    2016-01-01

    Down syndrome (DS), caused by trisomy of chromosome 21, is marked by intellectual disability (ID) and early onset of Alzheimer's disease (AD) neuropathology including hippocampal cholinergic projection system degeneration. Here we determined the effects of age and maternal choline supplementation (MCS) on hippocampal cholinergic deficits in Ts65Dn mice compared to 2N mice sacrificed at 6-8 and 14-18 months of age. Ts65Dn mice and disomic (2N) littermates sacrificed at ages 6-8 and 14-18 mos were used for an aging study and Ts65Dn and 2N mice derived from Ts65Dn dams were maintained on either a choline-supplemented or a choline-controlled diet (conception to weaning) and examined at 14-18 mos for MCS studies. In the latter, mice were behaviorally tested on the radial arm Morris water maze (RAWM) and hippocampal tissue was examined for intensity of choline acetyltransferase (ChAT) immunoreactivity. Hippocampal ChAT activity was evaluated in a separate cohort. ChAT-positive fiber innervation was significantly higher in the hippocampus and dentate gyrus in Ts65Dn mice compared with 2N mice, independent of age or maternal diet. Similarly, hippocampal ChAT activity was significantly elevated in Ts65Dn mice compared to 2N mice, independent of maternal diet. A significant increase with age was seen in hippocampal cholinergic innervation of 2N mice, but not Ts65Dn mice. Degree of ChAT intensity correlated negatively with spatial memory ability in unsupplemented 2N and Ts65Dn mice, but positively in MCS 2N mice. The increased innervation produced by MCS appears to improve hippocampal function, making this a therapy that may be exploited for future translational approaches in human DS. PMID:26391045

  5. 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.

  6. 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.

  7. 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

  8. 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

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

    Directory of Open Access Journals (Sweden)

    Hoang Nam Nguyen

    2015-02-01

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

  10. Electroacupuncture-Induced Cholinergic Nerve Activation Enhances the Hypoglycemic Effect of Exogenous Insulin in a Rat Model of Streptozotocin-Induced Diabetes

    Directory of Open Access Journals (Sweden)

    Yu-Chen Lee

    2011-01-01

    Full Text Available The aim of this study is to explore the mechanisms by which electroacupuncture (EA enhances the hypoglycemic effect of exogenous insulin in a streptozotocin- (STZ- diabetic rats. Animals in the EA group were anesthetized and subjected to the insulin challenge test (ICT and EA for 60 minutes. In the control group, rats were subjected to the same treatment with the exception of EA stimulation. Blood samples were drawn to measure changes in plasma glucose, free fatty acids (FFA, and insulin levels. Western blot was used to assay proteins involved in insulin signaling. Furthermore, atropine, hemicholinium-3 (HC-3, and Eserine were used to explore the relationship between EA and cholinergic nerve activation during ICT. EA augmented the blood glucose-lowering effects of EA by activating the cholinergic nerves in STZ rats that had been exposed to exogenous insulin. This phenomenon may be related to enhancement of insulin signaling rather than to changes in FFA concentration.

  11. The α7-nicotinic receptor is upregulated in immune cells from HIV-seropositive women: consequences to the cholinergic anti-inflammatory response.

    Science.gov (United States)

    Delgado-Vélez, Manuel; Báez-Pagán, Carlos A; Gerena, Yamil; Quesada, Orestes; Santiago-Pérez, Laura I; Capó-Vélez, Coral M; Wojna, Valerie; Meléndez, Loyda; León-Rivera, Rosiris; Silva, Walter; Lasalde-Dominicci, José A

    2015-12-01

    Antiretroviral therapy partially restores the immune system and markedly increases life expectancy of HIV-infected patients. However, antiretroviral therapy does not restore full health. These patients suffer from poorly understood chronic inflammation that causes a number of AIDS and non-AIDS complications. Here we show that chronic inflammation in HIV+ patients may be due to the disruption of the cholinergic anti-inflammatory pathway by HIV envelope protein gp120IIIB. Our results demonstrate that HIV gp120IIIB induces α7 nicotinic acetylcholine receptor (α7) upregulation and a paradoxical proinflammatory phenotype in macrophages, as activation of the upregulated α7 is no longer capable of inhibiting the release of proinflammatory cytokines. Our results demonstrate that disruption of the cholinergic-mediated anti-inflammatory response can result from an HIV protein. Collectively, these findings suggest that HIV tampering with a natural strategy to control inflammation could contribute to a crucial, unresolved problem of HIV infection: chronic inflammation. PMID:26719799

  12. Impairment of ATP hydrolysis decreases adenosine A1 receptor tonus favoring cholinergic nerve hyperactivity in the obstructed human urinary bladder.

    Science.gov (United States)

    Silva-Ramos, M; Silva, I; Faria, M; Magalhães-Cardoso, M T; Correia, J; Ferreirinha, F; Correia-de-Sá, P

    2015-12-01

    This study was designed to investigate whether reduced adenosine formation linked to deficits in extracellular ATP hydrolysis by NTPDases contributes to detrusor neuromodulatory changes associated with bladder outlet obstruction in men with benign prostatic hyperplasia (BPH). The kinetics of ATP catabolism and adenosine formation as well as the role of P1 receptor agonists on muscle tension and nerve-evoked [(3)H]ACh release were evaluated in mucosal-denuded detrusor strips from BPH patients (n = 31) and control organ donors (n = 23). The neurogenic release of ATP and [(3)H]ACh was higher (P bladders. Relaxation of detrusor contractions induced by acetylcholine required 30-fold higher concentrations of adenosine. Despite VAChT-positive cholinergic nerves exhibiting higher A(1) immunoreactivity in BPH bladders, the endogenous adenosine tonus revealed by adenosine deaminase is missing. Restoration of A1 inhibition was achieved by favoring (1) ATP hydrolysis with apyrase (2 U mL(-1)) or (2) extracellular adenosine accumulation with dipyridamole or EHNA, as these drugs inhibit adenosine uptake and deamination, respectively. In conclusion, reduced ATP hydrolysis leads to deficient adenosine formation and A(1) receptor-mediated inhibition of cholinergic nerve activity in the obstructed human bladder. Thus, we propose that pharmacological manipulation of endogenous adenosine levels and/or A(1) receptor activation might be useful to control bladder overactivity in BPH patients. PMID:26521170

  13. 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

  14. 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

  15. 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.

  16. Detecting a Cortical Fingerprint of Parkinson's Disease for Closed-Loop Neuromodulation.

    Science.gov (United States)

    Kern, Kevin; Naros, Georgios; Braun, Christoph; Weiss, Daniel; Gharabaghi, Alireza

    2016-01-01

    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. PMID:27065781

  17. 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

  18. [Involvement and plasticity of brainstem cholinergic neurons in cocaine-induced addiction].

    Science.gov (United States)

    Kaneda, Katsuyuki; Shinohara, Fumiya; Kurosawa, Ryo; Taoka, Naofumi; Ide, Soichiro; Minami, Masabumi

    2014-04-01

    Although the involvement and plasticity of the mesocorticolimbic dopamine (DA) system in cocaine-induced addiction have been studied extensively, the role of the brainstem cholinergic system in cocaine addiction remains largely unexplored. The laterodorsal tegmental nucleus (LDT) contains cholinergic neurons that innervate the ventral tegmental area (VTA) and is crucial for regulating the activity of VTA DA neurons, implying that LDT may also be associated with cocaine addiction. In this review, we summarize our recent findings showing that cholinergic transmission from the LDT to the VTA is involved in acquisition and expression of cocaine-induced conditioned place preference and that, after repeated cocaine exposures, these neurons exhibit synaptic plasticity, which is dependent on NMDA receptor activation, nitric oxide production, and the activity of medial prefrontal cortex. The findings strongly suggest that LDT cholinergic neurons may critically contribute to developing cocaine-induced addiction. PMID:24946392

  19. Choline metabolism as a basis for the selective vulnerability of cholinergic neurons

    Science.gov (United States)

    Wurtman, R. J.

    1992-01-01

    The unique propensity of cholinergic neurons to use choline for two purposes--ACh and membrane phosphatidylcholine synthesis--may contribute to their selective vulnerability in Alzheimer's disease and other cholinergic neurodegenerative disorders. When physiologically active, the neurons use free choline taken from the 'reservoir' in membrane phosphatidylcholine to synthesize ACh; this can lead to an actual decrease in the quantity of membrane per cell. Alzheimer's disease (but not Down's syndrome, or other neurodegenerative disorders) is associated with characteristic neurochemical lesions involving choline and ethanolamine: brain levels of these compounds are diminished, while those of glycerophosphocholine and glycerophosphoethanolamine (breakdown products of their respective membrane phosphatides) are increased, both in cholinergic and noncholinergic brain regions. Perhaps this metabolic disturbance and the tendency of cholinergic neurons to 'export' choline--in the form of ACh--underlie the selective vulnerability of the neurons. Resulting changes in membrane composition could abnormally expose intramembraneous proteins such as amyloid precursor protein to proteases.

  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. Neuroinflammation not associated with cholinergic degeneration in aged-impaired brain

    OpenAIRE

    McQuail, Joseph A.; Riddle, David R.; Nicolle, Michelle M.

    2010-01-01

    Degeneration of the cholinergic neurons in the basal forebrain and elevation of inflammatory markers are well-established hallmarks of Alzheimer's disease; however, the interplay of these processes in normal aging is not extensively studied. Consequently, we conducted a neuroanatomical investigation to quantify cholinergic neurons and activated microglia in the medial septum/vertical diagonal band (MS/VDB) of young (6 months) and aged (28 months) Fisher 344 × Brown Norway F1 rats. Aged rats i...

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

    OpenAIRE

    Luiten, PGM; DEJONG, GI; VANDERZEE, EA; vanDijken, H; van Dijken, H.

    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 general consensus as to the presence of nicotinic and muscarinic receptors in the domain of the capillary wall, their precise anatomical position is unknown. The subcellular localization of muscarinic re...

  3. Neurostimulation of the Cholinergic Anti-Inflammatory Pathway Ameliorates Disease in Rat Collagen-Induced Arthritis

    OpenAIRE

    Levine, Yaakov A; Koopman, Frieda A.; Faltys, Michael; Caravaca, April; Bendele, Alison; Zitnik, Ralph; Vervoordeldonk, Margriet J.; Tak, Paul Peter

    2014-01-01

    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...

  4. Gut feeling: MicroRNA discriminators of the intestinal TLR9–cholinergic links

    OpenAIRE

    Nadorp, Bettina; Soreq, Hermona

    2015-01-01

    The intestinal tissue notably responds to stressful, cholinergic and innate immune signals by microRNA (miRNA) changes, but whether and how those miRNA regulators modify the intestinal cholinergic and innate immune pathways remained unexplored. Here, we report changes in several miRNA regulators of cholinesterases (ChEs) and correspondingly modified ChE activities in intestine, splenocytes and the circulation of mice exposed to both stress and canonical or alternative Toll-Like Receptor 9 (TL...

  5. Higher sensitivity to cadmium induced cell death of basal forebrain cholinergic neurons: A cholinesterase dependent mechanism

    International Nuclear Information System (INIS)

    Cadmium is an environmental pollutant, which is a cause of concern because it can be greatly concentrated in the organism causing severe damage to a variety of organs including the nervous system which is one of the most affected. Cadmium has been reported to produce learning and memory dysfunctions and Alzheimer like symptoms, though the mechanism is unknown. On the other hand, cholinergic system in central nervous system (CNS) is implicated on learning and memory regulation, and it has been reported that cadmium can affect cholinergic transmission and it can also induce selective toxicity on cholinergic system at peripheral level, producing cholinergic neurons loss, which may explain cadmium effects on learning and memory processes if produced on central level. The present study is aimed at researching the selective neurotoxicity induced by cadmium on cholinergic system in CNS. For this purpose we evaluated, in basal forebrain region, the cadmium toxic effects on neuronal viability and the cholinergic mechanisms related to it on NS56 cholinergic mourine septal cell line. This study proves that cadmium induces a more pronounced, but not selective, cell death on acetylcholinesterase (AChE) on cholinergic neurons. Moreover, MTT and LDH assays showed a dose dependent decrease of cell viability in NS56 cells. The ACh treatment of SN56 cells did not revert cell viability reduction induced by cadmium, but siRNA transfection against AChE partially reduced it. Our present results provide new understanding of the mechanisms contributing to the harmful effects of cadmium on the function and viability of neurons, and the possible relevance of cadmium in the pathogenesis of neurodegenerative diseases

  6. Cholinergic-serotonergic imbalance contributes to cognitive and behavioral symptoms in Alzheimer's disease

    OpenAIRE

    Garcia-Alloza, M; Gil-Bea, F.J. (Francisco J.); Diez-Ariza, M. (Mónica); Chen, C. P.; Francis, P.T.; Lasheras, B.; Ramirez, M.J.

    2005-01-01

    Neuropsychiatric symptoms seen in Alzheimer's disease (AD) are not simply a consequence of neurodegeneration, but probably result from differential neurotransmitter alterations, which some patients are more at risk of than others. Therefore, the hypothesis of this study is that an imbalance between the cholinergic and serotonergic systems is related to cognitive symptoms and psychological syndromes of dementia (BPSD) in patients with AD. Cholinergic and serotonergic functions were assessed in...

  7. 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. PMID:25505106

  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. PMID:26388832

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

    Directory of Open Access Journals (Sweden)

    Kevin P Grace

    2015-09-01

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

  10. Impairment of reward-related learning by cholinergic cell ablation in the striatum.

    Science.gov (United States)

    Kitabatake, Yasuji; Hikida, Takatoshi; Watanabe, Dai; Pastan, Ira; Nakanishi, Shigetada

    2003-06-24

    The striatum in the basal ganglia-thalamocortical circuitry is a key neural substrate that is implicated in motor balance and procedural learning. The projection neurons in the striatum are dynamically modulated by nigrostriatal dopaminergic input and intrastriatal cholinergic input. The role of intrastriatal acetylcholine (ACh) in learning behaviors, however, remains to be fully clarified. In this investigation, we examine the involvement of intrastriatal ACh in different categories of learning by selectively ablating the striatal cholinergic neurons with use of immunotoxin-mediated cell targeting. We show that selective ablation of cholinergic neurons in the striatum impairs procedural learning in the tone-cued T-maze memory task. Spatial delayed alternation in the T-maze learning test is also impaired by cholinergic cell elimination. In contrast, the deficit in striatal ACh transmission has no effect on motor learning in the rota-rod test or spatial learning in the Morris water-maze test or on contextual- and tone-cued conditioning fear responses. We also report that cholinergic cell elimination adaptively up-regulates nicotinic ACh receptors not only within the striatum but also in the cerebral cortex and substantia nigra. The present investigation indicates that cholinergic modulation in the local striatal circuit plays a pivotal role in regulation of neural circuitry involving reward-related procedural learning and working memory. PMID:12802017

  11. 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.

  12. Hippocampal formation is involved in movement selection: evidence from medial septal cholinergic modulation and concurrent slow-wave (theta rhythm) recording.

    Science.gov (United States)

    Oddie, S D; Kirk, I J; Whishaw, I Q; Bland, B H

    1997-11-01

    Hippocampal rhythmical slow-wave field activity which occurs in response to sensory stimulation is predominantly cholinergic (atropine-sensitive theta rhythm), can precede movement initiation, and co-occurs during non-cholinergic theta rhythm associated with ongoing movement (atropine-resistant). This relationship suggests that theta rhythm plays some role in movement control. The present naturalistic experiments tested the idea that atropine-sensitive theta rhythm plays a role in sensory integration and planning required for initiating appropriate movements. One of a pair of hungry rats, the victim, implanted with hippocampal field recording electrodes, a septal injection cannula, and a posterior hypothalamic stimulating electrode, was given food which the other, the robber, tries to steal. Since the victim dodges from the robber with a latency, distance, and velocity dependent upon the size of the food, elapsed eating time, and proximity of the robber, the movement requires sensory integration and planning. Although eating behavior seemed normal, atropine-sensitive theta rhythm and dodging were disrupted by an infusion of a cholinergic antagonist into the medial septum. When the victim in turn attempted to steal the food back, Type 1 theta rhythm was present and robbery attempts seemed normal. Prior to cholinergic blockade, posterior hypothalamic stimulation produced theta rhythm and dodges, even in the absence of the robber, but following injections, atropine-sensitive theta rhythm and dodging were absent as the animals dropped the food and ran. The results provide the first evidence to link atropine-sensitive theta rhythm and hippocampal structures to a role in sensory integration and planning for the initiation of movement. PMID:9404626

  13. Behavioral deficits and cholinergic pathway abnormalities in male Sanfilippo B mice.

    Science.gov (United States)

    Kan, Shih-Hsin; Le, Steven Q; Bui, Quang D; Benedict, Braeden; Cushman, Jesse; Sands, Mark S; Dickson, Patricia I

    2016-10-01

    Sanfilippo B syndrome is a progressive neurological disorder caused by inability to catabolize heparan sulfate glycosaminoglycans. We studied neurobehavior in male Sanfilippo B mice and heterozygous littermate controls from 16 to 20 weeks of age. Affected mice showed reduced anxiety, with a decrease in the number of stretch-attend postures during the elevated plus maze (p=0.001) and an increased tendency to linger in the center of an open field (p=0.032). Water maze testing showed impaired spatial learning, with reduced preference for the target quadrant (p=0.01). In radial arm maze testing, affected mice failed to achieve above-chance performance in a win-shift working memory task (t-test relative to 50% chance: p=0.289), relative to controls (p=0.037). We found a 12.4% reduction in mean acetylcholinesterase activity (padult-onset dementias, including Alzheimer disease. Our results suggest that male Sanfilippo B mice display neurobehavioral deficits at a relatively early age, and that as in adult dementias, they may display deficits in cholinergic pathways. PMID:27340089

  14. Visual efference neuromodulates retinal timing: in vivo roles of octopamine, substance P, circadian phase, and efferent activation in Limulus.

    Science.gov (United States)

    Bolbecker, Amanda R; Lim-Kessler, Corrinne C M; Li, Jia; Swan, Alicia; Lewis, Adrienne; Fleets, Jennifer; Wasserman, Gerald S

    2009-08-01

    Efferent nerves coursing from the brain to the lateral eye of the horseshoe crab, Limulus polyphemus, increase its nighttime sensitivity to light. They release octopamine, which produces a categorical increase of photoreceptor response duration in vitro. Analogous in vivo timing effects on the electroretinogram (ERG) were demonstrated when octopamine was infiltrated into the eye of an otherwise intact animal; nighttime ERGs were longer than daytime ERGs. Related effects on the ERG were produced by daytime electrical stimulation of efferent fibers. Surprisingly, in a departure from effects predicted solely from in vitro octopamine data, nighttime ERG onsets were also accelerated relative to daytime ERG onsets. Drawing on earlier reports, these remarkable accelerations led to an examination of substance P as another candidate neuromodulator. It demonstrated that infiltrations of either modulator into the lateral eyes of otherwise intact crabs increased the amplitude of ERG responses but that each candidate modulator induced daytime responses that specifically mimicked one of the two particular aspects of the timing differences between day- and nighttime ERGs: octopamine increased the duration of daytime ERGs and substance P infiltrated during the day accelerated response onset. These results indicate that, in addition to octopamine's known role as an efferent neuromodulator that increases nighttime ERG amplitudes, octopamine clearly also affects the timing of photoreceptor responses. But these infiltration data go further and strongly suggest that substance P may also be released into the lateral eye at night, thereby accelerating the ERG's onset in addition to increasing its amplitude. PMID:19535477

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

    Directory of Open Access Journals (Sweden)

    Jun-Il Kang

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

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

    Directory of Open Access Journals (Sweden)

    Ehren L Newman

    2012-06-01

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

  17. Cuneiform neurons activated during cholinergically induced active sleep in the cat.

    Science.gov (United States)

    Pose, I; Sampogna, S; Chase, M H; Morales, F R

    2000-05-01

    In the present study, we report that the cuneiform (Cun) nucleus, a brainstem structure that before now has not been implicated in sleep processes, exhibits a large number of neurons that express c-fos during carbachol-induced active sleep (AS-carbachol). Compared with control (awake) cats, during AS-carbachol, there was a 671% increase in the number of neurons that expressed c-fos in this structure. Within the Cun nucleus, three immunocytochemically distinct populations of neurons were observed. One group consisted of GABAergic neurons, which predominantly did not express c-fos during AS-carbachol. Two other different populations expressed c-fos during this state. One of the Fos-positive (Fos(+)) populations consisted of a distinct group of nitric oxide synthase (NOS)-NADPH-diaphorase (NADPH-d)-containing neurons; the neurotransmitter of the other Fos(+) population remains unknown. The Cun nucleus did not contain cholinergic, catecholaminergic, serotonergic, or glycinergic neurons. On the basis of neuronal activation during AS-carbachol, as indicated by c-fos expression, we suggest that the Cun nucleus is involved, in an as yet unknown manner, in the physiological expression of active sleep. The finding of a population of NOS-NADPH-d containing neurons, which were activated during AS-carbachol, suggests that nitrergic modulation of their target cell groups is likely to play a role in active sleep-related physiological processes. PMID:10777795

  18. Fasting stimulates 2-AG biosynthesis in the small intestine: role of cholinergic pathways.

    Science.gov (United States)

    DiPatrizio, Nicholas V; Igarashi, Miki; Narayanaswami, Vidya; Murray, Conor; Gancayco, Joseph; Russell, Amy; Jung, Kwang-Mook; Piomelli, Daniele

    2015-10-15

    The endocannabinoids are lipid-derived signaling molecules that control feeding and energy balance by activating CB1-type cannabinoid receptors in the brain and peripheral tissues. Previous studies have shown that oral exposure to dietary fat stimulates endocannabinoid signaling in the rat small intestine, which provides positive feedback that drives further food intake and preference for fat-rich foods. We now describe an unexpectedly broader role for cholinergic signaling of the vagus nerve in the production of the endocannabinoid, 2-arachidonoyl-sn-glycerol (2-AG), in the small intestine. We show that food deprivation increases levels of 2-AG and its lipid precursor, 1,2-diacylglycerol, in rat jejunum mucosa in a time-dependent manner. This response is abrogated by surgical resection of the vagus nerve or pharmacological blockade of small intestinal subtype-3 muscarinic acetylcholine (m3 mAch) receptors, but not inhibition of subtype-1 muscarinic acetylcholine (m1 mAch). We further show that blockade of peripheral CB1 receptors or intestinal m3 mAch receptors inhibits refeeding in fasted rats. The results suggest that food deprivation stimulates 2-AG-dependent CB1 receptor activation through a mechanism that requires efferent vagal activation of m3 mAch receptors in the jejunum, which, in turn, may promote feeding after a fast. PMID:26290104

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

    Science.gov (United States)

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

    2016-01-01

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

  20. Changes in the cholinergic system of rat sciatic nerve and skeletal muscle following suspension induced disuse

    Science.gov (United States)

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

    1984-01-01

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

  1. Absence of cholinergic airway tone in normal BALB/c mice.

    Science.gov (United States)

    Larcombe, Alexander N; Zosky, Graeme R; Bozanich, Elizabeth M; Turner, Debra J; Hantos, Zoltan; Sly, Peter D

    2008-05-31

    Basal airway smooth muscle (ASM) tone has not been demonstrated in mice in vivo. To determine whether basal ASM tone is present in mouse airways we measured respiratory system impedance (Zrs) before and after either atropine or bilateral vagotomy. Zrs was measured using forced oscillations delivered via a wave-tube during slow ( approximately 35s) inflation-deflation maneuvers between transrespiratory pressures (Prs) of 0 and 20 cm H2O. A constant-phase tissue model was applied to the Zrs to calculate airway resistance (R aw), tissue damping (G) and elastance (H). Thoracic gas volume (TGV) was determined plethysmographically at Prs=0 cm H2O and by integration of the inspiratory flow. The relationship between conductance (G aw=1/R aw) and TGV during inflation was also examined. Neither atropine nor vagotomy produced any change in R aw, H, eta (=G/H), TGV or the slope of G aw vs. TGV that was different to that observed in the relevant control groups. These data show that BALB/c mice do not have cholinergic ASM tone in vivo. PMID:18440286

  2. 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

  3. 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

    2015-12-01

    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

  4. Effects of metoclopramide and domperidone on cholinergically mediated contractions of human isolated stomach muscle.

    Science.gov (United States)

    Sanger, G J

    1985-09-01

    The experiments examine the actions of metoclopramide and domperidone on the responses evoked by electrical field stimulation or by acetylcholine, in longitudinal muscle strips obtained from human stomach. Electrical field stimulation evoked contractions which were predominantly cholinergically mediated; metoclopramide 0.28-28 microM caused a concentration-dependent increase in the height of these contractions. In the presence of atropine and barium chloride, electrical stimulation evoked relaxations of the stomach muscle, probably by stimulating non-adrenergic, non-cholinergic inhibitory nerves; metoclopramide 28 microM had no effect on these relaxations. Metoclopramide 0.003-2.8 microM had no effect on contractions evoked by exogenous acetylcholine, although higher concentrations of the drug increased the contractions. The results suggest that in human isolated stomach, low concentrations of metoclopramide may increase electrically evoked cholinergic activity by increasing the release of neuronal acetylcholine. Stimulation by metoclopramide of cholinergic activity in the gut may therefore be an important mechanism by which the drug increases gastrointestinal motility during therapy. Cholinergically mediated contractions were not increased by domperidone, and other mechanism(s) of action may therefore be important for this drug. PMID:2867191

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

    Directory of Open Access Journals (Sweden)

    E. I. Zakharova

    2010-01-01

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

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    Stephen Grossberg

    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.

  8. 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. PMID:26834535

  9. Cerebral cortical astroglia from the trisomy 16 mouse, a model for Down syndrome, produce neuronal cholinergic deficits in cell culture

    OpenAIRE

    Nelson, P. G.; Fitzgerald, S.; Rapoport, S I; Neale, E A; Galdzicki, Z; Dunlap, V.; Bowers, L; v. Agoston, D.

    1997-01-01

    Trisomy 21 (Down syndrome) is associated with a high incidence of Alzheimer disease and with deficits in cholinergic function in humans. We used the trisomy 16 (Ts16) mouse model for Down syndrome to identify the cellular basis for the cholinergic dysfunction. Cholinergic neurons and cerebral cortical astroglia, obtained separately from Ts16 mouse fetuses and their euploid littermates, were cultured in various combinations. Choline acetyltransferase activity and cholinergic neuron number were...

  10. Axotomy-induced neurotrophic withdrawal causes the loss of phenotypic differentiation and downregulation of NGF signalling, but not death of septal cholinergic neurons

    Directory of Open Access Journals (Sweden)

    Inestrosa Nibaldo C

    2010-01-01

    Full Text Available Abstract Background Septal cholinergic neurons account for most of the cholinergic innervations of the hippocampus, playing a key role in the regulation of hippocampal synaptic activity. Disruption of the septo-hippocampal pathway by an experimental transection of the fimbria-fornix drastically reduces the target-derived trophic support received by cholinergic septal neurons, mainly nerve growth factor (NGF from the hippocampus. Axotomy of cholinergic neurons induces a reduction in the number of neurons positive for cholinergic markers in the medial septum. In several studies, the reduction of cholinergic markers has been interpreted as analogous to the neurodegeneration of cholinergic cells, ruling out the possibility that neurons lose their cholinergic phenotype without dying. Understanding the mechanism of cholinergic neurodegeneration after axotomy is relevant, since this paradigm has been extensively explored as an animal model of the cholinergic impairment observed in neuropathologies such as Alzheimer's disease. The principal aim of this study was to evaluate, using modern quantitative confocal microscopy, neurodegenerative changes in septal cholinergic neurons after axotomy and to assess their response to delayed infusion of NGF in rats. Results We found that there is a slow reduction of cholinergic cells labeled by ChAT and p75 after axotomy. However, this phenomenon is not accompanied by neurodegenerative changes or by a decrease in total neuronal number in the medial septum. Although the remaining axotomized-neurons appear healthy, they are unable to respond to delayed NGF infusion. Conclusions Our results demonstrate that at 3 weeks, axotomized cholinergic neurons lose their cholinergic phenotype without dying and down-regulate their NGF-receptors, precluding the possibility of a response to NGF. Therefore, the physiological role of NGF in the adult septal cholinergic system is to support phenotypic differentiation and not survival

  11. 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.

  12. 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.

  13. 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. PMID:26791829

  14. Dysregulated cholinergic network as a novel biomarker of poor prognostic in patients with head and neck squamous cell carcinoma

    International Nuclear Information System (INIS)

    In airways, a proliferative effect is played directly by cholinergic agonists through nicotinic and muscarinic receptors activation. How tumors respond to aberrantly activated cholinergic signalling is a key question in smoking-related cancer. This research was addressed to explore a possible link of cholinergic signalling changes with cancer biology. Fifty-seven paired pieces of head and neck squamous cell carcinoma (HNSCC) and adjacent non-cancerous tissue (ANCT) were compared for their mRNA levels for ACh-related proteins and ACh-hydrolyzing activity. The measurement in ANCT of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities (5.416 ± 0.501 mU/mg protein and 6.350 ± 0.599 mU/mg protein, respectively) demonstrated that upper respiratory tract is capable of controlling the availability of ACh. In HNSCC, AChE and BChE activities dropped to 3.584 ± 0.599 mU/mg protein (p = 0.002) and 3.965 ± 0.423 mU/mg protein (p < 0.001). Moreover, tumours with low AChE activity and high BChE activity were associated with shorter patient overall survival. ANCT and HNSCC differed in mRNA levels for AChE-T, α3, α5, α9 and β2 for nAChR subunits. Tobacco exposure had a great impact on the expression of both AChE-H and AChE-T mRNAs. Unaffected and cancerous pieces contained principal AChE dimers and BChE tetramers. The lack of nerve-born PRiMA-linked AChE agreed with pathological findings on nerve terminal remodelling and loss in HNSCC. Our results suggest that the low AChE activity in HNSCC can be used to predict survival in patients with head and neck cancer. So, the ChE activity level can be used as a reliable prognostic marker. The online version of this article (doi:10.1186/s12885-015-1402-y) contains supplementary material, which is available to authorized users

  15. Participation of the cholinergic system in the ethanol-induced suppression of paradoxical sleep in rats

    Directory of Open Access Journals (Sweden)

    L.A. Papale

    2008-09-01

    Full Text Available Sleep disturbance is among the many consequences of ethanol abuse in both humans and rodents. Ethanol consumption can reduce REM or paradoxical sleep (PS in humans and rats, respectively. The first aim of this study was to develop an animal model of ethanol-induced PS suppression. This model administered intragastrically (by gavage to male Wistar rats (3 months old, 200-250 g 0.5 to 3.5 g/kg ethanol. The 3.5 g/kg dose of ethanol suppressed the PS stage compared with the vehicle group (distilled water during the first 2-h interval (0-2 h; 1.3 vs 10.2; P < 0.001. The second aim of this study was to investigate the mechanisms by which ethanol suppresses PS. We examined the effects of cholinergic drug pretreatment. The cholinergic system was chosen because of the involvement of cholinergic neurotransmitters in regulating the sleep-wake cycle. A second set of animals was pretreated with 2.5, 5.0, and 10 mg/kg pilocarpine (cholinergic agonist or atropine (cholinergic antagonist. These drugs were administered 1 h prior to ethanol (3.5 g/kg or vehicle. Treatment with atropine prior to vehicle or ethanol produced a statistically significant decrease in PS, whereas pilocarpine had no effect on minutes of PS. Although the mechanism by which ethanol induces PS suppression is not fully understood, these data suggest that the cholinergic system is not the only system involved in this interaction.

  16. State dependency of the effects of microinjection of cholinergic drugs into the nucleus pontis oralis.

    Science.gov (United States)

    López-Rodríguez, F; Kohlmeier, K; Morales, F R; Chase, M H

    1994-06-27

    The microinjection of cholinergic drugs into the pontine reticular formation elicits active sleep-like states that are comprised of the principal physiological patterns of activity that characterize naturally-occurring active sleep, i.e., EEG desynchronization, PGO waves, rapid eye movements and atonia. We have reported that other behavioral states arise even when cholinergic drugs are injected into the exact same reticular location. The present study was conducted to explore the basis for the differences in the drug effect. A combination of acetylcholine and neostigmine was injected by microiontophoresis into the dorsal region of the nucleus pontis oralis in four chronic, unanesthetized cats. The states that were induced by cholinergic drug injection depended on the state of the animal at the time of the injection. When the animal was awake, cholinergic injections resulted in a waking-dissociated state, which was characterized by EEG desynchronization and muscle atonia in a cat that appeared to be awake and was able to track objects in its visual field. If the cat was in quiet sleep at the time of the injection, an active sleep-like state followed that was indistinguishable from naturally-occurring active sleep; on a few occasions following cholinergic injections during quiet sleep there was a quiet sleep-dissociated state, which was characterized by PGO waves and muscle atonia in the cat that by other indices appeared to be in quiet sleep. The results of this study indicate that the state of the animal at the time of drug injection is a critical variable that influences the responses which are induced by cholinergic stimulation of the pontine reticular formation. PMID:7953643

  17. Sexually dimorphic effects of the Lhx7 null mutation on forebrain cholinergic function.

    Science.gov (United States)

    Fragkouli, A; Stamatakis, A; Zographos, E; Pachnis, V; Stylianopoulou, F

    2006-01-01

    It has been reported recently that mice lacking both alleles of the LIM-homeobox gene Lhx7, display dramatically reduced number of forebrain cholinergic neurons. In the present study, we investigated whether the Lhx7 mutation affects male and female mice differently, given the fact that gender differences are consistently observed in forebrain cholinergic function. Our results show that in adult male as well as female Lhx7 homozygous mutants there is a dramatic loss of choline acetyltransferase immunoreactive forebrain neurons, both projection and interneurons. The reduction of forebrain choline acetyltransferase immunoreactive neurons in Lhx7 homozygous mutants is accompanied by a decrease of acetylcholinesterase histochemical staining in all forebrain cholinergic neuron target areas of both male and female homozygous mutants. Furthermore, there was an increase of M1-, but not M2-, muscarinic acetylcholine receptor binding site density in the somatosensory cortex and basal ganglia of only the female homozygous mutant mice. Such an increase can be regarded as a mechanism acting to compensate for the dramatically reduced cholinergic input, raising the possibility that the forebrain cholinergic system in female mice may be more plastic and responsive to situations of limited neurotransmitter availability. Finally, our study provides additional data for the sexual dimorphism of the forebrain cholinergic system, as female mice appear to have a lower density of M1-muscarinic acetylcholine receptors in the striatal areas of the basal ganglia and a higher density of M2-muscarinic acetylcholine receptors, in a number of cortical areas, as well as the striatal areas of the basal ganglia. PMID:16338089

  18. Activities of cholinergic proteins in APP/PS1 double transgenic mice

    Czech Academy of Sciences Publication Activity Database

    Málková, Barbora; Machová, Eva; Jakubík, Jan; Doležal, Vladimír

    Fyziologický ústav AV ČR, v. v. i.. Roč. 54, č. 3 (2005), 31P-31P ISSN 0862-8408. [Physiological Days /81./. 02.02.2005-04.02.2005, Košice] R&D Projects: GA AV ČR(CZ) IAA5011306; GA ČR(CZ) IAA5011206 Institutional research plan: CEZ:AV0Z5011922 Keywords : cholinergic neuron * APP/PS1 transgenic mice * cholinergic markers * Alzheimer ´s disease Subject RIV: ED - Physiology

  19. 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; Fisher, James P

    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...

  20. Neurofunctional imaging of the pancreas utilizing the cholinergic PET radioligand [18F]4-fluorobenzyltrozamicol

    International Nuclear Information System (INIS)

    The pancreas is one of the most heavily innervated peripheral organs in the body. Parasympathetic and sympathetic neurons terminate in the pancreas and provide tight control of endocrine and exocrine functions. The aim of this study was to determine whether the pancreas can be imaged with a radioligand that binds to specific neuroreceptors. Using fluorine-18 4-fluorobenzyltrozamicol (FBT), which binds to the presynaptic vesicular acetylcholine transporter, positron emission tomography scans were performed in four adult mice, two adult rhesus monkeys, and one adult human. In these mammals, the pancreas is intensely FBT avid, with uptake greater than in any other organ at 30, 60, and 90 min. The maximum standardized uptake value (SUV) ratios of pancreas to liver, for example, ranged from 1.4 to 1.7 in rhesus monkeys (mean 1.6; median 1.7) and from 1.9 to 4.7 (mean 3.24; median 3.02) in mice. The maximum SUV ratio of pancreas to liver in the human was 1.8. These data suggest that neuroreceptor imaging of the pancreas in vivo is feasible in animal models and humans. This imaging could allow researchers to interrogate functions under control of the autonomic nervous system in the pancreas, with applications possible in transplanted and native pancreata. Also, as beta cell function is intimately related to parasympathetic cholinergic input, FBT activity in the pancreas may correlate with insulin-producing beta cell mass. This could ultimately provide a method of in vivo imaging in animal models and humans for diabetes research. (orig.)

  1. Neurofunctional imaging of the pancreas utilizing the cholinergic PET radioligand [{sup 18}F]4-fluorobenzyltrozamicol

    Energy Technology Data Exchange (ETDEWEB)

    Clark, P.B.; Gage, H.D.; Brown-Proctor, C.; Buchheimer, N.; Morton, K.A. [Nuclear Medicine Section, Department of Radiology, Wake Forest University School of Medicine, Medical Center Blvd., NC 27157, Winston-Salem (United States); Calles-Escandon, J. [Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (United States); Mach, R.H. [Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri (United States)

    2004-02-01

    The pancreas is one of the most heavily innervated peripheral organs in the body. Parasympathetic and sympathetic neurons terminate in the pancreas and provide tight control of endocrine and exocrine functions. The aim of this study was to determine whether the pancreas can be imaged with a radioligand that binds to specific neuroreceptors. Using fluorine-18 4-fluorobenzyltrozamicol (FBT), which binds to the presynaptic vesicular acetylcholine transporter, positron emission tomography scans were performed in four adult mice, two adult rhesus monkeys, and one adult human. In these mammals, the pancreas is intensely FBT avid, with uptake greater than in any other organ at 30, 60, and 90 min. The maximum standardized uptake value (SUV) ratios of pancreas to liver, for example, ranged from 1.4 to 1.7 in rhesus monkeys (mean 1.6; median 1.7) and from 1.9 to 4.7 (mean 3.24; median 3.02) in mice. The maximum SUV ratio of pancreas to liver in the human was 1.8. These data suggest that neuroreceptor imaging of the pancreas in vivo is feasible in animal models and humans. This imaging could allow researchers to interrogate functions under control of the autonomic nervous system in the pancreas, with applications possible in transplanted and native pancreata. Also, as beta cell function is intimately related to parasympathetic cholinergic input, FBT activity in the pancreas may correlate with insulin-producing beta cell mass. This could ultimately provide a method of in vivo imaging in animal models and humans for diabetes research. (orig.)

  2. Investigation into the role of the cholinergic system in radiation-induced damage in the rat liver and ileum

    International Nuclear Information System (INIS)

    It has been previously shown that acetylcholine (ACh) may affect pro-inflammatory and anti-inflammatory cytokines. The role of the cholinergic system in radiation-induced inflammatory responses and tissue damage remains unclear. Therefore, the present study was designed to determine the radio-protective properties of the cholinergic system in the ileum and the liver of rats. Rats were exposed to 8-Gy single-fraction whole-abdominal irradiation and were then decapitated at either 36 h or 10 d post-irradiation. The rats were treated either with intraperitoneal physiological saline (1 ml/kg), physostigmine (80 μg/kg) or atropine (50 μg/kg) twice daily for 36 h or 10 d. Cardiac blood samples and liver and ileal tissues were obtained in which TNF-α, IL-1β and IL-10 levels were assayed using ELISA. In the liver and ileal homogenates, caspase-3 immunoblots were performed and mye-loperoxidase (MPO) activity was analyzed. Plasma levels of IL-1β and TNF-α increased significantly following radiation (P < 0.01 and P < 0.001, respectively) as compared with non-irradiated controls, and physostigmine treatment prevented the increase in the pro-inflammatory cytokines (P < 0.01 and P < 0.001, respectively). Plasma IL-10 levels were not found to be significantly changed following radiation, whereas physostigmine augmented IL-10 levels during the late phase (P < 0.01). In the liver and ileum homogenates, IL-1β and TNF-α levels were also elevated following radiation, and this effect was inhibited by physostigmine treatment but not by atropine. Similarly, physostigmine also reversed the changes in MPO activity and in the caspase-3 levels in the liver and ileum. Histological examination revealed related changes. Physostigmine experiments suggested that ACh has a radio-protective effect not involving the muscarinic receptors. (author)

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

    Science.gov (United States)

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

    2013-02-01

    Alzheimer's disease (AD) is characterized by degeneration of neocortex, limbic system, and basal forebrain, accompanied by accumulation of amyloid-β and tangle formation. Cerebrolysin (CBL), a peptide mixture with neurotrophic-like effects, is reported to improve cognition and activities of daily living in patients with AD. Likewise, CBL reduces synaptic and behavioral deficits in transgenic (tg) mice overexpressing the human amyloid precursor protein (hAPP). The neuroprotective effects of CBL may involve multiple mechanisms, including signaling regulation, control of APP metabolism, and expression of neurotrophic factors. We investigate the effects of CBL in the hAPP tg model of AD on levels of neurotrophic factors, including pro-nerve growth factor (NGF), NGF, brain-derived neurotrophic factor (BDNF), neurotropin (NT)-3, NT4, and ciliary neurotrophic factor (CNTF). Immunoblot analysis demonstrated that levels of pro-NGF were increased in saline-treated hAPP tg mice. In contrast, CBL-treated hAPP tg mice showed levels of pro-NGF comparable to control and increased levels of mature NGF. Consistently with these results, immunohistochemical analysis demonstrated increased NGF immunoreactivity in the hippocampus of CBL-treated hAPP tg mice. Protein levels of other neurotrophic factors, including BDNF, NT3, NT4, and CNTF, were unchanged. mRNA levels of NGF and other neurotrophins were also unchanged. Analysis of neurotrophin receptors showed preservation of the levels of TrKA and p75(NTR) immunoreactivity per cell in the nucleus basalis. Cholinergic cells in the nucleus basalis were reduced in the saline-treated hAPP tg mice, and treatment with CBL reduced these cholinergic deficits. These results suggest that the neurotrophic effects of CBL might involve modulation of the pro-NGF/NGF balance and a concomitant protection of cholinergic neurons. PMID:23152192

  4. 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

  5. Pitx3 deficiency in mice affects cholinergic modulation of GABAergic synapses in the nucleus accumbens

    NARCIS (Netherlands)

    de Rover, Mischa; Lodder, Johannes C.; Smidt, Marten P.; Brussaard, Arjen B.

    2006-01-01

    Pitx3 deficiency in mice affects cholinergic modulation of GABAergic synapses in the nucleus accumbens. J Neurophysiol 96: 2034-2041, 2006. First published July 12, 2006; doi:10.1152/jn.00333.2006. We investigated to what extent Pitx3 deficiency, causing hyperdopaminergic transmission in the nucleus

  6. Activation of vascular cholinergic and adrenergic receptors induced by gamma rays

    International Nuclear Information System (INIS)

    Activation of vascular cholinergic receptors and adrenoceptors plays an important role in vasomotoricity and peripheric vascular resistance. These factors are essential in maintaining a stable blood pressure. The aim of this study is to investigate the radiosensitivity differences between vascular cholinergic receptors and adrenoceptors, and consequently to determinate the effects of ionizing radiation (whole body irradiation) on contractile response regulation of vascular smooth muscle fibers VSMF isolated from rat portal vein. Our results show that Clonidine, (non-specific adrenergic agonist), and phenylephrine which is more specific α1-adrenoceptor agonist, increase the VSMF contractions. The maximum effect is obtained at 10-5 - 3.10-5 M. On irradiated rats (1-3-5 Gy), there is an important shift thus, the maximal response (Emax) can be obtained in lower concentrations of clonidine and phenylephrine. Irradiation deceases the contractile responses of VSMF mediated by cholinergic stimulation, in a dose dependant manner. With Emax 1 Gy>Emax 3 Gy>Emax 5 Gy. Irradiated muscular fibers became less sensitive to acetylcholine, thus 3.10-8 M. A. ch induced more than 50% of contraction force increase in normal conditions. This concentration induce generally a negligible effect after irradiation. The results reveal the existence of radiosensitivity differences between vascular cholinergic and adrenergic receptors. (author)

  7. An autoradiographic analysis of cholinergic receptors in mouse brain after chronic nicotine treatment

    International Nuclear Information System (INIS)

    Quantitative autoradiographic procedures were used to examine the effects of chronic nicotine infusion on the number of central nervous system nicotinic cholinergic receptors. Female DBA mice were implanted with jugular cannulas and infused with saline or various doses of nicotine (0.25, 0.5, 1.0 or 2.0 mg/kg/hr) for 10 days. The animals were then sacrificed and the brains were removed and frozen in isopentane. Cryostat sections were collected and prepared for autoradiographic procedures as previously described. Nicotinic cholinergic receptors were labeled with L-[3H]nicotine or alpha-[125I]bungarotoxin; [3H]quinuclidinyl benzilate was used to measure muscarinic cholinergic receptor binding. Chronic nicotine infusion increased the number of sites labeled by [3H]nicotine in most brain areas. However, the extent of the increase in binding as well as the dose-response curves for the increase were widely different among brain regions. After the highest treatment dose, binding was increased in 67 of 86 regions measured. Septal and thalamic regions were most resistant to change. Nicotinic binding measured by alpha-[125I]bungarotoxin also increased after chronic treatment, but in a less robust fashion. At the highest treatment dose, only 26 of 80 regions were significantly changes. Muscarinic binding was not altered after chronic nicotine treatment. These data suggest that brain regions are not equivalent in the mechanisms that regulate alterations in nicotinic cholinergic receptor binding after chronic nicotine treatment

  8. 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...

  9. Cholinergic Modulation during Acquisition of Olfactory Fear Conditioning Alters Learning and Stimulus Generalization in Mice

    Science.gov (United States)

    Pavesi, Eloisa; Gooch, Allison; Lee, Elizabeth; Fletcher, Max L.

    2013-01-01

    We investigated the role of cholinergic neurotransmission in olfactory fear learning. Mice receiving pairings of odor and foot shock displayed fear to the trained odor the following day. Pretraining injections of the nicotinic antagonist mecamylamine had no effect on subsequent freezing, while the muscarinic antagonist scopolamine significantly…

  10. Cholinergic modulation of the cerebral metabolic response to citalopram in Alzheimer's disease

    OpenAIRE

    Smith, Gwenn S.; Kramer, Elisse; Ma, Yilong; Hermann, Carol R.; Dhawan, Vijay; Chaly, Thomas; Eidelberg, David

    2009-01-01

    Pre-clinical and human neuropharmacological evidence suggests a role of cholinergic modulation of monoamines as a pathophysiological and therapeutic mechanism in Alzheimer's disease. The present study measured the effects of treatment with the cholinesterase inhibitor and nicotinic receptor modulator, galantamine, on the cerebral metabolic response to the selective serotonin reuptake inhibitor, citalopram. Seven probable Alzheimer's disease patients and seven demographically comparable contro...

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

    DEFF Research Database (Denmark)

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

    2005-01-01

    dorsal tegmental nuclei. This distribution suggests that the UII system is involved in functions regulated by acetylcholine, such as the sleep-wake cycle. Here, we tested the hypothesis that UII influences cholinergic PPT neuron activity and alters rapid eye movement (REM) sleep patterns in rats. Local...

  12. 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 Yi

    2015-03-01

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

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

    Directory of Open Access Journals (Sweden)

    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.

  14. The Cholinergic Signaling Responsible for the Expression of a Memory-Related Protein in Primary Rat Cortical Neurons.

    Science.gov (United States)

    Chen, Tsan-Ju; Chen, Shun-Sheng; Wang, Dean-Chuan; Hung, Hui-Shan

    2016-11-01

    Cholinergic dysfunction in the brain is closely related to cognitive impairment including memory loss. In addition to the degeneration of basal forebrain cholinergic neurons, deficits in the cholinergic receptor signaling may also play an important role. In the present study, to examine the cholinergic signaling pathways responsible for the induction of a memory-related postsynaptic protein, a cholinergic agonist carbachol was used to induce the expression of activity-regulated cytoskeleton associated protein (Arc) in primary rat cortical neurons. After pretreating neurons with various antagonists or inhibitors, the levels of carbachol-induced Arc protein expression were detected by Western blot analysis. The results show that carbachol induces Arc protein expression mainly through activating M1 acetylcholine receptors and the downstream phospholipase C pathway, which may lead to the activation of the MAPK/ERK signaling pathway. Importantly, carbachol-mediated M2 receptor activation exerts negative effects on Arc protein expression and thus counteracts the enhanced effects of M1 activation. Furthermore, it is suggested for the first time that M1-mediated enhancement of N-methyl-D-aspartate receptor (NMDAR) responses, leading to Ca(2+) entry through NMDARs, contributes to carbachol-induced Arc protein expression. These findings reveal a more complete cholinergic signaling that is responsible for carbachol-induced Arc protein expression, and thus provide more information for developing treatments that can modulate cholinergic signaling and consequently alleviate cognitive impairment. J. Cell. Physiol. 231: 2428-2438, 2016. © 2016 Wiley Periodicals, Inc. PMID:26895748

  15. Exercise leads to the re-emergence of the cholinergic/nestin neuronal phenotype within the medial septum/diagonal band and subsequent rescue of both hippocampal ACh efflux and spatial behavior.

    Science.gov (United States)

    Hall, Joseph M; Savage, Lisa M

    2016-04-01

    Exercise has been shown to improve cognitive functioning in a range of species, presumably through an increase in neurotrophins throughout the brain, but in particular the hippocampus. The current study assessed the ability of exercise to restore septohippocampal cholinergic functioning in the pyrithiamine-induced thiamine deficiency (PTD) rat model of the amnestic disorder Korsakoff Syndrome. After voluntary wheel running or sedentary control conditions (stationary wheel attached to the home cage), PTD and control rats were behaviorally tested with concurrent in vivo microdialysis, at one of two time points: 24-h or 2-weeks post-exercise. It was found that only after the 2-week adaption period did exercise lead to an interrelated sequence of events in PTD rats that included: (1) restored spatial working memory; (2) rescued behaviorally-stimulated hippocampal acetylcholine efflux; and (3) within the medial septum/diagonal band, the re-emergence of the cholinergic (choline acetyltransferase [ChAT+]) phenotype, with the greatest change occurring in the ChAT+/nestin+ neurons. Furthermore, in control rats, exercise followed by a 2-week adaption period improved hippocampal acetylcholine efflux and increased the number of neurons co-expressing the ChAT and nestin phenotype. These findings demonstrate a novel mechanism by which exercise can modulate the mature cholinergic/nestin neuronal phenotype leading to improved neurotransmitter function as well as enhanced learning and memory. PMID:26836322

  16. Maternal exposure to hexachlorophene targets intermediate-stage progenitor cells of the hippocampal neurogenesis in rat offspring via dysfunction of cholinergic inputs by myelin vacuolation

    International Nuclear Information System (INIS)

    Highlights: • The effect of maternal exposure to HCP on rat hippocampal neurogenesis was examined. • HCP induces myelin vacuolation of nerve tracts in the septal–hippocampal pathway. • Myelin changes suppress Chrnb2-mediated cholinergic inputs to the dentate gyrus. • SGZ apoptosis occurs via the mitochondrial pathway and targets type-2b cells. • Dysfunction of cholinergic inputs is related to type-2b SGZ cell apoptosis. - Abstract: Hexachlorophene (HCP) is known to induce myelin vacuolation corresponding to intramyelinic edema of nerve fibers in the central and peripheral nervous system in animals. This study investigated the effect of maternal exposure to HCP on hippocampal neurogenesis in rat offspring using pregnant rats supplemented with 0 (controls), 100, or 300 ppm HCP in the diet from gestational day 6 to day 21 after delivery. On postnatal day (PND) 21, the numbers of T box brain 2+ progenitor cells and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling+ apoptotic cells in the hippocampal subgranular zone (SGZ) decreased in female offspring at 300 ppm, which was accompanied by myelin vacuolation and punctate tubulin beta-3 chain staining of nerve fibers in the hippocampal fimbria. In addition, transcript levels of the cholinergic receptor, nicotinic beta 2 (Chrnb2) and B-cell CLL/lymphoma 2 (Bcl2) decreased in the dentate gyrus. HCP-exposure did not alter the numbers of SGZ proliferating cells and reelin- or calcium-binding protein-expressing γ-aminobutyric acid (GABA)-ergic interneuron subpopulations in the dentate hilus on PND 21 and PND 77. Although some myelin vacuolation remained, all other changes observed in HCP-exposed offspring on PND 21 disappeared on PND 77. These results suggest that maternal HCP exposure reversibly decreases type-2b intermediate-stage progenitor cells via the mitochondrial apoptotic pathway in offspring hippocampal neurogenesis at 300 ppm HCP. Neurogenesis may be affected by dysfunction of

  17. 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. PMID:26606423

  18. Rescue of NGF-deficient mice II: basal forebrain cholinergic projections require NGF for target innervation but not guidance.

    Science.gov (United States)

    Phillips, Heidi S; Nishimura, Merry; Armanini, Mark P; Chen, Karen; Albers, Kathryn M; Davis, Brian M

    2004-04-29

    Basal forebrain cholinergic (BFC) neurons are an important substrate of cognitive function and are hypothesized to require the presence of nerve growth factor (NGF) for survival and target innervation. NGF-deficient mice develop BFC neurons that extend projections into telencephalic targets, but the mice perish before innervation is fully established. Rescue of NGF-deficient mice by transgenic expression of NGF under the keratin promoter yields viable mice with disrupted CNS expression of NGF. In the current study, rescued NGF-deficient mice contain normal numbers of septal cholinergic neurons yet reveal severe compromise of cholinergic innervation of both cortex and hippocampus. Surprisingly, intracerebroventricular infusion of NGF into juvenile mice can induce an essentially normal pattern of cholinergic innervation of the hippocampus. These results indicate that NGF is required for induction of proper innervation by BFC neurons, but that the cellular pattern of expression of this factor is not critical for specifying the distribution of axon terminals. PMID:15093680

  19. Localization of the M2 muscarinic cholinergic receptor in dendrites, cholinergic terminals, and noncholinergic terminals in the rat basolateral amygdala: An ultrastructural analysis.

    Science.gov (United States)

    Muller, Jay F; Mascagni, Franco; Zaric, Violeta; Mott, David D; McDonald, Alexander J

    2016-08-15

    Activation of M2 muscarinic receptors (M2Rs) in the rat anterior basolateral nucleus (BLa) is critical for the consolidation of memories of emotionally arousing events. The present investigation used immunocytochemistry at the electron microscopic level to determine which structures in the BLa express M2Rs. In addition, dual localization of M2R and the vesicular acetylcholine transporter protein (VAChT), a marker for cholinergic axons, was performed to determine whether M2R is an autoreceptor in cholinergic axons innervating the BLa. M2R immunoreactivity (M2R-ir) was absent from the perikarya of pyramidal neurons, with the exception of the Golgi complex, but was dense in the proximal dendrites and axon initial segments emanating from these neurons. Most perikarya of nonpyramidal neurons were also M2R-negative. About 95% of dendritic shafts and 60% of dendritic spines were M2 immunoreactive (M2R(+) ). Some M2R(+) dendrites had spines, suggesting that they belonged to pyramidal cells, whereas others had morphological features typical of nonpyramidal neurons. M2R-ir was also seen in axon terminals, most of which formed asymmetrical synapses. The main targets of M2R(+) terminals forming asymmetrical (putative excitatory) synapses were dendritic spines, most of which were M2R(+) . The main targets of M2R(+) terminals forming symmetrical (putative inhibitory or neuromodulatory) synapses were unlabeled perikarya and M2R(+) dendritic shafts. M2R-ir was also seen in VAChT(+) cholinergic terminals, indicating a possible autoreceptor role. These findings suggest that M2R-mediated mechanisms in the BLa are very complex, involving postsynaptic effects in dendrites as well as regulating release of glutamate, γ-aminobutyric acid, and acetylcholine from presynaptic axon terminals. J. Comp. Neurol. 524:2400-2417, 2016. © 2016 Wiley Periodicals, Inc. PMID:26779591

  20. Visual efference in Limulus: in vitro temperature-dependent neuromodulation of photoreceptor potential timing by octopamine and substance P.

    Science.gov (United States)

    Lim-Kessler, Corrinne C M; Bolbecker, Amanda R; Li, Jia; Wasserman, Gerald S

    2008-01-01

    Efferents from the brain of Limulus course toward its lateral eye and release octopamine and substance P into it. These neurotransmitters have previously been found to act as neuromodulators in this visual system by altering the size of its responses to light. We report here that both also modulate the timing of the receptor potentials (RPs) evoked by brief light flashes and that these timing effects are temperature dependent. Specifically: We extend our previous report that octopamine prolongs ambient RPs in a categorical fashion and here demonstrate that it does the same at colder temperatures. Categorical means that a given RP is either clearly prolonged in a dramatic fashion or its duration is otherwise unremarkable. Octopamine also accelerates the onsets of RPs when they are evoked by weak flashes under cold temperatures. Contrariwise, substance P accelerates RPs at all temperatures and this acceleration dramatically reduces the sluggishness that is otherwise typically present at low temperatures. Quantitative analysis of intensity-response functions also demonstrated that light sensitivity under substance P is significantly augmented. The plain temporal antagonism between these two modulators demonstrates that the visual system of Limulus possesses a well-poised mechanism which could be used to adjust the timing of its neural processing to interface well with the temporal characteristics of those visual stimuli that are currently present. PMID:18282313

  1. Elimination of the vesicular acetylcholine transporter in the striatum reveals regulation of behaviour by cholinergic-glutamatergic co-transmission.

    OpenAIRE

    Monica S Guzman; Xavier De Jaeger; Sanda Raulic; Souza, Ivana A; Li, Alex X.; Susanne Schmid; Menon, Ravi S.; Gainetdinov, Raul R.; Caron, Marc G.; Robert Bartha; Prado, Vania F.; Prado, Marco A. M.

    2011-01-01

    Cholinergic neurons in the striatum are thought to play major regulatory functions in motor behaviour and reward. These neurons express two vesicular transporters that can load either acetylcholine or glutamate into synaptic vesicles. Consequently cholinergic neurons can release both neurotransmitters, making it difficult to discern their individual contributions for the regulation of striatal functions. Here we have dissected the specific roles of acetylcholine release for striatal-dependent...

  2. Cholinergic-mediated IP3-receptor activation induces long-lasting synaptic enhancement in CA1 pyramidal neurons

    OpenAIRE

    Fernández de Sevilla, D.; Núñez Molina, Ángel; Borde, M.; Malinow, R.; Buño, Washinton

    2008-01-01

    Cholinergic-glutamatergic interactions influence forms of synaptic plasticity that are thought to mediate memory and learning. We tested in vitro the induction of long-lasting synaptic enhancement at Schaffer collaterals by acetylcholine (ACh) at the apical dendrite of CA1 pyramidal neurons and in vivo by stimulation of cholinergic afferents. In vitro ACh induced a Ca2+ wave and synaptic enhancement mediated by insertion of AMPA receptors in spines. Activation of muscarinic ACh receptors (mAC...

  3. Loss of medial septum cholinergic neurons in THY-Tau22 mouse model: what links with tau pathology?

    Science.gov (United States)

    Belarbi, K; Burnouf, S; Fernandez-Gomez, F-J; Desmercières, J; Troquier, L; Brouillette, J; Tsambou, L; Grosjean, M-E; Caillierez, R; Demeyer, D; Hamdane, M; Schindowski, K; Blum, D; Buée, L

    2011-09-01

    Alzheimer's disease (AD) is a neurodegenerative disorder histologically defined by the cerebral accumulation of amyloid deposits and neurofibrillary tangles composed of hyperphosphorylated tau proteins. Loss of basal forebrain cholinergic neurons is another hallmark of the disease thought to contribute to the cognitive dysfunctions. To this date, the mechanisms underlying cholinergic neurons degeneration remain uncertain. The present study aimed to investigate the relationship between neurofibrillary degeneration and cholinergic defects in AD using THY-Tau22 transgenic mouse model exhibiting a major hippocampal AD-like tau pathology and hyperphosphorylated tau species in the septohippocampal pathway. Here, we report that at a time THY-Tau22 mice display strong reference memory alterations, the retrograde transport of fluorogold through the septohippocampal pathway is altered. This impairment is associated with a significant reduction in the number of choline acetyltransferase (ChAT)-immunopositive cholinergic neurons in the medial septum. Analysis of nerve growth factor (NGF) levels supports an accumulation of the mature neurotrophin in the hippocampus of THY-Tau22 mice, consistent with a decrease of its uptake or retrograde transport by cholinergic terminals. Finally, our data strongly support that tau pathology could be instrumental in the cholinergic neuronal loss observed in AD. PMID:21605043

  4. The distribution and morphological characteristics of cholinergic cells in the brain of monotremes as revealed by ChAT immunohistochemistry.

    Science.gov (United States)

    Manger, P R; Fahringer, H M; Pettigrew, J D; Siegel, J M

    2002-01-01

    The present study employs choline acetyltransferase (ChAT) immunohistochemistry to identify the cholinergic neuronal population in the central nervous system of the monotremes. Two of the three extant species of monotreme were studied: the platypus (Ornithorhynchus anatinus) and the short-beaked echidna (Tachyglossus aculeatus). The distribution of cholinergic cells in the brain of these two species was virtually identical. Distinct groups of cholinergic cells were observed in the striatum, basal forebrain, habenula, pontomesencephalon, cranial nerve motor nuclei, and spinal cord. In contrast to other tetrapods studied with this technique, we failed to find evidence for cholinergic cells in the hypothalamus, the parabigeminal nucleus (or nucleus isthmus), or the cerebral cortex. The lack of hypothalamic cholinergic neurons creates a hiatus in the continuous antero-posterior aggregation of cholinergic neurons seen in other tetrapods. This hiatus might be functionally related to the phenomenology of monotreme sleep and to the ontogeny of sleep in mammals, as juvenile placental mammals exhibit a similar combination of sleep elements to that found in adult monotremes. PMID:12476054

  5. Effects of 12-Week Bacopa monnieri Consumption on Attention, Cognitive Processing, Working Memory, and Functions of Both Cholinergic and Monoaminergic Systems in Healthy Elderly Volunteers

    Directory of Open Access Journals (Sweden)

    Tatimah Peth-Nui

    2012-01-01

    Full Text Available At present, the scientific evidence concerning the effect of Bacopa monnieri on brain activity together with working memory is less available. Therefore, we aimed to determine the effect of B. monnieri on attention, cognitive processing, working memory, and cholinergic and monoaminergic functions in healthy elderly. A randomized double-blind placebo-controlled design was utilized. Sixty healthy elderly subjects (mean age 62.62 years; SD 6.46, consisting of 23 males and 37 females, received either a standardized extract of B. monnieri (300 and 600 mg or placebo once daily for 12 weeks. The cholinergic and monoaminergic systems functions were determined using AChE and MAO activities. Working memory was assessed using percent accuracy and reaction time of various memory tests as indices, whereas attention and cognitive processing were assessed using latencies and amplitude of N100 and P300 components of event-related potential. All assessments were performed before treatment, every four weeks throughout study period, and at four weeks after the cessation of intervention. B. monnieri-treated group showed improved working memory together with a decrease in both N100 and P300 latencies. The suppression of plasma AChE activity was also observed. These results suggest that B. monnieri can improve attention, cognitive processing, and working memory partly via the suppression of AChE activity.

  6. Spontaneous Synaptic Activation of Muscarinic Receptors by Striatal Cholinergic Neuron Firing.

    Science.gov (United States)

    Mamaligas, Aphroditi A; Ford, Christopher P

    2016-08-01

    Cholinergic interneurons (CHIs) play a major role in motor and learning functions of the striatum. As acetylcholine does not directly evoke postsynaptic events at most striatal synapses, it remains unclear how postsynaptic cholinergic receptors encode the firing patterns of CHIs in the striatum. To examine the dynamics of acetylcholine release, we used optogenetics and paired recordings from CHIs and medium spiny neurons (MSNs) virally overexpressing G-protein-activated inwardly rectifying potassium (GIRK) channels. Due to the efficient coupling between endogenous muscarinic receptors and GIRK channels, we found that firing of individual CHIs resulted in monosynaptic spontaneous inhibitory post-synaptic currents (IPSCs) in MSNs. Paired CHI-MSN recordings revealed that the high probability of acetylcholine release at these synapses allowed muscarinic receptors to faithfully encode physiological activity patterns from individual CHIs without failure. These results indicate that muscarinic receptors in striatal output neurons reliably decode CHI firing. PMID:27373830

  7. Augmentation of cholinergic-mediated amylase release by forskolin in mouse parotid gland

    International Nuclear Information System (INIS)

    Cholinergic-mediated amylase release in mouse parotid acini was augmented by forskolin; the potency but not the maximal response to carbachol was altered. Amylase released by carbachol plus forskolin was dependent on extracellular calcium and was mimicked by the calcium ionophore, A23187 plus forskolin. Forskolin was also shown to enhance carbachol-stimulated 45Ca2+ uptake into isolated acini. Hydroxylamine, nitroprusside, and 8-bromo-c-GMP each in combination with forskolin mimicked the effects of carbachol plus forskolin on amylase release. In the presence of carbachol (10-8M) forskolin did not augment c-AMP levels. However, in the presence of carbachol (5 x 10-7 M) or hydroxylamine (50 μM) forskolin did significantly augment c-AMP accumulation. These results suggest that calcium and c-GMP may mediate the augmentation of cholinergic-mediated amylase release by effects on c-AMP metabolism. 21 references, 1 figure, 3 tables

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

    Science.gov (United States)

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

    1987-01-01

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

  9. Uranium chronic contamination effects on the cholinergic system: in vivo and in vitro approaches

    International Nuclear Information System (INIS)

    Uranium (U) is a heavy metal which occurs naturally in the environment. It is both a chemical and a radiological toxicant. The aim of this work was: (i) to assess the effects of U chronic exposure on the cholinergic system (biosynthesis and breakdown enzymes, receptors and on behaviour of adult, young or predisposed to neuro-degenerative illness (ApoE KO) rodents; (ii) to grasp the neurotoxic effects of U on human neuronal cells. In vivo, this work shows a structure- (cortex more sensitive than hippocampus), rodent model- (young more sensitive than adults), time- (sub-chronic exposure more harmful than chronic exposure), exposure level- and isotope-dependent effect of U. In vitro, the study underlined the neuro-cytotoxic U potential and the presence of uranium precipitates in cells. These results show the deleterious impact of U on neuronal cells, and demonstrate that U induces impairments on the cholinergic system and the behaviour of rodents. (author)

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

    Directory of Open Access Journals (Sweden)

    Zheng Cheng

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

  11. Attention, prediction and sequence learning : roles of the cholinergic basal forebrain and the retrosplenial cortex

    OpenAIRE

    Córdova, Christopher Andy

    2005-01-01

    Our ability to foresee and shape biologically important events relies on a combination of visuospatial attention, memory capacities, and an ability to learn new sequences of goal-directed action. A novel set of behavioral studies were conducted to investigate neurobiological processes that underlie selective attention and visuospatial sequence learning. The first experiment assessed a theorized computational role of basal forebrain cholinergic neurons in modulating attention by increasing sti...

  12. 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.

  13. Gut feeling: MicroRNA discriminators of the intestinal TLR9-cholinergic links.

    Science.gov (United States)

    Nadorp, Bettina; Soreq, Hermona

    2015-11-01

    The intestinal tissue notably responds to stressful, cholinergic and innate immune signals by microRNA (miRNA) changes, but whether and how those miRNA regulators modify the intestinal cholinergic and innate immune pathways remained unexplored. Here, we report changes in several miRNA regulators of cholinesterases (ChEs) and correspondingly modified ChE activities in intestine, splenocytes and the circulation of mice exposed to both stress and canonical or alternative Toll-Like Receptor 9 (TLR9) oligonucleotide (ODN) aptamer activators or blockers. Stressful intraperitoneal injection of saline, the anti-inflammatory TLR9 agonist mEN101 aptamer or the inflammation-activating TLR9 aptamer ODN 1826 all increased the expression of the acetylcholinesterase (AChE)-targeting miR-132. In comparison, mEN101 but neither ODN 1826 nor saline injections elevated intestinal miR-129-5p, miR-186 and miR-200c, all predicted to target both AChE and the homologous enzyme butyrylcholinesterase (BChE). In cultured immune cells, BL-7040, the human counterpart of mEN101, reduced AChE activity reflecting inflammatory reactions in a manner preventable by the TLR9 blocking ODN 2088. Furthermore, the anti-inflammatory BL-7040 TLR9 aptamer caused reduction in nitric oxide and AChE activity in both murine splenocytes and human mononuclear cells at molar concentrations four orders of magnitude lower than ODN 1826. Our findings demonstrate differential reaction of cholinesterase-targeting miRNAs to distinct TLR9 challenges, indicating upstream miRNA co-regulation of the intestinal alternative NFκB pathway and cholinergic signaling. TLR9 aptamers may hence potentiate miRNA regulation that enhances cholinergic signaling and the resolution of inflammation, which opens new venues for manipulating bowel diseases. PMID:26003847

  14. Disruption of cholinergic neurotransmission exacerbates Aβ-related cognitive impairment in preclinical Alzheimer's disease.

    Science.gov (United States)

    Lim, Yen Ying; Maruff, Paul; Schindler, Rachel; Ott, Brian R; Salloway, Stephen; Yoo, Don C; Noto, Richard B; Santos, Cláudia Y; Snyder, Peter J

    2015-10-01

    Disruption in cholinergic neurotransmission is one of the earliest neuropathological changes in preclinical Alzheimer's disease (AD) and may be associated with abnormal beta-amyloid (Aβ) accumulation. Therefore, disruption of cholinergic neurotransmission with scopolamine may unmask otherwise undetectable cognitive deficits in preclinical AD. To compare the effects of low-dose (0.20 mg s.c.) scopolamine on cognition between Aβ+ and Aβ- cognitively normal (CN) older adults using the Groton Maze Learning Test (GMLT). CN older adults completed the GMLT predose and then received scopolamine (0.20 mg) subcutaneously. Participants were reassessed 1-, 3-, 5-, 7-, and 8-hours post dose. All participants underwent positron emission tomography neuroimaging for Aβ using (18)F-florbetapir within 6 weeks of their baseline visit. Rhode Island Hospital Clinical Research Center, Providence, USA. CN older adults (n = 63), with a family history of AD and subjective memory complaints were enrolled (15 were classified as Aβ+ and 48 were classified as Aβ-). Cognition was assessed using the computerized GMLT at all predose and post-dose time points. At 5-hours post dose, the Aβ+ group performed significantly worse than the Aβ- group on all measures of learning efficiency and working memory and/or executive function (Cohen's d = 1.13-1.56). When participants were classified as having an abnormal response to scopolamine (based on change score at 5-hours post dose >0), 100% were correctly classified as Aβ+ and 67% as Aβ-. The results of this study suggest that diminished cholinergic tone likely occurs in preclinical AD, and as such, the use of a cholinergic stress test to perturb an already compromised neurotransmitter system may be an effective way of identifying CN older adults who are in this preclinical stage of AD. PMID:26233262

  15. Impairment of reward-related learning by cholinergic cell ablation in the striatum

    OpenAIRE

    Kitabatake, Yasuji; Hikida, Takatoshi; Watanabe, Dai; Pastan, Ira; Nakanishi, Shigetada

    2003-01-01

    The striatum in the basal ganglia-thalamocortical circuitry is a key neural substrate that is implicated in motor balance and procedural learning. The projection neurons in the striatum are dynamically modulated by nigrostriatal dopaminergic input and intrastriatal cholinergic input. The role of intrastriatal acetylcholine (ACh) in learning behaviors, however, remains to be fully clarified. In this investigation, we examine the involvement of intrastriatal ACh in different categories of...

  16. Nerve growth factor protects cholinergic neurons against quinolinic acid-induced excitotoxicity in wistar rats

    OpenAIRE

    Vasiljević Ivana D.; Jovanović Marina D.; Čolić Miodrag J.; Mićić D.; Ninković Milica; Maličević Živorad

    2004-01-01

    The etiology of neuronal death in neurodegenerative diseases, including Huntington's disease (HD) is still unknown. There could be a complex interplay between altered energy metabolism, excitotoxicity and oxidative stress. Excitotoxic striatal lesions induced by quinolinic acid (QA), were used to test for the neuroprotective actions of nerve growth factor (NGF) on striatal cholinergic and GABAergic neurons. QA is an endogenous excitotoxin acting on N-methyl-D-aspartate (NMDA) rec...

  17. Effectiveness of nootropic drugs with cholinergic activity in treatment of cognitive deficit: a review

    OpenAIRE

    Colucci, Luisa; Bosco, Massimiliano; Rosario Ziello, Antonio; Rea, Raffaele; Amenta, Francesco; Fasanaro, Angiola Maria

    2012-01-01

    Nootropics represent probably the first “smart drugs” used for the treatment of cognitive deficits. The aim of this paper is to verify, by a systematic analysis of the literature, the effectiveness of nootropics in this indication. The analysis was limited to nootropics with cholinergic activity, in view of the role played by acetylcholine in learning and memory. Acetylcholine was the first neurotransmitter identified in the history of neuroscience and is the main neurotransmitter of the peri...

  18. Muscarinic cholinergic receptor (M2) plays a crucial role in the development of myopia in mice

    OpenAIRE

    Barathi, Veluchamy A.; Kwan, Jia Lin; Tan, Queenie S. W.; Weon, Sung Rhan; Seet, Li Fong; Goh, Liang Kee; Vithana, Eranga N.; Beuerman, Roger W.

    2013-01-01

    SUMMARY Myopia is a huge public health problem worldwide, reaching the highest incidence in Asia. Identification of susceptible genes is crucial for understanding the biological basis of myopia. In this paper, we have identified and characterized a functional myopia-associated gene using a specific mouse-knockout model. Mice lacking the muscarinic cholinergic receptor gene (M2 ; also known as Chrm2) were less susceptible to lens-induced myopia compared with wild-type mice, which showed signif...

  19. Muscarinic cholinergic receptor (M2) plays a crucial role in the development of myopia in mice

    OpenAIRE

    Barathi, Veluchamy A.; Jia Lin Kwan; Tan, Queenie S. W.; Sung Rhan Weon; Li Fong Seet; Liang Kee Goh; Vithana, Eranga N.; Beuerman, Roger W.

    2013-01-01

    SUMMARY Myopia is a huge public health problem worldwide, reaching the highest incidence in Asia. Identification of susceptible genes is crucial for understanding the biological basis of myopia. In this paper, we have identified and characterized a functional myopia-associated gene using a specific mouse-knockout model. Mice lacking the muscarinic cholinergic receptor gene (M2; also known as Chrm2) were less susceptible to lens-induced myopia compared with wild-type mice, which showed sign...

  20. Cholinergic degeneration and memory loss delayed by vitamin E in a Down syndrome mouse model

    OpenAIRE

    Lockrow, Jason; Prakasam, Annamalai; Huang, Peng; Bimonte-Nelson, Heather; Sambamurti, Kumar; Granholm, Ann-Charlotte

    2008-01-01

    Down syndrome (DS) individuals develop several neuropathological hallmarks seen in Alzheimer's disease, including cognitive decline and the early loss of cholinergic markers in the basal forebrain. These deficits are replicated in the Ts65Dn mouse, which contains a partial trisomy of murine chromosome 16, the orthologous genetic segment to human chromosome 21. Oxidative stress levels are elevated early in DS, and may contribute to the neurodegeneration seen in these individuals. We evaluated ...

  1. Presenilin-1 Mutation Impairs Cholinergic Modulation of Synaptic Plasticity and Suppresses NMDA Currents in Hippocampus slices

    OpenAIRE

    Wang, Yue; Greig, Nigel H.; Yu, Qian-Sheng; Mattson, Mark P.

    2008-01-01

    Presenilin-1 (PS1) mutations cause many cases of early-onset inherited Alzheimer's disease, in part, by increasing the production of neurotoxic forms of amyloid β-peptide (A β). However, Aβ -independent effects of mutant PS1 on neuronal Ca2+ homeostasis and sensitivity to excitatory neurotransmitters have been reported. Here we show that cholinergic modulation of hippocampal synaptic plasticity is impaired in PS1 mutant knockin (PS1KI) mice. Whereas activation of muscarinic receptors enhances...

  2. Novel information on the non-neuronal cholinergic system in orthopedics provides new possible treatment strategies for inflammatory and degenerative diseases

    Directory of Open Access Journals (Sweden)

    Sture Forsgren

    2009-07-01

    Full Text Available Anti-cholinergic agents are used in the treatment of several pathological conditions. Therapy regimens aimed at up-regulating cholinergic functions, such as treatment with acetylcholinesterase inhibitors, are also currently prescribed. It is now known that not only is there a neuronal cholinergic system but also a non-neuronal cholinergic system in various parts of the body. Therefore, interference with the effects of acetylcholine (ACh brought about by the local production and release of ACh should also be considered. Locally produced ACh may have proliferative, angiogenic, wound-healing, and immunomodulatory functions. Interestingly, cholinergic stimulation may lead to anti-inflammatory effects. Within this review, new findings for the locomotor system of a more widespread non-neuronal cholinergic system than previously expected will be discussed in relation to possible new treatment strategies. The conditions discussed are painful and degenerative tendon disease (tendinopathy/tendinosis, rheumatoid arthritis, and osteoarthritis.

  3. 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.

  4. 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. PMID:27260186

  5. 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.

  6. [Bowel obstruction-induced cholinergic crisis with progressive respiratory failure following distigmine bromide treatment].

    Science.gov (United States)

    Kobayashi, Kazuki; Sekiguchi, Hiroshi; Sato, Nobuhiro; Hirose, Yasuo

    2016-03-01

    A 54-year-old female experienced rapid respiratory failure while being transported in an ambulance to our emergency department for evaluation and management of constipation and abdominal pain. The patient was on treatment with distigmine bromide for postoperative urination disorder and magnesium oxide for constipation. Increased salivary secretions, diminished respiratory excursion, type 2 respiratory failure (PaCO2 : 65 mmHg), low serum cholinesterase, and hypermagnesemia were detected. Imaging studies revealed that the patient had bilateral aspiration pneumonia, fecal impaction in the rectum, and a distended colon causing ileus. The patient was mechanically ventilated and was weaned off the ventilator on day 3. Therapeutic drug monitoring after discharge revealed that the serum level of distigmine bromide on admission was markedly elevated (377.8 ng/mL vs. the normal therapeutic level of 5-10 ng/mL). Distigmine bromide induced a cholinergic crisis with a resultant increase in airway secretions and respiratory failure. In this particular case, orally administered distigmine bromide was excessively absorbed because of prolonged intestinal transit time secondary to fecal impaction and sluggish bowel movement; this caused a cholinergic crisis and hypermagnesemia contributing to respiratory failure. Clinicians should be aware that bowel obstruction in a patient treated with distigmine bromide can increase the risk of a cholinergic crisis. PMID:27255021

  7. Somatostatin inhibits cANP-mediated cholinergic transmission in the myenteric plexus

    International Nuclear Information System (INIS)

    The mechanism by which somatostatin acts to modulate cholinergic transmission is not clear. In this study the authors investigated the role of the adenosine 3',5'-cyclic monophosphate (cAMP) system in mediating cholinergic transmission in the guinea pig myenteric plexus and examined the ability of somatostatin to alter acetylcholine (ACh) release stimulated by various cAMP agonists. Forskolin, 8-bromo-cAMP, vasoactive intestinal peptide (VIP), and cholera toxin each stimulated the release of [3H]ACh in a dose-related manner. Addition of theophylline enhanced the release of [3H]ACh stimulated by these cAMP agonists. The observations suggest that cAMP may serve as a physiological mediator for ACh release from myenteric neurons. Somatostatin inhibited release of [3H]ACh evoked by various cAMP agonists in a dose-related manner. Pretreatment with pertussis toxin antagonized the inhibitory effect of somatostatin on the release of [3H]ACh evoked by forskolin, VIP, or cholera toxin but had no effect on the inhibitory action of somatostatin on the release of [3H]ACh evoked by 8-bromo-cAMP. This suggests that the principal mechanism by which somatostatin inhibits cAMP-mediated cholinergic transmission is via activation of the inhibitory regulatory protein (Ni subunit) of adenyalte cyclase

  8. Nitrergic ventro-medial medullary neurons activated during cholinergically induced active (rapid eye movement) sleep in the cat.

    Science.gov (United States)

    Pose, I; Sampogna, S; Chase, M H; Morales, F R

    2011-01-13

    The rostral ventro-medial medullary reticular formation is a complex structure that is involved with a variety of motor functions. It contains glycinergic neurons that are activated during active (rapid eye movement (REM)) sleep (AS); these neurons appear to be responsible for the postsynaptic inhibition of motoneurons that occurs during this state. We have reported that neurons in this same region contain nitric oxide (NO) synthase and that they innervate brainstem motor pools. In the present study we examined the c-fos expression of these neurons after carbachol-induced active sleep (C-AS). Three control and four experimental cats were employed to identify c-fos expressing nitrergic neurons using immunocytochemical techniques to detect the Fos protein together with neuronal nitric oxide synthase (nNOS) or nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase activity. The classical neurotransmitter content of the nitrergic cells in this region was examined through the combination of immunocytochemical techniques for the detection of glutamate, glycine, choline acetyltransferase (ChAT), tyrosine hydroxilase (TH) or GABA together with nNOS. During C-AS, there was a 1074% increase in the number of nitrergic neurons that expressed c-fos. These neurons did not contain glycine, ChAT, TH or GABA, but a subpopulation (15%) of them displayed glutamate-like immunoreactivity. Therefore, some of these neurons contain both an excitatory neurotransmitter (glutamate) and an excitatory neuromodulator (NO); the neurotransmitter content of the rest of them remains to be determined. Because some of the nitrergic neurons innervate brainstem motoneurons it is possible that they participate in the generation of tonic and excitatory phasic motor events that occur during AS. We also suggest that these nitrergic neurons may be involved in autonomic regulation during this state. In addition, because NO has trophic effects on target neurons, the present findings represent the

  9. Oral Administration of Gintonin Attenuates Cholinergic Impairments by Scopolamine, Amyloid-β Protein, and Mouse Model of Alzheimer’s Disease

    OpenAIRE

    Kim, Hyeon-Joong; Shin, Eun-Joo; Lee, Byung-Hwan; Choi, Sun-Hye; Jung, Seok-Won; Cho, Ik-Hyun; Hwang, Sung-Hee; Kim, Joon Yong; Han, Jung-Soo; Chung, ChiHye; Jang, Choon-Gon; Rhim, Hyewon; Kim, Hyoung-Chun; Nah, Seung-Yeol

    2015-01-01

    Gintonin is a novel ginseng-derived lysophosphatidic acid (LPA) receptor ligand. Oral administration of gintonin ameliorates learning and memory dysfunctions in Alzheimer’s disease (AD) animal models. The brain cholinergic system plays a key role in cognitive functions. The brains of AD patients show a reduction in acetylcholine concentration caused by cholinergic system impairments. However, little is known about the role of LPA in the cholinergic system. In this study, we used gintonin to i...

  10. 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.

  11. 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.

  12. Cholinergic Enhancement of Frontal Lobe Activity in Mild Cognitive Impairment

    Science.gov (United States)

    Saykin, Andrew J.; Wishart, Heather A.; Rabin, Laura A.; Flashman, Laura A.; McHugh, Tara L.; Mamourian, Alexander C.; Santulli, Robert B.

    2004-01-01

    Cholinesterase inhibitors positively affect cognition in Alzheimer's disease (AD) and other conditions, but no controlled functional MRI studies have examined where their effects occur in the brain. We examined the effects of donepezil hydrochloride (Aricept[Registered sign]) on cognition and brain activity in patients with amnestic mild cognitive…

  13. 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.

  14. Unilateral neuromodulation of the ventromedial hypothalamus of the rat through deep brain stimulation

    Science.gov (United States)

    Lehmkuhle, M. J.; Mayes, S. M.; Kipke, D. R.

    2010-06-01

    This study offers evidence that long-term deep brain stimulation of the ventromedial hypothalamus (VMH) can alter weight gain in mammals without affecting feeding behavior. Animals stimulated unilaterally at high frequencies of 150 or 500 Hz demonstrated increased CO2 production that decreased from prestimulation levels after the stimulation was removed. Animals stimulated for up to 6 weeks gained weight at a lower rate than normal animals or animals implanted with an electrode but not stimulated. Stimulated animals exhibited normal food and water consumption. A significant decrease in efficiency was observed during stimulation that coincided with an increase in the amount of feces produced. Whereas the weight of control animals was significantly different from week to week, the weight of stimulated animals did not change accordingly. These data suggest that the VMH may be a viable target for long-term deep brain stimulation for modulation of the neural mechanisms of metabolism. The potential therapeutic effects of deep brain stimulation of the hypothalamus are discussed.

  15. Integrated device for combined optical neuromodulation and electrical recording for chronic in vivo applications

    Science.gov (United States)

    Wang, Jing; Wagner, Fabien; Borton, David A.; Zhang, Jiayi; Ozden, Ilker; Burwell, Rebecca D.; Nurmikko, Arto V.; van Wagenen, Rick; Diester, Ilka; Deisseroth, Karl

    2012-02-01

    Studying brain function and its local circuit dynamics requires neural interfaces that can record and stimulate the brain with high spatiotemporal resolution. Optogenetics, a technique that genetically targets specific neurons to express light-sensitive channel proteins, provides the capability to control central nervous system neuronal activity in mammals with millisecond time precision. This technique enables precise optical stimulation of neurons and simultaneous monitoring of neural response by electrophysiological means, both in the vicinity of and distant to the stimulation site. We previously demonstrated, in vitro, the dual capability (optical delivery and electrical recording) while testing a novel hybrid device (optrode-MEA), which incorporates a tapered coaxial optical electrode (optrode) and a 100 element microelectrode array (MEA). Here we report a fully chronic implant of a new version of this device in ChR2-expressing rats, and demonstrate its use in freely moving animals over periods up to 8 months. In its present configuration, we show the device delivering optical excitation to a single cortical site while mapping the neural response from the surrounding 30 channels of the 6 × 6 element MEA, thereby enabling recording of optically modulated single-unit and local field potential activity across several millimeters of the neocortical landscape.

  16. Nuclear organization of cholinergic, catecholaminergic, serotonergic and orexinergic systems in the brain of the Tasmanian devil (Sarcophilus harrisii).

    Science.gov (United States)

    Patzke, Nina; Bertelsen, Mads F; Fuxe, Kjell; Manger, Paul R

    2014-11-01

    This study investigated the nuclear organization of four immunohistochemically identifiable neural systems (cholinergic, catecholaminergic, serotonergic and orexinergic) within the brains of three male Tasmanian devils (Sarcophilus harrisii), which had a mean brain mass of 11.6g. We found that the nuclei generally observed for these systems in other mammalian brains were present in the brain of the Tasmanian devil. Despite this, specific differences in the nuclear organization of the cholinergic, catecholaminergic and serotonergic systems appear to carry a phylogenetic signal. In the cholinergic system, only the dorsal hypothalamic cholinergic nucleus could be observed, while an extra dorsal subdivision of the laterodorsal tegmental nucleus and cholinergic neurons within the gelatinous layer of the caudal spinal trigeminal nucleus were observed. Within the catecholaminergic system the A4 nucleus of the locus coeruleus complex was absent, as was the caudal ventrolateral serotonergic group of the serotonergic system. The organization of the orexinergic system was similar to that seen in many mammals previously studied. Overall, while showing strong similarities to the organization of these systems in other mammals, the specific differences observed in the Tasmanian devil reveal either order specific, or class specific, features of these systems. Further studies will reveal the extent of change in the nuclear organization of these systems in marsupials and how these potential changes may affect functionality. PMID:25150966

  17. Cholinergic activation enhances retinoic acid-induced differentiation in the human NB-4 acute promyelocytic leukemia cell line.

    Science.gov (United States)

    Chotirat, Sadudee; Suriyo, Tawit; Hokland, Marianne; Hokland, Peter; Satayavivad, Jutamaad; Auewarakul, Chirayu U

    2016-07-01

    The non-neuronal cholinergic system (NNCS) has been shown to play a role in regulating hematopoietic differentiation. We determined the expression of cholinergic components in leukemic cell lines by Western blotting and in normal leukocyte subsets by flow cytometry and found a heterogeneous expression of choline acetyltransferase (ChAT), acetylcholinesterase (AChE), choline transporter (CHT), M3 muscarinic acetylcholine receptor (M3-mAChR) and α7 nicotinic acetylcholine receptor (α7-nAChR). We then evaluated NNCS role in differentiation of human NB-4 acute promyelocytic leukemia cell line and discovered a dramatic induction of M3-mAChR after all-trans retinoic acid (ATRA) treatment (p<0.0001). Adding carbachol which is a cholinergic agonist to the ATRA treatment resulted in an increase of a granulocytic differentiation marker (CD11b) as compared with ATRA treatment alone (p<0.05), indicating that cholinergic activation enhanced ATRA in inducing NB-4 maturation. The combination of carbachol and ATRA treatment for 72h also resulted in decreased viability and increased cleaved caspase-3 expression when compared with ATRA treatment alone (p<0.05). However, this combination did not cause poly (ADP-ribose) polymerase (PARP) cleavage. Overall, we have shown that NB-4 cells expressed M3-mAChR in a differentiation-dependent manner and cholinergic stimulation induced maturation and death of ATRA-induced differentiated NB-4 cells. PMID:27282572

  18. Elimination of the vesicular acetylcholine transporter in the striatum reveals regulation of behaviour by cholinergic-glutamatergic co-transmission.

    Science.gov (United States)

    Guzman, Monica S; De Jaeger, Xavier; Raulic, Sanda; Souza, Ivana A; Li, Alex X; Schmid, Susanne; Menon, Ravi S; Gainetdinov, Raul R; Caron, Marc G; Bartha, Robert; Prado, Vania F; Prado, Marco A M

    2011-11-01

    Cholinergic neurons in the striatum are thought to play major regulatory functions in motor behaviour and reward. These neurons express two vesicular transporters that can load either acetylcholine or glutamate into synaptic vesicles. Consequently cholinergic neurons can release both neurotransmitters, making it difficult to discern their individual contributions for the regulation of striatal functions. Here we have dissected the specific roles of acetylcholine release for striatal-dependent behaviour in mice by selective elimination of the vesicular acetylcholine transporter (VAChT) from striatal cholinergic neurons. Analysis of several behavioural parameters indicates that elimination of VAChT had only marginal consequences in striatum-related tasks and did not affect spontaneous locomotion, cocaine-induced hyperactivity, or its reward properties. However, dopaminergic sensitivity of medium spiny neurons (MSN) and the behavioural outputs in response to direct dopaminergic agonists were enhanced, likely due to increased expression/function of dopamine receptors in the striatum. These observations indicate that previous functions attributed to striatal cholinergic neurons in spontaneous locomotor activity and in the rewarding responses to cocaine are mediated by glutamate and not by acetylcholine release. Our experiments demonstrate how one population of neurons can use two distinct neurotransmitters to differentially regulate a given circuitry. The data also raise the possibility of using VAChT as a target to boost dopaminergic function and decrease high striatal cholinergic activity, common neurochemical alterations in individuals affected with Parkinson's disease. PMID:22087075

  19. Elimination of the vesicular acetylcholine transporter in the striatum reveals regulation of behaviour by cholinergic-glutamatergic co-transmission.

    Directory of Open Access Journals (Sweden)

    Monica S Guzman

    2011-11-01

    Full Text Available Cholinergic neurons in the striatum are thought to play major regulatory functions in motor behaviour and reward. These neurons express two vesicular transporters that can load either acetylcholine or glutamate into synaptic vesicles. Consequently cholinergic neurons can release both neurotransmitters, making it difficult to discern their individual contributions for the regulation of striatal functions. Here we have dissected the specific roles of acetylcholine release for striatal-dependent behaviour in mice by selective elimination of the vesicular acetylcholine transporter (VAChT from striatal cholinergic neurons. Analysis of several behavioural parameters indicates that elimination of VAChT had only marginal consequences in striatum-related tasks and did not affect spontaneous locomotion, cocaine-induced hyperactivity, or its reward properties. However, dopaminergic sensitivity of medium spiny neurons (MSN and the behavioural outputs in response to direct dopaminergic agonists were enhanced, likely due to increased expression/function of dopamine receptors in the striatum. These observations indicate that previous functions attributed to striatal cholinergic neurons in spontaneous locomotor activity and in the rewarding responses to cocaine are mediated by glutamate and not by acetylcholine release. Our experiments demonstrate how one population of neurons can use two distinct neurotransmitters to differentially regulate a given circuitry. The data also raise the possibility of using VAChT as a target to boost dopaminergic function and decrease high striatal cholinergic activity, common neurochemical alterations in individuals affected with Parkinson's disease.

  20. 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

    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...... 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...

  1. 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

  2. The effect of prenatal gamma irradiation on the cholinergic enzymes of the brain in the 30-day-old squirrel monkey

    International Nuclear Information System (INIS)

    The effect of prenatal 60Co irradiation (10 and 100 rad) on the activity of the enzymes choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) in brains of 30-day-old squirrel monkeys was investigated. In the 100 rad group, there was a statistically significant increase in both enzyme activities in the visual and somatosensory cortex, the hippocampus and the caudate; a similar trend was observed in the motor, auditory and frontal cortical areas, the cerebellum and the thalamus. ChAT activity increased 32% more in the hippocampus and 23% more in the caudate than did AChE. Thus the ratio of degradation to synthesis of acetylcholine decreased significantly in these two areas. The 10-rad group showed no significant differences from the controls in any of the brain areas tested but this does not exclude the possibility that low dose effects on cholinergic enzymes may be apparent in a younger foetus. (U.K.)

  3. The value and cost of complexity in predictive modelling: role of tissue anisotropic conductivity and fibre tracts in neuromodulation

    Science.gov (United States)

    Salman Shahid, Syed; Bikson, Marom; Salman, Humaira; Wen, Peng; Ahfock, Tony

    2014-06-01

    . Significance. Results illustrate the need to rationally balance the role of model complexity, such as anisotropy in detailed current flow analysis versus value in clinical dose design. However, when extending our analysis to include axonal polarization, the results provide presumably clinically meaningful information. Hence the importance of model complexity may be more relevant with cellular level predictions of neuromodulation.

  4. Cytochemical demonstration of cholinergic, serotoninergic and peptidergic nerve elements in Gorgoderina vitelliloba (Trematoda: Digenea).

    Science.gov (United States)

    McKay, D M; Halton, D W; Johnston, C F; Fairweather, I; Shaw, C

    1991-02-01

    Standard enzyme cytochemical and indirect immunocytochemical techniques have been used in conjunction with light and confocal scanning laser microscopy (CSLM) to visualize cholinergic, serotoninergic and peptidergic nerve elements in whole-mount preparations of the amphibian urinary-bladder fluke, Gorgoderina vitelliloba. Cholinesterase (ChE) activity was localized in paired anterior ganglia, a connecting dorsal commissure and in the origins of the ventral nerve cords. Cholinergic ganglia were also evident in shelled embryos in the uterus. Serotonin-immunoreactivity (IR) was more extensive than ChE activity and was identified in both the central and peripheral nervous systems. Serotoninergic nerve fibres were associated with the somatic musculature and female reproductive ducts. Antisera to nine mammalian peptides and one invertebrate (FMRFamide) peptide have been used to investigate the peptidergic nervous system in the parasite. Immunoreactivity was obtained to five peptides, namely pancreatic polypeptide (PP), peptide YY (PYY), neuropeptide Y (NPY), substance P (SP) and FMRFamide. Peptidergic nerve fibres were found to be more abundant than demonstrable cholinergic or serotoninergic nerve fibres. NPY-IR was identified only in the main components of the central nervous system. However, PP- and PYY-IR occurred in the anterior ganglia, dorsal commissure, main nerve cords and in numerous small varicose fibres that ramified throughout the worm. Additionally, PP-immunoreactive nerve fibres were found to innervate the musculature of the female reproductive tracts. Six sites of IR were found in the acetabulum, using antisera directed towards the C-terminal end of PP and PYY, and these matched with the distribution of six non-ciliated rosette-like papillae observed by scanning electron microscopy. SP- and FMRFamide-IR were identified in the CNS, and FMRFamide-immunopositive nerve fibres were also evident in association with the gonopore cirrus region and with the

  5. Developmental alterations of the septohippocampal cholinergic projection in a lissencephalic mouse model.

    Science.gov (United States)

    Garcia-Lopez, Raquel; Pombero, Ana; Dominguez, Eduardo; Geijo-Barrientos, Emilio; Martinez, Salvador

    2015-09-01

    LIS1 is one of principal genes related with Type I lissencephaly, a severe human brain malformation characterized by abnormal neuronal migration in the cortex. The LIS1 gene encodes a brain-specific 45kDa non-catalytic subunit of platelet-activating factor (PAF) acetylhydrolase-1b (PAFAH1b), an enzyme that inactivates the PAF. We have studied the role of Lis1 using a Lis1/sLis1 murine model, which has deleted the first coding exon from Lis1 gene. Homozygous mice are not viable but heterozygous have shown a delayed corticogenesis and neuronal dysplasia, with enhanced cortical excitability. Lis1/sLis1 embryos also exhibited a delay of cortical innervation by the thalamocortical fibers. We have explored in Lis1/sLis1 mice anomalies in forebrain cholinergic neuron development, which migrate from pallium to subpallium, and functionally represent the main cholinergic input to the cerebral cortex, modulating cortical activity and facilitating attention, learning, and memory. We hypothesized that primary migration anomalies and/or disorganized cortex could affect cholinergic projections from the basal forebrain and septum in Lis1/sLis1 mouse. To accomplish our objective we have first studied basal forebrain neurons in Lis1/sLis1 mice during development, and described structural and hodological differences between wild-type and Lis1/sLis1 embryos. In addition, septohippocampal projections showed altered development in mutant embryos. Basal forebrain abnormalities could contribute to hippocampal excitability anomalies secondary to Lis1 mutations and may explain the cognitive symptoms associated to cortical displasia-related mental diseases and epileptogenic syndromes. PMID:26079645

  6. Characterization of a novel mechanism accounting for the adverse cholinergic effects of the anticancer drug irinotecan

    Science.gov (United States)

    Blandizzi, Corrado; De Paolis, Barbara; Colucci, Rocchina; Lazzeri, Gloria; Baschiera, Fabio; Del Tacca, Mario

    2001-01-01

    This study investigates the mechanisms accounting for the adverse cholinergic effects of the antitumour drug irinotecan. The activity of irinotecan and its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), was assayed in models suitable for pharmacological studies on cholinergic system. Irinotecan moderately inhibited human or electric eel acetylcholinesterase activity, SN-38 had no effect, whereas physostigmine blocked both the enzymes with high potency and efficacy. Irinotecan and SN-38 did not affect spontaneous or electrically-induced contractile activity of human colonic muscle. Acetylcholine and dimethylphenylpiperazinium (DMPP) caused phasic contractions or relaxations, respectively. Physostigmine enhanced the motor responses elicited by electrical stimulation. Although irinotecan and SN-38 did not modify the basal contractile activity of guinea-pig ileum longitudinal muscle strips, irinotecan 100 μM moderately enhanced cholinergic twitch contractions. Acetylcholine or DMPP caused phasic contractions, whereas physostigmine enhanced the twitch responses. Electrically-induced [3H]-acetylcholine release was reduced by irinotecan (100 μM) or physostigmine (0.1 μM). Intravenous irinotecan stimulated gastric acid secretion in rats, but no effects were obtained with SN-38, physostigmine or i.c.v. irinotecan. Hypersecretion induced by irinotecan was partly prevented by ondansetron, and unaffected by capsazepine. In the presence of atropine, vagotomy and systemic or vagal ablation of capsaicin-sensitive afferent fibres, irinotecan did not stimulate gastric secretion. The present results indicate that irinotecan and SN-38 do not act as specific acetylcholinesterase blockers or acetylcholine receptor agonists. It is rather suggested that irinotecan promotes a parasympathetic discharge to peripheral organs, mediated by capsaicin-sensitive vagal afferent fibres, and that serotonin 5-HT3 receptors are implicated in the genesis of vago-vagal reflex

  7. The cholinergic system in the olfactory center of the terrestrial slug Limax.

    Science.gov (United States)

    Matsuo, Ryota; Kobayashi, Suguru; Wakiya, Kyoko; Yamagishi, Miki; Fukuoka, Masayuki; Ito, Etsuro

    2014-09-01

    Acetylcholine plays various important roles in the central nervous system of invertebrates as well as vertebrates. In the olfactory center of the terrestrial slug Limax, the local field potential (LFP) oscillates, and the change in its oscillatory frequency is thought to correlate with the detection of odor that potentially changes an ongoing behavior of the animal. Acetylcholine is known to upregulate the frequency of the LFP oscillation, and is one of the candidates for the neurotransmitters that are involved in such higher cognitive functions. However, there have been no histological data on the cholinergic system in gastropods, nor are there data on the receptors that are responsible for the upregulation of the oscillatory frequency of LFP due to the lack of analytical tools (such as antibodies or cDNA sequence information on cholinergic system-related genes). Here we cloned the cDNAs of choline acetyltransferase (ChAT), acetylcholinesterase, vesicular acetylcholine transporter, and several nicotinic acetylcholine receptors (nAChRs), and investigated their localization in the brain of Limax. We also generated a polyclonal antibody against ChAT to examine its localization, and investigated pharmacologically the involvement of nAChRs in the LFP oscillation. Our data showed: 1) dense distribution of the neurons expressing mRNAs of ChAT and vesicular acetylcholine transporter in the olfactory center; 2) spatially unique expression patterns of different nAChRs in the olfactory center; 3) involvement of nAChRs in the upregulation of the oscillation; 4) localization of ChAT protein in nerve fibers and/or terminals; and 5) the presence of cholinergic nerves in the tentacles. PMID:24523205

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

    Directory of Open Access Journals (Sweden)

    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.

  9. [The role of the basal forebrain cholinergic dysfunction in pathogenesis of declarative memory disorder in Alzheimer's disease].

    Science.gov (United States)

    Mukhin, V N

    2013-06-01

    Alzheimer's disease is the most common cause of the declarative memory disorder: 30-40% cases of dementia among all of age groups, and 50-60% among the people older 65 years. In addition, disorder of declarative memory is the genuine symptom of the disease, which certainly appears on early stage of the disease and it is an obligate diagnostic symptom. Proponents of the "cholinergic theory" of pathogenesis of Alzheimer's disease suggest that the basis disorder of declarative memory is cholinergic dysfunction. Several neurodynamic mechanisms associated with declarative memory depend on the level of acetylcholine in hippocampus and neocortex. It is believed that dysfunction of the basal cholinergic system in Alzheimer's disease leads to the impairment of these mechanisms. In this review, we summarize available literature data concerning the mechanisms of Alzheimer's disease. PMID:24459876

  10. Cholinergic component in the human pancreatic secretory response to intraintestinal oleate.

    OpenAIRE

    Valenzuela, J E; Lamers, C B; Modlin, I. M.; Walsh, J H

    1983-01-01

    To determine the role of cholinergic reflexes on pancreatic secretory response to food, we studied the effect of atropine on amylase secretion in response to the octapeptide of cholecystokinin (CCK8) and to intraintestinal oleate. Four studies were done in six healthy volunteers. The duodenal content was aspirated by a double lumen tube while synthetic secretin (41 pmol/kg/h) was infused as a background in all the studies. Graded doses of CCK8 IV or 0.42 M oleate pH 9.4 at 25 ml/h into the in...

  11. 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

  12. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  14. Impaired hippocampal acetylcholine release parallels spatial memory deficits in Tg2576 mice subjected to basal forebrain cholinergic degeneration

    DEFF Research Database (Denmark)

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

    2013-01-01

    (BFCD) in 3 months old male Tg2576 mice to co-express cholinergic degeneration with Aβ overexpression as these characteristics constitutes key hallmarks of AD. At 9 months, SAP lesioned Tg2576 mice were cognitively impaired in two spatial paradigms addressing working memory and mid to long-term memory...... cortex and the reduction was comparable between groups. Our results suggest that partial BFCD acts collectively with increased levels of Aβ to induce cognitive decline and to compromise cholinergic release. Tg2576 mice with BFCD may constitute a new and suitable AD mouse model to study the interrelations...

  15. Investigation of non-cholinergic acetylcholinesterase, and related peptides in an in vitro preparation of the substantia nigra

    OpenAIRE

    Whyte, Kathryn Antonia.; Greenfield, Susan.; Susan Greenfield

    2001-01-01

    The primary role of acetylcholinesterase (AChE) is hydrolysis of acetylcholine (ACh). However, observations by numerous groups have suggested that AChE may have non-cholinergic functions. Furthermore, developmental roles for AChE and its related enzyme, butyrylcholinesterase (BuChE), which is also capable of ACh hydrolysis, have been postulated. One line of evidence to support a non-cholinergic role for AChE is the apparent disparity in several brain areas between the distribu...

  16. 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].

  17. Maternal choline supplementation differentially alters the basal forebrain cholinergic system of young-adult Ts65Dn and disomic mice

    Science.gov (United States)

    Kelley, Christy M.; Powers, Brian E.; Velazquez, Ramon; Ash, Jessica A.; Ginsberg, Stephen D.; Strupp, Barbara J.; Mufson, Elliott J.

    2014-01-01

    Down syndrome (DS), trisomy 21, is a multifaceted condition marked by intellectual disability and early presentation of Alzheimer’s disease (AD) neuropathological lesions including degeneration of the basal forebrain cholinergic neuron (BFCN) system. While DS is diagnosable during gestation, there is no treatment option for expectant mothers or DS individuals. Using the Ts65Dn mouse model of DS that displays age-related degeneration of the BFCN system, we investigated the effects of maternal choline supplementation on the BFCN system in adult Ts65Dn mice and disomic (2N) littermates at 4.3–7.5 mos of age. Ts65Dn dams were maintained on a choline supplemented diet (5.1 g/kg choline chloride) or a control, unsupplemented diet with adequate amounts of choline (1 g/kg choline chloride) from conception until weaning of offspring; postweaning, offspring were fed the control diet. Mice were transcardially perfused with paraformaldehyde, brains were sectioned, and immunolabeled for choline acetyltransferase (ChAT) or p75-neurotrophin receptor (p75NTR). BFCN number and size, the area of the regions, and the intensity of hippocampal labeling were determined. Ts65Dn unsupplemented mice displayed region- and immunolabel-dependent increased BFCN number, larger areas, smaller BFCNs, and overall increased hippocampal ChAT intensity compared with 2N unsupplemented mice. These effects were partially normalized by maternal choline supplementation. Taken together, the results suggest a developmental imbalance in the Ts65Dn BFCN system. Early maternal-diet choline supplementation attenuates some of the genotype-dependent alterations in the BFCN system, suggesting this naturally occurring nutrient as a treatment option for pregnant mothers with knowledge that their offspring is trisomy 21. PMID:24178831

  18. In vivo PET imaging of brain nicotinic cholinergic receptors

    International Nuclear Information System (INIS)

    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 α4β2 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, [18F]fluoro-A-85380 (Dolle et al., 1999). The [18F]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 [ 18F]fluoro-A-85380 at a tracer dose, the distribution of the radioactivity in the brain reflect the distribution of the 18F]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 [18F]fluoro-A-85380 and to assess the quantification of its nAChRs binding in the human brain with PET (Gallezot et a., 2005). The [18F]fluoro-A-85380 was also used in epileptic patients to whom a mutation in the α4 or β2 nAChRs subunit have been identified. We found that, in these patients, the pattern of the brain distribution of the radiotracer was found different when compared to the healthy subjects

  19. Positron emission tomography (PET) studies of dopaminergic/cholinergic interactions in the baboon brain

    Energy Technology Data Exchange (ETDEWEB)

    Dewey, S.L.; Brodie, J.D.; Fowler, J.S.; MacGregor, R.R.; Schlyer, D.J.; King, P.T.; Alexoff, D.L.; Volkow, N.D.; Shiue, C.Y.; Wolf, A.P. (Brookhaven National Lab., Upton, NY (USA))

    1990-01-01

    Interactions between the dopaminergic D2 receptor system and the muscarinic cholinergic system in the corpus striatum of adult female baboons (Papio anubis) were examined using positron emission tomography (PET) combined with (18F)N-methylspiroperidol (( 18F)NMSP) (to probe D2 receptor availability) and (N-11C-methyl)benztropine (to probe muscarinic cholinergic receptor availability). Pretreatment with benztropine, a long-lasting anticholinergic drug, bilaterally reduced the incorporation of radioactivity in the corpus striatum but did not alter that observed in the cerebellum or the rate of metabolism of (18F)NMSP in plasma. Pretreatment with unlabelled NMSP, a potent dopaminergic antagonist, reduced the incorporation of (N-11C-methyl)benztropine in all brain regions, with the greatest effect being in the corpus striatum greater than cortex greater than thalamus greater than cerebellum, but did not alter the rate of metabolism of the labelled benztropine in the plasma. These reductions in the incorporation of either (18F)NMSP or (N-11C-methyl)benztropine exceeded the normal variation in tracer incorporation in repeated studies in the same animal. This study demonstrates that PET can be used as a tool for investigating interactions between neurochemically different yet functionally linked neurotransmitters systems in vivo and provides insight into the consequences of multiple pharmacologic administration.

  20. Antagonist of the amylin receptor blocks beta-amyloid toxicity in rat cholinergic basal forebrain neurons.

    Science.gov (United States)

    Jhamandas, Jack H; MacTavish, David

    2004-06-16

    Salvage of cholinergic neurons in the brain through a blockade of the neurotoxic effects of amyloidbeta protein (Abeta) is one of the major, but still elusive, therapeutic goals of current research in Alzheimer's disease (AD). To date, no receptor has been unequivocally identified for Abeta. Human amylin, which acts via a receptor composed of the calcitonin receptor-like receptor and a receptor-associated membrane protein, possesses amyloidogenic properties and has a profile of neurotoxicity that is strikingly similar to Abeta. In this study, using primary cultures of rat cholinergic basal forebrain neurons, we show that acetyl-[Asn30, Tyr32] sCT(8-37) (AC187), an amylin receptor antagonist, blocks Abeta-induced neurotoxicity. Treatment of cultures with AC187 before exposure to Abeta results in significantly improved neuronal survival as judged by MTT and live-dead cell assays. Quantitative measures of Abeta-evoked apoptotic cell death, using Hoechst and phosphotidylserine staining, confirm neuroprotective effects of AC187. We also demonstrate that AC187 attenuates the activation of initiator and effector caspases that mediate Abeta-induced apoptotic cell death. These data are the first to show that expression of Abeta toxicity may occur through the amylin receptor and suggest a novel therapeutic target for the treatment of AD. PMID:15201330

  1. Functions of adrenergic and cholinergic nerves in canine effectors of seminal emission.

    Science.gov (United States)

    Arver, S; Sjöstrand, N O

    1982-05-01

    Spontaneous activity responses to acetylcholine (ACh), adrenaline (A), noradrenaline (NA) and barium chloride as well as the effects of various autonomic drugs on effects of field stimulation of nerves and muscle cells of isolated pieces or strips of cauda epididymidis, vas deferens, ampulla ductus deferentis and prostate of dog were studied. The main results and conclusions are: the muscles show little spontaneous activity but rhythmicity can easily be produced by e.g. stimulating agonists. The muscles are contracted by alpha-adrenoceptor stimulants. ACh has usually no or a very weak contractile effect in high concentrations. Muscles of young dogs are more sensitive to ACh. The excitatory innervation of the muscles is adrenergic and completely blocked by adrenergic neuron blockers as well as alpha-adrenoceptor blocking drugs. Stimulation of adrenergic nerves leads to maximum response already at low frequencies (4-6 Hz). This response is very similar to that provoked by a supramaximal dose of NA. Scopolamine enhances neurogenic contractile effects while physostigmine suppresses them. Hence cholinergic nerves may act by muscarinic prejunctional inhibition of the excitatory adrenergic neurotransmission rather than act directly upon the smooth muscle cells. Since secretory cells receive cholinergic innervation prejunctional inhibition of the adrenergic myomotor nerves may be of functional significance in at least the long copulatory events of the dog. PMID:6127870

  2. Preclinical Evidence for a Role of the Nicotinic Cholinergic System in Parkinson's Disease.

    Science.gov (United States)

    Perez, Xiomara A

    2015-12-01

    One of the primary deficits in Parkinson's disease (PD) is the loss of dopaminergic neurons in the substantia nigra pars compacta which leads to striatal dopaminergic deficits that underlie the motor symptoms associated with the disease. A plethora of animal models have been developed over the years to uncover the molecular alterations that lead to PD development. These models have provided valuable information on neurotransmitter pathways and mechanisms involved. One such a system is the nicotinic cholinergic system. Numerous studies show that nigrostriatal damage affects nicotinic receptor-mediated dopaminergic signaling; therefore therapeutic modulation of the nicotinic cholinergic system may offer a novel approach to manage PD. In fact, there is evidence showing that nicotinic receptor drugs may be useful as neuroprotective agents to prevent Parkinson's disease progression. Additional preclinical studies also show that nicotinic receptor drugs may be beneficial for the treatment of L-dopa induced dyskinesias. Here, we review preclinical findings supporting the idea that nicotinic receptors are valuable therapeutic targets for PD. PMID:26553323

  3. Local infusion of interleukin-6 attenuates the neurotoxic effects of NMDA on rat striatal cholinergic neurons.

    Science.gov (United States)

    Toulmond, S; Vige, X; Fage, D; Benavides, J

    1992-09-14

    The potential neuroprotective effects of IL-6 against the excitotoxic neuronal loss induced by N-methyl-D-aspartate (NMDA) have been studied. Infusion into the rat striatum of excitotoxic amounts (250 nmol) of NMDA resulted in a 45% decrease in striatal choline acetyl transferase activity (ChAT; a marker of cholinergic neurons) and glutamate decarboxylase (GAD, a marker of GABAergic neurons) at 2 days post-injection. Co-infusion of 10 U of IL-6 reduced the loss of ChAT activity to 21% but failed to prevent the loss of GAD activity. IL-6 per se, up to the dose of 500 U, failed to affect ChAT or GAD activities. The in vivo effects of IL-6 are not mediated by a direct antagonism of NMDA toxicity, since IL-6 (up to a concentration of 500 and 5000 U/ml, respectively) did not antagonize either the increase in cyclic GMP levels resulting from NMDA receptor activation in cerebellar slices or the glutamate-induced release of lactate dehydrogenase, an index of neurotoxicity, by cultured cortical neurons. These results suggest that the increase in IL-6 levels observed in experimental brain lesions may play a role in the protection and regeneration of cholinergic neurons. PMID:1331914

  4. 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.

  5. 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.

  6. Targeting the Cholinergic System for Neuroprotection and/or Enhancement of Functional Recovery Following Neurotrauma.

    Science.gov (United States)

    Huber, Kathleen B G; Uteshev, Victor V; Pauly, James R

    2016-01-01

    Development of novel pharmacotherapies for the treatment of traumatic injury to the nervous system has been ongoing for over 40 years. Despite many promising compounds discovered using animal models, no treatments have successfully translated into the clinic. The central dogma in this field is that brain trauma initiates a complex chain of biochemical events leading to secondary brain damage and sustained neurological deficits. The delayed secondary brain injury is likely to result from multiple insults including oxidative stress, mitochondrial dysfunction, breakdown of the blood brain barrier, dysregulated release of glutamate, pro-inflammatory cytokines, and other mediators. However, therapies targeting these systems have generally met with failure in clinical trials. The purpose of this review is to summarize the models used for preclinical neurotrauma research, provide a brief overview of previous failed clinical trials in head and spinal cord injury, and finally, to review involvement of the cholinergic system and discuss implications for future research. Possibilities and pitfalls of targeting the cholinergic system for neuroprotection and/or enhancement of functional recovery are also discussed. PMID:26818862

  7. The potential of radioiodinated (-)-m-iodovesamicol for diagnosing cholinergic deficit dementia

    International Nuclear Information System (INIS)

    We investigated changes in the brain distribution of (-)-[125I]-m-iodovesamicol [(-)-[125I]mIV] in cholinergic denervation rats produced by a unilateral lesion of the nucleus basalis magnocellularis (NBM). Dual-tracer ex vivo autoradiographic analysis using (-)-[125I]mIV and [99mTc]HMPAO was conducted to the effect of regional cerebral perfusion on the brain distribution of (-)-[125I]mIV in a unilateral NBM-lesioned rat. (-)-[125I]mIV binding in the ipsilateral cortex to the lesion significantly reduced by 10.4 %, compared with that in the contralateral cortex, while (-)-[125I]mIV binding in the ipsilateral caudate putamen, hippocampus and thalamus did not change. The rate of reduction in the (-)-[125I]mIV binding (10.4 %) was significantly higher than that of [99mTc]HMPAO accumulation (4.0%) in the ipsilateral cortex to the lesion (P < 0.01). These results suggested that radioiodinated (-)-mIV may be useful in the study of dementia characterized by degeneration of the cholinergic neurotransmitter system, such as Alzheimer's disease

  8. 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.

  9. 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

  10. Electron microscopic localization of M2-muscarinic receptors in cholinergic and noncholinergic neurons of the laterodorsal tegmental and pedunculopontine nuclei of the rat mesopontine tegmentum.

    Science.gov (United States)

    Garzón, Miguel; Pickel, Virginia M

    2016-10-15

    Muscarinic m2 receptors (M2Rs) are implicated in autoregulatory control of cholinergic output neurons located within the pedunculopontine (PPT) and laterodorsal tegmental (LTD) nuclei of the mesopontine tegmentum (MPT). However, these nuclei contain many noncholinergic neurons in which activation of M2R heteroceptors may contribute significantly to the decisive role of the LTD and PPT in sleep-wakefulness. We examined the electron microscopic dual immunolabeling of M2Rs and the vesicular acetylcholine transporter (VAchT) in the MPT of rat brain to identify the potential sites for M2R activation. M2R immunogold labeling was predominately seen in somatodendritic profiles throughout the PPT/LTD complex. In somata, M2R immunogold particles were often associated with Golgi lamellae and cytoplasmic endomembrannes, but were rarely in contact with the plasma membrane, as was commonly seen in dendrites. Approximately 36% of the M2R-labeled somata and 16% of the more numerous M2R-labeled dendrites coexpressed VAchT. M2R and M2R/VAchT-labeled dendritic profiles received synapses from inhibitory- and excitatory-type axon terminals, over 88% of which were unlabeled and others contained exclusively M2R or VAchT immunoreactivity. In axonal profiles M2R immunogold was localized to plasmalemmal and cytoplasmic regions and showed a similar distribution in many VAchT-negative glial profiles. These results provide ultrastructural evidence suggestive of somatic endomembrane trafficking of M2Rs, whose activation serves to regulate the postsynaptic excitatory and inhibitory responses in dendrites of cholinergic and noncholinergic neurons in the MPT. They also suggest the possibility that M2Rs in this brain region mediate the effects of acetylcholine on the release of other neurotransmitters and on glial signaling. J. Comp. Neurol. 524:3084-3103, 2016. © 2016 Wiley Periodicals, Inc. PMID:27038330

  11. Effect of corticosterone and adrenalectomy on NMDA-induced cholinergic cell death in rat magnocellular nucleus basalis

    NARCIS (Netherlands)

    Abraham, [No Value; Veenema, AH; Nyakas, C; Harkany, T; Bohus, BGJ; Luiten, PGM; Ábrahám, I.

    1997-01-01

    The present study demonstrates the effects of adrenalectomy and subcutaneously administered corticosterone on N-methyl-D-aspartate-induced neurodegeneration in the cholinergic magnocellular basal nucleus of the rat, NMDA was unilaterally injected into the nucleus basalis at different plasma corticos

  12. Subtle learning and memory impairment in an idiopathic rat model of Alzheimer's disease utilizing cholinergic depletions and β-amyloid.

    Science.gov (United States)

    Deibel, S H; Weishaupt, N; Regis, A M; Hong, N S; Keeley, R J; Balog, R J; Bye, C M; Himmler, S M; Whitehead, S N; McDonald, R J

    2016-09-01

    Alzheimer's disease (AD) is a disease of complex etiology, involving multiple risk factors. When these risk factors are presented concomitantly, cognition and brain pathology are more severely compromised than if those risk factors were presented in isolation. Reduced cholinergic tone and elevated amyloid-beta (Aβ) load are pathological hallmarks of AD. The present study sought to investigate brain pathology and alterations in learning and memory when these two factors were presented together in rats. Rats received either sham surgeries, cholinergic depletions of the medial septum, intracerebroventricular Aβ25-35 injections, or both cholinergic depletion and Aβ25-35 injections (Aβ+ACh group). The Aβ+ACh rats were unimpaired in a striatal dependent visual discrimination task, but had impaired acquisition in the standard version of the Morris water task. However, these rats displayed normal Morris water task retention and no impairment in acquisition of a novel platform location during a single massed training session. Aβ+ACh rats did not have exacerbated brain pathology as indicated by activated astroglia, activated microglia, or accumulation of Aβ. These data suggest that cholinergic depletions and Aβ injections elicit subtle cognitive deficits when behavioural testing is conducted shortly after the presentation of these factors. These factors might have altered hippocampal synaptic plasticity and thus resemble early AD pathology. PMID:27208489

  13. 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. PMID:26620541

  14. 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.

  15. Cholinergic deafferentation of the hippocampus causes non-temporally graded retrograde amnesia in an odor discrimination task.

    Science.gov (United States)

    Köppen, Jenny R; Stuebing, Sarah L; Sieg, Megan L; Blackwell, Ashley A; Blankenship, Philip A; Cheatwood, Joseph L; Wallace, Douglas G

    2016-02-15

    Dementia of the Alzheimer's type (DAT) is a neurodegenerative disorder marked by loss of hippocampal cholinergic tone and significant memory impairments, specifically for memories acquired prior to disease onset. The nature of this relationship, however, remains debated. The current study used the string pulling task to evaluate the temporal effects of odor discrimination learning in animals with selective cholinergic lesions to determine the role of the septohippocampal cholinergic system in mnemonic function. Rats with 192-IgG-Saporin lesions to the medial septum had a higher number of correct responses in the reversal training when compared to sham rats, suggesting an inability to retrieve the previously learned discrimination; however, no temporal gradient was observed. Furthermore, there were no group differences when learning a novel odor discrimination, demonstrating the ability for all rats to form new memories. These results establish a role for the cholinergic medial septum projections in long-term memory retrieval. The current study provides a behavioral assessment technique to investigate factors that influence mnemonic deficits associated with rodent models of DAT. PMID:26611564

  16. 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.

  17. 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.

  18. Effect of lead on cholinergic contractile function in the forestomach, ileum and colon of the male Wistar rat

    Energy Technology Data Exchange (ETDEWEB)

    Ryden, E.B.

    1986-01-01

    Gastrointestinal symptoms, including colic, are signs of lead poisoning in man, but the mechanism of these effects has not been elucidated. In order to understand the effects of lead on acetylcholine (ACh)-mediated responses, studies were undertaken to determine the isometric contractile response to methacholine, KCl and electric field stimulation in rat forestomach, ileum and colon under conditions of in vitro and in vivo treatment with lead acetate. Rats were dosed with 4% lead acetate in their diet, NIH-07, for 7 weeks, which resulted in renal and hematologic toxicity and blood lead levels of 180-389 ug/dl (1.2 x 10/sup -5/ M). Tissues from in vivo treated rats were exposed to 1.2 x 10/sup -5/ M lead acetate during in vitro contractile studies. E/sub max/ or ED/sub 50/ methacholine was not affected by 1.2 x 10/sup -5/ M lead acetate, administered in vitro to control tissue. In the forestomach, a 10-fold higher concentration of lead (16 x 10/sup -5/ M), administered in vitro, increased baseline tension and inhibition response to methacholine. However, in vivo lead treatment potentiated response to methacholine in the forestomach and increased baseline tension in the presence of physostigmine. The EFS response, attributable to ACh release, was not affected in the forestomach or ileum by 1.2 x 10/sup -5/ M in vitro lead treatment. These data indicate that lead, administered in vivo in concentrations which cause renal and hematologic toxicity, does not impair cholinergic contractile response in gastrointestinal smooth muscle. Instead, the response to methacholine may be potentiated in the forestomach. Possible mechanisms of lead-induced potentiation of baseline or evoked tension include increased levels of non-elicited ACh release, inhibition of acetylcholinesterase or sensitization of muscarinic receptors.

  19. Non-cholinergic component of rat splanchnic nerves predominates at low neuronal activity and is eliminated by naloxone.

    Science.gov (United States)

    Malhotra, R K; Wakade, A R

    1987-02-01

    1. Effects of nicotinic (mecamylamine) and muscarinic (atropine) receptor antagonists were investigated on the secretion of catecholamines evoked by stimulation of splanchnic nerve terminals and acetylcholine in the isolated perfused adrenal gland of the rat to determine whether non-cholinergic substances released from nerve terminals participate in the secretion of catecholamines. 2. Increasing the frequency of stimulation from 0.5 to 10 Hz (300 pulses) caused enhanced secretion of catecholamines (26-110 ng/collection period). After blockade of nicotinic and muscarinic receptors with mecamylamine and atropine, the secretion was reduced by 40, 65 and 80% at 0.5, 1 and 10 Hz, respectively. Acetylcholine-evoked secretion of catecholamines, which was roughly equivalent to that produced by stimulation at 10 Hz, was blocked by over 90% by the cholinergic antagonists. 3. Naloxone (3-300 microM) caused a concentration-dependent inhibition of catecholamine secretion evoked by stimulation of splanchnic nerves (1 Hz); acetylcholine-evoked secretion was much less affected by naloxone. 4. The secretion of catecholamines that remained after blockade of cholinergic receptors at different frequencies of stimulation (see 2 above) was almost completely inhibited by inclusion of 30 microM-naloxone in the medium. The inhibitory effect of naloxone was concentration dependent (3-30 microM) and reversible. 5. Splanchnic nerve-evoked secretion of catecholamines was facilitated by 400% in the presence of tetraethylammonium or tetraethylammonium plus mecamylamine and atropine. The facilitatory effect of tetraethylammonium was inversely related to the frequency of stimulation. 6. The residual secretion of catecholamines obtained after blockade of cholinergic receptors was facilitated by increasing concentrations of tetraethylammonium (1-5 mM). 30 microM-naloxone antagonized the facilitatory effects of tetraethylammonium at 1 and 3 mM by 60% and 25%, respectively, but failed at 5 m

  20. Cholinergic neurons and terminal fields revealed by immunohistochemistry for the vesicular acetylcholine transporter. II. The peripheral nervous system.

    Science.gov (United States)

    Schäfer, M K; Eiden, L E; Weihe, E

    1998-05-01

    The peripheral sympathetic and parasympathetic cholinergic innervation was investigated with antibodies directed against the C-terminus of the rat vesicular acetylcholine transporter. Immunohistochemistry for the vesicular acetylcholine transporter resulted in considerably more detailed visualization of cholinergic terminal fields in the peripheral nervous system than reported previously and was well suited to also identify cholinergic perikarya. Vesicular acetylcholine transporter immunoreactivity completely delineated the preganglionic sympathetic terminals in pre- and paravertebral sympathetic ganglia, and in the adrenal medulla as well as postganglionic cholinergic neurons in the paravertebral chain. Cholinergic terminals of sudomotor and vasomotor nerves of skeletal muscle were optimally visualized. Mixed peripheral ganglia, including periprostatic and uterovaginal ganglia, exhibited extensive preganglionic cholinergic innervation of both noradrenergic and cholinergic postganglionic principal neurons which were intermingled in these ganglia. Varicose vesicular acetylcholine transporter-positive fibres and terminals, representing the cranial parasympathetic innervation of the cerebral vasculature, of salivary and lacrimal glands, of the eye, of the respiratory tract and of the upper digestive tract innervated various target structures including seromucous gland epithelium and myoepithelium, respiratory epithelium, and smooth muscle of the tracheobronchial tree. The only macrovascular elements receiving vesicular acetylcholine transporter-positive innervation were the cerebral arteries. The microvasculature throughout the viscera, with the exception of lymphoid tissues, the liver and kidney, received vesicular acetylcholine transporter-positive innervation while the microvasculature of limb and trunk skeletal muscle appeared to be the only relevant somatic target of vesicular acetylcholine transporter innervation. Vesicular acetylcholine transporter

  1. 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.

  2. 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. PMID:26638718

  3. Brain gangliosides of a transgenic mouse model of Alzheimer's disease with deficiency in GD3-synthase: expression of elevated levels of a cholinergic-specific ganglioside, GT1aα

    Directory of Open Access Journals (Sweden)

    Toshio Ariga

    2013-05-01

    Full Text Available In order to examine the potential involvement of gangliosides in AD (Alzheimer's disease, we compared the ganglioside compositions of the brains of a double-transgenic (Tg mouse model [APP (amyloid precursor protein/PSEN1 (presenilin] of AD and a triple mutant mouse model with an additional deletion of the GD3S (GD3-synthase gene (APP/PSEN1/GD3S−/−. These animals were chosen since it was previously reported that APP/PSEN1/GD3S−/− triple-mutant mice performed as well as WT (wild-type control and GD3S−/− mice on a number of reference memory tasks. Cholinergic neuron-specific gangliosides, such as GT1aα and GQ1bα, were elevated in the brains of double-Tg mice (APP/PSEN1, as compared with those of WT mice. Remarkably, in the triple mutant mouse brains (APP/PSEN1/GD3S−/−, the concentration of GT1aα was elevated and as expected there was no expression of GQ1bα. On the other hand, the level of c-series gangliosides, including GT3, was significantly reduced in the double-Tg mouse brain as compared with the WT. Thus, the disruption of the gene of a specific ganglioside-synthase, GD3S, altered the expression of cholinergic neuron-specific gangliosides. Our data thus suggest the intriguing possibility that the elevated cholinergic-specific ganglioside, GT1aα, in the triple mutant mouse brains (APP/PSEN1/GD3S−/− may contribute to the memory retention in these mice.

  4. Control of luminescence from lantern shark (Etmopterus spinax) photophores

    OpenAIRE

    Claes, Julien M; Mallefet, Jérôme

    2011-01-01

    The velvet belly lantern shark (Etmopterus spinax) is a common deep-sea shark that has been used, in the recent years, as a model for experimental studies on physiological control of shark luminescence. These studies demonstrated that, unlike any other luminous organism, the luminescence of this shark was under a dual control of hormones and neurotransmitters (or neuromodulators). This paper, by making a short review of histological and pharmacological results from these studies, aims to prop...

  5. Regulatory changes in presynaptic cholinergic function assessed in rapid autopsy material from patients with Alzheimer disease: Implications for etiology and therapy

    International Nuclear Information System (INIS)

    Brain regions from patients with or without Alzheimer disease (AD) were obtained within 2 hr of death and examined for indices of presynaptic cholinergic function. Consistent with loss of cholinergic projections, cerebral cortical areas involved in AD exhibited decreased choline acetyltransferase activity. However, remaining nerve terminals in these regions displayed marked up-regulation of synaptosomal high affinity [3H]choline uptake, a result indicative of relative cholinergic hyperactivity. As choline uptake is also rate-limiting in acetylcholine biosynthesis, these findings have implications for both therapy and identification of causes contributing to neuronal death in AD

  6. Effectiveness of methylphenidate as augmentation therapy after failure of adjunctive neuromodulation for patients with treatment-refractory bipolar depression: a case report

    Directory of Open Access Journals (Sweden)

    Adida M

    2014-04-01

    Full Text Available Marc Adida,1,2 Jean-Michel Azorin1,21Sainte-Marguerite Hospital, Department of Psychiatry, Mediterranean University, 2Timone Health Campus, National Research Scientific Centre, Marseille, FranceAbstract: Adjunctive use of methylphenidate, a central stimulant, has been considered as a potential therapeutic choice for patients with refractory unipolar, geriatric, or bipolar depression, and depression secondary to medical illness. We present a case of bipolar depression in which the patient responded significantly to augmentation with methylphenidate, without any side effects, after failure of adjunctive repetitive transcranial magnetic stimulation and electroconvulsive therapy. Mr U, a 56-year-old man with bipolar I disorder, had melancholic symptoms during his sixth episode of bipolar depression. After failure of repetitive transcranial magnetic stimulation and electroconvulsive therapy, he was treated with fluoxetine 80 mg/day, duloxetine 360 mg/day, mirtazapine 60 mg/day, and sodium valproate 1,000 mg/day, with no improvement. We added methylphenidate at a dose of 10 mg/day for one week, which resulted in mild clinical improvement, and then methylphenidate extended-release 20 mg/day for one week, with significant clinical improvement. He tolerated his medications well. His clinical recovery was stable over one year. The patient's antidepressants and methylphenidate were gradually tapered and finally discontinued after one year with no withdrawal syndrome. To date, he remains well on sodium valproate as monotherapy and is being followed up at our bipolar department. This case suggests that methylphenidate augmentation might be a therapeutic option when treating highly treatment-resistant patients with bipolar depression, even if they had not responded to adjunctive neuromodulation. In these clinical situations, physicians might be interested in prescribing methylphenidate because of its efficacy and safety.Keywords: bipolar disorder, treatment

  7. Cholinergic and behavioral neurotoxicity of carbaryl and cadmium to larval rainbow trout (Oncorhynchus mykiss).

    Science.gov (United States)

    Beauvais, S L; Jones, S B; Parris, J T; Brewer, S K; Little, E E

    2001-05-01

    Pesticides and heavy metals are common environmental contaminants that can cause neurotoxicity to aquatic organisms, impairing reproduction and survival. Neurotoxic effects of cadmium and carbaryl exposures were estimated in larval rainbow trout (RBT; Oncorhynchus mykiss) using changes in physiological endpoints and correlations with behavioral responses. Following exposures, RBT were videotaped to assess swimming speed. Brain tissue was used to measure cholinesterase (ChE) activity, muscarinic cholinergic receptor (MChR) number, and MChR affinity. ChE activity decreased with increasing concentrations of carbaryl but not of cadmium. MChR were not affected by exposure to either carbaryl or cadmium. Swimming speed correlated with ChE activity in carbaryl-exposed RBT, but no correlation occurred in cadmium-exposed fish. Thus, carbaryl exposure resulted in neurotoxicity reflected by changes in physiological and behavioral parameters measured, while cadmium exposure did not. Correlations between behavior and physiology provide a useful assessment of neurotoxicity. PMID:11386719

  8. Cholinergic stimulation of pancreatic amylase release and muscarinic receptors: effect of ionophore A23187

    International Nuclear Information System (INIS)

    Dispersed rat pancreatic acini were incubated in 0.5 mM calcium medium with increasing concentrations of carbamylcholine, with or without the ionophore A23187 (10-6M). Addition of the ionophore reduced maximal amylase release, increased the maximal effective concentration of carbamylcholine and dramatically impaired the agonist's capacity to induce enzyme secretion at low concentration. The ionophore also abolished the inhibition of secretion observed at high carbamylcholine concentrations. These effects of the ionophore on the cholinergic secretory response cannot be explained by interaction at the muscarinic receptor since neither the Bmax, the affinity of the receptor for the [3H]QNB nor the binding of carbamylcholine were affected by the ionophore. It is suggested that for the conditions studied, the ionophore can interact with the secretory process at one or several points ulterior to the initial recognition site of carbamylcholine on its receptor. 30 references, 3 figures

  9. The development of the cholinergic system in rat hippocampus following postnatal X-irradiation

    International Nuclear Information System (INIS)

    Postnatal X-irradiation of the rat hippocampus results in a marked reduction in the number of the postnatally developing granular neurons in the dentate gyrus and also caused a marked increase in the specific activity of acetylcholinesterase (AChE) and choline acetyltransferase (CAT) and a slight but consistent increase in the activity per whole hippocampus of AChE. The effect of irradiation on the granular neurons and on the cholinergic enzymes was found to be dose and age dependent. Drastic increase in specific enzymatic activities is also observed in the irradiated cerebellum whose granular neurons differentiate postnatally and to a lesser extent in the cerebral cortex in which cell formation is accomplished prior to birth. (Auth.)

  10. Enhanced sensitivity of muscarinic cholinergic receptor associated with dopaminergic receptor subsensitivity after chronic antidepressant treatment

    International Nuclear Information System (INIS)

    The chronic effects of antidepressant treatment on striatal dopaminergic (DA) and muscarinic cholinergic (mACh) receptors of the rat brain have been examined comparatively in this study using 3H-spiroperidol (3H-SPD) and 3H-quinuclidinyl benzilate (3H-QNB) as the respective radioactive ligands. Imipramine and desipramine were used as prototype antidepressants. Although a single administration of imipramine or desipramine did not affect each receptor sensitivity, chronic treatment with each drug caused a supersensitivity of mACh receptor subsequent to DA receptor subsensitivity. Furthermore, it has been suggested that anti-mACh properties of imipramine or desipramine may not necessarily be related to the manifestation of mACh receptor supersensitivity and that sustained DA receptor subsensitivity may play some role in the alterations of mACh receptor sensitivity

  11. Memory in myasthenia gravis: neuropsychological tests of central cholinergic function before and after effective immunologic treatment.

    Science.gov (United States)

    Glennerster, A; Palace, J; Warburton, D; Oxbury, S; Newsom-Davis, J

    1996-04-01

    There are reports of central cholinergic deficits in myasthenia gravis (MG) describing impaired performance on a variety of tests of memory with varying benefits from plasmapheresis. We tested 11 patients with symptomatic MG at the start of a trial of immunosuppressive treatment (prednisolone plus azathioprine or placebo) and again when in remission. The tests included the Logical Memory and Design Reproduction parts of the Wechsler Memory Scale, the Rey Auditory Verbal Learning Test, Peterson-Peterson task, and an auditory vigilance task. Muscle strength improved significantly over the period of treatment, but overall performance on tests of memory or attention did not. These results fail to substantiate reports of functionally significant and reversible central deficits in myasthenia gravis. PMID:8780106

  12. 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.

    2016-01-01

    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. PMID:27193825

  13. 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, but...

  14. In vivo mapping of cholinergic neurons in the human brain using SPECT and IBVM

    International Nuclear Information System (INIS)

    In the search for an in vivo marker of cholinergic neuronal integrity, the authors extended to human use the tracer (-)-5-[123I]iodobenzovesamicol (IBVM)). IBVM, an analog of vesamicol that binds to the acetylcholine transporter on presynaptic vesicles, was prepared with specific activity greater than 1.11 x 109 MBq mmole-1. After intravenous injection of [123I]IBVM, body distribution studies (n = 5) and brain SPECT studies (n = 5) were performed on normal human subjects (n = 10). SPECT images of the brain were collected sequentially over the first 4.5 hr following injection, and again 18 hr later. Data were realigned and transformed to stereotaxic coordinates, and localized activities were extracted for tracer kinetic analysis. The cerebral tracer input function was determined from metabolite-corrected radial arterial blood samples. The best data fit was obtained using a three-compartment model, including terms reflecting cerebral blood volume, exchange of free tracer between plasma and brain and specific binding. Dissociation of bound tracer was negligible for up to 4 hr. For the fitted parameters reflecting transport (K1) and binding site density index (k3, co-efficients of variation were approximately 8% in cortical regions of interest. Relative distributions corresponded well with post-mortem immunohistochemical values reported for the acetylcholine-synthesizing enzyme choline acetyltransferase, k3 (IBVM binding site density index), and tracer activity distribution at 22 hr, but not at 4 hr after injection. SPECT imaging of [123I]IBVM succeeds as an in vivo measure of cholinergic neuronal integrity and should be useful for the study of cerebral degenerative processes such as Alzheimer's disease. 24 refs., 4 figs., 3 tabs

  15. Laminar pattern of cholinergic and adrenergic receptors in rat visual cortex using quantitative receptor autoradiography

    International Nuclear Information System (INIS)

    The laminar distribution of muscarinic acetylcholine receptors, including the M1-receptor subtype, of beta-adrenergic receptors, and noradrenaline uptake sites, was studied in the adult rat visual, frontal, somatosensory and motor cortex, using quantitative receptor autoradiography. In the visual cortex, the highest density of muscarinic acetylcholine receptors was found in layer I. From layer II/III to layer V binding decreases continueously reaching a constant binding level in layers V and VI. This laminar pattern of muscarinic receptor density differs somewhat from that observed in the non-visual cortical regions examined: layer II/III contained the highest receptor density followed by layer I and IV: lowest density was found in layer V and VI. The binding profile of the muscarinic cholinergic M1-subtype through the visual cortex shows a peak in cortical layer II and in the upper part of layer VI, whereas in the non-visual cortical regions cited the binding level was high in layer II/III, moderate in layer I and IV, and low in layer VI. Layers I to IV of the visual cortex contained the highest beta-adrenergic receptor densities, whereas only low binding levels were observed in the deeper layers. A similar laminar distribution was found also in the frontal, somatosensory and motor cortex. The density of noradrenaline uptake sites was high in all layers of the cortical regions studied, but with noradrenaline uptake sites somewhat more concentrated in the superficial layers than in deeper ones. The distinct laminar pattern of cholinergic and noradrenergic receptor sites indicates a different role for acetylcholine and noradrenaline in the functional anatomy of the cerebral cortex, and in particular, the visual cortex. (author)

  16. Treatment of Alzheimer's Disease: The Legacy of the Cholinergic Hypothesis, Neuroplasticity, and Future Directions.

    Science.gov (United States)

    Wesson Ashford, J

    2015-01-01

    In this issue, an article by Waring et al. provides a meta-analysis of the effects of apo-lipo-protein E (APOE) genotype on the beneficial effect of acetyl-cholinesterase inhibitors (AChEIs) in patients with Alzheimer's disease (AD). There was no significant effect found. As of 2015, AChEI medications are the mainstay of AD treatment, and APOE genotype is the most significant factor associated with AD causation. This lack of a significant effect of APOE is analyzed with respect to the "Cholinergic Hypothesis" of AD, dating from 1976, through the recognition that cholinergic neurons are not the sole target of AD, but rather that AD attacks all levels of neuroplasticity in the brain, an idea originated by Ashford and Jarvik in 1985 and which still provides the clearest explanation for AD dementia. The "Amyloid Hypothesis" is dissected back to the alpha/beta pathway switching mechanism affecting the nexin-amyloid pre-protein (NAPP switch). The NAPP switch may be the critical neuroplasticity component of all learning involving synapse remodeling and subserve all learning mechanisms. The gamma-secretase cleavage is discussed, and its normal complementary products, beta-amyloid and the NAPP intracellular domain (NAICD), appear to be involved in natural synapse removal, but the link to AD dementia may involve the NAICD rather than beta-amyloid. Understanding neuroplasticity and the critical pathways to AD dementia are needed to determine therapies and preventive strategies for AD. In particular, the effect of APOE on AD predisposition needs to be established and a means found to adjust its effect to prevent AD. PMID:26402763

  17. Glucocorticoid-cholinergic interactions in the dorsal striatum in memory consolidation of inhibitory avoidance training

    Directory of Open Access Journals (Sweden)

    Oscar eSanchez-Resendis

    2012-06-01

    Full Text Available Extensive evidence indicates that glucocorticoid hormones act in a variety of brain regions to enhance the consolidation of memory of emotionally motivated training experiences. We previously reported that corticosterone, the major glucocorticoid in the rat, administered into the dorsal striatum immediately after inhibitory avoidance training dose-dependently enhances memory consolidation of this training. There is also abundant evidence that the intrinsic cholinergic system of the dorsal striatum is importantly involved in memory consolidation of inhibitory avoidance training. However, it is presently unknown whether these two neuromodulatory systems interact within the dorsal striatum in the formation of long-term memory. To address this issue, we first investigated in male Wistar rats whether the muscarinic receptor agonist oxotremorine administered into the dorsal striatum immediately after inhibitory avoidance training enhances 48-h retention of the training. Subsequently, we examined whether an attenuation of glucocorticoid signaling by either a systemic administration of the corticosterone-synthesis inhibitor metyrapone or an intra-striatal infusion of the glucocorticoid receptor antagonist RU 38486 would block the memory enhancement induced by oxotremorine. Our findings indicate that oxotremorine dose-dependently enhanced 48-h retention latencies, but that the administration of either metyrapone or RU 38486 prevented the memory-enhancing effect of oxotremorine. In the last experiment, corticosterone was infused into the dorsal striatum together with the muscarinic receptor antagonist scopolamine immediately after inhibitory avoidance training. Scopolamine blocked the enhancing effect of corticosterone on 48-h retention performance. These findings indicate that there are mutual interactions between glucocorticoids and the striatal cholinergic system in enhancing the consolidation of memory of inhibitory avoidance training.

  18. Hormonal Responses to Cholinergic Input Are Different in Humans with and without Type 2 Diabetes Mellitus

    Science.gov (United States)

    Dunai, Judit; Kilpatrick, Rachel; Oestricker, Lauren Z.; Wallendorf, Michael J.; Patterson, Bruce W.; Reeds, Dominic N.; Wice, Burton M.

    2016-01-01

    Peripheral muscarinic acetylcholine receptors regulate insulin and glucagon release in rodents but their importance for similar roles in humans is unclear. Bethanechol, an acetylcholine analogue that does not cross the blood-brain barrier, was used to examine the role of peripheral muscarinic signaling on glucose homeostasis in humans with normal glucose tolerance (NGT; n = 10), impaired glucose tolerance (IGT; n = 11), and type 2 diabetes mellitus (T2DM; n = 9). Subjects received four liquid meal tolerance tests, each with a different dose of oral bethanechol (0, 50, 100, or 150 mg) given 60 min before a meal containing acetaminophen. Plasma pancreatic polypeptide (PP), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), glucose, glucagon, C-peptide, and acetaminophen concentrations were measured. Insulin secretion rates (ISRs) were calculated from C-peptide levels. Acetaminophen and PP concentrations were surrogate markers for gastric emptying and cholinergic input to islets. The 150 mg dose of bethanechol increased the PP response 2-fold only in the IGT group, amplified GLP-1 release in the IGT and T2DM groups, and augmented the GIP response only in the NGT group. However, bethanechol did not alter ISRs or plasma glucose, glucagon, or acetaminophen concentrations in any group. Prior studies showed infusion of xenin-25, an intestinal peptide, delays gastric emptying and reduces GLP-1 release but not ISRs when normalized to plasma glucose levels. Analysis of archived plasma samples from this study showed xenin-25 amplified postprandial PP responses ~4-fold in subjects with NGT, IGT, and T2DM. Thus, increasing postprandial cholinergic input to islets augments insulin secretion in mice but not humans. Trial Registration: ClinicalTrials.gov NCT01434901 PMID:27304975

  19. Cognitive Impairments Induced by Concussive Mild Traumatic Brain Injury in Mouse Are Ameliorated by Treatment with Phenserine via Multiple Non-Cholinergic and Cholinergic Mechanisms

    Science.gov (United States)

    Li, Yazhou; Yu, Qian-sheng; Barak, Shani; Tamargo, Ian A.; Rubovitch, Vardit; Holloway, Harold W.; Lehrmann, Elin; Wood, William H.; Zhang, Yongqing; Becker, Kevin G.; Perez, Evelyn; Van Praag, Henriette; Luo, Yu; Hoffer, Barry J.; Becker, Robert E.; Pick, Chaim G.; Greig, Nigel H.

    2016-01-01

    Traumatic brain injury (TBI), often caused by a concussive impact to the head, affects an estimated 1.7 million Americans annually. With no approved drugs, its pharmacological treatment represents a significant and currently unmet medical need. In our prior development of the anti-cholinesterase compound phenserine for the treatment of neurodegenerative disorders, we recognized that it also possesses non-cholinergic actions with clinical potential. Here, we demonstrate neuroprotective actions of phenserine in neuronal cultures challenged with oxidative stress and glutamate excitotoxicity, two insults of relevance to TBI. These actions translated into amelioration of spatial and visual memory impairments in a mouse model of closed head mild TBI (mTBI) two days following cessation of clinically translatable dosing with phenserine (2.5 and 5.0 mg/kg BID x 5 days initiated post mTBI) in the absence of anti-cholinesterase activity. mTBI elevated levels of thiobarbituric acid reactive substances (TBARS), a marker of oxidative stress. Phenserine counteracted this by augmenting homeostatic mechanisms to mitigate oxidative stress, including superoxide dismutase [SOD] 1 and 2, and glutathione peroxidase [GPx], the activity and protein levels of which were measured by specific assays. Microarray analysis of hippocampal gene expression established that large numbers of genes were exclusively regulated by each individual treatment with a substantial number of them co-regulated between groups. Molecular pathways associated with lipid peroxidation were found to be regulated by mTBI, and treatment of mTBI animals with phenserine effectively reversed injury-induced regulations in the ‘Blalock Alzheimer’s Disease Up’ pathway. Together these data suggest that multiple phenserine-associated actions underpin this compound’s ability to ameliorate cognitive deficits caused by mTBI, and support the further evaluation of the compound as a therapeutic for TBI. PMID:27254111

  20. Critical role of cholinergic transmission from the laterodorsal tegmental nucleus to the ventral tegmental area in cocaine-induced place preference

    OpenAIRE

    Shinohara, Fumiya; Kihara, Yukari; Ide, Soichiro; Minami, Masabumi; Kaneda, Katsuyuki

    2014-01-01

    Conditioned place preference (CPP) is widely used to investigate the rewarding properties of cocaine. Various brain regions and neurotransmitters are involved in developing cocaine CPP. However, the contribution of cholinergic transmission in the ventral tegmental area (VTA) to cocaine CPP remains largely unexplored. Here, we examined the role of cholinergic input arising from the laterodorsal tegmental nucleus (LDT) to the VTA in the acquisition and expression of cocaine CPP in rats. Intra-L...

  1. Effects of melatonin on learning abilities, cholinergic fibers and nitric oxide synthase expression in rat cerebral cortex

    Institute of Scientific and Technical Information of China (English)

    Bin Xu; Junpao Chen; Hailing Zhao

    2006-01-01

    BACKGROUND: Melatonin is a kind of hormones derived from pineal gland. Recent researches demonstrate that melatonin is characterized by anti-oxidation, anti-senility and destroying free radicals. While, effect and pathogenesis of pineal gland on learning ability should be further studied.OBJ ECTIVE: To investigate the effects of pinealectomy on learning abiliy, distribution of cholinesterase and expression of neuronal nitric oxide synthase (nNOS) in cerebral cortex of rats and probe into the effect of melatonin on learning ability, central cholinergic system and nNOS expression.DESIGN: Randomized grouping design and animal study.SETTING: Department of Neurology, the 187 Hospital of Chinese PLA.MATERIALS: A total of 12 male SD rats, of normal learning ability testing with Y-tape maze, of clean grade,weighing 190-210 g, aged 6 weeks, were selected in this study.METHODS: The experiment was carried out in the Department of Neurology, Zhujiang Hospital from July 1997to June 2000. All SD rats were divided into experimental group (n =6,pinealectomy) and control group (n =6, sham operation). Seven days later, rats in both two groups were continuously fed for 33 days. ①Learning ability test: The learning ability of rats was tested by trisection Y-type maze and figured as attempting times. ②Expression of acetylcholinesterase (AchE) was detected by enzyme histochemistry and nNOS was measured by SABC method. ③ Quantitative analysis of AchE fibers: AchE fibers density in unit area (surface density)was surveyed with Leica Diaplan microscope and Leica Quantimet 500+ image analytic apparatus and quantitative parameter was set up for AchE fibers covering density (μm2) per 374 693.656 μm2, moreover, the AchE fibers density was measured in Ⅱ -Ⅳ layers of motor and somatosensory cortex (showing three layers per field of vision at one time), in radiative, lacunaria and molecular layers of CA1, CA2 and CA3 areas, and in lamina multiforms of dentate gyrus. Three tissue slices

  2. Endosulfan and cholinergic (muscarinic) transmission: effect on electroencephalograms and [3H]quinuclidinyl benzilate in pigeon brain

    International Nuclear Information System (INIS)

    Single exposure of endosulfan (5 mg/kg) to pigeons (Columbia livia) caused neuronal hyperexcitability as evidence by spike discharges of 200-500 μV in the electroencephalograms (EEG) from the telencephalon and hyperstriatum, but there was not effect on the ectostriatal area. Cholinergic (muscarinic) receptor binding study using [3H]quinuclidinyl benzilate ([3H]QNB) as a specific ligand indicated that a single exposure to 5 mg/kg of endosulfan caused a significant increase in [3H]QNB binding to the striatal membrane. Behavior study further indicated that a single dose of 200 μg/kg of oxotremorine produced a significant induction in the tremor in endosulfan-pretreated pigeons. The results of this behavioral and biochemical study indicate the involvement of a cholinergic (muscarinic) transmitter system in endosulfan-induced neurotoxicity

  3. Neuromodulation approaches for the treatment of major depression: challenges and recommendations from a working group meeting Estratégias de neuromodulação para o tratamento da depressão maior: desafios e recomendações de uma força-tarefa

    OpenAIRE

    André Russowsky Brunoni; Chei Tung Teng; Claudio Correa; Marta Imamura; Joaquim P. Brasil-Neto; Raphael Boechat; Moacyr Rosa; Paulo Caramelli; Roni Cohen; Jose Alberto Del Porto; Paulo Sergio Boggio; Felipe Fregni

    2010-01-01

    The use of neuromodulation as a treatment for major depressive disorder (MDD) has recently attracted renewed interest due to development of other non-pharmacological therapies besides electroconvulsive therapy (ECT) such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), deep brain stimulation (DBS), and vagus nerve stimulation (VNS). METHOD: We convened a working group of researchers to discuss the updates and key challenges of neuromodulation use for...

  4. Do Different Neurons Age Differently? Direct Genome-Wide Analysis of Aging in Single Identified Cholinergic Neurons

    OpenAIRE

    Moroz, Leonid L.; Kohn, Andrea B.

    2010-01-01

    Aplysia californica is a powerful experimental system to study the entire scope of genomic and epigenomic regulation at the resolution of single functionally characterized neurons and is an emerging model in the neurobiology of aging. First, we have identified and cloned a number of evolutionarily conserved genes that are age-related, including components of apoptosis and chromatin remodeling. Second, we performed gene expression profiling of different identified cholinergic neurons between y...

  5. Anticholinergic-induced analgesia: possible role for the cholinergic system in abnormal sensory symptoms in Parkinson's disease.

    OpenAIRE

    Sandyk, R.

    1986-01-01

    Sensory symptoms related to pain perception have been reported to occur in 30-50% of parkinsonian patients. Two patients with Parkinson's disease are reported, in whom painful sensory phenomena preceded or accompanied the disease process. In both patients the sensory phenomena were unresponsive to therapy with oral narcotics, anti-inflammatory drugs or administration of levodopa/carbidopa. Benzhexol (4-6 mg/day) produced dramatic amelioration of symptoms, indicating a role for the cholinergic...

  6. Developmental Profile of the Aberrant Dopamine D2 Receptor Response in Striatal Cholinergic Interneurons in DYT1 Dystonia

    OpenAIRE

    Giuseppe Sciamanna; Annalisa Tassone; Giuseppina Martella; Georgia Mandolesi; Francesca Puglisi; Dario Cuomo; Grazia Madeo; Giulia Ponterio; David George Standaert; Paola Bonsi; Antonio Pisani

    2011-01-01

    BACKGROUND: DYT1 dystonia, a severe form of genetically determined human dystonia, exhibits reduced penetrance among carriers and begins usually during adolescence. The reasons for such age dependence and variability remain unclear. METHODS AND RESULTS: We characterized the alterations in D2 dopamine receptor (D2R) signalling in striatal cholinergic interneurons at different ages in mice overexpressing human mutant torsinA (hMT). An abnormal excitatory response to the D2R agonist quinpirole w...

  7. Synaptic vesicle cycling is not impaired in a glutamatergic and a cholinergic synapse that exhibit deficits in acidification and filling

    OpenAIRE

    Bento João Abreu; Luciana Ferreira Leite; Débora Lopes Oliveira; Ernani Amaral

    2012-01-01

    The purpose of the present work was to investigate synaptic vesicle trafficking when vesicles exhibit alterations in filling and acidification in two different synapses: a cholinergic frog neuromuscular junction and a glutamatergic ribbon-type nerve terminal in the retina. These synapses display remarkable structural and functional differences, and the mechanisms regulating synaptic vesicle cycling might also differ between them. The lipophilic styryl dye FM1-43 was used to monitor vesicle tr...

  8. Ethanolic Extract of the Seed of Zizyphus jujuba var. spinosa Ameliorates Cognitive Impairment Induced by Cholinergic Blockade in Mice

    OpenAIRE

    Lee, Hyung Eun; Lee, So Young; Kim, Ju Sun; Park, Se Jin; Kim, Jong Min; Lee, Young Woo; Jung, Jun Man; Kim, Dong hyun; Shin, Bum Young; Jang, Dae Sik; Kang, Sam Sik; Ryu, Jong Hoon

    2013-01-01

    In the present study, we investigated the effect of ethanolic extract of the seed of Zizyphus jujuba var. spinosa (EEZS) on cholinergic blockade-induced memory impairment in mice. Male ICR mice were treated with EEZS. The behavioral tests were conducted using the passive avoidance, the Y-maze, and the Morris water maze tasks. EEZS (100 or 200 mg/kg, p.o.) significantly ameliorated the scopolamine-induced cognitive impairment in our present behavioral tasks without changes of locomotor activit...

  9. Optogenetic control of human neurons in organotypic brain cultures

    DEFF Research Database (Denmark)

    Andersson, My; Avaliani, Natalia; Svensson, Andreas;

    2016-01-01

    Optogenetics is one of the most powerful tools in neuroscience, allowing for selective control of specific neuronal populations in the brain of experimental animals, including mammals. We report, for the first time, the application of optogenetic tools to human brain tissue providing a proof......-of-concept for the use of optogenetics in neuromodulation of human cortical and hippocampal neurons as a possible tool to explore network mechanisms and develop future therapeutic strategies....

  10. Optogenetic control of human neurons in organotypic brain cultures.

    Science.gov (United States)

    Andersson, My; Avaliani, Natalia; Svensson, Andreas; Wickham, Jenny; Pinborg, Lars H; Jespersen, Bo; Christiansen, Søren H; Bengzon, Johan; Woldbye, David P D; Kokaia, Merab

    2016-01-01

    Optogenetics is one of the most powerful tools in neuroscience, allowing for selective control of specific neuronal populations in the brain of experimental animals, including mammals. We report, for the first time, the application of optogenetic tools to human brain tissue providing a proof-of-concept for the use of optogenetics in neuromodulation of human cortical and hippocampal neurons as a possible tool to explore network mechanisms and develop future therapeutic strategies. PMID:27098488

  11. ESC-Derived Basal Forebrain Cholinergic Neurons Ameliorate the Cognitive Symptoms Associated with Alzheimer’s Disease in Mouse Models

    Directory of Open Access Journals (Sweden)

    Wei Yue

    2015-11-01

    Full Text Available Degeneration of basal forebrain cholinergic neurons (BFCNs is associated with cognitive impairments of Alzheimer’s disease (AD, implying that BFCNs hold potentials in exploring stem cell-based replacement therapy for AD. However, studies on derivation of BFCNs from embryonic stem cells (ESCs are limited, and the application of ESC-derived BFCNs remains to be determined. Here, we report on differentiation approaches for directing both mouse and human ESCs into mature BFCNs. These ESC-derived BFCNs exhibit features similar to those of their in vivo counterparts and acquire appropriate functional properties. After transplantation into the basal forebrain of AD model mice, ESC-derived BFCN progenitors predominantly differentiate into mature cholinergic neurons that functionally integrate into the endogenous basal forebrain cholinergic projection system. The AD mice grafted with mouse or human BFCNs exhibit improvements in learning and memory performances. Our findings suggest a promising perspective of ESC-derived BFCNs in the development of stem cell-based therapies for treatment of AD.

  12. Involvement of the Nonneuronal Cholinergic System in Bone Remodeling in Rat Midpalatal Suture after Rapid Maxillary Expansion

    Science.gov (United States)

    Guo, Jie; Wang, Lue; Miao, Cong; Ge, Lihua; Tian, Zhenchuan; Wang, Jianhong

    2016-01-01

    Few studies sought to analyze the expression and function of the nonneuronal acetylcholine system in bone remodeling in vivo due to the lack of suitable models. We established a rat maxilla expansion model in which the midline palatine suture of the rat was rapidly expanded under mechanical force application, inducing tissue remodeling and new bone formation, which could be a suitable model to investigate the role of the nonneuronal acetylcholine system in bone remodeling in vivo. During the expansion, the expression pattern changes of the nonneuronal cholinergic system components and the mRNA levels of OPG/RANKL were detected by immunohistochemistry or real-time PCR. The value of the RANKL/OPG ratio significantly increased after 1 day of expansion, indicating dominant bone resorption induced by the mechanical stimulation; however after 3 days of expansion, the value of the RANKL/OPG ratio significantly decreased, suggesting a dominant role of the subsequent bone formation process. Increasing expression of Ach was detected after 3 days of expansion which indicated that ACh might play a role in bone formation. The mRNA expression levels of other components also showed observable changes during the expansion which confirmed the involvement of the nonneuronal cholinergic system in the process of bone remodeling in vivo. Further researches are still needed to figure out the detailed functions of the nonneuronal cholinergic system and its components. PMID:27478838

  13. [Examination of ontogenetic-morphologic growth of cholinergic receptor system in isolated preparation of human trachea in vitro].

    Science.gov (United States)

    Islami, Hilmi; Sukalo, Aziz; Shabani, R; Disha, M; Kutllovci, S

    2006-01-01

    Morphologic growth of cholinergic bronchial respiratory system was examined at live and dead newborns. Tracheal smooth musculature was examined at 18 experimental preparations taken by the autopsy after exiting from different factors. Samples were divided into three groups based on gestational weeks. First group: from 23-29 gestational weeks (immature, N=5); second group: from 30-37 gestational weeks (premature, N=7); third group: from 38-41 gestational weeks (mature, N=6). Based on morphological examination of isolated preparations human trachea fingings are the following: in 23-29 week are found nerve endings with axo-axonal synapses mainly at ramification phase of lungs blood vessels net, without trachea bronchial innervations with axo-axonal synapses, and with perichondrial localization. In 30-37 gestational weeks axo-xonal synapses are found in between glands acinus's and vessels net, and also emphatic choline reactivity at lung ganglions: this suggests existing of cholinergic system at alive newborns. At 38-41 gestational weeks exists a wealthy nerve neuromuscular net in smooth tracheal musculature with different vesicles. Choline reactivity is emphasized peri and intrachondrial at lamina propria, at most around sensory glands and in smooth musculature. This suggests that there is no choline reactivity at epithelium and of existence of cholinergic system in tracheal bronchial smooth musculature. PMID:16425526

  14. The development neurotoxicity of ethanol: Cerebral cortical cholinergic alterations induced in artificially reared rats exposed to ethanol during the brain growth spurt

    International Nuclear Information System (INIS)

    It is hypothesized that cerebral cortical cholinergic neurotransmitter system alterations are induced by ethanol exposure during the vulnerable period of rapid brain growth. To test this proposal, on postnatal (PN) day 4, male Sprague Dawley rat pups were randomly assigned to either mother raised control (MRC) or artificially reared (AR) experimental groups. AR, ethanol-exposed (EE) pups received a liquid diet containing either 3%, 4%, or 5% (w/v) ethanol, while AR, cup-control (CC) pups isovolumetrically received an isocaloric, glucose-substituted diet. Acute effects of AR (CC vs MRC) and EE (EE vs CC) were determined in groups of pups sacrificed immediately following the termination of AR on PN8. Other groups of neonates were returned to foster dams on PN8 and maternally reared until sacrifice on PN20 to detect persistent or latent alternations. Although AR failed to perturb muscarinic receptor density at either age of assessment, it acutely and persistently decreased receptor affinity for (3H)QNB, and also the activities of both acetylcholinesterase and choline acetyltransferase

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

    Directory of Open Access Journals (Sweden)

    Jun Il Kang

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

  16. Muscarinic cholinergic receptor (M2 plays a crucial role in the development of myopia in mice

    Directory of Open Access Journals (Sweden)

    Veluchamy A. Barathi

    2013-09-01

    Myopia is a huge public health problem worldwide, reaching the highest incidence in Asia. Identification of susceptible genes is crucial for understanding the biological basis of myopia. In this paper, we have identified and characterized a functional myopia-associated gene using a specific mouse-knockout model. Mice lacking the muscarinic cholinergic receptor gene (M2; also known as Chrm2 were less susceptible to lens-induced myopia compared with wild-type mice, which showed significantly increased axial length and vitreous chamber depth when undergoing experimental induction of myopia. The key findings of this present study are that the sclera of M2 mutant mice has higher expression of collagen type I and lower expression of collagen type V than do wild-type mice and mice that are mutant for other muscarinic subtypes, and, therefore, M2 mutant mice were resistant to the development of experimental myopia. Pharmacological blockade of M2 muscarinic receptor proteins retarded myopia progression in the mouse. These results suggest for the first time a role of M2 in growth-related changes in extracellular matrix genes during myopia development in a mammalian model. M2 receptor antagonists might thus provide a targeted therapeutic approach to the management of this refractive error.

  17. Ligands for SPECT and PET imaging of muscarinic-cholinergic receptors of the heart and brain

    Energy Technology Data Exchange (ETDEWEB)

    Knapp, F.F. Jr.; McPherson, D.W.; Luo, H. [and others

    1995-06-01

    Interest in the potential use of cerebral SPECT and PET imaging for determination of the density and activity of muscarinic-cholinergic receptors (mAChR) has been stimulated by the changes in these receptors which occur in many neurological diseases. In addition, the important involvement of mAChR in modulating negative inotropic cardiac activity suggests that such receptor ligands may have important applications in evaluation of changes which may occur in cardiac disease. In this paper, the properties of several key muscarinic receptor ligands being developed or which have been used for clinical SPECT and PET are discussed. In addition, the ORNL development of the new iodinated IQNP ligand based on QNB and the results of in vivo biodistribution studies in rats, in vitro competitive binding studies and ex vivo autoradiographic experiments are described. The use of radioiodinated IQNP may offer several advantages in comparison to IQNB because of its easy and high yield preparation and high brain uptake and the potential usefulness of the {open_quotes}partial{close_quotes} subtype selective IONP isomers. We also describe the development of new IQNP-type analogues which offer the opportunity for radiolabeling with positron-emitting radioisotopes (carbon-11, fluorine-18 and bromine-76) for potential use with PET.

  18. Adrenergic and cholinergic responses in the uteroplacental vascular bed of the guinea pig

    International Nuclear Information System (INIS)

    The effects on uterine and maternal placental circulation of adrenergic and cholinergic drugs, injected selectively in the ovarian and uterine arteries of guinea pigs, were analysed by serial angiography. Noradrenaline, 0.5 nmol/kg, was found to cause a reduction in both ovarian and uterine blood flow, associated with arterial vasoconstriction and impairment of the placental circulation. This response could be prevented by α-adrenergic blockade with 25 nmol/kg phenoxybenzamine. At injection into the ovarian artery, phenoxybenzamine alone increased ovarian blood flow and elicited arterial vasodilatation. At injection into the uterine artery the response was more variable, but vasodilatation was observed in four animals of six. Acetylcholine, 0.5 to 5.0 nmol/kg, evoked an increase in both ovarian and uterine blood flow and arterial vasodilatation. When the dose was increased to 50 nmol/kg, dilatation of the extrinsic uterine arteries was maintained, but the placental circulation was reduced due to concomitant contraction of the myometrium. All the effects of acetylcholine could be blocked by prior administration of 10 nmol/kg atropine. This dose of atropine did not affect uterine or placental circulation when given alone. (Auth.)

  19. Deformation of attractor landscape via cholinergic presynaptic modulations: a computational study using a phase neuron model.

    Directory of Open Access Journals (Sweden)

    Takashi Kanamaru

    Full Text Available Corticopetal acetylcholine (ACh is released transiently from the nucleus basalis of Meynert (NBM into the cortical layers and is associated with top-down attention. Recent experimental data suggest that this release of ACh disinhibits layer 2/3 pyramidal neurons (PYRs via muscarinic presynaptic effects on inhibitory synapses. Together with other possible presynaptic cholinergic effects on excitatory synapses, this may result in dynamic and temporal modifications of synapses associated with top-down attention. However, the system-level consequences and cognitive relevance of such disinhibitions are poorly understood. Herein, we propose a theoretical possibility that such transient modifications of connectivity associated with ACh release, in addition to top-down glutamatergic input, may provide a neural mechanism for the temporal reactivation of attractors as neural correlates of memories. With baseline levels of ACh, the brain returns to quasi-attractor states, exhibiting transitive dynamics between several intrinsic internal states. This suggests that top-down attention may cause the attention-induced deformations between two types of attractor landscapes: the quasi-attractor landscape (Q-landscape, present under low-ACh, non-attentional conditions and the attractor landscape (A-landscape, present under high-ACh, top-down attentional conditions. We present a conceptual computational model based on experimental knowledge of the structure of PYRs and interneurons (INs in cortical layers 1 and 2/3 and discuss the possible physiological implications of our results.

  20. Low-level microwave irradiations affect central cholinergic activity in the rat

    Energy Technology Data Exchange (ETDEWEB)

    Lai, H.; Horita, A.; Chou, C.K.; Guy, A.W.

    1987-01-01

    Sodium-dependent high-affinity choline uptake was measured in various regions of the brains of rats irradiated for 45 min with either pulsed or continuous-wave low-level microwaves (2,450 MHz; power density, 1 mW/cm2; average whole-body specific absorption rate, 0.6 W/kg). Pulsed microwave irradiation (2-microseconds pulses, 500 pulses/s) decreased choline uptake in the hippocampus and frontal cortex but had no significant effect on the hypothalamus, striatum, and inferior colliculus. Pretreatment with a narcotic antagonist (naloxone or naltrexone; 1 mg/kg i.p.) blocked the effect of pulsed microwaves on hippocampal choline uptake but did not significantly alter the effect on the frontal cortex. Irradiation with continuous-wave microwaves did not significantly affect choline uptake in the hippocampus, striatum, and hypothalamus but decreased the uptake in the frontal cortex. The effect on the frontal cortex was not altered by pretreatment with narcotic antagonist. These data suggest that exposure to low-level pulsed or continuous-wave microwaves leads to changes in cholinergic functions in the brain.

  1. The role of substance P in respiratory control in the newborn : Effects of morphine and nicotine

    OpenAIRE

    Berner, Jonas

    2008-01-01

    We breathe in order to maintain oxygen, carbon dioxide and pH levels within the physiological range in response to the metabolic demands of the body. To achieve this, the respiratory control system is dependent on input from peripheral and/ central chemosensitive areas and on participation of different neuromodulator systems. This thesis focuses on the role of one of the neurotransmitters, substance P, involved in the complex and finely tuned control of respiration. It also ...

  2. A Rat Model of Alzheimer’s Disease Based on Abeta42 and Pro-oxidative Substances Exhibits Cognitive Deficit and Alterations in Glutamatergic and Cholinergic Neurotransmitter Systems

    Science.gov (United States)

    Petrasek, Tomas; Skurlova, Martina; Maleninska, Kristyna; Vojtechova, Iveta; Kristofikova, Zdena; Matuskova, Hana; Sirova, Jana; Vales, Karel; Ripova, Daniela; Stuchlik, Ales

    2016-01-01

    Alzheimer’s disease (AD) is one of the most serious human, medical, and socioeconomic burdens. Here we tested the hypothesis that a rat model of AD (Samaritan; Taconic Pharmaceuticals, USA) based on the application of amyloid beta42 (Abeta42) and the pro-oxidative substances ferrous sulfate heptahydrate and L-buthionine-(S, R)-sulfoximine, will exhibit cognitive deficits and disruption of the glutamatergic and cholinergic systems in the brain. Behavioral methods included the Morris water maze (MWM; long-term memory version) and the active allothetic place avoidance (AAPA) task (acquisition and reversal), testing spatial memory and different aspects of hippocampal function. Neurochemical methods included testing of the NR1/NR2A/NR2B subunits of NMDA receptors in the frontal cortex and CHT1 transporters in the hippocampus, in both cases in the right and left hemisphere separately. Our results show that Samaritan rats™ exhibit marked impairment in both the MWM and active place avoidance tasks, suggesting a deficit of spatial learning and memory. Moreover, Samaritan rats exhibited significant changes in NR2A expression and CHT1 activity compared to controls rats, mimicking the situation in patients with early stage AD. Taken together, our results corroborate the hypothesis that Samaritan rats are a promising model of AD in its early stages.

  3. [Tiotropium as a controller of bronchoconstriction].

    Science.gov (United States)

    Lubiński, Wojciech

    2004-05-01

    Cholinergic nerve fibres arise in the nucleus ambiguus and the dorsal motor nucleus of the vagus nerve in the brainstem. They travel down as the vagus nerve to parasympathetic ganglia placed in the walls of the airways. From these ganglia, short postganglionic fibres innervate airway smooth muscle and the submucosal glands in the lung. Activation of vagal nerve releases acetylcholine at the neuroeffector junctions, where it binds to postsynaptic receptors, resulting in bronchoconstrictions. The resting bronchomotor tone in normal airways has a cholinergic component mediated via muscarinic cholinergic receptors. The human airways have five subtypes of muscarinic cholinergic receptors: the M1 and M3 mediate bronchoconstriction and stimulation of mucus secretion, while M2 control the release of acetylcholine from M1 and M3 receptors through a negative-feedback mechanism. Anticholinergic bronchodilators act by blocking muscarinic receptors. Tiotropium bromide is cutting age anticholinergic bronchodilator. It dissociates more slowly from M1 and M3 than from M2 receptors and subsequently has a long and safety duration of action. In COPD patients tiotropium comparing to placebo, ipratropium and long acting beta agonists significantly improves lung function. It is an effective bronchodilator that reduces dyspnea, COPD exacerbations frequency and improves health status. This suggests that tiotropium will make an important contribution to chronic pulmonary disease therapy. PMID:15524023

  4. Potentiation of NMDA receptor-mediated transmission in striatal cholinergic interneurons.

    Science.gov (United States)

    Oswald, Manfred J; Schulz, Jan M; Kelsch, Wolfgang; Oorschot, Dorothy E; Reynolds, John N J

    2015-01-01

    Pauses in the tonic firing of striatal cholinergic interneurons (CINs) emerge during reward-related learning in response to conditioning of a neutral cue. We have previously reported that augmenting the postsynaptic response to cortical afferents in CINs is coupled to the emergence of a cell-intrinsic afterhyperpolarization (AHP) underlying pauses in tonic activity. Here we investigated in a bihemispheric rat-brain slice preparation the mechanisms of synaptic plasticity of excitatory afferents to CINs and the association with changes in the AHP. We found that high frequency stimulation (HFS) of commissural corticostriatal afferents from the contralateral hemisphere induced a robust long-term depression (LTD) of postsynaptic potentials (PSP) in CINs. Depression of the PSP of smaller magnitude and duration was observed in response to HFS of the ipsilateral white matter or cerebral cortex. In Mg(2+)-free solution HFS induced NMDA receptor-dependent potentiation of the PSP, evident in both the maximal slope and amplitude of the PSP. The increase in maximal slope corroborates previous findings, and was blocked by antagonism of either D1-like dopamine receptors with SCH23390 or D2-like dopamine receptors with sulpiride during HFS in Mg(2+)-free solution. Potentiation of the slower PSP amplitude component was due to augmentation of the NMDA receptor-mediated potential as this was completely reversed on subsequent application of the NMDA receptor antagonist AP5. HFS similarly potentiated NMDA receptor currents isolated by blockade of AMPA/kainate receptors with CNQX. The plasticity-induced increase in the slow PSP component was directly associated with an increase in the subsequent AHP. Thus plasticity of cortical afferent synapses is ideally suited to influence the cue-induced firing dynamics of CINs, particularly through potentiation of NMDA receptor-mediated synaptic transmission. PMID:25914618

  5. EVALUATION OF ANTI-CHOLINERGIC AND ANTI-ANAPHYLACTIC ACTIVITY OF SHIRISHADI POLYHERBAL COMPOUND

    Directory of Open Access Journals (Sweden)

    Kajaria Divya

    2012-02-01

    Full Text Available Asthma is a chronic inflammatory disease of airways with widespread narrowing of air passage which may be relieved spontaneously or as a result of therapy and, clinically it is characterized by paroxysms of dyspnea, cough and wheezing. Inflammation and broncho-constriction are the two major hallmarks in the pathology of Asthma. Shirishadi is a polyherbal drug used in the management of bronchial asthma by Ayurvedic practitioners from decades. Shirisha (Albezzia lebbeck, Nagarmotha (Cyprus rotandus and Kantakari (Solanum xanthocarpum are the ingredient herbs of this compound. Hence, the present investigation was undertaken to evaluate the bronchodilator and anti-anaphylactic activity of Shirishadi Polyherbal compound. Experimental models studied were egg albumin induced anaphylaxis in guinea pigs and Anti-Cholinergic activity was studied on Isolated Frog Heart and Frog Rectus Muscle. The extract produced 30+ 0.23% inhibition in maximum contraction produced by Acetylcholine which is much less than that produced by standard drug (99.9%, moreover the dose of extract that produced the visible effect is much higher than that used for therapeutic purpose suggesting that antiasthmatic effect of drug is not due to Acetylcholine antagonism activity. Neither Acetylcholine efficacy nor its potency decreases significantly with increasing dose of drug. Drug increased the cardiac tone and stimulate the cardiac contractility but unable to prevail over complete inhibition of heart rate produced by Acetylcholine. The drug produced significant protection against egg albumin induced anaphylactic shock characterized by decrease in intensity and delay in the development of symptoms of dyspnoea, asphyxia and collapse. All these findings reveal the bronchodilator and anti-anaphylactic activity of Shirishadi compound indicating its beneficial use in asthma.

  6. The placental cholinergic system: localization to the cytotrophoblast and modulation of nitric oxide

    Directory of Open Access Journals (Sweden)

    Fant Michael E

    2006-05-01

    Full Text Available Abstract Background The human placenta, a non-neuronal tissue, contains an active cholinergic system comprised of acetylcholine (ACh, choline acetyltransferase (ChAT, acetylcholinesterase (AChE, and high affinity muscarinic receptors. The cell(s of origin of placental ACh and its role in trophoblast function has not been defined. These studies were performed to define the cellular location of ACh synthesis (ChAT in the human placenta and to begin studying its functional role. Results Using immunohistochemical techniques, ChAT was observed primarily within the cytotrophoblasts of preterm placentae as well as some mesenchymal elements. Similar intense immunostaining of the cytotrophoblast was observed for endothelium-derived nitric oxide synthase (eNOS suggesting that ACh may interact with nitric oxide (NO-dependent signaling pathways. The ability of carbamylcholine (CCh, an ACh analogue, to stimulate a rise in intracellular Ca++ and NO production in trophoblasts was therefore tested using the BeWob30 choriocarcinoma cell as a model system. First, CCh significantly increased intracellular calcium as assessed by fluorescence microscopy. We then examined the ability of CCh to stimulate NO production by measuring total nitrite/nitrate production in conditioned media using chemiluminescence-based analysis. CCh, alone, had no effect on NO production. However, CCh increased measurable NO approximately 100% in the presence of 10 nM estradiol. This stimulatory effect was inhibited by 1 (microM scopolamine suggesting mediation via muscarinic receptors. Estradiol, alone, had no effect on total NO or eNOS protein or mRNA. Conclusion These data demonstrate that placental ChAT localizes to the cytotrophoblast and some mesenchymal cells in human placenta. It further suggests that ACh acts via muscarinic receptors on the trophoblast cell membrane to modulate NO in an estrogen-dependent manner.

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

    Directory of Open Access Journals (Sweden)

    James P Roach

    2015-08-01

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

  8. Alpha-asarone improves striatal cholinergic function and locomotor hyperactivity in Fmr1 knockout mice.

    Science.gov (United States)

    Qiu, Guozhen; Chen, Shengqiang; Guo, Jialing; Wu, Jie; Yi, Yong-Hong

    2016-10-01

    Hyperactivity is a symptom found in several neurological and psychiatric disorders, including Fragile X syndrome (FXS). The animal model of FXS, fragile X mental retardation gene (Fmr1) knockout (KO) mouse, exhibits robust locomotor hyperactivity. Alpha (α)-asarone, a major bioactive component isolated from Acorus gramineus, has been shown in previous studies to improve various disease conditions including central nervous system disorders. In this study, we show that treatment with α-asarone alleviates locomotor hyperactivity in Fmr1 KO mice. To elucidate the mechanism underlying this improvement, we evaluated the expressions of various cholinergic markers, as well as acetylcholinesterase (AChE) activity and acetylcholine (ACh) levels, in the striatum of Fmr1 KO mice. We also analyzed the AChE-inhibitory activity of α-asarone. Striatal samples from Fmr1 KO mice showed decreased m1 muscarinic acetylcholine receptor (m1 mAChR) expression, increased AChE activity, and reduced ACh levels. Treatment with α-asarone improved m1 mAChR expression and ACh levels, and attenuated the increased AChE activity. In addition, α-asarone dose-dependently inhibited AChE activity in vitro. These results indicate that direct inhibition of AChE activity and up-regulation of m1 mAChR expression in the striatum might contribute to the beneficial effects of α-asarone on locomotor hyperactivity in Fmr1 KO mice. These findings might improve understanding of the neurobiological mechanisms responsible for locomotor hyperactivity. PMID:27316341

  9. Adrenergic and cholinergic activity contributes to the cardiovascular effects of lionfish (Pterois volitans) venom.

    Science.gov (United States)

    Church, Jarrod E; Hodgson, Wayne C

    2002-06-01

    The aim of the present study was to further investigate the cardiovascular activity of Pterois volitans crude venom. Venom (0.6-18 microg protein/ml) produced dose- and endothelium-dependent relaxation in porcine coronary arteries that was potentiated by atropine (10nM), but significantly attenuated by the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine (NOLA; 0.1mM), by prior exposure of the tissue to stonefish antivenom (SFAV, 3 units/ml, 10 min), or by removal of extracellular Ca(2+). In rat paced left atria, venom (10 microg protein/ml) produced a decrease, followed by an increase, in contractile force. Atropine (0.5 microM) abolished the decrease in force and potentiated the increase. Propranolol (5 microM) did not affect the decrease in force but significantly attenuated the increase. In spontaneously beating right atria, venom (10 microg protein/ml) produced an increase in rate that was significantly attenuated by propranolol (5 microM). Prior incubation with SFAV (0.3 units/microg protein, 10 min) abolished both the inotropic and chronotropic responses to venom. In the anaesthetised rat, venom (100 micro protein/kg, i.v.) produced a pressor response, followed by a sustained depressor response. Atropine (1mg/kg, i.v.) potentiated the pressor response. The further addition of prazosin (50 microg/kg, i.v.) restored the original response to venom. Prior administration of SFAV (100 units/kg, i.v., 10 min) significantly attenuated the in vivo response to venom. It is concluded that P. volitans venom produces its cardiovascular effects primarily by acting on muscarinic cholinergic receptors and adrenoceptors. As SFAV neutralised many of the effects of P. volitans venom, we suggest that the two venoms share a similar component(s). PMID:12175616

  10. VPAC1 receptors regulate intestinal secretion and muscle contractility by activating cholinergic neurons in guinea pig jejunum.

    Science.gov (United States)

    Fung, Candice; Unterweger, Petra; Parry, Laura J; Bornstein, Joel C; Foong, Jaime P P

    2014-05-01

    In the gastrointestinal tract, vasoactive intestinal peptide (VIP) is found exclusively within neurons. VIP regulates intestinal motility via neurally mediated and direct actions on smooth muscle and secretion by a direct mucosal action, and via actions on submucosal neurons. VIP acts via VPAC1 and VPAC2 receptors; however, the subtype involved in its neural actions is unclear. The neural roles of VIP and VPAC1 receptors (VPAC1R) were investigated in intestinal motility and secretion in guinea pig jejunum. Expression of VIP receptors across the jejunal layers was examined using RT-PCR. Submucosal and myenteric neurons expressing VIP receptor subtype VPAC1 and/or various neurochemical markers were identified immunohistochemically. Isotonic muscle contraction was measured in longitudinal muscle-myenteric plexus preparations. Electrogenic secretion across mucosa-submucosa preparations was measured in Ussing chambers by monitoring short-circuit current. Calretinin(+) excitatory longitudinal muscle motor neurons expressed VPAC1R. Most cholinergic submucosal neurons, notably NPY(+) secretomotor neurons, expressed VPAC1R. VIP (100 nM) induced longitudinal muscle contraction that was inhibited by TTX (1 μM), PG97-269 (VPAC1 antagonist; 1 μM), and hyoscine (10 μM), but not by hexamethonium (200 μM). VIP (50 nM)-evoked secretion was depressed by hyoscine or PG97-269 and involved a small TTX-sensitive component. PG97-269 and TTX combined did not further depress the VIP response observed in the presence of PG97-269 alone. We conclude that VIP stimulates ACh-mediated longitudinal muscle contraction via VPAC1R on cholinergic motor neurons. VIP induces Cl(-) secretion directly via epithelial VPAC1R and indirectly via VPAC1R on cholinergic secretomotor neurons. No evidence was obtained for involvement of other neural VIP receptors. PMID:24578344

  11. Two types of functionally different GABAA receptors mediate GABA modulation of cholinergic transmission in cat terminal ileum.

    Science.gov (United States)

    Radomirov, R; Pencheva, N

    1995-08-01

    1. The effects of GABA (1 microM-2 mM) on longitudinally or circularly oriented organ bath preparations of cat terminal ileum consisted of a relaxation phase with an inhibition of the rhythmic spontaneous phasic contractions, followed by a phase of contractions characterized by an elevation in basal tone and an increase in amplitude of the spontaneous phasic contractions. 2. Muscimol (100 microM), but not baclofen (100 microM), mimicked the relaxation phase of the response to applied GABA (100 microM) in all tissue preparations. In addition, muscimol induced a phase of contractile activity in the circular muscle layer whilst baclofen exerted a 'GABA-like' contractile effect on the longitudinal muscle layer. Bicuculline (30 microM) or picrotoxinin (30 microM) antagonized the GABA- or muscimol-induced relaxations in all preparations and decreased the GABA- but not the baclofen-induced contractions of the longitudinal muscle layer. 3. Tetrodotoxin (0.5 microM) or atropine (0.1 microM) prevented the bicuculline-sensitive phases of the GABA or muscimol effects on both muscle layers but not the contractile effect of baclofen on the longitudinal muscle layer. 4. The bicuculline-sensitive phases of the GABA effect on both muscle layers were almost completely eliminated by 1 nM pirenzepine. At this concentration pirenzepine did not affect the electrically-evoked cholinergic twitch contractions or contractile responses to applied acetylcholine of both muscle layers. 5. During electrically-evoked cholinergic twitch contractions of both muscle layers, GABA (100 microM) had an inhibitory effect. The inhibition occurred in the presence of pirenzepine (1 nM) but not of bicuculline (30 microM). 6. It is suggested that two types of functionally different bicuculline-sensitive GABAA receptors mediate an exitatory presynaptic and an inhibitory prejunctional action of GABA on the cholinergic transmission in cat terminal ileum. PMID:8576270

  12. Central muscarinic cholinergic activation alters interaction between splenic dendritic cell and CD4+CD25- T cells in experimental colitis.

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    Peris Munyaka

    Full Text Available BACKGROUND: The cholinergic anti-inflammatory pathway (CAP is based on vagus nerve (VN activity that regulates macrophage and dendritic cell responses in the spleen through alpha-7 nicotinic acetylcholine receptor (a7nAChR signaling. Inflammatory bowel disease (IBD patients present dysautonomia with decreased vagus nerve activity, dendritic cell and T cell over-activation. The aim of this study was to investigate whether central activation of the CAP alters the function of dendritic cells (DCs and sequential CD4+/CD25-T cell activation in the context of experimental colitis. METHODS: The dinitrobenzene sulfonic acid model of experimental colitis in C57BL/6 mice was used. Central, intracerebroventricular infusion of the M1 muscarinic acetylcholine receptor agonist McN-A-343 was used to activate CAP and vagus nerve and/or splenic nerve transection were performed. In addition, the role of α7nAChR signaling and the NF-kB pathway was studied. Serum amyloid protein (SAP-A, colonic tissue cytokines, IL-12p70 and IL-23 in isolated splenic DCs, and cytokines levels in DC-CD4+CD25-T cell co-culture were determined. RESULTS: McN-A-343 treatment reduced colonic inflammation associated with decreased pro-inflammatory Th1/Th17 colonic and splenic cytokine secretion. Splenic DCs cytokine release was modulated through α7nAChR and the NF-kB signaling pathways. Cholinergic activation resulted in decreased CD4+CD25-T cell priming. The anti-inflammatory efficacy of central cholinergic activation was abolished in mice with vagotomy or splenic neurectomy. CONCLUSIONS: Suppression of splenic immune cell activation and altered interaction between DCs and T cells are important aspects of the beneficial effect of brain activation of the CAP in experimental colitis. These findings may lead to improved therapeutic strategies in the treatment of IBD.

  13. Effect of Ginger and Turmeric Rhizomes on Inflammatory Cytokines Levels and Enzyme Activities of Cholinergic and Purinergic Systems in Hypertensive Rats.

    Science.gov (United States)

    Akinyemi, Ayodele Jacob; Thomé, Gustavo Roberto; Morsch, Vera Maria; Bottari, Nathieli B; Baldissarelli, Jucimara; de Oliveira, Lizielle Souza; Goularte, Jeferson Ferraz; Belló-Klein, Adriane; Duarte, Thiago; Duarte, Marta; Boligon, Aline Augusti; Athayde, Margareth Linde; Akindahunsi, Akintunde Afolabi; Oboh, Ganiyu; Schetinger, Maria Rosa Chitolina

    2016-05-01

    Inflammation exerts a crucial pathogenic role in the development of hypertension. Hence, the aim of the present study was to investigate the effects of ginger (Zingiber officinale) and turmeric (Curcuma longa) on enzyme activities of purinergic and cholinergic systems as well as inflammatory cytokine levels in Nω-nitro-L-arginine methyl ester hydrochloride-induced hypertensive rats. The rats were divided into seven groups (n = 10); groups 1-3 included normotensive control rats, hypertensive (Nω-nitro-L-arginine methyl ester hydrochloride) rats, and hypertensive control rats treated with atenolol (an antihypertensive drug), while groups 4 and 5 included normotensive and hypertensive (Nω-nitro-L-arginine methyl ester hydrochloride) rats treated with 4 % supplementation of turmeric, respectively, and groups 6 and 7 included normotensive and hypertensive rats treated with 4 % supplementation of ginger, respectively. The animals were induced with hypertension by oral administration of Nω-nitro-L-arginine methyl ester hydrochloride, 40 mg/kg body weight. The results revealed a significant increase in ATP and ADP hydrolysis, adenosine deaminase, and acetylcholinesterase activities in lymphocytes from Nω-nitro-L-arginine methyl ester hydrochloride hypertensive rats when compared with the control rats. In addition, an increase in serum butyrylcholinesterase activity and proinflammatory cytokines (interleukin-1 and - 6, interferon-γ, and tumor necrosis factor-α) with a concomitant decrease in anti-inflammatory cytokines (interleukin-10) was observed in Nω-nitro-L-arginine methyl ester hydrochloride hypertensive rats. However, dietary supplementation of both rhizomes was efficient in preventing these alterations in hypertensive rats by decreasing ATP hydrolysis, acetylcholinesterase, and butyrylcholinesterase activities and proinflammatory cytokines in hypertensive rats. Thus, these activities could suggest a possible insight about the protective

  14. Chronic Treatment with Squid Phosphatidylserine Activates Glucose Uptake and Ameliorates TMT-Induced Cognitive Deficit in Rats via Activation of Cholinergic Systems

    Directory of Open Access Journals (Sweden)

    Hyun-Jung Park

    2012-01-01

    Full Text Available The present study examined the effects of squid phosphatidylserine (Squid-PS on the learning and memory function and the neural activity in rats with TMT-induced memory deficits. The rats were administered saline or squid derived Squid-PS (Squid-PS 50 mg kg−1, p.o. daily for 21 days. The cognitive improving efficacy of Squid-PS on the amnesic rats, which was induced by TMT, was investigated by assessing the passive avoidance task and by performing choline acetyltransferase (ChAT and acetylcholinesterase (AchE immunohistochemistry. 18F-Fluorodeoxyglucose and performed a positron emission tomography (PET scan was also performed. In the passive avoidance test, the control group which were injected with TMT showed a markedly lower latency time than the non-treated normal group (P<0.05. However, treatment of Squid-PS significantly recovered the impairment of memory compared to the control group (P<0.05. Consistent with the behavioral data, Squid-PS significantly alleviated the loss of ChAT immunoreactive neurons in the hippocampal CA3 compared to that of the control group (P<0.01. Also, Squid-PS significantly increased the AchE positive neurons in the hippocampal CA1 and CA3. In the PET analysis, Squid-PS treatment increased the glucose uptake more than twofold in the frontal lobe and the hippocampus (P<0.05, resp.. These results suggest that Squid-PS may be useful for improving the cognitive function via regulation of cholinergic enzyme activity and neural activity.

  15. Modulation of non-adrenergic, non-cholinergic neural bronchoconstriction in guinea-pig airways via GABAB-receptors.

    OpenAIRE

    Belvisi, M. G.; M. Ichinose; Barnes, P. J.

    1989-01-01

    1. Evidence suggests that gamma-aminobutyric acid (GABA) and its receptors are present in the peripheral nervous system. We have now investigated the effect of GABA and related substances on non-adrenergic, non-cholinergic (NANC) neurally-evoked bronchoconstriction in the anaesthetised guinea-pig. 2. Bilateral vagal stimulation (5 V, 5 ms, 3 or 5 Hz) for 30 s, after propranolol (1 mg kg-1 i.v.) and atropine (1 mg kg-1 i.v.) evoked a NANC bronchoconstrictor response manifest as a mean tracheal...

  16. Comparative Study of Korean White, Red, and Black Ginseng Extract on Cholinesterase Inhibitory Activity and Cholinergic Function

    OpenAIRE

    Lee, Mi Ra; Yun, Beom Sik; In, Oh Hyun; Sung, Chang Keun

    2011-01-01

    This study evaluated cholineresterase inhibitory activity of Korean white ginseng extract (WGE), red ginseng extract (RGE), and black ginseng extract (BGE) and the cholinergic effect on scopolamine (SCOP)-induced amnesic mice. WGE, RGE, and BGE inhibited acetylcholineserase (AChE), as well as butyrylcholineserase (BuChE) in a concentration-dependent manner. BGE presented strong inhibition of AChE with an IC50 value of 1.72 mg/mL, followed by WGE (5.89 mg/mL), RGE (6.30 mg/mL), respectively. T...

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

    Institute of Scientific and Technical Information of China (English)

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

    2011-01-01

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

  18. Visualization of ATP release in pancreatic acini in response to cholinergic stimulus. Use of fluorescent probes and confocal microscopy

    DEFF Research Database (Denmark)

    Sørensen, Christiane Elisabeth; Novak, Ivana

    2001-01-01

    receptors on pancreatic ducts. Thus, it was relevant to ask whether the upstream acini could be the source of releasable ATP and what the stimulus might be. We used freshly prepared rat pancreatic acini and applied conventional luminescence measurements of luciferin/luciferase reaction. As a new application...... partially overlapping with those marked by acridine orange and LysoTracker Red. In functional studies we show that native pancreatic acini release ATP in response to various stimuli but most importantly to cholinergic stimulation, a very likely physiological stimulus in this epithelium. In a close vicinity...

  19. Studying the central control of food intake and obesity in rats Estudando em ratos o controle central da ingestão alimentar e a obesidade

    OpenAIRE

    Eliane Beraldi Ribeiro

    2009-01-01

    The central nervous system regulates energy intake and expenditure through a complex network of neurotransmitters and neuromodulators. It is of great interest to understand the relevance of these systems to the physiological control of energy balance and to the disturbances of obesity. The present paper discusses some of the methods to address this field used at the laboratory of Endocrine Physiology of Universidade Federal de São Paulo. Initially, different experimental models of rat obesity...

  20. Further proof of the existence of a non-neuronal cholinergic system in the human Achilles tendon: Presence of the AChRα7 receptor in tendon cells and cells in the peritendinous tissue.

    Science.gov (United States)

    Forsgren, Sture; Alfredson, Håkan; Andersson, Gustav

    2015-11-01

    Human tendon cells have the capacity for acetylcholine (ACh) production. It is not known if the tendon cells also have the potential for ACh breakdown, nor if they show expression of the nicotinic acetylcholine receptor AChRα7 (α7nAChR). Therefore, tendon tissue specimens from patients with midportion Achilles tendinopathy/tendinosis and from normal midportion Achilles tendons were examined. Reaction for the degradative enzyme acetylcholinesterase (AChE) was found in some tenocytes in only a few tendinopathy tendons, and was never found in those of control tendons. Tenocytes displayed more regularly α7nAChR immunoreactivity. However, there was a marked heterogeneity in the degree of this reaction within and between the specimens. α7nAChR immunoreactivity was especially pronounced for tenocytes showing an oval/widened appearance. There was a tendency that the magnitude of α7nAChR immunoreactivity was higher in tendinopathy tendons as compared to control tendons. A stronger α7nAChR immunoreactivity than seen for tenocytes was observed for the cells in the peritendinous tissue. It is likely that the α7nAChR may be an important part of an auto-and paracrine loop of non-neuronal ACh that is released from the tendon cells. The effects may be related to proliferative and blood vessel regulatory functions as well as features related to collagen deposition. ACh can furthermore be of importance in leading to anti-inflammatory effects in the peritendinous tissue, a tissue nowadays considered to be of great relevance for the tendinopathy process. Overall, the findings show that tendon tissue, a tissue known to be devoid of cholinergic innervation, is a tissue in which there is a marked non-neuronal cholinergic system. PMID:25981114

  1. O uso da neuromodulação no tratamento das disfunções de eliminações Neuromodulation in the treatment of eliminations dysfunction syndrome

    Directory of Open Access Journals (Sweden)

    Lisieux Eyer de Jesus

    2007-12-01

    Full Text Available OBJETIVO: Apresentar a experiência clínica com o uso de neuromodulação através de eletroestimulação transcutânea no tratamento das disfunções de eliminação. MÉTODOS: Foram analisados retrospectivamente seis pacientes com disfunções de eliminação submetidos à neuromodulação através de eletroestimulação percutânea peri-sacral. Todos os pacientes incluídos eram refratários ao tratamento clínico convencional e a eletroestimulação foi utilizada como terapia de resgate. As sessões terapêuticas eram semanais e o seguimento mínimo foi de seis meses. RESULTADOS: Todos os pacientes obtiveram melhora clínica. Quatro pacientes não necessitaram de mais medicação. Todos aceitaram bem o tratamento e referiram melhora da qualidade de vida. CONCLUSÃO: A eletroestimulação percutânea mostrou-se útil no tratamento das disfunções do assoalho pélvico e da musculatura vesical.OBJECTIVE: To present a clinical trial with neuromodulation through percutaneous electrical stimulation in the treatment of elimination dysfunctions. METHODS: Six patients with dysfunctional elimination diagnosis were included and their data were analyzed retrospectively, regarding percutaneous sacral electrical stimulation. All the patients included, have had unsuccessful conventional treatments and the electrical stimulation was used as rescue therapy. All the sessions were applied in weekly fashion for six months. RESULTS: All the patients have had a positive clinical outcome, with four of them interrupting their medication. All the patients accepted well the therapy and referred an improvement in their quality of life. CONCLUSION: The electrical percutaneous stimulation, showed to be effective on vesical muscle and pelvic floor dysfunctions.

  2. Effectiveness of methylphenidate as augmentation therapy after failure of adjunctive neuromodulation for patients with treatment-refractory bipolar depression: a case report.

    Science.gov (United States)

    Adida, Marc; Azorin, Jean-Michel

    2014-01-01

    Adjunctive use of methylphenidate, a central stimulant, has been considered as a potential therapeutic choice for patients with refractory unipolar, geriatric, or bipolar depression, and depression secondary to medical illness. We present a case of bipolar depression in which the patient responded significantly to augmentation with methylphenidate, without any side effects, after failure of adjunctive repetitive transcranial magnetic stimulation and electroconvulsive therapy. Mr U, a 56-year-old man with bipolar I disorder, had melancholic symptoms during his sixth episode of bipolar depression. After failure of repetitive transcranial magnetic stimulation and electroconvulsive therapy, he was treated with fluoxetine 80 mg/day, duloxetine 360 mg/day, mirtazapine 60 mg/day, and sodium valproate 1,000 mg/day, with no improvement. We added methylphenidate at a dose of 10 mg/day for one week, which resulted in mild clinical improvement, and then methylphenidate extended-release 20 mg/day for one week, with significant clinical improvement. He tolerated his medications well. His clinical recovery was stable over one year. The patient's antidepressants and methylphenidate were gradually tapered and finally discontinued after one year with no withdrawal syndrome. To date, he remains well on sodium valproate as monotherapy and is being followed up at our bipolar department. This case suggests that methylphenidate augmentation might be a therapeutic option when treating highly treatment-resistant patients with bipolar depression, even if they had not responded to adjunctive neuromodulation. In these clinical situations, physicians might be interested in prescribing methylphenidate because of its efficacy and safety. PMID:24729710

  3. Synaptic vesicle cycling is not impaired in a glutamatergic and a cholinergic synapse that exhibit deficits in acidification and filling

    Directory of Open Access Journals (Sweden)

    Bento João Abreu

    2012-03-01

    Full Text Available The purpose of the present work was to investigate synaptic vesicle trafficking when vesicles exhibit alterations in filling and acidification in two different synapses: a cholinergic frog neuromuscular junction and a glutamatergic ribbon-type nerve terminal in the retina. These synapses display remarkable structural and functional differences, and the mechanisms regulating synaptic vesicle cycling might also differ between them. The lipophilic styryl dye FM1-43 was used to monitor vesicle trafficking. Both preparations were exposed to pharmacological agents that collapse ΔpH (NH4Cl and methylamine or the whole ΔµH+ (bafilomycin, a necessary situation to provide the driving force for neurotransmitter accumulation into synaptic vesicles. The results showed that FM1-43 loading and unloading in neuromuscular junctions did not differ statistically between control and experimental conditions (P > 0.05. Also, FM1-43 labeling in bipolar cell terminals proved highly similar under all conditions tested. Despite remarkable differences in both experimental models, the present findings show that acidification and filling are not required for normal vesicle trafficking in either synapse.O objetivo do presente trabalho foi investigar o tráfego de vesículas sinápticas quando estas apresentam alterações no armazenamento de neurotransmissores e acidificação em duas distintas sinapses: a junção neuromuscular colinérgica de rãs versus o terminal nervoso glutamatérgico do tipo ribbon em céulas bipolares da retina. Essas sinapses exibem notáveis diferenças estruturais e funcionais e os mecanismos de regulação de ciclo das vesículas sinápticas podem ser diferentes entre eles. Para monitorar o tráfego de vesícula, foi utilizado o marcador lipofílico FM1-43. Ambas as preparações foram expostas a agentes farmacológicos que provocam o colapso de ΔpH (NH4Cl e metilamina ou de todo ΔµH+ (bafilomicina, gradientes necessários para o ac

  4. Developmental profile of the aberrant dopamine D2 receptor response in striatal cholinergic interneurons in DYT1 dystonia.

    Directory of Open Access Journals (Sweden)

    Giuseppe Sciamanna

    Full Text Available BACKGROUND: DYT1 dystonia, a severe form of genetically determined human dystonia, exhibits reduced penetrance among carriers and begins usually during adolescence. The reasons for such age dependence and variability remain unclear. METHODS AND RESULTS: We characterized the alterations in D2 dopamine receptor (D2R signalling in striatal cholinergic interneurons at different ages in mice overexpressing human mutant torsinA (hMT. An abnormal excitatory response to the D2R agonist quinpirole was recorded at postnatal day 14, consisting of a membrane depolarization coupled to an increase in spiking frequency, and persisted unchanged at 3 and 9 months in hMT mice, compared to mice expressing wild-type human torsinA and non-transgenic mice. This response was blocked by the D2R antagonist sulpiride and depended upon G-proteins, as it was prevented by intrapipette GDP-β-S. Patch-clamp recordings from dissociated interneurons revealed a significant increase in the Cav2.2-mediated current fraction at all ages examined. Consistently, chelation of intracellular calcium abolished the paradoxical response to quinpirole. Finally, no gross morphological changes were observed during development. CONCLUSIONS: These results suggest that an imbalanced striatal dopaminergic/cholinergic signaling occurs early in DYT1 dystonia and persists along development, representing a susceptibility factor for symptom generation.

  5. Molecular imaging of cholinergic processes in prostate cancer using {sup 11}C-donepezil and {sup 18}F-FEOBV

    Energy Technology Data Exchange (ETDEWEB)

    Stokholm, Morten Gersel; Bender, Dirk; Jakobsen, Steen; Froekiaer, Joergen; Borghammer, Per [Aarhus University Hospital, Department of Nuclear Medicine and PET Centre, Aarhus C (Denmark); Hoeyer, Soeren [Aarhus University Hospital, Department of Histopathology, Aarhus C (Denmark); Borre, Michael [Aarhus University Hospital, Department of Urology, Aarhus C (Denmark)

    2016-05-15

    High-grade prostate cancer (PC) displays parasympathetic neoneurogenesis. We investigated the binding of two PET tracers that visualize cholinergic nerves in PC tissue using autoradiography. Prostatectomy tissue was subjected to autoradiography with {sup 11}C-donepezil and {sup 18}F-FEOBV and correlated with Gleason scores (GS). Regions of interest on the autoradiograms were defined and quantified. Tracer binding in cancer tissue regions was compared with that in normal tissue. We included 13 patients with biopsy-verified PC. In particular, {sup 11}C-donepezil uptake was higher in ''high-grade'' PC (GS ≥4 + 3) than in ''low-grade'' PC and benign hyperplasia. {sup 11}C-donepezil uptake ranged from a mean of 56 % higher (GS 3 + 3) to 409 % higher (GS 4 + 4), and {sup 18}F-FEOBV uptake ranged from 67 % higher (GS 3 + 3) to 194 % higher (GS 4 + 5). The uptake of both tracers was higher in PC with a high GS than in PC with a low GS, but the difference was significant only for {sup 11}C-donepezil (p = 0.003). Uptake of PET tracers binding to cholinergic nerves was markedly higher in PC with a high GS than in PC with a low GS. This finding implies that {sup 11}C-donepezil PET/CT may be able to differentiate between low-grade and high-grade PC. (orig.)

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

    Directory of Open Access Journals (Sweden)

    Paola Correa

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

  7. Molecular imaging of cholinergic processes in prostate cancer using 11C-donepezil and 18F-FEOBV

    International Nuclear Information System (INIS)

    High-grade prostate cancer (PC) displays parasympathetic neoneurogenesis. We investigated the binding of two PET tracers that visualize cholinergic nerves in PC tissue using autoradiography. Prostatectomy tissue was subjected to autoradiography with 11C-donepezil and 18F-FEOBV and correlated with Gleason scores (GS). Regions of interest on the autoradiograms were defined and quantified. Tracer binding in cancer tissue regions was compared with that in normal tissue. We included 13 patients with biopsy-verified PC. In particular, 11C-donepezil uptake was higher in ''high-grade'' PC (GS ≥4 + 3) than in ''low-grade'' PC and benign hyperplasia. 11C-donepezil uptake ranged from a mean of 56 % higher (GS 3 + 3) to 409 % higher (GS 4 + 4), and 18F-FEOBV uptake ranged from 67 % higher (GS 3 + 3) to 194 % higher (GS 4 + 5). The uptake of both tracers was higher in PC with a high GS than in PC with a low GS, but the difference was significant only for 11C-donepezil (p = 0.003). Uptake of PET tracers binding to cholinergic nerves was markedly higher in PC with a high GS than in PC with a low GS. This finding implies that 11C-donepezil PET/CT may be able to differentiate between low-grade and high-grade PC. (orig.)

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

    Science.gov (United States)

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

    2015-05-01

    The laterodorsal tegmental nucleus (LDT) is a brainstem nucleus implicated in reward processing and is one of the main sources of cholinergic afferents to the ventral tegmental area (VTA). Neuroplasticity in this structure may affect the excitability of VTA dopamine neurons and mesocorticolimbic circuitry. Here, we provide evidence that cocaine-induced intrinsic membrane plasticity in LDT cholinergic neurons is involved in addictive behaviors. After repeated experimenter-delivered cocaine exposure, ex vivo whole-cell recordings obtained from LDT cholinergic neurons revealed an induction of intrinsic membrane plasticity in regular- but not burst-type neurons, resulting in increased firing activity. Pharmacological examinations showed that increased riluzole-sensitive persistent sodium currents, but not changes in Ca(2+) -activated BK, SK or voltage-dependent A-type potassium conductance, mediated this plasticity. In addition, bilateral microinjection of riluzole into the LDT immediately before the test session in a cocaine-induced conditioned place preference (CPP) paradigm inhibited the expression of cocaine-induced CPP. These findings suggest that intrinsic membrane plasticity in LDT cholinergic neurons is causally involved in the development of cocaine-induced addictive behaviors. PMID:25712572

  9. Selective immunolesion of cholinergic neurons leads to long-term changes in 5-HT2A receptor levels in hippocampus and frontal cortex

    DEFF Research Database (Denmark)

    Severino, Maurizio; Pedersen, Anja F; Trajkovska, Viktorija;

    2007-01-01

    Although loss of cholinergic neurons in the basal forebrain is considered a key initial feature in Alzheimer's disease (AD), changes in other transmitter systems, including serotonin and 5-HT(2A) receptors, are also associated with early AD. The aim of this study was to investigate whether elimin...

  10. Loss of MeCP2 in cholinergic neurons causes part of RTT-like phenotypes via α7 receptor in hippocampus.

    Science.gov (United States)

    Zhang, Ying; Cao, Shu-Xia; Sun, Peng; He, Hai-Yang; Yang, Ci-Hang; Chen, Xiao-Juan; Shen, Chen-Jie; Wang, Xiao-Dong; Chen, Zhong; Berg, Darwin K; Duan, Shumin; Li, Xiao-Ming

    2016-06-01

    Mutations in the X-linked MECP2 gene cause Rett syndrome (RTT), an autism spectrum disorder characterized by impaired social interactions, motor abnormalities, cognitive defects and a high risk of epilepsy. Here, we showed that conditional deletion of Mecp2 in cholinergic neurons caused part of RTT-like phenotypes, which could be rescued by re-expressing Mecp2 in the basal forebrain (BF) cholinergic neurons rather than in the caudate putamen of conditional knockout (Chat-Mecp2(-/y)) mice. We found that choline acetyltransferase expression was decreased in the BF and that α7 nicotine acetylcholine receptor signaling was strongly impaired in the hippocampus of Chat-Mecp2(-/y) mice, which is sufficient to produce neuronal hyperexcitation and increase seizure susceptibility. Application of PNU282987 or nicotine in the hippocampus rescued these phenotypes in Chat-Mecp2(-/y) mice. Taken together, our findings suggest that MeCP2 is critical for normal function of cholinergic neurons and dysfunction of cholinergic neurons can contribute to numerous neuropsychiatric phenotypes. PMID:27103432

  11. Alterations in cholinergic sensitivity of respiratory neurons induced by pre-natal nicotine: a mechanism for respiratory dysfunction in neonatal mice

    OpenAIRE

    Coddou, Claudio; Bravo, Eduardo; Eugenín, Jaime

    2009-01-01

    Nicotine may link cigarette smoking during pregnancy with sudden infant death syndrome (SIDS). Pre-natal nicotine leads to diminished ventilatory responses to hypercarbia and reduced central chemoreception in mice at post-natal days 0–3. We studied how pre-natal nicotine exposure changes the cholinergic contribution to central respiratory chemoreception in neonatal isolated brainstem–spinal cord and slice preparations.

  12. Alterations of cholinergic markers in transgenic APPSWE/PS1DE9 and APPSWE/PS1A246E mouse models of Alzheimer´s disease

    Czech Academy of Sciences Publication Activity Database

    Machová, Eva; Jakubík, Jan; Michal, Pavel; Oksman, M.; Iivonen, H.; Tanila, H.; Doležal, Vladimír

    ISN, 2007. s. 52-52. [ISN Advanced School of Neurochemistry /8./. 15.08.2007-19.08.2007, Valladolid] R&D Projects: GA AV ČR(CZ) IAA500110703; GA MŠk(CZ) LC554 Institutional research plan: CEZ:AV0Z50110509 Keywords : spr2 * cholinergic markes * Alzheimer ´s disease Subject RIV: FH - Neurology

  13. Age- and Sex-Dependent Laterality of Rat Hippocampal Cholinergic System in Relation to Animal Models of Neurodevelopmental and Neurodegenerative Disorders

    Czech Academy of Sciences Publication Activity Database

    Krištofíková, Z.; Šťastný, F.; Bubeníková, V.; Druga, R.; Klaschka, Jan; Španiel, F.

    2004-01-01

    Roč. 29, č. 4 (2004), s. 671-680. ISSN 0364-3190 R&D Projects: GA MZd NF6031 Institutional research plan: CEZ:AV0Z1030915 Keywords : laterality * cholinergic * excitotoxic * rat model * schizophrenia * Alzheimer disease Subject RIV: BB - Applied Statistics, Operational Research Impact factor: 2.218, year: 2004

  14. Cholinesterases: structure of the active site and mechanism of the effect of cholinergic receptor blockers on the rate of interaction with ligands

    International Nuclear Information System (INIS)

    Modern views on the structure of cholinesterase active sites and the mechanism of their interaction with organophosphorus inhibitors are considered. The attention is focused on the mechanism of the effect of cholinergic receptor blockers, acetylcholine antagonists, on the rate of interaction of acetylcholine esterase with organophosphorus inhibitors.

  15. Quantitative autoradiography of muscarine cholinergic receptors and their M1 and M2 subtypes in the rat hippocampus. Influence of a mixed neutron-gamma irradiation. Preliminary study

    International Nuclear Information System (INIS)

    The muscarine cholinergic receptors and their M1 and M2 subtypes are studied by quantitative autoradiography in the hippocampus of 8 shams and 9 rats exposed to a mixed neutron-gamma irradiation at a dose of 8 Gy. 75 minutes post irradiation, no significative difference is noted

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

    Directory of Open Access Journals (Sweden)

    Benedikt Zujalovic

    2015-01-01

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

  17. 17 beta-estradiol enhances cortical cholinergic innervation and preserves synaptic density following excitotoxic lesions to the rat nucleus basalis magnocellularis

    NARCIS (Netherlands)

    Horvath, KM; Hartig, W; Van der Veen, R; Mulder, J; Ziegert, M; Van der Zee, EA; Harkany, T; Luiten, PGM; Keijser, Jan N.

    2002-01-01

    Estradiol exerts beneficial effects on neurodegenerative disorders associated with the decline of cognitive performance. The present study was designed to further investigate the effect of 17beta-estradiol on learning and memory, and to evaluate its neuroprotective action on cholinergic cells of the

  18. How reduction of theta rhythm by medial septum inactivation may covary with disruption of entorhinal grid cell responses due to reduced cholinergic transmission

    Directory of Open Access Journals (Sweden)

    Praveen K. Pilly

    2013-10-01

    Full Text Available Oscillations in the coordinated firing of brain neurons have been proposed to play important roles in perception, cognition, attention, learning, navigation, and sensory-motor control. The network theta rhythm has been associated with properties of spatial navigation, as has the firing of entorhinal grid cells and hippocampal place cells. Two recent studies reduced the theta rhythm by inactivating the medial septum (MS and demonstrated a correlated reduction in the characteristic hexagonal spatial firing patterns of grid cells. These results, along with properties of intrinsic membrane potential oscillations (MPOs in slice preparations of entorhinal cells, have been interpreted to support oscillatory interference models of grid cell firing. The current article shows that an alternative self-organizing map model of grid cells can explain these data about intrinsic and network oscillations without invoking oscillatory interference. In particular, the adverse effects of MS inactivation on grid cells can be understood in terms of how the concomitant reduction in cholinergic inputs may increase the conductances of leak potassium (K+ and slow and medium after-hyperpolarization (sAHP and mAHP channels. This alternative model can also explain data that are problematic for oscillatory interference models, including how knockout of the HCN1 gene in mice, which flattens the dorsoventral gradient in MPO frequency and resonance frequency, does not affect the development of the grid cell dorsoventral gradient of spatial scales, and how hexagonal grid firing fields in bats can occur even in the absence of theta band modulation. These results demonstrate how models of grid cell self-organization can provide new insights into the relationship between brain learning, oscillatory dynamics, and navigational behaviors.

  19. Sphenopalatine ganglion neuromodulation in migraine

    DEFF Research Database (Denmark)

    Khan, Sabrina; Schoenen, Jean; Ashina, Messoud

    2014-01-01

    OBJECTIVE: The objective of this article is to review the prospect of treating migraine with sphenopalatine ganglion (SPG) neurostimulation. BACKGROUND: Fuelled by preliminary studies showing a beneficial effect in cluster headache patients, the potential of treating migraine with neurostimulation...... has gained increasing interest within recent years, as current treatment strategies often fail to provide adequate relief from this debilitating headache. Common migraine symptoms include lacrimation, nasal congestion, and conjunctival injection, all parasympathetic manifestations. In addition......, studies have suggested that parasympathetic activity may also contribute to the pain of migraineurs. The SPG is the largest extracranial parasympathetic ganglion of the head, innervating the meninges, lacrimal gland, nasal mucosa, and conjunctiva, all structures involved in migraine with cephalic...

  20. Perioral Dermatitis after Dental Filling in a 12-Year-Old Girl: Involvement of Cholinergic System in Skin Neuroinflammation?

    Directory of Open Access Journals (Sweden)

    Fabrizio Guarneri

    2008-01-01

    Full Text Available The etiopathogenesis of perioral dermatitis (PD is still unknown and, consequently, medical treatment is difficult, not precisely defined, and often unsatisfactory. On the basis of a peculiar case that appeared soon after multiple dental fillings with a mercury-containing amalgam, we proposed that neurogenic inflammation could play a role in the pathogenesis of PD. According to the new findings provided by clinical and basic research, neurogenic inflammation has a relevant part in the pathogenesis of many cutaneous diseases. We report a similar case of PD, taking into account, more specifically, the possible involvement of the cholinergic system. Also in this case, PD seems to be mainly related to the mercury contained in dental fillings and/or its organic compounds formed by oral/gut bacteria. We examined the possible role of these substances as causes of PD, providing new information on the possible cross-talk between neuroimmunodermatology and potential triggers of PD.

  1. [Advances in the research of effects of cholinergic anti-inflammatory pathway on vital organ function and its mechanism].

    Science.gov (United States)

    Li, X H; Yao, Y M

    2016-07-20

    Serious major burns, trauma and surgical stress can easily develop into sepsis, and further result in septic shock or even multiple organ dysfunction syndrome (MODS). The mechanism of MODS is complicated, including excessive inflammation, immune dysfunction, coagulation disorder, and ischemia-reperfusion injury. Recent studies have demonstrated that the nervous system could significantly and quickly suppress systemic inflammatory response via the vagus nerve, which might improve multiple organ damage following acute injury. This article is to brief our understanding concerning the structure characteristics of cholinergic anti-inflammatory pathway, and its effects on vital organ function and the regulatory mechanism, which might be of great significance to seek a novel way for interventional strategy of MODS. PMID:27464633

  2. Effects of trihexyphenidyl and L-dopa on brain muscarinic cholinergic receptor binding measured by positron emission tomography

    International Nuclear Information System (INIS)

    The effects of pharmacological intervention on brain muscarinic cholinergic receptor (mAChR) binding were assessed in seven patients with Parkinson's disease by positron emission tomography and carbon-11 labelled N-methyl-4-piperidyl benzilate ([11C]NMPB). [11C]NMPB was injected twice, approximately 2 hours apart, in each patient, to assess the effect of single doses of 4 mg of trihexyphenidyl (n=5) or 400 mg of L-dopa with 57 mg of benserazide (n=2) on the binding parameter of mAChRs (K3). There was a mean 28% inhibition of K3 values in the brain in the presence of trihexyphenidyl, which was assumed to reflect mAChR occupancy. No significant change in K3 was observed in the presence of L-dopa. This study demonstrates the feasibility of measuring mAChR occupancy by an anticholinergic medication with PET

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

    International Nuclear Information System (INIS)

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

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

    Institute of Scientific and Technical Information of China (English)

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

    2009-01-01

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

  5. Evidence for broad versus segregated projections from cholinergic and noradrenergic nuclei to functionally and anatomically discrete subregions of prefrontal cortex

    Directory of Open Access Journals (Sweden)

    Daniel J. Chandler

    2012-05-01

    Full Text Available The prefrontal cortex (PFC is implicated in a variety of cognitive and executive operations. However, this region is not a single functional unit; rather, it is composed of several functionally and anatomically distinct networks, including anterior cingulate cortex (ACC, medial prefrontal cortex (mPFC and orbitofrontal cortex (OFC. These prefrontal subregions serve dissociable behavioral functions, and are unique in their afferent and efferent connections. Each of these subregions is innervated by ascending cholinergic and noradrenergic systems, each of which likewise has a distinct role in cognitive function; yet the distribution and projection patterns of cells in the source nuclei for these pathways have not been examined in great detail. In this study, fluorescent retrograde tracers were injected into ACC, mPFC and OFC, and labeled cells were identified in the cholinergic nucleus basalis of Meynert (NBM and noradrenergic nucleus locus coeruleus (LC. Injections into all three cortical regions consistently labeled cells primarily ipsilateral to the injection site with a minimal contralateral component. In NBM, retrogradely labeled neurons were scattered throughout the rostral half of the nucleus, whereas those in LC tended to cluster in the core of the nucleus, and were rarely localized within the rostral or caudal poles. In NBM, more than half of all retrogradely labeled cells possessed axon collaterals projecting two or more PFC subregions. In LC, however, only 4.3% of retrogradely labeled neurons possessed collaterals targeting any two prefrontal subregions simultaneously, and no cells were identified that projected to all three regions. Of all labeled LC neurons, 49.3% projected only to mPFC, 28.5% projected only to OFC, and 18.0% projected only to ACC. These findings suggest that subsets of LC neurons may be capable of modulating neuronal activity in individual prefrontal subregions independently, whereas assemblies of NBM cells may exert

  6. Prolactin release during exercise in normal and adrenodemedullated untrained rats submitted to central cholinergic blockade with atropine.

    Science.gov (United States)

    Lima, N R; Pereira, W; Reis, A M; Coimbra, C C; Marubayashi, U

    2001-12-01

    To study the role of the central cholinergic system in pituitary prolactin (PRL) release during exercise we injected atropine (5 x 10(-7) mol) into the lateral cerebral ventricle of intact or adrenodemedullated (ADM) untrained rats, at rest or submitted to exercise on a treadmill (18 m x min(-1), 5% grade) until exhaustion. The rats were implanted with chronic jugular catheters for blood sampling and with unilateral intracerebroventricular (icv) cannulas placed in the right lateral ventricle. Blood prolactin concentrations were measured before and every 10 min after the start of exercise for a period of 60 min. After the animals started running, plasma prolactin levels rose rapidly in both normal and ADM rats, reaching near maximum at 10 min. Close to exhaustion (19.8 +/- 2.9 min for intact rats and 23.5 +/- 4.1 min for ADM) they were still high, remained increased until 30 min, and returned to preexercise levels at 40 min. Icv injections of atropine decreased the time to exhaustion by 67% in intact rats and by 96.2% in ADM and also reduced the exercise-induced PRL release in both intact (50%) and ADM rats (90%). The results showed that prolactin release induced by exercise was dependent on the exercise workload and could be observed as early as after 10 min of running, remaining increased until 30 min. These data indicate that adrenodemedullation does not affect prolactin secretion induced by exercise, although adrenodemedullated rats proved to be more sensitive to the reducing effect of central cholinergic blockade on their maximal capacity for exercise. PMID:11716582

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-03-02

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

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

    Directory of Open Access Journals (Sweden)

    B. Cam-Etoz

    2012-03-01

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

  9. Effects of mercuric chloride and methyl mercury on cholinergic neuromuscular transmission in the guinea-pig ileum

    International Nuclear Information System (INIS)

    The effects of mercuric chloride (HgCl2) and methyl mercury (MeHg) were examined on basal mechanical activity and electrically-induced neurogenic cholinergic contractions (twitch contractions) in longitudinal muscle-myenteric plexus strips from guinea-pig distal ileum. Both compounds at 0.3-3 μM slightly enhanced the amplitude of twitch contractions in ∼50% preparations. This effect was probably due to facilitation of acetylcholine (ACh) release since 0.1 and 1 μM mercurials increased electrically-evoked tritium outflow from [3H]choline preloaded muscle layer with attached myenteric plexus. Conversely, higher mercury concentrations inhibited twitch contractions (HgCl2 IC50 = 21.3±6.4 μM; MeHg IC50 = 45.1±5.5 μM), as well as contractions to exogenous ACh (0.1 μM) in resting preparations, and concomitantly increased the basal tone. The former effects possibly reflected an anti muscarinic activity of mercury, while the latter was related to alterations of calcium homeostasis in the effector cells. Indeed, the effect of HgCl2 on basal tone was antagonized by the Ca2+ entry blocker nifedipine (3, 10, 30 nM), indicating Hg-induced facilitation of Ca2+ influx through voltage-dependent channels. On the whole, our results suggest that cholinergic neuromuscular transmission and Ca2+-dependent mechanisms underlying smooth muscle contractility are targets for mercury toxicity in the intestine. (au) 51 refs

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

    International Nuclear Information System (INIS)

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

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

    Directory of Open Access Journals (Sweden)

    Naitao Wang

    2016-05-01

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

  12. Nuevas Terapias: Estimulación eléctrica percutánea en dolor lumbar y cervical New therapies: Neuromodulation in the treatment of low back and cervical pain

    Directory of Open Access Journals (Sweden)

    V. Villanueva

    2007-04-01

    Full Text Available La elevada incidencia y prevalencia del dolor lumbar y del cervical en las sociedades industrializadas hace que se consideren patologías de primer orden en los sistemas sanitarios, ya que además del elevado consumo de recursos sanitarios generan una importante pérdida de horas laborales. Son múltiples las opciones terapéuticas para el tratamiento de estos procesos, planteándose la estimulación eléctrica percutánea (PNT como una novedad dentro del abanico de posibilidades de tratamiento. Como característica diferencial con otros sistemas de neuromodulación resulta menos invasiva y con un perfil de seguridad y eficacia realmente notable. Presentamos una recopilación de los datos publicados más relevantes que avalan esta técnica y un breve comentario de los resultados preliminares de su utilización en nuestro país.The high incidence and prevalence of low back and cervical pain in industrialized societies ensues its importance for health systems. These conditions generate a high consumption of health resources and a significant loss of working hours. Among the therapeutic options for the treatment of these processes, Percutaneous Neuromodulation Therapy (PNT is an innovative procedure within the range of therapies available. PNT, unlike other neuromodulation systems, is less invasive and has a considerable safety and efficacy profile. A review of the relevant published data regarding this technique and a brief report on its preliminary results for its use in our country are made.

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

    OpenAIRE

    Vijayaraghavan, Swetha; Karami, Azadeh; Aeinehband, Shahin; Behbahani, Homira; Grandien, Alf; Nilsson, Bo; Ekdahl, Kristina N.; Lindblom, Rickard P. F.; Piehl, Fredrik; Darreh-Shori, Taher

    2013-01-01

    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 effici...

  14. Changes of cholinergic markers and muscarinic transmission in young and aged APP/PS1 double transgenic mice model of Alzheimer´s disease

    Czech Academy of Sciences Publication Activity Database

    Machová, Eva; Jakubík, Jan; Michal, Pavel; Oksman, M.; Iivonen, H.; Tanila, H.; Doležal, Vladimír

    Fyziologický ústav AV ČR, v. v. i.. Roč. 56, č. 3 (2007), 20P-21P ISSN 0862-8408. [Fyziologické dny /83./. 06.02.2007-08.02.2007, Brno] R&D Projects: GA MŠk(CZ) LC554; GA AV ČR IAA5011206 Institutional research plan: CEZ:AV0Z50110509 Keywords : cpr1 * cholinergic markers * muscarinic transmission * Alzheimer ´s disease Subject RIV: FH - Neurology

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

    Science.gov (United States)

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

    2014-11-15

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

  16. Liang-Ge-San, a classic traditional Chinese medicine formula, protects against lipopolysaccharide-induced inflammation through cholinergic anti-inflammatory pathway.

    Science.gov (United States)

    Liu, Jun-Shan; Wei, Xi-Duan; Lu, Zi-Bin; Xie, Pei; Zhou, Hong-Ling; Chen, Yu-Yao; Ma, Jia-Mei; Yu, Lin-Zhong

    2016-04-19

    Liang-Ge-San (LGS) is a classic formula in traditional Chinese medicine, which is widely used to treat acute lung injury (ALI), pharyngitis and amygdalitis in clinic. However, the underlying mechanisms remain poorly defined. In this study, we discovered that LGS exerted potent anti-inflammatory effects in lipopolysaccharide (LPS)-induced inflammation. We found that LGS significantly depressed the production of IL-6 and TNF-α in LPS-stimulated RAW 264.7 macrophage cells. The degradation and phosphorylation of IκBα and the nuclear translocation of NF-κB p65 were also inhibited. Moreover, LGS activated α7 nicotinic cholinergic receptor (α7nAchR). The blockage of α7nAchR by selective inhibitor methyllycaconitine (MLA) or α7nAchR siRNA attenuated the inhibitory effects of LGS on IκBα, NF-κB p65, IL-6 and TNF-α. Critically, LGS significantly inhibited inflammation in LPS-induced ALI rats through the activation of NF-κB signaling pathway. However, these protective effects could be counteracted by the treatment of MLA. Taken together, we first demonstrated anti-inflammatory effects of LGS both in vitro and in vivo through cholinergic anti-inflammatory pathway. The study provides a rationale for the clinical application of LGS as an anti-inflammatory agent and supports the critical role of cholinergic anti-inflammatory pathway in inflammation. PMID:27034013

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

    Science.gov (United States)

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

    2016-06-01

    Schizophrenia (SZ) is a psychiatric disorder characterized by cognitive dysfunction within the realm of attentional processing. Reduced P3a and P3b event-related potentials (ERPs), indexing involuntary and voluntary attentional processing respectively, have been consistently observed in SZ patients who also express prominent cholinergic deficiencies. The involvement of the brain's cholinergic system in attention has been examined for several decades; however, further inquiry is required to further comprehend how abnormalities in this system affect neighbouring neurotransmitter systems and contribute to neurocognitive deficits. The objective of this pilot study was to examine the moderating role of the CHRNA4 (rs1044396), CHRNA7 (rs3087454), and SLC5A7 (rs1013940) genes on ERP indices of attentional processing in healthy volunteers (N=99; Caucasians and non-Caucasians) stratified by genotype and assessed using the auditory P300 "oddball" paradigm. Results indicated significantly greater P3a and P3b-indexed attentional processing for CT (vs. CC) CHRNA4 carriers and greater P3b for AA (vs. CC) CHRNA7 carriers. SLC5A7 allelic variants did not show significant differences in P3a and P3b processing. These findings expand our knowledge on the moderating effect of cholinergic genes on attention and could help inform targeted drug developments aimed at restoring attention deficits in SZ patients. PMID:27109789

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

    Directory of Open Access Journals (Sweden)

    Fivos Panetsos

    2014-11-01

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

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

    Directory of Open Access Journals (Sweden)

    Sen Hu

    2013-01-01

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

  20. Chemical and radiological effects of chronic ingestion of uranium in the rat brain: biochemical impairment of dopaminergic, serotonergic and cholinergic neuro-transmissions

    International Nuclear Information System (INIS)

    Uranium is an environmental ubiquitous metal-trace element. It has both chemical and radiological toxicity. After chronic ingestion, uranium can distribute in any part of the body and accumulate in the brain. The aims of this study was 1) to determine and estimate the effects of uranium on dopaminergic, serotoninergic and cholinergic systems and 2) to measure the uranium amount in the brain, after chronic exposure by ingestion of depleted (D.U.) or enriched (E.U.) uranium during 1.5 to 18 months at 40 mg.L-1 (40 ppm) in different rat brain areas. At any time of exposure, the results show that both the neurotransmission alterations and the uranium brain accumulation were moderate, area specific, time-evolutive and depended on uranium specific activity. After D.U. exposure, monoamine perturbations are chronic and progressive. On the contrary, monoamine alterations occurred only after long term of E.U. exposure. These mono-aminergic modifications are not always dependent on uranium accumulation in brain areas. Moreover, although the cholinergic system was not affected at both 1.5 and 9 months of D.U. exposure, the alteration of ChE activity after E.U. exposure are both dependent on uranium accumulation in brain areas and on uranium specific activity. After E.U. exposure, cholinergic modification and uranium accumulation in hippocampus could partially explain the short-term memory disturbances which have been previously reported. (author)

  1. Effects of excitation of sensory pathways on the membrane potential of cat masseter motoneurons before and during cholinergically induced motor atonia.

    Science.gov (United States)

    Kohlmeier, K A; López-Rodríguez, F; Morales, F R; Chase, M H

    1998-09-01

    Electrical stimulation of the nucleus pontis oralis during wakefulness enhances somatic reflex activity; identical stimuli during the motor atonia of active (rapid eye movement) sleep induces reflex suppression. This phenomenon, which is called reticular response-reversal, is based upon the generation of excitatory postsynaptic potential activity in motoneurons during wakefulness and inhibitory postsynaptic potential activity during the motor atonia of active sleep. In the present study, instead of utilizing artificial electrical stimulation to directly excite brainstem structures, we sought to examine the effects on motoneurons of activation of sensory pathways by exogenously applied stimuli (auditory) and by stimulation of a peripheral (sciatic) nerve. Accordingly, we examined the synaptic response of masseter motoneurons prior to and during cholinergically induced motor atonia in a pharmacological model of active sleep-specific motor atonia, the alpha-chloralose-anesthetized cat, to two different types of afferent input, one of which has been previously demonstrated to elicit excitatory motor responses during wakefulness. Following the pontine injection of carbachol, auditory stimuli (95 dB clicks) elicited a hyperpolarizing potential in masseter motoneurons. Similar responses were obtained upon stimulation of the sciatic nerve. Responses of this nature were never seen prior to the injection of carbachol. Thus, stimulation of two different afferent pathways (auditory and somatosensory) that produce excitatory motor responses during wakefulness instead, during motor atonia, results in the inhibition of masseter motoneurons. The switching of the net result of the synaptic response from one of potential motor excitation to primarily inhibition in response to the activation of sensory pathways was comparable to the phenomenon of reticular response-reversal. This is the first report to examine the synaptic mechanisms whereby exogenously or peripherally applied

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

    Directory of Open Access Journals (Sweden)

    Shaffer Eldon

    2006-02-01

    Full Text Available Abstract Background Excess cholesterol in bile and in blood is a major risk factor for the respective development of gallbladder disease and atherosclerosis. This lipid in excess negatively impacts the functioning of other smooth muscles, including the intestine. Serotonin is an important mediator of the contractile responses of the small intestine. Drugs targeting the serotonin receptor are used as prokinetic agents to manage intestinal motor disorders, in particular irritable bowel syndrome. Thus, tegaserod, acting on 5-HT4 receptor, ideally should obviate detrimental effects of excessive cholesterol on gastrointestinal smooth muscle. In this study we examined the effect of tegaserod on cholesterol-induced changes in the contractile responses of intestinal smooth muscle. Methods The effects of a high cholesterol (1% diet on the in vitro contractile responses of jejunal longitudinal smooth muscle from Richardson ground squirrels to the cholinergic agonist carbachol were examined in the presence or absence of tetrodrodotoxin (TTX. Two groups of animals, fed either low (0.03% or high cholesterol rat chow diet, were further divided into two subgroups and treated for 28 days with either vehicle or tegaserod. Results The high cholesterol diet increased, by nearly 2-fold, contractions of the jejunal longitudinal smooth muscle elicited by carbachol. These cholinergic contractions were mediated by muscarinic receptors since they were blocked by scopolamine, a muscarinic receptor antagonist, but not by the nicotinic receptor antagonist, hexamethonium. Tegaserod treatment, which did not affect cholinergic contractions of tissues from low cholesterol fed animals, abrogated the increase caused by the high cholesterol diet. With low cholesterol diet TTX enhanced carbachol-evoked contractions, whereas this action potential blocker did not affect the augmented cholinergic contractions seen with tissues from animals on the high cholesterol diet. Tegaserod

  3. Controlling

    OpenAIRE

    Lohnická, Jitka

    2009-01-01

    This thesis deals with the description and analysis of controlling methods in one unnamed company, which is the subsidiary of multinational corporation. Controlling, its function, objectives and controlling methods are theoretically defined in the thesis. The practical part of the thesis is focused on methods of planning in the company, its system of calculations, responsibility centres and reporting.

  4. Effects of Suanzaoren Decoction on cognitive function and cholinergic system in sleep deprived rats%酸枣仁汤对睡眠剥夺大鼠认知功能和胆碱能系统的影响

    Institute of Scientific and Technical Information of China (English)

    张斌; 张晓双; 白黎明

    2015-01-01

    目的:考察酸枣仁汤(SZRT )对睡眠剥夺大鼠认知功能和胆碱能系统的影响。方法雄性大鼠随机分为5组即大平台对照组、睡眠剥夺组及SZRT高、中、低剂量组,釆用改良多平台法建立大鼠睡眠剥夺模型、Y型电迷宫测定学习记忆、HE染色观察大鼠海马组织形态学、比色法测定海马Ach含量及AChE与ChA T的活性。结果与睡眠剥夺组相比,Y‐迷宫,SZRT 高剂量组错误次数减少,主动回避率增多。SZRT可减轻睡眠剥夺大鼠海马锥体细胞损伤,酸枣仁汤高、中剂量组可提高海马Ach含量,降低AChE活性,提高ChAT活性。结论 SZRT能改善睡眠剥夺大鼠所致的学习记忆下降,可能与保护胆碱能系统有关。%Objective To investigate the effects of Suanzaoren Decoction (SZRT ) on cognitive function and cholinergic system in sleep deprived rats .Methods Rats were randomly divided into 5 groups ,big platform control group ,sleep deprived group ,high ,medium and low dose group of SZRT .The rat model of sleep deprived was established with modified multiple platform method .Learning and memory of rats were tested by Y‐type maze .The histomorphology in hippocampal was observed by HE staining .The contents of acetylcholine ,activity of choline acetyltransferase and cholinesterase of rat hippocampal were determined by colorimetry .Results Compared with sleep deprived group ,high‐dose group can significantly decrease the error number and increase the active avoid‐ance .SZRT can reduce the hippocampal pyramidal cells injury .High and medium‐dose group can obviously increase the content of acetylcholine ,increase cholinesterase and decrease choline acetyltransferase activity in hippocampal .Conclusion SZRT can im‐prove the learning and memory in rats after sleep deprivation ,which probably was related to the protection of cholinergic system .

  5. Experiment K-7-18: Effects of Spaceflight in the Muscle Adductor Longus of Rats Flown in the Soviet Biosatellite Cosmos 2044. Part 2; Quantitative Autoradiographic Analysis of Gaba (Benzodiazepine) and Muscarinic (Cholinergic) Receptors in the Forebrain of Rats Flown on Cosmos 2044

    Science.gov (United States)

    Wu, L.; Daunton, N. G.; Krasnov, I. B.; DAmelio, F.; Hyde, T. M.; Sigworth, S. K.

    1994-01-01

    Quantitative autoradiographic analysis of receptors for GABA and acetylcholine in the forebrain of rats flown on COSMOS 2044 was undertaken as part of a joint US-Soviet study to determine the effects of microgravity on the central nervous system, and in particular on the sensory and motor portions of the forebrain. Changes in binding of these receptors in tissue from animals exposed to microgravity would provide evidence for possible changes in neural processing as a result of exposure to microgravity. Tritium-labelled diazepam and Quinuclidinyl-benzilate (QNB) were used to visualize GABA (benzodiazepine) and muscarinic (cholinergic) receptors, respectively. The density of tritium-labelled radioligands bound to various regions in the forebrain of both flight and control animals were measured from autoradiograms. Data from rats flown in space and from ground-based control animals that were not exposed to microgravity were compared.

  6. Effects of chronic exposure to benzalkonium chloride in Oncorhynchus mykiss: cholinergic neurotoxicity, oxidative stress, peroxidative damage and genotoxicity.

    Science.gov (United States)

    Antunes, S C; Nunes, B; Rodrigues, S; Nunes, R; Fernandes, J; Correia, A T

    2016-07-01

    Benzalkonium chloride (BAC) is one of the most used conservatives in pharmaceutical preparations. However, its use is limited to a small set of external use formulations, due to its high toxicity. Benzalkonium chloride effects are related to the potential exertion of deleterious effects, mediated via oxidative stress and through interaction with membrane enzymes, leading to cellular damage. To address the ecotoxicity of this specific compound rainbow trouts were chronically exposed to BAC at environmental relevant concentrations (ranging from 0.100 to 1.050mg/L), and the biological response of cholinergic neurotoxicity, modulation of the antioxidant defense, phase II metabolism, lipid peroxidation and genotoxicity was studied. The obtained results showed a dual pattern of antioxidant response, with significant alterations in catalase activity (starting at 0.180mg/L), and lipid peroxidation, for intermediate (0.180 and 0.324mg/L) concentrations. No significant alterations occurred for glutathione-S-transferases activity. An unexpected increased of the acetylcholinesterase activity was also recorded for the individuals exposed to higher concentrations of BAC (starting at 0.180mg/L). Furthermore, exposure to BAC resulted in the establishment of genotoxic alterations, observable (for the specific case of the comet assay results) for all tested BAC concentrations. However, and considering that the oxidative response was not devisable, other mechanisms may be involved in the genotoxic effects reported here. PMID:27280532

  7. Antibodies in Cerebrospinal Fluid of Some Alzheimer Disease Patients Recognize Cholinergic Neurons in the Rat Central Nervous System

    Science.gov (United States)

    McRae-Degueurce, Amanda; Booj, Serney; Haglid, Kenneth; Rosengren, Lars; Karlsson, Jan Erik; Karlsson, Ingvar; Wallin, Anders; Svennerholm, Lars; Gottfries, Carl-Gerhard; Dahlstrom, Annica

    1987-12-01

    The etiology of Alzheimer disease is unclear. However, immunological aberrations have been suggested to be critical factors in the pathogenesis of this neurodegenerative disease. This study was carried out to investigate if cerebrospinal fluid (CSF) from Alzheimer disease patients contains antibodies that recognize specific neuronal populations in the rat central nervous system. The results indicate that in a subgroup of patients this is indeed the case. The antibodies reported in this study have the following properties: (i) they recognize neuronal populations and components in the medial septum and spinal motor neurons in rats perfused with a mixture that fixes small neurotransmitter molecules; (ii) adsorption of the patient CSF with staphylococcal protein A-Sepharose and using a polyclonal antiserum against human IgG3 indicates that the immunocytochemical reaction in these brain regions is mainly due to the subclass IgG3; and (iii) the CSF immunocytochemical reaction is blocked by preincubation of the sections with a rabbit anti-acetylcholine antiserum. These results provide evidence that antibodies in the CSF of some, but not all, Alzheimer disease patients recognize acetylcholine-like epitopes in cholinergic neurons in the rat central nervous system.

  8. Kinetics of in vivo binding of antagonist to muscarinic cholinergic receptor in the human heart studied by Positron Emission Tomography

    Energy Technology Data Exchange (ETDEWEB)

    Syrota, A.; Paillotin, G.; Davy, J.M.; Aumont, M.C.

    1984-08-27

    Positron Emission Tomography (PET) was used to analyze in vivo antagonist binding to human myocardial muscarinic cholinergic receptor. The methiodide salt of the muscarinic antagonist, quinuclidinyl benzilate (MQNB), was labeled with the positron emitter, Carbon-11, and injected intravenously to 8 normal subjects. /sup 11/C-MQNB concentration was determined in vivo in the ventricular septum from 40 cross-sectional images acquired at the same transverse level over a period of 70 minutes. In 4 subjects, various amounts of unlabeled atropine were rapidly injected at 20 minutes to study whether atropine competitively inhibited MQNB. The kinetics of binding of /sup 11/C-MQNB were not the same in vivo and in vitro. The apparent dissociation rate of /sup 11/C-MQNB in vivo was much slower (by 1 to 2 orders of magnitude) than that observed in vitro with /sup 3/H-QNB. After atropine injection, /sup 11/C-MQNB dissociated from its binding sites at a rate that apparently depended on the amount of atropine present. /sup 11/C-MQNB kinetics were analyzed with a mathematical model which assumes the existence of a boundary layer containing free ligand in the vicinity of the binding sites. The dissociation rate of the radioligand depends on the probability of its rebinding to a free receptor site. 11 references, 1 table.

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

    Institute of Scientific and Technical Information of China (English)

    Zhi-zhong GUAN

    2008-01-01

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

  10. Cholinergic modulation of auditory steady-state response in the auditory cortex of the freely moving rat.

    Science.gov (United States)

    Zhang, J; Ma, L; Li, W; Yang, P; Qin, L

    2016-06-01

    As disturbance in auditory steady-state response (ASSR) has been consistently found in many neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia, there is considerable interest in the development of translational rat models to elucidate the underlying neural and neurochemical mechanisms involved in ASSR. This is the first study to investigate the effects of the non-selective muscarinic antagonist scopolamine and the cholinesterase inhibitor donepezil (also in combination with scopolamine) on ASSR. We recorded the local field potentials through the chronic microelectrodes implanted in the auditory cortex of freely moving rat. ASSRs were recorded in response to auditory stimuli delivered over a range of frequencies (10-80Hz) and averaged over 60 trials. We found that a single dose of scopolamine produced a temporal attenuation in response to auditory stimuli; the most attenuation occurred at 40Hz. Time-frequency analysis revealed deficits in both power and phase-locking to 40Hz. Donepezil augmented 40-Hz steady-state power and phase-locking. Scopolamine combined with donepezil had an enhanced effect on the phase-locking, but not power of ASSR. These changes induced by cholinergic drugs suggest an involvement of muscarinic neurotransmission in auditory processing and provide a rodent model investigating the neurochemical mechanism of neurophysiological deficits seen in patients. PMID:26964684

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

    Directory of Open Access Journals (Sweden)

    Luis Armando Sawada

    2014-01-01

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

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

    Science.gov (United States)

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

    2014-01-01

    Libidibia ferrea (LF) is a medicinal plant that holds many pharmacological properties. We evaluated the antinociceptive effect in the LF aqueous seed extract and Lipidic Portion of Libidibia ferrea (LPLF), partially elucidating their mechanisms. Histochemical tests and Gas chromatography of the LPLF were performed to characterize its fatty acids. Acetic acid-induced abdominal constriction, formalin-induced pain, and hot-plate test in mice were employed in the study. In all experiments, aqueous extract or LPLF was administered systemically at the doses of 1, 5, and 10 mg/kg. LF aqueous seed extract and LPLF demonstrated a dose-dependent antinociceptive effect in all tests indicating both peripheral anti-inflammatory and central analgesia properties. Also, the use of atropine (5 mg/kg), naloxone (5 mg/kg) in the abdominal writhing test was able to reverse the antinociceptive effect of the LPLF, indicating that at least one of LF lipids components is responsible for the dose related antinociceptive action in chemical and thermal models of nociception in mice. Together, the present results suggested that Libidibia ferrea induced antinociceptive activity is possibly related to its ability to inhibit opioid, cholinergic receptors, and cyclooxygenase-2 pathway, since its main component, linoleic acid, has been demonstrated to produce such effect in previous studies. PMID:24860820

  13. The cholinergic antagonist gymnodimine improves Aβ and tau neuropathology in an in vitro model of Alzheimer disease.

    Science.gov (United States)

    Alonso, Eva; Vale, Carmen; Vieytes, Mercedes R; Laferla, Frank M; Giménez-Llort, Lydia; Botana, Luis M

    2011-01-01

    Gymnodimine (GYM) is a marine phycotoxin with a macrocyclic imine structure, isolated from extracts of the dinoflagellate Karenia selliformis known to act as a cholinergic antagonist with subtype selectivity. However, no data on the chronic effects of this compound has been reported so far. In this work, we evaluated the effect of long term exposure of cortical neurons to gymnodimine in the progress of Alzheimer disease (AD) pathology in vitro. Treatment of cortical neurons with 50 nM gymnodimine decreased the intracellular amyloid beta (Aβ) accumulation and the levels of the hyperphosphorylated isoforms of tau protein recognized by AT8 and AT100 antibodies. These results are suggested to be mediated by the increase in the inactive isoform of the glycogen synthase kinase-3 (phospho GSK-3 Ser9), the decrease in the levels of the active isoform of the ERK1/2 kinase and the increase in acetylcholine (Ach) synthesis elicited by long term exposure of cortical neurons to the toxin. Moreover, gymnodimine decreased glutamate-induced neurotoxicity in vitro. Altogether these results indicate that the marine phycotoxin gymnodimine may constitute a valuable tool for the development of drugs to treat neurodegenerative diseases. PMID:21691095

  14. Dexmedetomidine attenuates inflammatory reaction in the lung tissues of septic mice by activating cholinergic anti-inflammatory pathway.

    Science.gov (United States)

    Liu, Zhaoguo; Wang, Yueping; Wang, Yaoqi; Ning, Qiaoqing; Zhang, Yong; Gong, Chunzhi; Zhao, Wenxiang; Jing, Guangjian; Wang, Qianqian

    2016-06-01

    Dexmedetomidine (Dex) is a highly selective α2-adrenergic receptor agonist that is widely used for sedation in intensive care units and in clinical anesthesia. Dex has also been shown to possess anti-inflammatory benefits. However, the underlying mechanism by which Dex relieves the inflammatory reaction in the lung tissues of septic mice has not been fully elucidated. In this study, we aimed to evaluate the protective effects and possible mechanism of Dex on the sepsis-induced lung inflammatory response in mice. Sepsis was induced in mice models through the intraperitoneal injection of lipopolysaccharide (LPS). The preemptive administration of Dex substantially abated sepsis-induced pulmonary edema, pulmonary histopathological changes, and NF-κB p65 activity. The production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) at both the mRNA and protein levels was also reduced. Moreover, these effects were significantly blocked by the α7 nicotinic acetylcholine receptor (α7nAChR) antagonist α-bungarotoxin (α-Bgt). α-Bgt aggravated pulmonary edema and pulmonary histopathological changes, as well as increased NF-κB p65 activity and TNF-α and IL-6 expression at both the mRNA and protein levels. The overall results demonstrate that Dex inhibits the LPS-induced inflammatory reaction in the lung tissues of septic mice partly through the α7nAChR-dependent cholinergic anti-inflammatory pathway. PMID:27074053

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

    Directory of Open Access Journals (Sweden)

    Huan Wang

    2015-01-01

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

  16. Cholinergic muscarinic receptor activation augments murine intestinal epithelial cell proliferation and tumorigenesis

    International Nuclear Information System (INIS)

    Previously, we showed that M3 muscarinic receptor (M3R; gene name Chrm3) deficiency attenuates murine intestinal neoplasia, supporting the hypothesis that muscarinic receptors play an important role in intestinal tumorigenesis. To test this hypothesis, in the present study we treated mice with bethanechol, a non-selective muscarinic receptor agonist without nicotinic receptor activity, and examined its effects on azoxymethane (AOM)-induced colon neoplasia. Mice were provided with drinking water containing 400 μg/mL bethanechol chloride or water without additions (control) for a total of 20 weeks, a period that included the initial 6 weeks when mice received intraperitoneal injections of AOM. When euthanized at week 20, control mice had 8.0 ± 1.3 tumors per animal, whereas bethanechol-treated mice had 10.4 ± 1.5 tumors per mouse (mean ± SE; P = 0.023), a 30% increase. Strikingly, tumor volume per animal was increased 52% in bethanechol-treated compared with control mice (179.7 ± 21.0 vs. 111. 8 ± 22.4 mm3; P = 0.047). On histological examination, bethenechol-treated mice also had more adenocarcinomas per animal (8.0 ± 1.0 vs. 4.1 ± 0.6 for control mice, P = 0.0042). Cell proliferation in both normal mucosa and adenocarcinomas was increased in bethanechol-treated compared to control mice. Also, in tumors, bethanechol treatment increased expression of Chrm3, Egfr and post-Egfr signaling molecules Myc and cyclin D1. Bethanechol treatment increased the thickness of normal colonic mucosa and the expression of selected matrix metalloproteinase (Mmp) genes, including Mmp7, Mmp10 and Mmp13. These findings support a prominent role for muscarinic receptors in colon neoplasia, and identify post-receptor signaling molecules as potential therapeutic targets

  17. Pulmonary function, cholinergic bronchomotor tone, and cardiac autonomic abnormalities in type 2 diabetic patients

    Directory of Open Access Journals (Sweden)

    Melo E.

    2003-01-01

    Full Text Available This prospective study analyzed the involvement of the autonomic nervous system in pulmonary and cardiac function by evaluating cardiovascular reflex and its correlation with pulmonary function abnormalities of type 2 diabetic patients. Diabetic patients (N = 17 and healthy subjects (N = 17 were evaluated by 1 pulmonary function tests including spirometry, He-dilution method, N2 washout test, and specific airway conductance (SGaw determined by plethysmography before and after aerosol administration of atropine sulfate, and 2 autonomic cardiovascular activity by the passive tilting test and the magnitude of respiratory sinus arrhythmia (RSA. Basal heart rate was higher in the diabetic group (87.8 ± 11.2 bpm; mean ± SD than in the control group (72.9 ± 7.8 bpm, P<0.05. The increase of heart rate at 5 s of tilting was 11.8 ± 6.5 bpm in diabetic patients and 17.6 ± 6.2 bpm in the control group (P<0.05. Systemic arterial pressure and RSA analysis did not reveal significant differences between groups. Diabetes intragroup analysis revealed two behaviors: 10 patients with close to normal findings and 7 with significant abnormalities in terms of RSA, with the latter subgroup presenting one or more abnormalities in other tests and clear evidence of cardiovascular autonomic dysfunction. End-expiratory flows were significantly lower in diabetic patients than in the control group (P<0.05. Pulmonary function tests before and after atropine administration demonstrated comparable responses by both groups. Type 2 diabetic patients have cardiac autonomic dysfunction that is not associated with bronchomotor tone alterations, probably reflecting a less severe impairment than that of type 1 diabetes mellitus. Yet, a reduction of end-expiratory flow was detected.

  18. Time course effects of lithium administration on spatial memory acquisition and cholinergic marker expression in rats

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    M H Karimfar

    2009-08-01

    Full Text Available Background: The effects of chronic lithium exposure on spatial memory in rats remain controversial. In this study a time course of the effects of lithium, administered systemically, on spatial memory acquisition in Morris water maze was investigated. Material and Methods: Lithium (600 mg/L was administered to four groups of rats in their drinking water; the first group of animals received lithium for one week, the second group for two weeks, the third group for three weeks, and the fourth group for four weeks.  As controls, four groups of animals received only normal drinking water for the same period of time.  Toward the end of their lithium or water treatment, all animals were trained for four days; each day included one block and each block contained four trials.  Test trials were conducted 48 hrs after completion of the lithium treatment. Escape latency, traveled distance and swimming speed were evaluated during testing trials. Brain tissues from animals were processed according to the standard protocols for immunohistochemical analysis.  Results: Lithium treatment decreased escape latency and traveled distance, but not swimming speed, compared with controls, suggesting significant spatial memory acquisition enhancement by lithium. Quantitative analysis showed that lithium, particularly after four weeks of exposure, significantly increased the number and density of immunostained ChAT-containing (choline acetyltransferase neurons in the medial septal area in comparison with control groups.  There was also a significant correlation between the number of immunostained ChAT neurons and behavioral measures. Conclusion: These results suggest that chronic oral administration of lithium causes spatial memory acquisition improvement in rats and an increase in ChAT immunostaining levels in medial septal nuclei.

  19. Generation patterns of four groups of cholinergic neurons in rat cervical spinal cord: a combined tritiated thymidine autoradiographic and choline acetyltransferase immunocytochemical study

    International Nuclear Information System (INIS)

    This report examines the generation of cholinergic neurons in the spinal cord in order to determine whether the transmitter phenotype of neurons is associated with specific patterns of neurogenesis. Previous immunocytochemical studies identified four groups of choline acetyltransferase (ChAT)-positive neurons in the cervical enlargement of the rat spinal cord. These cell groups vary in both somatic size and location along the previously described ventrodorsal neurogenic gradient of the spinal cord. Thus, large (and small) motoneurons are located in the ventral horn, medium-sized partition cells are found in the intermediate gray matter, small central canal cluster cells are situated within lamina X, and small dorsal horn neurons are scattered predominantly through laminae III-V. The relationships among the birthdays of these four subsets of cholinergic neurons have been examined by combining 3H-thymidine autoradiography and ChAT immunocytochemistry. Embryonic day 11 was the earliest time that neurons were generated within the cervical enlargement. Large and small ChAT-positive motoneurons were produced on E11 and 12, with 70% of both groups being born on E11. ChAT-positive partition cells were produced between E11 and 13, with their peak generation occurring on E12. Approximately 70% of the cholinergic central canal cluster and dorsal horn cells were born on E13, and the remainder of each of these groups was generated on E14. Other investigators have shown that all neurons within the rat cervical spinal cord are produced in a ventrodorsal sequence between E11 and E16. In contrast, ChAT-positive neurons are born only from E11 to E14 and are among the earliest cells generated in the ventral, intermediate, and dorsal subdivisions of the spinal cord

  20. Synthesis of radiotracers for studying muscarinic cholinergic receptors in the living human brain using positron emission tomography: [11C]dexetimide and [11C]levetimide

    International Nuclear Information System (INIS)

    The localization and quantitation of muscarinic cholinergic receptors (m-AChR) in the living human brain using a non-invasive method such as positron emission tomography (PET) may provide valuable information about receptor changes which have been observed post mortem in patients with Huntington's chorea and Alzheimer's dementia, as well as normal brain mechanisms mediated by the m-AChR. We chose to label dexetimide as a radiotracer for studying the m-AChR and levetimide as a radiotracer for assessing non-specific binding associated with the in vivo receptor binding studies. (author)