Sleep deprivation has been shown to exacerbate pain sensitivity and may contribute to the onset of chronic pain, yet the precise neural mechanisms underlying this association remain elusive. In our study, we explored the contribution of cholinergic neurons within the medial habenula (MHb) to hyperalgesia induced by sleep deprivation in rats. Our findings indicate that the activity of MHb cholinergic neurons diminishes during sleep deprivation and that chemogenetic stimulation of these neurons can mitigate the results. Interestingly, we did not find a direct response of MHb cholinergic neurons to pain stimulation. Further investigation identified the interpeduncular nucleus (IPN) and the paraventricular nucleus of the thalamus (PVT) as key players in the pro-nociceptive effect of sleep deprivation. Stimulating the pathways connecting the MHb to the IPN and PVT alleviated the hyperalgesia. These results underscore the important role of MHb cholinergic neurons in modulating pain sensitivity linked to sleep deprivation, highlighting potential neural targets for mitigating sleep deprivation-induced hyperalgesia.
Animals ; Habenula/physiology* ; Sleep Deprivation/physiopathology* ; Cholinergic Neurons/physiology* ; Male ; Hyperalgesia/physiopathology* ; Rats, Sprague-Dawley ; Rats ; Interpeduncular Nucleus/physiology* ; Pain Threshold/physiology* ; Midline Thalamic Nuclei/physiology* ; Neural Pathways/physiopathology*

Acetylcholine (ACh) is an important neuromodulator in various cognitive functions. However, it is unclear how ACh influences neural circuit dynamics by altering cellular properties. Here, we investigated how ACh influences reverberatory activity in cultured neuronal networks. We found that ACh suppressed the occurrence of evoked reverberation at low to moderate doses, but to a much lesser extent at high doses. Moreover, high doses of ACh caused a longer duration of evoked reverberation, and a higher occurrence of spontaneous activity. With whole-cell recording from single neurons, we found that ACh inhibited excitatory postsynaptic currents (EPSCs) while elevating neuronal firing in a dose-dependent manner. Furthermore, all ACh-induced cellular and network changes were blocked by muscarinic, but not nicotinic receptor antagonists. With computational modeling, we found that simulated changes in EPSCs and the excitability of single cells mimicking the effects of ACh indeed modulated the evoked network reverberation similar to experimental observations. Thus, ACh modulates network dynamics in a biphasic fashion, probably by inhibiting excitatory synaptic transmission and facilitating neuronal excitability through muscarinic signaling pathways.
Cholinergic Agents/pharmacology* ; Acetylcholine/metabolism* ; Neurons/metabolism* ; Synaptic Transmission/physiology*

The rostral ventrolateral medulla (RVLM) is a key region in cardiovascular regulation. It has been demonstrated that cholinergic synaptic transmission in the RVLM is enhanced in hypertensive rats. Angiotensin-converting enzyme 2 (ACE2) in the brain plays beneficial roles in cardiovascular function in hypertension. The purpose of this study was to determine the effect of ACE2 overexpression in the RVLM on cholinergic synaptic transmission in spontaneously hypertensive rats (SHRs). Four weeks after injecting lentiviral particles containing enhanced green fluorescent protein and ACE2 bilaterally into the RVLM, the blood pressure and heart rate were notably decreased. ACE2 overexpression significantly reduced the concentration of acetylcholine in microdialysis fluid from the RVLM and blunted the decrease in blood pressure evoked by bilateral injection of atropine into the RVLM in SHRs. In conclusion, we suggest that ACE2 overexpression in the RVLM attenuates the enhanced cholinergic synaptic transmission in SHRs.
Acetylcholine ; metabolism ; Animals ; Blood Pressure ; physiology ; Cardiovascular System ; metabolism ; Cholinergic Neurons ; metabolism ; Hypertension ; metabolism ; Male ; Peptidyl-Dipeptidase A ; metabolism ; Rats ; Rats, Inbred SHR ; metabolism

The autonomic nervous system plays critical roles in maintaining homeostasis in humans, directly regulating inflammation by altering the activity of the immune system. The cholinergic anti-inflammatory pathway is a well-studied neuroimmune interaction involving the vagus nerve. CD4-positive T cells expressing β2 adrenergic receptors and macrophages expressing the alpha 7 subunit of the nicotinic acetylcholine receptor in the spleen receive neurotransmitters such as norepinephrine and acetylcholine and are key mediators of the cholinergic anti-inflammatory pathway. Recent studies have demonstrated that vagus nerve stimulation, ultrasound, and restraint stress elicit protective effects against renal ischemia-reperfusion injury. These protective effects are induced primarily via activation of the cholinergic anti-inflammatory pathway. In addition to these immunological roles, nervous systems are directly related to homeostasis of renal physiology. Whole-kidney three-dimensional visualization using the tissue clearing technique CUBIC (clear, unobstructed brain/body imaging cocktails and computational analysis) has illustrated that renal sympathetic nerves are primarily distributed around arteries in the kidneys and denervated after ischemia-reperfusion injury. In contrast, artificial renal sympathetic denervation has a protective effect against kidney disease progression in murine models. Further studies are needed to elucidate how neural networks are involved in progression of kidney disease.
Acetylcholine ; Arteries ; Autonomic Nervous System ; Cholinergic Neurons ; Homeostasis ; Humans ; Immune System ; Inflammation ; Kidney Diseases ; Kidney ; Macrophages ; Nervous System ; Neurotransmitter Agents ; Norepinephrine ; Optogenetics ; Physiology ; Receptors, Adrenergic ; Receptors, Nicotinic ; Reperfusion Injury ; Spleen ; Sympathectomy ; Sympathetic Nervous System ; T-Lymphocytes ; Ultrasonography ; Vagus Nerve ; Vagus Nerve Stimulation

Epilepsy is a chronic neurological disorder, which is not only related to the imbalance between excitatory glutamic neurons and inhibitory GABAergic neurons, but also related to abnormal central cholinergic regulation. This article summarizes the scientific background and experimental data about cholinergic dysfunction in epilepsy from both cellular and network levels, further discusses the exact role of cholinergic system in epilepsy. In the cellular level, several types of epilepsy are believed to be associated with aberrant metabotropic muscarinic receptors in several different brain areas, while the mutations of ionotropic nicotinic receptors have been reported to result in a specific type of epilepsy-autosomal dominant nocturnal frontal lobe epilepsy. In the network level, cholinergic projection neurons as well as their interaction with other neurons may regulate the development of epilepsy, especially the cholinergic circuit from basal forebrain to hippocampus, while cholinergic local interneurons have not been reported to be associated with epilepsy. With the development of optogenetics and other techniques, dissect and regulate cholinergic related epilepsy circuit has become a hotspot of epilepsy research.
Acetylcholine ; physiology ; Basal Forebrain ; pathology ; Brain Chemistry ; genetics ; physiology ; Cholinergic Neurons ; chemistry ; classification ; pathology ; physiology ; Epilepsy ; genetics ; pathology ; physiopathology ; Epilepsy, Frontal Lobe ; genetics ; GABAergic Neurons ; physiology ; Hippocampus ; pathology ; Humans ; Mutation ; genetics ; physiology ; Neurons ; Non-Neuronal Cholinergic System ; genetics ; physiology ; Receptors, Muscarinic ; genetics ; physiology ; Receptors, Nicotinic ; genetics ; physiology ; Synaptic Transmission ; genetics ; physiology

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 by cholinergic deficits. MATERIALS AND METHODS: We lesioned basal forebrain cholinergic neurons in rats using 192 immunoglobulin G-saporin. After 3 weeks, lesioned animals underwent water maze testing or were analyzed by 18F-2-fluoro-2-deoxyglucose positron emission tomography. RESULTS: During water maze probe testing, performance of the lesioned group decreased with respect to time spent in the target quadrant and platform zone. Cingulate cortex glucose metabolism in the lesioned group decreased, compared with the normal group. Additionally, acetylcholinesterase activity and glutamate decarboxylase 65/67 expression declined in the cingulate cortex. CONCLUSION: Our results reveal that spatial memory impairment in animals with selective basal forebrain cholinergic neuron damage is associated with a functional decline in the GABAergic and cholinergic system associated with cingulate cortex glucose hypometabolism.
Acetylcholine/metabolism ; Alzheimer Disease ; Animals ; Antibodies, Monoclonal/*pharmacology ; Basal Forebrain/*drug effects/metabolism ; Cholinergic Agents/administration & dosage/*pharmacology ; Cholinergic Neurons/*drug effects/metabolism ; Fluorodeoxyglucose F18 ; GABAergic Neurons/*drug effects/metabolism ; Glucose/*metabolism ; Gyrus Cinguli/*drug effects/metabolism ; Humans ; Injections ; Maze Learning ; Motor Activity/physiology ; Positron-Emission Tomography ; Rats ; Ribosome Inactivating Proteins, Type 1/*pharmacology

OBJECTIVETo investigate the effect of total fiavonoids from Chrysanthemun morifolium (TFCM) on learning and memory, and cholinergic system function in aging mice.

METHODSThe aging mice model was established by subcutaneous injection of D-galactose. ICR mice were divided into five groups (n=10): contrA group, model group, and TFCM groups. Mice in TFCM groups were given TFCM (50,100 or 150 mg/kg) by gastric irrigation once a day. Learning and memory ability were evaluated by Morris water maze test. The MDA content, SOD and Ach E activity were also measured.

RESULTSCompared with control group, learning and memory ability declined in the D-galactose-induced aging mice; meanwhile MDA content and AchE activity increased, SOD activity decreased. Treatment with TFCM (100, 150 mg/kg) ameliorated the decrease in learning and memory ability of aging mice. Compared with model group, TFCM (100, 150 mg/kg) could also decrease MDA content and Ach E activity, and increase SOD activity in aging mice.

CONCLUSIONTFCM may improve the learning and memory ability of aging mice. The mechanism is involved in its antioxidative characteristic and improvement of central cholinergic system function.

Aging ; drug effects ; physiology ; Animals ; Antioxidants ; pharmacology ; Cholinergic Fibers ; physiology ; Cholinergic Neurons ; physiology ; Chrysanthemum ; chemistry ; Female ; Flavonoids ; isolation & purification ; pharmacology ; Learning ; drug effects ; Male ; Memory ; drug effects ; Mice ; Mice, Inbred ICR

OBJECTIVETo investigate the relation between the progressive effects of chronic intermittent hypoxia (CIH) on cognitive function and the change of cholinergic neuron.

METHODSForty adult male Sprague-Dawley rats were randomly averagely divided into four groups: control group, CIH 1 week group, CIH 3 week group and CIH 5 week group. The cognitive function was assessed by the Morris Water Maze. The necrosis neurons in prefrontal cortex and hippocampus were observed and counted. The cholin acetyltransferase (ChAT) immunostained cells in prefrontal cortex and hippocampus were identified and quantitated.

RESULTSThe spatial learning and memory impairments progressed from 1 to 5 5 weeks in rats. Compared with the control group, the cognitive impairments in CIH5w group were significant (P < 0.05). The degeneration or necrosis neurons in prefrontal cortex and hippocampus were significantly increased in CIH rats, and worsen gradually along with the hypoxia. The ChAT immunostained cells in prefrontal cortex and hippocampus were gradually reduced. The ChAT immunostained cells of prefrontal cortex and hippocampus in CIH3w group and CIH5w group were less than that in control group (P < 0.05).

CONCLUSIONChronic intermittent hypoxia induced slowly progressive spatial learning and memory impairments in rats, which maybe associated with the damage of neurons and the reduction of ChAT in prefrontal cortex and hippocampus.

Animals ; Cholinergic Fibers ; pathology ; physiology ; Cholinergic Neurons ; pathology ; physiology ; Cognition ; physiology ; Hippocampus ; cytology ; physiopathology ; Hypoxia ; physiopathology ; Male ; Maze Learning ; physiology ; Memory Disorders ; etiology ; physiopathology ; Prefrontal Cortex ; cytology ; physiopathology ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo examine the effect of acetylcholine (ACh) on the electric activities of pain-excitation neurons (PEN) and pain-inhibitation neurons (PIN) in the hippocampal CA1 area of normal rats or morphinistic rats, and to explore the role of ACh in regulation of pain perception in CA1 area under normal condition and morphine addiction.

METHODSThe trains of electric impulses applied to sciatic nerve were set as noxious stimulation. The discharges of PEN and PIN in the CA1 area were recorded extracellularly by glass microelectrode. We observed the influence of intracerebroventricular (i.c.v.) injection of ACh and atropine on the noxious stimulation-evoked activities of PEN and PIN in the CA1 area.

RESULTSNoxious stimulation enhanced the electric activity of PEN and depressed that of PIN in the CA1 area of both normal and addiction rats. In normal rats, ACh decrease the pain-evoked discharge frequency of PEN, while increased the frequency of PIN. These effects reached the peak value at 4 min after injection of ACh. In morphinistic rats, ACh also inhibited the PEN electric activity and potentialized the PIN electric activity, but the maximum effect appeared at 6 min after administration. The ACh-induced responses were significantly blocked by muscarinic receptor antagonist atropine.

CONCLUSIONCholinergic neurons and muscarinic receptors in the hippocampal CA1 area are involved in the processing of nociceptive information and they may play an analgesia role in pain modulation. Morphine addiction attenuated the sensitivity of pain-related neurons to the noxious information.

Acetylcholine ; administration & dosage ; metabolism ; Adaptation, Physiological ; drug effects ; physiology ; Animals ; Electric Stimulation ; Evoked Potentials ; physiology ; Female ; Hippocampus ; cytology ; metabolism ; Injections, Intraventricular ; Male ; Morphine ; pharmacology ; Morphine Dependence ; metabolism ; Narcotics ; pharmacology ; Neuronal Plasticity ; physiology ; Neurons ; drug effects ; physiology ; Pain ; metabolism ; Pain Threshold ; physiology ; Rats ; Rats, Wistar ; Receptors, Cholinergic ; drug effects ; metabolism ; Sciatic Nerve ; physiopathology ; Signal Transduction ; physiology

OBJECTIVETo establish an artificial somatic-autonomic reflex arc in rats and observe the following distributive changes of neural fibers in the bladder.

METHODSAdult Sprague-Dawley rats were randomly divided into three groups: control group, spinal cord injury (SCI) group, and reinnervation group. DiI retrograde tracing was used to verify establishment of the model and to investigate the transport function of the regenerated efferent axons in the new reflex arc. Choline acetyltransferase (ChAT) in the DiI-labeled neurons was detected by immunohistochemistry. Distribution of neural fibers in the bladder was observed by acetylcholine esterase staining.

RESULTSDiI-labeled neurons distributed mainly in the left ventral horn from L3 to L5, and some of them were also ChAT-positive. The neural fibers in the bladder detrusor reduced remarkably in the SCI group compared with the control (P < 0.05). After establishment of the somatic-autonomic reflex arc in the reinnervation group, the number of ipsilateral fibers in the bladder increased markedly compared with the SCI group (P < 0.05), though still much less than that in the control (P < 0.05).

CONCLUSIONThe efferent branches of the somatic nerves may grow and replace the parasympathetic preganglionic axons through axonal regeneration. Acetylcholine is still the major neurotransmitter of the new reflex arc. The controllability of detrusor may be promoted when it is reinnervated by the pelvic ganglia efferent somatic motor fibers from the postganglionic axons.

Acetylcholinesterase ; biosynthesis ; Anastomosis, Surgical ; Animals ; Autonomic Fibers, Preganglionic ; physiology ; Cholinergic Fibers ; metabolism ; Immunohistochemistry ; Motor Neurons ; cytology ; metabolism ; Nerve Regeneration ; physiology ; Neural Pathways ; cytology ; metabolism ; Rats ; Rats, Sprague-Dawley ; Reflex ; physiology ; Spinal Cord Injuries ; physiopathology ; Spinal Nerve Roots ; surgery ; Urinary Bladder ; innervation ; physiology ; surgery ; Urinary Bladder, Neurogenic ; surgery