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International Journal of Molecular... Sep 2022Locomotion is a basic motor act essential for survival. Amongst other things, it allows animals to move in their environment to seek food, escape predators, or seek... (Review)
Review
Locomotion is a basic motor act essential for survival. Amongst other things, it allows animals to move in their environment to seek food, escape predators, or seek mates for reproduction. The neural mechanisms involved in the control of locomotion have been examined in many vertebrate species and a clearer picture is progressively emerging. The basic muscle synergies responsible for propulsion are generated by neural networks located in the spinal cord. In turn, descending supraspinal inputs are responsible for starting, maintaining, and stopping locomotion as well as for steering and controlling speed. Several neurotransmitter systems play a crucial role in modulating the neural activity during locomotion. For instance, cholinergic inputs act both at the spinal and supraspinal levels and the underlying mechanisms are the focus of the present review. Much information gained on supraspinal cholinergic modulation of locomotion was obtained from the lamprey model. Nicotinic cholinergic inputs increase the level of excitation of brainstem descending command neurons, the reticulospinal neurons (RSNs), whereas muscarinic inputs activate a select group of hindbrain neurons that project to the RSNs to boost their level of excitation. Muscarinic inputs also reduce the transmission of sensory inputs in the brainstem, a phenomenon that could help in sustaining goal directed locomotion. In the spinal cord, intrinsic cholinergic inputs strongly modulate the activity of interneurons and motoneurons to control the locomotor output. Altogether, the present review underlines the importance of the cholinergic inputs in the modulation of locomotor activity in vertebrates.
Topics: Animals; Cholinergic Agents; Lampreys; Locomotion; Motor Neurons; Neurotransmitter Agents; Spinal Cord
PubMed: 36142651
DOI: 10.3390/ijms231810738 -
Neuron Nov 2022In this issue of Neuron, Li et al. (2022) identify and genetically target two sub-populations of cholinergic neurons in the basal forebrain. They show that these...
In this issue of Neuron, Li et al. (2022) identify and genetically target two sub-populations of cholinergic neurons in the basal forebrain. They show that these cholinergic subtypes have distinct projection patterns, electrophysiological phenotypes, and behavioral functions.
Topics: Basal Forebrain; Cholinergic Neurons; Electrophysiological Phenomena; Cholinergic Agents
PubMed: 36395751
DOI: 10.1016/j.neuron.2022.10.009 -
Scientific Reports Aug 2020Wild mushroom foraging involves a high risk of unintentional consumption of poisonous mushrooms which is a serious health concern. This problem arises due to the close...
Wild mushroom foraging involves a high risk of unintentional consumption of poisonous mushrooms which is a serious health concern. This problem arises due to the close morphological resemblances of toxic mushrooms with edible ones. The genus Inocybe comprises both edible and poisonous species and it is therefore important to differentiate them. Knowledge about their chemical nature will unambiguously determine their edibility and aid in an effective treatment in case of poisonings. In the present study, the presence of volatile toxic metabolites was verified in Inocybe virosa by gas chromatography. Methyl palmitate, phenol, 3,5-bis (1,1-dimethyl ethyl) and phytol were the identified compounds with suspected toxicity. The presence of the toxin muscarine was confirmed by liquid chromatography. The in vitro study showed that there was negligible effect of the digestion process on muscarine content or its toxicity. Therefore, the role of muscarine in the toxicity of Inocybe virosa was studied using a bioassay wherein metameters such as hypersalivation, immobility, excessive defecation, heart rate and micturition were measured. Administration of muscarine resulted in an earlier onset of symptoms and the extract showed a slightly stronger muscarinic effect in comparison to an equivalent dose of muscarine estimated in it. Further, the biological fate of muscarine was studied by pharmacokinetics and gamma scintigraphy in New Zealand white rabbits. Significant amount of the toxin was rapidly and effectively concentrated in the thorax and head region. This study closely explains the early muscarinic response such as miosis and salivation in mice. By the end of 24 h, a relatively major proportion of muscarine administered was accumulated in the liver which stands as an explanation to the hepatotoxicity of Inocybe virosa. This is one of the rare studies that has attempted to understand the toxic potential of muscarine which has previously been explored extensively for its pharmaceutical applications.
Topics: Agaricales; Animals; Brain Chemistry; Cell Line; Cell Survival; Female; Gas Chromatography-Mass Spectrometry; Humans; Mice; Muscarine; Palmitates; Phenol; Phytol; Rabbits; Thorax; Toxins, Biological
PubMed: 32792538
DOI: 10.1038/s41598-020-70196-7 -
Advanced Biology Sep 2022Tumor cells modulate and are modulated by their microenvironments, which include the nervous system. Accumulating evidence links the overexpression and activity of... (Review)
Review
Tumor cells modulate and are modulated by their microenvironments, which include the nervous system. Accumulating evidence links the overexpression and activity of nicotinic and muscarinic cholinergic receptor subtypes to tumorigenesis in breast, ovarian, prostate, gastric, pancreatic, and head and neck cancers. Nicotinic and muscarinic receptors have downstream factors are associated with angiogenesis, cell proliferation and migration, antiapoptotic signaling, and survival. Clinical trials analyzing the efficacy of various therapies targeting cholinergic signaling or downstream pathways of acetylcholine have shed promising light on novel cancer therapeutics. Although the evidence for cholinergic signaling involvement in tumor development is substantial, a more detailed understanding of the acetylcholine-induced mechanisms of tumorigenesis remains to be unlocked. Such an understanding would enable the development of clinical applications ranging from the identification of novel biomarkers to the utilization of existing drugs to modulate cholinergic signaling to the development of novel cancer therapies, as discussed in this review.
Topics: Acetylcholine; Carcinogenesis; Cholinergic Agents; Humans; Neoplasms; Nicotine; Receptors, Cholinergic; Receptors, Muscarinic; Receptors, Nicotinic; Tumor Microenvironment
PubMed: 35858206
DOI: 10.1002/adbi.202200053 -
Trends in Neurosciences Aug 2020Recent studies provided strong evidence that deficits in cholinergic signaling cause disorders of cognition and affect conscious processing. Technical advances that... (Review)
Review
Recent studies provided strong evidence that deficits in cholinergic signaling cause disorders of cognition and affect conscious processing. Technical advances that combine molecular approaches, in vivo recordings in awake behaving animals, human brain imaging, and genetics have strengthened our understanding of the roles of nicotinic acetylcholine receptors (nAChRs) in the modulation of cognitive behavior and network dynamics. Here, we review the emergent role of nAChRs in high-order cognitive processes and discuss recent work implicating cholinergic circuits in cognitive control, including conscious processing.
Topics: Animals; Brain; Cholinergic Agents; Cognition; Humans; Neurons; Receptors, Nicotinic
PubMed: 32591156
DOI: 10.1016/j.tins.2020.06.001 -
Annual Review of Pharmacology and... Jan 2021Herein, I intend to capture highlights shared with my academic and research colleagues over the 60 years I devoted initially to my graduate and postdoctoral training and...
Herein, I intend to capture highlights shared with my academic and research colleagues over the 60 years I devoted initially to my graduate and postdoctoral training and then to academic endeavors starting as an assistant professor in a new medical school at the University of California, San Diego (UCSD). During this period, the Department of Pharmacology emerged from a division within the Department of Medicine to become the first basic science department, solely within the School of Medicine at UCSD in 1979. As part of the school's plans to reorganize and to retain me at UCSD, I was appointed as founding chair. Some years later in 2002, faculty, led largely within the Department of Pharmacology and by practicing pharmacists within UCSD Healthcare, started the independent Skaggs School of Pharmacy and Pharmaceutical Sciences with a doctor of pharmacy (PharmD) program, where I served as the founding dean. My career pathway, from working at my family-owned pharmacy to chairing a department in a school of medicine and then becoming the dean of a school of pharmacy at a research-intensive, student-centered institution, involved some risky decisions. But the academic, curricular, and accreditation challenges posed were met by a cadre of creative faculty colleagues. I offer my experiences to individuals confronted with a multiplicity of real or imagined opportunities in academic health sciences, the related pharmaceutical industry, and government oversight agencies.
Topics: Capsules; Cholinergic Agents; Humans
PubMed: 33411578
DOI: 10.1146/annurev-pharmtox-061020-050936 -
Journal of Food Biochemistry Dec 2022Alzheimer's disease (AD), the most prevalent neurodegenerative disorder, is largely associated with cognitive disability, amnesia, and abnormal behavior, which accounts... (Review)
Review
Alzheimer's disease (AD), the most prevalent neurodegenerative disorder, is largely associated with cognitive disability, amnesia, and abnormal behavior, which accounts for about two third of people with dementia worldwide. A growing body of research demonstrates that AD is connected to several factors, such as aberrant accumulation of amyloid-beta (Aβ), increase in the hyperphosphorylation of Tau protein, and the formation of neurofibrillary tangles, mitochondrial dysfunction, and inordinate production of reactive oxygen species (ROS). Despite remarkable efforts to realize the etiology and pathophysiology of AD, until now, scientists have not developed and introduced medications that can permanently cease the progression of AD. Thus, nowadays, research on the role of natural products in the treatment and prevention of AD has attracted great attention. Kaempferol (KMP), one of the prominent members of flavonols, exerts its ameliorative actions via attenuating oxidative stress and inflammation, reducing Aβ-induced neurotoxicity, and regulating the cholinergic system. Therefore, in this review article, we outlined the possible effects of KMP in the prevention and treatment of AD. PRACTICAL APPLICATIONS: Kaempferol (KMP) exerts its ameliorative actions against AD via attenuating oxidative stress and inflammation, reducing Aβ-induced neurotoxicity, and regulating the cholinergic system. The beneficial effects of KMP were addressed in both in vitro and in vivo studies; however, conducting further research can warrant its long-term effects as a safe agent. Therefore, after confirming its favorable functions in the prevention and treatment of AD, it could be used as a safe and effective agent.
Topics: Humans; Alzheimer Disease; Kaempferols; Amyloid beta-Peptides; Oxidative Stress; Cholinergic Agents
PubMed: 35929364
DOI: 10.1111/jfbc.14375 -
Molecular Neurodegeneration Apr 2023Abnormal tau accumulation and cholinergic degeneration are hallmark pathologies in the brains of patients with Alzheimer's disease (AD). However, the sensitivity of...
BACKGROUND
Abnormal tau accumulation and cholinergic degeneration are hallmark pathologies in the brains of patients with Alzheimer's disease (AD). However, the sensitivity of cholinergic neurons to AD-like tau accumulation and strategies to ameliorate tau-disrupted spatial memory in terms of neural circuits still remain elusive.
METHODS
To investigate the effect and mechanism of the cholinergic circuit in Alzheimer's disease-related hippocampal memory, overexpression of human wild-type Tau (hTau) in medial septum (MS)-hippocampus (HP) cholinergic was achieved by specifically injecting pAAV-EF1α-DIO-hTau-eGFP virus into the MS of ChAT-Cre mice. Immunostaining, behavioral analysis and optogenetic activation experiments were used to detect the effect of hTau accumulation on cholinergic neurons and the MS-CA1 cholinergic circuit. Patch-clamp recordings and in vivo local field potential recordings were used to analyze the influence of hTau on the electrical signals of cholinergic neurons and the activity of cholinergic neural circuit networks. Optogenetic activation combined with cholinergic receptor blocker was used to detect the role of cholinergic receptors in spatial memory.
RESULTS
In the present study, we found that cholinergic neurons with an asymmetric discharge characteristic in the MS-hippocampal CA1 pathway are vulnerable to tau accumulation. In addition to an inhibitory effect on neuronal excitability, theta synchronization between the MS and CA1 subsets was significantly disrupted during memory consolidation after overexpressing hTau in the MS. Photoactivating MS-CA1 cholinergic inputs within a critical 3 h time window during memory consolidation efficiently improved tau-induced spatial memory deficits in a theta rhythm-dependent manner.
CONCLUSIONS
Our study not only reveals the vulnerability of a novel MS-CA1 cholinergic circuit to AD-like tau accumulation but also provides a rhythm- and time window-dependent strategy to target the MS-CA1 cholinergic circuit, thereby rescuing tau-induced spatial cognitive functions.
Topics: Animals; Humans; Mice; Alzheimer Disease; Cholinergic Agents; Cholinergic Neurons; Hippocampus; Memory Consolidation; Memory Disorders; tau Proteins
PubMed: 37060096
DOI: 10.1186/s13024-023-00614-7 -
International Review of Neurobiology 2021Adolescence is a transitional period between childhood and adulthood, in which the individual undergoes significant cognitive, behavioral, physical, emotional, and... (Review)
Review
Adolescence is a transitional period between childhood and adulthood, in which the individual undergoes significant cognitive, behavioral, physical, emotional, and social developmental changes. During this period, adolescents engage in experimentation and risky behaviors such as licit and illicit drug use. Adolescents' high vulnerability to abuse drugs and natural reinforcers leads to greater risk for developing substance use disorders (SUDs) during adulthood. Accumulating evidence indicates that the use and abuse of licit and illicit drugs during adolescence and emerging adulthood can disrupt the cholinergic system and its processes. This review will focus on the effects of peri-adolescent nicotine and/or alcohol use, or exposure, on the cholinergic system during adulthood from preclinical and clinical studies. This review further explores potential cholinergic agents and pharmacological manipulations to counteract peri-adolescent nicotine and/or alcohol abuse.
Topics: Adolescent; Cholinergic Agents; Humans; Substance-Related Disorders
PubMed: 34696873
DOI: 10.1016/bs.irn.2021.07.008 -
Annals of Clinical and Translational... Dec 2023Further understanding of the function and regulatory mechanism of cholinergic neural circuits and related neurodegenerative diseases. (Review)
Review
OBJECTIVE
Further understanding of the function and regulatory mechanism of cholinergic neural circuits and related neurodegenerative diseases.
METHODS
This review summarized the research progress of the central cholinergic nervous system, especially for the cholinergic circuit of the medial septal nucleus-hippocampus, vertical branch of diagonal band-hippocampus, basal nucleus of Meynert-cerebral cortex cholinergic loop, amygdala, pedunculopontine nucleus, and striatum-related cholinergic loops.
RESULTS
The extensive and complex fiber projection of cholinergic neurons form the cholinergic neural circuits, which regulate several nuclei in the brain through neurotransmission and participate in learning and memory, attention, emotion, movement, etc. The loss of cholinergic neurotransmitters, the reduction, loss, and degeneration of cholinergic neurons or abnormal theta oscillations and cholinergic neural circuits can induce cognitive disorders such as AD, PD, PDD, and DLB.
INTERPRETATION
The projection and function of cholinergic fibers in some nuclei and the precise regulatory mechanisms of cholinergic neural circuits in the brain remain unclear. Further investigation of cholinergic fiber projections in various brain regions and the underlying mechanisms of the neural circuits are expected to open up new avenues for the prevention and treatment of senile neurodegenerative diseases.
Topics: Humans; Central Nervous System; Hippocampus; Cerebral Cortex; Neurodegenerative Diseases; Cholinergic Agents
PubMed: 37846148
DOI: 10.1002/acn3.51920