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Journal of Pharmacological and... 2023The central nervous system of hard ticks (Ixodidae) consists of a concentrated merged nerve mass known as the synganglion. Although knowledge of tick neurobiology has...
The central nervous system of hard ticks (Ixodidae) consists of a concentrated merged nerve mass known as the synganglion. Although knowledge of tick neurobiology has dramatically improved over the last two decades, this is the first time that isolation and electrophysiological recordings have been carried out on tick neurons from the synganglion. Method: We developed a simple protocol for synganglion neuron isolation and used a whole-cell patch clamp to measure ionic currents induced by acetylcholine, nicotine and muscarine. Relatively large neurons (∼ 25 μm and ∼ 35 μm) were isolated and 1 mM acetylcholine was used to induce strong inward currents of -0.38 ± 0.1 nA and - 1.04 ± 0.1 nA, respectively, with the corresponding cell capacitances being at around 142 pF and 188 pF. In addition, successive application of 1 mM acetylcholine through ∼25 μm and ∼ 35 μm cells for increasing amounts of time resulted in a rapid reduction in current amplitudes. We also found that acetylcholine-evoked currents were associated with a reversible increase in intracellular calcium levels for each neuronal type. In contrast, 1 mM muscarine and nicotine induced a strong and non-reversible increase in intracellular calcium levels. This study serves as a proof of concept for the mechanical isolation of tick synganglion neurons followed by their electrophysiological recording. This approach will aid investigations into the pharmacological properties of tick neurons and provides the tools needed for the identification of drug-targeted sites and effective tick control measures.
Topics: Animals; Ixodes; Nicotine; Acetylcholine; Calcium; Muscarine; Neurons
PubMed: 37866797
DOI: 10.1016/j.vascn.2023.107473 -
Central Nervous System Agents in... 2022The nervous system regulates the visual system through neurotransmitters that play an important role in visual and ocular functions. One of those neurotransmitters is...
The nervous system regulates the visual system through neurotransmitters that play an important role in visual and ocular functions. One of those neurotransmitters is acetylcholine, a key molecule that plays a variety of biological functions. Moreover, acetylcholinesterase, the enzyme responsible for the hydrolysis of acetylcholine, is implicated in cholinergic function. However, several studies have demonstrated that in addition to their enzymatic functions, acetylcholinesterase exerts non-catalytic functions. In recent years, the importance of evaluating all possible functions of acetylcholine-acetylcholinesterase has been shown. Nevertheless, there is evidence suggesting that cholinesterase activity in the eye can regulate some biological events both in structures of the anterior and posterior segment of the eye and, therefore, in the visual information that is processed in the visual cortex. Hence, the evaluation of cholinesterase activity could be a possible marker of alterations in cholinergic activity in both ocular and systemic diseases.
Topics: Acetylcholinesterase; Acetylcholine; Cholinesterase Inhibitors; Cholinergic Agents; Neurotransmitter Agents
PubMed: 35431003
DOI: 10.2174/1871524922666220414093730 -
American Journal of Physiology. Cell... Dec 2023A role of Yes1-associated transcriptional regulator (YAP) and WW domain-containing transcription regulator 1 (TAZ) in vascular and gastrointestinal contractility due to...
A role of Yes1-associated transcriptional regulator (YAP) and WW domain-containing transcription regulator 1 (TAZ) in vascular and gastrointestinal contractility due to control of myocardin (Myocd) expression, which in turn activates contractile genes, has been demonstrated. Whether this transcriptional hierarchy applies to the urinary bladder is unclear. We found that YAP/TAZ are expressed in human detrusor myocytes and therefore exploited the model for the deletion of YAP/TAZ. Recombination occurred in detrusor, and YAP/TAZ transcripts were reduced by >75%. Bladder weights were increased (by ≈22%), but histology demonstrated minimal changes in the detrusor, while arteries in the mucosa were inflamed. Real-time quantitative reverse transcription PCR (RT-qPCR) using the detrusor demonstrated reductions of (-79 ± 18%) and serum response factor () along with contractile genes. In addition, the cholinergic receptor muscarinic 2 () and were suppressed (-80 ± 23% and -80 ± 10%), whereas minute increases of and were seen. Unlike YAP/TAZ-deficient arteries, SRY (sex-determining region Y)-box 9 () did not increase, and no chondrogenic differentiation was apparent. Reductions of smooth muscle myosin heavy chain 11 (Myh11), myosin light-chain kinase gene (Mylk), and Chrm3 were seen at the protein level. Beyond restraining the smooth muscle cell (SMC) program of gene expression, YAP/TAZ depletion silenced SMC-specific splicing, including exon 2a of . Reduced contractile differentiation was associated with weaker contraction in response to myosin phosphatase inhibition (-36%) and muscarinic activation (reduced by 53% at 0.3 µM carbachol). Finally, short-term overexpression of constitutively active YAP in human embryonic kidney 293 (HEK293) cells increased myocardin (greater than eightfold) along with archetypal target genes, but contractile genes were unaffected or reduced. YAP and TAZ thus regulate myocardin expression in the detrusor, and this is important for SMC differentiation and splicing as well as for contractility. This study addresses the hypothesis that YAP and TAZ have an overarching role in the transcriptional hierarchy in the smooth muscle of the urinary bladder by controlling myocardin expression. Using smooth muscle-specific and inducible deletion of YAP and TAZ in adult mice, we find that YAP and TAZ control myocardin expression, contractile differentiation, smooth muscle-specific splicing, and bladder contractility. These effects are largely independent of inflammation and chondrogenic differentiation.
Topics: Adult; Mice; Humans; Animals; Urinary Bladder; HEK293 Cells; Intracellular Signaling Peptides and Proteins; Cell Differentiation; Inflammation; Cholinergic Agents
PubMed: 37927241
DOI: 10.1152/ajpcell.00270.2023 -
Biochemical Society Transactions Apr 2023Barbeau's seesaw hypothesis of dopamine-acetylcholine balance has predominated movement disorders literature for years. Both the simplicity of the explanation and the... (Review)
Review
Barbeau's seesaw hypothesis of dopamine-acetylcholine balance has predominated movement disorders literature for years. Both the simplicity of the explanation and the matching efficacy of anticholinergic treatment in movement disorders seem to support this hypothesis. However, evidence from translational and clinical studies in movement disorders indicates that many features of this simple balance are lost, broken, or absent from movement disorders models or in imaging studies of patients with these disorders. This review reappraises the dopamine-acetylcholine balance hypothesis in light of recent evidence and describes how the Gαi/o coupled muscarinic M4 receptor acts in opposition to dopamine signaling in the basal ganglia. We highlight how M4 signaling can ameliorate or exacerbate movement disorders symptoms and physiological correlates of these symptoms in specific disease states. Furthermore, we propose future directions for investigation of this mechanisms to fully understand the potential efficacy of M4 targeting therapeutics in movement disorders. Overall, initial evidence suggest that M4 is a promising pharmaceutical target to ameliorate motor symptoms of hypo- and hyper-dopaminergic disorders.
Topics: Humans; Acetylcholine; Receptor, Muscarinic M4; Dopamine; Movement Disorders; Cholinergic Agents
PubMed: 37013974
DOI: 10.1042/BST20220525 -
Psychopharmacology Aug 2019Many physiological and pathological changes in brain function manifest in eye-movement control. As such, assessment of oculomotion is an invaluable part of a clinical...
Many physiological and pathological changes in brain function manifest in eye-movement control. As such, assessment of oculomotion is an invaluable part of a clinical examination and affords a non-invasive window on several key aspects of neuronal computation. While oculomotion is often used to detect deficits of the sort associated with vascular or neoplastic events; subtler (e.g. pharmacological) effects on neuronal processing also induce oculomotor changes. We have previously framed oculomotor control as part of active vision, namely, a process of inference comprising two distinct but related challenges. The first is inferring where to look, and the second is inferring how to implement the selected action. In this paper, we draw from recent theoretical work on the neuromodulatory control of active inference. This allows us to simulate the sort of changes we would expect in oculomotor behaviour, following pharmacological enhancement or suppression of key neuromodulators-in terms of deciding where to look and the ensuing trajectory of the eye movement itself. We focus upon the influence of cholinergic and GABAergic agents on the speed of saccades, and consider dopaminergic and noradrenergic effects on more complex, memory-guided, behaviour. In principle, a computational approach to understanding the relationship between pharmacology and oculomotor behaviour affords the opportunity to estimate the influence of a given pharmaceutical upon neuronal function, and to use this to optimise therapeutic interventions on an individual basis.
Topics: Cholinergic Agents; Computer Simulation; Eye Movements; GABA Agents; Humans; Memory; Models, Neurological; Neurons; Saccades
PubMed: 30982126
DOI: 10.1007/s00213-019-05240-0 -
Life Sciences Nov 2023Abnormal cardiac metabolism or cardiac metabolic remodeling is reported before the onset of heart failure with reduced ejection fraction (HFrEF) and is known to trigger... (Review)
Review
Abnormal cardiac metabolism or cardiac metabolic remodeling is reported before the onset of heart failure with reduced ejection fraction (HFrEF) and is known to trigger and maintain the mechanical dysfunction and electrical, and structural abnormalities of the ventricle. A dysregulated cardiac autonomic tone characterized by sympathetic overdrive with blunted parasympathetic activation is another pathophysiological hallmark of HF. Emerging evidence suggests a link between autonomic nervous system activity and cardiac metabolism. Chronic β-adrenergic activation promotes maladaptive metabolic remodeling whereas cholinergic activation attenuates the metabolic aberrations through favorable modulation of key metabolic regulatory molecules. Restoration of sympathovagal balance by neuromodulation strategies is emerging as a novel nonpharmacological treatment strategy in HF. The current review attempts to evaluate the 'neuro-metabolic axis' in HFrEF and whether neuromodulation can mitigate the adverse metabolic remodeling in HFrEF.
Topics: Humans; Heart Failure; Stroke Volume; Heart; Autonomic Nervous System; Cholinergic Agents
PubMed: 37774940
DOI: 10.1016/j.lfs.2023.122122 -
The Journal of Allergy and Clinical... Dec 2020
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Anti-Asthmatic Agents; Asthma; Cholinergic Agents; Humans; Practice Guidelines as Topic
PubMed: 32603663
DOI: 10.1016/j.jaci.2020.06.014 -
Archives of Medical Research May 2020The production of new neurons continues in the adult mammalian brain because of the sustained proliferation and differentiation of neural stem cells (NSCs) in neurogenic... (Review)
Review
The production of new neurons continues in the adult mammalian brain because of the sustained proliferation and differentiation of neural stem cells (NSCs) in neurogenic regions. The subventricular zone (SVZ), lining the lateral ventricle, and the subgranular zone (SGZ), which is in the dentate gyrus (DG) of the hippocampus, are the central regions of neurogenesis in the brain. Neurogenesis brings great hope for repairing a damaged brain and motivates researchers to detect the controlling signals of this process. Neurogenesis is regulated by intracellular and extracellular mechanisms that are influenced by neurogenic microenvironments. Recent experimental evidence suggests that the cholinergic system and nicotinic acetylcholine receptors (nAChRs) can directly regulate postnatal neurogenesis via specific mechanisms in these regions. In this review, we outline the cholinergic projections to the neurogenic niches and explain how the cholinergic system may regulate the formation of new neurons. We also discuss the intrinsic signaling pathways by which this system affects neurogenesis.
Topics: Cholinergic Agents; Humans; Neurogenesis; Nicotine; Non-Neuronal Cholinergic System; Signal Transduction
PubMed: 32279909
DOI: 10.1016/j.arcmed.2020.03.014 -
Neuroscience Jul 2020Since the pioneering works of Ricardo Miledi, the neuromuscular junction represents the best example of a synapse where ACh is the neurotransmitter acting on nicotinic... (Review)
Review
Since the pioneering works of Ricardo Miledi, the neuromuscular junction represents the best example of a synapse where ACh is the neurotransmitter acting on nicotinic ACh receptors. ATP, co-released with ACh, is promptly degraded to Ado, which acts as a modulator of the cholinergic synaptic activity. Consequently, both ACh and adenosine play a crucial role in controlling the nerve-muscle communication. Apart from their role in the context of synaptic transmission, ACh and adenosine are autocrinally released by skeletal muscle cells, suggesting also a non nerve-driven function of these molecules. Indeed, the existence of cholinergic and adenosinergic systems has been widely described in many other non neuronal cell types. In this review, we will describe the two systems and their interplay in non-innervated differentiating skeletal muscle cells, and in innervated adult skeletal muscle fibers. We believe that the better comprehension of the interactions between the activity of nAChRs and adenosine could help the knowledge of skeletal muscle physiology. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.
Topics: Acetylcholine; Cholinergic Agents; Muscle, Skeletal; Neuromuscular Junction; Synaptic Transmission
PubMed: 31121259
DOI: 10.1016/j.neuroscience.2019.05.020 -
The American Journal of Psychiatry Jan 2021
Topics: Child; Cholinergic Agents; Corpus Striatum; Humans; Interneurons; Obsessive-Compulsive Disorder
PubMed: 33384008
DOI: 10.1176/appi.ajp.2020.20111598