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Neuroscience Oct 2023While the functional and behavioral role of the medial habenula (MHb) is still emerging, recent data indicate an involvement of this nuclei in regulating mood, aversion,...
While the functional and behavioral role of the medial habenula (MHb) is still emerging, recent data indicate an involvement of this nuclei in regulating mood, aversion, and addiction. Unique to the MHb is a large cluster of cholinergic neurons that project to the interpeduncular nucleus and densely express acetylcholine receptors (AChRs) suggesting that the activity of these cholinergic neurons may be regulated by ACh itself. Whether endogenous ACh from within the habenula regulates cholinergic neuron activity has not been demonstrated. Supporting a role for ACh in modulating MHb activity, acetylcholinesterase inhibitors increased the firing rate of MHb cholinergic neurons in mouse habenula slices, an effect blocked by AChR antagonists and mediated by ACh which was detected via expressing fluorescent ACh sensors in MHb in vivo. To test if cholinergic afferents innervate MHb cholinergic neurons, we used anterograde and retrograde viral tracing to identify cholinergic inputs. Surprisingly, tracing experiments failed to detect cholinergic inputs into the MHb, including from the septum, suggesting that MHb cholinergic neurons may release ACh within the MHb to drive cholinergic activity. To test this hypothesis, we expressed channelrhodopsin in a portion of MHb cholinergic neurons while recording from non-opsin-expressing neurons. Light pulses progressively increased activity of MHb cholinergic neurons indicating feed-forward activation driven by MHb ACh release. These data indicate MHb cholinergic neurons may utilize a unique feed-forward mechanism to synchronize and increase activity by releasing local ACh.
Topics: Mice; Animals; Acetylcholine; Habenula; Acetylcholinesterase; Cholinergic Neurons; Cholinergic Agents
PubMed: 37572877
DOI: 10.1016/j.neuroscience.2023.07.030 -
European Journal of Medicinal Chemistry Dec 2023Our research group recently identified a rearrangement product of pirenzepine as starting point for a comprehensive rational drug design approach towards orthosteric...
Our research group recently identified a rearrangement product of pirenzepine as starting point for a comprehensive rational drug design approach towards orthosteric muscarinic acetylcholine receptor ligands. Chemical reduction and bioscaffold hop lead to the development of sixteen promising compounds featuring either a benzimidazole or carbamate moiety, all exhibiting comparable pharmacophoric characteristics. The synthesized compounds were characterized by NMR, HR-MS, and RP-HPLC techniques. Subsequent evaluation encompassed binding affinity assessment on CHO-hM cells, mode of action determination, and analysis of physico-chemical parameters. The CNS MPO score indicated favorable drug-like attributes and potential CNS activity for the antagonistic ligands. The most promising compounds displayed K-values within a desirable low nanomolar range, and their structural features allow for potential carbon-11 radiolabeling. Our optimization efforts resulted in compounds with a remarkable 138-fold increase in binding affinity compared to the previously mentioned rearrangement product towards human M, suggesting their prospective utility in positron emission tomography applications.
Topics: Humans; Muscarine; Muscarinic Antagonists; Ligands; Protein Binding
PubMed: 37897926
DOI: 10.1016/j.ejmech.2023.115891 -
Journal of Neurochemistry Aug 2017Acetylcholine (ACh) plays an important role in memory function and has been implicated in aging-related dementia, in which the impairment of hippocampus-dependent... (Review)
Review
Acetylcholine (ACh) plays an important role in memory function and has been implicated in aging-related dementia, in which the impairment of hippocampus-dependent learning strongly manifests. Cholinergic neurons densely innervate the hippocampus, mediating the formation of episodic as well as semantic memory. Here, we will review recent findings on acetylcholine's modulation of memory function, with a particular focus on hippocampus-dependent learning, and the circuits involved. In addition, we will discuss the complexity of ACh actions in memory function to better understand the physiological role of ACh in memory. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms.
Topics: Acetylcholine; Aging; Animals; Cholinergic Agents; Hippocampus; Humans; Learning; Memory
PubMed: 28791706
DOI: 10.1111/jnc.14052 -
Neuropharmacology Mar 2012Effective treatment of the cognitive symptoms of schizophrenia has remained an elusive goal. Despite the intense focus on treatments acting at or via cholinergic... (Review)
Review
Effective treatment of the cognitive symptoms of schizophrenia has remained an elusive goal. Despite the intense focus on treatments acting at or via cholinergic mechanisms, little remains known about the dynamic cholinergic abnormalities that contribute to the manifestation of the cognitive symptoms in patients. Evidence from basic neuroscientific and psychopharmacological investigations assists in proposing detailed cholinergic mechanisms and treatment targets for enhancement of attentional performance. Dynamic, cognitive performance-dependent abnormalities in cholinergic activity have been observed in animal models of the disorder and serve to further refine such proposals. Finally, the potential usefulness of individual groups of cholinergic drugs and important issues concerning the interactions between pro-cholinergic and antipsychotic treatments are addressed. The limited evidence available from patient studies and animal models indicates pressing research needs in order to guide the development of cholinergic treatments of the cognitive symptoms of schizophrenia.
Topics: Animals; Antipsychotic Agents; Attention; Cholinergic Agents; Cognition Disorders; Humans; Schizophrenia; Signal Transduction
PubMed: 21156184
DOI: 10.1016/j.neuropharm.2010.12.001 -
The Canadian Journal of Cardiology May 2019
Topics: Adrenergic Agents; Antihypertensive Agents; Cholinergic Agents; Humans; Hypertension; Receptors, Muscarinic
PubMed: 30954389
DOI: 10.1016/j.cjca.2019.02.003 -
Current Neuropharmacology 2015The central cholinergic system has been implicated in the pathophysiology of mood disorders. An imbalance in central cholinergic neurotransmitter activity has been... (Review)
Review
The central cholinergic system has been implicated in the pathophysiology of mood disorders. An imbalance in central cholinergic neurotransmitter activity has been proposed to contribute to the manic and depressive episodes typical of these disorders. Neuropharmacological studies into the effects of cholinergic agonists and antagonists on mood state have provided considerable support for this hypothesis. Furthermore, recent clinical studies have shown that the pan-CHRM antagonist, scopolamine, produces rapid-acting antidepressant effects in individuals with either major depressive disorder (MDD) or bipolar disorder (BPD), such as bipolar depression, contrasting the delayed therapeutic response of conventional mood stabilisers and antidepressants. This review presents recent data from neuroimaging, post-mortem and genetic studies supporting the involvement of muscarinic cholinergic receptors (CHRMs), particularly CHRM2, in the pathophysiology of MDD and BPD. Thus, novel drugs that selectively target CHRMs with negligible effects in the peripheral nervous system might produce more rapid and robust clinical improvement in patients with BPD and MDD.
Topics: Animals; Brain; Cholinergic Agents; Humans; Mood Disorders; Psychotropic Drugs; Receptors, Muscarinic
PubMed: 26630954
DOI: 10.2174/1570159x13666150612230045 -
PLoS Computational Biology Jun 2022General anesthetics work through a variety of molecular mechanisms while resulting in the common end point of sedation and loss of consciousness. Generally, the...
General anesthetics work through a variety of molecular mechanisms while resulting in the common end point of sedation and loss of consciousness. Generally, the administration of common anesthetics induces reduction in synaptic excitation while promoting synaptic inhibition. Exogenous modulation of the anesthetics' synaptic effects can help determine the neuronal pathways involved in anesthesia. For example, both animal and human studies have shown that exogenously induced increases in acetylcholine in the brain can elicit wakeful-like behavior despite the continued presence of the anesthetic. However, the underlying mechanisms of anesthesia reversal at the cellular level have not been investigated. Here we apply a computational model of a network of excitatory and inhibitory neurons to simulate the network-wide effects of anesthesia, due to changes in synaptic inhibition and excitation, and their reversal by cholinergic activation through muscarinic receptors. We use a differential evolution algorithm to fit model parameters to match measures of spiking activity, neuronal connectivity, and network dynamics recorded in the visual cortex of rodents during anesthesia with desflurane in vivo. We find that facilitating muscarinic receptor effects of acetylcholine on top of anesthetic-induced synaptic changes predicts the reversal of anesthetic suppression of neurons' spiking activity, functional connectivity, as well as pairwise and population interactions. Thus, our model predicts a specific neuronal mechanism for the cholinergic reversal of anesthesia consistent with experimental behavioral observations.
Topics: Acetylcholine; Anesthesia; Anesthetics, General; Animals; Cerebral Cortex; Cholinergic Agents
PubMed: 35737717
DOI: 10.1371/journal.pcbi.1009743 -
Current Topics in Behavioral... 2020The central cholinergic system is one of the most important modulator neurotransmitter system implicated in diverse behavioral processes. Activation of the basal... (Review)
Review
The central cholinergic system is one of the most important modulator neurotransmitter system implicated in diverse behavioral processes. Activation of the basal forebrain cortical cholinergic input system represents a critical step in cortical information processing. This chapter explores recent developments illustrating cortical cholinergic transmission mediate defined cognitive operations, which is contrary to the traditional view that acetylcholine acts as a slowly acting neuromodulator that influences arousal cortex-wide. Specifically, we review the evidence that phasic cholinergic signaling in the prefrontal cortex is a causal mediator of signal detection. In addition, studies that support the neuromodulatory role of cholinergic inputs in top-down attentional control are summarized. Finally, we review new findings that reveal sex differences and hormonal regulation of the cholinergic-attention system.
Topics: Acetylcholine; Attention; Cholinergic Agents; Cognition; Female; Male; Prefrontal Cortex
PubMed: 32447715
DOI: 10.1007/7854_2020_133 -
Evidence Report/technology Assessment... Apr 2004
Meta-Analysis Review
Topics: Cholinergic Agents; Cognition; Complementary Therapies; Dementia; Dementia, Vascular; Disease Progression; Humans; Neurotransmitter Agents; Nootropic Agents; United States
PubMed: 15279402
DOI: No ID Found -
Journal of Neurochemistry Aug 2017Three-finger fold toxins are miniproteins frequently found in Elapidae snake venoms. This fold is characterized by three distinct loops rich in β-strands and emerging... (Review)
Review
Three-finger fold toxins are miniproteins frequently found in Elapidae snake venoms. This fold is characterized by three distinct loops rich in β-strands and emerging from a dense, globular core reticulated by four highly conserved disulfide bridges. The number and diversity of receptors, channels, and enzymes identified as targets of three-finger fold toxins is increasing continuously. Such manifold diversity highlights the specific adaptability of this fold for generating pleiotropic functions. Although this toxin superfamily disturbs many biological functions by interacting with a large diversity of molecular targets, the most significant target is the cholinergic system. By blocking the activity of the nicotinic and muscarinic acetylcholine receptors or by inhibiting the enzyme acetylcholinesterase, three-finger fold toxins interfere most drastically with neuromuscular junction functioning. Several of these toxins have become powerful pharmacological tools for studying the function and structure of their molecular targets. Most importantly, since dysfunction of these receptors/enzyme is involved in many diseases, exploiting the three-finger scaffold to create novel, highly specific therapeutic agents may represent a major future endeavor. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms.
Topics: Acetylcholine; Animals; Cholinergic Agents; Humans; Models, Molecular; Receptors, Muscarinic; Snake Venoms; Toxins, Biological
PubMed: 28326549
DOI: 10.1111/jnc.13975