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Scientific Reports Dec 2022Inhibitory control is a key executive function that limits unnecessary thoughts and actions, enabling an organism to appropriately execute goal-driven behaviors. The...
Inhibitory control is a key executive function that limits unnecessary thoughts and actions, enabling an organism to appropriately execute goal-driven behaviors. The efficiency of this inhibitory capacity declines with normal aging or in neurodegenerative dementias similar to memory or other cognitive functions. Acetylcholine signaling is crucial for executive function and also diminishes with aging. Acetylcholine's contribution to the aging- or dementia-related decline in inhibitory control, however, remains elusive. We addressed this in Drosophila using a Go/No-Go task that measures inhibition capacity. Here, we report that inhibition capacity declines with aging in wild-type flies, which is mitigated by lessening acetylcholine breakdown and augmented by reducing acetylcholine biosynthesis. We identified the mushroom body (MB) γ neurons as a chief neural site for acetylcholine's contribution to the aging-associated inhibitory control deficit. In addition, we found that the MB output neurons MBON-γ2α'1 having dendrites at the MB γ2 and α'1 lobes and axons projecting to the superior medial protocerebrum and the crepine is critical for sustained movement suppression per se. This study reveals, for the first time, the central role of acetylcholine in the aging-associated loss of inhibitory control and provides a framework for further mechanistic studies.
Topics: Animals; Acetylcholine; Synaptic Transmission; Aging; Causality; Cognition; Drosophila
PubMed: 36463374
DOI: 10.1038/s41598-022-25402-z -
CNS Drugs Nov 2018Opioid overdoses recently became the leading cause of accidental death in the US, marking an increase in the severity of the opioid use disorder (OUD) epidemic that is... (Review)
Review
Opioid overdoses recently became the leading cause of accidental death in the US, marking an increase in the severity of the opioid use disorder (OUD) epidemic that is impacting global health. Current treatment protocols for OUD are limited to opioid medications, including methadone, buprenorphine, and naltrexone. While these medications are effective in many cases, new treatments are required to more effectively address the rising societal and interpersonal costs associated with OUD. In this article, we review the opioid and cholinergic systems, and examine the potential of acetylcholine (ACh) as a treatment target for OUD. The cholinergic system includes enzymes that synthesize and degrade ACh and receptors that mediate the effects of ACh. ACh is involved in many central nervous system functions that are critical to the development and maintenance of OUD, such as reward and cognition. Medications that target the cholinergic system have been approved for the treatment of Alzheimer's disease, tobacco use disorder, and nausea. Clinical and preclinical studies suggest that medications such as cholinesterase inhibitors and scopolamine, which target components of the cholinergic system, show promise for the treatment of OUD and further investigations are warranted.
Topics: Acetylcholine; Analgesics, Opioid; Animals; Cholinergic Agents; Humans; Non-Neuronal Cholinergic System; Opioid-Related Disorders
PubMed: 30259415
DOI: 10.1007/s40263-018-0572-y -
Journal of Neurochemistry Aug 2017Deciphering neuronal pathways that reactivate spinal central pattern generators (CPGs) and modulate the activity of spinal motoneurons in mammals in the absence of... (Review)
Review
Deciphering neuronal pathways that reactivate spinal central pattern generators (CPGs) and modulate the activity of spinal motoneurons in mammals in the absence of supraspinal control is important for understanding of neural control of movement and for developing novel therapeutic approaches to improve the mobility of spinal cord injury patients. Previously, we showed that the sacral and lumbar cholinergic system could potently modulate the locomotor CPGs in newborn rodents. Here, we review these and our more recent studies of sacral relay neurons with lumbar projections to the locomotor CPGs and to lumbar motoneurons and demonstrate that sacral and lumbar cholinergic components have the capacity to control the frequency of the locomotor CPGs and at the same time the motor output of the activated lumbar motoneurons during motor behavior. A model describing the suggested ascending sacro-lumbar connectivity involved in modulation of the locomotor rhythm by sacral cholinergic components is proposed and discussed. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms.
Topics: Acetylcholine; Animals; Cholinergic Agents; Humans; Locomotion; Lumbar Vertebrae; Motor Activity; Motor Neurons
PubMed: 28791705
DOI: 10.1111/jnc.14065 -
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 -
PloS One 2022The physiology and pathophysiology of the exocrine pancreas are in close connection to changes in intra-cellular Ca2+ concentration. Most of our knowledge is based on in...
The physiology and pathophysiology of the exocrine pancreas are in close connection to changes in intra-cellular Ca2+ concentration. Most of our knowledge is based on in vitro experiments on acinar cells or acini enzymatically isolated from their surroundings, which can alter their structure, physiology, and limit our understanding. Due to these limitations, the acute pancreas tissue slice technique was introduced almost two decades ago as a complementary approach to assess the morphology and physiology of both the endocrine and exocrine pancreas in a more conserved in situ setting. In this study, we extend previous work to functional multicellular calcium imaging on acinar cells in tissue slices. The viability and morphological characteristics of acinar cells within the tissue slice were assessed using the LIVE/DEAD assay, transmission electron microscopy, and immunofluorescence imaging. The main aim of our study was to characterize the responses of acinar cells to stimulation with acetylcholine and compare them with responses to cerulein in pancreatic tissue slices, with special emphasis on inter-cellular and inter-acinar heterogeneity and coupling. To this end, calcium imaging was performed employing confocal microscopy during stimulation with a wide range of acetylcholine concentrations and selected concentrations of cerulein. We show that various calcium oscillation parameters depend monotonically on the stimulus concentration and that the activity is rather well synchronized within acini, but not between acini. The acute pancreas tissue slice represents a viable and reliable experimental approach for the evaluation of both intra- and inter-cellular signaling characteristics of acinar cell calcium dynamics. It can be utilized to assess many cells simultaneously with a high spatiotemporal resolution, thus providing an efficient and high-yield platform for future studies of normal acinar cell biology, pathophysiology, and screening pharmacological substances.
Topics: Acetylcholine; Acinar Cells; Animals; Calcium; Calcium, Dietary; Ceruletide; Mice; Microscopy, Confocal; Pancreas
PubMed: 35657915
DOI: 10.1371/journal.pone.0268644 -
The Journals of Gerontology. Series A,... Jul 2008Deficits in cholinergic function have been postulated to cause delirium and cognitive decline. This review examines current understanding of the cholinergic deficiency... (Review)
Review
Deficits in cholinergic function have been postulated to cause delirium and cognitive decline. This review examines current understanding of the cholinergic deficiency hypothesis in delirium by synthesizing evidence on potential pathophysiological pathways. Acetylcholine synthesis involves various precursors, enzymes, and receptors, and dysfunction in these components can lead to delirium. Insults to the brain, like ischemia and immunological stressors, can precipitously alter acetylcholine levels. Imbalances between cholinergic and other neurotransmitter pathways may result in delirium. Furthermore, genetic, enzymatic, and immunological overlaps exist between delirium and dementia related to the cholinergic pathway. Important areas for future research include identifying biomarkers, determining genetic contributions, and evaluating response to cholinergic drugs in delirium. Understanding how the cholinergic pathway relates to delirium may yield innovative approaches in the diagnosis, prevention, and treatment of this common, costly, and morbid condition.
Topics: Acetylcholine; Brain; Delirium; Dementia; Humans; Neurotransmitter Agents; Receptors, Neurotransmitter
PubMed: 18693233
DOI: 10.1093/gerona/63.7.764 -
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 -
Journal of the Royal Society, Interface Nov 2017Biological systems-like ourselves-are constantly faced with uncertainty. Despite noisy sensory data, and volatile environments, creatures appear to actively maintain...
Biological systems-like ourselves-are constantly faced with uncertainty. Despite noisy sensory data, and volatile environments, creatures appear to actively maintain their integrity. To account for this remarkable ability to make optimal decisions in the face of a capricious world, we propose a generative model that represents the beliefs an agent might possess about their own uncertainty. By simulating a noisy and volatile environment, we demonstrate how uncertainty influences optimal epistemic (visual) foraging. In our simulations, saccades were deployed less frequently to regions with a lower sensory precision, while a greater volatility led to a shorter inhibition of return. These simulations illustrate a principled explanation for some cardinal aspects of visual foraging-and allow us to propose a correspondence between the representation of uncertainty and ascending neuromodulatory systems, complementing that suggested by Yu & Dayan (Yu & Dayan 2005 , 681-692. (doi:10.1016/j.neuron.2005.04.026)).
Topics: Acetylcholine; Bayes Theorem; Computer Simulation; Learning; Markov Chains; Models, Neurological; Norepinephrine; Systems Biology; Uncertainty
PubMed: 29167370
DOI: 10.1098/rsif.2017.0376 -
Acta Crystallographica. Section F,... Sep 2022The affinity and thermodynamic parameters for the interactions of two naturally occurring neurotoxins, (+)-anatoxin-a and (-)-hosieine-A, with acetylcholine-binding...
The affinity and thermodynamic parameters for the interactions of two naturally occurring neurotoxins, (+)-anatoxin-a and (-)-hosieine-A, with acetylcholine-binding protein were investigated using a fluorescence-quenching assay and isothermal titration calorimetry. The crystal structures of their complexes with acetylcholine-binding protein from Aplysia californica (AcAChBP) were determined and reveal details of molecular recognition in the orthosteric binding site. Comparisons treating AcAChBP as a surrogate for human α4β2 and α7 nicotinic acetylcholine receptors (nAChRs) suggest that the molecular features involved in ligand recognition and affinity for the protein targets are conserved. The ligands exploit interactions with similar residues as the archetypal nAChR agonist nicotine, but with greater affinity. (-)-Hosieine-A in particular has a high affinity for AcAChBP driven by a favorable entropic contribution to binding. The ligand affinities help to rationalize the potent biological activity of these alkaloids. The structural data, together with comparisons with related molecules, suggest that there may be opportunities to extend the hosieine-A scaffold to incorporate new interactions with the complementary side of the orthosteric binding site. Such a strategy may guide the design of new entities to target human α4β2 nAChR that may have therapeutic benefit.
Topics: Acetylcholine; Carrier Proteins; Crystallography, X-Ray; Cyanobacteria Toxins; Heterocyclic Compounds, 4 or More Rings; Humans; Ligands; Nicotinic Agonists; Receptors, Nicotinic; Tropanes
PubMed: 36048081
DOI: 10.1107/S2053230X22007762 -
Current Opinion in Neurobiology Jun 2017The pattern of sleep in the fur seal, a semiaquatic pinniped, has several striking behavioral and physiological adaptations that allow this species to inhabit both the... (Review)
Review
The pattern of sleep in the fur seal, a semiaquatic pinniped, has several striking behavioral and physiological adaptations that allow this species to inhabit both the land and water environment. These features include unihemispheric slow wave sleep (USWS, also being unihemispheric waking), the ability to maintain movement for stabilization of the sleep posture and to briefly open one eye while having a sleep electroencephalogram (EEG) in one hemisphere. In vivo microdialysis studies suggest that acetylcholine release is required for cortical activation during USWS, and that monoamines are not required for USWS. The need to breathe, to maintain efficient thermoregulation, and to avoid predation have shaped the sleep patterns in semiaquatic fur seals as in fully aquatic cetaceans.
Topics: Acetylcholine; Animals; Electroencephalography; Fur Seals; Sleep
PubMed: 28505502
DOI: 10.1016/j.conb.2017.04.009