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Proceedings of the National Academy of... Sep 2023Foraging theory prescribes when optimal foragers should leave the current option for more rewarding alternatives. Actual foragers often exploit options longer than... (Randomized Controlled Trial)
Randomized Controlled Trial
Foraging theory prescribes when optimal foragers should leave the current option for more rewarding alternatives. Actual foragers often exploit options longer than prescribed by the theory, but it is unclear how this foraging suboptimality arises. We investigated whether the upregulation of cholinergic, noradrenergic, and dopaminergic systems increases foraging optimality. In a double-blind, between-subject design, participants (N = 160) received placebo, the nicotinic acetylcholine receptor agonist , a noradrenaline reuptake inhibitor , or a preferential dopamine reuptake inhibitor , and played the role of a farmer who collected milk from patches with different yield. Across all groups, participants on average overharvested. While methylphenidate had no effects on this bias, nicotine, and to some extent also reboxetine, significantly reduced deviation from foraging optimality, which resulted in better performance compared to placebo. Concurring with amplified goal-directedness and excluding heuristic explanations, nicotine independently also improved trial initiation and time perception. Our findings elucidate the neurochemical basis of behavioral flexibility and decision optimality and open unique perspectives on psychiatric disorders affecting these functions.
Topics: Humans; Acetylcholine; Methylphenidate; Nicotine; Norepinephrine; Reboxetine; Double-Blind Method
PubMed: 37639601
DOI: 10.1073/pnas.2305596120 -
Nature Reviews. Neuroscience Apr 2023Acetylcholine plays an essential role in fundamental aspects of cognition. Studies that have mapped the activity and functional connectivity of cholinergic neurons have... (Review)
Review
Acetylcholine plays an essential role in fundamental aspects of cognition. Studies that have mapped the activity and functional connectivity of cholinergic neurons have shown that the axons of basal forebrain cholinergic neurons innervate the pallium with far more topographical and functional organization than was historically appreciated. Together with the results of studies using new probes that allow release of acetylcholine to be detected with high spatial and temporal resolution, these findings have implicated cholinergic networks in 'binding' diverse behaviours that contribute to cognition. Here, we review recent findings on the developmental origins, connectivity and function of cholinergic neurons, and explore the participation of cholinergic signalling in the encoding of cognition-related behaviours.
Topics: Humans; Acetylcholine; Basal Forebrain; Cholinergic Agents; Cognition; Signal Transduction
PubMed: 36823458
DOI: 10.1038/s41583-023-00677-x -
Journal of Neuroscience Research Dec 2019The striatum plays a central role in guiding numerous complex behaviors, ranging from motor control to action selection and reward learning. The diverse responsibilities... (Review)
Review
The striatum plays a central role in guiding numerous complex behaviors, ranging from motor control to action selection and reward learning. The diverse responsibilities of the striatum are reflected by the complexity of its organization. In this review, we will summarize what is currently known about the compartmental layout of the striatum, an organizational principle that is crucial for allowing the striatum to guide such a diverse array of behaviors. We will focus on the anatomical and functional properties of striosome (patch) and matrix compartments of the striatum, and how the engagement of these compartments is uniquely controlled by their afferents, intrinsic properties, and neuromodulation. We will give examples of how advances in technology have opened the door to functionally dissecting the striatum's compartmental design, and close by offering thoughts on the future and relevance for human disease.
Topics: Acetylcholine; Animals; Brain; Corpus Striatum; Dopamine; Glutamic Acid; Humans; Models, Neurological; Neural Pathways; Neurons; Receptors, Opioid, mu; Substance P; Synapses; gamma-Aminobutyric Acid
PubMed: 31489687
DOI: 10.1002/jnr.24522 -
ELife May 2020The neurotransmitter acetylcholine influences how male finches perform courtship songs by acting on a region of the premotor cortex called HVC.
The neurotransmitter acetylcholine influences how male finches perform courtship songs by acting on a region of the premotor cortex called HVC.
Topics: Acetylcholine; Animals; Finches; Male; Motor Cortex; Vocalization, Animal
PubMed: 32425156
DOI: 10.7554/eLife.57515 -
Molecules (Basel, Switzerland) Feb 2022The cholinergic interneurons of the striatum account for a small fraction of all striatal cell types but due to their extensive axonal arborization give the striatum the... (Review)
Review
The cholinergic interneurons of the striatum account for a small fraction of all striatal cell types but due to their extensive axonal arborization give the striatum the highest content of acetylcholine of almost any nucleus in the brain. The prevailing theory of striatal cholinergic interneuron signaling is that the numerous varicosities on the axon produce an extrasynaptic, volume-transmitted signal rather than mediating rapid point-to-point synaptic transmission. We review the evidence for this theory and use a mathematical model to integrate the measurements reported in the literature, from which we estimate the temporospatial distribution of acetylcholine after release from a synaptic vesicle and from multiple vesicles during tonic firing and pauses. Our calculations, together with recent data from genetically encoded sensors, indicate that the temporospatial distribution of acetylcholine is both short-range and short-lived, and dominated by diffusion. These considerations suggest that acetylcholine signaling by cholinergic interneurons is consistent with point-to-point transmission within a steep concentration gradient, marked by transient peaks of acetylcholine concentration adjacent to release sites, with potential for faithful transmission of spike timing, both bursts and pauses, to the postsynaptic cell. Release from multiple sites at greater distance contributes to the ambient concentration without interference with the short-range signaling. We indicate several missing pieces of evidence that are needed for a better understanding of the nature of synaptic transmission by the cholinergic interneurons of the striatum.
Topics: Acetylcholine; Animals; Corpus Striatum; Humans; Interneurons; Synaptic Transmission
PubMed: 35208986
DOI: 10.3390/molecules27041202 -
Molecular Neurobiology Jul 2023The vertebrate neuromuscular junction (NMJ) is a specialised chemical synapse involved in the transmission of bioelectric signals between a motor neuron and a skeletal... (Review)
Review
The vertebrate neuromuscular junction (NMJ) is a specialised chemical synapse involved in the transmission of bioelectric signals between a motor neuron and a skeletal muscle fiber, leading to muscle contraction. Typically, the NMJ is a tripartite synapse comprising (a) a presynaptic region represented by the motor nerve ending, (b) a postsynaptic skeletal motor endplate area, and (c) perisynaptic Schwann cells (PSCs) that shield the motor nerve terminal. Increasing evidence points towards the role of PSCs in the maintenance and control of neuromuscular integrity, transmission, and plasticity. Acetylcholine (ACh) is the main neurotransmitter at the vertebrate skeletal NMJ, and its role is fine-tuned by co-released purinergic neuromodulators, like adenosine 5'-triphosphate (ATP) and its metabolite adenosine (ADO). Adenine nucleotides modulate transmitter release and expression of postsynaptic ACh receptors at motor synapses via the activation of P2Y and P2X receptors. Endogenously generated ADO modulates ACh release by acting via co-localised inhibitory A and facilitatory A receptors on motor nerve terminals, whose tonic activation depends on the neuronal firing pattern and their interplay with cholinergic receptors and neuropeptides. Thus, the concerted action of adenine nucleotides, ADO, and ACh/neuropeptide co-transmitters is paramount to adapting the neuromuscular transmission to the working load under pathological conditions, like Myasthenia gravis. Unravelling these functional complexities prompted us to review our knowledge about the way purines orchestrate neuromuscular transmission and plasticity in light of the tripartite synapse concept, emphasising the often-forgotten role of PSCs in this context.
Topics: Synapses; Neuromuscular Junction; Adenosine; Adenosine Triphosphate; Motor Neurons; Acetylcholine
PubMed: 37016047
DOI: 10.1007/s12035-023-03317-8 -
Frontiers in Neural Circuits 2023Acetylcholine and GABA are often co-released, including from VIP-expressing neurons of the cortex, cortically-projecting neurons of the globus pallidus externus and...
Acetylcholine and GABA are often co-released, including from VIP-expressing neurons of the cortex, cortically-projecting neurons of the globus pallidus externus and basal forebrain, and hippocampal-projecting neurons of the medial septum. The co-release of the functionally antagonistic neurotransmitters GABA and acetylcholine (ACh) greatly expands the possible functional effects of cholinergic neurons and provides an additional exogenous source of inhibition to the cortex. Transgene expression suggests that nearly all forebrain cholinergic neurons in mice at some point in development express , which encodes the vesicular GABA transporter (VGAT). To determine the degree of co-expression of GABA and Ach handling proteins, we measured expression in adult mice of , and (which encode GAD67 and GAD65, respectively, the GABA synthetic enzymes) in cholinergic neurons using fluorescent hybridization. We found that only a subset of cholinergic neurons express the necessary machinery for GABA release at a single time in adult mice. This suggests that GABA co-release from cholinergic neurons is dynamic and potentially developmentally regulated. By measuring expression of , , and in the basal forebrain and medial septum in mice from post-natal day 0 to 28, we noted abundant yet variable expressions of GABAergic markers across early development, which are subsequently downregulated in adulthood. This is in contrast with the forebrain-projecting pedunculopontine nucleus, which showed no evidence of co-expression of GABAergic genes. These results suggest that expression of GABA signaling machinery in the cortically-projecting cholinergic system peaks during early development before settling at a non-zero level that is maintained through adulthood.
Topics: Mice; Animals; Acetylcholine; In Situ Hybridization, Fluorescence; gamma-Aminobutyric Acid; Cholinergic Neurons; Cerebral Cortex; Gene Expression; Choline O-Acetyltransferase
PubMed: 37035505
DOI: 10.3389/fncir.2023.1125071 -
Nature Reviews. Immunology Sep 2019Tuft cells are rare, secretory epithelial cells that generated scant immunological interest until contemporaneous reports in 2016 linked tuft cells with type 2 immunity... (Review)
Review
Tuft cells are rare, secretory epithelial cells that generated scant immunological interest until contemporaneous reports in 2016 linked tuft cells with type 2 immunity in the small intestine. Tuft cells have the capacity to produce an unusual spectrum of biological effector molecules, including IL-25, eicosanoids implicated in allergy (such as cysteinyl leukotrienes and prostaglandin D) and the neurotransmitter acetylcholine. In most cases, the extracellular signals controlling tuft cell effector function are unknown, but signal transduction is thought to proceed via canonical, G protein-coupled receptor-dependent pathways involving components of the signalling pathway used by type II taste bud cells to sense sweet, bitter and umami compounds. Tuft cells are ideally positioned as chemosensory sentinels that can detect and relay information from diverse luminal substances via what appear to be stereotyped outputs to initiate both positive and aversive responses through populations of immune and neuronal cells. Despite recent insights, numerous questions remain regarding tuft cell lineage, diversity and effector mechanisms and how tuft cells interface with the immunological niche in the tissues where they reside.
Topics: Acetylcholine; Animals; Cell Lineage; Eicosanoids; Humans; Interleukin-17; Intestinal Mucosa; Intestine, Small; Receptors, G-Protein-Coupled; Signal Transduction; Succinic Acid
PubMed: 31114038
DOI: 10.1038/s41577-019-0176-x -
Cell Reports Oct 2022Cholinergic interneurons (CINs) are essential elements of striatal circuits and functions. Although acetylcholine signaling via muscarinic receptors (mAChRs) has been...
Cholinergic interneurons (CINs) are essential elements of striatal circuits and functions. Although acetylcholine signaling via muscarinic receptors (mAChRs) has been well studied, more recent data indicate that postsynaptic nicotinic receptors (nAChRs) located on striatal GABAergic interneurons (GINs) are equally critical. One example is that CIN stimulation induces large disynaptic inhibition of striatal projection neurons (SPNs) mediated by nAChR activation of GINs. Although these circuits are ideally positioned to modulate striatal output, the neurons involved are not definitively identified because of an incomplete mapping of CINs-GINs interconnections. Here, we show that CINs modulate four GINs populations via an intricate mechanism involving co-activation of presynaptic and postsynaptic mAChRs and nAChRs. Using optogenetics, we demonstrate the participation of tyrosine hydroxylase-expressing GINs in the disynaptic inhibition of SPNs via heterotypic electrical coupling with neurogliaform interneurons. Altogether, our results highlight the importance of CINs in regulating GINs microcircuits via complex synaptic/heterosynaptic mechanisms.
Topics: Acetylcholine; Tyrosine 3-Monooxygenase; Corpus Striatum; Interneurons; Cholinergic Agents; Receptors, Muscarinic; Receptors, Nicotinic; Cholinergic Neurons
PubMed: 36288709
DOI: 10.1016/j.celrep.2022.111531 -
Current Protocols Feb 2023The serine hydrolase acetylcholinesterase (AChE) is an important neuronal enzyme which catalyzes the hydrolysis of the neurotransmitter acetylcholine and other choline...
The serine hydrolase acetylcholinesterase (AChE) is an important neuronal enzyme which catalyzes the hydrolysis of the neurotransmitter acetylcholine and other choline esters. The breakdown of acetylcholine by AChE terminates synaptic transmission and regulates neuromuscular communication. AChE inhibition is a common mode of action of various insecticides, such as carbamates and organophosphorus pesticides. Freshwater planarians, especially the species Dugesia japonica, have been shown to possess AChE activity and to be a suitable alternative model for studying the effects of pesticides in vivo. AChE activity can be quantified in homogenates using the Ellman assay. However, this biochemical assay requires specialized equipment and large numbers of planarians. Here, we present a protocol for visualizing AChE activity in individual planarians. Activity staining can be completed in several hours and can be executed using standard laboratory equipment (a fume hood, nutator, and light microscope with imaging capability). We describe the steps for preparing the reagents, and the staining and imaging of the planarians. Planarians are treated with 10% acetic acid and fixed with 4% paraformaldehyde and then incubated in a staining solution containing the substrate acetylthiocholine. After incubation in the staining solution for 3.5 hr on a nutator at 4°C, or stationary on ice, planarians are washed and mounted for imaging. Using exposure to an organophosphorus pesticide as an example, we show how AChE inhibition leads to a loss of staining. Thus, this simple method can be used to qualitatively evaluate AChE inhibition due to chemical exposure or RNA interference, providing a new tool for mechanistic studies of effects on the cholinergic system. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Preparing the staining solution Basic Protocol 2: Fixing, staining, and imaging whole-mount planarian specimens for visualization of acetylcholinesterase activity.
Topics: Animals; Acetylcholinesterase; Planarians; Organophosphorus Compounds; Pesticides; Acetylcholine; Fresh Water
PubMed: 36799654
DOI: 10.1002/cpz1.674