MeCP2 in cholinergic interneurons of nucleus accumbens regulates fear learning.
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ABSTRACT:
SUBMITTER: Zhang Y
PROVIDER: S-EPMC7259956 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundEnvironmental reward-predictive stimuli provide a major source of motivation for adaptive reward pursuit behavior. This cue-motivated behavior is known to be mediated by the nucleus accumbens (NAc) core. The cholinergic interneurons in the NAc are tonically active and densely arborized and thus well suited to modulate NAc function. However, their causal contribution to adaptive behavior remains unknown. Here we investigated the function of NAc cholinergic interneurons in cue-motivated behavior.MethodsWe used chemogenetics, optogenetics, pharmacology, and a translationally analogous Pavlovian-to-instrumental transfer behavioral task designed to assess the motivating influence of a reward-predictive cue over reward-seeking actions in male and female rats.ResultsThe data show that NAc cholinergic interneuron activity critically opposes the motivating influence of appetitive cues. Chemogenetic inhibition of NAc cholinergic interneurons augmented cue-motivated behavior. Optical stimulation of acetylcholine release from NAc cholinergic interneurons prevented cues from invigorating reward-seeking behavior, an effect that was mediated by activation of β2-containing nicotinic acetylcholine receptors.ConclusionsNAc cholinergic interneurons provide a critical regulatory influence over adaptive cue-motivated behavior and therefore are a potential therapeutic target for the maladaptive cue-motivated behavior that marks many psychiatric conditions, including addiction and depression.
| S-EPMC7003647 | biostudies-literature
Project description:The release of dopamine from terminals in the NAc is regulated by a number of factors, including voltage-gated ion channels, D2-autoreceptors, and nAChRs. Cholinergic interneurons (CINs) drive dopamine release through activation of nAChRs on dopamine terminals. Using cyclic voltammetry in mouse brain slices, nAChR-dependent spontaneous dopamine transients and the mechanisms underlying the origin were examined in the NAc. Spontaneous events were infrequent (0.3 per minute), but the rate and amplitude were increased after blocking Kv channels with 4-aminopyridine. Although the firing frequency of CINs was increased by blocking glutamate reuptake with TBOA and the Sk blocker apamin, only 4-aminopyridine increased the frequency of dopamine transients. In contrast, inhibition of CIN firing with the μ/δ selective opioid [Met5]enkephalin (1 μm) decreased spontaneous dopamine transients. Cocaine increased the rate and amplitude of dopamine transients, suggesting that the activity of the dopamine transporter limits the detection of these events. In the presence of cocaine, the rate of spontaneous dopamine transients was further increased after blocking D2-autoreceptors. Blockade of muscarinic receptors had no effect on evoked dopamine release, suggesting that feedback inhibition of acetylcholine release was not involved. Thus, although spontaneous dopamine transients are reliant on nAChRs, the frequency was not strictly governed by the activity of CINs. The increase in frequency of spontaneous dopamine transients induced by cocaine was not due to an increase in cholinergic tone and is likely a product of an increase in detection resulting from decreased dopamine reuptake.SIGNIFICANCE STATEMENT The actions of dopamine in the NAc are thought to be responsible for endogenous reward and the reinforcing properties of drugs of abuse, such as psychostimulants. The present work examines the mechanisms underlying nAChR-induced spontaneous dopamine release. This study demonstrates that spontaneous dopamine release is (1) dependent of the activation of nicotinic receptors, (2) independent on the spontaneous activity of cholinergic interneurons, and (3) that cocaine increased the detection of dopamine transients by prolonging the presence and increasing the diffusion of dopamine in the extracellular space. The release of acetylcholine is therefore responsible for spontaneous dopamine transients, and cocaine augments dopamine tone without altering activity of cholinergic interneurons.
| S-EPMC5338756 | biostudies-literature
Project description:Cholinergic interneurons (ChIs) in the nucleus accumbens (NAc) play a central role in motivated behaviors and associated disorders. However, while the activation of ChIs has been well studied in the dorsal striatum, little is known about how they are engaged in the NAc. Here, we find that the ventral hippocampus (vHPC) and the paraventricular nucleus of the thalamus (PVT) are the main excitatory inputs to ChIs in the NAc medial shell. While the PVT activates ChIs, the vHPC evokes a pronounced pause in firing through prominent feedforward inhibition. In contrast to the dorsal striatum, this inhibition reflects strong connections onto ChIs from local parvalbumin interneurons. Our results reveal the mechanisms by which different long-range inputs engage ChIs, highlighting fundamental differences in local connectivity across the striatum.
| S-EPMC9302453 | biostudies-literature
Project description:A large number of studies have demonstrated that the nucleus accumbens (NAC) is a critical site in the neuronal circuits controlling reward responses, motivation, and mood, but the neuronal cell type(s) underlying these processes are not yet known. Identification of the neuronal cell types that regulate depression-like states will guide us in understanding the biological basis of mood and its regulation by diseases like major depressive disorder. Taking advantage of recent findings demonstrating that the serotonin receptor chaperone, p11, is an important molecular regulator of depression-like states, here we identify cholinergic interneurons (CINs) as a primary site of action for p11 in the NAC. Depression-like behavior is observed in mice after decrease of p11 levels in NAC CINs. This phenotype is recapitulated by silencing neuronal transmission in these cells, demonstrating that accumbal cholinergic neuronal activity regulates depression-like behaviors and suggesting that accumbal CIN activity is crucial for the regulation of mood and motivation.
| S-EPMC3396525 | biostudies-other
Project description:BackgroundCholinergic interneurons (ChINs) in the nucleus accumbens (NAc) play critical roles in processing information related to reward. However, the contribution of ChINs to the emergence of addiction-like behaviors and its underlying molecular mechanisms remain elusive.MethodsWe employed cocaine self-administration to identify two mouse subpopulations: susceptible and resilient to cocaine seeking. We compared the subpopulations for physiological responses with single-unit recording of NAc ChINs, and for gene expression levels with RNA sequencing of ChINs sorted using fluorescence-activated cell sorting. To provide evidence for a causal relationship, we manipulated the expression level of dopamine D2 receptor (DRD2) in ChINs in a cell type-specific manner. Using optogenetic activation combined with a double whole-cell recording, the effect of ChIN-specific DRD2 manipulation on each synaptic input was assessed in NAc medium spiny neurons in a pathway-specific manner.ResultsSusceptible mice showed higher levels of nosepoke responses under a progressive ratio schedule, and impairment in extinction and punishment procedures. DRD2 was highly abundant in the NAc ChINs of susceptible mice. Elevated abundance of DRD2 in NAc ChINs was sufficient and necessary to express high cocaine motivation, putatively through reduction of ChIN activity during cocaine exposure. DRD2 overexpression in ChINs mimicked cocaine-induced effects on the dendritic spine density and the ratios of excitatory inputs between two distinct medium spiny neuron cell types, while DRD2 depletion precluded cocaine-induced synaptic plasticity.ConclusionsThese findings provide a molecular mechanism for dopaminergic control of NAc ChINs that can control the susceptibility to cocaine-seeking behavior.
| S-EPMC7584775 | biostudies-literature
Project description:BackgroundThe nucleus accumbens (NAc) controls multiple facets of impulsivity but is a heterogeneous brain region with diverse microcircuitry. Prior literature links impulsive behavior in rodents to gamma-aminobutyric acid signaling in the NAc. Here, we studied the regulation of impulsive behavior by fast-spiking interneurons (FSIs), a strong source of gamma-aminobutyric acid-mediated synaptic inhibition in the NAc.MethodsMale and female transgenic mice expressing Cre recombinase in FSIs allowed us to identify these sparsely distributed cells in the NAc. We used a 5-choice serial reaction time task to measure both impulsive action and sustained attention. During the 5-choice serial reaction time task, we monitored FSI activity with fiber photometry calcium imaging and manipulated FSI activity with chemogenetic and optogenetic methodology. We used electrophysiology, optogenetics, and fluorescent in situ hybridization to confirm these methods were robust and specific to FSIs.ResultsIn mice performing the 5-choice serial reaction time task, NAc FSIs showed sustained activity on trials ending with correct responses, but FSI activity declined over time on trials ending with premature responses. The number of premature responses increased significantly after sustained chemogenetic inhibition or temporally delimited optogenetic inhibition of NAc FSIs, without any changes in response latencies or general locomotor activity.ConclusionsThese experiments provide strong evidence that NAc FSIs constrain impulsive actions, most likely through gamma-aminobutyric acid-mediated synaptic inhibition of medium spiny projection neurons. Our findings may provide insight into the pathophysiology of disorders associated with impulsivity and may inform the development of circuit-based therapeutic interventions.
| S-EPMC6823148 | biostudies-literature
Project description:Animals studies support the notion that striatal cholinergic interneurons (ChIs) play a central role in basal ganglia function by regulating associative learning, reward processing, and motor control. In the nucleus accumbens (NAc), a brain region that mediates rewarding properties of substance abuse, acetylcholine regulates glutamatergic, dopaminergic, and GABAergic neurotransmission in naïve mice. However, it is unclear how ChIs orchestrate the control of these neurotransmitters/modulators to determine the synaptic excitability of medium spiny neurons (MSNs), the only projecting neurons that translate accumbens electrical activity into behavior. Also unknown is the impact of binge alcohol drinking on the regulation of dopamine D1- and D2 receptor-expressing MSNs (D1- and D2-MSNs, respectively) by ChIs. To investigate this question, we optogenetically stimulated ChIs while recording evoked and spontaneous excitatory postsynaptic currents (sEPSCs) in nucleus accumbens core D1- and D2-MSN of ChAT.ChR2.eYFPxDrd1.tdtomato mice. In alcohol-naïve mice, we found that stimulating NAc ChIs decreased sEPSCs frequency in both D1- and D2-MSNs, presumably through a presynaptic mechanism. Interestingly, ChI stimulation decreased MSN synaptic excitability through different mechanisms in D1- vs. D2-MSNs. While decrease of ChI-mediated sEPSCs frequency in D1-MSNs was mediated by dopamine, the same effect in D2-MSNs resulted from a direct control of glutamate release by ChIs. Interestingly, after 2 weeks of binge alcohol drinking, optogenetic stimulation of ChIs enhanced glutamate release in D1-MSNs, while its effect on D2-MSNs remained unchanged. Taken together, these data suggest that cholinergic interneurons could be a key target for regulation of NAc circuitry and for alcohol consumption.
| S-EPMC9797504 | biostudies-literature
Project description:Acetylcholine is widely believed to modulate the release of dopamine in the striatum of mammals. Experiments in brain slices clearly show that synchronous activation of striatal cholinergic interneurons is sufficient to drive dopamine release via axo-axonal stimulation of nicotinic acetylcholine receptors. However, evidence for this mechanism in vivo has been less forthcoming. A recent paper in eLife (Mohebi et al., 2023) reported that, in awake behaving rats, optogenetic activation of striatal cholinergic interneurons with blue light readily evokes dopamine release measured with the red fluorescent sensor RdLight1. Here, we show that blue light alone alters the fluorescent properties of RdLight1 in a manner that may be misconstrued as phasic dopamine release, and that this artefactual photoactivation can account for the effects attributed to cholinergic interneurons. Our findings indicate that measurements of dopamine using the red-shifted fluorescent sensor RdLight1 should be interpreted with caution when combined with optogenetics. In light of this and other publications that did not observe large acetylcholine-evoked dopamine transients in vivo, the conditions under which such release occurs in behaving animals remain unknown.
| S-EPMC10802245 | biostudies-literature
Project description:Cholinergic interneurons (ChINs) in the nucleus accumbens (NAc) play critical roles in processing information related to reward. However, the contribution of ChINs to development of addiction-like behaviors and the underlying mechanisms remain unknown. Here, using mouse models, we assessed drug seeking behaviors under a prolonged progressive ratio schedule of cocaine self-administration to reliably separate mice susceptible or resilient to express addiction-like behaviors based on motivation to earn cocaine. Cell type-specific RNA sequencing in NAc ChINs and the differential expression analysis identified 2,909 differentially expressed genes from susceptible versus resilient mice, which comprise 1,685 upregulated genes and 1,224 downregulated genes. Our cell type-specific transcriptome data will serve as a valuable and widely applicable resource for investigating molecular mechanism of cocaine addiction and in turn facilitate development of novel therapeutic targets to treat addictive disorders.
2020-10-28 | GSE130376 | GEO
Project description:Parvalbumin-expressing (PV+) interneurons of the nucleus accumbens (NAc) play an essential role in the addictive-like behaviors induced by psychostimulant exposure. To identify molecular mechanisms of PV+ neuron plasticity, we isolated interneuron nuclei from the NAc of male and female mice following acute or repeated exposure to amphetamine (AMPH) and sequenced for cell type-specific RNA expression and chromatin accessibility. AMPH regulated the transcription of hundreds of genes in PV+ interneurons, and this program was largely distinct from that regulated in other NAc GABAergic neurons. Chromatin accessibility at enhancers predicted cell-type specific gene regulation, identifying transcriptional mechanisms of differential AMPH responses. Finally, we assessed expression of PV-enriched, AMPH-regulated genes in an Mecp2 mutant mouse strain that shows heightened behavioral sensitivity to psychostimulants to explore the functional importance of this transcriptional program. Together these data provide novel insight into the cell-type specific programs of transcriptional plasticity in NAc neurons that underlie addictive-like behaviors.
| S-EPMC9378812 | biostudies-literature