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Selective filtering of excitatory inputs to nucleus accumbens by dopamine and serotonin.

ABSTRACT: The detailed mechanisms by which dopamine (DA) and serotonin (5-HT) act in the nucleus accumbens (NAc) to influence motivated behaviors in distinct ways remain largely unknown. Here, we examined whether DA and 5-HT selectively modulate excitatory synaptic transmission in NAc medium spiny neurons in an input-specific manner. DA reduced excitatory postsynaptic currents (EPSCs) generated by paraventricular thalamus (PVT) inputs but not by ventral hippocampus (vHip), basolateral amygdala (BLA), or medial prefrontal cortex (mPFC) inputs. In contrast, 5-HT reduced EPSCs generated by inputs from all areas except the mPFC. Release of endogenous DA and 5-HT by methamphetamine (METH) and (±)3,4-methylenedioxymethamphetamine (MDMA), respectively, recapitulated these input-specific synaptic effects. Optogenetic inhibition of PVT inputs enhanced cocaine-conditioned place preference, whereas mPFC input inhibition reduced the enhancement of sociability elicited by MDMA. These findings suggest that the distinct, input-specific filtering of excitatory inputs in the NAc by DA and 5-HT contribute to their discrete behavioral effects.

SUBMITTER: Christoffel DJ

PROVIDER: S-EPMC8214692 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Selective filtering of excitatory inputs to nucleus accumbens by dopamine and serotonin.

Christoffel Daniel J DJ Walsh Jessica J JJ Hoerbelt Paul P Heifets Boris D BD Llorach Pierre P Lopez Ricardo C RC Ramakrishnan Charu C Deisseroth Karl K Malenka Robert C RC

Proceedings of the National Academy of Sciences of the United States of America 20210601 24

The detailed mechanisms by which dopamine (DA) and serotonin (5-HT) act in the nucleus accumbens (NAc) to influence motivated behaviors in distinct ways remain largely unknown. Here, we examined whether DA and 5-HT selectively modulate excitatory synaptic transmission in NAc medium spiny neurons in an input-specific manner. DA reduced excitatory postsynaptic currents (EPSCs) generated by paraventricular thalamus (PVT) inputs but not by ventral hippocampus (vHip), basolateral amygdala (BLA), or m ...[more]

PMID: 34103400

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Project description:The nucleus accumbens (NAc) is the ventral part of the striatum and the interface between cognition, emotion, and action. It is composed of three major subnuclei: i.e., NAc core (NAcC), lateral shell (NAcLS), and medial shell (NAcMS), which exhibit functional heterogeneity. Thus, determining the synaptic inputs of the subregions of the NAc is important for understanding the circuit mechanisms involved in regulating different functions. Here, we simultaneously labeled subregions of the NAc with cholera toxin subunit B conjugated with multicolor Alexa Fluor, then imaged serial sections of the whole brain with a fully automated slide scanning system. Using the interactive WholeBrain framework, we characterized brain-wide inputs to the NAcC subdomains, including the rostral, caudal, dorsal, and ventral subdomains (i.e., rNAcC, cNAcC, dNAcC, and vNAcC, respectively) and the NAc subnuclei. We found diverse brain regions, distributed from the cerebrum to brain stem, projecting to the NAc. Of the 57 brain regions projecting to the NAcC, the anterior olfactory nucleus (AON) exhibited the greatest inputs. The input neurons of rNAcC and cNAcC are two distinct populations but share similar distribution over the same upstream brain regions, whereas the input neurons of dNAcC and vNAcC exhibit slightly different distributions over the same upstream regions. Of the 55 brain regions projecting to the NAcLS, the piriform area contributed most of the inputs. Of the 72 brain regions projecting to the NAcMS, the lateral septal nucleus contributed most of the inputs. The input neurons of NAcC and NAcLS share similar distributions, whereas the NAcMS exhibited brain-wide distinct distribution. Thus, the NAcC subdomains appeared to share the same upstream brain regions, although with distinct input neuron populations and slight differences in the input proportions, whereas the NAcMS subnuclei received distinct inputs from multiple upstream brain regions. These results lay an anatomical foundation for understanding the different functions of NAcC subdomains and NAc subnuclei.

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.

Dataset Information

Selective filtering of excitatory inputs to nucleus accumbens by dopamine and serotonin.

Publications

Selective filtering of excitatory inputs to nucleus accumbens by dopamine and serotonin.

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