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The NeuroD6 Subtype of VTA Neurons Contributes to Psychostimulant Sensitization and Behavioral Reinforcement.

ABSTRACT: Reward-related behavior is complex and its dysfunction correlated with neuropsychiatric illness. Dopamine (DA) neurons of the ventral tegmental area (VTA) have long been associated with different aspects of reward function, but it remains to be disentangled how distinct VTA DA neurons contribute to the full range of behaviors ascribed to the VTA. Here, a recently identified subtype of VTA neurons molecularly defined by NeuroD6 (NEX1M) was addressed. Among all VTA DA neurons, less than 15% were identified as positive for NeuroD6. In addition to dopaminergic markers, sparse NeuroD6 neurons expressed the vesicular glutamate transporter 2 (Vglut2) gene. To achieve manipulation of NeuroD6 VTA neurons, NeuroD6(NEX)-Cre-driven mouse genetics and optogenetics were implemented. First, expression of vesicular monoamine transporter 2 (VMAT2) was ablated to disrupt dopaminergic function in NeuroD6 VTA neurons. Comparing Vmat2lox/lox;NEX-Cre conditional knock-out (cKO) mice with littermate controls, it was evident that baseline locomotion, preference for sugar and ethanol, and place preference upon amphetamine-induced and cocaine-induced conditioning were similar between genotypes. However, locomotion upon repeated psychostimulant administration was significantly elevated above control levels in cKO mice. Second, optogenetic activation of NEX-Cre VTA neurons was shown to induce DA release and glutamatergic postsynaptic currents within the nucleus accumbens. Third, optogenetic stimulation of NEX-Cre VTA neurons in vivo induced significant place preference behavior, while stimulation of VTA neurons defined by Calretinin failed to cause a similar response. The results show that NeuroD6 VTA neurons exert distinct regulation over specific aspects of reward-related behavior, findings that contribute to the current understanding of VTA neurocircuitry.

SUBMITTER: Bimpisidis Z

PROVIDER: S-EPMC6565376 | biostudies-literature | 2019 May/Jun

REPOSITORIES: biostudies-literature

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The NeuroD6 Subtype of VTA Neurons Contributes to Psychostimulant Sensitization and Behavioral Reinforcement.

Bimpisidis Zisis Z König Niclas N Stagkourakis Stefanos S Zell Vivien V Vlcek Bianca B Dumas Sylvie S Giros Bruno B Broberger Christian C Hnasko Thomas S TS Wallén-Mackenzie Åsa Å

eNeuro 20190501 3

Reward-related behavior is complex and its dysfunction correlated with neuropsychiatric illness. Dopamine (DA) neurons of the ventral tegmental area (VTA) have long been associated with different aspects of reward function, but it remains to be disentangled how distinct VTA DA neurons contribute to the full range of behaviors ascribed to the VTA. Here, a recently identified subtype of VTA neurons molecularly defined by NeuroD6 (NEX1M) was addressed. Among all VTA DA neurons, less than 15% were i ...[more]

PMID: 31097625

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Project description:Drug-induced alterations in transcriptional regulation play a central role in establishing the persistent neuroplasticities that occur during drug addiction. Additionally, changes in gene expression associated with drug administration provide valuable insight into the molecular basis of drug abuse. The molecular mechanisms that underlie susceptibility to psychostimulant addiction remain unknown. Identifying the common gene transcriptional responses to psychostimulants can provide a mechanistic insight to elucidate the molecular nature of drug dependence. Male Wistar rats (4 weeks old) were acclimatized for a week to their housing conditions prior to experiments. Thereafter, they were divided into two groups: (cohort 1) 4 groups of rats (n=12 rats per group) given saline only (i.p., "drug-naive" rats); and (cohort 2): 3 groups of rats given either methamphetamine, amphetamine or methylphenidate (5 mg/kg,i.p., M-CM-"M-bM-^BM-,M-EM-^Sdrug-pretreated") for 7 days (2x daily) prior to behavioral assays. Conditioned place preference (CPP) tests were conducted a day after the final drug administration. Rats which showed CPP were evaluated for self-administration of the psychostimulants. [Cohort 1] A day after the final self-administration test, brains of 2-3 rats from each subgroups (i.e. those which showed the most robust self-administration), as well as 5 rats from the control group were removed for microarray analysis. The striatum (rostral part of the caudate putamen and the nucleus accumbens [NAc]) and the prefrontal cortex were dissected and immediately frozen at -70M-CM-^BM-BM-0C. Total RNA was isolated and gene expression profiling was conducted on independent pools of total RNA from 2-5 animals per group. [Cohort 2] A day after the final self-administration test, brains of 3 rats from each subgroups (i.e. those which showed the most robust self-administration), as well as 3 rats from the control group were removed for microarray analysis. The striatum (rostral part of the caudate putamen and the nucleus accumbens [NAc]) and the prefrontal cortex were dissected and immediately frozen at -70M-BM-0C. Total RNA was isolated and gene expression profiling was conducted on independent pools of total RNA from three animals per group.

Dataset Information

The NeuroD6 Subtype of VTA Neurons Contributes to Psychostimulant Sensitization and Behavioral Reinforcement.

Publications

The NeuroD6 Subtype of VTA Neurons Contributes to Psychostimulant Sensitization and Behavioral Reinforcement.

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