Egr2 induction in spiny projection neurons of the ventrolateral striatum contributes to cocaine place preference in mice.

Diptendu Mukherjee,Ami Citri,Hagit Turm,Maya Groysman,Ben Jerry Gonzales,Reut Ashwal-Fluss

doi:10.7554/elife.65228

Diptendu Mukherjee, Ami Citri + Show 4 more

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https://doi.org/10.7554/elife.65228

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Abstract

Drug addiction develops due to brain-wide plasticity within neuronal ensembles, mediated by dynamic gene expression. Though the most common approach to identify such ensembles relies on immediate early gene expression, little is known of how the activity of these genes is linked to modified behavior observed following repeated drug exposure. To address this gap, we present a broad-to-specific approach, beginning with a comprehensive investigation of brain-wide cocaine-driven gene expression, through the description of dynamic spatial patterns of gene induction in subregions of the striatum, and finally address functionality of region-specific gene induction in the development of cocaine preference. Our findings reveal differential cell-type specific dynamic transcriptional recruitment patterns within two subdomains of the dorsal striatum following repeated cocaine exposure. Furthermore, we demonstrate that induction of the IEG Egr2 in the ventrolateral striatum, as well as the cells within which it is expressed, are required for the development of cocaine seeking.

Highlights

Psychostimulant addiction is characterized by life-long behavioral abnormalities, driven by circuit-specific modulation of gene expression (Nestler, 2014; Nestler and Lüscher, 2019; Salery et al, 2020; Steiner, 2016)
We initially focused on baseline shifts in gene expression, comparing naïve mice to mice exposed repeatedly to cocaine, as well as to mice following 21 days of abstinence from repeated cocaine exposure (Figure 1C; Figure 1–figure supplement 3A; refer to Supplementary file 2 for list of differentially expressed genes and normalized counts)
Using single molecule fluorescence in-situ hybridization, we reported region-specific rules governing the recruitment of striatal assemblies following a single acute exposure to cocaine (Gonzales et al, 2020). We revisited this spatial analysis, applying smFISH to expand the investigation of the striatal distribution of the immediate-early gene (IEG) Arc, Egr2, Fos and Nr4a1 throughout the development of cocaine sensitization [Figure 2; Figure 2–figure supplement 1, 2; (results from (Gonzales et al, 2020) serve as a reference for the effects of acute cocaine exposure)] Addressing an overview of induced expression of these IEGs, we observed robust induction of Arc, Egr2, Nr4a1 and Fos following acute cocaine exposure, which was dampened following repeated exposure to cocaine and reinstated following a challenge dose of cocaine, in-line with the results described in Figure 1 (Figure 2A-C)

Summary

Introduction

Psychostimulant addiction is characterized by life-long behavioral abnormalities, driven by circuit-specific modulation of gene expression (Nestler, 2014; Nestler and Lüscher, 2019; Salery et al, 2020; Steiner, 2016). IEG induction has been utilized to support the identification of functional neuronal assemblies mediating the development of cocaine-elicited behaviors [“cocaine ensembles”; (Bobadilla et al, 2020; Cruz et al, 2013)]. Within these striatal structures, the principal neuronal type is the spiny projection neuron (SPN), which is comprised of two competing subtypes, defined by their differential expression of dopamine receptors. The VLS subregion partially overlaps with a lateral striatum segment enriched for Gpr155 expression, defined in recent molecular striatal subdivisions 61 (Märtin et al, 2019; Ortiz et al, 2020)

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