Medial habenula cholinergic signaling regulates cocaine‐associated relapse‐like behavior

Abstract

Propensity to relapse, even following long periods of abstinence, is a key feature in substance use disorders. Relapse and relapse-like behaviors are known to be induced, in part, by re-exposure to drug-associated cues. Yet, while many critical nodes in the neural circuitry contributing to relapse have been identified and studied, a full description of the networks driving reinstatement of drug-seeking behaviors is lacking. One area that may provide further insight to the mechanisms of relapse is the habenula complex, an epithalamic region composed of lateral and medial (MHb) substructures, each with unique cell and target populations. Although well conserved across vertebrate species, the functions of the MHb are not well understood. Recent research has demonstrated that the MHb regulates nicotine aversion and withdrawal. However, it remains undetermined whether MHb function is limited to nicotine and aversive stimuli or if MHb circuit regulates responses to other drugs of abuse. Advances in circuit-level manipulations now allow for cell-type and temporally specific manipulations during behavior, specifically in spatially restrictive brain regions, such as the MHb. In this study, we focus on the response of the MHb to reinstatement of cocaine-associated behavior, demonstrating that cocaine-primed reinstatement of conditioned place preference engages habenula circuitry. Using chemogenetics, we demonstrate that MHb activity is sufficient to induce reinstatement behavior. Together, these data identify the MHb as a key hub in the circuitry underlying reinstatement and may serve as a target for regulating relapse-like behaviors.

HDAC3-Mediated Repression of the Nr4a Family Contributes to Age-Related Impairments in Long-Term Memory

“…Surgery. All mice received surgery 2 weeks before behavior, as described previously (White et al, 2016;Alaghband et al, 2018;Lopez et al, 2018). Briefly, mice were anesthetized with isoflurane, placed in a stereotaxic apparatus, and injection needles were slowly lowered to the dorsal hippocampus (0.2 mm/15 s).…”

“…Experimental design and statistical analysis. Sample sizes were similar to those generally used in the field, including those reported in previous publications (Vogel-Ciernia et al, 2013;Kwapis et al, 2018;Lopez et al, 2018) although no statistical methods were used to predetermine sample sizes. All behavior was recorded for offline analysis.…”

Increased cocaine self‐administration in rats lacking the serotonin transporter: a role for glutamatergic signaling in the habenula

“…Raphe serotonergic neurons project to various brain regions implicated in anxiety, depression and drug addiction, including the habenula (Hb) (Metzger et al, 2017;Zhang et al, 2018): a serotonergic circuitry, in fact, exists from the dorsal raphe nucleus to the Hb, and from the Hb back to the dorsal raphe nucleus, through the rostral tegmental area and interpeduncular nucleus. The Hb is a small conserved epithalamic structure that has recently received increasing attention in addiction research (Gao et al, 2018;López et al, 2018;Meye et al, 2017;Meye et al, 2015;Zapata et al, 2017) and it contributes to the induction of negative emotional states in drug addiction (Batalla et al, 2017;Klein et al, 2018).…”

An optimized procedure for robust volitional drug intake in mice

“…The goal of preclinical SUD work is to understand drugtaking behavior on a mechanistic level that would allow for the development of novel pharmacotherapeutic targets for treatment in clinical populations [63][64][65]. In recent years, the field has focused on identifying the various molecular and circuity adaptations induced by drugs of abuse and underlying drug-associated behaviors [66][67][68][69][70][71][72][73][74][75]. However, our ability to effectively characterize the components driving drug-seeking and addictive phenotypes depend entirely on having translational and rigorous mouse models of volitional drug consumption.…”