Cell Type–Specific Loss of BDNF Signaling Mimics Optogenetic Control of Cocaine Reward

Abstract

The nucleus accumbens is a key mediator of cocaine reward, but the distinct roles of the two subpopulations of nucleus accumbens projection neurons, those expressing dopamine D1 vs. D2 receptors, are poorly understood. We show that deletion of TrkB, the brain-derived neurotrophic factor (BDNF) receptor, selectively from D1+ or D2+ neurons oppositely affects cocaine reward. Since loss of TrkB in D2+ neurons increases their neuronal excitability, we next used optogenetic tools to control selectively the firing rate of D1+ and D2+ nucleus accumbens neurons and studied consequent effects on cocaine reward. Activation of D2+ neurons, mimicking the loss of TrkB, suppresses cocaine reward, with opposite effects induced by activation of D1+ neurons. These results provide insight into the molecular control of D1+ and D2+ neuronal activity as well as the circuit level contribution of these cell types to cocaine reward.The nucleus accumbens (NAc) plays a crucial role in mediating the rewarding effects of drugs of abuse (1). However, little is known about the specific function of the two major populations of NAc projection neurons, which together comprise >95% of all NAc neurons, in regulating these behaviors. These neurons, like those in the dorsal striatum, are medium spiny neurons (MSNs) divided into two subtypes based on their distinct projections through cortical-basal ganglia circuits and their differential gene expression, including enrichment of dopamine D1 vs. D2 receptors (2). These two MSN subtypes, in dorsal striatum, exert balanced but antagonistic influences on their downstream outputs and behaviors, most notably motor behaviors (3-5), but their role, in NAc, in regulating reward behaviors still needs to be determined.While activation of both D1 and D2 receptors contributes to the rewarding effects of cocaine (6), current biochemical evidence has focused primarily on cocaine-induced molecular and structural changes in D1+ MSNs (7-11). For example, the extracellular signal-regulated kinase (ERK) pathway is induced in D1+ MSNs after cocaine exposure (8), an effect thought to be mediated directly via activation of D1 receptors (12,13). However, ERK activation by cocaine may occur through other mechanisms, such as brain-derived

Toll-Like Receptor 4 Deficiency Causes Reduced Exploratory Behavior in Mice Under Approach-Avoidance Conflict

“…MSNs primarily express D1-like or D2-like dopamine receptors. Though we were not in a position to address the identity of c-Fos-positive neurons in TLR4 -/-mice in the current study, we think these neurons may be D2-MSNs as activation of these neurons mainly controls aversive behaviors [37][38][39]. It is well-known that D2-MSNs are inhibited by DA [40], and xenobiotic activation of TLR4 results in an increase in DA in the NAc [20,33].…”

Optogenetics in neuroscience: what we gain from studies in mammals

“…So it is important to distinguish the different roles of vari- The results showed a decrease of pERK42 and pERK44 expression when activating D1-positive neurons while no significant changes were found during the activation of D2-positive neurons [56] . Interneurons in the NAc also take part in addiction.…”

Comorbidité entre la dépression et l’addiction

“…Les neurones du NAc se différencient par leur signature moléculaire, mais aussi par leurs contributions aux réponses adaptatives induites par les drogues. Ainsi, les neurones épineux moyens de la voie striatonigrale sont impliqués dans la réponse de récompense initiale, et dans la sensibilisation locomotrice induite par la cocaïne [13,14]. D'un point de vue moléculaire, la cocaïne induit une réponse distincte dans ces neurones, qui commence par l'activation des MAP (mitogen-activated protein) kinases et aboutit à l'expression des gènes de réponse précoce que sont c-fos et zif-268 [15].…”

“…D'un point de vue moléculaire, la cocaïne induit une réponse distincte dans ces neurones, qui commence par l'activation des MAP (mitogen-activated protein) kinases et aboutit à l'expression des gènes de réponse précoce que sont c-fos et zif-268 [15]. L'inactivation de ces neurones par voie optogénétique 2 réduit l'effet appétitif de la cocaïne, alors que leur activation l'augmente [13]. Le système sérotoninergique est la cible principale des antidépres-seurs.…”

“…Ainsi, l'activation des neurones moyens épineux de la voie directe (exprimant le DRD1) par optogénétique augmente la réponse de préférence de place conditionnée à la cocaïne, alors que l'activation des neurones de la voie indirecte (exprimant DRD2) la réduit [13]. Pour distinguer entre ces sous-types, nous avons déve-loppé un vecteur viral permettant l'expression d'un ARN interférent de type shARN dirigé spécifiquement contre p11 uniquement dans les cellules exprimant la Cre recombinase (via l'excision d'une cassette stop comme décrit précédemment).…”