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

Protracted social isolation of adult mice induced behavioral, transcriptional and ultrastructural changes in oligodendrocytes of the prefrontal cortex (PFC) and impaired adult myelination. Social re-integration was sufficient to normalize behavioral and transcriptional changes. Short periods of isolation affected chromatin and myelin, but did not induce behavioral changes. Thus, myelinating oligodendrocytes in the adult PFC respond to social interaction with chromatin changes, suggesting that myelination acts as a form of adult plasticity.

Addictive drugs cause persistent restructuring of several neuronal cell types in the brain’s limbic regions thought to be responsible for long-term behavioral plasticity driving addiction. Although these structural changes are well documented in nucleus accumbens medium spiny neurons, little is known regarding the underlying molecular mechanisms. Additionally, it remains unclear whether structural plasticity and its synaptic concomitants drive addictive behaviors, or whether they reflect homeostatic compensations to the drug not related to addiction per se. Here, we discuss recent paradoxical data, which either support or oppose the hypothesis that drug-induced changes in dendritic spines drive addictive behavior. We define areas where future investigation can provide a more detailed picture of drug-induced synaptic reorganization, including ultrastructural, electrophysiological, and behavioral studies.

Cocaine-induced alterations in gene expression cause changes in neuronal morphology and behavior that may underlie cocaine addiction. We identified an essential role for histone 3 lysine 9 (H3K9) dimethylation and the lysine dimethyltransferase G9a in cocaine-induced structural and behavioral plasticity. Repeated cocaine administration reduced global levels of H3K9 dimethylation in the nucleus accumbens. This reduction in histone methylation was mediated through the repression of G9a in this brain region, which was regulated by the cocaine-induced transcription factor ΔFosB. Using conditional mutagenesis and viral-mediated gene transfer, we found that G9a downregulation increased dendritic spine plasticity of nucleus accumbens neurons and enhanced preference for cocaine, thereby establishing a crucial role for histone methylation in the long-term actions of cocaine.Repeated cocaine exposure is characterized by persistent changes in gene expression and altered neuronal morphology within the nucleus accumbens (NAc), a key component of the brain's reward circuitry (1-2). Chromatin remodeling is important in aberrant transcriptional changes in this brain region that may underlie aspects of cocaine addiction (3-9). Cocaine regulation of chromatin structure in the NAc results, in part, from direct cocaine-induced modifications of the chromatin enzymatic machinery, leading to changes in histone acetylation *To whom correspondence should be addressed. eric.nestler@mssm.edu. I certify that none of the materials included within the manuscript entitled Essential Role of the Histone Methyltransferase G9a in Cocaineinduced Plasticity have been previously published or are under consideration elsewhere, including on the Internet.All work involving the use of animals was conducted in accordance with institutional and IACUC guidelines at both The