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This study shows that cocaine strengthens glutamatergic transmission, reduces K + channel function and drives hyperexcitability in lateral habenula neurons projecting to the rostromedial tegmental nucleus. The authors also show that GluA1 trafficking mediates these cellular modifications and is instrumental in a drug-mediated depressive-like phenotype. Addictive substances mediate positive and negative states promoting persistent drug use. However, substrates for aversive effects of drugs remain elusive. We found that, in mouse lateral habenula (LHb) neurons targeting the rostromedial tegmental nucleus, cocaine enhanced glutamatergic transmission, reduced K + currents and increased excitability. GluA1 trafficking in LHb was instrumental for these cocaine-evoked modifications and drug-driven aversive behaviors. Altogether, our results suggest that long-lasting adaptations in LHb shape negative symptoms after drug taking.

Appetite and drug addiction Disruptions in dopamine signalling have been implicated in psychiatric disorders, such as schizophrenia and drug addiction. The phosphoprotein DARPP-32 is a prominent mediator of dopamine signalling in the striatum, a part of the brain where dopaminergic activation has been linked to reward and learning. Now a novel signal transduction cascade involving nuclear accumulation of DARPP-32 has been discovered, induced by both drugs of abuse and natural stimuli such as food. Disruption of this cascade alters the behavioural effects of the drugs and decreases motivation for food, suggesting a role for this mechanism in the in vivo actions of dopamine signalling. Dopamine orchestrates motor behaviour and reward-driven learning. Perturbations of dopamine signalling have been implicated in several neurological and psychiatric disorders, and in drug addiction. The actions of dopamine are mediated in part by the regulation of gene expression in the striatum, through mechanisms that are not fully understood. Here we show that drugs of abuse, as well as food reinforcement learning, promote the nuclear accumulation of 32-kDa dopamine-regulated and cyclic-AMP-regulated phosphoprotein (DARPP-32). This accumulation is mediated through a signalling cascade involving dopamine D1 receptors, cAMP-dependent activation of protein phosphatase-2A, dephosphorylation of DARPP-32 at Ser 97 and inhibition of its nuclear export. The nuclear accumulation of DARPP-32, a potent inhibitor of protein phosphatase-1, increases the phosphorylation of histone H3, an important component of nucleosomal response. Mutation of Ser 97 profoundly alters behavioural effects of drugs of abuse and decreases motivation for food, underlining the functional importance of this signalling cascade.

Gene transcription is essential for learning, but the precise role of transcription factors that control expression of many other genes in specific learning paradigms is yet poorly understood. Zif268 (Krox24/Egr-1) is a transcription factor and an immediate-early gene associated with memory consolidation and reconsolidation, and induced in the striatum after addictive drugs exposure. In contrast, very little is known about its physiological role at early stages of operant learning. We investigated the role of Zif268 in operant conditioning for food. Zif268 expression was increased in all regions of the dorsal striatum and nucleus accumbens in mice subjected to the first session of operant conditioning. In contrast, Zif268 increase in the dorsomedial caudate-putamen and nucleus accumbens core was not detected in yoked mice passively receiving the food reward. This indicates that Zif268 induction in these structures is linked to experiencing or learning contingency, but not to reward delivery. When the task was learned (5 sessions), Zif268 induction disappeared in the nucleus accumbens and decreased in the medial caudate-putamen, whereas it remained high in the lateral caudate-putamen, previously implicated in habit formation. In transgenic mice expressing green fluorescent protein (GFP) in the striatonigral neurons, Zif268 induction occured after the first training session in both GFP-positive and negative neurons indicating an enhanced Zif268 expression in both striatonigral and striatopallidal neurons. Mutant mice lacking Zif268 expression obtained less rewards, but displayed a normal discrimination between reinforced and non-reinforced targets, and an unaltered approach to food delivery box. In addition, their motivation to obtain food rewards, evaluated in a progressive ratio schedule, was blunted. In conclusion, Zif268 participates in the processes underlying performance and motivation to execute food-conditioned instrumental task.

The firing of mesolimbic dopamine neurons is important for drug-induced reinforcement, although underlying genetic factors remain poorly understood. In a recent genome-wide association metaanalysis of alcohol intake, we identified a suggestive association of SNP rs26907 in the ras-specific guanine-nucleotide releasing factor 2 (RASGRF2) gene, encoding a protein that mediates Ca ²⁺-dependent activation of the ERK pathway. We performed functional characterization of this gene in relation to alcohol-related phenotypes and mesolimbic dopamine function in both mice and adolescent humans. Ethanol intake and preference were decreased in Rasgrf2 ⁻/⁻ mice relative to WT controls. Accordingly, ethanol-induced dopamine release in the ventral striatum was blunted in Rasgrf2 ⁻/⁻ mice. Recording of dopamine neurons in the ventral tegmental area revealed reduced excitability in the absence of Ras-GRF2, likely because of lack of inhibition of the I A potassium current by ERK. This deficit provided an explanation for the altered dopamine release, presumably linked to impaired activation of dopamine neurons firing. Functional neuroimaging analysis of a monetary incentive–delay task in 663 adolescent boys revealed significant association of ventral striatal activity during reward anticipation with a RASGRF2 haplotype containing rs26907, the SNP associated with alcohol intake in our previous metaanalysis. This finding suggests a link between the RASGRF2 haplotype and reward sensitivity, a known risk factor for alcohol and drug addiction. Indeed, follow-up of these same boys at age 16 y revealed an association between this haplotype and number of drinking episodes. Together, these combined animal and human data indicate a role for RASGRF2 in the regulation of mesolimbic dopamine neuron activity, reward response, and alcohol use and abuse.

The strength of synaptic connections in the mammalian brain can influence social status. In 1859, Charles Darwin introduced the key concept of natural selection—that in the struggle for survival and reproduction, individuals compete for the same resources. Hence, animals living in a social environment can establish dominance hierarchies within a short time, which remain stable during the existence of the group ( 1 ). This ranking within social communities has a fundamental advantage—it eliminates conflict in the group, which minimizes energy expenditure and violence, thereby allowing resource sharing ( 2 ). On page 693 of this issue, Wang et al. ( 3 ) demonstrate that encoding of social dominance in mice involves specific synapses in cortical regions of the brain.

The mesolimbic dopamine system, composed primarily of dopaminergic neurons in the ventral tegmental area that project to striatal structures, is considered to be the key mediator of reinforcement-related mechanisms in the brain. Prompted by a genome-wide association meta-analysis implicating the Ras-specific guanine nucleotide-releasing factor 2 (RASGRF2) gene in the regulation of alcohol intake in men, we have recently shown that male Rasgrf2−/− mice exhibit reduced ethanol intake and preference accompanied by a perturbed mesolimbic dopamine system. We therefore propose that these mice represent a valid model to further elucidate the precise genes and mechanisms regulating mesolimbic dopamine functioning. Transcriptomic data from the nucleus accumbens (NAcc) of male Rasgrf2−/− mice and wild-type controls were analyzed by weighted gene coexpression network analysis (WGCNA). We performed follow-up genetic association tests in humans using a sample of male adolescents from the IMAGEN study characterized for binge drinking (n = 905) and ventral striatal activation during an fMRI reward task (n = 608). The WGCNA analyses using accumbal transcriptomic data revealed 37 distinct “modules,” or functionally related groups of genes. Two of these modules were significantly associated with Rasgrf2 knockout status: M5 (p < 0.001) and M6 (p < 0.001). In follow-up translational analyses we found that human orthologues for the M5 module were significantly (p < 0.01) enriched with genetic association signals for binge drinking in male adolescents. Furthermore, the most significant locus, originating from the EH-domain containing 4 (EHD4) gene (p < 0.001), was also significantly associated with altered ventral striatal activity in male adolescents performing an fMRI reward task (pempirical < 0.001). It was not possible to determine the extent to which the M5 module was dysregulated in Rasgrf2−/− mice by perturbed mesolimbic dopamine signalling or by the loss of Rasgrf2 function in the NAcc. Taken together, our findings indicate that the accumbal M5 module, initially identified as being dysregulated in male Rasgrf2−/− mice, is also relevant for human alcohol-related phenotypes potentially through the modulation of reinforcement mechanisms in the NAcc. We therefore propose that the genes comprising this module represent important candidates for further elucidation within the context of alcohol-related phenotypes.

The firing of mesolimbic dopamine neurons is important for drug-induced reinforcement, although underlying genetic factors remain poorly understood. In a recent genome-wide association metaanalysis of alcohol intake, we identified a suggestive association of SNP rs26907 in the ras-specific guanine-nucleotide releasing factor 2 (RASGRF2) gene, encoding a protein that mediates Ca2+-dependent activation of the ERK pathway. We performed functional characterization of this gene in relation to alcohol-related phenotypes and mesolimbic dopamine function in both mice and adolescent humans. Ethanol intake and preference were decreased in Rasgrf2−/− mice relative to WT controls. Accordingly, ethanol-induced dopamine release in the ventral striatum was blunted in Rasgrf2−/− mice. Recording of dopamine neurons in the ventral tegmental area revealed reduced excitability in the absence of Ras-GRF2, likely because of lack of inhibition of the IA potassium current by ERK. This deficit provided an explanation for the altered dopamine release, presumably linked to impaired activation of dopamine neurons firing. Functional neuroimaging analysis of a monetary incentive–delay task in 663 adolescent boys revealed significant association of ventral striatal activity during reward anticipation with a RASGRF2 haplotype containing rs26907, the SNP associated with alcohol intake in our previous metaanalysis. This finding suggests a link between the RASGRF2 haplotype and reward sensitivity, a known risk factor for alcohol and drug addiction. Indeed, follow-up of these same boys at age 16 y revealed an association between this haplotype and number of drinking episodes. Together, these combined animal and human data indicate a role for RASGRF2 in the regulation of mesolimbic dopamine neuron activity, reward response, and alcohol use and abuse.

Dopamine orchestrates motor behavior and reward-driven learning. Perturbations of dopamine signaling have been implicated in several neurological and psychiatric disorders, and in drug addiction. The actions of dopamine are mediated in part by the regulation of gene expression in the striatum, through mechanisms that are not fully understood. Here, we show that drugs of abuse, as well as natural reinforcement learning, promote the nuclear accumulation of dopamine- and cAMP-regulated phosphoprotein Mr=32,000 (DARPP-32). This accumulation is mediated through a signaling cascade involving dopamine D1 receptors, cAMP-dependent activation of protein phosphatase-2A, dephosphorylation of DARPP-32 at Ser-97 and inhibition of its nuclear export. The nuclear accumulation of DARPP-32, a potent inhibitor of protein phosphatase-1, increases phosphorylation of histone H3, an important component of nucleosomal response. Mutation of Ser-97 profoundly alters behavioral effects of drugs of abuse, and decreases motivation for food, underlining the functional importance of this signaling cascade.

The cellular identity of thalamocortical neurons (TCNs), namely their firing properties, dictates brain-wide activity patterns, such as sleep spindles. Transcription factors are critical to the determination of cellular identity. Previously, we discovered that a subset of TCNs express the transcription factor, Shox2, and, in a global Shox2 KO, established that TCNs within the anterior nucleus of the thalamus rely on the expression of Shox2 to regulate key ion channels that are necessary to maintain their firing properties. From this, we hypothesized that Shox2 expression, through the regulation of firing properties of TCNs, is critical for the thalamocortical circuit to generate spindle oscillations. We exploited the somatosensory thalamocortical circuit to investigate this by creating a primary somatosensory thalamus (VB) Shox2 knockdown mouse model. We delivered Cre into the VB of P21 Shox2fl/fl mice using viral infection and compared in vitro, patch-clamp recordings from Shox2+ and Shox2 knockdown TCNs, finding that Shox2 expression is indeed critical to maintain burst and tonic firing properties of VB TCNs. Since Shox2 is important developmentally and firing from TCNs to cortex during development structures the circuit, we performed ultrasound-guided P3 injections at P3 to generate an early-stage, Shox2 VB knockdown, but found no changes in the layer four, barrel map (VB cortical target). Despite this, Shox2 knockdown mice exhibit reduced sleep-spindle EEG density. Further, key behaviors associated with spindles and proper VB thalamic function—memory consolidation and somatosensory perception—are significantly impaired. These results indicate that the impact on spindle function is likely due to cell autonomous changes to TCNs rather than circuit changes, confirming our hypothesis that Shox2 is necessary for normal thalamic spindle function and implicating a potential role for Shox2 in autism and schizophrenia pathologies.