Mice experiencing repeated aggression develop a long-lasting aversion to social contact, which can be normalized by chronic, but not acute, administration of antidepressant. Using viral-mediated, mesolimbic dopamine pathway-specific knockdown of brain-derived neurotrophic factor (BDNF), we showed that BDNF is required for the development of this experience-dependent social aversion. Gene profiling in the nucleus accumbens indicates that local knockdown of BDNF obliterates most of the effects of repeated aggression on gene expression within this circuit, with similar effects being produced by chronic treatment with antidepressant. These results establish an essential role for BDNF in mediating long-term neural and behavioral plasticity in response to aversive social experiences.

Circadian rhythms and the genes that make up the molecular clock have long been implicated in bipolar disorder. Genetic evidence in bipolar patients suggests that the central transcriptional activator of molecular rhythms, CLOCK, may be particularly important. However, the exact role of this gene in the development of this disorder remains unclear. Here we show that mice carrying a mutation in the Clock gene display an overall behavioral profile that is strikingly similar to human mania, including hyperactivity, decreased sleep, lowered depression-like behavior, lower anxiety, and an increase in the reward value for cocaine, sucrose, and medial forebrain bundle stimulation. Chronic administration of the mood stabilizer lithium returns many of these behavioral responses to wild-type levels. In addition, the Clock mutant mice have an increase in dopaminergic activity in the ventral tegmental area, and their behavioral abnormalities are rescued by expressing a functional CLOCK protein via viral-mediated gene transfer specifically in the ventral tegmental area. These findings establish the Clock mutant mice as a previously unrecognized model of human mania and reveal an important role for CLOCK in the dopaminergic system in regulating behavior and mood. bipolar disorder ͉ circadian rhythms ͉ dopamine

DeltaFosB (a truncated form of FosB) and CREB (cAMP response element binding protein) are transcription factors induced in the brain's reward pathways after chronic exposure to drugs of abuse. However, their mechanisms of action and the genes they regulate remain unclear. Using microarray analysis in the nucleus accumbens of inducible transgenic mice, we found that CREB and a dominant-negative CREB have opposite effects on gene expression, as do prolonged expression of DeltaFosB and the activator protein-1 (AP-1) antagonist DeltacJun. However, unlike CREB, short-term and prolonged DeltaFosB induction had opposing effects on gene expression. Gene expression induced by short-term DeltaFosB and by CREB was strikingly similar, and both reduced the rewarding effects of cocaine, whereas prolonged DeltaFosB expression increased drug reward. Gene expression after a short cocaine treatment was more dependent on CREB, whereas gene expression after a longer cocaine treatment became increasingly DeltaFosB dependent. These findings help define the molecular functions of CREB and DeltaFosB and identify clusters of genes that contribute to cocaine addiction.

Although there are clear interactions between circadian rhythms and drug addiction, mechanisms for such interactions remain unknown. Here we establish a role for the Clock gene in regulating the brain's reward circuit. Mice lacking a functional Clock gene display an increase in cocaine reward and in the excitability of dopamine neurons in the midbrain ventral tegmental area, a key brain reward region. These phenotypes are associated with increased expression and phosphorylation of tyrosine hydroxylase (the rate-limiting enzyme in dopamine synthesis), as well as changes in several genes known to regulate dopamine activity in the ventral tegmental area. These findings demonstrate the involvement of a circadian-associated gene, Clock, in regulating dopamine function and cocaine reward.circadian rhythms ͉ dopamine ͉ drug addiction ͉ tyrosine hydroxylase D rug addiction is associated with disruptions in sleep and circadian rhythmicity (1-3). Moreover, in animal models of addiction, several reward-related behaviors exhibit clear circadian regulation. For example, levels of drug self administration and drug-induced locomotor sensitization vary according to the day͞night cycle (4-6). These observations suggest interactions between the brain's circadian and reward systems.Although many of the genes involved in circadian rhythms are expressed outside the suprachiasmatic nucleus (SCN), the brain's master circadian pacemaker, and are found in limbic regions of the brain, little is known about their function in these other brain regions. The first indication that circadian-associated genes may be involved in drug-related behaviors came from studies in Drosophila, which showed that behavioral sensitization to cocaine depended on expression of Period, Clock, Cycle, and Doubletime (7). More recently, it was reported that locomotor sensitization and conditioned preference for cocaine are abnormal in mice lacking the Period-1 (mPer1) or Period-2 (mPer2) gene (6). These genes are induced as well by cocaine in the dorsal striatum and nucleus accumbens, brain regions important for cocaine's behavioral effects (8, 9). Although these findings support a role for circadian-associated genes in behavioral responses to drugs of abuse, little is known about the mechanisms by which these genes function, or are regulated, within the brain's reward and motor circuits.Cocaine and other drugs of abuse produce their behavioral effects in part by modulating dopamine neurotransmission in the midbrain ventral tegmental area (VTA), a key component of the brain's reward circuit (10). Several interactions between dopamine and circadian function have been reported. For example, dopamine neurons in the retina regulate adaptations to light (11). Moreover, dopamine D1 receptors in the prenatal SCN are necessary for synchronizing the master circadian clock during development (12). However, a direct link between circadian genes and the VTA dopamine reward system has not been described. CLOCK is a member of the basic helix-loop-helix-PAS (PER-ARNT-SIM) transc...