Current treatments for depression are inadequate for many individuals, and progress in understanding the neurobiology of depression is slow. Several promising hypotheses of depression and antidepressant action have been formulated recently. These hypotheses are based largely on dysregulation of the hypothalamic-pituitary-adrenal axis and hippocampus and implicate corticotropin-releasing factor, glucocorticoids, brain-derived neurotrophic factor, and CREB. Recent work has looked beyond hippocampus to other brain areas that are also likely involved. For example, nucleus accumbens, amygdala, and certain hypothalamic nuclei are critical in regulating motivation, eating, sleeping, energy level, circadian rhythm, and responses to rewarding and aversive stimuli, which are all abnormal in depressed patients. A neurobiologic understanding of depression also requires identification of the genes that make individuals vulnerable or resistant to the syndrome. These advances will fundamentally improve the treatment and prevention of depression.

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.

The leptin hormone is critical for normal food intake and metabolism. While leptin receptor (Lepr) function has been well studied in the hypothalamus, the functional relevance of Lepr expression in the ventral tegmental area (VTA) has not been investigated. The VTA contains dopamine neurons that are important in modulating motivated behavior, addiction, and reward. Here, we show that VTA dopamine neurons express Lepr mRNA and respond to leptin with activation of an intracellular JAK-STAT pathway and a reduction in firing rate. Direct administration of leptin to the VTA caused decreased food intake while long-term RNAi-mediated knockdown of Lepr in the VTA led to increased food intake, locomotor activity, and sensitivity to highly palatable food. These data support a critical role for VTA Lepr in regulating feeding behavior and provide functional evidence for direct action of a peripheral metabolic signal on VTA dopamine neurons.

Understanding the fate of adult-generated neurons and the mechanisms that influence them requires consistent labeling and tracking of large numbers of stem cells. We generated a nestin-CreER T2 /R26R-yellow fluorescent protein (

The transcription factor cAMP response element (CRE)-binding protein (CREB) has been shown to regulate neural plasticity. Drugs of abuse activate CREB in the nucleus accumbens, an important part of the brain's reward pathways, and local manipulations of CREB activity have been shown to affect cocaine reward, suggesting an active role of CREB in adaptive processes that follow exposure to drugs of abuse. Using CRE-LacZ reporter mice, we show that not only rewarding stimuli such as morphine, but also aversive stimuli such as stress, activate CRE-mediated transcription in the nucleus accumbens shell. Using viral-mediated gene transfer to locally alter the activity of CREB, we show that this manipulation affects morphine reward, as well as the preference for sucrose, a more natural reward. We then show that local changes in CREB activity induce a more general syndrome, by altering reactions to anxiogenic, aversive, and nociceptive stimuli as well. Increased CREB activity in the nucleus accumbens shell decreases an animal's responses to each of these stimuli, whereas decreased CREB activity induces an opposite phenotype. These results show that environmental stimuli regulate CRE-mediated transcription within the nucleus accumbens shell, and that changes in CREB activity within this brain area subsequently alter gating between emotional stimuli and their behavioral responses. This control appears to be independent of the intrinsic appetitive or aversive value of the stimulus. The potential relevance of these data to addiction and mood disorders is discussed.T ranscription factors, by regulating protein expression, participate in neural plasticity and adaptation. Stimuli that change transcriptional activity in a brain structure may alter over time the way information is processed by that structure. At more integrated levels, this plasticity can lead to changes in the interaction between an individual and its environment. Examples include learning processes, and changes in perception, interpretation, and behavioral responses to environmental stimuli. The cAMP response element (CRE)-binding protein, CREB, is a constitutively expressed transcription factor activated by phosphorylation through the cAMP pathway and other intracellular signaling cascades (1). Within the central nervous system, CREB has been associated with learning and memory (2-6), as well as with molecular and behavioral changes induced by antidepressants (7, 8) and drugs of abuse (9-15). In these latter cases, changes in second messenger pathways activating CREB (7, 9), changes in CREB levels (12), and changes in CRE-mediated transcription (8, 15) have been observed in several discrete brain areas.The nucleus accumbens, a forebrain structure critical for reward and motivation (16-23), has a key role in reinforcing properties of drugs of abuse (12,(17)(18)(19)(20)(21). Chronic exposure to cocaine or to several other drugs of abuse increases cAMP levels and cAMP-dependent protein kinase (PKA) activity in the nucleus accumbens (9, 12). These adaptations cause...

A single exposure to cocaine rapidly induces the brief activation of several immediate early genes, but the role of such short-term regulation in the enduring consequences of cocaine use is poorly understood. We found that 4 h of intravenous cocaine self-administration in rats induced a transient increase in brain-derived neurotrophic factor (BDNF) and activation of TrkB-mediated signaling in the nucleus accumbens (NAc). Augmenting this dynamic regulation with five daily NAc BDNF infusions caused enduring increases in cocaine self-administration, and facilitated relapse to cocaine seeking in withdrawal. In contrast, neutralizing endogenous BDNF regulation with intra-NAc infusions of antibody to BDNF subsequently reduced cocaine self-administration and attenuated relapse. Using localized inducible BDNF knockout in mice, we found that BDNF originating from NAc neurons was necessary for maintaining increased cocaine self-administration. These findings suggest that dynamic induction and release of BDNF from NAc neurons during cocaine use promotes the development and persistence of addictive behavior.

Smoking decreases appetite and smokers often report that they smoke to control their weight. Understanding the neurobiological mechanisms underlying the anorexic effects of smoking would facilitate the development of novel treatments to help with smoking cessation and to prevent or treat obesity. Using a combination of pharmacological, molecular genetic, electrophysiological and feeding studies, we found that activation of hypothalamic α3β4 nicotinic acetylcholine receptors (nAChRs) leads to activation of pro-opiomelanocortin (POMC) neurons. POMC neurons and subsequent activation of melanocortin 4 receptors were critical for nicotinic-induced decreases in food intake in mice. This study demonstrates that nicotine decreases food intake and bodyweight by influencing the hypothalamic melanocortin system and identifies critical molecular and synaptic mechanisms involved in nicotine-induced decreases in appetite.

Regulators of G protein signaling (RGS) are a family of proteins known to accelerate termination of effector stimulation after G protein receptor activation. RGS9-2, a brain-specific splice variant of the RGS9 gene, is highly enriched in striatum and also expressed at much lower levels in periaqueductal gray and spinal cord, structures known to mediate various actions of morphine and other opiates. Morphine exerts its acute rewarding and analgesic effects by activation of inhibitory guanine nucleotide-binding regulatory protein-coupled opioid receptors, whereas chronic morphine causes addiction, tolerance to its acute analgesic effects, and profound physical dependence by sustained activation of these receptors. We show here that acute morphine administration increases expression of RGS9-2 in NAc and the other CNS regions, whereas chronic exposure decreases RGS9-2 levels. Mice lacking RGS9 show enhanced behavioral responses to acute and chronic morphine, including a dramatic increase in morphine reward, increased morphine analgesia with delayed tolerance, and exacerbated morphine physical dependence and withdrawal. These findings establish RGS9 as a potent negative modulator of opiate action in vivo, and suggest that opiate-induced changes in RGS9 levels contribute to the behavioral and neural plasticity associated with chronic opiate administration. R egulators of G protein signaling (RGS) share a 130-aa RGS (GTPase-activating) domain, which binds to the GTP-bound form of G␣i or G␣q and accelerates the termination of effector stimulation (1-3). RGS proteins are thereby thought to repress the signaling efficacy of receptors coupled to these G proteins. In addition, many of the 25 mammalian RGS proteins known to date contain domains that provide them with additional anchoring or scaffolding properties (4-6). Thus, the net effect of RGS proteins on G protein-coupled receptor signaling in vivo may be complicated and difficult to ascertain from in vitro studies alone.In brain, RGS proteins show distinct regional and cellular distributions (7). A prominent example is RGS9, which exists in two forms, RGS9-1 and RGS9-2, that are generated by alternative splicing (8, 9). These proteins differ at their C terminus only, with RGS9-1 containing 18 unique C-terminal amino acids and RGS9-2 containing 209 unique C-terminal amino acids. RGS9-1 is expressed solely in retina, where it is implicated in regulating phototransduction (9, 10). By contrast, RGS9-2 is expressed solely in brain, where it shows a distinctive pattern of expression in brain regions important for the actions of opiate drugs (7,8). RGS9-2 is highly enriched in striatum (including the ventral striatum or nucleus accumbens, NAc), a region important for opiate reward, but is also present at much lower levels in periaqueductal gray and spinal cord, structures important for opiate analgesia (11).We have demonstrated previously that RGS9-2 can negatively modulate opioid receptor function in cultured Xenopus melanophores in vitro (8,12). These findings, coupled with...