While stressful life events are an important cause of psychopathology, most individuals exposed to adversity maintain normal psychological functioning. The molecular mechanisms underlying such resilience are poorly understood. Here, we demonstrate that an inbred population of mice subjected to social defeat can be separated into susceptible and unsusceptible subpopulations that differ along several behavioral and physiological domains. By a combination of molecular and electrophysiological techniques, we identify signature adaptations within the mesolimbic dopamine circuit that are uniquely associated with vulnerability or insusceptibility. We show that molecular recapitulations of three prototypical adaptations associated with the unsusceptible phenotype are each sufficient to promote resistant behavior. Our results validate a multidisciplinary approach to examine the neurobiological mechanisms of variations in stress resistance, and illustrate the importance of plasticity within the brain's reward circuits in actively maintaining an emotional homeostasis.

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.

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 (

Despite abundant expression of DNA methyltransferases (Dnmt’s) in brain, the regulation and behavioral role of DNA methylation remain poorly understood. We find that Dnmt3a expression is regulated in mouse nucleus accumbens (NAc) by chronic cocaine and chronic social defeat stress. Moreover, NAc specific manipulations that block DNA methylation potentiate cocaine reward and exert antidepressant-like effects, whereas NAc specific Dnmt3a overexpression attenuates cocaine reward and is pro-depressant. On a cellular level, we show that chronic cocaine selectively increases thin dendritic spines on NAc neurons and that DNA methylation is both necessary and sufficient to mediate these effects. These data establish the importance of Dnmt3a in the NAc in regulating cellular and behavioral plasticity to emotional stimuli.

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...

Recent work implicates regulation of neurogenesis as a form of plasticity in the adult rat hippocampus. Given the known effects of opiates such as morphine and heroin on hippocampal function, we examined opiate regulation of neurogenesis in this brain region. Chronic administration of morphine decreased neurogenesis by 42% in the adult rat hippocampal granule cell layer. A similar effect was seen in rats after chronic self-administration of heroin. Opiate regulation of neurogenesis was not mediated by changes in circulating levels of glucocorticoids, because similar effects were seen in rats that received adrenalectomy and corticosterone replacement. These findings suggest that opiate regulation of neurogenesis in the adult rat hippocampus may be one mechanism by which drug exposure influences hippocampal function. Opiates are among the most commonly abused illegal drugs in the United States (1, 2). Several reports suggest that chronic exposure to opiates, such as morphine and heroin, can result in cognitive deficits (3-5). For example, heroin users have poorer performance on attention, verbal fluency, and memory tasks than controls (3), and rats chronically exposed to morphine show impaired acquisition of reference memory (5). Such findings suggest that long-term opiate use may produce maladaptive plasticity in brain structures involved in learning and memory, such as the hippocampus.One aspect of the mammalian hippocampus that recently has received considerable attention is the birth of new neurons that occurs in the dentate gyrus throughout the lifetime of the animal (6-8). This phenomenon has been described in rodents, nonhuman primates, and, most recently, humans (9-12). Research suggests that cells are born in the subgranular zone of the dentate gyrus, migrate into the granule cell layer and express neuronal markers (8,13,14), extend processes to CA3 pyramidal neurons (15, 16), receive synaptic connections (10, 13, 16), and demonstrate long-term potentiation (17). Although a growing number of pharmacological and environmental manipulations have been shown to influence adult neurogenesis, the functional implication of the newly born neurons remains poorly understood (see Discussion). It has been proposed that the thousands of new neurons born each day in the adult rodent hippocampus may contribute to a variety of hippocampal-related functions, including learning and memory (6, 7).Drugs of abuse, including opiates, can significantly alter the birth of neural progenitors during early stages of development (18)(19)(20), yet it remains unclear what effect drug exposure has on the birth of neural progenitors in the mature brain. Here we examine the consequence of long-term opiate exposure on the birth of new neurons in the adult rat hippocampus. Materials and MethodsAnimals and Drug Treatment. Adult, male Sprague-Dawley rats (initial weight 275-300 g; Charles River Breeding Laboratories) were used for all experiments. For chronic morphine treatment, rats were given sham surgery (n ϭ 10) or a morphine pellet (75 ...

The transcriptional program that controls adult neurogenesis is unknown. We generated mice with an inducible stem cell–specific deletion of Neurod1, resulting in substantially fewer newborn neurons in the hippocampus and olfactory bulb. Thus, Neurod1 is cell-intrinsically required for the survival and maturation of adult-born neurons.

Acute seizures after a severe brain insult can often lead to epilepsy and cognitive impairment. Aberrant hippocampal neurogenesis follows the insult but the role of adult-generated neurons in the development of chronic seizures or associated cognitive deficits remains to be determined. Here we show that ablation of adult neurogenesis prior to pilocarpine-induced acute seizures in mice leads to a reduction in chronic seizure frequency. We also show that ablation of neurogenesis normalizes epilepsy-associated cognitive deficits. Remarkably, the effect of ablating adult neurogenesis prior to acute seizures is long-lasting as it suppresses chronic seizure frequency for nearly one year. These findings establish a key role of neurogenesis in chronic seizure development and associated memory impairment and suggest that targeting aberrant hippocampal neurogenesis may reduce recurrent seizures and restore cognitive function following a pro-epileptic brain insult.