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ATP-dependent chromatin remodeling proteins are being implicated increasingly in the regulation of complex behaviors, including models of several psychiatric disorders. Here, we demonstrate that Bazlb, an accessory subunit of the ISWI family of chromatin remodeling complexes, is upregulated in the nucleus accumbens (NAc), a key brain reward region, in both chronic cocaine-treated mice and mice that are resilient to chronic social defeat stress. In contrast, no regulation is seen in mice that are susceptible to this chronic stress. Viral-mediated overexpression of Baz1b, along with its associated subunit Smarca5, in mouse NAc is sufficient to potentiate both rewarding responses to cocaine, including cocaine self-administration, and resilience to chronic social defeat stress. However, despite these similar, proreward behavioral effects, genome-wide mapping of BAZ1B in NAc revealed mostly distinct subsets of genes regulated by these chromatin remodeling proteins after chronic exposure to either cocaine or social stress. Together, these findings suggest important roles for BAZ1B and its associated chromatin remodeling complexes in NAc in the regulation of reward behaviors to distinct emotional stimuli and highlight the stimulus-specific nature of the actions of these regulatory proteins. [ABSTRACT FROM AUTHOR]

Depression and anxiety disorders are more prevalent in females, but the majority of research in animal models, the first step in finding new treatments, has focused predominantly on males. Here we report that exposure to subchronic variable stress (SCVS) induces depressionassociated behaviors in female mice, whereas males are resilient as they do not develop these behavioral abnormalities. In concert with these different behavioral responses, transcriptional analysis of nucleus accumbens (NAc), a major brain reward region, by use of RNA sequencing (RNA-seq) revealed markedly different patterns of stress regulation of gene expression between the sexes. Among the genes displaying sex differences wasDNAmethyltransferase 3a (Dnmt3a), which shows a greater induction in females after SCVS. Interestingly, Dnmt3a expression levelswereincreasedintheNAcofdepressedhumans,aneffectseeninbothmalesandfemales.LocaloverexpressionofDnmt3ainNAcrendered male micemoresusceptible to SCVS, whereasDnmt3aknock-out in this region rendered femalesmoreresilient, directly implicating this gene in stress responses. Associated with this enhanced resilience of female mice upon NAc knock-out of Dnmt3a was a partial shift of the NAc female transcriptome toward the male pattern after SCVS. These data indicate that males and females undergo different patterns of transcriptional regulation in response to stress and that aDNAmethyltransferase in NAc contributes to sex differences in stress vulnerability. [ABSTRACT FROM AUTHOR]

ΔFosB, a Fosb gene product, is induced in nucleus accumbens (NAc) and caudate-putamen (CPu) by repeated exposure to drugs of abuse such as cocaine. This induction contributes to aberrant patterns of gene expression and behavioral abnormalities seen with repeated drug exposure. Here, we assessed whether a remote history of cocaine exposure in rats might alter inducibility of the Fosb gene elicited by subsequent drug exposure. We show that prior chronic cocaine administration, followed by extended withdrawal, increases inducibility of Fosb in NAc, as evidenced by greater acute induction of ΔFosB mRNA and faster accumulation of ΔFosB protein after repeated cocaine reexposure. No such primed Fosb induction was observed in CPu; in fact, subsequent acute induction of ΔFosB mRNA was suppressed in CPu. These abnormal patterns of Fosb expression are associated with chromatin modifications at the Fosb gene promoter. Prior chronic cocaine administration induces a long-lasting increase in RNA polymerase II (Pol II) binding at the Fosb promoter in NAc only, suggesting that Pol II "stalling" primes Fosb for induction in this region upon reexposure to cocaine. Acocaine challenge then triggers the release of Pol II from the gene promoter, allowing for more rapid Fosb transcription. A cocaine challenge also decreases repressive histone modifications at the Fosb promoter in NAc, but increases such repressive marks and decreases activating marks in CPu. These results provide new insight into the chromatin dynamics at the Fosb promoter and reveal a novel mechanism for primed Fosb induction in NAc upon reexposure to cocaine. [ABSTRACT FROM AUTHOR]

Electrolytic lesions to the amygdala, a limbic structure implicated in stress-related behaviors and memory modulation, have been shown to prevent stress-induced impairments of hippocampal long-term potentiation (LTP) and spatial memory in rats. The present study investigated the role of intrinsic amygdalar neurons in mediating stress effects on the hippocampus by microinfusing the GABAA receptor agonist muscimol into the amygdala and examining stress effects on Schaffer collateral/commissural-CA1 LTP and spatial memory. The critical period of the amygdalar contribution to stress effects on hippocampal functions was determined by applying muscimol either before stress or immediately after stress. Our results indicate that intra-amygdalar muscimol infusions before uncontrollable restraint-tailshock stress effectively blocked stress-induced physiological and behavioral effects. Specifically, hippocampal slices prepared from vehicle-infused stressed animals exhibited markedly impaired LTP, whereas slices obtained from muscimol-infused stressed animals demonstrated robust LTP comparable with that of unstressed animals. Correspondingly, vehicle-infused stressed animals displayed impaired spatial memory (on a hidden platform version of the Morris water maze task), whereas muscimol-infused stressed animals revealed unimpaired spatial memory. In contrast to prestress muscimol effects, however, immediate poststress infusions of muscimol into the amygdala failed to interfere with stress impairments of LTP and spatial memory. Together, these results suggest that the amygdalar neuronal activity during stress, but not shortly after stress, is essential for the emergence of stress-induced alterations in hippocampal LTP and memory. [ABSTRACT FROM AUTHOR]

In the fear conditioning literature, it is generally hypothesized that neurons in the basolateral amygdalar complex (BLA) (lateral and basal nuclei) support the formation of conditioned fear memory and project to neurons in the central nucleus (CeA) for the expression of conditioned fear responses. According to this serial processing-transmission view, damage to either BLA or CeA would comparably disrupt the expression of a variety of conditioned fear responses. In the present study, we further investigated the roles of BLA and CeA in fear conditioning by concurrently assessing freezing and 22 kHz ultrasonic vocalization (USV) as dependent measures of fear in rats. Selective neurotoxins, NMDA for the BLA and ibotenic acid for the CeA, were used to destroy intrinsic neurons [evidenced by thionin dye and NeuN (neuronal nuclei) antibody stainings] without damaging the fibers of passage (confirmed by myelin staining). During the 10 tone-footshock paired training, postshock freezing and USV responses were significantly impaired in BLA-lesioned animals, whereas CeA-lesioned animals exhibited only mild deficits. Similarly, conditioned fear responses assessed 24 hr after training were severely reduced in BLA-lesioned animals but not in CeA-lesioned animals. In contrast to ibotenic lesions of the CeA, small electrolytic lesions of the CeA strongly affected both postshock and conditioned freezing and USV. Together, these results do not support the currently espoused BLA-to-CeA serial processing-transmission view of fear conditioning. Instead, the expression of conditioned fear appears to primarily involve BLA projections that course through the CeA en route to downstream fear response structures. [ABSTRACT FROM AUTHOR]