ABSTRACT
Given both the high prevalence of anxiety disorders in women and the fact that little is known about the mechanisms of gender differences in anxiety, our primary aim in this study was to investigate the neurobiological mechanisms underlying sex differences in social anxiety-like behavior in rats. Through the use of zif268 antisense oligodeoxynucleotides (zif ASO), we induced a temporary downregulation of zif268 expression in the medial prefrontal cortex of male and female rats and found that zif268 ASO male rats show more social anxiety-like behaviors when compared with control male rats in the social interaction test. In fact, zif268 ASO males displayed social anxiety-like behaviors, which were similar to control females, thus downregulation of zif268 expression in the mPFC of male rats eliminated sex differences previously found in the social anxiety-like behavior tests. Interestingly, zif268 ASO in female rats had no effect on their social interaction. Our novel findings have led us to ascertain that sexually dimorphic zif268 expression in the mPFC is a key molecular factor in mediating sex-specific anxiety-like behavior in the social interaction test.
Subject(s)
Early Growth Response Protein 1/metabolism , Interpersonal Relations , Sex Characteristics , Analysis of Variance , Animals , Behavior, Animal/drug effects , Dose-Response Relationship, Drug , Early Growth Response Protein 1/chemistry , Early Growth Response Protein 1/genetics , Estradiol/pharmacology , Estrogens/pharmacology , Estrous Cycle/drug effects , Estrous Cycle/physiology , Exploratory Behavior/drug effects , Female , Gene Expression Regulation/drug effects , Male , Oligodeoxyribonucleotides/pharmacology , Ovariectomy/methods , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Stress, Psychological/metabolism , Stress, Psychological/pathology , Vaginal Smears/methodsABSTRACT
Changes in gene expression contribute to the long-lasting regulation of the brain's reward circuitry seen in drug addiction; however, the specific genes regulated and the transcriptional mechanisms underlying such regulation remain poorly understood. Here, we used chromatin immunoprecipitation coupled with promoter microarray analysis to characterize genome-wide chromatin changes in the mouse nucleus accumbens, a crucial brain reward region, after repeated cocaine administration. Our findings reveal several interesting principles of gene regulation by cocaine and of the role of DeltaFosB and CREB, two prominent cocaine-induced transcription factors, in this brain region. The findings also provide comprehensive insight into the molecular pathways regulated by cocaine-including a new role for sirtuins (Sirt1 and Sirt2)-which are induced in the nucleus accumbens by cocaine and, in turn, dramatically enhance the behavioral effects of the drug.
