Epigenetic regulation of Cdk5 in cognition and emotion

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PROJECT SUMMARY Negative valence states can be modeled in mice using fear conditioning and reward seeking (an example of frustrative nonreward). Such states lead to transcriptional aberrations at the level of both individual genes and genome-wide; these changes are also sexually dimorphic. One gene of considerable interest is cyclin-dependent kinase 5 (Cdk5). While most prior studies have focused on the mechanisms of Cdk5 protein activation and signaling in stress-evoked behavior, we recently reported that cocaine exposure and fear conditioning lead to transcriptional regulation of Cdk5 in male mouse brain. This proposal will directly examine the connection between Cdk5 gene activation and Cdk5 protein activity. Furthermore, there is emerging evidence that Cdk5-associated histone modifications correlate with drug-, and fear-induced Cdk5 expression. The current proposal explores the functional relevance of stress-induced histone modifications at the murine Cdk5 locus across multiple behavioral paradigms using the innovative approach of locus-specific epigenetic editing. This approach allows us to recapitulate endogenous mechanisms of gene expression, avoiding non-physiologically relevant changes in protein expression resulting from traditional knockout or overexpression. Furthermore, we apply cell-type specific analyses to elucidate Cdk5 function in brain regions across the corticostriatal-limbic circuitry in the regulation of negative valence states. This proposal will examine the direct functional relevance of sex-specific, epigenetic regulation of Cdk5 by fear conditioning (Aim 1) and cocaine seeking during abstinence (Aim 2) using targeted epigenetic editing. Sex- and region- specific phosphoproteomic profiling will be applied to define relevant Cdk5 targets. Identification of the precise transcriptional and epigenetic mechanisms by which stress regulates specific gene expression is critical for the development of targeted antidepressant treatments.