Jarid1c is an X-linked gene expressed more highly in females than in males, suggesting that it may contribute to the effect of sex chromosome complement (XX vs. XY) on behaviors such as aggression. Jarid1c encodes a histone demethylase that represses expression of specific genes. The JARID1C enzyme plays an important role in brain development and function; patients with JARID1C mutations suffer from symptoms including mental retardation, elevated aggression, defective social interaction, language development, and seizure. We hypothesize that Jarid1c is implicated in the sex chromosome effect on aggression. Three related aims are proposed to test this hypothesis. Aim1 will identify genes that are differentially expressed between XX and XY mice, and genes that show different chromatin modifications in specific brain regions. These genes are candidates for causing the behavioral differences between XX and XY mice. Aim 2 will examine the effects of aggression on gene expression and chromatin modifications. Aim 3 will test the effects of knocking down Jarid1c expression in specific brain regions on behavior, gene expression, and chromatin modifications. The feasibility of siRNA treatment has been confirmed in our pilot study which detected changes in behaviors and gene expression. Hippocampal Jarid1c k/d mice were deficient in their performance in the object recognition test; furthermore, prefrontal cortical Jarid1c k/d mice were more anxious than controls in the open field test. Gene expression arrays indicated genes involved in GABAergic neurotransmission were up-regulated in both hippocampal and cortical Jarid1c k/d mice, suggesting GABA receptor signaling as a candidate mediating Jarid1c's effects on brain and behavior. A better understanding of Jarid1c's involvement in brain function and behavior will provide insights in novel molecular mechanisms underlying brain sexual differentiation, aggression regulation, as well as behaviors and emotions (e.g. episodic memory and anxiety). PUBLIC HEALTH RELEVANCE: Sex differences are persistently found in aggressive behavior and related psychological disorders such as conduct disorder and antisocial personality. In mice, aggression is influenced by both steroid hormones and sex chromosomes. We propose to test the possible connection between aggression and an X-linked gene whose mutations in human cause the clinical feature of aggression.