Understanding the mechanisms by which brain function leads to psychiatric and behavioral disorders is critical to the discovery of better treatment options and more effective prevention. An important clue to understanding the etiology of these disorders lies in the fact that there are often significant gender biases in the incidence of diagnosis. How fundamental mechanisms of neural development differ in males and females provides valuable insight into not only how sex differences in these disorders might arise, but the developmental pathways that might increase risk for diagnosis. Steroid hormones act on nuclear receptors, which as transcription factors regulate fundamental processes of neural development. We have previously reported a remarkable sex difference in nuclear progesterone receptor (PR) expression in the medial preoptic nucleus (MPN) of rats and mice in which males express significantly higher levels of PR than females through much of perinatal development, representing one of the earliest and largest sex differences reported in the mammalian brain. This suggests the existence of a developmental window during which the male MPN is more sensitive to progestins than the female MPN. The main hypothesis of this proposal is that sex differences in PR expression during perinatal life are critical for the sexual differentiation of gene regulation in MPN, MPN connectivity, and MPN-dependent behavior.
Aim 1 will use the high throughput technique of RNAseq to sequence the transcriptome of neonatal male and female PR knockout (PRKO) and wildtype mice.
Aim 2 will investigate the role of PR in the sexual differentiation of serotonergic innervation of MPN and will determine if PR expressing cells in MPN are postsynaptic targets for serotonin and if PR expressing cells in the midbrain raphe are serotonergic and project to MPN.
Aim 3 will test the hypothesis that PR is critical for the masculinization of intermale aggression by testosterone and will examine whether serotonergic synaptic activity is a mechanism by which PR masculinizes MPN function. Findings from these experiments will have implications for understanding the neurodevelopmental mechanisms underlying behavioral disorders, particularly those involving aggression in boys.
Behavioral disorders diagnosed in infancy or childhood often show strong gender biases (i.e., much more prevalent in males than females), suggesting that sex differences in early brain development may cause male brains to be more vulnerable to disturbances. Understanding how fundamental mechanisms of neural development differ in males and females provides valuable insight into the developmental pathways that may increase the risk for diagnosis. Using transgenic mice and rats, this proposal will employ the high throughput technique of RNA sequencing to compare gene expression patterns between male and female mice that express PR or do not express functional PR. In addition, experiments examine the role of progesterone receptor (PR) in the development of sex differences in medial preoptic nucleus connectivity and in aggressive behavior later in life.
