Micrornas and the Sex Specific Development of the Neonatal Brain: A Point of Vulnerability to the Programming Effects of Prenatal Stress
Epidemiological studies have linked prenatal stress to increases in the incidence of neurodevelopmental disorders, including schizophrenia and autism spectrum disorders, associations that are often sex-dependent. In addition, biological sex is a strong predictor of many aspects of these disorders, including incidence, presentation, and therapeutic outcomes. While many factors contribute to these effects, sex-specific responses to fetal antecedents during key developmental windows are likely involved. The male brain is organized in a sex specific manner by a surge of testes-synthesized testosterone during the perinatal period. In appropriate cell populations this testosterone is converted to estrogen by a neuronal-specific aromatase where it acts through estrogen receptors to masculinize the neural substrate. While the primary effector, estrogen, is shared, the cellular processes responsible for this divergent development vary widely across brain regions. miRNAs, with their ability to regulate the expression of hundreds of genes, may be an exciting and novel regulatory mechanism poised to translate this estrogen signal into brain region-specific responses. The work in this dissertation identifies sexual differentiation of the brain as a point of sex-specific vulnerability to the multigenerational programming effects of early prenatal stress. Paternal (F1) prenatal stress exposure attenuates the perinatal testosterone surge, leading to dysmasculinized physiology, including increased stress sensitivity, in second-generation (F2) male offspring. Further, we reveal a novel role for the miRNA environment in programming the neurodevelopmental effects of paternal stress exposure and, more generally, in organizing the sexually dimorphic brain. Finally, we empirically map miRNA recognition elements across the transcriptome of the neonatal hypothalamus by Argonaute HITS-CLIP, and identify a network of genes targeted by organizational estrogen with functional relevance to sexual differentiation of the brain. Together these findings point to a developmental window of susceptibility during which the programming effects of early prenatal stress exposure may manifest. As such, identifying sex-specific developmental processes affected during this window, such as the dynamic changes in the miRNA environment we have highlighted, may lead to novel therapeutic targets or biomarkers predictive for neurodevelopmental disorders.