Transgenerational epigenetic mechanisms of stress axis programming

Altered stress reactivity is a predominant feature of sex-biased neuropsychiatric diseases, with hyperreactivity and hyporeactivity of the hypothalamic-pituitary-adrenal (HPA) stress reported in affective, neurotic, and psychotic disorders. Stress dysregulation may precede symptom onset, and has been characterized as a vulnerability that predisposes males and females to disease. Environmental factors, particularly prior stress history, contribute to the developmental programming of stress reactivity in exposed individuals and their offspring. Epigenetic marks in the brain are uniquely positioned to act at the interface of stress and lasting changes in behavior and physiology, and epigenetic signatures in germ cells are similarly poised to communicate experience-dependent information across generations. In this dissertation, mouse models are used to examine the consequences of chronic stress on later stress reactivity, and to define the molecular mechanisms involved in transgenerational and brain programming. Results of the first set of studies revealed that paternal exposure to chronic variable stress elicits a reduced HPA axis response in offspring, and that nine microRNAs (miRs) increased in the sperm of stressed sires mediate this transmission, as zygote microinjection of the nine miRs remarkably recapitulated of the paternal stress phenotype. Broad repression of the hypothalamic transcriptome following paternal stress or miR-microinjection suggested that epigenetic reprogramming underlies altered offspring stress reactivity. Further, targeted degradation of maternal mRNA transcripts in miR-microinjected zygotes provided the first step in the complex regulatory cascade by which sperm miRs impact the adult offspring brain. The final study offers evidence of the direct reprogramming of neurodevelopment by chronic stress, highlighting the disruption of sex differences in the prefrontal cortex by peripubertal stress as particularly relevant to the onset of sex-biased neuropsychiatric diseases. Together, research presented in this dissertation support that epigenetic mechanisms mediate the transgenerational transmission of chronic stress and allow lifetime adversity to program later stress dysregulation