Understanding cellular and molecular legacies of paternal stress

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PROJECT SUMMARY: Famines, the Holocaust and other natural and anthropogenic events are providing evidence that the effects of trauma and stress extend beyond the ancestral generation and affect mental health in offspring. Remedying parental behavior that is perturbed by stress and mitigating stress during pregnancy have received attention for their utility in halting such legacies of stress. In contrast, less is known about how to halt legacies of paternal stress that occurred prior to conception of the affected offspring. To fill this gap in knowledge, we must first understand how stress-induced alterations in paternal sperm perturb neurobiology and derail mental health. With this intent, our goal is to determine how cell-type specific offspring neurobiology is impacted by stress-induced alterations in sperm RNA that have emerged as one mechanism via which paternal lineages bequeath legacies of stress to offspring. To achieve this goal, we rely on our experience studying legacies of paternal stress, learning and memory in mice and build on unpublished data demonstrating that injections of RNA from sperm of male mice exposed to stress into single cell zygotes resulted in deficits in extinction learning in adulthood. To begin our investigation into the neurobiological mechanisms that might underlie these deficits in extinction learning being set into motion by RNA in sperm exposed to stress, we propose a focus on glucocorticoid receptors (GRs) in the infra-limbic prefrontal cortex (IL-PFC), lactate-based activity of neurons in the IL-PFC, and development of the IL-PFC. Our focus is shaped by the following background. First, the IL-PFC is important for extinction learning. Second, epigenetic-based regulation of the GR gene has received the most attention in studies that have investigated intergenerational legacies of stress arising from abusive care-giving and gestational stress, in both humans and rodents. Third, lactate-based signaling between astrocytes and neurons is an important mode of communication between these cell types, plays a role in learning and memory, and is perturbed in offspring by ante-natal stress. Fourth, altered development of the PFC in humans and rodents as a consequence of impoverished caregiving and gestational stress derails behavior in offspring during adulthood. Motivated by this background, we hypothesize that deficits in extinction learning that are set into motion by RNA contained in sperm of mice exposed to stress result in part, from altered GR availability in the IL-PFC, disrupted lactate-based activity of IL-PFC neurons, and an immaturity of the adult IL-PFC. To test this hypothesis, we will use biochemistry, molecular genetics, developmental biology and in vivo manipulation of neuronal activity with a focus on the IL- PFC of animals generated from embryos into which RNA from sperm of male mice exposed to stress had been injected. Via cell- and region-specific investigations, our work will provide new insights into how stress- induced alterations in sperm RNA are translated into neurobiological legacies and may have translational impact by identifying biology that could be therapeutically targeted to lighten the burden of such legacies.