# Understanding cellular and molecular legacies of paternal stress

> **NIH NIH R56** · CHILDREN'S HOSPITAL OF LOS ANGELES · 2023 · $721,108

## Abstract

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studying legacies of paternal stress, learning and memory in mice and build on unpublished data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 in...

## Key facts

- **NIH application ID:** 10694000
- **Project number:** 5R56MH128427-02
- **Recipient organization:** CHILDREN'S HOSPITAL OF LOS ANGELES
- **Principal Investigator:** Brian George DIAS
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $721,108
- **Award type:** 5
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10694000

## Citation

> US National Institutes of Health, RePORTER application 10694000, Understanding cellular and molecular legacies of paternal stress (5R56MH128427-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10694000. Licensed CC0.

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