# Modulation of the neuroendocrine control of reproduction by early-life and adult stress and their interactions

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $39,531

## Abstract

Project Summary
Adverse childhood experiences (ACEs) have profound consequences for physiological development and are
an important social determinant of health. ACEs can alter reproductive outcomes including age at menarche,
engagement in risky sexual behaviors, and fertility. Early-life stress can also shape the way an individual
responds to stress in adulthood, promoting either resiliency or susceptibility to later stress. Adult stress has
been independently demonstrated to disrupt fertility. Two neuroendocrine axes play key roles regulating both
the stress response (hypothalamo-pituitary-adrenal [HPA] axis) and reproduction (hypothalamo-pituitary-
gonadal [HPG] axis). Corticotropin-releasing hormone (CRH) is the main central neurohormone for the
hypothalamic component of the HPA axis, released by neurons in the paraventricular nucleus (PVN). CRH also
serves as a signaling neuropeptide outside of the PVN, regulating other components of the stress response
including emotional and behavioral aspects. Gonadotropin-releasing hormone (GnRH) neurons in the
hypothalamus are the final common pathway for the central control of reproduction. GnRH neurons receive
input from many afferent populations, including kisspeptin neurons in the anteroventral periventricular nucleus
(AVPV). GnRH leads to the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from
the pituitary gland, thus stimulating synthesis of sex steroids. In females, estradiol switches from a negative to
positive feedback action during the preovulatory stage, leading to a surge in GnRH and LH release that
promotes ovulation. Critically, acute stress can disrupt this LH surge, and this disruption may involve CRH
neurons. To investigate the neural mechanisms by which acute stress disrupts the LH surge, and to determine
if a history of ACEs modulates this phenomenon, we must turn to animal models. Rodent models share core
components of the reproductive system with humans, and they permit the use of genetic tools to interrogate
biological circuits. Here, we will use a limited bedding and nesting (LBN) model for early-life stress and an
acute, layered, psychosocial stress (ALPS) paradigm for adult stress. In Aim 1, we will investigate how these
stressors alter the intrinsic electrophysiological properties of and fast-synaptic input to GnRH neurons on the
afternoon of proestrus, corresponding to the timing of the LH surge. This aim will also test the hypothesis that
early-life stress of the LBN model confers resilience to the effects of acute stress on reproduction in adulthood.
In Aim 2, channelrhodopsin-assisted circuit mapping (CRACM) will be employed to interrogate the functional
connection between CRH and GnRH neurons and AVPV kisspeptin neurons. In vivo chemogenetic tools will
address if activation of CRH neurons that project to the AVPV is sufficient to disrupt the LH surge and
necessary for stress to disrupt the surge on proestrus. The proposed studies will provide ke...

## Key facts

- **NIH application ID:** 10463246
- **Project number:** 1F31HD108872-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Amanda Gail Gibson
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $39,531
- **Award type:** 1
- **Project period:** 2022-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463246

## Citation

> US National Institutes of Health, RePORTER application 10463246, Modulation of the neuroendocrine control of reproduction by early-life and adult stress and their interactions (1F31HD108872-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10463246. Licensed CC0.

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