# Investigating steroid hormones, neurosteroids, and perineuronal nets in early life adversity-induced changes in hippocampal function

> **NIH NIH R01** · PRINCETON UNIVERSITY · 2024 · $640,485

## Abstract

PROJECT DESCRIPTION
Early life adversity predisposes individuals to develop anxiety and mood disorders. More women
than men have these diagnoses, and times of hormonal change, including puberty, postpartum,
and menopause, are associated with increased risk of emotional dysfunction. Neuronal
oscillations in the anterior hippocampus of humans are associated with anxiety and memory
consolidation. In rodents, neuronal oscillations in the ventral hippocampus (vHIP), considered
analogous to the anterior hippocampus, have been linked to avoidance behavior and memory
function. The early life adversity paradigm of maternal separation with early weaning (MSEW)
alters vHIP neuronal oscillations and behavior in male mice. MSEW also increases expression of
vHIP perineuronal nets, extracellular matrix structures that surround inhibitory interneurons and
are known to restrict plasticity. Females show similar changes in vHIP function after MSEW, but
only in the diestrus stage of the estrous cycle, a time characterized by a relatively high ratio of
progesterone to estradiol. In the vHIP, progesterone is converted to the neurosteroid
allopregnanolone, which binds to inhibitory GABAA  subunit extrasynaptic receptors, and
increases tonic inhibition. During diestrus, MSEW females have higher progesterone to
allopregnanolone ratios in the vHIP than control-reared females and blocking progesterone
receptors restores MSEW behavior to control levels. The masking of MSEW effects during other
stages of the estrous cycle raises questions about protective mechanisms, with estradiol being a
potential candidate. The broad, long-term objectives of this proposal are to investigate potential
roles for progesterone, allopregnanolone, and estradiol in early life adversity effects on vHIP
neuronal oscillations and behavior in both sexes. More specifically, we will use RT-qPCR, in situ
hybridization, ELISA, and mass spectrometry to better understand the influence of MSEW on
vHIP gene expression and steroid content, as well as pharmacological and viral manipulations of
steroids and PNN components in wildtype and transgenic mice. These approaches will be used
to assess the underpinnings of MSEW-induced changes in vHIP function using high-resolution
confocal imaging of immunolabeled perineuronal nets and GABAA  subunit receptors, in vivo
electrophysiology, and behavioral analyses. Taken together, the findings of the proposed
experiments will advance our understanding of how steroid hormones and neurosteroids confer
vulnerability or protection after early life adversity in female and male mice.

## Key facts

- **NIH application ID:** 10982863
- **Project number:** 2R01MH117459-06A1
- **Recipient organization:** PRINCETON UNIVERSITY
- **Principal Investigator:** Elizabeth Gould
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $640,485
- **Award type:** 2
- **Project period:** 2018-08-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10982863

## Citation

> US National Institutes of Health, RePORTER application 10982863, Investigating steroid hormones, neurosteroids, and perineuronal nets in early life adversity-induced changes in hippocampal function (2R01MH117459-06A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10982863. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*