# ESTROGEN-INDUCIBLE PNNS ENHANCE EXCITATORY SYNAPTIC STRENGTH ONTO GABA NEURONS IN THE MEPD TO PREVENT OBESITY AND METABOLIC DYSREGULATION

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $429,653

## Abstract

PROJECT SUMMARY
Perineuronal nets (PNNs) are condensed extracellular matrix around a subset of neurons. PNNs can provide
physical protection and ion buffering for neurons and regulate their synaptic plasticity and intracellular signaling.
Recent evidence indicates that PNNs enmesh GABA neurons in the arcuate nucleus of the hypothalamus (ARH)
to regulate energy and glucose homeostasis. However, little is known about the potential metabolic function of
PNNs in other brain regions that are also implicated in metabolic health.
 We observed abundant PNNs in the posterodorsal medial amygdala (MePD) and found that PNN-enmeshed
neurons in the MePD are mostly GABA neurons. Digestion of PNNs drastically reduces excitability and synaptic
activity of these GABAMePD neurons. Importantly, we showed that chronic disruption of MePD PNNs leads to
hyperphagia and modest weight/fat gain in chow-fed mice. On the other hand, chronic increases in MePD PNNs
result in lower body weight/fat in chow-fed mice. These results suggest that MePD PNNs and PNNs-enmeshed
GABAMePD neurons are required to prevent overeating and obesity. We will follow up these findings to establish
the function of MePD PNNs (Aim 1) and GABAMePD (Aim 2) neurons in energy and glucose homeostasis.
Meanwhile, we will delineate the mechanisms by which PNNs regulate excitability and synaptic activity of
GABAMePD neurons.
 17β-estradiol (E2) can act on estrogen receptor-α (ERα) to regulate energy and glucose balance in both
females and males. Previous reports showed that ERα in many brain regions mediates the metabolic effects of
E2 only in female mice, but not male mice. Our pilot observations indicate that E2 can increase PNNs in MePD
in both male and female mice. Importantly, loss of ERα in the medial amygdala (containing the MePD) causes
obesity not only in female mice, but also in male mice, suggesting the potential metabolic role of MePD in male
metabolic health. In Aim 3, we will follow up these findings to test whether E2 induces PNNs to facilitate GABA
neurons in the MePD to prevent obesity and metabolic dysregulation in both male and female mice.
 Together, we will reveal a new metabolic regulation mechanism: E2-ERα-PNNs-GABAMePD-energy/glucose
homeostasis. Our studies will advance our understanding about the estrogen biology in both female and male
metabolism and the metabolic role of PNNs in a new brain region MePD. Finally, we will identify a unique
anorexigenic GABA population, which is different from previous reported orexigenic GABA neural populations in
many other brain regions.

## Key facts

- **NIH application ID:** 10911924
- **Project number:** 5R01DK136627-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Chunmei Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $429,653
- **Award type:** 5
- **Project period:** 2023-08-24 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10911924

## Citation

> US National Institutes of Health, RePORTER application 10911924, ESTROGEN-INDUCIBLE PNNS ENHANCE EXCITATORY SYNAPTIC STRENGTH ONTO GABA NEURONS IN THE MEPD TO PREVENT OBESITY AND METABOLIC DYSREGULATION (5R01DK136627-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10911924. Licensed CC0.

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