# The Potential Role of CRF Neurons in Mediating Onset of Stress-induced Susceptibility via PVT-BNST Connectivity

> **NIH NIH F31** · EMORY UNIVERSITY · 2020 · $50,520

## Abstract

Project Summary
Major Depressive Disorder (MDD) is the most common psychiatric disorder with a lifetime prevalence of 1 in 5,
treatment for which is currently suboptimal. Deficits in ability to cope with ongoing chronic stressors are one of
the chief predisposing factors to MDD. Neurons of the Paraventricular Thalamus (PVT) are critical in emotional
arousal and orchestrate adaptive stress-relevant neurohumoral responses. Furthermore, a synaptic target of
the PVT, the oval nucleus of the Bed Nucleus of the Stria Terminals (BNSTov), regulates behavioral responses
to stress through Corticotropin-Releasing Factor (CRF)-releasing neurons. The PVT is critical in regulating
relevant neurohumoral responses to chronic stress, thought to occur via CRF-neurons of a PVT-BNSTov
circuit. Additionally, I have preliminary electrophysiological and single-cell qRT-PCR data in the rat and tissue
micropunches in the mouse, that chronic stress accompanies increases in neuronal excitability and
enhancement of crf and crf receptor 1 gene expression selectively in the BNSTov. Given that these cells are
under direct PVT synaptic influence, this could represent a PVT-mediated adaptive response. Interestingly,
unlike in acute stress, in chronic stress, PVT mediated adaptive neural responses appear to be temporally
independent of the actual behavioral expression of that stress adaptation. Therefore, this PVT-BNSTov circuit
may underlie the latency in the conversion of chronic stress into depressive-like behaviors. To determine the
time course wherein stress-induced depressive-like behavior emerges, I employed the Chronic Social Defeat
Stress (CSDS) paradigm in mice, and conducted social interaction/sucrose preference testing at various stress
duration lengths of 4-10 days. I observed that between 7 and 10 days of CSDS, animals underwent a switch
from social approach (“resilient”) to socially avoidant (“susceptible”) phenotypes. The electrophysiological and
molecular substrates underlying this rapid behavioral shift remains unknown. I hypothesize that PVT-BNSTov
connectivity may govern the temporal emergence of stress susceptibility in the face of persistent
psychosocial stress, through PVT synaptic influence on CRF BNSTov neurons. I plan to investigate this
functional PVT-BNSTov circuit using electrophysiological, single-cell transcriptomics, and advanced optical
circuit dissection methods (DREADDs). First, I will establish functional connectivity by correlating tract tracing
and c-Fos activity with the co-occurrence over the time period capturing the behavioral switch (aim 1). Then, I
will record in ex-vivo whole-cell patch clamp the intrinsic neuronal properties and procure the cytoplasm for
single-cell qRT-PCR analysis in cells before or after the behavioral transition (aim 2). Lastly, I will establish the
necessity of the PVT-BNST circuit in mediating the temporal onset of susceptibility via time- and circuit-specific
manipulations using DREADDs (aim 3). This proposed s...

## Key facts

- **NIH application ID:** 9975633
- **Project number:** 5F31MH114624-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** SHEROD E HAYNES
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2018-07-10 → 2021-11-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975633

## Citation

> US National Institutes of Health, RePORTER application 9975633, The Potential Role of CRF Neurons in Mediating Onset of Stress-induced Susceptibility via PVT-BNST Connectivity (5F31MH114624-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9975633. Licensed CC0.

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