# Disentangling stress-induced transcriptional and functional heterogeneity of the midbrain

> **NIH NIH F31** · UNIVERSITY OF WASHINGTON · 2020 · $40,767

## Abstract

PROJECT SUMMARY
Coping with stress is a pervasive issue in day-to-day life, with chronic stress unearthing neuropsychiatric disor-
ders in susceptible individuals. Stress-induced disorders include massive public health issues such as anxiety,
depression and addiction. Despite our knowledge of the clinical pathologies associated with stress, the precise
neural substrates of stress signaling remain unclear, and it is thus exceedingly difficult to develop therapeutic
strategies for certain neuropsychiatric disorders. One brain region influenced by chronic stress is the ventral
tegmental area (VTA), a heterogeneous midbrain area. The VTA is cellularly diverse, possessing dopaminergic
(DA), GABAergic (GABA) and glutamatergic (Glu) neurons that together govern and coordinate motivated be-
haviors. It is challenging to interpret the impact of chronic stress on VTA neurophysiology, as VTA neurons
display differing firing patterns depending on the context, longevity and intensity of the stressor. It is also likely
that there are cell-type-dependent responses to stress in the VTA. Therefore, I hypothesize that chronic stress
elicits cell-type-specific transcriptional changes, leading to functional adaptations in VTA neuronal activity. To
critically test how chronic stress impacts VTA neurophysiology, I propose to directly and chronically administer
corticosterone (cort) to male and female mice. Following cort administration, I will first employ Drop-seq, a high-
throughput single cell RNA-seq (scRNAseq) method, to profile VTA gene expression changes at a single-cell
level resultant from chronic stress (Aim 1). Next, I will utilize patch-clamp electrophysiology and single-cell qPCR
to measure membrane properties and synaptic activity of stress-modulated VTA neurons in a cell-type-specific
manner. Using single-cell qPCR, I will measure changes in not only stress signaling- and neurotransmitter-re-
lated genes, but will also measure alterations in genetic markers identified from Drop-seq (Aim 2). Here, I will
attribute physiology and anatomy to gene expression, providing a more complete understanding of how chronic
stress modulates VTA neurons at both a molecular and physiological level. Results from these experiments will
also provide candidate genetic markers for highly-targeted behavioral studies that will elucidate how discrete cell
populations in the VTA orchestrate motivated behaviors under stress. Together, these aims will promote our
understanding of the precise neural circuits that are dysregulated in mental illness, contributing to the search for
effective treatments.

## Key facts

- **NIH application ID:** 9965644
- **Project number:** 5F31MH117931-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Rhiana Catherine Simon
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $40,767
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9965644

## Citation

> US National Institutes of Health, RePORTER application 9965644, Disentangling stress-induced transcriptional and functional heterogeneity of the midbrain (5F31MH117931-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9965644. Licensed CC0.

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