# Circuit Mechanisms for Conditioned Stress Regulation of Addiction

> **NIH NIH K99** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2021 · $149,040

## Abstract

Converging epidemiological studies indicate that a life-threatening event increases the incidence of post-
traumatic stress disorder (PTSD), which carries a 30-50% comorbidity with substance use disorders (SUDs).
Such comorbidity results in greater drug use and poorer treatment outcomes. The proposed research builds
upon my recent publication, where I showed a remarkable overlap between the enduring neuroadaptations
produced in nucleus accumbens core (NAcore) excitatory transmission after acute restraint stress and drug use.
Recently, I paired a stressful event with a novel odor and found that the stress-conditioned odor alone induced
cocaine seeking. In NAcore, ~95% of neurons are medium spiny neurons (MSNs) chemically coded as
selectively expressing D1 or D2 dopamine receptors. Different studies showed that D1 activation generally
promotes and D2 activation inhibits behaviors during drug seeking. At molecular level, I observed that activated
matrix metalloproteases signal through β3-integrins and are required for the transient synaptic plasticity (t-SP)
characteristic of drug seeking elicited by cocaine cues. Here, I will examine the role of D1- and D2-MSN neuronal
activity in response to stress-conditioned cues and determine if the changes in neuronal activity encode coping
behavior or cocaine seeking. Furthermore, I will determine if changes in activity in D1- and D2-MSNs are integrin-
mediated. To accomplish this, I will be trained in vivo single cell Ca2+ transients in real time. I will also use
DREADDS technology for cell-type specific modulation and Cre-dependent shRNA for cell-specific target protein
knockdown. In the K99 aims, I propose to determine if exposure to stress-conditioned cues elicit different patterns
of activity during defensive burying (DB) (Aim 1). I will selectively inactivate D1- or D2-MSNs during restraint
stress to evaluate the necessity of each cell type for encoding coping during DB (Aim 2A) and I will evaluate if
the activity in either cell type is dependent upon β3-integrin signaling using Cre-dependent shRNA knockdown
(Aim 2B). MUSC provides an ideal research environment in which to attain this training and complete these aims,
as it boasts one of the leading neuroscience departments for addiction research with multi-PI center grants. This
training will enhance my qualifications for transitioning to an independent tenure-track faculty position at a major
research institution, which is my ultimate goal. Moreover, Dr. Kalivas is a well-established mentor who has
demonstrated abundant success in facilitating the transition of his postdoctoral trainees to faculty positions. Once
I achieve a faculty appointment during the R00 period, I will determine if the changes in Ca2+ transient in D1- or
D2-MSNs during stress-conditioned cues are similar to those observed during stress-induced cocaine seeking
(Aim 3). I will examine the necessity of each cell type for encoding cocaine seeking (Aim 4A) and I will evaluate
if the a...

## Key facts

- **NIH application ID:** 10410019
- **Project number:** 3K99DA047426-02S1
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Constanza Garcia Keller
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $149,040
- **Award type:** 3
- **Project period:** 2019-07-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10410019

## Citation

> US National Institutes of Health, RePORTER application 10410019, Circuit Mechanisms for Conditioned Stress Regulation of Addiction (3K99DA047426-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10410019. Licensed CC0.

---

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