# Treating PTSD and depression: Mechanisms of pharmacotherapy and psychotherapy in rats

> **NIH VA I01** · SOUTH TEXAS VETERANS HEALTH CARE SYSTEM · 2021 · —

## Abstract

Current pharmacological treatments for PTSD and comorbid depression are inadequate. These stress-
related psychiatric illnesses of high significance and impact to the veteran population, and finding more effective
treatments would satisfy a tremendous gap in veterans’ health care. Evidence-based behavioral therapies, such
as exposure therapy, are promising, but they also have limited efficacy. The lack of effective treatment arises,
in part, from our lack of knowledge of the neurobiological mechanisms underlying these illnesses, the altered
regulatory processes that lead to pathology, the neural systems that mediate the dimensions of cognition and
adaptive coping behavior that are disrupted in these illnesses, and the mechanisms responsible for effective
therapeutic response in any modality, pharmacological or behavioral. Such knowledge may inform a more
targeted approach to increase therapeutic efficacy. To better study these processes, in the previous grant period
we developed, validated and characterized extinction learning in rats as a model of exposure therapy in comorbid
PTSD and depression. We demonstrated the efficacy of extinction in reversing behavioral and physiological
deficits following chronic unpredictable stress. We showed that these effects were dependent upon activity in
the medial prefrontal cortex (mPFC) during extinction for the therapeutic effects seen 24 hrs after treatment. And
we showed that the therapeutic effects of extinction were dependent on the induction of de novo protein synthesis
in the mPFC, which we believe represents the initiation of processes related to plasticity and changes in circuit
function in this brain region. In this proposal for renewal, we will characterize the precise circuit-level plasticity
and signaling mechanisms that underlie the therapeutic effects of extinction on a range of behavioral measures
modeling different dimensions of comorbid PTSD and depression after chronic unpredictable stress exposure.
 In aim 1, using a virogenetic inhibitory DREADD strategy, we will investigate the role of specific efferent
projections of the infralimbic (IL) and prelimbic (PL) sub-regions of mPFC to target regions that mediate specific
behavioral response domains relevant to comorbid PTSD and depression, and to the therapeutic efficacy of
exposure therapy. In aim 2, we will investigate the role of afferent projections to the IL and PL cortices arising
from the mediodorsal thalamus and the ventral hippocampus in the therapeutic effects of extinction. We will also
test the hypothesis that BDNF signaling during extinction, induced specifically by activity in ventral hippocampal
afferent, initiates signal transduction processes in the mPFC necessary for the plasticity that is ultimately
responsible for the beneficial behavioral effects seen 24 hours after extinction. With this knowledge, in aim 3,
we will then test a rational adjunct treatment strategy combining a sub-effective extinction protocol with a sub-
e...

## Key facts

- **NIH application ID:** 10250669
- **Project number:** 2I01BX003512-05A2
- **Recipient organization:** SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
- **Principal Investigator:** David A Morilak
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2017-01-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10250669

## Citation

> US National Institutes of Health, RePORTER application 10250669, Treating PTSD and depression: Mechanisms of pharmacotherapy and psychotherapy in rats (2I01BX003512-05A2). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10250669. Licensed CC0.

---

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