# Enhancement of exposure therapy, modeled by extinction learning in rats, using transcranial direct current stimulation

> **NIH VA I01** · SOUTH TEXAS VETERANS HEALTH CARE SYSTEM · 2024 · —

## Abstract

Posttraumatic stress disorder (PTSD) is debilitating illness, impairing health, well-being, and productivity of
25-30% of combat veterans. Currently approved drug treatments are largely ineffective. Behavioral therapies,
including exposure therapy, can be more effective for some, but efficacy is also limited by many factors, including
the duration of treatment and the anxiety and distress it can produce, both of which contribute to a high rate of
attrition. Many patients cease treatment before completing the full course of therapy, so anything that can
enhance the effectiveness of exposure therapy and accelerate clinical improvement would be highly beneficial.
Thus, there is a need to identify and investigate new adjunct treatments that can enhance the efficacy of
exposure therapy. Exposure therapy is a form of extinction learning. To investigate the mechanisms underlying
the beneficial effects of exposure therapy and identify potential entry points for intervention that may enhance it,
we have developed extinction learning as a valid preclinical model of exposure therapy in rats. We showed that
treating rats with extinction learning was effective in reversing several behaviors impaired by exposure to chronic
unpredictable stress (CUS), that model key symptom dimensions of PTSD. However, our standard 16-trial
extinction model was fully effective in restoring stress-impaired behaviors that resemble components of PTSD,
which made it impossible to detect improvements in efficacy. Therefore, to be able to detect increased efficacy
with adjunct treatment, we developed a sub-effective 8-trial extinction procedure, and validated its ability to detect
improved efficacy with adjunct treatment. The first purpose of the current renewal is to now use this sub-effective
extinction model to test transcranial direct current stimulation (tDCS), a non-invasive, painless, easily
administered neuromodulatory treatment, as a potential adjunct strategy to enhance the plasticity induced by
extinction in the infralimbic cortex (IL), a sub-region of ventral medial prefrontal cortex (mPFC) that has been
implicated in PTSD. Aim 1 will test the hypotheses that tDCS will: a) enhance the efficacy of 8-tone extinction in
restoring cognitive flexibility mediated in IL, and improve other PTSD-like behaviors mediated by sub-cortical
targets of IL; b) enhance the rescue of afferent-evoked responses in mPFC that have been compromised by
CUS; and c) enhance the activation by 8-tone extinction of mPFC and its downstream targets that mediate
stress-compromised behaviors. We previously showed that activation of the projection from ventral hippocampus
(vHipp) to mPFC is important for the therapeutic effects of extinction. In the last grant period, L-655,708, a
negative allosteric modulator of a5-GABAA receptors expressed selectively in the hippocampus, was studied as
a potential therapy for stress-impaired behaviors. Because a5 NAMs increase vHipp activity, in Aim 2 we will
test TB2100...

## Key facts

- **NIH application ID:** 10916833
- **Project number:** 2I01BX000559-12A2
- **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:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2011-01-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10916833

## Citation

> US National Institutes of Health, RePORTER application 10916833, Enhancement of exposure therapy, modeled by extinction learning in rats, using transcranial direct current stimulation (2I01BX000559-12A2). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10916833. Licensed CC0.

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