# Sub-thalamic modulation of learning-related dimensions of PTSD.

> **NIH NIH R01** · CHILDREN'S HOSPITAL OF LOS ANGELES · 2022 · $426,423

## Abstract

PROJECT SUMMARY
 Post-Traumatic Stress Disorder (PTSD) is a devastating neuropsychiatric disorder that develops after
trauma. The expression of debilitating fear toward stimuli previously associated with trauma even after they no
longer pose a threat is a core pathology of PTSD. Such maladaptive fear is caused by an inability to learn that
the stimuli that had been previously linked to trauma are no longer threatening when presented in safe
contexts and with no aversive outcome. These deficits in extinction learning are a highly prevalent symptom of
PTSD and significantly hamper quality of life. Efforts to reduce deficits in extinction learning have focused on
understanding the contributions of regions like the amygdala, prefrontal cortex, hippocampus and
periaqueductal gray to this process. Despite progress made from this focus, sertraline and paroxetine are the
only FDA-approved treatments for PTSD. These drugs are serotonin selective reuptake inhibitors and
antidepressants. As such they improve mood-related symptoms of PTSD but do not directly address learning-
related symptoms like deficits in extinction learning. With 24 million Americans living with PTSD, there is a
need for new therapeutic options to treat deficits in extinction learning. Dopamine plays an important role in
extinction learning and drugs that increase dopamine levels like methylphenidate and MDMA improve
extinction learning. However, these drugs are not specific to the dopaminergic system and could result in
substance abuse disorders, in part, via their action on dopaminergic cells in the ventral tegmental area. In this
proposal, we propose to study whether dopaminergic cells in a sub-thalamic nucleus called the zona incerta
(ZI) can reduce deficits in extinction learning via dopamine-mediated signaling. To test this hypothesis, we will
combine auditory fear conditioning in mice with pharmacological, molecular-genetic, viral-mediated circuit
tracing, optogenetic and chemogenetic methodology. More specifically, we will trace the connectivity of
dopaminergic cells in the ZI, manipulate the activity of these cells and perturb function of specific dopaminergic
receptors during extinction training while examining the consequence of these manipulations on extinction
learning. Additionally, we will examine how these dopaminergic cells respond to extinction training after
exposure to stress – a factor that impairs extinction learning. Successful outcomes from our work could
highlight a novel function for dopaminergic cells in the ZI in modulating fear-related extinction learning. Our
results may have translational impact by suggesting that stimulating ZI-located dopaminergic cells and
administering dopamine receptor agonists during exposure therapy may improve extinction learning and
reduce maladaptive fear that accompanies PTSD.

## Key facts

- **NIH application ID:** 10397476
- **Project number:** 5R01MH120133-05
- **Recipient organization:** CHILDREN'S HOSPITAL OF LOS ANGELES
- **Principal Investigator:** Brian George DIAS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $426,423
- **Award type:** 5
- **Project period:** 2020-09-04 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10397476

## Citation

> US National Institutes of Health, RePORTER application 10397476, Sub-thalamic modulation of learning-related dimensions of PTSD. (5R01MH120133-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10397476. Licensed CC0.

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