# Molecular mechanisms underlying sub-thalamic influences on extinction learning

> **NIH NIH R01** · CHILDREN'S HOSPITAL OF LOS ANGELES · 2024 · $732,367

## Abstract

PROJECT SUMMARY. The expression of debilitating fear toward stimuli previously associated with trauma even
after they no longer pose a threat is a core pathology of Post-Traumatic Stress Disorder (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. These deficits in extinction learning are a highly prevalent dimension of PTSD and
significantly hamper quality of life. Cognitive Behavioral Therapy in isolation or in combination with
pharmacotherapies are the most widely used treatments to rescue deficits in extinction learning. Such treatments
are effective in approximately 50% of treated cases, emphasizing that there is room to more effectively rescue
deficits in extinction learning. One way to achieve this objective is to first understand how extinction learning is
facilitated by molecular and cellular processes in neural circuitry that influences extinction learning. While several
neuromodulators have been implicated in the pathophysiology of PTSD, among them, dopamine has been
shown to play a central role in extinction learning. Most of our understanding of dopaminergic influences on
extinction learning has come from a focus on the A10 cluster of dopaminergic cells in the ventral tegmental area
(VTA). However, A10 cells are one of several distinct clusters of dopaminergic cells that are evolutionarily
conserved in the mammalian brain. Gaining an appreciation for how dopaminergic cells outside of the VTA may
influence extinction learning will significantly advance our understanding of how dopaminergic signaling
modulates extinction learning. More importantly, leveraging any promise that manipulating dopaminergic cells
may hold to reduce deficits in extinction learning requires understanding molecular pathways and physiological
principles that are shared by or unique to dopaminergic cell clusters across the brain to influence extinction
learning. Our long-term goal is to determine how dopaminergic cells outside of the VTA contribute to extinction
learning and recall. To achieve this goal, our immediate objective with this proposal is to determine molecular
and cellular mechanisms in A13 dopaminergic cells in the zona incerta (ZI) that contribute to extinction learning.
To do so, we build on our work that has studied the influences of the ZI and of A13 cells on extinction learning.
We will combine auditory fear conditioning in mice with intersectional molecular-genetics, inducible RNAi,
optogenetic-based interference of protein action, and manipulation of cellular firing after activity-based tagging
of neuronal ensembles to study molecular pathways and cellular processes that afford A13 cells the ability to
influence extinction learning. This work will illuminate basic neurobiology underlying a clinically important
dimension of PTSD (extinction learning). Positive results will highlight highly conserved processes via which
many brain regions including...

## Key facts

- **NIH application ID:** 10978973
- **Project number:** 1R01MH134873-01A1
- **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:** 2024
- **Award amount:** $732,367
- **Award type:** 1
- **Project period:** 2024-08-09 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10978973

## Citation

> US National Institutes of Health, RePORTER application 10978973, Molecular mechanisms underlying sub-thalamic influences on extinction learning (1R01MH134873-01A1). Retrieved via AI Analytics 2026-06-15 from https://api.ai-analytics.org/grant/nih/10978973. Licensed CC0.

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