# Investigating the role of synaptic inhibition in the midline thalamus plays in the selection of defensive behaviors

> **NIH NIH FI2** · U.S. NATIONAL INSTITUTE OF MENTAL HEALTH · 2022 · —

## Abstract

PROJECT SUMMARY
Maladaptive avoidance behaviors underlie several anxiety-related disorders, many of which are not treated
appropriately. Surprisingly, the neural mechanisms that underlie avoidance are poorly understood. Here, I seek
to expand on recent evidence from our laboratory which supports the idea that anatomical projections from the
posterior paraventricular nucleus of the thalamus (pPVT) to the nucleus accumbens (pPVTNAc) drive active
avoidance behavior. Specifically, I will test the hypothesis that dynamic modulation of inhibitory inputs onto
pPVTNAc cells shapes the selection of defensive behaviors. This prediction is based on the notion that in an
active avoidance behavioral task failure to perform avoidance is associated with the expression of freezing
behavior (a defensive response elicited by imminent threats) and the concomitant attenuation of pPVTNAc
activity, suggesting that these two events are related. The central amygdala (CeA), a region composed of
GABAergic neurons, is critical for driving conditioned defensive responses to imminent threat, including freezing.
Notably, recent anatomical evidence shows that the CeA sends projections to the pPVT (CeApPVT), making
it a suitable candidate for mediating defensive transitions via the PVT. However, what role CeApPVT
projections and GABAergic inhibition in general play in the selection of defensive behaviors has received little
attention. Therefore, the objective of the proposed research is to independently assess the contribution of
GABAergic transmission and the role of CeApPVT projections in the emergence and selection of defensive
behaviors. My central hypothesis is that the CeA inhibits pPVTNAc neurons to suppress active avoidance and
promote freezing. In preliminary studies we observed that GABAergic transmission onto pPVTNAc cells was
suppressed during avoidance and increased during freezing. Additionally, we found that the CeA sends inhibitory
projections to the pPVT. To expand on these observations, I have outlined the following research plan. In Aim 1,
I will utilize the recently developed pharmacological tool DART in parallel with genetic knockout and
overexpression techniques to provide two independent methods of suppressing and enhancing GABAergic
signaling onto pPVTNAC cells. This will test the prediction that GABAergic inhibition of pPVTNAc neurons
suppresses avoidance behaviors, and that in contrast disinhibition of this pathway promotes avoidance. In Aim
2, I will combine ex vivo electrophysiology with in vivo optogenetics and fiber photometry to determine whether
CeA inhibition of the pPVT shapes the selection of defensive behaviors by inhibiting pPVTNAc cells. Execution
of this proposal will allow me to learn, further develop, and master the use of relevant neuroscience techniques,
such as AAV-mediated target vector delivery for the monitoring and manipulation of neural circuits, and in vivo
optogenetics and fiber photometry. In addition, these finding...

## Key facts

- **NIH application ID:** 10500079
- **Project number:** 1FI2GM146653-01
- **Recipient organization:** U.S. NATIONAL INSTITUTE OF MENTAL HEALTH
- **Principal Investigator:** John Joseph O'Malley
- **Activity code:** FI2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10500079

## Citation

> US National Institutes of Health, RePORTER application 10500079, Investigating the role of synaptic inhibition in the midline thalamus plays in the selection of defensive behaviors (1FI2GM146653-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10500079. Licensed CC0.

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