# Role of locus coeruleus-paraventricular thalamic projections in social threat processing

> **NIH NIH R21** · CHILDREN'S HOSP OF PHILADELPHIA · 2024 · $218,784

## Abstract

SUMMARY
The paraventricular nucleus of the thalamus (PVT) regulates motivated behaviors including behaviors induced
by stress exposure. The PVT receives extensive projections from the locus coeruleus (LC), an important
component of the stress response system that mediates arousal and cognitive aspects of the stress response
and the primary source of norepinephrine (NE) in the brain. Thus, both the PVT and the LC play important
roles in arousal and attention during stress, thus contributing to positive and negative valence states, RDoC
constructs important in multiple psychopathologies. However, the role of LC projections to the PVT in
mediating responses to stress has received little to no attention. Our previous work on the PVT in rats
showed that the posterior division of the PVT (pPVT) preferentially regulates responses to repeated stress.
Further, preliminary data suggest that neuronal activity in the pPVT is higher in animals susceptible to
repeated social defeat compared to resilient and control animals. Susceptibility to defeat is associated with
greater stimulatory inputs to LC cells. These data suggest that activity of LC projections to pPVT are
enhanced in individuals susceptible to the effects of repeated social defeat. Based on preliminary and
published data, the central hypothesis of this exploratory/developmental proposal is that elevations in
activity of LC/NE projections to pPVT lead to susceptibility to social defeat. Both male and female mice
will be studied. Experiments will use the GRABNE sensor to assess NE release through fiber photometry in
the pPVT during repeated social defeat and will use chemogenetics to inhibit pPVT-projecting LC cells in
DBH-cre mice. We expect that NE release in the pPVT will be highest after defeat in mice that go on to be
socially avoidant/susceptible and that inhibition of pPVT-projecting LC-NE cells during social defeat will
reduce social avoidance thereby reducing susceptibility to defeat. We further expect greater NE release and
less of an impact of LC-pPVT inhibition in female compared to male mice. The completion of these studies
will provide the first information on how LC-NE inputs to the PVT regulate stress responses and the
first information on sex differences in functions of these inputs. Elucidating the impact of NE release in
the pPVT and of activity in pPVT-projecting LC cells will provide new mechanistic insights into individual
differences in the response to stress.

## Key facts

- **NIH application ID:** 10798232
- **Project number:** 5R21MH131932-02
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** SEEMA BHATNAGAR
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $218,784
- **Award type:** 5
- **Project period:** 2023-03-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10798232

## Citation

> US National Institutes of Health, RePORTER application 10798232, Role of locus coeruleus-paraventricular thalamic projections in social threat processing (5R21MH131932-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10798232. Licensed CC0.

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