# Examining orexinergic modulation of the paraventricular nucleus of the thalamus as a novel therapeutic for PTSD and comorbid psychosis

> **NIH NIH F31** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2022 · $33,372

## Abstract

Project Abstract
Post-traumatic stress disorder (PTSD) is a prevalent condition that afflicts approximately 8% of the United States
population. In addition to core symptoms of the disorder, up to 64% of individuals diagnosed with PTSD
experience symptoms of psychosis, such as hallucinations and delusions. Although the incidence of this
comorbidity is high, treatment for PTSD and comorbid psychosis remains inadequate. However, recent work has
demonstrated the antipsychotic potential of orexin receptor antagonists in a rodent model used to study PTSD.
Selective and nonselective orexin receptor antagonists, when administered systemically, can alleviate
psychosis-like neurophysiological and behavioral deficits in a rodent model used to study PTSD. Orexin
receptors are expressed throughout the brain but the paraventricular nucleus of the thalamus (PVT) receives the
highest concentration of orexin fibers, suggesting orexin receptor antagonists can significantly inhibit activity of
the PVT. It has been shown that chemogenetic activation of projections from the PVT to the nucleus accumbens
(NAc) increase dopamine neuron activity in the ventral tegmental area, which underlies psychosis-like behavior.
Further, the PVT is a stress-sensitive region and discrete projections from the PVT to the NAc become activated
following stressful events. Taken together, these data suggest that stress increases the activity of PVT NAc
projections and this heightened activity results in an increase in downstream dopamine neuron activity. Orexin
receptors are highly expressed within the PVT; therefore, it is further hypothesized that orexin receptor
antagonists alleviate psychosis-like behavior by inhibiting the activity of PVT NAc projections following stress.
In the current proposal two-day inescapable footshock will be used to induce stress-related pathophysiology in
Sprague Dawley rats. Aim 1 will test the hypothesis that footshock stress-induced increases in the firing rate of
PVT NAc projecting neurons are reversible by selective orexin receptor antagonists. Aim 2 will test the
hypothesis that inhibition of PVT NAc projections will normalize stress-induced increases in dopamine neuron
activity and reverse deficits in prepulse inhibition of startle. The proposed studies will examine the role of
PVT NAc projections in mediating psychosis-like behavior and examine the direct effect of selective orexin
receptor antagonists on PVT NAc projections, following stress. Ultimately this proposal aims to uncover novel
therapeutic targets that will alleviate symptoms of psychosis associated with PTSD.
My long-term goal is to become an independent neuroscientist that studies circuit-level alterations contributing
to psychiatric disorders. The research plan described above will provide me with scientific training in techniques,
such as fiber photometry and chemogenetics, that I will utilize throughout my career to examine and manipulate
neuronal circuits. Further, I will present data...

## Key facts

- **NIH application ID:** 10465407
- **Project number:** 1F31MH127890-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Hannah Reiley
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $33,372
- **Award type:** 1
- **Project period:** 2022-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10465407

## Citation

> US National Institutes of Health, RePORTER application 10465407, Examining orexinergic modulation of the paraventricular nucleus of the thalamus as a novel therapeutic for PTSD and comorbid psychosis (1F31MH127890-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10465407. Licensed CC0.

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