# Sex Differences in the Neurobiological Significance of Orexin Stress Signaling

> **NIH NIH R15** · UNIVERSITY OF SOUTH DAKOTA · 2021 · $427,255

## Abstract

Recent metanalyses suggest that neurocircuits in males and females are not equally affected by stress
exposure, such that females have demonstrably higher rates of psychological disorders, and males, higher
rates of suicide. Genetic markers associated with stress responsiveness, expressed in basolateral
amygdala (BLA) and prefrontal cortex (PFC), may help explain differences in females and males. The
prelimbic (PrL) PFC innervates specific cells in the anterior BLA (aBLA) expressing the Rspo2 genetic
marker, forming a pro-stress circuit. A parallel anti-stress circuit also exists connecting infralimbic (IL) PFC
neurons carrying the Drd1 genetic marker, to posterior BLA (pBLA) cells that express Ppp1r1b. These two
microcircuits produce variable stress responsivity, that when favoring pro-stress PrL-aBLA/Rspo2 activity,
results in exaggerated stress reactivity and potentially leads to affective psychological disorders. These
microcircuits are modulated by orexins/hypocretins (Orx) by means of Orx1 and Orx2 receptor subtypes,
specifically localized to pro-stress (PrL-aBLA/Rspo2 Orx1) and anti-stress (IL/Drd1-pBLA/Ppp1r1b Orx2)
elements of this circuitry. Activation of BLA Orx1 and Orx2 receptors are also functionally opposed, and
differentially trigger enhanced or inhibited stress responsiveness. The data suggest that interplay between
Orx1- and Orx2-stimulated circuits control the output of stress responsivity. Females have elevated
expression of Orx2 receptors. The focus is to determine whether the balance between activation of these
two microcircuits, and the sexual differences in stress responsivity, is governed by density of Orx2 anti-
stress receptors and which specific molecular cascades are present. We propose to examine the molecular
systems that appear downstream of Orx2 receptor activation, by which stress responsivity is reduced, in
two stable phenotypes: stress-reactive individuals that exhibit enhanced fear conditioning, and individuals
that exhibit active avoidance of stress. Aim 1: BLA and PFC Orx2 receptors modify PLC to mToR signaling.
The intracellular molecular signaling pathway, PLC or mToR, triggered by Orx2 determines the functional
outcome. Measuring PLC and mToR transcripts and proteins using laser microdissection of genetically
marked cell-specific PrL-aBLA/Rspo2 pro-stress and IL/Drd1-pBLA/Ppp1r1b anti-stress microcircuits will
allow phenotype, sexual, and circuit level disparity in activation. Another molecular change that will produce
sexual distinctions in stress responsivity is Orx2 activity homologously increasing the number of available
Orx2 receptors. Aim 2: Up-regulation of BLA Orx2 receptor expression reduces stress responsiveness in
females compared with males. We posit that differences between females and males stem from molecular
actions that increase Orx2 receptors strategically placed to inhibit pro-stress circuitry, especially in those
individuals that exhibit enhanced fear conditioning. Changeable molecular...

## Key facts

- **NIH application ID:** 10291077
- **Project number:** 1R15MH125306-01A1
- **Recipient organization:** UNIVERSITY OF SOUTH DAKOTA
- **Principal Investigator:** CLIFF H SUMMERS
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $427,255
- **Award type:** 1
- **Project period:** 2021-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10291077

## Citation

> US National Institutes of Health, RePORTER application 10291077, Sex Differences in the Neurobiological Significance of Orexin Stress Signaling (1R15MH125306-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10291077. Licensed CC0.

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