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Sex Divergent Circuits Governing Stress Effects on Reward Learning

Award Number: R01MH142833
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/02/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Sex Divergent Circuits Governing Stress Effects on Reward Learning - SUMMARY Stress impacts learning processes resulting in long-lasting changes in cue-driven behavior. While prior studies have largely focused on stress-enhanced fear learning, human studies demonstrate that stress also regulates reward learning, with subsequent effects on extinction and decision making. Importantly, stress can modulate behavior in a sex-dependent manner. Therefore, to mitigate the maladaptive consequences of stress, we must first identify how stress impacts neural circuits controlling reward learning in both males and females. To address this, we developed a procedure where rats are exposed to stress prior to training on an associative learning task with food rewards. Stress produced a persistent increase in conditioned responding when administered to males as well as females in metestrus/diestrus. In contrast, females experiencing stress during proestrus/estrus exhibited a persistent reduction in conditioned responding. Furthermore, stress produced subsequent extinction learning alterations only in males. Therefore, the net effect of stress on cue-driven actions are wholly determined by sex and the estrous cycle. In this proposal, we will identify the intrinsic neurobiological factors that gate the effect of stress on cue-driven behavior (Aims 1-2) and establish targets to prevent the maladaptive effects of stress (Aim 3). Our data collectively indicate that stress regulates reward learning by engaging distinct dopamine circuits in males and females. We found that stress-enhanced conditioned responding in males is accompanied by elevated dopamine release in the ventral lateral striatum (VLS). In contrast, preliminary data in females indicate the cycle-dependent effect of stress on behavior is linked to dopamine in the ventral medial striatum (VMS). Here, we will use optogenetics coupled with in vivo dopamine recordings to determine if stress controls reward learning by impacting VLS dopamine in males and VMS dopamine in females (Aim 1-Wanat). Since stress produces functional changes in dopamine neurons in a sex- and estrous-specific manner, we will delineate how stress alters the electrophysiological and molecular phenotypes of VLS- and VMS-projecting dopamine neurons (Aim 2-Beckstead). Dopamine neuron activity is known to fluctuate throughout the estrous cycle in females, with firing greatest during estrus when estradiol levels are high. Since estradiol levels peak during proestrus/estrus and fall during metestrus/diestrus, we will determine if estradiol acts on dopamine neurons to gate the effect of stress on reward learning (Aim 3-Beckstead and Wanat). In sum, this proposal will determine how stress engages reward circuits to regulate cue-driven behaviors in males and females.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $798,616 )
2026	2026	THE UNIVERSITY OF TEXAS AT SAN ANTONIO	1 UTSA CIR	SAN ANTONIO	TX	78249	BEXAR	USA	Mental Health Research Grants	000	1	9/4/2026	NEW	$798,616
														Subtotal = $798,616

Grand Total All Awards = $798,616

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Sex Divergent Circuits Governing Stress Effects on Reward Learning

Award Number: R01MH142833

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/02/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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