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Developmental programming of stress-sensitive neural circuits underlying social behavior

Award Number: R01MH135937
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/22/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Developmental programming of stress-sensitive neural circuits underlying social behavior - Project summary Exposure to social stressors is an important risk factor for the development of mental illnesses such as anxiety, depression, and post-traumatic stress disorder. Stress-related mental illnesses are more common in women than men, and these differences arise during adolescence. Androgens work to change brain structure and function during adolescence, how this transformation impacts behavior is poorly understood. We will test the hypothesis that the activation of androgen receptors during puberty permanently programs neural circuits of social behavior to be less sensitive to social stress. Our studies will be conducted using California mice (Peromyscus californicus), an ideal model system for studying adolescent development. In this species adolescence lasts almost twice as long as conventional mice and rats, which will allow us to apply advanced neuroscience and molecular methods in way that would be difficult or impossible in standard model systems. In adult California mice, females but not males exposed to social defeat stress orient towards an unfamiliar target mouse while simultaneously avoiding it, a behavior we define as social vigilance. However, in juvenile California mice, social stress increases social vigilance in both males and females. In males, prepubertal castration results in female-typical social vigilance responses in adulthood, while pubertal treatment with the non-aromatizable androgen dihydrotestosterone reduces sensitivity to social stress in both males and females. We will test the hypothesis that activation of the androgen receptor (AR) during puberty permanently programs neural circuits of social behavior to be less sensitive to social stress. First, we will use CRISPR-based gene editing to knock-down AR expression in ventral hippocampus (vHPC) neurons projecting to the bed nucleus of the stria terminalis (BNST) or nucleus accumbens (NAc). The prolonged development of this species will allow us to knock-down AR expression before the onset of adolescent development. Second, we will use state-of-the-art sequencing methods to identify AR genomic binding sites in the vHPC and assess maturation of hippocampal cells with single-cell resolution. Finally, we will determine how circuit-specific AR knock-down alters membrane excitability of vHPC neurons using whole- cell slice electrophysiology. These analyses bridge the gap between the molecular and behavioral data in the other aims. Our team is ideally suited to execute these studies. Dr. Trainor is a leader in developing the California mouse stress model and open access tools. Dr. Tollkuhn is a leader in the application of modern sequencing methods to identify the molecular mechanisms of sexual differentiation of the brain. Dr. Robison is a leading expert in the use of electrophysiological approaches to study the impact of stress on neural circuits. The proposed studies will be the first to identify androgen-dependent molecular pathways activated during adolescent development in neural circuits that drive translationally relevant behavioral responses to stress.


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 = $753,229 )
2026	2026	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Mental Health Research Grants	000	3	2/19/2026	NON-COMPETING CONTINUATION	$753,229
														Subtotal = $753,229

Issue Date FY: 2025 ( Subtotal = $757,764 )
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Mental Health Research Grants	000	2	1/24/2025	NON-COMPETING CONTINUATION	$644,100
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Mental Health Research Grants	001	2	9/19/2025	NON-COMPETING CONTINUATION	$113,664
														Subtotal = $757,764

Issue Date FY: 2024 ( Subtotal = $788,612 )
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Mental Health Research Grants	000	1	4/22/2024	NEW	$712,794
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Mental Health Research Grants	001	1	6/7/2024	NEW	$75,818
														Subtotal = $788,612

Grand Total All Awards = $2,299,605

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Developmental programming of stress-sensitive neural circuits underlying social behavior

Award Number: R01MH135937

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/22/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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