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Molecular Mechanisms Underlying the sex-Depended Maturation of Modulatory Systems.

Award Number: R01MH130582
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Molecular Mechanisms Underlying the sex-Depended Maturation of Modulatory Systems. - PROJECT SUMMARY/ABSTRACT Males are diagnosed with autism spectrum disorder (ASD) at least four times as frequently as females, but the molecular underpinnings of male predominance remain elusive. Serotonergic (5-HT) neurons in the raphe nuclei (RN) extend axonal projections throughout the brain and regulate many essential brain function, including social behaviors. Importantly, abnormal development of the 5-HT system has been described in ASD. 5-HT signaling in the brain differs in males and females, but molecular mechanisms regulating sex-dependent 5-HT synaptic function are largely unknown. The overarching goal of this proposal is to elucidate molecular mechanisms underlying sex-dependent 5-HT synapse development and function, and determine sex-dependent effects of 5- HT on social behavior by focusing on the trans-synaptic molecules Neurexins (Nrxns), a well-accepted risk factor for neurodevelopmental disorders, including ASD. The formation and regulation of synapses are fundamental biological processes in brain development and function. These events require trans-synaptic protein-protein interactions to functionally regulate pre- and postsynaptic structures that determine synaptic function. Neurexins (Nrxns) are presynaptic cell-adhesion molecules and involved in synapse formation and regulation through trans-synaptic protein interactions with postsynaptic adhesion molecules such as neuroligins. Importantly, Nrxn and 5-HT mutant mouse models display deficits in social cognitive behaviors which are reminiscent of ASD. Despite evidence that synapse specification relies on Nrxn function and that appropriate 5-HT signaling impacts social cognitive behaviors, the role of Nrxns in 5-HT synaptic transmission and sex-dependent Nrxn functions is unknown. Our central hypothesis is that the 5-HT system undergoes sex-specific modulation or development. To test this hypothesis, we will identify how Nrxn proteins specifically shape the development and function of the 5- HT system in males and females. This will reveal a previously unexplored 5-HT system architecture that shapes 5-HT neurotransmission and behavior. We will determine i) Nrxn gene(s) important for sex-dependent development of 5-HT release in the RN and hippocampus (Aim 1), ii) Nrxn gene(s) important for sex-dependent development of 5-HT system structure in the hippocampus (Aim 2), and iii) Nrxn gene(s) important for sex- dependent social behavior (Aim 3). We anticipate that our investigation of sex-specific consequences of abnormal 5-HT signaling will profoundly advance our understanding of sex-specific behaviors. Our work should thus contribute to the elucidation of the molecular mechanisms that contribute to the male prevalence of ASD, as well as identify novel therapeutic targets to treat cognitive behavioral deficits in neurodevelopmental and neuropsychiatric disorders such as ASD.


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: 2025 ( Subtotal = $522,143 )
2025	2025	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Mental Health Research Grants	000	4	6/24/2025	NON-COMPETING CONTINUATION	$522,143
														Subtotal = $522,143

Issue Date FY: 2024 ( Subtotal = $570,144 )
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Mental Health Research Grants	000	3	7/26/2024	NON-COMPETING CONTINUATION	$570,144
														Subtotal = $570,144

Issue Date FY: 2023 ( Subtotal = $644,422 )
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Mental Health Research Grants	000	2	7/21/2023	NON-COMPETING CONTINUATION	$644,422
														Subtotal = $644,422

Issue Date FY: 2022 ( Subtotal = $655,350 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Mental Health Research Grants	000	1	8/31/2022	NEW	$655,350
														Subtotal = $655,350

Grand Total All Awards = $2,392,059

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Molecular Mechanisms Underlying the sex-Depended Maturation of Modulatory Systems.

Award Number: R01MH130582

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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