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Sex-dependent role of 5HT1A receptors in adult neurogenesis and hippocampal function

Award Number: R01MH122692
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Sex-dependent role of 5HT1A receptors in adult neurogenesis and hippocampal function - The serotonin (5HT) system has been widely implicated in the pathophysiology of stress-induced mood disorders, such as anxiety and major depression. Selective serotonin reuptake inhibitors (SSRIs) are the most widely used antidepressants for treating these disorders. Strongly linked to both mood disorders and the efficacy of SSRI treatment is the regulation of adult hippocampal neurogenesis, a process of generating new neurons from neural precursor cells (NPCs) in the adult dentate gyrus (DG). Importantly, stress, mood disorders, and SSRI treatment have all been shown to alter the 5HT system and influence adult hippocampal neurogenesis, suggesting that 5HT signaling is critical for regulating this process. Currently, we have limited understanding of serotonergic regulation of adult hippocampal neurogenesis, largely due to the broad action of 5HT on the neurogenic niche and lack of information on the expression patterns of 5HT receptors in adult-born cells. Identification of cell-type specific expression of 5HT receptors is challenging because 5HT is capable of binding to 14 distinct 5HT receptor subtypes. To fill these gaps in our understanding, we performed preliminary studies and demonstrated that functional 5HT1A receptors (5HT1ARs) are expressed early in adult NPCs, including type 1 neural stem cells and type 2a early neural progenitors. Strikingly, the functional 5HT1ARs in NPCs are only found in female (but not male) mice. Supporting sex-dependent expression of 5HT1ARs in NPCs, we found that selective deletion of 5HT1ARs in adult NPCs leads to a significant reduction of newborn cells derived from NPCs only in females (not males). These results suggest that expression of 5HT1ARs in NPCs are required for proper lineage progression of NPCs in a sex-dependent manner. These interesting findings sparked several immediate directions we propose to pursue: In Aim 1, we will examine cell-autonomous and sex-dependent contributions of 5HT1ARs to early neurogenic responses induced by external and serotonergic circuit stimuli; In Aim 2, we will investigate the causal role of membrane potential in regulating development of normal and 5HT1AR-deficient adult NPCs; In Aim 3, we will examine the role of 5HT1AR-deleted newborn neurons in hippocampal network activity and hippocampus-dependent behavior.


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: 2024 ( Subtotal = $571,019 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	000	5	12/6/2023	NON-COMPETING CONTINUATION	$513,918
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	001	5	7/1/2024	NON-COMPETING CONTINUATION	$57,101
														Subtotal = $571,019

Issue Date FY: 2023 ( Subtotal = $571,019 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	000	4	11/25/2022	NON-COMPETING CONTINUATION	$513,918
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	001	4	2/27/2023	NON-COMPETING CONTINUATION	$57,101
														Subtotal = $571,019

Issue Date FY: 2022 ( Subtotal = $571,019 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	001	3	6/7/2022	NON-COMPETING CONTINUATION	$57,102
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	000	3	11/22/2021	NON-COMPETING CONTINUATION	$513,917
														Subtotal = $571,019

Issue Date FY: 2021 ( Subtotal = $571,019 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	001	2	4/21/2021	NON-COMPETING CONTINUATION	$57,102
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	000	2	1/6/2021	NON-COMPETING CONTINUATION	$513,917
														Subtotal = $571,019

Issue Date FY: 2020 ( Subtotal = $601,071 )
2020	2020	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	000	1	1/30/2020	NEW	$601,071
														Subtotal = $601,071

Grand Total All Awards = $2,885,147

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Sex-dependent role of 5HT1A receptors in adult neurogenesis and hippocampal function

Award Number: R01MH122692

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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