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Connectivity, activity, and function of a hypothalamic pathway in female social behaviors

Award Number: R01HD104565
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Connectivity, activity, and function of a hypothalamic pathway in female social behaviors - Project Summary/Abstract We propose to understand at cellular and circuit levels how Kiss1-expressing neurons in the anteroventral periventricular hypothalamus (AVPV) regulate female mating behavior. The ventromedial hypothalamus ventrolateralis (VMHvl) and AVPV have been shown to influence diverse female reproductive behaviors and physiology. We recently showed that presynaptic termini of progesterone receptor (PR)-expressing neurons of the VMHvl (Pvl) exhibit significant plasticity in the AVPV across the ovarian cycle. Optogenetic inhibition of this projection of Pvl neurons to the AVPV essentially eliminates female sexual behavior. In preliminary studies, we find that the subset of AVPV neurons expressing the neuropeptide Kisspeptin (Kiss1) are innervated by Pvl neurons, and that Kiss1+ AVPV (Kavpv) neurons are important for regulating female sexual behavior in vivo. Our proposed work is distinct from previous AVPV studies in that we will perform our unbiased circuit mapping, imaging, and functional studies focusing exclusively on Kavpv neurons. The AVPV is heterogeneous not only molecularly but also functionally, and brain-wide connections and behavioral contributions of distinct AVPV neuronal subtypes remain poorly understood. Moreover, and in contrast to prior work in this region, our studies will assess Kavpv neuronal connectivity and function across distinct phases of the female cycle, thereby shedding new light into how physiologically distinct hormonal states influence Kavpv neurons and behavior. In Aim 1, we will map the presynaptic inputs and postsynaptic projections of Kavpv neurons in an unbiased, brain- wide manner and validate the synaptic connectivity across the estrus cycle using electrophysiology and in vivo 2-photon imaging. In Aim 2, we will determine the activity patterns of Kavpv neurons in female during sexual and other social behaviors in freely moving animals. In Aim 3, we will test whether acute manipulation of Kavpv neurons is essential for and, even when females are in a hormonal state that renders them unreceptive, sufficient to induce female sexual behavior. The two PIs have complementary expertise for the proposed studies, and the team is therefore well suited for this project. In summary, if successful our studies will uncover mechanisms whereby an ovarian hormone sensitive hypothalamic circuit regulates female sexual and reproductive behaviors. Health Relatedness: It is well known that ovarian sex hormones can influence behavioral, cognitive, and emotive states in women. How these hormones regulate distinct behaviors and other states at the level of specific neurons and synapses is poorly understood. In addition, translational research has identified diverse neuro- psychiatric illnesses that are influenced by these hormones. Our basic research proposal, if successful, will provide new insights into how ovarian hormone sensitive hypothalamic pathways regulate social interactions in healthy animal models, and they have the potential to suggest new research avenues in translational work focused on ovarian sex hormone influenced neural circuits in disease states.


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 = $449,817 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	000	5	3/18/2025	NON-COMPETING CONTINUATION	$449,817
														Subtotal = $449,817

Issue Date FY: 2024 ( Subtotal = $494,797 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	000	4	1/26/2024	NON-COMPETING CONTINUATION	$449,817
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	001	4	5/16/2024	NON-COMPETING CONTINUATION	$44,980
														Subtotal = $494,797

Issue Date FY: 2023 ( Subtotal = $500,442 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	000	3	2/22/2023	NON-COMPETING CONTINUATION	$500,442
														Subtotal = $500,442

Issue Date FY: 2022 ( Subtotal = $501,743 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	001	2	4/25/2022	NON-COMPETING CONTINUATION	$50,177
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	000	2	2/11/2022	NON-COMPETING CONTINUATION	$451,566
														Subtotal = $501,743

Issue Date FY: 2021 ( Subtotal = $503,593 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	000	1	4/29/2021	NEW	$506,569
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	001	1	6/23/2021	NEW	-$2,976
														Subtotal = $503,593

Grand Total All Awards = $2,450,392

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Connectivity, activity, and function of a hypothalamic pathway in female social behaviors

Award Number: R01HD104565

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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