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Brain-spanning and scale-crossing circuitry mediating drive function and dysfunction

Award Number: R01MH086373
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2010
PERIOD OF PERFORMANCE END DATE: 10/31/2025

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Brain-spanning and scale-crossing circuitry mediating drive function and dysfunction - This proposal is designed to provide circuit-dynamics understanding of anhedonia, a psychiatric symptom domain of enormous clinical significance that is well-suited for study in laboratory animals. This work, alongside our recently-developed methods for obtaining brainwide cellular-resolution activity readout and control, has created a powerful and fortuitous alignment enabling us to bridge local and global neuronal dynamics, and to identify brain-spanning circuitry mediating behavioral drives, conflicts, and resolutions. In Aim 1, we identify single-cell-resolved orbitofrontal (OFC) dynamics underlying distinct consummatory behaviors. We have developed a temporally-precise alternative-choice mouse-behavioral paradigm, crucially designed for compatibility with our wide-field cellular-resolution imaging/recording methods, in which mice select among multiple motivational drives, and adjust action planning in light of internal or external context. We apply this paradigm along with our cellular-resolution readouts and analyses, beginning with addressing both hunger and thirst in OFC. We identify dynamics of motivational drive resolution both in the presence or absence of controlled internal states, and in the presence or absence of external (social) context, using our new methods; we hypothesize from prior work (Jennings et al., Nature 2019) that resolution of these conflicts will depend upon not only the motivational (internal) state of the animal but also the external context. In Aim 2, we map causal global dynamics of motivational drive conflict and resolution, quantifying the high-speed cellular-resolution brainwide circuit dynamics underlying these motivational drive interactions (drives naturally-occurring; or, to leverage our fast electrophysiological readout, instead induced in temporally- precise fashion by optogenetically driving AGRP neurons in the case of hunger, and/or SFO inputs to the MnPO in the case of thirst, using our established models and methods; Allen et al., Science 2019; Jennings et al., Nature 2019; Marshel et al., Science 2019). Identification of novel region-specific dynamics in conditions of varying motivational drive and social context will feed back to inform Aim 1 imaging workflow, already with a firm foundation from our prior work imaging OFC states corresponding to social and thirst drive interaction. In Aim 3, we define cells underlying inter-drive competition and corresponding brainwide dynamics. Multiple single cells identified by natural activity will be optogenetically targeted with our unique wide-field and high-resolution spatial light-guidance technology. We register cellular ensembles observed to be naturally and causally involved, to detailed 3D intact-tissue (STARmap) transcriptomic information from the same cells in the same organism. Alignment with wiring-based anatomy and deep molecular datastreams allow cell-type- resolved and single cell-level insight into, and targeting of, survival drive competition and resolution processes, with both basic significance and relevance to brain disease. Together, the approaches proposed here will integrate novel technology to probe causal underpinnings of key symptom domains in freely-moving mammals.


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 = $741,509 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	15	11/20/2024	NON-COMPETING CONTINUATION	$630,284
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	001	15	6/10/2025	NON-COMPETING CONTINUATION	$111,225
														Subtotal = $741,509

Issue Date FY: 2024 ( Subtotal = $756,012 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	001	14	8/14/2024	NON-COMPETING CONTINUATION	$75,600
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	14	10/20/2023	NON-COMPETING CONTINUATION	$680,412
														Subtotal = $756,012

Issue Date FY: 2023 ( Subtotal = $688,891 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	001	13	2/21/2023	NON-COMPETING CONTINUATION	$68,888
2023	2023	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	13	11/1/2022	NON-COMPETING CONTINUATION	$620,003
														Subtotal = $688,891

Issue Date FY: 2022 ( Subtotal = $734,618 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	12	10/26/2021	NON-COMPETING CONTINUATION	$661,156
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	001	12	5/11/2022	NON-COMPETING CONTINUATION	$73,462
														Subtotal = $734,618

Issue Date FY: 2021 ( Subtotal = $770,539 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	001	11	12/1/2020	COMPETING CONTINUATION	$693,487
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	002	11	5/4/2021	COMPETING CONTINUATION	$77,052
2021	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	003	10	8/9/2021	NON-COMPETING CONTINUATION	$0
2021	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	10	11/30/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $770,539

Issue Date FY: 2019 ( Subtotal = $657,120 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	10	4/6/2019	NON-COMPETING CONTINUATION	$657,120
														Subtotal = $657,120

Issue Date FY: 2018 ( Subtotal = $657,120 )
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	9	4/25/2018	NON-COMPETING CONTINUATION	$657,120
														Subtotal = $657,120

Issue Date FY: 2017 ( Subtotal = $684,489 )
2017	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	8	4/5/2017	NON-COMPETING CONTINUATION	$616,041
2017	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	001	8	8/11/2017	NON-COMPETING CONTINUATION	$68,448
														Subtotal = $684,489

Issue Date FY: 2016 ( Subtotal = $697,457 )
2016	2016	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	7	4/1/2016	NON-COMPETING CONTINUATION	$697,457
														Subtotal = $697,457

Issue Date FY: 2015 ( Subtotal = $786,259 )
2015	2015	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	6	7/15/2015	COMPETING CONTINUATION	$786,259
														Subtotal = $786,259

Issue Date FY: 2014 ( Subtotal = $388,958 )
2014	2014	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	5	4/10/2014	NON-COMPETING CONTINUATION	$388,958
														Subtotal = $388,958

Issue Date FY: 2013 ( Subtotal = $372,453 )
2013	2013	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	4	7/2/2013	NON-COMPETING CONTINUATION	$372,453
														Subtotal = $372,453

Issue Date FY: 2012 ( Subtotal = $387,018 )
2012	2012	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	3	5/21/2012	NON-COMPETING CONTINUATION	$387,018
														Subtotal = $387,018

Issue Date FY: 2011 ( Subtotal = $386,090 )
2011	2011	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	2	4/13/2011	NON-COMPETING CONTINUATION	$358,228
2011	2011	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	001	2	7/18/2011	NON-COMPETING CONTINUATION	$27,862
														Subtotal = $386,090

Issue Date FY: 2010 ( Subtotal = $397,103 )
2010	2010	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	1	7/14/2010	NEW	$397,103
														Subtotal = $397,103

Grand Total All Awards = $9,105,636

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Brain-spanning and scale-crossing circuitry mediating drive function and dysfunction

Award Number: R01MH086373

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2010

PERIOD OF PERFORMANCE END DATE: 10/31/2025

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