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Region-Specific, Inducible Axonal Tract-Tracing in the Brain

Award Number: R01MH070053
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2004
PERIOD OF PERFORMANCE END DATE: 10/31/2024

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Region-Specific, Inducible Axonal Tract-Tracing in the Brain - Project Summary/Abstract How neural circuits control complex behaviors is a fundamental problem in neuroscience. Optogenetic tools have transformed our ability to identify genetically marked neuronal subpopulations of interest (NSOIs), which serve as “points-of-entry” to behaviorally relevant circuits. However, a gap remains between the identification of such NSOIs, and the ability to identify and map their downstream target neurons (DTNs); identification of such DTNs is a crucial step in further tracing the circuit. To fill this gap, we will combine optogenetic stimulation of NSOIs with single-cell RNA sequencing (scRNAseq), automated immediate early gene (IEG) mapping, anatomical tracing and electrophysiology in candidate downstream target regions (CDTRs), to identify DTNs of NSOIs in the ventromedial hypothalamus (VMH), which controls aggression, defense and other emotional behaviors. The long-term goal is to elucidate the neural circuits that control decisions between complex social and defensive behaviors. The overall objective of this application is to develop a general approach for identifying and functionally characterizing DTNs of any NSOI of interest. Proof- of-principle for these methods will be obtained by applying them to NSOIs in VMH which have previously been shown to robustly control social and defensive behaviors. Preliminary studies have revealed that optogenetic stimulation of estrogen receptor-1 (Esr1)-expressing neurons in VMHvl in solitary animals can be used to map candidate DTNs throughout the brain, using serial-2-photon tomographic analysis of c-fos expression. This approach will be used to identify candidate DTNs, using scRNAseq and activity-dependent marking systems. The central objective of this proposal is to molecularly identify, and determine the behavioral function, and downstream connectivity, of DTNs to which VMHvlEsr1 neurons (and other behaviorally relevant VMH NSOIs) project. The rationale for this research is that solving this general problem is essential to making forward progress in mapping the circuitry that governs complex behaviors. In Aim 1, we will develop an approach for unbiased brain-wide mapping of DTNs activated by optogenetic stimulation of a genetically defined NSOI. In Aim 2, we will develop and apply a new method, opto-Act-seq, to transcriptomically identify activated DTNs in CDTRs. In Aim 3, we will identify projection DTNs (DTN-PNs) that are monosynaptic targets of the NSOIs, using the novel methods “opto-TRACM” and “CRACM/TRACM-guided Patch-seq”. In Aim IV, we will determine the functional role of DTN-PNs in social behaviors using “multiplex opto-TRACM.” The contribution will be to develop a new approach to identify functionally and behaviorally relevant downstream targets of NSOIs in a systematic, brain-wide manner. This contribution is significant because it allows unbiased, global mapping of downstream circuits activated by a given NSOI. The approach is innovative, because it will develop novel tools, and apply them to a behaviorally important circuit. The work proposed in this application will, therefore, both advance knowledge in this specific field, and will also provide tools for investigators study other circuits.


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 = -$116,190 )
2025	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	20	3/20/2025	NON-COMPETING CONTINUATION	-$116,190
														Subtotal = -$116,190

Issue Date FY: 2024 ( Subtotal = $634,659 )
2024	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	001	20	6/27/2024	NON-COMPETING CONTINUATION	$63,466
2024	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	20	10/26/2023	NON-COMPETING CONTINUATION	$571,193
														Subtotal = $634,659

Issue Date FY: 2023 ( Subtotal = $634,659 )
2023	2023	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	001	19	1/20/2023	NON-COMPETING CONTINUATION	$63,466
2023	2023	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	19	11/14/2022	NON-COMPETING CONTINUATION	$571,193
														Subtotal = $634,659

Issue Date FY: 2022 ( Subtotal = $634,659 )
2022	2022	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	18	10/26/2021	NON-COMPETING CONTINUATION	$571,192
2022	2022	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	001	18	5/10/2022	NON-COMPETING CONTINUATION	$63,467
														Subtotal = $634,659

Issue Date FY: 2021 ( Subtotal = $634,659 )
2021	2021	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	001	17	4/7/2021	NON-COMPETING CONTINUATION	$63,467
2021	2021	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	17	10/28/2020	NON-COMPETING CONTINUATION	$571,192
														Subtotal = $634,659

Issue Date FY: 2020 ( Subtotal = $668,063 )
2020	2020	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	002	16	3/11/2020	COMPETING CONTINUATION	$66,805
2020	2020	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	004	16	9/3/2020	COMPETING CONTINUATION	$65,423
2020	2020	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	001	16	12/13/2019	COMPETING CONTINUATION	$601,258
2020	2018	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	15	12/11/2019	NON-COMPETING CONTINUATION	$0
2020	2018	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	003	15	9/3/2020	NON-COMPETING CONTINUATION	-$65,423
														Subtotal = $668,063

Issue Date FY: 2018 ( Subtotal = $416,250 )
2018	2018	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	15	4/19/2018	NON-COMPETING CONTINUATION	$416,250
														Subtotal = $416,250

Issue Date FY: 2017 ( Subtotal = $416,250 )
2017	2017	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	001	14	8/11/2017	NON-COMPETING CONTINUATION	$41,625
2017	2017	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	14	4/11/2017	NON-COMPETING CONTINUATION	$374,625
														Subtotal = $416,250

Issue Date FY: 2016 ( Subtotal = $416,250 )
2016	2016	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	13	3/31/2016	NON-COMPETING CONTINUATION	$416,250
														Subtotal = $416,250

Issue Date FY: 2015 ( Subtotal = $416,250 )
2015	2015	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	12	7/27/2015	NON-COMPETING CONTINUATION	$416,250
														Subtotal = $416,250

Issue Date FY: 2014 ( Subtotal = $416,250 )
2014	2014	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	001	11	6/12/2014	COMPETING CONTINUATION	$416,250
2014	2013	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	10	6/7/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $416,250

Issue Date FY: 2013 ( Subtotal = $384,912 )
2013	2013	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	10	4/25/2013	NON-COMPETING CONTINUATION	$400,950
2013	2013	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	001	10	7/10/2013	NON-COMPETING CONTINUATION	-$16,038
														Subtotal = $384,912

Issue Date FY: 2012 ( Subtotal = $400,950 )
2012	2012	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	9	3/15/2012	NON-COMPETING CONTINUATION	$400,950
														Subtotal = $400,950

Issue Date FY: 2011 ( Subtotal = $400,950 )
2011	2011	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	001	8	6/30/2011	NON-COMPETING CONTINUATION	$36,450
2011	2011	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	8	3/21/2011	NON-COMPETING CONTINUATION	$364,500
														Subtotal = $400,950

Issue Date FY: 2010 ( Subtotal = $405,000 )
2010	2010	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	7	3/26/2010	NON-COMPETING CONTINUATION	$405,000
														Subtotal = $405,000

Issue Date FY: 2009 ( Subtotal = $403,437 )
2009	2009	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	001	6	5/8/2009	COMPETING CONTINUATION	$403,437
2009	2008	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	5	1/21/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $403,437

Issue Date FY: 2008 ( Subtotal = $304,755 )
2008	2008	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	5	12/18/2007	NON-COMPETING CONTINUATION	$304,755
														Subtotal = $304,755

Issue Date FY: 2007 ( Subtotal = $304,755 )
2007	2007	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	4	12/6/2006	NON-COMPETING CONTINUATION	$304,755
														Subtotal = $304,755

Issue Date FY: 2006 ( Subtotal = $313,856 ) (Continued on the next page)
Grand Total All Awards = $8,733,194

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Region-Specific, Inducible Axonal Tract-Tracing in the Brain

Award Number: R01MH070053

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2004

PERIOD OF PERFORMANCE END DATE: 10/31/2024

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