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Functional and anatomical characterization of the striosomal system

Award Number: R01MH060379
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/03/2000
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Functional and anatomical characterization of the striosomal system - The striatum is critically important to health and well-being, and to our ability to adapt behaviorally to our environment. As the great input-output center of the basal ganglia, the striatum receives projections from all parts of the neocortex including mood-related areas connecting to specialized striatal zones called striosomes, and sensorimotor areas projecting to action control circuits, involving mainly the other compartment, the matrix. Crucially, the striatum is the main target of the tract input carrying dopamine (DA) from the substantia nigra pars compacta (SNc), which degenerates in Parkinson’s disease. Striosomes project back to the SNc, so as to form the nigro-striato-nigral loop famed in the clinic. The DA SNc cells not only modulate movement initiation, but also mood, vigor, learning and decision-making. The ‘return’ striatonigral tract mainly arises in striosomes. Thus striosomes are strategically wired to directly influence these DA neurons. Due to formidable technical hurdles, the functions of this critical part of the nigro-striato-nigral loop remain unclear. Yet, there are clues about the functions. Previous studies suggest that striosomes could process mood-related cortical information and send the resultant neural signals to DA neurons in SNc. Models suggest, among others, that striosomes could serve as critics in actor-critic reinforcement learning models. However, critically lacking is the understanding of the relationship between the striosome-matrix axis—striosomes (S) receiving limbic, and the surrounding matrix (M) receiving sensorimotor/associative cortical inputs—and the D1-D2 axis of the striatum—composed of direct (D1) movement-promoting striatal projection neurons (dSPNs) and indirect (D2) movement-suppressing iSPNs, due to the lack of experimental tools to dissociate the two axes. We have overcome some of the technical hurdles and propose to address these issues guided by our overarching hypotheses, that the cortico-striosomal circuit gates the state transitions of brain networks underlying mood, motivation, or vigor of action; that this circuit modulates learning processes through its powerful connections with DA-containing SNc neurons; and that striosome-dopamine circuits can adjust functional balance across distinct SPN subtypes with identities multiplexed across S-M compartments and D1-D2 pathways. We will use intersect methods in mice to dissect individual SPN subtypes according to their D1-D2 and S-M identities, DA sensors to measure DA release under the control of the striatonigral path, and chemogenetics to manipulate each component of the nigro-striato-nigral circuit so as to assess its causal role in behavior. Thus, we are fully equipped, standing on our groundworks that found that cost-benefit, approach-avoidance conflict recruit the cortico-striosomal circuit, that identified by snRNA-seq differential gene-expression patterns of individual SPN subtypes, and that have developed strategies for simultaneously recording and individually manipulating the SPN subtypes. This work is directly in line with the goals of the NIMH to advance human health and well-beings by directly addressing profoundly important gaps in knowledge about key functional circuits affected in a range of mental health disorders.


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 = $329,588 )
2025	2025	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	24	2/14/2025	NON-COMPETING CONTINUATION	$329,588
														Subtotal = $329,588

Issue Date FY: 2024 ( Subtotal = $387,750 )
2024	2024	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	23	1/12/2024	NON-COMPETING CONTINUATION	$348,975
2024	2024	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	001	23	7/22/2024	NON-COMPETING CONTINUATION	$38,775
														Subtotal = $387,750

Issue Date FY: 2023 ( Subtotal = $387,750 )
2023	2023	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	001	22	5/1/2023	NON-COMPETING CONTINUATION	$387,750
2023	2022	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	21	3/17/2023	COMPETING CONTINUATION	$0
2023	2022	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	003	21	6/29/2023	COMPETING CONTINUATION	$0
2023	2021	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	002	20	6/29/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $387,750

Issue Date FY: 2022 ( Subtotal = $387,750 )
2022	2022	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	21	3/24/2022	COMPETING CONTINUATION	$387,750
														Subtotal = $387,750

Issue Date FY: 2021 ( Subtotal = $386,750 )
2021	2021	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	20	2/12/2021	NON-COMPETING CONTINUATION	$386,750
														Subtotal = $386,750

Issue Date FY: 2020 ( Subtotal = $386,750 )
2020	2020	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	19	3/25/2020	NON-COMPETING CONTINUATION	$386,750
														Subtotal = $386,750

Issue Date FY: 2019 ( Subtotal = $386,750 )
2019	2019	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	18	3/6/2019	NON-COMPETING CONTINUATION	$386,750
														Subtotal = $386,750

Issue Date FY: 2018 ( Subtotal = $386,750 )
2018	2018	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	002	17	4/19/2018	NON-COMPETING CONTINUATION	$386,750
2018	2017	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	001	16	12/5/2017	COMPETING CONTINUATION	$68,810
2018	2016	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	15	12/5/2017	EXTENSION WITH OR WITHOUT FUNDS	-$68,810
														Subtotal = $386,750

Issue Date FY: 2017 ( Subtotal = $386,750 )
2017	2017	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	001	16	6/21/2017	COMPETING CONTINUATION	$386,750
2017	2016	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	15	6/16/2017	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $386,750

Issue Date FY: 2016 ( Subtotal = $390,609 )
2016	2016	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	15	2/9/2016	EXTENSION WITH OR WITHOUT FUNDS	$390,609
														Subtotal = $390,609

Issue Date FY: 2015 ( Subtotal = $390,918 )
2015	2015	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	14	2/10/2015	NON-COMPETING CONTINUATION	$390,918
														Subtotal = $390,918

Issue Date FY: 2014 ( Subtotal = $382,144 )
2014	2014	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	13	4/2/2014	NON-COMPETING CONTINUATION	$382,144
														Subtotal = $382,144

Issue Date FY: 2013 ( Subtotal = $367,253 )
2013	2013	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	001	12	6/27/2013	NON-COMPETING CONTINUATION	$22,953
2013	2013	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	12	2/5/2013	NON-COMPETING CONTINUATION	$344,300
														Subtotal = $367,253

Issue Date FY: 2012 ( Subtotal = $371,726 )
2012	2012	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	11	3/9/2012	COMPETING CONTINUATION	$371,726
														Subtotal = $371,726

Issue Date FY: 2011 ( Subtotal = $326,700 )
2011	2011	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	001	10	6/9/2011	NON-COMPETING CONTINUATION	$29,700
2011	2011	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	10	2/2/2011	NON-COMPETING CONTINUATION	$297,000
														Subtotal = $326,700

Issue Date FY: 2010 ( Subtotal = $330,000 )
2010	2010	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	9	1/19/2010	NON-COMPETING CONTINUATION	$330,000
														Subtotal = $330,000

Issue Date FY: 2009 ( Subtotal = $330,000 )
2009	2009	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	001	8	7/13/2009	NON-COMPETING CONTINUATION	$33,000
2009	2009	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	8	3/13/2009	NON-COMPETING CONTINUATION	$297,000
														Subtotal = $330,000

Issue Date FY: 2008 ( Subtotal = $320,105 )
2008	2008	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	7	2/15/2008	NON-COMPETING CONTINUATION	$320,105
														Subtotal = $320,105

Issue Date FY: 2007 ( Subtotal = $320,393 )
2007	2007	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	6	2/1/2007	COMPETING CONTINUATION	$320,393
														Subtotal = $320,393

Issue Date FY: 2004 ( Subtotal = $243,388 )
2004	2004	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	5	8/6/2004	NON-COMPETING CONTINUATION	$243,388
														Subtotal = $243,388

Grand Total All Awards = $8,255,093

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Functional and anatomical characterization of the striosomal system

Award Number: R01MH060379

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/03/2000

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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