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The molecular and cellular basis of cortical interneuron divergence

Award Number: R37MH071679
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/13/2005
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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The molecular and cellular basis of cortical interneuron divergence - Project Summary In this grant we propose three aims focused on exploring the predictions of these gene regulatory networks (GRN) by examining how critical transcription factors influence parvalbumin (PV) and somatostatin (SST) cortical interneurons (cINs) at early and late points in development (1a), as well as explore the role of candidate disease genes that affect these populations (1b). In the next two aims we then focus upon SST cINs as they settle within particular cortex laminae to explore how extrinsic signals contribute to their diversity (2a,b) how mutations in the laminar specific genes Fezf2 and Tbr1 affect SST cIN lamination, as well as using these methods in the context of our gene regulatory networks (GRN) strategy to identify molecules that affects these events(3a,b). This will allow us to test our hypothesis that cINs emerges from a combination of a genetic program initiated upon them becoming postmitotic combined with non-autonomous signals from pyramidal neurons at their settling position within cortical laminae. A chief goal of my laboratory is to determine how changes in gene regulation create cortical interneuron diversity and how perturbations in these programs result in brain disease. By joining efforts with the Bonneau laboratory, whose expertise is in computational biology, we propose to both create and test GRNs for parvalbumin and somatostatin cortical interneurons across development. Combining this with the Fishell laboratory’s expertise in development, genetics and circuit formation, we will explore in aims 2 and 3 the mechanisms by which non- autonomous cues from pyramidal neurons shape developmental programs in SST cINs, as well as their synaptic connectivity. Together, this grant represents a broad scale effort to both develop and test the robustness of GRNs by applying them to understanding gene regulation in developing cortical interneurons, as well as to determine the extrinsic environmental signals from pyramidal cells that shape both the development and connectivity of developing interneurons. From our preliminary data it is evident that canonical cortical circuits are much more precise and specific to particular subtypes. By defining their relationships, as well as the molecular mechanisms that dictate their synaptic specificity, this work will greatly increase both our understanding of cINs, as well as the microcircuits they contribute to. This in turn will greatly extend our understanding of how discrete cIN and pyramidal neurons interact in the obligate lock and key mechanisms that allow their assembly.


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: 2026 ( Subtotal = $825,250 )
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	21	2/6/2026	NON-COMPETING CONTINUATION	$825,250
														Subtotal = $825,250

Issue Date FY: 2025 ( Subtotal = $825,250 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	001	20	9/19/2025	NON-COMPETING CONTINUATION	$123,788
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	20	12/18/2024	NON-COMPETING CONTINUATION	$701,462
														Subtotal = $825,250

Issue Date FY: 2024 ( Subtotal = $825,250 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	001	19	7/9/2024	NON-COMPETING CONTINUATION	$82,525
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	19	1/3/2024	NON-COMPETING CONTINUATION	$742,725
														Subtotal = $825,250

Issue Date FY: 2023 ( Subtotal = $825,250 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	001	18	1/26/2023	NON-COMPETING CONTINUATION	$82,525
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	18	12/21/2022	NON-COMPETING CONTINUATION	$742,725
														Subtotal = $825,250

Issue Date FY: 2022 ( Subtotal = $824,438 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	002	17	6/29/2022	COMPETING CONTINUATION	$0
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	001	17	6/27/2022	COMPETING CONTINUATION	$82,443
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	17	3/1/2022	COMPETING CONTINUATION	$741,995
														Subtotal = $824,438

Grand Total All Awards = $4,125,438

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The molecular and cellular basis of cortical interneuron divergence

Award Number: R37MH071679

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/13/2005

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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