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Organization and Circuit Interactions of Thalamocortical Attentional Networks in Health and Disease

Award Number: R01MH118500
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Organization and Circuit Interactions of Thalamocortical Attentional Networks in Health and Disease - Thalamocortical networks consist of two parallel circuits that involve distinct thalamic and cortical neurons and have distinct nuclear, areal, and laminar distribution. A more specialized ‘core’ system consists of excitatory thalamic neurons that focally target the middle cortical layers, as classically described for sensory systems. A more diffuse ‘matrix’ system consists of excitatory thalamic neurons that broadly target the upper layers of multiple areas, integrating information across cortices. Growing evidence suggests differential involvement of core and matrix systems in the vital processes of sleep, attentional modulation and states of vigilance, multimodal integration, cognition, emotion, and action, and in the disruption of these processes in schizophrenia. However, little is known about the organization of these networks in the human brain and the distinct mechanisms of disruption of core vs matrix systems in schizophrenia and associated sleep disorders. Our overarching hypothesis is that core and matrix thalamocortical circuits vary in parallel with the systematic variation of cortical laminar structure and exhibit graded connection patterns, function, and dysfunction, such that the most plastic thalamocortical circuits allow functional flexibility but are also more vulnerable to disruption in psychiatric diseases, and prominently in schizophrenia. Based on this, we will test the hypotheses that core and matrix pathways differ in density, structure, termination pattern, and interactions with cortical inhibitory interneurons in prefrontal cortices and exhibit distinct pathophysiology in schizophrenia, with matrix circuits primarily affected along with their preferential innervation of limbic medial and orbital prefrontal areas, whereas core circuits will mostly affect lateral prefrontal cortices. The goal of the proposed studies is to investigate the unknown circuit interactions between core and matrix thalamocortical systems in humans, then compare and cross-validate these findings in rhesus macaques, using archival postmortem tissue and identical approaches, so we can then reliably study their pathophysiology in schizophrenia. We will use high-resolution microscopy to label and image pathways at multiple scales, from system to synapse in the brains of both species and will additionally use tract- tracing in monkeys and neurochemical labeling to cross-validate circuit interactions. We will study the density, caliber, and myelination of axons in core vs matrix pathways and estimate the g-ratio, which is directly associated with the speed of conduction, and thus reflects axonal function and integrity. Then we will use the novel quantitative circuit data to computationally model core and matrix thalamocortical network dynamics and disruptions in schizophrenia and associated sleep disorders. Our proposed studies are predicated on primate specializations that likely underlie normal and pathologic function through thalamus and cortex in primates, including humans. The proposed studies will yield novel data on the as-yet unknown neurochemical and synaptic organization and interactions of core and matrix circuits in primates, which critically affect the dynamics of sensory, affective, and goal directed processes, and are disrupted heterogeneously in schizophrenia.


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 = $685,487 )
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Mental Health Research Grants	001	7	3/5/2025	NON-COMPETING CONTINUATION	$685,487
2025	2023	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Mental Health Research Grants	000	5	3/3/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $685,487

Issue Date FY: 2024 ( Subtotal = $824,998 )
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Mental Health Research Grants	001	6	6/30/2024	COMPETING CONTINUATION	$824,998
2024	2023	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Mental Health Research Grants	000	5	6/21/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $824,998

Issue Date FY: 2023 ( Subtotal = $460,899 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Mental Health Research Grants	000	5	12/6/2022	NON-COMPETING CONTINUATION	$414,810
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Mental Health Research Grants	001	5	2/17/2023	NON-COMPETING CONTINUATION	$46,089
														Subtotal = $460,899

Issue Date FY: 2022 ( Subtotal = $460,899 )
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Mental Health Research Grants	000	4	12/3/2021	NON-COMPETING CONTINUATION	$414,809
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Mental Health Research Grants	001	4	5/23/2022	NON-COMPETING CONTINUATION	$46,090
														Subtotal = $460,899

Issue Date FY: 2021 ( Subtotal = $460,899 )
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Mental Health Research Grants	001	3	4/14/2021	NON-COMPETING CONTINUATION	$46,090
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Mental Health Research Grants	000	3	12/11/2020	NON-COMPETING CONTINUATION	$414,809
														Subtotal = $460,899

Issue Date FY: 2020 ( Subtotal = $485,158 )
2020	2020	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Mental Health Research Grants	001	2	3/11/2020	NON-COMPETING CONTINUATION	$48,516
2020	2020	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Mental Health Research Grants	000	2	12/13/2019	NON-COMPETING CONTINUATION	$436,642
														Subtotal = $485,158

Issue Date FY: 2019 ( Subtotal = $505,158 )
2019	2019	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Mental Health Research Grants	001	1	9/24/2019	NEW	$0
2019	2019	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Mental Health Research Grants	000	1	2/15/2019	NEW	$505,158
														Subtotal = $505,158

Grand Total All Awards = $3,883,498

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Organization and Circuit Interactions of Thalamocortical Attentional Networks in Health and Disease

Award Number: R01MH118500

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/15/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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