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Developmental Mechanisms of Fine-scale Cortico-cortical Circuit Formation

Award Number: R01NS128771
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Developmental Mechanisms of Fine-scale Cortico-cortical Circuit Formation - Project Summary Cortico-cortical projection neurons (CCPNs) connect cortical areas with each other to facilitate sensory processing and execute appropriate motor actions. Defects in intra-cortical connectivity are associated with a variety of neural circuit disorders such as dyslexia, autism, and schizophrenia. Because these diseases have genetic components and potentially arise from altered brain development, it is important to understand how CCPNs know which area to target and which synaptic inputs to receive. The long-term goal of my research program is to gain mechanistic insights into cortical circuit assembly at the single cell level in an effort to understand underpinnings of neurodevelopmental disorders and develop new therapies. In doing so, we will be able to identify molecular and genetic mechanisms that link gene expression and neural activity to neuronal connectivity. The objective of this proposal is to identify mechanisms by which long-range cortico-cortical neuronal connectivity is established in the mammalian cortex using the mouse visual system as a model. Our central hypothesis is that V1 neurons, projecting to the AL (anterolateral: V1→AL) or the PM (posteromedial: V1→PM) higher visual areas, differ in timing and molecular regulation of their axonal projection development, and their input versus output connectivity is specified by two distinct rules: early specification and synaptic pruning mechanism, respectively. We will test this hypothesis with the following aims: 1) we will determine the patterns and timing of cortico-cortical neuronal projection development in the mouse visual cortex. 2) we will determine the roles of Teneurins, cell-adhesion molecules, in specifying the projection identities of V1→AL and V1→PM neurons. 3) we will determine developmental principles of ‘like-to-like’ cortico-cortical feedback circuit formation. This research is significant because elucidating the developmental mechanisms of neural circuit assembly will provide cell-type or circuit-specific therapeutic interventions for specific aspects of neurodevelopmental and psychiatric disorder phenotypes. The proposed research is innovative because we are using and developing the technical solutions to allow us to target gene expression and capture the rapid developmental connectivity dynamics of layer- and projection-specific cortical neurons. Results will provide a comprehensive understanding of how a long-range connectivity network arises at the cellular level. This new knowledge will have a positive impact on the neuroscience field as it will establish a solid foundation to provide connectivity-based therapeutic interventions for neurodevelopmental 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 = $442,732 )
2025	2025	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/30/2025	NON-COMPETING CONTINUATION	$442,732
														Subtotal = $442,732

Issue Date FY: 2024 ( Subtotal = $421,760 )
2024	2024	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/2/2024	NON-COMPETING CONTINUATION	$421,760
														Subtotal = $421,760

Issue Date FY: 2023 ( Subtotal = $440,573 )
2023	2023	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/1/2023	NEW	$440,573
														Subtotal = $440,573

Grand Total All Awards = $1,305,065

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Developmental Mechanisms of Fine-scale Cortico-cortical Circuit Formation

Award Number: R01NS128771

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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