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Transcriptional basis of stereotyped neural architectures

Award Number: R00MH128772
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Transcriptional basis of stereotyped neural architectures - ABSTRACT Recent advances in high-resolution volumetric imaging and single-cell RNA sequencing have enabled the characterization of neuronal diversity and the genetic programs that specify identity. Meanwhile, our understanding of the diversity of synapses and their genetic underpinnings remains limited. Decoding the genetic programs responsible for the formation and maintenance of neural architectures can help us understand the functional role of synapses in the brain and offer entry points towards designing genetic targets for the treatment of mental health disorders related to brain connectivity. Based on the evidence of conservation of neural architectures in a wide range of neural systems and strong preliminary results in C. elegans, I hypothesize that synaptic connectivity is genetically encoded. Specifically, I hypothesize that complimentary gene combinations specify pre-synaptic neurons and their post-synaptic neural partners (resembling a key-and-lock combination). Single-cell RNA sequencing and single-cell resolution connectivity datasets make this hypothesis testable. I will test this hypothesis in two parallel aims using the computational Network Differential Gene Expression (nDGE) tool I have pioneered. This technique integrates single-cell resolution gene expression data with single-cell resolution connectivity to assign statistical significance to combinatorial genetic patterns enriched in synaptically connected neurons. Across two aims, I will investigate the transcriptional encoding of the structural and functional connectome of C. elegans (Aim 1) and the micro-connectivity of pyramidal cells and interneurons in the CA1 region of the rodent hippocampus (Aim 2). To accomplish these aims, I will build additional computational tools to extract a functional connectome in C. elegans (Aim 1b) and harmonize spatial transcriptomic data with functional calcium imaging data in the rodent hippocampus (Aim 2a). Together, these aims will provide two substantial entry points towards elucidating the genetic programming of neural architectures across multiple animal nervous systems. Additionally, these aims will generate valuable computational tools for the benefit of the molecular and systems neuroscience community as a whole. The multiple animal approach will ensure the robustness and biological validity of the computational models and tools that I will introduce to the neuroscience community. During the K99 phase of this award, occurring within Columbia's vibrant neuroscience community, I will be mentored by Dr. Liam Paninski, Dr. Oliver Hobert, and Dr. Attila Losonczy while consulting with Dr. Larry Abbott, and Dr. Ashok Litwin-Kumar. These professors represent diverse expertise in computational, molecular, and systems-level neuroscience in C. elegans and rodent models. They will guide me to hone my computational skills further and provide needed training in molecular and circuit neurobiology during my transition to becoming an independent computational investigator at the interface of molecular and systems neuroscience.


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 = $207,857 )
2025	2025	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Mental Health Research Grants	000	4	4/17/2025	NON-COMPETING CONTINUATION	$207,857
														Subtotal = $207,857

Issue Date FY: 2024 ( Subtotal = $322,046 )
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Mental Health Research Grants	001	3	4/26/2024	EXTENSION WITH OR WITHOUT FUNDS	$0
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Mental Health Research Grants	002	3	8/8/2024	EXTENSION WITH OR WITHOUT FUNDS	$77,509
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Mental Health Research Grants	000	3	4/25/2024	EXTENSION WITH OR WITHOUT FUNDS	$244,537
														Subtotal = $322,046

Grand Total All Awards = $529,903

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Transcriptional basis of stereotyped neural architectures

Award Number: R00MH128772

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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