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Experimental and modeling investigations into microcircuit, cellular and subcellular determinants of hippocampal ensemble recruitment to contextual representations

Award Number: R01MH124867
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Although neuroscience has recently provided a great deal of information about how neurons represent and encode behaviorally relevant information at the population level, the fundamental question of how individual neurons are selected and recruited to memory coding ensembles has been difficult to address. Our group has been at the forefront of developing experimental methods that allow high-resolution monitoring of identified neurons, monitoring subcellular events in dendrites and axons, all of which can now be done in awake behaving animals. We propose to use these experimental methods in combination with circuit modeling to provide a deep understanding of how the neurons in the mouse hippocampus are recruited to neural ensembles during contextual memory encoding. Because much is known about the excitatory and inhibitory cell types involved and their network connections at the main CA1 output node of the rodent hippocampus, this circuit represents a tractable target for the first major effort to elucidate the microcircuit/cellular/subcellular mechanisms of cell- selection at a mechanistic level comparable to that achieved in the study of simple invertebrate systems. Aim 1 is aimed at characterizing collective inhibitory dynamics in CA1 during contextual learning. Aim 2 deals with the events that occur in cell bodies and dendrites of CA1 pyramidal cells during contextual leaning, including targeted manipulation in identified inhibitory cells types and understanding the fundamental network architecture by which cellular activity patterns conducive to memory encoding are regulated. Aim 3 deals with how the information that is encoded during contextual learning converges onto individual CA1 pyramidal cells during contextual learning. Finally, Aim 4 builds upon recent work indicating that CA1 pyramidal cells can be reliably recruited to memory coding ensembles through a plasticity mechanism that requires dendritic spikes and somatic bursting activity. We will use optogenetic means to create artificial firing fields in neurons and determine whether these cells can encode context-related and reinforcement related signals; we will also interfere with local circuit inhibition to determine whether cell selection through plasticity is regulated by inhibition. Throughout the proposal we will leverage unprecedentedly close interplay between experiment and computation by using a biophysically detailed model of the hippocampal CA1 microcircuit. To the extent that the model can account for the experimental observations, we can use it to understand underlying network principles and design interventional experiments to validate this understanding. To the extent that the model cannot explain results, it will help point us to aspects of network function that require further elucidation. Taken together, Aims 1-4 provide a tractable path to a major breakthrough in understanding how cognitively important neural activity dynamics are generated at the microcircuit-, cellular- and subcellular-levels.


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: 2024 ( Subtotal = $612,763 )
2024	2024	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	4	11/3/2023	NON-COMPETING CONTINUATION	$612,763
														Subtotal = $612,763

Issue Date FY: 2023 ( Subtotal = $647,053 )
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	001	3	3/1/2023	NON-COMPETING CONTINUATION	$64,705
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	3	11/22/2022	NON-COMPETING CONTINUATION	$582,348
														Subtotal = $647,053

Issue Date FY: 2022 ( Subtotal = $683,002 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	001	2	6/21/2022	NON-COMPETING CONTINUATION	$68,301
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	2	12/6/2021	NON-COMPETING CONTINUATION	$614,701
														Subtotal = $683,002

Issue Date FY: 2021 ( Subtotal = $737,969 )
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	1	12/23/2020	NEW	$629,598
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	001	1	5/10/2021	NEW	$108,371
														Subtotal = $737,969

Grand Total All Awards = $2,680,787

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Experimental and modeling investigations into microcircuit, cellular and subcellular determinants of hippocampal ensemble recruitment to contextual representations

Award Number: R01MH124867

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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