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The Heart and the Mind: An Integrative Approach to Brain-Body Interactions in the Zebrafish

Award Number: U19NS104653
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/25/2017
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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The Heart and the Mind: An Integrative Approach to Brain-Body Interactions in the Zebrafish - Our current U19 has focused primarily on Exteroception, which can be defined as the accumulated sensory experience originating from events in the outside world. However, all neural computation takes place in the context of the body, which is subject to the dynamics of hunger, fatigue, motivation and diurnal cycles. The information that reaches the brain from the organs and receptors inside of the body, summarized under the umbrella term of Interoception, is therefore overlaid onto exteroceptive computations. This adds behavioral variability to any animal task, from changing vigor to altering valence of rewards to vetoing responses altogether. To better understand such embodied computation, we will first incorporate cardiac and respiratory variables that dynamically report basic internal states to our standard behavioral classification methods, and we will include detailed characterization and modeling of the autonomic and intracardiac nervous system in our functional imaging studies. Finally, as a critical resource for the description and validation of the generated neural circuit models, we will create a complete body-and-brain connectome of the larval zebrafish. This research plan is aligned with the three levels of understanding articulated by David Marr more than thirty years ago, who emphasized the importance of considering Evolutionary Principles, Algorithmic Representation and Hardware Implementation as a unified and interconnected approach for understanding the brain. Following this framework, we first try to isolate aspects of fish behavior that are adapted to their native environment and context. We next use a variety of controlled behavioral assays to extract the algorithmic rules that govern the dynamics of modular sensorimotor transformations, and that are augmented by knowledge about internal state changes as reflected by observed modulation of cardiac and respiratory activity. To characterize the hardware implementation of these explicit and latent behavioral algorithms, we propose to first measure cellular activity using brain-wide functional light imaging of the central, the autonomic and the intracardiac nervous systems (CNS, ANS and ICNS). We next will use these comprehensive datasets to generate realistic circuit models of the observed dynamics. These models will then guide a series of circuit dissection experiments, such as optogenetic perturbations of specific cell types, targeted patch-clamp physiology and sparse connectomics tracing, allowing us to validate, extend, and constrain our models. We note that this approach also affords us the opportunity to discover new circuit elements and circuit motifs, and novel ways to implement computational algorithms by the brain. Another extension of our current U19 is the addition of a dynamical modeling framework for these behaviors, where animals can interact flexibly with the environment, and where we consider multiple time scales of interaction. We believe that this constitutes a different and perhaps ethologically more relevant approach when compared to the highly constrained, simplified and repetitive challenges we used before. Further, this framework is well suited in characterizing the continuous process of cardiac control and its interaction with behavioral modulation.


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 = $3,370,159 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	9/2/2025	NON-COMPETING CONTINUATION	$3,370,159
														Subtotal = $3,370,159

Issue Date FY: 2024 ( Subtotal = $3,299,514 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	8	8/28/2024	NON-COMPETING CONTINUATION	$0
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	8/16/2024	NON-COMPETING CONTINUATION	$3,299,514
2024	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	3/11/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $3,299,514

Issue Date FY: 2023 ( Subtotal = $3,778,811 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	7	9/4/2023	SUPPLEMENT FOR EXPANSION	$59,801
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	7	9/1/2023	NON-COMPETING CONTINUATION	$3,719,010
2023	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	8/30/2023	COMPETING CONTINUATION	$79,513
2023	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	8/30/2023	NON-COMPETING CONTINUATION	-$79,513
														Subtotal = $3,778,811

Issue Date FY: 2022 ( Subtotal = $3,820,430 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	8/19/2022	COMPETING CONTINUATION	$3,820,430
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	9/19/2022	COMPETING CONTINUATION	$0
														Subtotal = $3,820,430

Issue Date FY: 2021 ( Subtotal = $3,629,683 )
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	8/17/2021	NON-COMPETING CONTINUATION	$3,629,683
2021	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/31/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $3,629,683

Issue Date FY: 2020 ( Subtotal = $3,661,127 )
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	8/18/2020	NON-COMPETING CONTINUATION	$3,661,127
														Subtotal = $3,661,127

Issue Date FY: 2019 ( Subtotal = $3,663,406 )
2019	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	8/2/2019	NON-COMPETING CONTINUATION	$3,663,406
														Subtotal = $3,663,406

Issue Date FY: 2018 ( Subtotal = $3,665,549 )
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/31/2018	NON-COMPETING CONTINUATION	$3,665,549
														Subtotal = $3,665,549

Issue Date FY: 2017 ( Subtotal = $3,797,509 )
2017	2017	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/22/2017	NEW	$3,797,509
														Subtotal = $3,797,509

Grand Total All Awards = $32,686,188

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The Heart and the Mind: An Integrative Approach to Brain-Body Interactions in the Zebrafish

Award Number: U19NS104653

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/25/2017

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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