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Defining the functional organization of cerebellar output circuits that control feeding behavior

Award Number: R01DK124801
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary In addition to motor and classical conditioning functions, the cerebellum contributes to motivation and reward processes that underlie complex behaviors. To influence non-motor processes, such as feeding and food- seeking behaviors, it is thought that the cerebellum modulates cortical and subcortical feeding centers. The only path through which the cerebellum can influence feeding control is through cerebellar output circuits in the deep cerebellar nuclei (DCN). Yet little is known about how DCN circuits are organized and whether distinct pathways are dedicated to feeding and food-seeking behaviors. The recent identification of discrete subsets of DCN neurons that project to thalamic, subthalamic and hypothalamic brain regions indicates the existence of neural subtype organization to cerebellar output. Based on published and preliminary data, the primary hypotheses of this proposal are that: 1) distinct DCN-mediated pathways project to known feeding centers to influence food intake; and 2) these features identify distinct DCN circuits essential for feeding and/or metabolism; and finally, 3) dedicated DCN-mediated pathways are engaged during feeding, and influence the neural activity of specific neuronal subtypes in key feeding centers. This proposal will test these hypotheses through three aims. Aim 1 delineates distinctions in target selectivity of specific DCN circuits. We will employ conditional viral tracing, and genetic fate-mapping methods to define the output connectivity of DCN subpopulations to feeding centers (paraventricular nucleus, lateral hypothalamus, arcuate nucleus and zona incerta), which we hypothesize influence feeding behavior. Additionally, we will determine if major subclasses of arcuate neurons (e.g. POMC or AgRP) are linked to the DCN with specific Cre-lines and trans-synaptic rabies virus. In Aim 2, we will define the role of DCN circuits in feeding control through optogenetic activation and silencing of discrete neuronal subpopulations in the DCN. Specifically, we will examine how selective neural manipulation of anatomically- defined DCN pathways influences food intake and metabolism, and dissociate output pathways for motor control. Finally, the experiments in Aim 3 will determine the activity profile of discrete DCN neuronal subpopulations, and how activity in these subpopulations changes neural activity of known feeding circuits in freely moving mice during food intake using deep-brain imaging. By defining the anatomical and functional organization of cerebellar output pathways, and their activity dynamics involved in feeding behavior, these aims provide insight into more general mechanisms of how cerebellum controls motivation and reward circuits, and establish a framework for exploring the more enigmatic cognitive roles of the cerebellum. A more comprehensive understanding of cerebellar function will provide greater insight into how neurological disorders and injuries disrupt food intake, and lay the groundwork for development of novel treatment strategies for obesity and eating 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: 2024 ( Subtotal = $508,855 )
2024	2024	THE SCINTILLON INSTITUTE	6868 NANCY RIDGE DR	SAN DIEGO	CA	92121	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/20/2024	NON-COMPETING CONTINUATION	$508,855
														Subtotal = $508,855

Issue Date FY: 2023 ( Subtotal = $568,735 )
2023	2023	SCINTILLON INSTITUTE	6868 NANCY RIDGE DR	SAN DIEGO	CA	92121	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/24/2023	NON-COMPETING CONTINUATION	$568,735
2023	2022	SCINTILLON INSTITUTE	6868 NANCY RIDGE DR	SAN DIEGO	CA	92121	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	6/8/2023	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $568,735

Issue Date FY: 2022 ( Subtotal = $986,461 )
2022	2022	SCINTILLON INSTITUTE,THE	6868 NANCY RIDGE DR	SAN DIEGO	CA	92121	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	8/23/2022	SUPPLEMENT FOR EXPANSION	$428,564
2022	2022	SCINTILLON INSTITUTE,THE	6868 NANCY RIDGE DR	SAN DIEGO	CA	92121	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	4/6/2022	NON-COMPETING CONTINUATION	$55,790
2022	2022	SCINTILLON INSTITUTE,THE	6868 NANCY RIDGE DR	SAN DIEGO	CA	92121	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/27/2022	NON-COMPETING CONTINUATION	$502,107
														Subtotal = $986,461

Issue Date FY: 2021 ( Subtotal = $579,227 )
2021	2021	SCINTILLON INSTITUTE,THE	6868 NANCY RIDGE DR	SAN DIEGO	CA	92121	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/15/2021	NEW	$579,227
														Subtotal = $579,227

Grand Total All Awards = $2,643,278

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Defining the functional organization of cerebellar output circuits that control feeding behavior

Award Number: R01DK124801

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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