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Genetic Dissection of Catecholaminergic Innervation of the Cognitive Cerebellum

Award Number: R01MH116883
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Genetic Dissection of Catecholaminergic Innervation of the Cognitive Cerebellum - Studies in humans and non-human primates have identified a region of the dentate nucleus of the cerebellum (DCN), or lateral nucleus in rodents (LCN), which is activated during performance of cognitive tasks involving complex spatial and sequential planning. We have previously shown that the dopamine D1 receptor marks a population of neurons in the LCN with similar spatial distribution and regulates cognitive performance on several tasks related to attention and working memory, and has connections with other parts of the brain that are classically involved in these functions. The DCN is implicated in cognitive function in humans with psychiatric illnesses, but virtually nothing is known about its basic anatomical and functional organization. Unraveling this will set the stage for precision therapeutics in the cognitive domain, an area where we have few options to offer patients. We hypothesized that the locus ceruleus is the principal source of both dopamine and norepinephrine release in LCN, catecholamines are required for cerebellar enhancement of attention and working memory tasks, and locus ceruleus neurons release catecholamines in a phasic manner. We have mapped projections of the LC to DCN, and have found that when we electrically stimulate the LC, we can observe catecholamine release in the LCN with fast scan cyclic voltammetry in anesthetized animals. We have also found that when we turn off tyrosine hydroxylase expression in the LCN, we get abnormal performance on sensory discrimination, working memory, and impulsive behaviors. Here we propose to establish the basic electrophysiological, anatomical, and behavioral function of these pathways using Cre driver mouse lines in combination with advanced techniques in viral-based circuit dissection. Successful completion of our proposed aims will provide novel insight into the basic organization of the LCN and establish a framework for novel, precision therapeutics to assist patients with cognitive dysfunction.


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 = -$56,026 )
2025	2022	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Mental Health Research Grants	000	5	10/21/2024	NON-COMPETING CONTINUATION	-$56,026
														Subtotal = -$56,026

Issue Date FY: 2022 ( Subtotal = $326,930 )
2022	2022	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Mental Health Research Grants	000	5	6/22/2022	NON-COMPETING CONTINUATION	$326,930
														Subtotal = $326,930

Issue Date FY: 2021 ( Subtotal = $327,321 )
2021	2021	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Mental Health Research Grants	000	4	6/8/2021	NON-COMPETING CONTINUATION	$327,321
														Subtotal = $327,321

Issue Date FY: 2020 ( Subtotal = $662,397 )
2020	2020	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Mental Health Research Grants	002	3	7/24/2020	NON-COMPETING CONTINUATION	$327,689
2020	2020	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Mental Health Research Grants	003	3	7/31/2020	SUPPLEMENT FOR EXPANSION	$334,708
2020	2019	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Mental Health Research Grants	001	2	3/23/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$34,283
2020	2018	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Mental Health Research Grants	000	1	3/23/2020	NEW	-$34,283
														Subtotal = $662,397

Issue Date FY: 2019 ( Subtotal = $333,448 )
2019	2019	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Mental Health Research Grants	000	2	7/27/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$333,448
2019	2018	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Mental Health Research Grants	001	1	8/1/2019	NEW	$0
														Subtotal = $333,448

Issue Date FY: 2018 ( Subtotal = $366,778 )
2018	2018	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Mental Health Research Grants	000	1	8/28/2018	NEW	$366,778
														Subtotal = $366,778

Grand Total All Awards = $1,960,848

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Genetic Dissection of Catecholaminergic Innervation of the Cognitive Cerebellum

Award Number: R01MH116883

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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