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Neurobiology of stress in the cerebellar circuitry

Award Number: R01MH129300
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/09/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Neurobiology of stress in the cerebellar circuitry - ABSTRACT Social isolation (SI) during childhood increases the susceptibility to neuropsychiatric disorders, including anxiety disorders, depression, and cognitive impairments. Limited treatment for these disorders highlights the importance of identifying new therapeutic targets. Recent evidence has underscored the role of the cerebellum in early-life stress. For example, the neonatal cerebellum contains the highest level of glucocorticoid receptor (GR) in the entire brain, indicating that the cerebellum is enriched in the molecular machinery for processing the stress response. The cerebellum is extensively connected to brain networks that are sensitive to psychological stress. However, whether and how SI stress regulates gene expression in the cerebellum to result in cerebellar dysfunction and maladaptive behaviors remain elusive. To address the knowledge gap, we isolated experimental mice in singly housed cages. They displayed behavioral changes reminiscent of high anxiety, depression, and social memory loss. Moreover, we found that SI impaired intrinsic excitability of Purkinje cells (PCs), the sole output neurons in the cerebellar cortex. And cerebellar gene expression was highly responsive to stress stimuli such as an elevation of corticosterone, a stress hormone, in rodents. These findings fuel our central hypothesis that SI impairs the cerebellar output activity by specifically affecting the intrinsic excitability of PCs; and restoring PC excitability rectifies SI-caused behavioral deficits via the cerebello-cortical networks. To test the hypothesis, we propose a multidisciplinary approach with three specific aims: (1) Determine the molecular basis of reduced PC intrinsic excitability by SI. We will employ two genome-wide RNA sequencing techniques to obtain an unbiased view of transcriptional signatures and epigenetic modifications of SI as well as to identify SI-responsive ion channels in PCs, e.g., Kv1.5. PC-specific knockout of GR will uncover the GR-dependent genomic reprogramming by SI. (2) Define the significance of PC activity in systemic response to SI. Using viral gene transfer, we will gain precise spatiotemporal control of PC excitability to test the necessity and sufficiency of cerebellar activity in mediating the system-wide response to SI. (3) Specify the cerebellum-cortex gateways underlying maladaptive behaviors of SI. Our efforts will be focused on dissecting the neural circuits that connect the cerebellum to the downstream sub/cortical areas and their contributions to the behavioral phenotypes of SI. Completion of this work will advance our understanding of the molecular, cellular and circuitry mechanisms underpinning the non-conventional role of the cerebellum in the stress response, and the results will ultimately help develop novel therapeutic strategies to improve mental health.


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: 2026 ( Subtotal = $387,500 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Mental Health Research Grants	000	5	2/20/2026	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2025 ( Subtotal = $387,500 )
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Mental Health Research Grants	000	4	4/22/2025	NON-COMPETING CONTINUATION	$329,375
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Mental Health Research Grants	001	4	9/23/2025	NON-COMPETING CONTINUATION	$58,125
														Subtotal = $387,500

Issue Date FY: 2024 ( Subtotal = $387,500 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Mental Health Research Grants	001	3	7/30/2024	NON-COMPETING CONTINUATION	$38,750
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Mental Health Research Grants	000	3	2/15/2024	NON-COMPETING CONTINUATION	$348,750
														Subtotal = $387,500

Issue Date FY: 2023 ( Subtotal = $387,500 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Mental Health Research Grants	000	2	2/10/2023	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2022 ( Subtotal = $387,500 )
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Mental Health Research Grants	000	1	5/1/2022	NEW	$387,500
														Subtotal = $387,500

Grand Total All Awards = $1,937,500

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Neurobiology of stress in the cerebellar circuitry

Award Number: R01MH129300

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/09/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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