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Astrocyte-Neuron Interaction in the Dorsal Striatum and Ethanol-Seeking Behaviors

Award Number: R01AA029258
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Astrocyte-Neuron Interaction in the Dorsal Striatum and Ethanol-Seeking Behaviors - Project Summary The main goal of our proposal is to investigate the role of astrocytes in the dorsal striatum (DS), which regulates goal-directed and habitual reward-seeking behaviors in mice. The DS has a critical role in shaping goal-directed and habitual actions, which are the main determinants for the reward-dependent decision-making process. Astrocytic processes in close proximity to the synaptic milieu clear glutamate, which protects neurons from excitotoxicity. Our recent studies revealed that chemogenetic activation of dorsomedial striatum (DMS) astrocyte enhances the activities of indirect medium spiny neurons (iMSNs), but not dMSNs in the DMS. The DMS is known to regulate goal-directed actions as lesions or inactivation of DMS render actions habitual instead of goal-directed. Conversely, the dorsolateral striatum (DLS) is necessary for habitual actions as lesions or temporary inactivation of DLS bias behavior towards goal- directed actions. Since GABAergic iMSNs project to external globus pallidus (GPe), we also examined the role of astrocyte in the GPe. Interestingly, both chemogenetic astrocyte activation of DMS and GPe promotes transition from habitual to goal-directed ethanol-seeking behaviors. However, the precise role of astrocytes in the DMS-GPe or DLS-GPe circuits in regulating habitual ethanol seeking behavior has not been explored. Based on our findings, we hypothesize that astrocyte activities differentially regulate MSNs activities in the DMS and DLS, thereby determine goal-directed and habitual ethanol-seeking behaviors. To investigate this hypothesis, we propose three aims. First, we will determine how activation of astrocyte activities differentially regulates the alcohol-induced changes in glutamatergic and GABAergic signaling of the DMS and DLS. Second, we plan to examine the role of DMS and DLS astrocyte activation in goal- directed or habitual ethanol-seeking behaviors. Finally, we will investigate the effect of ablation of DMS- GPe and DLS-GPe circuits in goal-directed or habitual ethanol-seeking behaviors. Our study will elucidate the neural mechanisms encoding goal-directed and habitual ethanol-containing reward-seeking behaviors. We will provide a rational path for the development of new therapeutic methods for the treatment of AUD.


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 = $357,750 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	000	5	5/1/2025	NON-COMPETING CONTINUATION	$357,750
														Subtotal = $357,750

Issue Date FY: 2024 ( Subtotal = $376,091 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	000	4	2/24/2024	NON-COMPETING CONTINUATION	$321,975
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	003	4	7/23/2024	SUPPLEMENT FOR EXPANSION	-$113,397
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	001	4	3/26/2024	SUPPLEMENT FOR EXPANSION	$131,738
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	002	4	5/10/2024	NON-COMPETING CONTINUATION	$35,775
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	004	4	7/24/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $376,091

Issue Date FY: 2023 ( Subtotal = $357,750 )
2023	2023	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	000	3	2/24/2023	NON-COMPETING CONTINUATION	$357,750
														Subtotal = $357,750

Issue Date FY: 2022 ( Subtotal = $357,750 )
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	001	2	6/20/2022	NON-COMPETING CONTINUATION	$35,775
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	000	2	3/2/2022	NON-COMPETING CONTINUATION	$321,975
														Subtotal = $357,750

Issue Date FY: 2021 ( Subtotal = $357,750 )
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	000	1	5/31/2021	NEW	$357,750
														Subtotal = $357,750

Grand Total All Awards = $1,807,091

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Astrocyte-Neuron Interaction in the Dorsal Striatum and Ethanol-Seeking Behaviors

Award Number: R01AA029258

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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