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Prefrontal cortical microcircuit mechanisms for reciprocal interactions between arousal and ethanol consumption

Award Number: R01AA030594
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: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Prefrontal cortical microcircuit mechanisms for reciprocal interactions between arousal and ethanol consumption - Project Summary/Abstract Alcohol use disorder (AUD) exacts a major personal, economical, and societal toll. Given its high lifetime prevalence, there is an urgent need to understand neurobiological mechanisms underlying AUD pathophysiology to develop effective therapeutic strategies. Dysfunction of stress-related neuroendocrine and autonomic arousal pathways are highly associated with alcohol-related behaviors. Repeated alcohol use increases arousal. Moreover, higher arousal levels in treatment-seeking AUD patients correlates with higher rates of relapse. These findings suggest reciprocal interactions between arousal and alcohol use, such that higher basal arousal promotes alcohol drinking, which further exacerbates arousal. A challenge in understanding the neurobiological mechanisms mediating interactions between arousal and drinking is the lack of preclinical animal models that allow quantification of drinking together with longitudinal measurements of arousal and neuronal activity. We addressed this by designing a voluntary ethanol consumption paradigm for head-fixed mice combined with two- photon calcium imaging for neuronal activity recordings and pupillometry for measuring arousal. Our preliminary experiments show that the anterior cingulate cortex (ACC) subdivision of the prefrontal cortex potently increases arousal. Basal levels of arousal and arousal-related ACC activity are correlated with the amount of ethanol consumption, suggesting that the ACC contributes to arousal modulation of drinking. Cortical activity is critically shaped by inhibition from local interneurons. The vasoactive intestinal polypeptide (VIP) expressing interneurons are particularly important as they inhibit other interneurons, leading to disinhibitory excitation of the ACC. We hypothesize that ACC VIP neurons are a key node for reciprocal interactions between arousal and ethanol consumption. In Aims 1 and 2, we test the hypothesis that VIP neuron-mediated disinhibition increases arousal and ethanol consumption. In Aim 3, we will determine if repeated ethanol consumption increases VIP-mediated disinhibition, leading to hyperarousal that further promotes drinking. We will test these hypotheses using a combination of advanced approaches including multicolor two-photon calcium imaging, multicolor optogenetics, machine vision-assisted closed-loop optogenetics, and ex-vivo slice electrophysiology. Together, these mechanistic studies will determine how VIP neurons both contribute to and are affected by drinking, establishing them as a key therapeutic target for modulating drinking driven by aberrant arousal.


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 = $512,565 )
2025	2025	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Alcohol Research Programs	000	3	7/9/2025	NON-COMPETING CONTINUATION	$512,565
														Subtotal = $512,565

Issue Date FY: 2024 ( Subtotal = $512,565 )
2024	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Alcohol Research Programs	000	2	5/27/2024	NON-COMPETING CONTINUATION	$512,565
														Subtotal = $512,565

Issue Date FY: 2023 ( Subtotal = $572,188 )
2023	2023	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Alcohol Research Programs	000	1	9/1/2023	NEW	$572,188
														Subtotal = $572,188

Grand Total All Awards = $1,597,318

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Prefrontal cortical microcircuit mechanisms for reciprocal interactions between arousal and ethanol consumption

Award Number: R01AA030594

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: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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