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Assessing the contributions of the ventral subiculum to the nucleus accumbens shell projection in a novel ethanol self-administration choice paradigm

Award Number: F31AA032154
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Assessing the contributions of the ventral subiculum to the nucleus accumbens shell projection in a novel ethanol self-administration choice paradigm - PROJECT SUMMARY The progression of recreational drinking to alcohol use disorder (AUD) is characterized by increased seeking behavior and loss of intake control, with individuals continuing to use alcohol despite experiencing negative consequences. While one operant paradigm has been developed to assess operant alcohol self-administration in a manner that can procedurally separate the appetitive (seeking) vs. consummatory facets of behavior, no studies have yet leveraged this model to investigate these independent aspects of alcohol self-administration in the presence of an alternative reinforcer, an astonishing gap in the literature given that six of the eleven diagnostic criteria of AUD are related to the individual allocating behavior towards alcohol compared to alternative reinforcers. The paucity of translational models of operant alcohol choice self-administration may contribute to the continued mystery of the circuitry underlying maladaptive alcohol seeking, precluding the discovery of therapeutic targets. The present study proposes a novel operant self-administration choice paradigm which will be used to assess the role that the ventral subiculum of the hippocampus to the nucleus accumbens shell projection (vSub-NAc) has on alcohol seeking. Preliminary findings from our lab demonstrate that chemogenetic inhibition of the vSub-NAc produces a uniform reduction in alcohol seeking with minimal effects on consumption without altering seeking or intake of a sucrose solution in a separate cohort of animals. Both our lab and others have additionally shown that chronic intermittent ethanol (CIE) not only produces heightened excitability in vSub, but also results in escalation of seeking and intake. Despite these advances, it remains unknown how the vSub-NAc projection modulates operant choice behavior when a subject can respond for ethanol and an alternative reinforcer, whether the behavioral outcome of vSub-NAc inhibition would differ between CIE-exposed subjects vs. AIR controls, and how sex as a biological variable might mediate these synaptic and behavioral consequences. Therefore, the overarching goal of this proposal is to implement a multidisciplinary approach to test the hypotheses that CIE results in reallocation of behavior towards alcohol and away from an alternative reinforcer via hyperexcitation of the vSub-NAc projection, suggesting that inhibition of this projection will redirect operant choice behavior towards an alternative reinforcer. Aim 1 will employ optogenetic techniques to selectively activate or inhibit the vSub-NAc during alcohol vs. sucrose operant choice self-administration. In Aim 2, we will use CIE as a model of alcohol dependence coupled with optogenetic circuit manipulations to determine if this circuit has unique behavioral effects when assessed in alcohol dependent vs. non-dependent subjects. These studies may identify a novel behavioral mechanism through which the vSub-NAc exerts control over alcohol self-administration, with the potential to provide further evidence that targeting this circuit may have therapeutic value in treating 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 = $49,538 )
2025	2025	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	2	8/20/2025	NON-COMPETING CONTINUATION	$49,538
														Subtotal = $49,538

Issue Date FY: 2024 ( Subtotal = $48,974 )
2024	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	1	8/27/2024	NEW	$48,974
2024	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	001	1	8/27/2024	NEW	$0
														Subtotal = $48,974

Grand Total All Awards = $98,512

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Assessing the contributions of the ventral subiculum to the nucleus accumbens shell projection in a novel ethanol self-administration choice paradigm

Award Number: F31AA032154

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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