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Synaptic Correlates of Vulnerability and Resilience to Alcohol Use Disorder

Award Number: R37AA017531
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: 05/01/2009
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Synaptic Correlates of Vulnerability and Resilience to Alcohol Use Disorder - Although individuals with anxiety disorders are more likely to develop alcohol use disorder (AUD) than healthy controls, the neural substrates responsible for this heightened risk are poorly understood. These dual diagnoses are also associated with greater symptom severity of both disorders and poor treatment outcomes. The central goal of this project is to employ neurobiological and behavioral approaches in rodent models to identify neural circuit adaptations that play a causal role in promoting increased risk of developing AUD and anxiety disorders. To that end, we have established a rodent adolescent social isolation model (aSI) that engenders many behaviors associated with greater risk of developing AUD and anxiety disorders. Relative to rats reared in groups throughout adolescence (aGH), aSI rats exhibit increases in anxiety-like behaviors, novelty responding, impulsivity, and aggression in adulthood. aSI rats also display impaired fear extinction and long-lasting increases in voluntary ethanol drinking. Neurobiological studies revealed that aSI promotes increases in the excitability of glutamatergic projection neurons in the basolateral amygdala (BLA), a brain region integral to anxiety-like and motivated behaviors, as well as increased synaptic activity in areas that receive dense innervation from the BLA. It has also recently been discovered that BLA projection neurons are not homogenous. Rather, these cells are distributed into two distinct clusters along the anterior- posterior axis and form largely non-overlapping circuits in downstream brain regions. Activation of anterior BLA (aBLA) circuits promotes aversion/anxiogenesis whereas activation of posterior BLA (pBLA) circuits elicits rewarding/anxiolytic behaviors. Based on these findings, this project will test the hypothesis that aSI shifts the excitatory/inhibitory balance between these opposing amygdala circuits, leading to excessive excitability within aBLA pathways, and that these maladaptive changes play a causal role in the “addiction vulnerable” phenotypes promoted by aSI. A secondary hypothesis to be investigated is that aSI promotes similar adaptations in male and female rats but that the behavioral phenotypes that emerge are sexually dimorphic. Additional studies will also seek to identify novel pharmacological approaches to restore normal aBLA/pBLA excitability. Collectively, this project will provide critical new insight into the circuitry underlying vulnerability to AUD and anxiety disorders and potentially lead to the identification of novel and much needed treatments for individuals suffering from these frequently co-occurring diseases. RELEVANCE (See instructions): These studies will employ a rodent model that promotes an “addiction vulnerable” phenotype to identify circuit-specific neural adaptations responsible for these behaviors. Studies will also seek to identify novel interventions to reverse these maladaptive changes. Collectively, these studies will help to identify specific neural pathways associated with AUD and comorbid anxiety disorders and potentially identify novel treatments for individuals afflicted with these diseases.


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 = -$6,790 )
2025	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	15	9/15/2025	NON-COMPETING CONTINUATION	-$6,790
														Subtotal = -$6,790

Issue Date FY: 2023 ( Subtotal = $348,750 )
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	15	5/1/2023	NON-COMPETING CONTINUATION	$348,750
														Subtotal = $348,750

Issue Date FY: 2022 ( Subtotal = $348,750 )
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	14	5/3/2022	NON-COMPETING CONTINUATION	$348,750
														Subtotal = $348,750

Issue Date FY: 2021 ( Subtotal = $348,750 )
2021	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	13	4/16/2021	NON-COMPETING CONTINUATION	$348,750
														Subtotal = $348,750

Issue Date FY: 2020 ( Subtotal = $348,750 )
2020	2020	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	12	5/6/2020	NON-COMPETING CONTINUATION	$348,750
														Subtotal = $348,750

Issue Date FY: 2019 ( Subtotal = $348,750 )
2019	2019	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	11	5/10/2019	EXTENSION WITH OR WITHOUT FUNDS	$348,750
2019	2019	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	002	11	9/10/2019	EXTENSION WITH OR WITHOUT FUNDS	$4,868
2019	2018	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	001	10	9/10/2019	NON-COMPETING CONTINUATION	-$4,868
														Subtotal = $348,750

Issue Date FY: 2018 ( Subtotal = $348,750 )
2018	2018	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	10	4/25/2018	NON-COMPETING CONTINUATION	$348,750
														Subtotal = $348,750

Issue Date FY: 2017 ( Subtotal = $348,750 )
2017	2017	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	9	4/18/2017	NON-COMPETING CONTINUATION	$313,875
2017	2017	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	001	9	7/27/2017	NON-COMPETING CONTINUATION	$34,875
														Subtotal = $348,750

Issue Date FY: 2016 ( Subtotal = $348,750 )
2016	2016	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	8	4/22/2016	NON-COMPETING CONTINUATION	$348,750
														Subtotal = $348,750

Issue Date FY: 2015 ( Subtotal = $337,923 )
2015	2015	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	7	4/17/2015	NON-COMPETING CONTINUATION	$337,923
														Subtotal = $337,923

Issue Date FY: 2014 ( Subtotal = $346,125 )
2014	2014	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	6	4/4/2014	COMPETING CONTINUATION	$334,013
2014	2014	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	001	6	4/14/2014	COMPETING CONTINUATION	$12,112
														Subtotal = $346,125

Grand Total All Awards = $3,467,258

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Synaptic Correlates of Vulnerability and Resilience to Alcohol Use Disorder

Award Number: R37AA017531

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: 05/01/2009

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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