Tuesday, July 1, 2025 7/1/2025

5/11 Microglial MyD88 in Mouse Models of Excessive Alcohol Intake

Award Number: U01AA029969
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/10/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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5/11 Microglial MyD88 in Mouse Models of Excessive Alcohol Intake - Abstract Repeated alcohol exposure can be a potent neuroinflammatory stimulus. Alcohol activates microglia within the brain via toll-like-receptors (TLRs); this activation leads to production of inflammatory mediators which contribute to dependence and abuse 4,5. Fast spiking parvalbumin positive (PV+) GABAergic interneurons (PVIs) are critical for normal brain function. PVIs are often surrounded by specialized extracellular matrix molecules called perineuronal nets (PNNs) which protect and buffer them from inflammation and oxidative stress. Notably, increased PNNs are implicated in alcohol use disorder (AUD), which may be due to a locking in of critical neuroplasticity mechanisms that underlie habitual behavior such as drug seeking in the face of adverse consequences 2. Our preliminary data show that mice with microglial-specific ablation of the critical TLR adaptor molecule myeloid differentiation primary response 88 [MyD88] (Cx3cr1-CreBT-MyD88f/f [hereafter called Cre+ mice ]) exhibit decreased proinflammatory responses (e.g. IL-1, TNF) to a lipopolysaccharide (LPS) injection compared to Cre- controls, as expected. Surprisingly, however, in response to LPS, male (but not female) Cre+ mice exhibit increased numbers of PVIs and PV/PNN interactions within the frontal cortex. Cre+ male mice further exhibit markedly increased alcohol intake in an acute drinking-in-the dark (DID) protocol compared to controls, consistent with findings from previous INIA-Neuroimmune projects using MyD88-/- (knockout) mice and chronic alcohol paradigms 6. Taken together, these data suggest microglia critically regulate PVI number and/or PNN envelopment in response to inflammatory signals via MyD88 signaling, and that increased PVI/PNN interactions in the absence of MyD88 may underlie increased drinking in Cre+ mice. The overall goal of this proposal is to test this hypothesis. Aim 1 will determine if microglial-MyD88 regulates the number of PVIs and/or PNN interactions directly in response to chronic alcohol by assessing the phagocytosis of PVI-specific inhibitory synapses and PNNs by microglia. Aim 2 will determine if microglial-MyD88 regulates the number of PVIs and/or PNN interactions indirectly in response to chronic alcohol by assessing the secretome of microglia and the production of PNN components by astrocytes and PVIs. Aim 3 will determine the role of PVIs and/or PNN interactions in excessive drinking behavior in mice with and without microglial MyD88 by assessing the impact of (1) degrading PNNs and (2) chemogenetic inhibition vs. activation of microglia on excessive drinking. This is an innovative new project designed to complement existing strengths of several other INIA-Neuroimmune investigators. If completed, these data would be the first to show a direct role for microglia in PVI/PNN development and their role in excessive drinking, which could lead to novel treatment options.


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 = $354,555 )
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Alcohol Research Programs	000	4	3/4/2025	NON-COMPETING CONTINUATION	$354,555
														Subtotal = $354,555

Issue Date FY: 2024 ( Subtotal = $394,308 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Alcohol Research Programs	000	3	2/5/2024	NON-COMPETING CONTINUATION	$354,878
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Alcohol Research Programs	001	3	5/21/2024	NON-COMPETING CONTINUATION	$39,430
														Subtotal = $394,308

Issue Date FY: 2023 ( Subtotal = $394,654 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Alcohol Research Programs	000	2	2/1/2023	NON-COMPETING CONTINUATION	$394,654
														Subtotal = $394,654

Issue Date FY: 2022 ( Subtotal = $394,988 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Alcohol Research Programs	001	1	3/22/2022	NEW	$0
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Alcohol Research Programs	000	1	2/9/2022	NEW	$394,988
														Subtotal = $394,988

Grand Total All Awards = $1,538,505

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5/11 Microglial MyD88 in Mouse Models of Excessive Alcohol Intake

Award Number: U01AA029969

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 02/10/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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