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Interneuron circadian rhythms and tau-dependent network excitability in Alzheimer's disease pathogenesis

Award Number: F31AG092133
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2025
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Interneuron circadian rhythms and tau-dependent network excitability in Alzheimer's disease pathogenesis - ABSTRACT Alzheimer’s disease (AD) is the most common neurodegenerative disease, affecting more than 6 million Americans. As AD only continues to increase in prevalence, new therapeutic approaches are needed to combat this disease. A combination of clinical, neuroimaging, and neurophysiological studies have provided converging evidence that network hyperexcitability, including mostly subclinical epileptiform activity, is an important aspect of the early stages of AD. Many AD models exhibit similar network hyperexcitability that is dependent on both APP/Aβ and tau. Because network hyperexcitability can potentially be targeted by a variety of treatment approaches, a better understanding of the underlying mechanisms is needed. Circadian variation is a prominent aspect of AD-related network hyperexcitability, which occurs mainly during the inactive phase in both AD patients and mouse models. Emerging data from both human and animal models indicate that neural excitability is under circadian control. Diurnal changes in inhibition may drive this, as there is a relative increase in levels of cortical inhibition during the inactive phase corresponding to lower cortical excitability. Parvalbumin- positive (PV) interneurons are one of the most abundant interneuron types in the hippocampus and cortex; however, they are one of the multiple subtypes of inhibitory interneurons derived from the medial ganglionic eminence that interact to maintain cortical network dynamics. Preliminary data suggests altered clock gene expression in PV interneurons, increased epileptiform activity, and behavioral disinhibition in the hAPPJ20 model. Many important questions remain, including the functional and molecular mechanisms in MGE-derived inhibitory interneurons that contribute to circadian- and tau-mediated EA in AD models with increased levels of APP/Aβ. Thus, the current proposal will test the novel concept that circadian rhythms in cortical MGE-derived interneurons play a critical role in modulating network excitability and behavior. My overarching hypothesis is that altered clock gene rhythms in MGE-CINs contribute to network hyperexcitability and behavioral abnormalities, which can be corrected by tau reduction. I will test this hypothesis using single-molecule fluorescent in situ hybridization to quantify clock-gene transcript expression, electroencephalography to assess network hyperexcitability, and machine learning pipelines to analyze open-field videos for behavior. For these studies I will use hAPPJ20 mice, a commonly used model of AD with overexpression of APP & Aβ crossed with Tau+/- mice for my experimental groups for Aim 1. I will use Lhx6-Cre mice crossed with Bmalfl/fl to create a line of mice with the circadian clock ablated in only cortical MGE-interneurons, which will then again be crossed with Tau+/- for Aim 2 experiments. Overall, the work proposed will provide insights into the circadian mechanisms driving network hyperexcitability and behavioral changes in AD.


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: 2026 ( Subtotal = $44,404 )
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	2	8/28/2026	NON-COMPETING CONTINUATION	$44,404
														Subtotal = $44,404

Issue Date FY: 2025 ( Subtotal = $40,828 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	1	8/20/2025	NEW	$40,828
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	001	1	8/20/2025	NEW	$0
														Subtotal = $40,828

Grand Total All Awards = $85,232

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Interneuron circadian rhythms and tau-dependent network excitability in Alzheimer's disease pathogenesis

Award Number: F31AG092133

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2025

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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