Molecular Determinants of Age-Related Cognitive Decline in the Basal Forebrain to Lateral Entorhinal Cortex Circuit

The entorhinal cortex (EC) is a critical mediator of cortico-hippocampal communication and thus essential for memory. Numerous studies identify the EC as the first brain region to display age-related changes such as accumulation of tau protein as related to Alzheimer’s disease (AD). Structural and functional changes to the EC have been found to precede and even predict future cognitive impairment. The EC is comprised of two subdivisions that are anatomically and functionally distinct, the lateral EC (LEC) and medial EC (MEC). Human studies have found that of these, the LEC is the earliest affected by age. I have previously found that loss of basal forebrain cholinergic input (BFCN) to the LEC is a critical component of LEC-related cognitive impairment and an early feature of the aging pathology. Cholinergic neurons are essential for normal attention, mood, and memory. Marked reductions of cholinergic neurons are a hallmark of AD. Despite the importance of each of these regions to pathological aging, the molecular determinants of the selective and early vulnerability in the BFCN to EC circuit is not known. The proposed studies will identify molecular signatures of vulnerability and the sequence of events that ultimately renders the BFCN to EC circuit particularly vulnerable to age. Using transcriptomics, high-resolution microscopy, and behavioral assays, I will identify the unique signatures of BFCN and LEC vulnerability in aging. Aim 1 studies will focus on the BFCN, classifying young and aged BFCNs based on their unique gene expression profiles, identifying LEC-projecting BFCNs, and evaluating the consequences of targeted LEC disruption on subsequent behavior, BFCN integrity and the BFCN transcriptome. In parallel, Aim 2 studies will focus on the LEC, classifying young and aged LEC neurons based on their gene expression profiles, evaluating the integrity of LEC neurons in aged animals, and evaluating the consequences of targeted BFCN disruption on subsequent behavior, LEC integrity and the LEC transcriptome. Taken together, the goal of this proposal is to identify the signatures of vulnerability in the circuit between the BFCN and LEC in aging and evaluate whether LEC dysfunction or BFCN deterioration drives circuit decline. In addition, the datasets generated from these studies will allow targeted assessments of the LEC or BFCN subpopulations in the future with the hopes of finding novel targets for ADRD treatments. Using the data generated from the K22 Career Transition Award, my goal is to launch an independent research program which will take a translational approach toward understanding circuit mechanisms underlying neurodegenerative and neuropsychiatric disorders associated with age. This grant will provide me with the key resources to begin my career as an independent investigator. Project Number: 1K22AG088111-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Mala Ananth | Institution: UNIVERSITY OF GEORGIA, ATHENS, GA | Award Amount: $198,352 | Activity Code: K22 | Study Section: Career Development for Established Investigators and Conference Grants Study Section[AGCD-4] View on NIH RePORTER: https://reporter.nih.gov/project-details/10946930