Several studies have identified the entorhinal cortex (EC) as one of the earliest brain regions to exhibit age-related alterations, including the accumulation of tau protein associated with Alzheimer’s disease (AD). Structural and functional abnormalities within the EC have been shown to occur prior to, and even predict, future cognitive decline. The EC consists of two anatomically and functionally distinct subdivisions: the lateral entorhinal cortex (LEC) and the medial entorhinal cortex (MEC). Among these, human studies indicate that the LEC is particularly susceptible to early aging-related pathology.

Previous research has demonstrated that the loss of basal forebrain cholinergic neuron (BFCN) input to the LEC plays a crucial role in LEC-associated cognitive impairment and represents an early feature of aging pathology. Cholinergic neurons are essential for regulating attention, memory, and mood, and significant cholinergic degeneration is a defining hallmark of AD. Despite the critical involvement of both the BFCN and EC regions in pathological aging, the molecular mechanisms underlying the selective vulnerability of the BFCN-to-EC circuit remain unclear.

The proposed research aims to identify the molecular signatures associated with vulnerability in this neural circuit and determine the sequence of events that contributes to its increased susceptibility during aging. Using transcriptomic analyses, high-resolution imaging, and behavioral assessments, the studies will characterize the unique molecular and functional changes occurring in BFCNs and the LEC with age.

Aim 1 will focus on BFCNs by classifying young and aged cholinergic neurons according to their gene expression profiles, identifying BFCNs that project specifically to the LEC, and examining how targeted disruption of the LEC affects behavior, BFCN integrity, and the BFCN transcriptome.

In parallel, Aim 2 will investigate the LEC by characterizing young and aged LEC neurons based on their transcriptomic profiles, assessing neuronal integrity in aged animals, and evaluating the effects of targeted BFCN disruption on behavior, LEC integrity, and LEC gene expression patterns.

Collectively, this project seeks to define the molecular signatures of vulnerability within the BFCN–LEC circuit during aging and determine whether dysfunction in the LEC or degeneration of BFCNs is the primary driver of circuit decline. Furthermore, the datasets generated from these studies will provide a valuable resource for future targeted investigations of specific LEC and BFCN subpopulations, with the long-term goal of identifying novel therapeutic targets for Alzheimer’s disease and related dementias (ADRD).

Source: https://research.uga.edu/research-insights/molecular-determinant-of-age-related-cognitive-decline-in-the-basal-forebrain-to-lateral-entorhinal-cortex-circuit/