Implications of long-range Mossy Cell signaling and connectivity in AD

Univ Of North Carolina Chapel Hill, Chapel Hill NC

Investigators

Abstract

Abstract Alzheimer’s Disease (AD) has been identified as one of the highest priority neurobiological diseases in need of research advancement, due to the progressive memory and emotional impairments inflicted on patients, and the excessive burden for caregivers and families. Due to the continued lack of effective preventative treatments for AD, it is imperative to identify ways to remediate the cognitive and affective impairments associated with the disease, and it appears that a more synaptic and circuity focused approach may be necessary. The hippocampus is one of the earliest regions in human and animal models to present with AD pathology and synaptic disfunction, and it has established roles in both memory and emotional regulation. The dentate gyrus (DG), in particular, undergoes many important circuitry and excitability changes in human cases of AD. As the first stop in the tri- synaptic loop, DG has significant control over downstream activation of the CA3 and CA1 regions of the hippocampus. Furthermore, since CA1 and subiculum project to many other structures throughout the brain, important for memory consolidation and animal behavior, activity balance in the DG may impart brain-wide functional connectivity changes under pathological conditions. Our previous research found that glutamatergic Mossy Cells (MCs) in the DG have the unique capability to recruit either excitatory or inhibitory neurons depending on the extent of MC activation. More recently, it has been discovered that MCs play a much more significant role in hippocampal circuitry than previously thought, as these cells have unique anatomical projection patterns that not only cross to the contralateral hemisphere, but also project longitudinally, along the entire dorsal-ventral axis of the hippocampus. Our preliminary data acquired from the 5xFAD rodent model of AD has identified a specific decrease in activity states of the dorsal population of MCs by 4.5 months of age, and a loss in overall DG granule cell activity. Because of the unique anatomical characteristics of hippocampal MCs, and due to the potential of dorsal MCs to regulate activity of DG granule cells throughout the hippocampus, we postulate that loss of dorsal MC signaling is one of the key circuit deficiencies contributing to cognitive and affective deficiencies in AD. By utilizing activity-dependent stimulation of dorsally targeted populations of MCs, we aim to characterize the breakdown of excitatory and inhibitory control throughout the different regions of the diseased hippocampus. We will use a combination of in vivo calcium imaging, chemogenetic stimulation of dorsal MCs, small animal behavioral analysis, and awake small-animal fMRI scanning in mouse models of AD to examine the effect MCs have on hippocampal activity and functional connectivity throughout the brain. Identification of discrete network components with the potential to compensate for improper excitatory/inhibitory balance and connectivity will greatly inform on the potential for circuity-based interventions to address the cognitive and affective impairments of AD.