PROJECT SUMMARY / ABSTRACT Spatial disorientation (SD) or wandering is a key feature of Alzheimer’s Disease (AD), affecting up to 93% of people living with AD. SD is characterized by inability to navigate even familiar environments, and brain regions involved in spatial navigation and memory are compromised in AD. One such brain region is the retrosplenial cortex, a vital node for integration of orientation-relevant inputs for spatial navigation and memory. Lesion studies revealed that retrosplenial damage results in SD and anterograde amnesia, mirroring some navigational and memory deficits seen in AD. Retrosplenial hypometabolism is a well-known AD feature, suggesting that dysfunction of the retrosplenial cortex is an important factor in AD pathophysiology. We identified a unique, region-defining cell-type that is the key recipient of elemental orientation information in the granular retrosplenial cortex (RSG): the low-rheobase (LR). LR cells comprise ~80% of all pyramidal neurons in RSG L2/3. Unlike neighboring excitatory cell types, LR cells are non-adapting, have high input resistance, narrower spike width, and distinctly low rheobase. We showed that LR cells selectively receive inputs from the anterior thalamus (ATh) (which contains head direction cells). These orientation-relevant inputs largely avoid the neighboring regular-spiking (RS) pyramidal cells, highlighting the importance of LR cells in supporting RSG spatial orientation functions and the potential importance of understanding how LR neurons and their inputs are altered in AD. To date, no studies have explored cell-type-specific alterations in RSG circuits in AD models, representing an important gap in knowledge. Thus, there is a critical need to pinpoint components of the RSG circuit that are impaired in AD models. In this project, we will systematically dissect RSG circuitry in AD murine genetic models. Our central hypothesis is that RSG circuits will be impaired in a cell-type specific way in preclinical AD, depending on the precise circuit connectivity of the neuron. In Aim 1, we will study the biophysical changes in each cell type at two age points in two distinct mouse models of AD that both show deficits in spatial orientation-related behaviors. We will do so in both male and female mice. This will help to generate a cell-type specific physiological map of RSG dysfunction in AD. RSG dysfunction in AD may not be entirely due to changes to neurons within the RSG. In Aim 2, using optogenetics and pharmacology, we will dissect how cholinergic inputs control RSG neurons themselves (Aim 2A) and the ATh synapses onto RSG neurons (Aim 2B) in AD+ versus null littermates. This will again be studied across both male and female mice at two age points in two preclinical models of AD. The completion of these Aims will help to identify precise, cell-type-specific components of the RSG circuit that are impaired in Alzheimer’s disease. This will in turn help to develop more precise circuit-...