Project Summary In the US, Alzheimer’s disease (AD) is the sixth leading cause of death, affects 11% of the population over age 65, and costs $355 billion each year. One of the first impairments in AD is spatial memory, which involves the hippocampal area CA1. CA1 encodes new information, driven by inputs from medial entorhinal cortex (MEC), and retrieves and consolidates old information, driven by inputs from hippocampal area CA3. Hippocampal inhibitory neurons, which are lost early in AD, can reduce the influence of, or gate, these inputs. However, we do not understand how loss or dysfunction of inhibitory neurons in AD affects inputs to CA1 and how this subsequently disrupts spatial representations and thus memory. This proposal will explore the dynamics of inputs to CA1, as gated by inhibitory neurons, and its effects on spatial memory, as an avenue for AD treatment. My central hypothesis is that loss of CA1 somatostatin-expressing inhibitory neurons ungates MEC inputs to CA1 during retrieval and consolidation, destabilizing spatial maps and impairing memory in AD. I will examine this hypothesis using a chronic recoverable implant design I have developed which enables simultaneous recording from dozens of neurons in CA1, CA3, and MEC. I will record neural activity while wild type and AD model mice encode, consolidate, and retrieve memories in a spatial alternation task and spatial contexts. During these three memory phases, I will measure: CA3 and MEC input drive to CA1 and its dynamics over learning (Aim 1), the relationship between CA1, CA3, and MEC spatial maps (Aim 2), and the firing patterns of CA1 somatostatin- expressing and parvalbumin-expressing inhibitory neurons (Aim 3.1). I will then stimulate each inhibitory neuron type in aged AD model mice during each of the three memory phases to rescue the deficits identified in Aims 1, 2, and 3.1 (Aim 3.2). This research will advance our understanding of how the hippocampus dynamically encodes, retrieves, and consolidates information, how it goes awry in AD, and how it can be treated, advancing Goal 1B of the National Plan to Address AD. My expertise in spatial memory, in vivo electrophysiology, and AD makes me uniquely qualified to pursue this novel line of research at the intersection of basic and translational neuroscience. These aims will be supported by an exceptional mentoring team of Drs. Lisa Giocomo, Tony Wyss-Coray, and Scott Linderman, advisory team of Drs. John Huguenard, Ivan Soltesz, and Gareth Howell, and training environment of Stanford University. This research will provide me with crucial training in neural data statistics, mechanisms of neurodegeneration, evidenced-based inclusive mentorship, and lab management. This project and the training it provides will open new lines of inquiry about the role of hippocampal inhibitory neurons in healthy, aged, and AD conditions and facilitate my transition to an independent faculty position.