From Molecules to Behavior: Understanding How Aging Impacts Entorhinal-based Navigation

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SUMMARY As the most significant risk factor for Alzheimer's disease (AD) and other dementias, aging causes the gradual decline of specific cognitive abilities, like spatial memory, reducing independence and quality of life.1-3 However, the neurobiological mechanisms underlying aging-mediated cognitive decline remain unclear, limiting the development of therapies that extend the brain's healthspan.2 To advance our mechanistic understanding of spatial memory decline in healthy and diseased brain aging, the proposed study will simultaneously characterize and then correlate molecular, cellular, and circuit-level changes in the medial entorhinal cortex (MEC), a brain region critical for spatial memory and impacted by molecular pathology in pre-clinical AD.4,5 In young rodents and primates, MEC neuron firing patterns represent position, speed, head direction, and environmental landmarks, facilitating goal-directed navigation and spatial memory.6-12 How MEC spatial coding changes and functionally supports spatial memory in aged animals is unknown. To address this, I propose to record from MEC neurons at high density using Neuropixels probes as young and aged mice navigate virtual- reality (VR) environments. I will quantify how aging impacts single-unit MEC properties, such as position- and speed-coding fidelity and stability, and, in turn, spatial memory, measured as the rate of learning and alternating between rewarded VR locations (Aim 1). In young animals, theta rhythm organizes MEC activity and supports spatial memory, but its functional status in aged animals is not understood. Thus, I will also analyze how aging impacts theta-rhythmic coordination of activity across populations of MEC neurons (Aim 2). After recording, I will define gene expression changes with age in MEC neurons using single nucleus RNA- sequencing (snRNAseq) (Aim 3). Ultimately, I will correlate altered gene expression with MEC coding and spatial memory dysfunction to identify targets for future therapies to rejuvenate the aging brain and to treat age-modulated dementias like AD. Given my previous experience investigating molecular changes in aging and neurodegeneration that compromise hippocampus-dependent spatial memory, I am well-equipped to execute these experiments. Pursuing these aims will also cultivate new skills necessary for me to excel as future independent investigator, including robustly collecting and analyzing large-scale neural and transcriptomic datasets. I will conduct this work under the sponsorship of Lisa Giocomo, PhD: a global expert in electrophysiology and the neural systems that support navigation and spatial memory. As a collaborator and a co-sponsor, respectively, Saul Villeda, PhD and Tony Wyss-Coray, PhD will contribute expertise leveraging large-scale molecular datasets to generate insights about brain aging. Their collective support and Stanford's rigorous training environment will ensure this project's completion and my development into an innovative physician scientist empowered to develop therapies that ameliorate brain aging and neurodegeneration.