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

> **NIH NIH F30** · STANFORD UNIVERSITY · 2023 · $40,363

## Abstract

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
ph...

## Key facts

- **NIH application ID:** 10786033
- **Project number:** 5F30AG079494-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Charlotte Sophia Herber
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $40,363
- **Award type:** 5
- **Project period:** 2022-09-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10786033

## Citation

> US National Institutes of Health, RePORTER application 10786033, From Molecules to Behavior: Understanding How Aging Impacts Entorhinal-based Navigation (5F30AG079494-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10786033. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*