# Cell-type-specific dissection of retrosplenial circuits in preclinical models of Alzheimer's disease

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $42,459

## Abstract

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-...

## Key facts

- **NIH application ID:** 10900895
- **Project number:** 1F31AG087629-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Chloe Isabella Rybicki-Kler
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $42,459
- **Award type:** 1
- **Project period:** 2024-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10900895

## Citation

> US National Institutes of Health, RePORTER application 10900895, Cell-type-specific dissection of retrosplenial circuits in preclinical models of Alzheimer's disease (1F31AG087629-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10900895. Licensed CC0.

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