# Multimodal ventral tegmental area decrements in a mouse Alzheimer's model

> **NIH NIH F31** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2024 · $37,793

## Abstract

The aging population continues to grow, as does the prevalence of Alzheimer’s disease (AD),
necessitating disease altering therapies. While AD is often characterized by a decline in working memory, it is
also highly comorbid with depression, apathy, and other non-cognitive impairments. Due to the prominent
memory deficits seen in AD patients, the bulk of research in the field has focused on cortical and hippocampal
pathophysiology. However, AD pathology develops throughout the brain, and its associated conditions
implicate subcortical structures, specifically the midbrain dopaminergic system. Recently, reports in both
animal models and humans indicate that the ventral tegmental area (VTA) to hippocampus circuit may be
disrupted in AD. Interestingly, a report in a mouse model indicates that cells in the medial VTA, which project
predominantly to corticolimbic structures, are preferentially affected, suggesting differential subpopulations of
VTA dopaminergic neurons are affected by AD pathology. The field is currently limited by a lack of information
on how heterogeneity affects pathophysiological predisposition in the ventral midbrain. This proposal aims to
elucidate the underlying mechanisms of cognitive and non-cognitive deficits in AD and its related dementias.
The experiments in this proposal will use an established mouse model that expresses mutant amyloid and tau
to investigate this gap in the collective knowledge. The general strategy will be to use animals of 3, 6, and 12
months of age, representing well defined pathological timepoints in hippocampal pathology. We will isolate
subpopulations of VTA cells through immunohistochemistry, single cell sequencing, and retrograde tracing.
Following sacrifice, we will record electrophysiological parameters, perform RNA-sequencing, and
morphological reconstruction of single VTA dopaminergic neurons of transgenic and non-transgenic mice. Aim
1 will construct a spatiotemporal timeline of amyloid and tau accumulation across cortical and subcortical
structures. Aim 2 will investigate intrinsic dopaminergic properties including neurite length, action potential
generation, the ion channel conductances that govern firing, and single cell transcriptomic profile.
Understanding cellular and circuit decrements occurring outside of cortical regions is key to development of
efficacious treatments. These studies aim to establish dopaminergic processes in AD pathophysiology, to
understand how single cell heterogeneity predisposes cells to functional decline, and to identify novel targets
for intervention in AD.

## Key facts

- **NIH application ID:** 10898764
- **Project number:** 5F31AG079620-03
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Harris Blankenship
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $37,793
- **Award type:** 5
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898764

## Citation

> US National Institutes of Health, RePORTER application 10898764, Multimodal ventral tegmental area decrements in a mouse Alzheimer's model (5F31AG079620-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10898764. Licensed CC0.

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