# Effects of normal aging on the transcriptomic and physiological profiles of layer 3 pyramidal neurons in diverse neocortical areas of the monkey

> **NIH NIH R21** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2022 · $206,250

## Abstract

The higher order dorsolateral prefrontal cortex (LPFC) and the limbic anterior cingulate cortex (ACC) are key
areas in the frontal neural network that mediates executive cognitive functions, which often decline during normal
aging. There is strong evidence that layer 3 (L3) pyramidal cells in these higher-order areas are selectively
vulnerable during normal aging in the primate, especially compared to those in sensory cortices such as the
primary visual cortex (V1). Indeed, extensive morphologic, electrophysiological and structural age-related
changes are present in LPFC but not V1 L3 pyramidal cells in the rhesus monkey. However, the mechanisms
underlying these area-specific vulnerabilities, and whether LPFC and ACC exhibit similar vulnerability to aging,
is not known. The overall hypothesis of this proposal is that LPFC and ACC L3 pyramidal cells share
transcriptomic and phenotypic profiles that are highly distinct from V1 neurons, and that underlie selective
vulnerability of these frontal areas to age-related synaptic dysfunction and hyperexcitability. The cognitive status
of young and aged rhesus monkeys will be assessed on a battery of behavioral as part of other projects. Single-cell Patch-Seq transcriptomic assessment of physiologically characterized L3 pyramidal cells in acute slices of
LPFC, ACC and V1 prepared from these monkeys will then be performed. Transcriptomic findings will be
validated with RNAscope in situ hybridization and immunohistochemical assessment of proteins on/in biocytin
filled, morphologically characterized neurons. This project has two aims: 1) assessment of the transcriptomic
profiles of physiologically-characterized pyramidal cells in young vs. aged LPFC, ACC and V1. We will use whole-cell patch-clamp recordings to quantify over 30 physiological variables in L3 pyramidal cells and then harvest
these cells for Patch-Seq to determine their transcriptomic profiles. 2) assessment of the morphology and protein
expression of pyramidal cells in young vs. aged LPFC, ACC and V1. We will characterize protein expression on
a separate subset of non-harvested but biocytin-filled morphologically characterized cells and thus validate Aim
1 gene expression findings. Data on specific age-related genetic changes in expression of ion channels and
synaptic markers in individual L3 neurons will be related to age-related changes in genes for oxidative stress,
inflammation, and neurodegeneration such as caspase 3 and TNFα. The project will reveal mechanisms
underlying differential age-related neuronal dysfunction and mechanisms that can compensate for changes to
restore cellular function, and thus has broad implications for therapeutic strategies to reduce cognitive decline
during normal aging. This study will form the basis of future studies to investigate relationships and co-dependence of age-related cellular changes in a variety of cell types, laminae and cortical areas during aging
that can be correlated with cognitive performance ...

## Key facts

- **NIH application ID:** 10491682
- **Project number:** 5R21AG072069-02
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** JENNIFER I LUEBKE
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $206,250
- **Award type:** 5
- **Project period:** 2021-09-30 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10491682

## Citation

> US National Institutes of Health, RePORTER application 10491682, Effects of normal aging on the transcriptomic and physiological profiles of layer 3 pyramidal neurons in diverse neocortical areas of the monkey (5R21AG072069-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10491682. Licensed CC0.

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