# Mechanisms of Age-related Cognitive Decline in the Rhesus Monkey

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2021 · $558,505

## Abstract

During normal aging in the rhesus monkey, pyramidal cells in the dorsolateral prefrontal cortex (LPFC)
undergo significant structural and functional changes that are likely associated with cognitive impairment, while
pyramidal cells in the primary visual cortex (V1) are comparatively spared. The overall hypothesis of this
project is that selective vulnerability of neurons and associated networks in LPFC compared to V1 during aging
is due to a greater susceptibility to increases in oxidative stress, inflammation, and vascular dysfunction in
LPFC than in V1. We further hypothesize that intervention with the potent antioxidant and anti-inflammatory
polyphenol curcumin will prevent or reduce age-related dysfunction on multiple scales- from the molecular to
the behavioral level. This project has three aims: 1) To assess the biomarker and ultrastructural characteristics
of V1 and dlPFC neuropil. In situ immunofluorescence multiplexing of ~30 protein biomarkers will be used to
determine the molecular phenotype of neurons, glia, vasculature and surrounding neuropil with a GE Global
Research platform tailored for use in brain tissue, enabling quantitative, multimarker analyses with high
throughput. Using 2D and 3D electron microscopy, inhibitory and excitatory synapses, mitochondria, myelin
and axons of neurons as well as microglia and vascular elements will be quantitatively characterized. 2) To
characterize the physiological and morphological properties of layer 3 (L3) pyramidal neurons and of
interneurons in V1 and dlPFC across the adult lifespan of rhesus monkeys. Using whole-cell patch-clamp
recordings we will assess passive membrane properties, AP firing patterns and underlying ionic currents, as
well as excitatory and inhibitory postsynaptic currents of L3 excitatory and inhibitory neurons in in vitro slices of
PFC and V1. We will then characterize the morphological properties (e.g. dendritic topology, density and
detailed morphology of dendritic spines and neurotransmitter receptor and transporter distribution, as well as
oxidative stress markers) of these same neurons using immunohistochemistry and ultra-high resolution
confocal laser scanning microscopy. 3) To use computational models of V1 and dlPFC networks to predict the
functional consequences—at the single neuron, network and behavioral levels—of changes revealed in Aims 1
and 2. Simplified models of LPFC and V1 neurons will be incorporated into model networks capable of
persistent neural activity, oculomotor spatial working memory, and visual orientation tuning. Unique to this
proposal is the combination of state-of-the art anatomical, physiological, and computational approaches
together with concurrent behavioral assessment of the aging monkey under control conditions and following
therapeutic treatment with curcumin. This project will yield entirely novel and critically needed information on
the neural substrates of cognitive decline in the aging primate and provide important insight int...

## Key facts

- **NIH application ID:** 10102160
- **Project number:** 5R01AG059028-04
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** PATRICK R HOF
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $558,505
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10102160

## Citation

> US National Institutes of Health, RePORTER application 10102160, Mechanisms of Age-related Cognitive Decline in the Rhesus Monkey (5R01AG059028-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10102160. Licensed CC0.

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