# Dysregulated frontal-sensory network and cognitive control by Alzheimer's disease pathology

> **NIH NIH RF1** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $2,011,345

## Abstract

Cognitive decline is one of frequent challenges accompanying Alzheimer's disease (AD). However, little is known
about the link between AD pathology and neural circuit mechanisms especially in frontal cortex essential for
cognitive control behavior. Amyloid-β (Aβ) accumulation has been implicated as an upstream event in AD
pathogenesis. Aβ-induced changes in synaptic function in experimental models of AD pathology suggest that
Aβ may affect neural circuit connectivity essential for cognitive control behavior. Identification of cognitive circuit
network vulnerable to Aβ accumulation would allow mitigating cognitive deficits in in AD. The goal of this study
is to examine to what extent a frontal cognitive control circuit and associated network is vulnerable to early AD
pathology. A recent study in mice demonstrated that frontal-sensory projections from anterior cingulate area
(ACA) to visual cortex (VIS) (ACAvis) plays a causal role in cognitive control by improving attention especially
after errors. In this study, we will analyze APP knock-in (KI) mice, which expresses mutant human APP under
the endogenous mouse promoter while avoiding overexpression-associated artifacts, and test a hypothesis that
AD-related amyloid pathology disrupts top-down frontal-sensory projection (Aim1) and frontal cholinergic
neuromodulation (Aim2), and that the interaction between these systems contributes to cognitive control deficit
(Aim3). To test this hypothesis, we will apply circuit specific approaches to monitor and manipulate neural activity
in ACAvis projection neurons and basal forebrain cholinergic neurons during free moving cognitive control task
using five choice serial reaction time task in APP KI mice.

## Key facts

- **NIH application ID:** 10905428
- **Project number:** 1RF1AG085887-01A1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Hirofumi Morishita
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,011,345
- **Award type:** 1
- **Project period:** 2024-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10905428

## Citation

> US National Institutes of Health, RePORTER application 10905428, Dysregulated frontal-sensory network and cognitive control by Alzheimer's disease pathology (1RF1AG085887-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10905428. Licensed CC0.

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