# Role of adolescent stress in the acceleration of Alzheimer's disease related-cognitive impairment

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2022 · $371,250

## Abstract

PROJECT SUMMARY/ABSTRACT
The primary goal of our NIMH R01 project (R01MH116869) is to elucidate the role of adolescent stress on social
cognition in the postpartum period. We have discovered that adolescent psychosocial stress, in conjunction with
the stressful events of pregnancy/delivery, leads to long-lasting deficits in social behaviors in the postpartum
period. We have also demonstrated that the social behavioral deficits in stressed dams are caused by
glucocorticoid receptor (GR)-mediated functional alteration of anterior insula (AI)-prelimbic cortex (PrL)
projections. These results show the causal role of enhanced GR signaling in the AI-PrL pathway underlying
adolescent stress-induced social behavioral deficits in the postpartum period. Recent studies demonstrate that
females have a significantly greater risk for the development of Alzheimer’s disease (AD) than males. Early life
stress drives the progression of AD and exacerbates symptoms. Pathology in AI and dorsal anterior cingulate
cortex [dACC, homologous to the PrL in rodents] have been implicated in AD. However, the mechanisms
underlying the deficits at the circuit level remain unclear. By modifying the protocol of our ongoing R01 project,
we may be able to explore the relationship between the dysfunction of this circuit and the acceleration of the
AD-related phenotypes in females. In this proposed supplemental study, we will test the hypothesis that
adolescent social isolation, in conjunction with the stressful events of pregnancy/delivery, accelerates the onset
of AD-related deficits in social behaviors via AI-PrL functional alterations. To address our hypothesis, we will
pursue the following specific two Aims: In Aim 1, we will examine whether adolescent social isolation
accelerates the onset of AD-related deficits in social behaviors in 5xFAD dams. Plasma corticosterone levels,
plaques of Aβ and amyloid, and synaptic density will be measured to examine the effects of adolescent stress
on regulation of the HPA axis and AD-related neuropathology in 5xFAD dams. In Aim 2, we will investigate how
mediation of the AI-PrL projections, a novel cortico-cortical pathway, alters social behaviors in 5xFAD dams
exposed to adolescent social isolation. This supplemental study will generate critical data to understand the
influence of adolescent psychosocial stress on neuronal function and behavior in the context of AD. The finding
will also stimulate research to manipulate a specific circuit at a critical period in order to intervene in AD-related
pathology and symptoms.

## Key facts

- **NIH application ID:** 10494601
- **Project number:** 3R01MH116869-04S1
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Minae Niwa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $371,250
- **Award type:** 3
- **Project period:** 2022-05-05 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10494601

## Citation

> US National Institutes of Health, RePORTER application 10494601, Role of adolescent stress in the acceleration of Alzheimer's disease related-cognitive impairment (3R01MH116869-04S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10494601. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*