# Estrogen depletion as a risk factor for Neuropsychiatric Symptoms associated with aging

> **NIH NIH R21** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2022 · $373,788

## Abstract

Neuropsychiatric Symptoms (NPS) associated with Alzheimer’s Disease and related dementias
(ADRD) include agitation, hallucinations, confusion and depression and are associated with disease severity,
often precipitating the transition to assisted living facilities. Despite widespread prevalence, efficacious
treatments for NPS remain elusive. ~40% of patients with dementia in assisted living facilities are treated with
antipsychotic medications (off-label) to manage NPS despite limited efficacy, concerns regarding safety and
compromised quality of life. Sex differences in the prevalence and severity of NPS are reported yet the
contributing factors are not well understood. NPS symptoms resemble hallmark positive, negative and
cognitive symptoms as well as sleep disturbances associated with schizophrenia. These behavioral and
functional commonalities between NPS in ADRD and schizophrenia suggest plausible similarities in etiology
and risk factors. One primary hypothesis for the etiology of schizophrenia is glutamate hypofunction,
specifically decreased ionotropic glutamate N-methyl-D-aspartate receptor (NMDAR) function. In humans and
animals, NMDAR antagonism produces psychotomimetic- and depression-like symptoms, impairs cognition
and disrupts sleep, modelling all symptom clusters of both conditions. Investigating factors associated with
aging that influence NMDAR function holds promise for understanding neurobiology and treatment of NPS.
Estrogen is hypothesized to have neuroprotective effects in females. Estrogen depletion post menopause
represents a risk factor for cognitive decline, schizophrenia, reduced antipsychotic efficacy and likely NPS
associated with ADRDs. Estrogen also influences NMDAR subunit composition and function. We propose to
investigate estrogen depletion on cognition, brain function, and NMDAR subunit expression and function
combining rodent models of menopause and schizophrenia-like symptoms to model NPS in ADRD, as well as
responsivity to the atypical antipsychotic medication, olanzapine, commonly used to treat NPS with known
reductions in efficacy in post-menopausal women. Electroencephalography (EEG) will be employed which
provides a translational measure of brain function and sleep across species. In both human and animals
NMDAR antagonism induced excessive increases in high frequency gamma oscillations which correlates with
cognitive impairments and psychotomimetic-like effects. To examine the impact of estrogen depletion on
cognition, NMDAR function and antipsychotic-like effects, we will use ovariectomized rats (Ovx), a model of
surgical menopause where gonadal hormones are depleted, in the presence or absence of 17β-estradiol, an
estrogen steroid derivative used as a hormone replacement therapy in post-menopausal women. Using
translational cognitive assessments and EEG, we will test the hypothesis that estrogen is protective against
NMDAR antagonist-induced disruptions, confers sensitivity to antipsychotic-like activi...

## Key facts

- **NIH application ID:** 10431599
- **Project number:** 1R21AG077271-01
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Robert Warren Gould
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $373,788
- **Award type:** 1
- **Project period:** 2022-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10431599

## Citation

> US National Institutes of Health, RePORTER application 10431599, Estrogen depletion as a risk factor for Neuropsychiatric Symptoms associated with aging (1R21AG077271-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10431599. Licensed CC0.

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