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

与阿尔茨海默病和相关痴呆相关的神经精神症状(NPS

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 activity and that altered NMDAR function is attributed to estrogen-dependent alterations in NR2A/B subunit expression.