Understanding hippocampal excitatory and inhibitory circuits during perimenopause in alzheimer's disease mice

The National Institute on Aging awarded Rosalind Franklin University of Medicine & Science $696,253 on September 1, 2026, under the Aging Research program (CFDA 93.866) to investigate how hormonal fluctuations during perimenopause alter hippocampal neural circuits and accelerate Alzheimer's disease pathology in female mice.

The recipient will use 4-vinylcyclohexene diepoxide (VCD) to chemically induce ovarian failure in AppNLGF knock-in AD model mice, mimicking human perimenopause transition. Research will examine how perimenopause disrupts hippocampal cell types and neural activity patterns, focusing on dorsal and ventral hippocampal regions implicated in anxiety-like behaviors and memory decline observed in female AD mice during this transition. The work will measure neuronal ensemble activation, parvalbumin-positive inhibitory neuron activity, and behavioral outcomes including anxiety and fear memory to determine whether perimenopause accelerates AD-related neural and behavioral phenotypes.

Performance occurs in North Chicago, Illinois, with a period of performance from September 1, 2026, through May 31, 2031. This is a Project Grant, the standard assistance type for NIH research awards.

Abstract

Ovarian hormones exert effects on brain regions like the hippocampus that modulate learning and memory. Fluctuations in these hormones during menopause transition (perimenopause) impact cognition and are linked to alzheimer's disease (ad) risk. For example, early surgical menopause in women increases dementia risk by 2-fold and results in more ad pathology. Perimenopause and menopause transitions are an individualized experience yielding variations in symptomology depending on natural or surgical transition and age of onset. Some women report minimal cognitive decline while others have profound memory disturbances that are not reversed postmenopause. While there is a rich literature on the reproductive tract and aging, IT is still unknown how menopause transition alters brain-wide networks and increases ad risk. Here we aim to determine how menopause transition periods alter hippocampal cell types and neural activity and how these changes may accelerate ad pathology. To obtain a more complete picture of behavior and neuronal changes during the perimenopause transition we will mimic human menopause in mice using the chemical, 4-vinylcyclohexene diepoxide (VCD) to accelerate ovarian failure (AOF). Data collected in my lab revealed that appnlgf (knock-in ad model) mice in perimenopause exhibit increased anxiety-like behavior, and weight gain, and decreased fear memory in postmenopause compared to ad mice with typical hormone levels. Our prior work demonstrated that ad drives abnormal anxiety-like behaviors in females via the dorsal (DH) and ventral hippocampus (VH). IT is possible that perimenopause disrupts VH activity, accelerating ad neural and behavioral phenotypes. Specifically, we'VE observed decreased neuronal ensemble activation in the dorsal (DCA3) and increased parvalbumin (PV+) inhibitory activation in the ventral CA1 (VCA1) in female ad mice. IT is established that the VCA1 sends excitatory projections to the DCA3 which promotes spatial object recognition memory. Therefore, our conceptual framework is that PV+ inhibitory interneurons are increased in the VCA1 during perimenopause resulting in a decrease of excitatory activation in the DCA3 which will promote cognitive decline and ad pathology. In aim 1, we will use microscopy to determine VCA1 and DCA3 alterations in activated PV+ interneurons throughout menopause transition periods. In aim 2, we will measure neural activity in the DCA3 using miniscope technology and ablate specific hormone receptors to gain an understanding of how menopause transitions and hormones impact neural activity. Lastly, in aim 3 we will chronically chemogenetically manipulate the VCA1ÀDCA3 circuit in an attempt to restore e/i imbalance throughout menopause transitions.