Project 1 - The Estrogens, Cardiometabolic Health, and Female Cognitive Aging Program Project at Tulane University

Project 1:

Impact of hypertension and high-fat diet on mechanisms by which estradiol affects the hippocampal memory system

The overall hypothesis of Project 1 is that in aging females, cardiometabolic disease, due to associated dysfunction of the ubiquitin/proteasome system, disrupts the ability of estrogens to regulate levels of estrogen receptor (ER) ɑ in the hippocampus, regulation that is necessary for midlife estradiol treatment to exert lasting positive impacts on memory during aging.

A schematic diagram showing the diverging effects of estrogens on the hippocampus and memory in both healthy and unhealthy females.

Hypothesized model by which effects of estrogens on the hippocampus and memory diverge in healthy and unhealthy females. If individuals are healthy when treatment with estrogens is initiated, estrogens can act through a functional ubiquitin / proteasome system to protect hippocampal ERα from degradation. Once elevated levels are achieved, they will persist, creating a positive feedback loop and prolonged enhanced cognition. If individuals are unhealthy when treatment with estrogens is initiated, estrogens are unable to act to protect ERα in the hippocampus from degradation and has no effect on levels of ERα – a critical factor in the ability of estrogens to impact memory. Created with BioRender.com

Graphic of the brain with the hippocampus highlighted.

Aim 1:

Individual Differences

Aim 1 will determine if individual differences in cardiometabolic health prior to and/or after onset of estradiol treatment are associated with the ability of estradiol to positively impact memory and the hippocampus.

Administer estradiol immediately or after a delay following ovariectomy
Assess relationships between measures of body fat accumulation, glucose regulation, cardiovascular function, and hippocampal function and memory from middle to old age

Aim 2:

Metabolic Health

Aim 2 will determine if estradiol effects on the hippocampal memory system in aging females are impacted by obesity and impaired glucose regulation

Expose middle-aged female rats to high-fat or control diets before or after initiation of midlife estradiol treatment
Assess effects on hippocampus ERα levels, measures of hippocampal function and memory
Determine if manipulations that increase levels of hippocampal ERα differentially affect memory and the hippocampus in aging females on high-fat or control diets

Red and purple-ish blue, fluorescent image of the hippocampus

Multi-colored 3D protein model of estrogen receptor alpha

Aim 3:

Cardiovascular Health

Aim 3 will determine if effects of estradiol treatment on the hippocampal memory system in aging females are impacted by cardiovascular disease.

Use an angiotensin II-dependent hypertensive rat model that is initiated before or after initiation of midlife estradiol treatment
Assess effects on hippocampus ERα levels, measures of hippocampal function and memory
Determine if manipulations that increase levels of hippocampal ERα differentially affect memory and the hippocampus in aging females without or without hypertension

Project 1: