Project 4 - The Estrogens, Cardiometabolic Health, and Female Cognitive Aging Program Project at Tulane University

Project 4:

Impact of estradiol on the central regulation of glucose homeostasis and subsequent implications for hippocampal function

The overall hypothesis of Project 4 is that insulin resistance caused by high-fat diet impairs downstream signaling pathways necessary for estradiol’s beneficial influence on central regulation of glucose homeostasis, hippocampal LTP, and hippocampus-dependent cognitive function.

Schematic showing side by side of E2 in metabolically healthy aging (in green) and metabolically unhealthy aging (in red). Arrows show relative increase or decrease in cognition, metabolism, and insulin resistance between the two groups. A smaller arrow indicates smaller decrease in cognition in healthy aging, an upright arrow shows an increase in metabolism in healthy aging and a smaller upright arrow shows a smaller increase in insulin resistance in healthy aging. A larger, downwards arrow shows a greater decrease in cognition in unhealthy aging, a downward arrow shows a decrease in metabolism in unhealthy again and a larger, upright arrow shows a greater increase in insulin resistance in unhealthy aging.

Hypothesized model by which effects of estrogens on the central regulation of glucose homeostasis and subsequent implications for hippocampal function diverge under conditions of healthy and unhealthy aging. Insulin resistance caused by high fat diet impairs downstream signaling pathways necessary for beneficial influence of estrogens on central regulation of glucose homeostasis, hippocampal LTP, and hippocampus-dependent cognitive function.

Aim 1:

Hypothalamus

Determine the effect of midlife estradiol treatment on paraventricular nucleus (PVN) neurons in control and high-fat diet fed mice.

Establish the cellular properties of preautonomic PVN neurons after midlife estradiol treatment in control and high-fat diet fed mice
Determine the effects of estradiol and insulin on PI3K pathway

Aim 2:

Hippocampus

Determine the effect of midlife estradiol treatment on synaptic plasticity and cellular properties in the hippocampus of control and high-fat diet fed mice.

Determine whether insulin resistance impairs estradiol’s effects on hippocampal synaptic plasticity
Assess the effects of PI3K pathway activation on hippocampal pyramidal cells

A red fluorescent image of the hippocampus.

A graph showing the trend between glycemia in milligrams per deciliter over time titled “Glucose Tolerance Test”. A blue line increases from 150 to around 550 and then gradually decreases back down to around 200 mg/dl.

Aim 3:

Metabolism and Behavior

Determine the effect of midlife estradiol treatment on glucose homeostasis and cognition in control and high-fat diet fed mice.

Determine the effects of midlife estradiol treatment on glucose homeostasis, body composition, and energy homeostasis in control and high-fat diet fed mice
Assess interaction between midlife estradiol treatment and high-fat diet on cognitive function

Project 4: