MECHANISMS OF REPRODUCTIVE AGING

Project: Research project

Project Details

Description

DESCRIPTION: (Scanned from the applicant's description): Despite intense
investigation, the mechanisms underlying reproductive aging in females remains
poorly understood. A hypothalamic defect is suggested to play a role, as prior
to becoming acyclic, middle-aged rats display a significant attenuation of the
proestrous LH surge and possess a significantly lower number of activated GnRH
neurons in the hypothalamus. We hypothesized that the decreased activation of
GnRH neurons on proestrus in the middle-aged rat could be due to a defect in
the glutamate system, which is a major excitatory transmitter system regulating
GnRH secretion. Our preliminary studies support this hypothesis as we
demonstrated that the GnRH response to glutamate agonists is significantly
attenuated in the middle-aged rat on proestrous. The mechanism responsible for
the attenuated GnRH response to glutamate in the middle-aged proestrous rat
remains unclear and is the primary focus of this grant. Aim 1 will use
microdialysis to measure glutamate and aspartate release rates in the
hypothalamus of the middle-aged and young proestrous rat in order to determine
whether there is a compromised excitatory amino drive to GnRH neurons. Aim 2
will establish whether the reduced glutamate responsiveness in the middle-aged
rat on proestrus could be due to an age-related reduction in ionotropic
glutamate receptors in the hypothalamus. Aim 3 will examine the status of
anchoring/clustering proteins for glutamate receptors (PSD95, Chapsyn-1 10,
GRIP) in the middle-aged proestrous rat since a defect in these proteins would
lead to ineffective synaptic targeting, clustering and anchoring of glutamate
receptors, with a corresponding loss of glutamate action. Aim 4 will determine
whether an age-related defect exists in the nitric oxide (NO) system in the
hypothalamus, since NO is a major regulator of GnRH neuronal activation and a
key mediator of glutamate effects. To prove causation between an identified
defect and the attenuated LH surge, we will use retroviral gene transfer
technology to correct the defect and see if this leads to reinstatement of the
LH surge and extends cyclicity. As a whole, the proposed studies will provide
important insights as to why glutamate signaling is compromised in the
hypothalamus of the middle-aged rat, and will advance our understanding of
reproductive aging.
StatusFinished
Effective start/end date4/1/013/31/06

ASJC

  • Medicine(all)