2006 AFAR Research Grant: Hypothalamic Neurotransmission and Reproductive Senecence

Please give a brief summary of your AFAR research project.
Reproductive aging is a complex process that not only affects fertility, but also confers increased risk for a myriad of health related problems that include, but are not limited to osteoporosis, heart disease, diabetes mellitus and cognitive dysfunction. In the wake of the Women's Health Initiative study challenging the benefits of exogenous hormonal replacement, a need to identify and understand the factors that catapult women into reproductive senescence has become a topic of paramount concern. While it is certain that ovarian failure ultimately defines the menopause and reproductive senescence, the role of the brain, specifically the hypothalamus (a region of the brain critically involved in reproduction), is less clear.

Brain cells use chemical messages to communicate. The hypothalamus integrates excitatory (glutamate) and inhibitory (GABA) chemical messages from other cells, translates and transmits the message to the pituitary (another region of the brain important in reproduction) which then communicates with the ovaries. The pubertal transition is dependent upon changes in the pattern of excitatory and inhibitory chemical messages processed by the hypothalamus. Very little is known about the role of the hypothalamus and these chemical signals in the onset and progression of reproductive senescence. It is possible that like the pubertal transition, reproductive aging is due to a changes in the chemical signals (glutamate and GABA) processed by the hypothalamus. The intent of this project is to investigate if age-related changes in glutamate and GABA, excitatory and inhibitory neurochemical signals respectively, transmitted to hypothalamus impact the onset of reproductive senescence. We hypothesize in the absence of overt ovarian failure; the transition into reproductive senescence is characterized by an age-related impairment in glutamate and GABA signals transmitted to the hypothalamus. As a consequence, altered hypothalamic to pituitary communication ensues, thereby contributing to ovarian hypofunction. In order to understand the cascade of neurochemical events contributing to the initiation and maintenance of reproductive senescence, we propose a series of studies that use in vivo intracerebral microdialysis and intracerebral ventricular drug infusion in young and middle-aged rats demonstrating evidence of reproductive senescence to investigate age-related changes in excitatory and inhibitory messages being received and processed by the hypothalamus. Preliminary studies strongly suggest that independent of gonadal failure, reduced excitatory and increased inhibitory messages sent to the hypothalamus significantly contribute to the onset of reproductive senescence. Preliminaries studies also suggest that increasing excitatory input to the hypothalamus may afford the restoration of reproductive function in middle-aged rats. Comprehension of the cellular mechanisms that contribute to reproductive aging will provide insight into the neural pathways mitigating the onset and clinicopathology that define age-related infertility and the menopausal transition.

What problems are you addressing and what specific questions will your research seek to answer?
The problem that we address is reproductive senescence and the role of the hypothalamus, a brain region important in reproduction.

What aspects of your project are most interesting from a scientific point of view?
The part of my project that is most interesting from a scientific point of view is that in absence of overt ovarian failure, the brain may be independently contributing to the process of reproductive senescence.

What are the implications of your research for age-related diseases and disorders?
Comprehension of the cellular mechanisms that contribute to reproductive aging will provide insight into the neural pathways mitigating the onset and clinicopathology that defines the menopausal transition and age-related infertility.

Return to 2006 AFAR Grantees