Emerging evidence indicates dendrites of GnRH neurons are morphologically and functionally more complex than was previously appreciated. These findings raise tantalizing issues in neuronal processing with direct implications for generation of action potentials in GnRH neurons and by extension, control of reproductive hormone secretion. The goal of this proposal is to generate significant new insights with respect to dendritic processing in GnRH neurons, viewed within the framework of single neuron dynamics (Specific Aims 1 and 2) and the neural networks in which they are embedded (Specific Aim 3). Biophysical considerations suggest that dendrites of GnRH neurons would provide an ideal substrate for generation of repetitive action potentials, the pattern of neuronal firing that is implicated in hormone secretion. Thus, Specific Aim 1 tests the hypothesis that dendrites of GnRH neurons contribute to repetitive firing in hypothalamic GnRH neurons in slices. Dendrites of GnRH neurons express voltage gated sodium channels. Other neurons whose dendrites generate sodium-based action potentials possess additional active properties such as NMDA-mediated potentials, which can fundamentally change the integrative function of neurons.
Specific Aim 2 will test the hypothesis that GnRH neurons exhibit sub-threshold amplification of excitatory inputs and plateau potentials in response to NMDA receptor activation in dendrites. Using anatomical labeling, Specific Aim 3 will first define the location of synapses on GnRH neurons of afferent fibers arising from two key regions of the hypothalamus, the lateral septum and the arcuate nuclei. Using electrophysiological approaches in living GnRH neurons, Specific Aim 3 will test the hypothesis that fibers from these regions preferentially elicit somatic or dendritic action potentials. Further, in Specific Aims 2 and 3, we will determine whether input from GABA neurons acts as a local """"""""gain"""""""" control which is regulated by gonadal steroids. Taken together, these studies will contribute to the new view of the importance of dendrites in the output of GnRH neurons and, by extension, the control of fertility in normal and pathological states.
Neurons contained within the brain region called the hypothalamus control sexual reproduction through the intermittent release of gonadotropin releasing hormone (GnRH). The goal of the present proposal is to understand how dendrites of GnRH-containing neurons contribute to generation of action potentials in GnRH neurons, the control of reproductive hormone secretion and the central regulation of fertility in normal and pathological states.
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