The long-term objective of the proposal is to understand how synaptic input controls firing in gonadotropin releasing-hormone (GnRH) neurons. GnRH neurons have a limited number of synaptic inputs and express relatively small synaptic currents. This has complicated our understanding of the role of synaptic input and suggested it may not be a critical determinate of firing. Anatomical studies, however, have indicated that synaptic input to GnRH neurons changes during reproductive transitions. Thus, while synaptic input likely makes important contributions to control of GnRH neuronal firing, its precise contribution remains uncertain. The experiments in the proposal take advantage of emerging and innovative research strategies to understand regulation of GnRH neuronal firing by synaptic input.
Specific Aim 1 proposes functional mapping of intact circuitry to individual GnRH neurons.
Specific Aim 1 tests the hypothesis that synaptic input controlling GnRH neurons arises from regions outside those containing GnRH somata. This challenges the prevailing dogma in neurosecretory systems, namely, that synaptic regulation occurs via local circuitry.
Specific Aim 2 incorporates living GnRH neurons into simulated synaptic activity in order to directly determine if physiological levels of excitatory input can drive repetitive action potentials. Moreover, it examines interaction between glutamatergic and GABAergic excitation.
Specific Aim 3 will determine relative contributions of proximal and distal synapses in the control of firing. Using a model of GnRH neurons derived from electrophysiological properties and anatomical reconstructions, it tests the hypothesis that synapses on somata and proximal dendrites contribute equally to firing.
Specific Aim 4 uses a combination of electrophysiological recordings and modeling to determine whether dendrites of GnRH neurons express active properties. This builds on emerging evidence in other neuronal systems indicating dendrites may not function as simple passive conduits for synaptic currents. The proposed experiments will make substantial contributions to our understanding of the function of individual GnRH neurons and how individual GnRH neurons behave in networks.
