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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD045436-02
Application #
6896514
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Lamar, Charisee A
Project Start
2004-06-01
Project End
2008-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
2
Fiscal Year
2005
Total Cost
$206,550
Indirect Cost
Name
Emory University
Department
Physiology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Hemond, Peter J; O'Boyle, Michael P; Roberts, Carson B et al. (2012) Simulated GABA synaptic input and L-type calcium channels form functional microdomains in hypothalamic gonadotropin-releasing hormone neurons. J Neurosci 32:8756-66
Gay, Vernon L; Hemond, Peter J; Schmidt, Deena et al. (2012) Hormone secretion in transgenic rats and electrophysiological activity in their gonadotropin releasing-hormone neurons. Am J Physiol Endocrinol Metab 303:E243-52
Roberts, C B; O'Boyle, M P; Suter, K J (2009) Dendrites determine the contribution of after depolarization potentials (ADPs) to generation of repetitive action potentials in hypothalamic gonadotropin releasing-hormone (GnRH) neurons. J Comput Neurosci 26:39-53
Roberts, C B; Hemond, P; Suter, K J (2008) Synaptic integration in hypothalamic gonadotropin releasing hormone (GnRH) neurons. Neuroscience 154:1337-51
Roberts, Carson B; Campbell, Rebecca E; Herbison, Allan E et al. (2008) Dendritic action potential initiation in hypothalamic gonadotropin-releasing hormone neurons. Endocrinology 149:3355-60
Suter, K J; O'Farrell, L (2008) Impaired episodic LH secretion in female mice with GFP in GnRH neurons. Am J Physiol Endocrinol Metab 295:E130-6
Roberts, C B; Best, J A; Suter, K J (2006) Dendritic processing of excitatory synaptic input in hypothalamic gonadotropin releasing-hormone neurons. Endocrinology 147:1545-55