Neural plasticity enables the nervous system to adapt to environmental change. The objective of the proposed experiments is to understand the cellular and molecular control of neuronal plasticity using the gonadotropin releasing-hormone (GnRH1)-containing neurons in the hypothalamus as a model system. Knowledge of the mechanisms that regulate changes in individual neuron morphology and synapse formation is critically important for understanding normal function and plasticity in the adult vertebrate brain. However, little is known about the genetic regulation of structural neuronal changes and their functional consequences for neuron activity. To test hypotheses about how and how quickly the plasticity of GnRH1 neurons is regulated, the well-described teleost fish model Astatotilapia burtoni will be used. A. burtoni GnRH1 neurons are plastic over short time scales in adults, enlarging eight-fold and dramatically increasing their dendritic arbors when males switch from a subordinate (non-reproductive) to a dominant (reproductive) state.
Two specific aims are proposed: 1) To measure the temporal sequence of structural gene activation responsible for environmentally-induced reversible GnRH1 neuronal plasticity. Laser capture of individual GnRH1 neurons followed by complementary microarray and candidate gene approaches will identify structural genes that regulate adaptive changes in GnRH1 neuron morphology. This set of experiments will reveal the molecular players implicated in neuronal plasticity and their time couse of activation. 2) To test the functional role(s) of a candidate molecule, target of rapamycin (TOR), in controlling plasticity and function of GnRH1 neurons. I will inhibit TOR protein function during times of maximal plastic change in GnRH1 neurons, and measure GnRH1 neuron functional output. These experiments will show whether TOR is required for GnRH1 plasticity in animals that are naturally induced to become reproductively competent, and whether specific structural changes are necessary for proper GnRH1 neuron function. These data will provide an understanding of the causal relationships between GnRH1 neuron morphology, structural gene activation, and functional output. Results will identify how neuronal plasticity is regulated and how it controls reproductive competence in vertebrates. Using the gene expression data, I will be able to develop an hypothesis of how structural genes interact to further our understanding of the inherent flexibility in individual neurons.
Understanding how neuronal plasticity is affected by the social environment, and what genes are involved in proper GnRH1 neuron morphology and function in vertebrates, will be valuable for developing therapies for neuroendocrine disorders, leading to overall improved public health.
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