The adult hippocampus continuously generates new dentate granule neurons from neural stem cells. A number of factors that preferentially activate hippocampal circuits, such as exercise, enriched environment, and many pathological conditions, regulate new neuron development. Neurons transmit activity from cell to cell mainly through synapses. However, synapses of new neurons do not form until at least two weeks after birth. This suggests the presence of diffusible factors from active circuits to regulate new neuron development. This speculation has motivated us to examine signaling pathways reacting to circuit activity to regulate new neuron development. Sphingolipid signaling recently caught massive attention because of its role in mediating activity across cells in the immune system. In a pilot study, we tested the existence of this pathway in the dentate gyrus and found that sphingosine 1-phosphate receptor 1 (S1PR1) is enriched in new neurons. Moreover, both sphingosine kinase 1 and SPNS2 are enriched in existing but not new dentate granule cells. We therefore speculate that the SPNS2-S1PR1 pathway transmits the existing circuit activity to regulate the integration of newborn neurons. To test this hypothesis, we propose the following experiments: First, we will genetically perturb theSPNS2-S1PR1 pathway and test optogenetic activation of dentate granule cells-induced development of new dentate granule cells. Second, in the S1PR1 over-expressing new dentate granule cells, we will use a retroviral method to manipulate the Cdc42 and Akt pathways to examine their roles in mediating the S1PR1 regulation to new neuron development. We will perform the same genetic manipulation of the Cdc42 and Akt pathways in optogenetic-induced development of new dentate granule cells. Third, we will use pilocarpine-induced seizures as a model system to test the development of new neurons after genetically manipulating the SPNS2-S1PR1 pathway. Moreover, we will monitor epileptic activity after disrupting the SPNS2-S1PR1 pathway of new neurons. Our proposal aims to reveal the role of the SPNS2-S1PR1 pathway in propagating neural circuit activity to regulate new neuron development. This study will provide insights towards understanding how existing neural circuits dictate the development of new neurons. Our results may introduce a novel therapeutic target for the treatment of epilepsy.
Disease, degeneration or traumatic injury of the nervous system are among the greatest public health concerns in the United States and are generally considered irreparable, often causing catastrophic damage to the functional capacity of the individual. Now, however, characterization of neural stem cells residing within specific germinal centers of the brain and in cell culture raises hope that functional regeneration of nervous tissue may be feasible, if we learn to exploit adult neurogenesis for clinical benefit. The research proposal here aims to study how existing brain cells control the integration of new members derived from endogenous neural stem cells. If successful, this proposal will lead to improved understanding of neural stem cell biology, possibly leading to the development of new drugs for repair and regeneration of the nervous system.
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