Glial Influences on Auditory Brainstem Development

项目总结

PROJECT SUMMARY Central auditory processing relies on precise networks of connections, beginning at the level of the auditory brainstem. The assembly of auditory circuitry during development requires multiple mechanisms to regulate axon growth, synaptogenesis, and pruning of axons and dendritic arbors. Neurodevelopmental disorders can lead to errors in these processes and can be associated with difficulties in auditory processing and communication. The overall goal of our research is to identify the cellular and molecular mechanisms that lead to precise formation of these auditory circuits. In particular, we are interested in identifying the functions of glial cells, non-neuronal cells that communicate with neurons and provide multiple functions throughout the developing and mature brain. We previously showed that glial cells influence synaptogenesis and dendritic maturation in the avian auditory brainstem. Here we expand on these findings to investigate the developmental roles of microglia in the mammalian auditory brainstem. Our studies will focus on three specific aims. First, we will determine the function of microglia in synaptic maturation and synaptic pruning in auditory pathways. We will use high resolution imaging approaches to investigate the roles of microglia and their signaling pathways in the formation of excitatory and inhibitory synapses in the auditory brainstem. Additionally, we will test whether microglia contribute to pruning of synapses in a specialized auditory pathway. Second, we will test determine the importance of microglia in auditory brainstem function. Using both genetic and pharmacological approaches to alter microglial signaling pathways or microglial numbers, we will determine the roles of microglia during development and maintenance of auditory brainstem responses. Third, we will investigate the role of microglia defining a critical period for lesion-induced synaptogenesis. We found that microglia peak in number in the medial nucleus of the trapezoid body at a time when this critical period closes. We will use genetic and pharmacological models to explore the contributions of microglia to developmental plasticity and to maturation of stable circuitry.