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.

Public Health Relevance

Hearing depends on precisely organized neuronal circuitry. Defects in central auditory circuitry can lead to language difficulties, problems with sound perception, or tinnitus. An understanding of how these circuits are assembled during development will aid in our understanding of developmental disorders that lead to hearing or communications problems.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC010796-07
Application #
9282739
Study Section
Auditory System Study Section (AUD)
Program Officer
Cyr, Janet
Project Start
2011-06-03
Project End
2021-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
7
Fiscal Year
2017
Total Cost
$364,375
Indirect Cost
$119,580
Name
University of California Irvine
Department
Other Basic Sciences
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92617
Cramer, Karina S; Rubel, Edwin W (2016) Glial Cell Contributions to Auditory Brainstem Development. Front Neural Circuits 10:83
Rotschafer, Sarah E; Allen-Sharpley, Michelle R; Cramer, Karina S (2016) Axonal Cleaved Caspase-3 Regulates Axon Targeting and Morphogenesis in the Developing Auditory Brainstem. Front Neural Circuits 10:84
Cramer, K S; Gabriele, M L (2014) Axon guidance in the auditory system: multiple functions of Eph receptors. Neuroscience 277:152-62
Allen-Sharpley, Michelle R; Tjia, Michelle; Cramer, Karina S (2013) Selective tracing of auditory fibers in the avian embryonic vestibulocochlear nerve. J Vis Exp :e50305
Allen-Sharpley, Michelle R; Tjia, Michelle; Cramer, Karina S (2013) Differential roles for EphA and EphB signaling in segregation and patterning of central vestibulocochlear nerve projections. PLoS One 8:e78658
Korn, Matthew J; Koppel, Scott J; Li, Lan H et al. (2012) Astrocyte-secreted factors modulate the developmental distribution of inhibitory synapses in nucleus laminaris of the avian auditory brainstem. J Comp Neurol 520:1262-77
Korn, Matthew J; Koppel, Scott J; Cramer, Karina S (2011) Astrocyte-secreted factors modulate a gradient of primary dendritic arbors in nucleus laminaris of the avian auditory brainstem. PLoS One 6:e27383