Hearing relies on transmission of sound-evoked responses through very precisely arranged neuronal connections. Defects in this circuitry can lead to impairments in sound perception, language, and communication. A central goal in auditory neuroscience is to understand the developmental mechanisms that assemble this circuitry. This knowledge will facilitate the development of molecular and cellular therapies to correct congenital or acquired deficits in auditory processing. The avian brainstem provides an elegant model, as the circuitry is well characterized and readily accessible. In this pathway n. magnocellularis (NM) receives ipsilateral input from cochlear ganglion cell axons and in turn projects bilaterally to n. laminaris (NL). This projection is specialized for the computation of interaural time differences, a major cue used in sound source localization. The goal of this study is to identify the mechanisms underlying maturation of this pathway. An important consideration is the interaction between neurons and glia, which are essential for normal development and response to injury. While many developmental functions for glial cells have been identified, the role that they play in the assembly of auditory circuitry is largely unknown. We have identified the spatiotemporal appearance of glia that reside in the auditory brainstem. Astrocytes emerge prior to the maturation of inhibitory synapses in NL and prior to a period of extensive dendritic remodeling. The proposed studies will determine the role of brainstem astrocytes on NL development. First, the effect of astrocyte co-cultures and astrocyte conditioned medium on NL dendritic morphology will be determined. Second, the effects of astrocytes on the maturation and distribution of inhibitory inputs to NL will be determined. Third, the molecular signals required for these astrocyte functions will be explored. Receptor tyrosine kinases of the Eph and Trk families are expressed in auditory neurons and glia and have demonstrated roles in auditory system development. These experiments will determine whether they are necessary for astrocyte regulation of NL neurons. Together these studies will provide insight into neuron-glial interactions in auditory system development that will contribute to understanding auditory function and treating disorders of auditory processing.
Hearing depends on precisely organized networks of neurons that receive input from the ears. Defects in central auditory circuitry can lead to language difficulties, problems with sound perception, or tinnitus. An understanding of how these networks are assembled during maturation will aid in the development of treatments to improve congenital or acquired hearing problems.
|Rotschafer, Sarah E; Cramer, Karina S (2017) Developmental Emergence of Phenotypes in the Auditory Brainstem Nuclei of Fmr1 Knockout Mice. eNeuro 4:|
|Cramer, Karina S; Miko, Ilona J (2016) Eph-ephrin signaling in nervous system development. F1000Res 5:|
|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, Karina S; Rubel, Edwin W (2016) Glial Cell Contributions to Auditory Brainstem Development. Front Neural Circuits 10:83|
|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|