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Glial cell expansion and intercellular signaling in the developing Medial Nucleus of the Trapezoid Body Ashley Nicole Brandebura Neural circuit formation is a complex process involving coordinated communication between neurons, glia and vascular-associated cells (VACs). Each cell type is responsible for a unique transcriptional and translational contribution to tissue maturation. Deciphering the intercellular signaling patterns which guide neural circuit formation during normal development is thus an essential step in understanding which components of neural circuit formation go awry in neurodevelopmental disorders. The medial nucleus of the trapezoid body (MNTB), located in the auditory brainstem, was used as a model system to study the dynamics of neural circuit formation because it contains a mostly homogenous population of postsynaptic neurons and the largest nerve terminal in the central nervous system, the calyx of Held (CH). We conducted an extensive cell counting study using light microscopy to characterize changes in the neuronal:nonneuronal cell ratio across development of the MNTB. Using cell type-specific antibodies we obtained the relative percentages of each cell type at P3 and P6, key timepoints for CH growth and refinement to mono-innervation. Significant increases in the glial cell percentage are due mostly to an increase in percentage of oligodendrocytes. Using proliferation and mitotic markers, we demonstrated that oligodendrocytes locally divide within the boundaries of the MNTB during this timeframe. Changes in the neuronal:nonneuronal cell ratio aided in interpretation of transcriptional data obtained from a previously conducted developmental microarray study performed in the MNTB. In the microarray study, many up-regulated transcripts were known to be more highly expressed in glial cells in other brain regions. By connecting cell numbers to transcript level, we were able to determine whether a transcript highly expressed in glial cells was detected as up-regulated due to increases in cell number or due to true transcriptional up-regulation on a per cell basis. In a second study, single cell RNASequencing (scRNA-Seq) allowed us to generate cell type-specific transcriptional profiles for each major cell type in the MNTB. These data added cell type-specific expression information to the developmentally regulated transcripts identified in the microarray study, many of which were previously unassigned to a specific cell type. We identified transcripts related to several major intercellular signaling pathways at P3, including FGF, Delta-Notch, TGFβ and VEGF pathways. In many cases the direction of signaling between cell types could be determined based on expression patterns of transcripts encoding for ligands and their cognate receptors. Most interestingly, we were able to tie transcriptional data with structural changes that occur during MNTB tissue maturation, such as perineuronal net formation and angiogenesis. The combination of cell counting data, temporal transcriptional data at the tissue level and cell typespecific transcriptional data at the single cell level offers a broad picture of the process of neural circuit formation in the MNTB and provides a solid foundation to develop and test new mechanistic hypotheses.

Glial cell expansion and intercellular signaling in the developing Medial Nucleus of the Trapezoid Body (MNTB)