Date of Completion

Spring 5-1-2023

Thesis Advisor(s)

Joanne Conover

Honors Major

Physiology and Neurobiology

Abstract

This project is the first step in identifying the molecular mechanisms that support movement and distribution of neural stem cells that migrate from the lateral ventricles to the olfactory bulb (OB) and ventral medial prefrontal cortex (VMPFC, humans). In rodents, the forebrain rostral migratory stream (RMS) is the only postnatal long-range pathway involved in neuroblast cell migration. It consists of fasciculated chains of neuroblasts that migrate through a dense meshwork of astrocytes to finally integrate within the olfactory bulb. What exactly guides new neuron distribution and coordinates this extensive migration still remains unclear.

Ephs/ephrins are well known for coordinating and directing cell migration during developmental periods in many organ systems, including the brain. The Eph receptor tyrosine kinase can transduce signals through its interactions with ephrin ligands through direct cell-cell contact and both Ephs and Ephrins are expressed abundantly at the SVZ, RMS, and OB, making them potential candidates for regulating neuroblast migration. Our main goal is to determine if specific Eph/Ephrins are involved in the migration and distribution of neuroblasts within the OB of mouse brains.

Previously, the Conover lab found the EphA4 receptor is a key player in RMS organization as it is expressed in both RMS neuroblasts and astrocytes. Specifically, EphA4-/- mice show disorganized migration with neuroblast deviating from the RMS, loss of neuroblast fasciculation, disoriented astrocyte meshwork and a reduction of cells that get to the OB (Todd et al. 2017).

We hypothesize the differential co-expression of specific Ephs/ephrins in newly migrated inhibitory interneuron populations of mice plays a role in their guidance to either the periglomerular layer or granule cell layer of the OB. Similarly, in humans we predict that single-cell specific Eph/Ephrin expression patterns will map to both the RMS and medial migratory stream (MMS), as well as to the target regions of the OB and VMPFC. Ultimately, our findings will be used to infer specific molecular mechanisms that direct specific neuroblast subpopulation to their proper destination during OB development.

Based on information found from mouse brain tissue and the utilization of single-cell analysis techniques, we will then use mass cytometry and immunohistochemistry to examine differential Ephs/ephrins protein expression patterns through subcellular resolution imaging. We will also identify Eph/Ephrin expression patterns in the human brain at various ages and create a spatial 3D model of human neuroblast migration pathways to understand what healthy Eph/Ephrin expression patterns look like. Irregularities would allow us to better understand the disease dynamics affecting human subventricular zone (SVZ) neurogenesis at critical stages of human maturity. We will also be able to compare developmental time points of the human brain to create a timeline of RMS and MMS development.

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