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Deconstruction of neural circuits provides insights into complex network function

  • Author(s): Sternfeld, Matthew
  • Advisor(s): Pfaff, Samuel L.
  • et al.
Abstract

The neuronal subtypes that compose the locomotor central pattern generator (CPG) are found in the ventral horn of the spinal cord. Numerous studies have ablated neuronal subtypes and observed the altered activity in an experimental design called fictive locomotion. These ablation studies have provided great insight into the locomotor CPG, but the remaining network is still complex, making it difficult to obtain deep insight into how the circuit actually functions. To simplify this network, we set out to generate an in vitro stand-in for the locomotor CPG that involved differentiating mouse embryonic stem cells (mESCs) into the neurons that comprise the locomotor CPG.

This dissertation describes a series of original work that aims to elucidate the contributions that different cellular components play in the final output of the locomotor CPG. The first chapter is an introduction into the developmental processes of spinal cord development and the diseases that result when such patterning does not occur properly.

The second chapter proceeds from this review to describe a unique and powerful new technique that allows us to separate the complex locomotor CPG into its cardinal neuronal subtypes. From these component parts, we then generated highly defined de novo networks to determine how a network composed of individual neuronal subtypes behaved. Finally, we mixed one inhibitory neuronal subtype into different pure excitatory neuronal subtype based networks. From these mixing studies we were able to determine that this one inhibitory neuronal subtype has strikingly diverse functions in different excitatory networks.

The third chapter discusses future directions for the work described in Chapter 2. Initially I explain how an extension of the experiments conducted in Chapter 2 could be used to address remaining questions about the locomotor CPG. From there I move on to describe how alterations to the basic experimental designs from Chapter 2 would allow for new, diverse, and exciting experimental questions to be asked. All together, Chapter 3 expands upon the work I have conducted in graduate school and suggests different sets of experiments that I believe would result in many interesting works in their own right.

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