Semester

Summer

Date of Graduation

2022

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Medicine

Committee Chair

Eric Tucker

Committee Member

Peter Mathers

Committee Member

Ariel Agmon

Committee Member

Candice Brown

Committee Member

Sadie Bergeron

Abstract

The cerebral cortex is responsible for a wide variety of high-level functions including cognition, sensory perception, fine motor control, and the orchestration of body movements. The cortex is comprised of cortical excitatory neurons and inhibitory interneurons, which are arranged in a highly organized fashion into different layers and regions. These two types of cells operate in a delicate balance between excitation and inhibition, which is critical for proper cortical circuitry. In order for the cortex to execute its numerous functions, it must both send and receive input to other brain regions through axonal connections. The organization within the cortex and orchestration of connections with other brain regions is established from very early in development, and disruptions occurring even during embryogenesis can lead to lasting changes in cortical circuitry. Neurodevelopmental disorders such as autism, epilepsy, and schizophrenia are thought to arise from disturbances in the formation of cortical circuits, which can occur years before a disease physically manifests. Therefore, it is critical to understand the fundamental mechanisms responsible for early circuitry formation in order to gain better insight into the causes of these diseases.

This dissertation explores the role of the c-Jun N-terminal kinase (JNK) signaling pathway in early forebrain development. A novel genetic knockout mouse model is used to eliminate all of JNK signaling in vivo from a population of cells that gives rise to cortical inhibitory interneurons. In Chapter 2, I provide evidence that JNK signaling is required for the proper migration of interneurons during embryonic development and their correct laminar allocation in the early postnatal cortical wall. This is demonstrated through both in vivo genetic approaches and ex vivo pharmacological inhibition of JNK signaling, and utilizes live-imaging techniques to assess the dynamic properties of migratory interneurons. In Chapter 3, I discovered a novel, non-autonomous requirement for JNK signaling in the pathfinding of thalamocortical axons. When JNK signaling is eliminated in the ventral telencephalon, it causes a misrouting of the thalamocortical axons that normally traverse through this territory. These are the first studies examining the complete loss of JNK function from cells located in the forebrain in vivo, and provide novel insight into the roles of JNK signaling in the development of cortical inhibitory interneurons and thalamocortical axons. Understanding the genetic regulation of forebrain development will help uncover potential causes of neurodevelopmental disorders, and can ultimately lead to better treatment of these devastating diseases.

Embargo Reason

Publication Pending

Available for download on Wednesday, July 21, 2021

Included in

Neurosciences Commons

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