In the proposed study, I will establish fundamental principles relating structure, function, and migration in developing neurons and circuits. Neuronal migration occurs throughout the central nervous system during development, and abnormal migration contributes to a wide variety of neurological disorders, including ataxia, seizures, schizophrenia, and epilepsy. By applying a unique combination of state-of-the-art techniques and available resources in the larval zebrafish model, I hope to shed light on the complex roles of migration in circuit formation, by studying the effect of normal and abnormal migration on the development of facial branchiomotor neurons (FBMNs) in the hindbrain. These neurons undergo an early, dramatic caudal migration that is likely to serve an important functional role, bringing FBMNs closer to respiratory reflex circuits in the caudal hindbrain. Othe laboratories studying the mechanisms of migration have generated a wide variety of zebrafish mutants that specifically disrupt caudal FBMN migration without adversely affecting the general health of the animal. These circumstances present a unique opportunity to gain a foothold in the complex relationship between migration and functional development, with important consequences for our understanding of neuronal migration disorders.
In Aim 1, I will define the normal endpoint of functional development by studying the functional and morphological properties of postmigratory FBMNs in larval zebrafish. I will use patch recording to quantify intrinsic physiological and rhythmic response properties of FBMNs, which likely support the role of these cells in respiratory behavior. I will also visualize the location and extent of their denditic arbors, reflecting the brain region where these neurons receive synaptic inputs. Pilot data indicates that this approach will be fruitful in describing important postmigratory FBMN traits to provide the foundation for explorations of when these properties develop with respect to migration and how they change when migration is disrupted.
In Aim 2, I will explore the development of FBMN structural and functional properties during migration in zebrafish embryos to relate the progress of functional development with the migratory process. I will combine traditional intracellular recordings with calcium imaging (using a recently piloted transgenically expressed indicator) to trace the appearance of important structural and functional landmarks found in Aim 1 in order to determine which traits fail to develop until caudal migration is complete.
In Aim 3, I will determine how the structural and functional properties of FBMNs are affected by disruptions to caudal migration in mutant zebrafish larvae. Using the methods of Aim 1 and armed with the knowledge gained in Aim 2, I will look for patterns in structural and functional differences between FBMNs with normal and abnormal caudal migration, to reveal the capacity (or lack thereof) of the nervous system to compensate for abnormal migration.
As the brain develops, many neurons travel long distances away from their birthplace through a process called neuronal migration. Abnormal neuronal migration is associated with over twenty-five neurological disorders, including schizophrenia, epilepsy, and ataxia. This project will use a population of migrating cranial motor neurons in the zebrafish hindbrain to explore how the functional properties of neurons develop during migration and how they change when genetic mutations disrupt proper migration.
|McArthur, Kimberly L; Fetcho, Joseph R (2017) Key Features of Structural and Functional Organization of Zebrafish Facial Motor Neurons Are Resilient to Disruption of Neuronal Migration. Curr Biol 27:1746-1756.e5|
|Chen, Shijia; Chiu, Cindy N; McArthur, Kimberly L et al. (2016) TRP channel mediated neuronal activation and ablation in freely behaving zebrafish. Nat Methods 13:147-50|