Most of the motor output from the nervous system arises from hindbrain and spinal cord, so understanding the organization of networks in these regions is critical for understanding normal movements as well as their disruption by injury or disease. Our work focuses on revealing principles that underlie the development and functional organization of circuits controlling movement through studies of transparent zebrafish where we can literally watch the brain as it develops and image the activity of neurons during behavior. The hindbrain of young zebrafish is built via a simple plan with gross cell types arranged in columns defined by transmitter and transcription factors and arranged within columns by age and functional properties - a plan likely shared by all vertebrates, including ourselves. The proposed work explores major implications of this plan. Neurons in the young hindbrain are recruited by age and location, with younger, more dorsal ones recruited in slow movements and ventral older ones recruited with faster movements. Importantly, as faster networks are recruited, activity in slower ones is suppressed.
Aim 1 is directed toward finding the pathway at the cellular level that implements this suppression. The orderly engagement of networks according to age and speed implies that circuits are wired up in a roughly age ordered way.
Aim 2 is directed toward exploring optogenetically the extent of these age ordered interactions in hindbrain. This early order is evident in the larval zebrafish brain at a time when it is freely swimming, feeding and respiring. The adult hindbrain, however, looks very different with neurons sometimes clustered into nuclei, but most of them spread more diffusely in the so-called reticular formation. The animal continues to produce the same general classes of behaviors as the transformation from the young to the adult brain occurs. This raises the question of how a simple early pattern is transformed with age, while maintaining function.
In Aim 3 we will address this question by using our ability to image the same fish over weeks to directly visualize patterns of migration of neurons out of the orderly larval pattern during development, monitor their structural changes over time in vivo, and assess the function of the individual cells over time with calcium imaging. Finally, the substantial migration that must underlie the transformations in hindbrain raises the question of exactly what significance there is to this migration. The facial motoneurons in hindbrain migrate a long distance caudally from their site of origin. The molecular mechanisms of this migration have been studied in depth, with the generation of migration-defective mutant lines. There is, however, almost no information about the functional consequences of this migration.
In Aim 4, we will study the structure, activity, age order, and inputs to the facial motoneurons in normal fish and mutants without migration to reveal what is altered in the absence of migration and what is resilient to disruptions of migration. Understanding this is critical for insight into what produces disease states, such as abnormal motor development, that are associated with disrupted migration. 1
Our ability to move depends critically on assembling complex neural circuits in the brain that control which muscles are active at particular times to allow effortless movements. Disruptions of circuits associated with injury, disease, and disrupted development lead to many devastating disorders, such as Parkinson's disease, Huntington's disease, paralysis and epilepsy. Our work is directed toward understanding the developmental and functional rules governing the assembly of circuits in the hindbrain and spinal cord that allow us to move properly and that must be repaired after injury and disease.
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