SUMMARY The long-term goal of this project is to understand the developmental mechanisms underlying neural connectiv- ity within sensorimotor reflex circuits in our brain. Reflex circuits enable individual sensory inputs to elicit func- tionally appropriate stereotyped motor outputs, suggesting fine-scale connection specificity between the sensory and motor systems. However, in the brain, neurons responsible for different functions are often continuously aligned on topographic maps, with functionally different neurons being intermingled at the boundary regions between functional groups. It is poorly understood how functionally different neighbors on a topographic map are distinguished during reflex circuit development so that they can invariably generate appropriate responses to sensory information. We have established the vagus nerve in larval zebrafish as an efficient system in which to address this long-standing mystery in brain circuit development. The vagus nerve exits the hindbrain and branches widely to innervate the pharynx, larynx, stomach, heart and other visceral organs. This nerve carries both sensory and motor axons, each of which participates in one of several polysynaptic reflex circuits including the pharyngeal reflex and baroreflex. Our group has discovered that vagus motor neurons and sensory axons are co-organized in a continuous topographic map that is detectable within the larval zebrafish hindbrain. Our pre- liminary data support that local sensory inputs to the vagus sensory system selectively activate functionally ap- propriate groups of vagal motor neurons with a strikingly fine-scale connection specificity that distinguishes adjacent functionally different neurons. In order to investigate the mechanism underlying this functional sepa- ration, we will investigate the contribution of neural activity in vagal motor neurons for fine-scale connection specificity (Aim 1), and we will determine the structural basis of vagal reflex circuit refinement via transsynaptic labeling (Aim 2). The successful outcome of these aims will provide neurophysiological and neuroanatomical insights into fine-scale connection specificity at the level of entire sensorimotor reflex circuits in the vertebrate brain. The larval zebrafish has emerged as a premiere system in which to study developmental neurobiology, and the tools we develop in the vagus system will be generally applicable to questions about the role of neural activity in other aspects of nervous system development.