Good control of posture and orientation is vital for animals as they make movements or navigate the environment. Vertebrates rely on the vestibulospinal system to translate gravity sensations from the inner ear into appropriate compensatory trunk (axial) and limb movements to stabilize and orient themselves. Although this system exists in all vertebrates and is crucial for survival, research on it has languished du to the technical difficulties in recording from vestibular and spinal neurons, especially during animal motion. My long-term goal is to define the means by which vestibular and cerebellar pathways influence spinal circuit activity patterns to fine-tune behavioral outputs. The objective of this proposal is to determine how vestibular signals are translated into appropriate compensatory postural adjustments by defining the synaptic circuit by which vestibular neurons govern the activity of spinal motor neurons and interneurons. To surmount the technical difficulties that have limited prior efforts, I propose to use the larval zebrafish. Zebrafish are n excellent system for this line of research because of the accessibility of their brainstem and spinal column, and the strong homologies between zebrafish and mammalian spinal circuits. Thus, circuit mapping between the brainstem and spinal cord can be performed with much greater ease than in mammalian systems, and the results are likely to be applicable across vertebrates. Microcircuit activity can then be translated into behavioral output due to the relativ simplicity of the zebrafish body plan, yielding a complete picture of this vital sensorimotor transformation.
In Aim 1, a combination of calcium signaling and electrophysiology in vivo will be used to examine differential recruitment of dorsal and ventral musculature while the animal attempts to right itself from side-lying to upright. The requirement for vestibular signals will be tested in mutant animals missing their otoliths (gravity sensors). These experiments will identify how motor pools are activated by vestibular signals to drive self-righting.
In Aim 2, vestibular neurons will be stimulated during in vivo recordings from identified spinal motor neurons to test how vestibulospinal drive is distributed to the appropriate pools of motor neurons for self-righting. Finally, Aim 3 will extend this research to spinal interneurons, to identify how descending inputs regulate interneuronal circuits for highly specific modulation of movement. Impairments in vestibulospinal signaling can cause vertigo and falls, a major health hazard in the elderly. Thus, a complete sensory-to-motor analysis of vestibulospinal signaling will advance our understanding of descending control of behavior and potentially identify strategies for improving human postural control.
Vertigo and falls represent a major health hazard in the elderly and those with common neuropathic ailments like diabetes. Although falls are frequently due to impairments in the balance system, it is not known how balance signals from the inner ear normally interact with the spinal cord to drive movements that help maintain posture. This proposal seeks to identify the precise connections between the inner ear and the spinal cord that underlie compensatory postural adjustments, providing the basis for future therapeutic interventions in humans with balance deficits.
|Bagnall, Martha W; McLean, David L (2014) Modular organization of axial microcircuits in zebrafish. Science 343:197-200|
|Kishore, Sandeep; Bagnall, Martha W; McLean, David L (2014) Systematic shifts in the balance of excitation and inhibition coordinate the activity of axial motor pools at different speeds of locomotion. J Neurosci 34:14046-54|