Clarifying how neural circuits shape forelimb behaviors can provide insight into motor dysfunction caused by disease or injury, and can potentially improve diagnosis and treatment. The precision of skilled forelimb movements is thought to depend on the conveyance of internal copies of motor commands to cerebellar circuits that refine motor behavior. The inability to access internal copy pathways selectively, however, has made it difficult to assess their function. The goal of this proposal is to evaluate how forelimb behavior is controlled by a set of cervical propriospinal neurons (PNs) that have a simple anatomical means by which to convey copies of pre-motor signals internally;PNs receive descending motor command input, and send bifurcating axonal output to forelimb motor neurons as well as to the lateral reticular nucleus (LRN), a pre-cerebellar relay. These dual projections raise the issue of whether information relayed by the PN internal copy branch regulates forelimb movement. We took advantage of the genetic tractability of mice to: i) ablate PNs, uncovering a selective disruption of reaching behavior;and ii) manipulate PN axonal input to the LRN selectively, revealing a rapid cerebellar-motor feedback loop. Based on these observations, we hypothesize that PN internal feedback circuits contribute to the on-line correction of motor output during reaching. In this proposal, I aim to address three central questions about the organization and function of the PN circuit. During the K99 phase of the award, I will identify which aspects of forelimb movement recruit this feedback pathway by characterizing the dynamics of PN-LRN circuit activity during behavior (Aim 1). To enable assessment of the role of PN feedback, I will develop viral tools to inhibit the PN-LRN circuit, and behavioral approaches to introduce precisely timed perturbations of the limb (Aim 2;K99). With these methods in hand, during the R00 phase I will silence PN output during imposed limb perturbation to investigate the contribution of PN feedback to on-line reaching correction (Aim 2;R00). Finally, I will characterize the supraspinal circuits that are recruited by PN feedback durin reaching correction (Aim 3). Together, these studies will help clarify how cerebellar feedback pathways establish motor precision. The training plan, under the primary mentorship of Dr. Thomas Jessell at Columbia University, provides a comprehensive strategy for acquiring the necessary experimental and professional skills within an exemplary and collaborative neuroscience environment. An experienced team of mentors and collaborators will provide training in skills critical for my short- and long-term success, including: in vivo imaging of neurl activity, acute silencing of synaptic output, electrophysiological mapping of neural circuits, and rigorous design of forelimb behavioral assays. Focused mentor guidance, alongside frequent data presentation and formal and informal instruction, will provide the communication and leadership skills vital for my transition to independence. In the long-term, this support will equi me to lead a laboratory that merges molecular and systems approaches to explore the neural basis of skilled movement.
Dexterous movements of the arm and hand are critical motor functions often affected by neurodegenerative disease and injury, yet the neural circuits that control these movements remain poorly understood. Using the genetic accessibility of mice to define the function of internal feedback circuits that shape limb movement can contribute to our understanding of the neural control of behavior, and may also have implications for our understanding and treatment of motor deficits caused by disease or injury, as well as the effective design of assistive brain-machine interface and robotic technologies. More generally, the forelimb motor system represents one of the more promising avenues for pursuing the important alliance of mouse and primate research into conserved aspects of mammalian neural function.
|Azim, Eiman; Alstermark, Bror (2015) Skilled forelimb movements and internal copy motor circuits. Curr Opin Neurobiol 33:16-24|
|Azim, Eiman; Fink, Andrew J P; Jessell, Thomas M (2014) Internal and External Feedback Circuits for Skilled Forelimb Movement. Cold Spring Harb Symp Quant Biol 79:81-92|
|Azim, Eiman (2014) Neuroscience. Shortcuts and checkpoints on the road to skilled movement. Science 346:554-5|