Whole circuit optical interrogation of the neural mechanisms mediating force production

The National Institute of Neurological Disorders and Stroke awarded The Trustees of the University of Pennsylvania $100,228 on September 30, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) to conduct optical interrogation of neural mechanisms mediating force production.

The recipient will employ in vivo two-photon calcium imaging to record motor neuron activity and proprioceptive inputs in mice during licking and biting—complex, precisely controlled orofacial behaviors. The research addresses how motor neurons are recruited during naturalistic behavior, testing whether the "size principle" (which posits that motor pool recruitment is determined by intrinsic motor neuron properties) generalizes beyond simplified laboratory tasks or whether motor neurons are recruited flexibly and independently in response to behavioral demands. By measuring activity patterns within motor pools and their proprioceptive feedback connections during these behaviors, the study will clarify how sensory feedback coordinates motor neuron recruitment.

Performance occurs in Philadelphia, Pennsylvania, with an ultimate completion date of May 31, 2029. The assistance type is a Project Grant, which supports investigator-initiated extramural research exploring fundamental structure and function of the brain and nervous system.

Abstract

Producing even seemingly simple movements, like biting into food, requires the precise coordination of the many motor neurons innervating each involved muscle. How this coordination is accomplished is a fundamental question in motor control. A long-standing theory proposes that all motor neurons innervating the same muscle (a motor pool) are recruited by a common set of presynaptic inputs and that recruitment order is thus determined by the intrinsic properties of each motor neuron. While support for this "size principle" has been observed during simplified behavioral tasks, IT remains unclear whether IT generalizes to naturalistic behaviors or whether motor neurons are recruited flexibly and independently by distinct inputs to meet behavioral demands. Sensory feedback from proprioceptors shapes motor neuron activity, but the structure of this feedback and its role in recruiting motor neurons during naturalistic behavior remain poorly defined. Further study into how proprioceptive feedback coordinates motor neurons during simple and complex is necessary to understand how synaptic inputs shape motor neuron activity. A complete understanding of motor neuron recruitment requires the direct recording of a population of motor neurons and their inputs in vivo, during behavior. In part due to technical challenges, prior studies of limb-innervating motor neurons, (which reside in the ventral spinal cord), have not been able to achieve this. To fill this significant GAP in the field, i am leveraging the accessibility of motor neurons in the brainstem that control orofacial movements. I developed a preparation that, for the first time, enables in vivo two-photon CA2+ imaging of motor neurons and their proprioceptive inputs in mice during licking and biting - two complex, precisely controlled orofacial behaviors. I will first measure the activity patterns within a motor pool and assess whether they are consistent with recruitment by shared or independent inputs (aim 1). Second, i will investigate what aspects of orofacial behavior are encoded by type IA proprioceptors, and whether they provide heterogeneous feedback onto individual motor neurons within a single pool (aim 2). This work will extend our understanding of how the CNS coordinates motor output under naturalistic conditions, provide a framework for dissecting the role of additional motor neurons inputs, and will more generally improve our fundamental understanding of the neural control of movement across health and disease.