Sensory feedback regarding limb position is critical for normal locomotion and adaptation to external perturbations during movement. Feedback relating to rapid changes in muscle stretch, conveyed to the spinal cord by proprioceptive Ia sensory afferents, is especially important in this regard. While Ia afferents make some monosynaptic connections with motor neurons (MNs), direct proprioceptive influence on MN activity is exceptional;in general, proprioceptive feedback to MNs is indirect via interneuronal circuits of the spinal cord. These circuits integrate sensory feedback with centrally generated patterns of activity to modulate MN responses. Despite the importance of these more complex circuits in shaping motor output, very little is known about how these circuits are formed. Developmental mechanisms that control the establishment of proprioceptive input to interneuronal circuits, even those containing a single interneuron class, are virtually unknown. One simple sensory-motor circuit is responsible for reciprocal inhibition (RI), which acts to prevent co- contraction of antagonist flexor and extensor muscles at a joint. This sensory-motor circuit contains a single class of interneuron, the glycinergic Ia inhibitory interneuron (IaIN). These interneurons receive sensory information about muscle stretch through monosynaptic inputs from Ia afferents supplying specific muscles. Normal development of RI requires assembly of multiple, modular circuits responding to activation of Ia afferents arising from specific muscles and inhibiting functionally appropriate MN targets. What developmental mechanisms guide this process? Activity-induced RI circuit modulation in early postnatal animals suggests the possibility that activity-dependent mechanisms may be involved in the establishment of Ia sensory afferent connections with functionally appropriate subsets of IaINs. Experiments presented in this proposal will directly test this hypothesis by investigating the status of afferent connectivity with RI circuits at the initial stages of its development. We will test the necessity and sufficiency of proprioceptive afferent activity in the process of afferent segregation onto subsets of IaINs using genetic strategies in mice. Development of reciprocal inhibition mediated by IaINs is fundamental to the development of normal locomotion, and reduced RI is associated with abnormal voluntary movement and locomotion. Understanding the progression and mechanisms of normal RI development will provide an important context and perspective for understanding the expression of abnormal motor behaviors in disease and injury states.

Public Health Relevance

Reciprocal inhibition of antagonist muscles is controlled by spinal neurons and is influenced by sensory feedback. It is critical for normal movement, but very little is known about how it develops. This project investigates the mechanisms of normal reciprocal inhibition development to better understand its function in childhood movement disorders such as cerebral palsy.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Sensorimotor Integration Study Section (SMI)
Program Officer
Chen, Daofen
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wright State University
Other Basic Sciences
Schools of Medicine
United States
Zip Code
Floyd, Taylor L; Dai, Yiyun; Ladle, David R (2018) Characterization of calbindin D28k expressing interneurons in the ventral horn of the mouse spinal cord. Dev Dyn 247:185-193
Sonner, Patrick M; Ladle, David R (2018) Facilitation of antagonist motor output through short-latency sensory pathways during postnatal development in the mouse. Neurosci Lett 674:36-41
O'Toole, Sean M; Ferrer, Monica M; Mekonnen, Jennifer et al. (2017) Dicer maintains the identity and function of proprioceptive sensory neurons. J Neurophysiol 117:1057-1069
Sonner, Martha J; Walters, Marie C; Ladle, David R (2017) Analysis of Proprioceptive Sensory Innervation of the Mouse Soleus: A Whole-Mount Muscle Approach. PLoS One 12:e0170751
Dallman, Marisela A; Ladle, David R (2013) Quantitative analysis of locomotor defects in neonatal mice lacking proprioceptive feedback. Physiol Behav 120:97-105
Sonner, Patrick M; Ladle, David R (2013) Early postnatal development of GABAergic presynaptic inhibition of Ia proprioceptive afferent connections in mouse spinal cord. J Neurophysiol 109:2118-28