A fundamentally important question in neuroscience is how sensory feedback and supraspinal commands control the spinal motor programs that control movement. This study will begin to address this issue by examining the connectivity and function of excitatory neurons in the dorsal spinal cord, focusing primarily on cells that express the nuclear orphan receptor RORa. Preliminary findings from the Goulding lab indicate that these sensory interneurons receive convergent inputs from descending motor pathways and from cutaneous sensory afferents. More importantly, loss of the RORa interneurons results in a pronounced motor defect, suggesting these cells form an important excitatory relay that connects sensory and descending pathways to the spinal motor system. In this study, we will use the RORa interneurons to address three important questions that are required to understand how sensory and descending control pathways interface with the spinal motor circuitry. The first involves identifying the source of inputs to the RORa interneurons, using a new genetic transsynaptic tracing system that was developed in the Goulding lab. This will lead to a better understanding of how neurons in the dorsal horn integrate sensory and descending commands (Aim 1). The second is to identify the neurons in the spinal cord that are innervated by RORa interneurons, with a particular focus on neurons that have previously been demonstrated to be key components of the locomotor circuitry (Aim 2). Finally, the role that RORa neurons and other dorsal interneuron cell types play in eliciting and shaping movement will be analyzed by genetic manipulations that use conditional reporter mice to either ablate and silence neurons, or activate them optogenetically (Aim 3). This study, when completed, will be the first to comprehensively analyze the contribution that a population of sensory interneurons makes to motor control. It will provide insights into how the spinal cord integrates tactile sensor stimuli with descending signals from motor centers in the brain to control locomotor movements. The information gained from these studies will aid the generation of new therapeutic approaches for functional recovery following spinal cord injury. It will also provide novel insight into the descending command pathways that control movement and locomotion, whose functioning is compromised in motor disorders such as Parkinson's Disease.

Public Health Relevance

Descending control systems and sensory feedback play critical roles in controlling essential motor behaviors such as locomotion. How these pathways intersect with and control the spinal motor system remains largely unknown. Studies in this proposal will dissect the functional organization of excitatory relay pathways in the dorsal spinal cord that transmit cutaneous and corticospinal signals to spinal motor circuits in order to gain a better understanding of the control systems that initiate and shape locomotor movements and protective reflexes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS080586-02
Application #
8613513
Study Section
Special Emphasis Panel (ZRG1-IFCN-Z (02))
Program Officer
Chen, Daofen
Project Start
2013-02-15
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$406,597
Indirect Cost
$197,011
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Duan, Bo; Cheng, Longzhen; Bourane, Steeve et al. (2014) Identification of spinal circuits transmitting and gating mechanical pain. Cell 159:1417-32