Locomotion is a fundamental and vital animal behavior which relies on the activities of diverse neuronal classes residing within the brainstem and spinal cord. Spinal motor neurons play a central role in coordinating locomotor behaviors, and are engaged by networks of local interneurons that facilitate the rhythm and pattern of limb muscle activation. The basic genetic programs that govern connectivity between spinal interneurons and motor neurons are poorly understood due in large part to the complexity of the hundreds of muscle groups targeted by spinal locomotor circuits. In this exploratory proposal, we will assess the composition and connectivity of locomotor circuits in the little skate Leucoraja erinacea, a primitive cartilaginous fish that displays walking behaviors highly similar to those of tetrapods. Remarkably, we have found that the molecular profiles of fin-innervating motor neurons in Leucoraja are nearly identical to those of tetrapods. Leucoraja generates bipedal locomotion using 8 anatomically well-defined pelvic fin muscles, although the neural circuits that generate this behavior are uncharacterized. In this proposal we will determine the subtype identities and connectivity of spinal motor neurons, interneurons, and muscle in Leocoraja. We will also explore the utility of Leucoraja for assessing motor circuit connectivity programs using viral trans-synaptic tracing assays and electrophysiology.
In Aim 1 we will assess the circuit composition and connectivity of motor neurons and interneurons in Leucoraja, and explore the role signaling through Hox transcription factors in the regional allocation of motor neuron columnar and pool subtype identities.
In Aim2 we will use viral tracing assays to determine the pattern of connectivity between spinal interneurons and motor neurons, and explore the workings of the intraspinal central pattern generators (CPGs) that coordinate the activation of fin muscles during walking and swimming. By exploiting the relatively simple neuromusculature architecture of this primitive vertebrate, and building off our in depth knowledge of neural specification programs in the mammalian spinal cord, these studies could provide insights into the basic mechanisms through which motor circuits are assembled.

Public Health Relevance

A major goal in the neural sciences has been to understand how neuronal cell types are specified during development, and to resolve how subtype identity contributes to the specificity of synaptic connections within neural circuits. The overall goal of this proposal is to develop the ?walking fish? Leucoraja erinacea as a novel model organism to study the assembly of the spinal circuits that govern locomotion. Analysis of circuit assembly in this relatively simple vertebrate model could provide insights into the basic principles governing the wiring of spinal circuits in mammals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS099933-02
Application #
9336984
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Chen, Daofen
Project Start
2016-09-01
Project End
2018-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
New York University
Department
Neurology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10010
Jung, Heekyung; Baek, Myungin; D'Elia, Kristen P et al. (2018) The Ancient Origins of Neural Substrates for Land Walking. Cell 172:667-682.e15
Dasen, Jeremy S (2017) Master or servant? emerging roles for motor neuron subtypes in the construction and evolution of locomotor circuits. Curr Opin Neurobiol 42:25-32