Interneurons in the spinal cord are integral components of the neural networks that control posture and movement. We have characterized a number of embryonic interneuron (IN) cell types in the spinal cord with the long term goal of defining their functional contribution to the neural circuitry that controls locomotion. These studies have led to the identification of two classes of inhibitory spinal neurons, V1 and V2B neurons, both of which project ipsilaterally within the ventral horn. Our preliminary evidence indicates that these IN cell types connect to motor neurons and other CPG neurons. In this proposal we will use a combination of genetic, anatomical and electrophysiological approaches to characterize these two cell types and determine their functions in locomotor behaviors. We will perform whole cell recordings on V1 INs to delineate their cellular properties. We will ask whether subsets of V1 INs exhibit specificity in their synaptic connections with motor neurons. We will test our hypothesis that V1 INs provide early cycle inhibition during locomotion to motor neurons. The function of the V1 INs in awake behaving animals will be examined using a novel system that we have developed for acutely silencing neurons in mice. Our analysis of the V2B IN population will focus on characterizing the morphology, neurotransmitter phenotype and connectivity of these neurons. We will determine whether V2B INs are rhythmically active during locomotion, and are thus likely candidates for providing phasic ipsilateral inhibition to other locomotor neurons. Finally, we will test our hypothesis that V2B INs play an essential role in securing flexor-extensor motor activity in the mammalian locomotor CPG. These studies will provide valuable insights into the development and organization of locomotor circuits in the mammalian spinal cord. More importantly, they will lay the groundwork for strategies to treat spinal cord injury and degeneration disorders that affect normal voluntary movements.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37NS037075-14
Application #
8255556
Study Section
Sensorimotor Integration Study Section (SMI)
Program Officer
Chen, Daofen
Project Start
1998-04-01
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
14
Fiscal Year
2012
Total Cost
$530,557
Indirect Cost
$254,943
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Zhang, Jingming; Lanuza, Guillermo M; Britz, Olivier et al. (2014) V1 and v2b interneurons secure the alternating flexor-extensor motor activity mice require for limbed locomotion. Neuron 82:138-50
Li, Yan; Stam, Floor J; Aimone, James B et al. (2013) Molecular layer perforant path-associated cells contribute to feed-forward inhibition in the adult dentate gyrus. Proc Natl Acad Sci U S A 110:9106-11
Stam, Floor J; Hendricks, Timothy J; Zhang, Jingming et al. (2012) Renshaw cell interneuron specialization is controlled by a temporally restricted transcription factor program. Development 139:179-90
Grossmann, Katja S; Giraudin, Aurore; Britz, Olivier et al. (2010) Genetic dissection of rhythmic motor networks in mice. Prog Brain Res 187:19-37
Garcia-Campmany, Lidia; Stam, Floor J; Goulding, Martyn (2010) From circuits to behaviour: motor networks in vertebrates. Curr Opin Neurobiol 20:116-25
Goulding, Martyn (2009) Circuits controlling vertebrate locomotion: moving in a new direction. Nat Rev Neurosci 10:507-18
Lin, Wei; Metzakopian, Emmanouil; Mavromatakis, Yannis E et al. (2009) Foxa1 and Foxa2 function both upstream of and cooperatively with Lmx1a and Lmx1b in a feedforward loop promoting mesodiencephalic dopaminergic neuron development. Dev Biol 333:386-96
Zhang, Ying; Narayan, Sujatha; Geiman, Eric et al. (2008) V3 spinal neurons establish a robust and balanced locomotor rhythm during walking. Neuron 60:84-96