Spinal networks pattern motor output and given the large repertoire of motor actions it is not surprising that spinal interneurons form one of the mor complex local networks in the CNS. Unfortunately, there is very incomplete knowledge about how many classes of interneurons exist, their properties and connections. This information is however essential not only to understand motor function, but also the many motor syndromes of neonates and how disease or injury affects these circuits in adult. Recently a new conceptual framework to understand spinal interneurons was prompted by the discovery of a few canonical embryonic classes, conserved from fish to mammals, and that diversify into the large variety of adult phenotypes. In previous grant cycles we established that temporal control of neurogenesis and distinct transcription factor expression generate different inhibitory interneurons from a class known as V1. V1- derived interneurons include those that mediate recurrent inhibition of motoneurons (Renshaw cells) and many that control the reciprocal inhibition of motoneurons with antagonist actions (flexor-extensor: Ia inhibitory interneurons, IaINs). Thus, we divided V1s in an early generated group (that includes Renshaw cells and lack expression of FoxP2) and a late generated group (that includes IaINs and are FoxP2+). Despite these advances we do not have yet a complete scheme of V1 interneuron variety and function, in good part because lack of information about their basic cellular properties, specially their output characteristics in ters of axon projections, connections and firing. Here we hypothesize that early and late born V1s differ in these characteristics.
In aim 1 we will analyze V1 axon projections at the segmental level.
Aim 2 will analyze differences in intersegmental connections.
Aim 3 will analyze the firing properties of different V1 groups. Finally, we will also test whether some of these properties are under the control of FoxP2. Validation of our hypotheses would suggest that early V1s might be adapted for synaptic integration and long lasting modulation of synaptic inputs on motoneuron dendrites, while late V1's might be best adapted to exert phasic proximal inhibition of motoneuron firing, predominantly in the evolutionary more novel reciprocal circuits that control limb function.
Our goal is to understand the organization and development of the spinal cord during the maturation of motor behaviors like locomotion. Human infants, similar to mice, undergo a long period of motor function maturation that ultimately reflects the development of the neural control circuits that generate them. The work will use mouse models to investigate the development of these circuits. This information is essential to understand normal motor development and also the many newborn motor syndromes that currently have unknown etiologies.
|Siembab, Valerie C; Gomez-Perez, Laura; Rotterman, Travis M et al. (2016) Role of primary afferents in the developmental regulation of motor axon synapse numbers on Renshaw cells. J Comp Neurol 524:1892-919|
|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|
|Alvarez, Francisco J; Benito-Gonzalez, Ana; Siembab, Valerie C (2013) Principles of interneuron development learned from Renshaw cells and the motoneuron recurrent inhibitory circuit. Ann N Y Acad Sci 1279:22-31|
|Wootz, Hanna; Fitzsimons-Kantamneni, Eileen; Larhammar, Martin et al. (2013) Alterations in the motor neuron-renshaw cell circuit in the Sod1(G93A) mouse model. J Comp Neurol 521:1449-69|
|van Zundert, Brigitte; Izaurieta, Pamela; Fritz, Elsa et al. (2012) Early pathogenesis in the adult-onset neurodegenerative disease amyotrophic lateral sclerosis. J Cell Biochem 113:3301-12|
|Chen, Weisheng V; Alvarez, Francisco J; Lefebvre, Julie L et al. (2012) Functional significance of isoform diversification in the protocadherin gamma gene cluster. Neuron 75:402-9|
|Wu, Linying; Sonner, Patrick M; Titus, David J et al. (2011) Properties of a distinct subpopulation of GABAergic commissural interneurons that are part of the locomotor circuitry in the neonatal spinal cord. J Neurosci 31:4821-33|
|O'Donovan, Michael J; Bonnot, Agnes; Mentis, George Z et al. (2010) Mechanisms of excitation of spinal networks by stimulation of the ventral roots. Ann N Y Acad Sci 1198:63-71|
|Mentis, George Z; Alvarez, Francisco J; Shneider, Neil A et al. (2010) Mechanisms regulating the specificity and strength of muscle afferent inputs in the spinal cord. Ann N Y Acad Sci 1198:220-30|
|Siembab, Valerie C; Smith, Courtney A; Zagoraiou, Laskaro et al. (2010) Target selection of proprioceptive and motor axon synapses on neonatal V1-derived Ia inhibitory interneurons and Renshaw cells. J Comp Neurol 518:4675-701|
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