Chapter 6 - Spinal interneurons providing input to the final common path during locomotion
Introduction
A critical question in neuroscience is how neural circuits produce behavior. In the early twentieth century, Sherrington studied neural circuits responsible for motor reflexes and muscle contraction (Creed et al., 1932). His work spawned generations of scientists investigating the neural control of movement (Stuart, 2005). The honorees of this symposium are several generations removed from Sherrington; their contributions to our understanding of the circuits underlying rhythmic movement are legion. There is no doubt that our current understanding of breathing, walking, and chewing can be attributed in large measure to the efforts of Jack Feldman, Serge Rossignol, and James Lund.
It is almost the centenary of the publication of Thomas Graham Brown's works demonstrating that the mammalian spinal cord has the intrinsic capacity to produce locomotor activity (Brown, 1911, Brown, 1914). Our understanding of the spinal circuits responsible for this behavior in terms of connectivity, neuronal intrinsic properties, and modulation has been steadily increasing (for review, see Goulding, 2009, Grillner, 2006, Kiehn, 2006). Although descending and sensory inputs are critical for normal locomotion, the spinal locomotor network, or “central pattern generator” (CPG), regulates the basic rhythm (or speed) and pattern (or coordination) of walking, as well as the degree of motoneuron output (leading to strength of muscle contraction) during locomotion. One strategy in defining the neural network underlying locomotion is to use a bottom-up approach in which the network is described by peeling back the layers starting from the neurons that generate the output of the circuit—motoneurons or “the final common path” (Creed et al., 1932). Hence, in this chapter, we will focus on last-order spinal interneurons—those neurons that project to and synapse directly with motoneurons and thus produce the motor output of locomotion.
Many classes of spinal interneurons have been identified based upon anatomical and electrophysiological characteristics in the cat (Jankowska, 2008) and based upon genetic characteristics in the mouse (Goulding, 2009). Given the diversity of spinal interneurons and the difficulty in identifying them, it would be reasonable to ask the question: how would one know if any particular interneuron is directly involved in controlling motoneuron activity during locomotion? To answer this question, a list of criteria could be developed (cf. Brownstone and Wilson, 2008); one could then determine whether or not the criteria are fulfilled for any given neuronal population. Given that motoneurons receive alternating excitatory and inhibitory input during locomotion (Jordan, 1983, Perret, 1983), tentative criteria lists for both excitatory (Table 1) and inhibitory (Table 2) last-order interneurons can be proposed. It is expected that these lists will be modified as further data regarding locomotor networks is obtained. It should also be recognized that each subset of these last-order interneurons (i.e., excitatory and inhibitory) likely comprises more than one population of neurons. Hence, a single population may not fulfill all criteria (particularly related to their inputs). In addition, it is now recognized that there are also last-order spinal modulatory inputs to motoneurons (Miles et al., 2007, Zagoraiou et al., 2009). These will be considered separately below.
From the time of Sherrington to recent years, mammalian locomotor circuits have been explored largely in the cat, in which several populations of last-order neurons have been identified. In recent years, attention has turned to the mouse spinal cord. Advances in molecular biology have generated new tools to dissect, study, and manipulate these circuits, with one aim being to identify interneurons responsible for rhythmic motor output. In particular, these advances have led to the use of fluorescent proteins as markers of gene expression (Chalfie et al., 1994, Zacharias et al., 2000) and tools to activate or silence (Zhang et al., 2007) neurons; these tools will be important in determining whether neurons meet the criteria and are involved in locomotor behavior.
Here, we will briefly review some last-order interneuronal populations in mammals that may be involved in the regulation of motoneuron activity during locomotion. It should be noted that even though many of these populations have been found to be rhythmically active during locomotion, none has been found to be critical for the production of motor neuron output during locomotion. The interneurons we will discuss are depicted in Fig. 1. Although the neurons defined in the cat seem to be distinct from those described in rodents, there has been recent progress to relate these functionally and molecularly defined populations. Note that we will not discuss the fundamental work done in invertebrates (see Marder and Bucher, 2007 for review) or lower vertebrates (see Grillner et al., 2008 for review), nor will we discuss the experimental approaches to studying these neurons in humans (see Hultborn and Nielsen, 2007).
Section snippets
Renshaw cells
The first two sources of inhibition to motoneurons to be described were Renshaw cells (RCs) (Eccles et al., 1954, Renshaw, 1941, Renshaw, 1946) and Ia inhibitory interneurons (IaINs) (Jankowska and Roberts, 1972). RCs are responsible for “recurrent inhibition”—they receive inputs from α-motoneuron axon collaterals (Eccles et al., 1954, Lamotte D'incamps and Ascher, 2008), and in turn monosynaptically inhibit α-motoneurons (as well as γs) through glycinergic/GABAergic synapses (Geiman et al.,
Group I excitatory interneurons
Similar to the identification of inhibitory spinal interneurons in the cat, excitatory spinal interneurons have been identified primarily based on their connectivity. The best described source of sensory-derived motoneuron excitation is the direct monosynaptic Ia afferent excitation of motoneurons originating from muscle spindles responsive to muscle stretch. Whether Ia axons, which are rhythmically depolarized during fictive locomotion (Duenas and Rudomin, 1988, Gossard, 1996), contribute to
Spinal modulatory neurons
During locomotion, the postspike after hyperpolarization is modulated in spinal motoneurons (Brownstone et al., 1992a). We have recently demonstrated that this modulation can be produced by activity in neurons supplying the prominent cholinergic C-boutons synapsing on motoneuronal somata (Miles et al., 2007). The neurons supplying these C-boutons are the medial partition neurons (Miles et al., 2007; named by Barber et al., 1984). These neurons, identified by expression of the transcription
Concluding remarks
In this chapter, we have briefly outlined some last-order interneurons identified in the cat and mouse. While the adult cat preparation has been very useful for the physiological identification of interneurons and the mouse has been useful for molecular identification and manipulation, it is the combination of these approaches, physiological and molecular, that will lead to our understanding of the spinal control of movement.
It is likely that there is significant redundancy in these circuits.
Acknowledgments
We thank Elzbieta Jankowska for her insightful comments on a previous version of this chapter. R. M. B. is supported by grants from the Canadian Institutes of Health Research, while T. V. B. is funded by a fellowship from the Canadian Institutes of Health Research. This chapter is dedicated to the memory of James Lund, a leading contributor to Canadian physiological research as well as in the field of control of rhythmic movements.
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2022, Journal of Electromyography and KinesiologyCitation Excerpt :Motor neurons receive synaptic input from afferent feedback from peripheral joint mechanoreceptors (Conway et al., 1995), descending pathways from the motor cortex (Negro and Farina, 2011), and descending pathways from the reticular formation (Baker, 2011). Motor neuron inputs are also modulated by pre-synaptic excitatory and inhibitory spinal interneurons (Brownstone and Bui, 2010) and a variety of neuromodulators (Johnson and Heckman, 2014). Motor units are, therefore, the “final common pathway” by which multiple excitatory and inhibitory inputs are filtered to then activate skeletal muscle (Enoka and Farina, 2021).
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