SUMMARY Pain processing in the spinal cord has been postulated to rely on nociceptive transmission (T) neurons receiving inputs from nociceptors and Aβ mechanoreceptors, with Aβ inputs gated through feed-forward activation of spinal inhibitory neurons (IN). Here we used intersectional genetic manipulations to identify these critical components of pain transduction. Marking and ablating six populations of spinal excitatory and inhibitory neurons, coupled with behavioral and electrophysiological analysis, showed that excitatory neurons expressing somatostatin (SOM) represent T-type cells, whose ablation causes loss of mechanical pain. Inhibitory neurons marked by the expression of dynorphin (Dyn) represent IN-type neurons, which are necessary to gate Aβ fibers from activating SOM+ neurons to evoke pain. Therefore, peripheral mechanical nociceptors and Aβ mechanoreceptors, together with spinal SOM+ excitatory and Dyn+ inhibitory neurons form a microcircuit that transmits and gates mechanical pain.

Neurobiologists have long sought to understand how circuits in the nervous system are organized and generate the precise neural outputs that underlie particular behaviors. The motor circuits in the spinal cord that control locomotion and are commonly referred to as central pattern generator (CPG) networks, provide an experimentally tractable model system for investigating how moderately complex ensembles of neurons generate select motor behaviors. The advent of novel molecular genetic techniques coupled with recent advances in our knowledge of spinal cord development means that a comprehensive understanding of how the motor circuitry is organized and operates may now be within our grasp.Motor tasks are key components of the behavioral repertoire of all animals [1][2][3] . While animals typically exhibit quite varied and complex patterns of motor activity, many of the simpler motor behaviours they display -breathing, chewing, peristalsis, swimming, scratching and walking -are well suited to experimental analysis [4][5][6][7][8][9][10][11][12][13] . The analysis of motor behaviors has long been at the centre of efforts to understand how the nervous system is organized and functions, with Sherrington's studies providing important insights into the integrative nature of neural pathways, the reflex arc and the control of reciprocal motor actions by central inhibitory pathways 14 . Sherrington's efforts were based on his recognition that motor neurons as neural effectors for motor actions constitute "the final common pathway". Subsequent studies in the cat, by Eccles, Lundberg, Jankowska and colleagues went a long way toward defining the spinal reflex circuitry, including the properties of the constituent interneurons and their actions on motor neurons 15 -18. Whereas Sherrington favoured the idea that complex motor behaviors, including locomotion, were generated by chains of reflex actions 14, Brown countered this idea by providing evidence that intrinsic networks in the spinal cord can generate rhythmic locomotor-like patterns of activity 19 . This observation gave rise to the concept of the central pattern generator (CPG), a neuronal network that is capable of generating an organized pattern of motor activity independently of sensory inputs, which was first described in invertebrates 20 . In the spinal cord, such networks function as local "control and command" centers 11 -13 , 21 to generate rhythmic axial and limb movements. Descending inputs from the brainstem, basal ganglia and cortex control the selection and shaping of outputs from the locomotor CPG, with further layers of modulation coming from sensory and vestibular pathways that converge on CPG neurons ( Figure 1) [22][23][24][25] .The vertebrate locomotor CPG comprises a distributed network of interneurons and motor neurons, which upon appropriate stimulation, generates an organized motor rhythm that replicates the patterns of motor activity seen during repetitive locomotor tasks such as walking and swimming (Figure 2). The central organizing feat...

We describe the isolation and characterization of Pax‐3, a novel murine paired box gene expressed exclusively during embryogenesis. Pax‐3 encodes a 479 amino acid protein with an Mr of 56 kd containing both a paired domain and a paired‐type homeodomain. The Pax‐3 protein is a DNA binding protein that specifically recognizes the e5 sequence present upstream of the Drosophila even‐skipped gene. Pax‐3 transcripts are first detected in 8.5 day mouse embryos where they are restricted to the dorsal part of the neuroepithelium and to the adjacent segmented dermomyotome. During early neurogenesis, Pax‐3 expression is limited to mitotic cells in the ventricular zone of the developing spinal cord and to distinct regions in the hindbrain, midbrain and diencephalon. In 10–12 day embryos, expression of Pax‐3 is also seen in neural crest cells of the developing spinal ganglia, the craniofacial mesectoderm and in limb mesenchyme of 10 and 11 day embryos.

Association and relay neurons that are generated in the dorsal spinal cord play essential roles in transducing somatosensory information. During development, these two major neuronal classes are delineated by the expression of the homeodomain transcription factor Lbx1. Lbx1 is expressed in and required for the correct specification of three early dorsal interneuron populations and late-born neurons that form the substantia gelatinosa. In mice lacking Lbx1, cells types that arise in the ventral alar plate acquire more dorsal identities. This results in the loss of dorsal horn association interneurons, excess production of commissural neurons, and disrupted sensory afferent innervation of the dorsal horn. Lbx1, therefore, plays a critical role in the development of sensory pathways in the spinal cord that relay pain and touch.

The sequential stepping of left and right limbs is a fundamental motor behavior that underlies walking movements. This relatively simple locomotor behavior is generated by the rhythmic activity of motor neurons under the control of spinal neural networks known as central pattern generators (CPGs) that comprise multiple interneuron cell types. Little, however, is known about the identity and contribution of defined interneuronal populations to mammalian locomotor behaviors. We show a discrete subset of commissural spinal interneurons, whose fate is controlled by the activity of the homeobox gene Dbx1, has a critical role in controlling the left-right alternation of motor neurons innervating hindlimb muscles. Dbx1 mutant mice lacking these ventral interneurons exhibit an increased incidence of cobursting between left and right flexor/extensor motor neurons during drug-induced locomotion. Together, these findings identify Dbx1-dependent interneurons as key components of the spinal locomotor circuits that control stepping movements in mammals.