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Mechanical hypersensitivity is a debilitating symptom associated with millions of chronic pain patients. It exists in distinct forms, including brush-evoked dynamic and filament-evoked punctate. Here we report that dynamic mechanical hypersensitivity induced by nerve injury or inflammation was compromised in mice with ablation of spinal VT3Lbx1 neurons defined by coexpression of VGLUT3Cre and Lbx1Flpo, as indicated by the loss of brush-evoked nocifensive responses and conditional place aversion. Electrophysiological recordings show that VT3Lbx1 neurons form morphine-resistant polysynaptic pathways relaying inputs from low-threshold Aβ mechanoreceptors to lamina I output neurons. Meanwhile, the subset of somatostatin (SOM) lineage neurons preserved in VT3Lbx1 neuron-ablated mice is largely sufficient to mediate von Frey filament-evoked punctate mechanical hypersensitivity, including both morphine-sensitive and morphine-resistant forms. Furthermore, acute silencing of VT3Lbx1 neurons attenuated pre-established dynamic mechanical hypersensitivity induced by nerve injury, suggesting these neurons as a potential cellular target for treating this form of neuropathic pain.

A circuit controlling mechanical itch Considerable progress has been made in understanding and treating chemically induced itch. However, little is known about the mechanisms underlying mechanically evoked itch. Bourane et al. produced a model of mechanical itch by reducing the number of neuropeptide Y–expressing inhibitory spinal interneurons. This led to a selective increase in mechanically evoked itch-like behavior in mice. In contrast, chemically evoked itch or pain behavior remained unaffected. Science , this issue p. 550

SummarySensory circuits in the dorsal spinal cord integrate and transmit multiple cutaneous sensory modalities including the sense of light touch. Here, we identify a population of excitatory interneurons (INs) in the dorsal horn that are important for transmitting innocuous light touch sensation. These neurons express the ROR alpha (RORα) nuclear orphan receptor and are selectively innervated by cutaneous low threshold mechanoreceptors (LTMs). Targeted removal of RORα INs in the dorsal spinal cord leads to a marked reduction in behavioral responsiveness to light touch without affecting responses to noxious and itch stimuli. RORα IN-deficient mice also display a selective deficit in corrective foot movements. This phenotype, together with our demonstration that the RORα INs are innervated by corticospinal and vestibulospinal projection neurons, argues that the RORα INs direct corrective reflex movements by integrating touch information with descending motor commands from the cortex and cerebellum.

Pain information 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 (INs). 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) include T-type cells, whose ablation causes loss of mechanical pain. Inhibitory neurons marked by the expression of dynorphin (Dyn) represent INs, 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. PAPERCLIP

Inhibitory neurons in the spinal cord perform dedicated roles in processing somatosensory information and shaping motor behaviors that range from simple protective reflexes to more complex motor tasks such as locomotion, reaching and grasping. Recent efforts examining inhibition in the spinal cord have been directed toward determining how inhibitory cell types are specified and incorporated into the sensorimotor circuitry, identifying and characterizing molecularly defined cohorts of inhibitory neurons and interrogating the functional contribution these cells make to sensory processing and motor behaviors. Rapid progress is being made on all these fronts, driven in large part by molecular genetic and optogenetic approaches that are being creatively combined with neuroanatomical, electrophysiological and behavioral techniques.

BMP activity is essential for many steps of neural development, including the initial role in neural induction and the control of progenitor identities along the dorsal-ventral axis of the neural tube. Taking advantage of chick in ovo electroporation, we show a novel role for BMP7 at the time of neurogenesis initiation in the spinal cord. Using in vivo loss-of-function experiments, we show that BMP7 activity is required for the generation of three discrete subpopulations of dorsal interneurons: dI1-dI3-dI5. Analysis of the BMP7 mouse mutant shows the conservation of this activity in mammals. Furthermore, this BMP7 activity appears to be mediated by the canonical Smad pathway, as we demonstrate that Smad1 and Smad5 activities are similarly required for the generation of dI1-dI3-dI5. Moreover, we show that this role is independent of the patterned expression of progenitor proteins in the dorsal spinal cord, but depends on the BMP/Smad regulation of specific proneural proteins, thus narrowing this BMP7 activity to the time of neurogenesis. Together, these data establish a novel role for BMP7 in primary neurogenesis, the process by which a neural progenitor exits the cell cycle and enters the terminal differentiation pathway. © 2012. Published by The Company of Biologists Ltd., Trabajo financiado por el Instituto de Biología Molecular de Barcelona/CSIC [BFU2010-18959 y CSD2007-00008] y por el Medical Research Council [U117560541].

Neural networks in the hindbrain and spinal cord generate the simple patterns of motor activity that are necessary for breathing and locomotion. These networks function autonomously, producing simple yet flexible rhythmic motor behaviours that are highly responsive to sensory inputs and central control. This review outlines recent advances in our understanding of the genetic programmes controlling the assembly and functioning of circuits in the hindbrain and spinal cord that are responsible for respiration and locomotion. In addition, we highlight the influence that target-derived retrograde signaling and experience-dependent mechanisms have on establishing connectivity, particularly with respect to sensory afferent innervation of the spinal cord.

Here we show that Smad3, a transforming growth factor β(TGFβ)/activin signaling effector, is expressed in discrete progenitor domains along the dorsoventral axis of the developing chick spinal cord. Restriction of Smad3 expression to the dP6-p2 and p3 domains together with exclusion from the motoneuron progenitor domain, are the result of the activity of key transcription factors responsible for patterning the neural tube. Smad3-mediated TGFβ activity promotes cell-cycle exit and neurogenesis by inhibiting the expression of Id proteins, and activating the expression of neurogenic factors and the cyclin-dependent-kinase-inhibitor p27kip1. Furthermore, Smad3 activity induces differentiation of selected neuronal subtypes at the expense of other subtypes. Within the intermediate and ventral domains, Smad3 promotes differentiation of ventral interneurons at the expense of motoneuron generation. Consequently, the absence of Smad3 expression from the motoneuron progenitor domain during pattern formation of the neural tube is a prerequisite for the correct generation of spinal motoneurons.