Publications by authors named "Martyn Goulding"

60 Publications

Spinal Interneurons as Gatekeepers to Neuroplasticity after Injury or Disease.

J Neurosci 2021 Feb 20;41(5):845-854. Epub 2021 Jan 20.

Department of Neurobiology and Anatomy, and the Marion Murray Spinal Cord Research Center, Drexel University, Philadelphia, Pennsylvania, 19129

Spinal interneurons are important facilitators and modulators of motor, sensory, and autonomic functions in the intact CNS. This heterogeneous population of neurons is now widely appreciated to be a key component of plasticity and recovery. This review highlights our current understanding of spinal interneuron heterogeneity, their contribution to control and modulation of motor and sensory functions, and how this role might change after traumatic spinal cord injury. We also offer a perspective for how treatments can optimize the contribution of interneurons to functional improvement.
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http://dx.doi.org/10.1523/JNEUROSCI.1654-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880285PMC
February 2021

Phox2a Defines a Developmental Origin of the Anterolateral System in Mice and Humans.

Cell Rep 2020 Nov;33(8):108425

Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Integrated Program in Neuroscience, McGill University, Montréal, QC H3A 2B4, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada; Division of Experimental Medicine, McGill University, Montréal, QC H3A 2B2, Canada. Electronic address:

Anterolateral system neurons relay pain, itch, and temperature information from the spinal cord to pain-related brain regions, but the differentiation of these neurons and their specific contribution to pain perception remain poorly defined. Here, we show that most mouse spinal neurons that embryonically express the autonomic-system-associated Paired-like homeobox 2A (Phox2a) transcription factor innervate nociceptive brain targets, including the parabrachial nucleus and the thalamus. We define the Phox2a anterolateral system neuron birth order, migration, and differentiation and uncover an essential role for Phox2a in the development of relay of nociceptive signals from the spinal cord to the brain. Finally, we also demonstrate that the molecular identity of Phox2a neurons is conserved in the human fetal spinal cord, arguing that the developmental expression of Phox2a is a prominent feature of anterolateral system neurons.
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http://dx.doi.org/10.1016/j.celrep.2020.108425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713706PMC
November 2020

Mechanical Allodynia Circuitry in the Dorsal Horn Is Defined by the Nature of the Injury.

Neuron 2021 01 11;109(1):73-90.e7. Epub 2020 Nov 11.

Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA; Pittsburgh Center for Pain Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA; Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA. Electronic address:

The spinal dorsal horn is a major site for the induction and maintenance of mechanical allodynia, but the circuitry that underlies this clinically important form of pain remains unclear. The studies presented here provide strong evidence that the neural circuits conveying mechanical allodynia in the dorsal horn differ by the nature of the injury. Calretinin (CR) neurons in lamina II inner convey mechanical allodynia induced by inflammatory injuries, while protein kinase C gamma (PKCγ) neurons at the lamina II/III border convey mechanical allodynia induced by neuropathic injuries. Cholecystokinin (CCK) neurons located deeper within the dorsal horn (laminae III-IV) are important for both types of injuries. Interestingly, the Maf subset of CCK neurons is composed of transient vesicular glutamate transporter 3 (tVGLUT3) neurons, which convey primarily dynamic allodynia. Identification of an etiology-based circuitry for mechanical allodynia in the dorsal horn has important implications for the mechanistic and clinical understanding of this condition.
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http://dx.doi.org/10.1016/j.neuron.2020.10.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806207PMC
January 2021

A Functional Topographic Map for Spinal Sensorimotor Reflexes.

Neuron 2021 01 11;109(1):91-104.e5. Epub 2020 Nov 11.

Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address:

Cutaneous somatosensory modalities play pivotal roles in generating a wide range of sensorimotor behaviors, including protective and corrective reflexes that dynamically adapt ongoing movement and posture. How interneurons (INs) in the dorsal horn encode these modalities and transform them into stimulus-appropriate motor behaviors is not known. Here, we use an intersectional genetic approach to functionally assess the contribution that eight classes of dorsal excitatory INs make to sensorimotor reflex responses. We demonstrate that the dorsal horn is organized into spatially restricted excitatory modules composed of molecularly heterogeneous cell types. Laminae I/II INs drive chemical itch-induced scratching, laminae II/III INs generate paw withdrawal movements, and laminae III/IV INs modulate dynamic corrective reflexes. These data reveal a key principle in spinal somatosensory processing, namely, sensorimotor reflexes are driven by the differential spatial recruitment of excitatory neurons.
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http://dx.doi.org/10.1016/j.neuron.2020.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790959PMC
January 2021

Parallel ascending spinal pathways for affective touch and pain.

Nature 2020 11 28;587(7833):258-263. Epub 2020 Oct 28.

Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA.

The anterolateral pathway consists of ascending spinal tracts that convey pain, temperature and touch information from the spinal cord to the brain. Projection neurons of the anterolateral pathway are attractive therapeutic targets for pain treatment because nociceptive signals emanating from the periphery are channelled through these spinal projection neurons en route to the brain. However, the organizational logic of the anterolateral pathway remains poorly understood. Here we show that two populations of projection neurons that express the structurally related G-protein-coupled receptors (GPCRs) TACR1 and GPR83 form parallel ascending circuit modules that cooperate to convey thermal, tactile and noxious cutaneous signals from the spinal cord to the lateral parabrachial nucleus of the pons. Within this nucleus, axons of spinoparabrachial (SPB) neurons that express Tacr1 or Gpr83 innervate distinct sets of subnuclei, and strong optogenetic stimulation of the axon terminals induces distinct escape behaviours and autonomic responses. Moreover, SPB neurons that  express Gpr83 are highly sensitive to cutaneous mechanical stimuli and receive strong synaptic inputs from both high- and low-threshold primary mechanosensory neurons. Notably, the valence associated with activation of SPB neurons that express Gpr83 can be either positive or negative, depending on stimulus intensity. These findings reveal anatomically, physiologically and functionally distinct subdivisions of the SPB tract that underlie affective aspects of touch and pain.
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http://dx.doi.org/10.1038/s41586-020-2860-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666110PMC
November 2020

Identification of Spinal Neurons Contributing to the Dorsal Column Projection Mediating Fine Touch and Corrective Motor Movements.

Neuron 2019 11 2;104(4):749-764.e6. Epub 2019 Oct 2.

Department of Molecules - Signaling - Development, Max Planck Institute of Neurobiology, 82152 Martinsried, Germany. Electronic address:

Tactile stimuli are integrated and processed by neuronal circuits in the deep dorsal horn of the spinal cord. Several spinal interneuron populations have been implicated in tactile information processing. However, dorsal horn projection neurons that contribute to the postsynaptic dorsal column (PSDC) pathway transmitting tactile information to the brain are poorly characterized. Here, we show that spinal neurons marked by the expression of Zic2cre mediate light touch sensitivity and textural discrimination. A subset of Zic2cre neurons are PSDC neurons that project to brainstem dorsal column nuclei, and chemogenetic activation of Zic2 PSDC neurons increases sensitivity to light touch stimuli. Zic2 neurons receive direct input from the cortex and brainstem motor nuclei and are required for corrective motor movements. These results suggest that Zic2 neurons integrate sensory input from cutaneous afferents with descending signals from the brain to promote corrective movements and transmit processed touch information back to the brain. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.neuron.2019.08.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814917PMC
November 2019

Spinal Neuropeptide Y1 Receptor-Expressing Neurons Form an Essential Excitatory Pathway for Mechanical Itch.

Cell Rep 2019 07;28(3):625-639.e6

Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address:

Acute itch can be generated by either chemical or mechanical stimuli, which activate separate pathways in the periphery and spinal cord. While substantial progress has been made in mapping the transmission pathway for chemical itch, the central pathway for mechanical itch remains obscure. Using complementary genetic and pharmacological manipulations, we show that excitatory neurons marked by the expression of the neuropeptide Y1 receptor (Y1 neurons) form an essential pathway in the dorsal spinal cord for the transmission of mechanical but not chemical itch. Ablating or silencing the Y1 neurons abrogates mechanical itch, while chemogenetic activation induces scratching. Moreover, using Y1 conditional knockout mice, we demonstrate that endogenous neuropeptide Y (NPY) acts via dorsal-horn Y1-expressing neurons to suppress light punctate touch and mechanical itch stimuli. NPY-Y1 signaling thus regulates the transmission of innocuous tactile information by establishing biologically relevant thresholds for touch discrimination and mechanical itch reflexes.
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http://dx.doi.org/10.1016/j.celrep.2019.06.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709688PMC
July 2019

Neuronal diversity in the somatosensory system: bridging the gap between cell type and function.

Curr Opin Neurobiol 2019 06 4;56:167-174. Epub 2019 Apr 4.

Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Rd, La Jolla, CA 92037, USA. Electronic address:

A recent flurry of genetic studies in mice have provided key insights into how the somatosensory system is organized at a cellular level to encode itch, pain, temperature, and touch. These studies are largely predicated on the idea that functional cell types can be identified by their unique developmental provenance and gene expression profile. However, the extent to which gene expression profiles can be correlated with functional cell types and circuit organization remains an open question. In this review, we focus on recent progress in characterizing the sensory afferent and dorsal horn neuron cell types that process cutaneous somatosensory information and ongoing circuit studies that are beginning to bridge the divide between cell type and function.
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http://dx.doi.org/10.1016/j.conb.2019.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583900PMC
June 2019

Identifying the pathways required for coping behaviours associated with sustained pain.

Nature 2019 01 10;565(7737):86-90. Epub 2018 Dec 10.

Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Animals and humans display two types of response to noxious stimuli. The first includes reflexive defensive responses that prevent or limit injury; a well-known example of these responses is the quick withdrawal of one's hand upon touching a hot object. When the first-line response fails to prevent tissue damage (for example, a finger is burnt), the resulting pain invokes a second-line coping response-such as licking the injured area to soothe suffering. However, the underlying neural circuits that drive these two strings of behaviour remain poorly understood. Here we show in mice that spinal neurons marked by coexpression of TAC1 and LBX1 drive coping responses associated with pain. Ablation of these spinal neurons led to the loss of both persistent licking and conditioned aversion evoked by stimuli (including skin pinching and burn injury) that-in humans-produce sustained pain, without affecting any of the reflexive defensive reactions that we tested. This selective indifference to sustained pain resembles the phenotype seen in humans with lesions of medial thalamic nuclei. Consistently, spinal TAC1-lineage neurons are connected to medial thalamic nuclei by direct projections and via indirect routes through the superior lateral parabrachial nuclei. Furthermore, the anatomical and functional segregation observed at the spinal level also applies to primary sensory neurons. For example, in response to noxious mechanical stimuli, MRGPRD- and TRPV1-positive nociceptors are required to elicit reflexive and coping responses, respectively. Our study therefore reveals a fundamental subdivision within the cutaneous somatosensory system, and challenges the validity of using reflexive defensive responses to measure sustained pain.
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http://dx.doi.org/10.1038/s41586-018-0793-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461409PMC
January 2019

Timing Mechanisms Underlying Gate Control by Feedforward Inhibition.

Neuron 2018 09 16;99(5):941-955.e4. Epub 2018 Aug 16.

Dana-Farber Cancer Institute and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

The gate control theory proposes that Aβ mechanoreceptor inputs to spinal pain transmission T neurons are gated via feedforward inhibition, but it remains unclear how monosynaptic excitation is gated by disynaptic inhibitory inputs that arrive later. Here we report that Aβ-evoked, non-NMDAR-dependent EPSPs in T neurons are subthreshold, allowing time for inhibitory inputs to prevent action potential firing that requires slow-onset NMDAR activation. Potassium channel activities-including I, whose sizes are established constitutively by Preprodynorphin-derived inhibitory neurons-either completely filter away Aβ inputs or make them subthreshold, thereby creating a permissive condition to achieve gate control. Capsaicin-activated nociceptor inputs reduce I and sensitize the T neurons, allowing Aβ inputs to cause firing before inhibitory inputs arrive. Thus, distinct kinetics of glutamate receptors and electric filtering by potassium channels solve the timing problem underlying the gating by feedforward inhibition, and their modulation offers a way to bypass the gate control.
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http://dx.doi.org/10.1016/j.neuron.2018.07.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309466PMC
September 2018

Corticospinal Circuits from the Sensory and Motor Cortices Differentially Regulate Skilled Movements through Distinct Spinal Interneurons.

Cell Rep 2018 05;23(5):1286-1300.e7

Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Electronic address:

Little is known about the organizational and functional connectivity of the corticospinal (CS) circuits that are essential for voluntary movement. Here, we map the connectivity between CS neurons in the forelimb motor and sensory cortices and various spinal interneurons, demonstrating that distinct CS-interneuron circuits control specific aspects of skilled movements. CS fibers originating in the mouse motor cortex directly synapse onto premotor interneurons, including those expressing Chx10. Lesions of the motor cortex or silencing of spinal Chx10 interneurons produces deficits in skilled reaching. In contrast, CS neurons in the sensory cortex do not synapse directly onto premotor interneurons, and they preferentially connect to Vglut3 spinal interneurons. Lesions to the sensory cortex or inhibition of Vglut3 interneurons cause deficits in food pellet release movements in goal-oriented tasks. These findings reveal that CS neurons in the motor and sensory cortices differentially control skilled movements through distinct CS-spinal interneuron circuits.
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http://dx.doi.org/10.1016/j.celrep.2018.03.137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608728PMC
May 2018

Locomotion Control: Brainstem Circuits Satisfy the Need for Speed.

Curr Biol 2018 03;28(6):R256-R259

Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address:

Three new and closely complementary studies have defined the architecture of the circuits underlying the descending control of locomotion, identifying neurons that drive fast motor responses and those that seem to be specialised for exploratory behaviors.
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http://dx.doi.org/10.1016/j.cub.2018.01.068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942195PMC
March 2018

RORβ Spinal Interneurons Gate Sensory Transmission during Locomotion to Secure a Fluid Walking Gait.

Neuron 2017 12 7;96(6):1419-1431.e5. Epub 2017 Dec 7.

Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address:

Animals depend on sensory feedback from mechanosensory afferents for the dynamic control of movement. This sensory feedback needs to be selectively modulated in a task- and context-dependent manner. Here, we show that inhibitory interneurons (INs) expressing the RORβ orphan nuclear receptor gate sensory feedback to the spinal motor system during walking and are required for the production of a fluid locomotor rhythm. Genetic manipulations that abrogate inhibitory RORβ IN function result in an ataxic gait characterized by exaggerated flexion movements and marked alterations to the step cycle. Inactivation of RORβ in inhibitory neurons leads to reduced presynaptic inhibition and changes to sensory-evoked reflexes, arguing that the RORβ inhibitory INs function to suppress the sensory transmission pathways that activate flexor motor reflexes and interfere with the ongoing locomotor program. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.neuron.2017.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828033PMC
December 2017

Spinal Circuits for Touch, Pain, and Itch.

Annu Rev Physiol 2018 02 27;80:189-217. Epub 2017 Sep 27.

Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA; email:

The exteroceptive somatosensory system is important for reflexive and adaptive behaviors and for the dynamic control of movement in response to external stimuli. This review outlines recent efforts using genetic approaches in the mouse to map the spinal cord circuits that transmit and gate the cutaneous somatosensory modalities of touch, pain, and itch. Recent studies have revealed an underlying modular architecture in which nociceptive, pruritic, and innocuous stimuli are processed by distinct molecularly defined interneuron cell types. These include excitatory populations that transmit information about both innocuous and painful touch and inhibitory populations that serve as a gate to prevent innocuous stimuli from activating the nociceptive and pruritic transmission pathways. By dissecting the cellular composition of dorsal-horn networks, studies are beginning to elucidate the intricate computational logic of somatosensory transformation in health and disease.
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http://dx.doi.org/10.1146/annurev-physiol-022516-034303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891508PMC
February 2018

A V0 core neuronal circuit for inspiration.

Nat Commun 2017 09 15;8(1):544. Epub 2017 Sep 15.

Paris-Saclay Institute of Neuroscience, 1 Avenue de la Terrasse, 91190, Gif sur Yvette, France.

Breathing in mammals relies on permanent rhythmic and bilaterally synchronized contractions of inspiratory pump muscles. These motor drives emerge from interactions between critical sets of brainstem neurons whose origins and synaptic ordered organization remain obscure. Here, we show, using a virus-based transsynaptic tracing strategy from the diaphragm muscle in the mouse, that the principal inspiratory premotor neurons share V0 identity with, and are connected by, neurons of the preBötzinger complex that paces inspiration. Deleting the commissural projections of V0s results in left-right desynchronized inspiratory motor commands in reduced brain preparations and breathing at birth. This work reveals the existence of a core inspiratory circuit in which V0 to V0 synapses enabling function of the rhythm generator also direct its output to secure bilaterally coordinated contractions of inspiratory effector muscles required for efficient breathing.The developmental origin and functional organization of the brainstem breathing circuits are poorly understood. Here using virus-based circuit-mapping approaches in mice, the authors reveal the lineage, neurotransmitter phenotype, and connectivity patterns of phrenic premotor neurons, which are a crucial component of the inspiratory circuit.
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http://dx.doi.org/10.1038/s41467-017-00589-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601429PMC
September 2017

Identification of spinal circuits involved in touch-evoked dynamic mechanical pain.

Nat Neurosci 2017 Jun 24;20(6):804-814. Epub 2017 Apr 24.

Dana-Farber Cancer Institute and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.

Mechanical hypersensitivity is a debilitating symptom for millions of chronic pain patients. It exists in distinct forms, including brush-evoked dynamic and filament-evoked punctate hypersensitivities. We reduced dynamic mechanical hypersensitivity induced by nerve injury or inflammation in mice by ablating a group of adult spinal neurons defined by developmental co-expression of VGLUT3 and Lbx1 (VT3 neurons): the mice lost brush-evoked nocifensive responses and conditional place aversion. Electrophysiological recordings show that VT3 neurons form morphine-resistant polysynaptic pathways relaying inputs from low-threshold Aβ mechanoreceptors to lamina I output neurons. The subset of somatostatin-lineage neurons preserved in VT3-neuron-ablated mice is largely sufficient to mediate morphine-sensitive and morphine-resistant forms of von Frey filament-evoked punctate mechanical hypersensitivity. Furthermore, acute silencing of VT3 neurons attenuated pre-established dynamic mechanical hypersensitivity induced by nerve injury, suggesting that these neurons may be a cellular target for treating this form of neuropathic pain.
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http://dx.doi.org/10.1038/nn.4549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470641PMC
June 2017

Anatomical and Molecular Properties of Long Descending Propriospinal Neurons in Mice.

Front Neuroanat 2017 6;11. Epub 2017 Feb 6.

School of Biomedical Sciences and Pharmacy, University of NewcastleCallaghan, NSW, Australia; Hunter Medical Research InstituteNewcastle, NSW, Australia.

Long descending propriospinal neurons (LDPNs) are interneurons that form direct connections between cervical and lumbar spinal circuits. LDPNs are involved in interlimb coordination and are important mediators of functional recovery after spinal cord injury (SCI). Much of what we know about LDPNs comes from a range of species, however, the increased use of transgenic mouse lines to better define neuronal populations calls for a more complete characterisation of LDPNs in mice. In this study, we examined the cell body location, inhibitory neurotransmitter phenotype, developmental provenance, morphology and synaptic inputs of mouse LDPNs throughout the cervical and upper thoracic spinal cord. LDPNs were retrogradely labelled from the lumbar spinal cord to map cell body locations throughout the cervical and upper thoracic segments. Ipsilateral LDPNs were distributed throughout the dorsal, intermediate and ventral grey matter as well as the lateral spinal nucleus and lateral cervical nucleus. In contrast, contralateral LDPNs were more densely concentrated in the ventromedial grey matter. Retrograde labelling in and mice showed the majority of inhibitory LDPNs project either ipsilaterally or adjacent to the midline. Additionally, we used several transgenic mouse lines to define the developmental provenance of LDPNs and found that V2b positive neurons form a subset of ipsilaterally projecting LDPNs. Finally, a population of Neurobiotin (NB) labelled LDPNs were assessed in detail to examine morphology and plot the spatial distribution of contacts from a variety of neurochemically distinct axon terminals. These results provide important baseline data in mice for future work on their role in locomotion and recovery from SCI.
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http://dx.doi.org/10.3389/fnana.2017.00005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292581PMC
February 2017

Speed and segmentation control mechanisms characterized in rhythmically-active circuits created from spinal neurons produced from genetically-tagged embryonic stem cells.

Elife 2017 02 14;6. Epub 2017 Feb 14.

Gene Expression Laboratory, Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, United States.

Flexible neural networks, such as the interconnected spinal neurons that control distinct motor actions, can switch their activity to produce different behaviors. Both excitatory (E) and inhibitory (I) spinal neurons are necessary for motor behavior, but the influence of recruiting different ratios of E-to-I cells remains unclear. We constructed synthetic microphysical neural networks, called circuitoids, using precise combinations of spinal neuron subtypes derived from mouse stem cells. Circuitoids of purified excitatory interneurons were sufficient to generate oscillatory bursts with properties similar to in vivo central pattern generators. Inhibitory V1 neurons provided dual layers of regulation within excitatory rhythmogenic networks - they increased the rhythmic burst frequency of excitatory V3 neurons, and segmented excitatory motor neuron activity into sub-networks. Accordingly, the speed and pattern of spinal circuits that underlie complex motor behaviors may be regulated by quantitatively gating the intra-network cellular activity ratio of E-to-I neurons.
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http://dx.doi.org/10.7554/eLife.21540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5308898PMC
February 2017

Early Somatostatin Interneuron Connectivity Mediates the Maturation of Deep Layer Cortical Circuits.

Neuron 2016 Feb;89(3):521-35

NYU Neuroscience Institute and the Department of Neuroscience and Physiology, Smilow Research Center, New York University School of Medicine, 522 First Avenue, New York, NY 10016, USA. Electronic address:

The precise connectivity of somatostatin and parvalbumin cortical interneurons is generated during development. An understanding of how these interneuron classes incorporate into cortical circuitry is incomplete but essential to elucidate the roles they play during maturation. Here, we report that somatostatin interneurons in infragranular layers receive dense but transient innervation from thalamocortical afferents during the first postnatal week. During this period, parvalbumin interneurons and pyramidal neurons within the same layers receive weaker thalamocortical inputs, yet are strongly innervated by somatostatin interneurons. Further, upon disruption of the early (but not late) somatostatin interneuron network, the synaptic maturation of thalamocortical inputs onto parvalbumin interneurons is perturbed. These results suggest that infragranular somatostatin interneurons exhibit a transient early synaptic connectivity that is essential for the establishment of thalamic feedforward inhibition mediated by parvalbumin interneurons.
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http://dx.doi.org/10.1016/j.neuron.2015.11.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861073PMC
February 2016

Gate control of mechanical itch by a subpopulation of spinal cord interneurons.

Science 2015 Oct;350(6260):550-4

Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.

Light mechanical stimulation of hairy skin can induce a form of itch known as mechanical itch. This itch sensation is normally suppressed by inputs from mechanoreceptors; however, in many forms of chronic itch, including alloknesis, this gating mechanism is lost. Here we demonstrate that a population of spinal inhibitory interneurons that are defined by the expression of neuropeptide Y::Cre (NPY::Cre) act to gate mechanical itch. Mice in which dorsal NPY::Cre-derived neurons are selectively ablated or silenced develop mechanical itch without an increase in sensitivity to chemical itch or pain. This chronic itch state is histamine-independent and is transmitted independently of neurons that express the gastrin-releasing peptide receptor. Thus, our studies reveal a dedicated spinal cord inhibitory pathway that gates the transmission of mechanical itch.
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http://dx.doi.org/10.1126/science.aac8653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4700934PMC
October 2015

A genetically defined asymmetry underlies the inhibitory control of flexor-extensor locomotor movements.

Elife 2015 Oct 14;4. Epub 2015 Oct 14.

Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, United States.

V1 and V2b interneurons (INs) are essential for the production of an alternating flexor-extensor motor output. Using a tripartite genetic system to selectively ablate either V1 or V2b INs in the caudal spinal cord and assess their specific functions in awake behaving animals, we find that V1 and V2b INs function in an opposing manner to control flexor-extensor-driven movements. Ablation of V1 INs results in limb hyperflexion, suggesting that V1 IN-derived inhibition is needed for proper extension movements of the limb. The loss of V2b INs results in hindlimb hyperextension and a delay in the transition from stance phase to swing phase, demonstrating V2b INs are required for the timely initiation and execution of limb flexion movements. Our findings also reveal a bias in the innervation of flexor- and extensor-related motor neurons by V1 and V2b INs that likely contributes to their differential actions on flexion-extension movements.
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http://dx.doi.org/10.7554/eLife.04718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604447PMC
October 2015

Identification of a spinal circuit for light touch and fine motor control.

Cell 2015 Jan;160(3):503-15

Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address:

Sensory 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.
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http://dx.doi.org/10.1016/j.cell.2015.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4431637PMC
January 2015

Identification of spinal circuits transmitting and gating mechanical pain.

Cell 2014 Dec 20;159(6):1417-1432. Epub 2014 Nov 20.

Dana-Farber Cancer Institute and Department of Neurobiology, Harvard Medical School, 1 Jimmy Fund Way, Boston, Massachusetts 02115, USA.

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:
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http://dx.doi.org/10.1016/j.cell.2014.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4258511PMC
December 2014

Neurogenin3 restricts serotonergic neuron differentiation to the hindbrain.

J Neurosci 2014 Nov;34(46):15223-33

Developmental Neurobiology Laboratory, Instituto Leloir and Consejo Nacional de Investigaciones Científicas y Técnicas (IIBBA-CONICET), Buenos Aires 1405, Argentina,

The development of the nervous system is critically dependent on the production of functionally diverse neuronal cell types at their correct locations. In the embryonic neural tube, dorsoventral signaling has emerged as a fundamental mechanism for generating neuronal diversity. In contrast, far less is known about how different neuronal cell types are organized along the rostrocaudal axis. In the developing mouse and chick neural tube, hindbrain serotonergic neurons and spinal glutamatergic V3 interneurons are produced from ventral p3 progenitors, which possess a common transcriptional identity but are confined to distinct anterior-posterior territories. In this study, we show that the expression of the transcription factor Neurogenin3 (Neurog3) in the spinal cord controls the correct specification of p3-derived neurons. Gain- and loss-of-function manipulations in the chick and mouse embryo show that Neurog3 switches ventral progenitors from a serotonergic to V3 differentiation program by repressing Ascl1 in spinal p3 progenitors through a mechanism dependent on Hes proteins. In this way, Neurog3 establishes the posterior boundary of the serotonergic system by actively suppressing serotonergic specification in the spinal cord. These results explain how equivalent p3 progenitors within the hindbrain and the spinal cord produce functionally distinct neuron cell types.
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http://dx.doi.org/10.1523/JNEUROSCI.3403-14.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608453PMC
November 2014

Lhx1 maintains synchrony among circadian oscillator neurons of the SCN.

Elife 2014 Jul 17;3:e03357. Epub 2014 Jul 17.

Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States

The robustness and limited plasticity of the master circadian clock in the suprachiasmatic nucleus (SCN) is attributed to strong intercellular communication among its constituent neurons. However, factors that specify this characteristic feature of the SCN are unknown. Here, we identified Lhx1 as a regulator of SCN coupling. A phase-shifting light pulse causes acute reduction in Lhx1 expression and of its target genes that participate in SCN coupling. Mice lacking Lhx1 in the SCN have intact circadian oscillators, but reduced levels of coupling factors. Consequently, the mice rapidly phase shift under a jet lag paradigm and their behavior rhythms gradually deteriorate under constant condition. Ex vivo recordings of the SCN from these mice showed rapid desynchronization of unit oscillators. Therefore, by regulating expression of genes mediating intercellular communication, Lhx1 imparts synchrony among SCN neurons and ensures consolidated rhythms of activity and rest that is resistant to photic noise.
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http://dx.doi.org/10.7554/eLife.03357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4137275PMC
July 2014

Inhibition downunder: an update from the spinal cord.

Curr Opin Neurobiol 2014 Jun 17;26:161-6. Epub 2014 Apr 17.

Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.

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.
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http://dx.doi.org/10.1016/j.conb.2014.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059017PMC
June 2014

V1 and v2b interneurons secure the alternating flexor-extensor motor activity mice require for limbed locomotion.

Neuron 2014 Apr;82(1):138-50

Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address:

Reciprocal activation of flexor and extensor muscles constitutes the fundamental mechanism that tetrapod vertebrates use for locomotion and limb-driven reflex behaviors. This aspect of motor coordination is controlled by inhibitory neurons in the spinal cord; however, the identity of the spinal interneurons that serve this function is not known. Here, we show that the production of an alternating flexor-extensor motor rhythm depends on the composite activities of two classes of ventrally located inhibitory neurons, V1 and V2b interneurons (INs). Abrogating V1 and V2b IN-derived neurotransmission in the isolated spinal cord results in a synchronous pattern of L2 flexor-related and L5 extensor-related locomotor activity. Mice lacking V1 and V2b inhibition are unable to articulate their limb joints and display marked deficits in limb-driven reflex movements. Taken together, these findings identify V1- and V2b-derived neurons as the core interneuronal components of the limb central pattern generator (CPG) that coordinate flexor-extensor motor activity.
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http://dx.doi.org/10.1016/j.neuron.2014.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096991PMC
April 2014

Functional subpopulations of V3 interneurons in the mature mouse spinal cord.

J Neurosci 2013 Nov;33(47):18553-65

Departments of Medical Neuroscience, and Mathematics and Statistics, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada, and Molecular Neurobiology Laboratory, the Salk Institute for Biological Studies, La Jolla, California 92037.

V3 interneurons (INs) are a major group of excitatory commissural interneurons in the spinal cord, and they are essential for producing a stable and robust locomotor rhythm. V3 INs are generated from the ventral-most progenitor domain, p3, but migrate dorsally and laterally during postmitotic development. At birth, they are located in distinctive clusters in the ventral horn and deep dorsal horn. To assess the heterogeneity of this genetically identified group of spinal INs, we combined patch-clamp recording and anatomical tracing with cluster analysis. We examined electrophysiological and morphological properties of mature V3 INs identified by their expression of tdTomato fluorescent proteins in Sim1(Cre/+); Rosa(floxstop26TdTom) mice. We identified two V3 subpopulations with distinct intrinsic properties and spatial distribution patterns. Ventral V3 INs, primarily located in lamina VIII, possess a few branching processes and were capable of generating rapid tonic firing spikes. By contrast, dorsal V3 INs exhibited a more complex morphology and relatively slow average spike frequency with strong adaptation, and they also displayed large sag voltages and post-inhibitory rebound potentials. Our data suggested that hyperpolarization-activated cation channel currents and T-type calcium channel currents may account for some of the membrane properties of V3 INs. Finally, we observed that ventral and dorsal V3 INs were active in different ways during running and swimming, indicating that ventral V3 INs may act as premotor neurons and dorsal V3 INs as relay neurons mediating sensory inputs. Together, we detected two physiologically and topographically distinct subgroups of V3 INs, each likely playing different roles in locomotor activities.
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http://dx.doi.org/10.1523/JNEUROSCI.2005-13.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3894417PMC
November 2013

A transcription factor code defines nine sensory interneuron subtypes in the mechanosensory area of the spinal cord.

PLoS One 2013 4;8(11):e77928. Epub 2013 Nov 4.

Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America.

Interneurons in the dorsal spinal cord process and relay innocuous and nociceptive somatosensory information from cutaneous receptors that sense touch, temperature and pain. These neurons display a well-defined organization with respect to their afferent innervation. Nociceptive afferents innervate lamina I and II, while cutaneous mechanosensory afferents primarily innervate sensory interneurons that are located in lamina III-IV. In this study, we outline a combinatorial transcription factor code that defines nine different inhibitory and excitatory interneuron populations in laminae III-IV of the postnatal cord. This transcription factor code reveals a high degree of molecular diversity in the neurons that make up laminae III-IV, and it lays the foundation for systematically analyzing and manipulating these different neuronal populations to assess their function. In addition, we find that many of the transcription factors that are expressed in the dorsal spinal cord at early postnatal times continue to be expressed in the adult, raising questions about their function in mature neurons and opening the door to their genetic manipulation in adult animals.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0077928PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3817166PMC
August 2014