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30 Publications

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    03/22/18 | A Neural Circuit for the Suppression of Pain by a Competing Need State.
    Alhadeff AL, Su Z, Hernandez E, Klima ML, Phillips SZ, Holland RA, Guo C, Hantman AW, De Jonghe BC, Betley JN
    Cell. 2018 Mar 22;173(1):140-52. doi: 10.1016/j.cell.2018.02.057

    Hunger and pain are two competing signals that individuals must resolve to ensure survival. However, the neural processes that prioritize conflicting survival needs are poorly understood. We discovered that hunger attenuates behavioral responses and affective properties of inflammatory pain without altering acute nociceptive responses. This effect is centrally controlled, as activity in hunger-sensitive agouti-related protein (AgRP)-expressing neurons abrogates inflammatory pain. Systematic analysis of AgRP projection subpopulations revealed that the neural processing of hunger and inflammatory pain converge in the hindbrain parabrachial nucleus (PBN). Strikingly, activity in AgRP → PBN neurons blocked the behavioral response to inflammatory pain as effectively as hunger or analgesics. The anti-nociceptive effect of hunger is mediated by neuropeptide Y (NPY) signaling in the PBN. By investigating the intersection between hunger and pain, we have identified a neural circuit that mediates competing survival needs and uncovered NPY Y1 receptor signaling in the PBN as a target for pain suppression.

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    12/31/17 | A topographic axis of transcriptional identity in thalamus.
    Phillips JW, Schulman A, Hara E, Liu C, Shields BC, Korff W, Lemire A, Dudman JT, Nelson SB, Hantman AW
    bioRxiv. 2017 Dec 31:241315. doi: 10.1101/241315

    A fundamental goal in neuroscience is to uncover common principles by which different modalities of information are processed. In the mammalian brain, thalamus acts as the essential hub for forebrain circuits handling inputs from sensory, motor, limbic, and cognitive pathways. Whether thalamus imposes common transformations on each of these modalities is unknown. Molecular characterization offers a principled approach to revealing the organization of thalamus. Using near-comprehensive and projection-specific transcriptomic sequencing, we found that almost all thalamic nuclei fit into one of three profiles. These profiles lie on a single axis of genetic variance which is aligned with the mediolateral spatial axis of thalamus. Genes defining this axis of variance include receptors and ion channels, providing a systematic diversification of input/output transformations across the topography of thalamus. Single cell transcriptional profiling revealed graded heterogeneity within individual thalamic nuclei, demonstrating that a spectrum of cell types and potentially diverse input/output transforms exist within a given thalamic nucleus. Together, our data argue for an archetypal organization of pathways serving diverse input modalities, and provides a comprehensive organizational scheme for thalamus.

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    01/31/17 | A brainstem-spinal cord inhibitory circuit for mechanical pain modulation by GABA and Enkephalins.
    François A, Low SA, Sypek EI, Christensen AJ, Sotoudeh C, Beier KT, Ramakrishnan C, Ritola KD, Sharif-Naeini R, Deisseroth K, Delp SL, Malenka RC, Luo L, Hantman AW, Scherrer G
    Neuron. 2017 Jan 31;93(4):822-39. doi: 10.1016/j.neuron.2017.01.008

    Pain thresholds are, in part, set as a function of emotional and internal states by descending modulation of nociceptive transmission in the spinal cord. Neurons of the rostral ventromedial medulla (RVM) are thought to critically contribute to this process; however, the neural circuits and synaptic mechanisms by which distinct populations of RVM neurons facilitate or diminish pain remain elusive. Here we used in vivo opto/chemogenetic manipulations and trans-synaptic tracing of genetically identified dorsal horn and RVM neurons to uncover an RVM-spinal cord-primary afferent circuit controlling pain thresholds. Unexpectedly, we found that RVM GABAergic neurons facilitate mechanical pain by inhibiting dorsal horn enkephalinergic/GABAergic interneurons. We further demonstrate that these interneurons gate sensory inputs and control pain through temporally coordinated enkephalin- and GABA-mediated presynaptic inhibition of somatosensory neurons. Our results uncover a descending disynaptic inhibitory circuit that facilitates mechanical pain, is engaged during stress, and could be targeted to establish higher pain thresholds.

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    10/19/16 | A designer AAV variant permits efficient retrograde access to projection neurons.
    Tervo DG, Hwang B, Viswanathan S, Gaj T, Lavzin M, Ritola KD, Lindo S, Michael S, Kuleshova E, Ojala D, Huang C, Gerfen CR, Schiller J, Dudman JT, Hantman AW, Looger LL, Schaffer DV, Karpova AY
    Neuron. 2016 Oct 19;92(2):372-82. doi: 10.1016/j.neuron.2016.09.021

    Efficient retrograde access to projection neurons for the delivery of sensors and effectors constitutes an important and enabling capability for neural circuit dissection. Such an approach would also be useful for gene therapy, including the treatment of neurodegenerative disorders characterized by pathological spread through functionally connected and highly distributed networks. Viral vectors, in particular, are powerful gene delivery vehicles for the nervous system, but all available tools suffer from inefficient retrograde transport or limited clinical potential. To address this need, we applied in vivo directed evolution to engineer potent retrograde functionality into the capsid of adeno-associated virus (AAV), a vector that has shown promise in neuroscience research and the clinic. A newly evolved variant, rAAV2-retro, permits robust retrograde access to projection neurons with efficiency comparable to classical synthetic retrograde tracers and enables sufficient sensor/effector expression for functional circuit interrogation and in vivo genome editing in targeted neuronal populations. VIDEO ABSTRACT.

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    08/17/16 | Satb2 stations neurons along reflex arcs.
    Hantman AW, Kaltschmidt JA
    Neuron. 2016 Aug 17;91(4):711-3. doi: 10.1016/j.neuron.2016.08.005

    The nociceptive flexor withdrawal reflex has an august place in the history of neuroscience. In this issue of Neuron, Hilde et al. (2016) advance our understanding of this reflex by characterizing the molecular identity and circuit connectivity of component interneurons. They assess how a DNA-binding factor Satb2 controls cell position, molecular identity, pre-and postsynaptic targeting, and function of a population of inhibitory sensory relay interneurons that serve to integrate both proprioceptive and nociceptive afferent information.

    The nociceptive flexor withdrawal reflex has an august place in the history of neuroscience. In this issue of Neuron, Hilde et al. (2016) advance our understanding of this reflex by characterizing the molecular identity and circuit connectivity of component interneurons. They assess how a DNA-binding factor Satb2 controls cell position, molecular identity, pre-and postsynaptic targeting, and function of a population of inhibitory sensory relay interneurons that serve to integrate both proprioceptive and nociceptive afferent information.

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    12/03/15 | Cortex commands the performance of skilled movement.
    Guo J, Graves AR, Guo WW, Zheng J, Lee A, Rodríguez-González J, Li N, Macklin JJ, Phillips JW, Mensh BD, Branson K, Hantman AW
    eLife. 2015 Dec 3;4:. doi: 10.7554/eLife.10774

    Mammalian cerebral cortex is accepted as being critical for voluntary motor control, but what functions depend on cortex is still unclear. Here we used rapid, reversible optogenetic inhibition to test the role of cortex during a head-fixed task in which mice reach, grab, and eat a food pellet. Sudden cortical inhibition blocked initiation or froze execution of this skilled prehension behavior, but left untrained forelimb movements unaffected. Unexpectedly, kinematically normal prehension occurred immediately after cortical inhibition even during rest periods lacking cue and pellet. This 'rebound' prehension was only evoked in trained and food-deprived animals, suggesting that a motivation-gated motor engram sufficient to evoke prehension is activated at inhibition's end. These results demonstrate the necessity and sufficiency of cortical activity for enacting a learned skill.

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    02/26/13 | Convergence of pontine and proprioceptive streams onto multimodal cerebellar granule cells.
    Huang C, Sugino K, Shima Y, Guo C, Bai S, Mensh BD, Nelson SB, Hantman AW
    eLife. 2013 Feb 26;2:e00400. doi: 10.7554/eLife.00400

    Cerebellar granule cells constitute the majority of neurons in the brain and are the primary conveyors of sensory and motor-related mossy fiber information to Purkinje cells. The functional capability of the cerebellum hinges on whether individual granule cells receive mossy fiber inputs from multiple precerebellar nuclei or are instead unimodal; this distinction is unresolved. Using cell-type-specific projection mapping with synaptic resolution, we observed the convergence of separate sensory (upper body proprioceptive) and basilar pontine pathways onto individual granule cells and mapped this convergence across cerebellar cortex. These findings inform the long-standing debate about the multimodality of mammalian granule cells and substantiate their associative capacity predicted in the Marr-Albus theory of cerebellar function. We also provide evidence that the convergent basilar pontine pathways carry corollary discharges from upper body motor cortical areas. Such merging of related corollary and sensory streams is a critical component of circuit models of predictive motor control. DOI:

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    10/01/10 | Clarke’s column neurons as the focus of a corticospinal corollary circuit.
    Hantman AW, Jessell TM
    Nature Neuroscience. 2010 Oct;13(10):1233-9. doi: 10.1038/nn.2637

    Proprioceptive sensory signals inform the CNS of the consequences of motor acts, but effective motor planning involves internal neural systems capable of anticipating actual sensory feedback. Just where and how predictive systems exert their influence remains poorly understood. We explored the possibility that spinocerebellar neurons that convey proprioceptive sensory information also integrate information from cortical command systems. Analysis of the circuitry and physiology of identified dorsal spinocerebellar tract neurons in mouse spinal cord revealed distinct populations of Clarke’s column neurons that received direct excitatory and/or indirect inhibitory inputs from descending corticospinal axons. The convergence of these descending inhibitory and excitatory inputs to Clarke’s column neurons established local spinal circuits with the capacity to mark or modulate incoming proprioceptive input. Together, our genetic, anatomical and physiological results indicate that Clarke’s column spinocerebellar neurons nucleate local spinal corollary circuits that are relevant to motor planning and evaluation.

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    11/07/05 | Molecular and genetic features of a labeled class of spinal substantia gelatinosa neurons in a transgenic mouse.
    Hantman AW, Perl ER
    Journal of Computational Neuroscience. 2005 Nov 7;492(1):90-100. doi: doi: 10.1002/cne.20709

    Genetic incorporation in a mouse of a transgene containing the prion promoter and the green fluorescent protein (GFP) coding sequence labels a set of substantia gelatinosa (SG) neurons (SG-GFP) homogenous in morphology, electrophysiology, and γ-amino-butyric acid expression. In the present analysis the SG-GFP neurons are established to have protein kinase C-βII immunoreactivity and to lack evidence for the presence of calbindin D-28k, parvalbumin, and protein kinase C-γ. These neurons were hyperpolarized by mediators of descending control, norepinephrine and serotonin. Sequential polymerase chain reactions established the insertion of the transgene to be in the receptor protein tyrosine phosphatase kappa (RPTP-κ) and the laminin receptor 1 (ribosomal protein SA) pseudogene 1 locus. RPTP-κ expression in both GFP-labeled dorsal root ganglia and SG neurons raises the possibility that homophilic interactions of RPTP-κ contribute to establishment of connections between specific classes of primary afferent and SG neurons.

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    01/28/04 | Morphological and physiological features of a set of spinal substantia gelatinosa neurons defined by green fluorescent protein expression.
    Hantman AW, van den Pol AN, Perl ER
    The Journal of Neuroscience. 2004 Jan 28;24:836-42. doi: 10.1523/JNEUROSCI.4221-03.2004

    The spinal substantia gelatinosa (SG) is known to be involved in the manipulation of nociceptive and thermal primary afferent input; however, the interrelationships of its neuronal components are poorly understood. As a step toward expanding understanding, we took a relatively unique approach by concentrating on a set of SG neurons selectively labeled by green fluorescent protein (GFP) in a transgenic mouse. These GFP-expressing SG neurons prove to have homogenous morphological and electrophysiological properties, are systematically spaced in the SG, contain GABA, receive C-fiber primary afferent input, and upregulate c-Fos protein in response to noxious stimuli. Together, the properties established for these GFP-labeled neurons are consistent with a modular SG organization in which afferent activity related to nociception or other C-fiber signaling are subject to integration/modulation by repeating, similar circuits of neurons.

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