Projects

Organization of the dorsal horn neuronal circuitry

The spinal dorsal horn harbors a sophisticated network of different types of excitatory and inhibitory interneurons whose functions are only recently beginning to emerge.  We use the translating ribosome affinity purification (TRAP) technique to collect genes specifically translated in subsets of dorsal horn neurons to identify marker genes of dorsal horn interneurons with defined functions in sensory processing. Rabies and herpes virus dependent approaches for transsynaptic tracing allow us also to map synaptic input and output of these neuron populations. Pharmacogenetic and optogenetic techniques and the expression of bacterial toxins from murine transgenes or viral vectors are then applied to characterize the function of these neuron populations in vivo. The development and application of dual recombinase systems is another tool that we have recently added to our repertoire. On the long-term we aim at the generation of a comprehensive map of the dorsal horn neuronal circuitry.

Selected publications:

  • Foster E, Wildner H, Tudeau L, Haueter S, Ralvenius WT, Jegen M, Johannssen H, Hösli L, Haenraets K, Ghanem A, Conzelmann KK, Bösl M, Zeilhofer HU (2015) Targeted ablation, silencing and activation establish glycinergic dorsal horn neurons as key components of a spinal gate for pain and itch. Neuron 85, 1289-1304.
  • Punnakkal P, von Schoultz C, Haenraets K, Wildner H, Zeilhofer HU (2014) Morphological, biophysical and synaptic properties of glutamatergic neurons of the mouse spinal dorsal horn. J Physiol 592, 759-776.
  • Wildner H, Das Gupta R, Bröhl D, Heppenstall PA, Zeilhofer HU, Birchmeier C (2013) Genome-wide expression analysis of Ptf1a- and Ascl1-deficient mice reveals new markers for distinct dorsal horn Interneuron populations contributing to nociceptive reflex plasticity. J Neurosci 33, 7299-7307.

Pain and itch control through inhibitory neurotransmission in the dorsal horn

Inhibitory dorsal neurons exert a powerful control over the relay of pain and itch signals to the brain. A large body of evidence indicates that this inhibitory control is diminished in chronic pain states. In a series of studies our group has identified subtypes of GABAA and glycine receptors that are enriched in dorsal horn circuits and whose activation inhibits pain. We study the effects of GABAA and glycine receptor modulators on isolated receptors in recombinant systems, on native receptors in spinal cord slices and in vivo in genetically modified mice. We currently capitalize on the results of these studies to develop compounds that alleviate pain without the typical side effects of classical centrally acting analgesics or typical GABAergic drugs.

          Selected publications:

  • Acuña MA, Yévenes GE, Ralvenius RT, Benke D, Di Lio A, Lara CO, Muñoz B, Burgos CF, Moraga-Cid G, Corringer P-J, Zeilhofer HU (2016) Phosphorylation state-dependent modulation of spinal glycine receptors alleviates inflammatory pain. J Clin Invest 126, 2547-2560.
  • Ralvenius WT, Benke D, Acuña MA, Rudolph U, Zeilhofer HU (2015) Analgesia and unwanted benzodiazepine effects in point-mutated mice expressing only one benzodiazepine-sensitive GABAA receptor subtype. Nat Commun 6, 6803.
  • Knabl J, Witschi R, Hösl K, Reinold H, Zeilhofer U, Ahmadi S, Brockhaus J, Sergejeva M, Hess A, Brune K, Fritschy JM, Rudolph U, Möhler H, Zeilhofer HU (2008) Reversal of pathological pain through specific spinal GABAA receptor subtypes. Nature 451, 330-334.

Present and last Funding (last 5 years)

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