Projects

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:

• Frezel N, Ranucci M, Foster E, Wende H, Pelczar P, Mendes R, Ganley RP, Werynska K, d'Aquin S, Beccarini C, Birchmeier C, Zeilhofer HU, Wildner H. c-Maf-positive spinal cord neurons are critical elements of a dorsal horn circuit for mechanical hypersensitivity in neuropathy. Cell Rep. 2023 Apr 25;42(4):112295.
• Ganley RP, de Sousa MM, Werder K, Öztürk T, Mendes R, Ranucci M, Wildner H, Zeilhofer HU. Targeted anatomical and functional identification of antinociceptive and pronociceptive serotonergic neurons that project to the spinal dorsal horn. Elife. 2023 Feb 8;12:e78689.
• Albisetti GW, Ganley RP, Pietrafesa F, Werynska K, Magalhaes de Sousa M, Sipione R, Scheurer L, Bösl MR, Pelczar P, Wildner H, Zeilhofer HU. Inhibitory Kcnip2 neurons of the spinal dorsal horn control behavioral sensitivity to environmental cold. Neuron. 2023 Jan 4;111(1):92-105.e5.

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 GABA_A and glycine receptors that are enriched in dorsal horn circuits and whose activation inhibits pain. We study the effects of GABA_A 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:

• Neumann E, Cramer T, Acuña MA, Scheurer L, Beccarini C, Luscher B, Wildner H, Zeilhofer HU. γ1 GABA_A receptors in spinal nociceptive circuits. J Neurosci. 2024 Aug 26:e0591242024. Online ahead of print.

• Werynska K, Neumann E, Cramer T, Ganley RP, Gingras J, Zeilhofer HU. A phospo-deficient α3 glycine receptor mutation alters synaptic glycine and GABA release in mouse spinal dorsal horn neurons. J Physiol. 2023 Sep;601(18):4121-4133.

• Neumann E, Küpfer L, Zeilhofer HU. The α2/α3GABAA receptor modulator TPA023B alleviates not only the sensory but also the tonic affective component of chronic pain in mice. Pain. 2021 Feb 1;162(2):421-431.
• Tudeau L, Acuña MA, Albisetti GW, Neumann E, Ralvenius WT, Scheurer L, Poe M, Cook JM, Johannssen HC, Zeilhofer HU. Mice lacking spinal α2GABA_A receptors: Altered GABAergic neurotransmision, diminished GABAergic antihyperalgesia, and potential compensatory mechanisms preventing a hyperalgesic phenotype. Brain Res. 2020 Aug 15;1741:146889.
• Ralvenius WT, Neumann E, Pagani M, Acuña MA, Wildner H, Benke D, Fischer N, Rostaher A, Schwager S, Detmar M, Frauenknecht K, Aguzzi A, Hubbs JL, Rudolph U, Favrot C, Zeilhofer HU. Itch suppression in mice and dogs by modulation of spinal α2 and α3GABA_A receptors. Nat Commun. 2018 Aug 13;9(1):3230.