Somatosensory Circuits in the Central Nervous System

Sammanfattning: Spinal glycinergic neurons prevent spontaneous sensations of pain and itch, and development of persistent pain and itch conditions. The glycine receptor alpha 3 subunit (GLRA3) is suggested to be involved in certain inflammatory models, but not in acute nociception. In paper I, we found that spinal Glra3-Cre neurons mediate compound 48/80- and chloroquine-evoked itch. This population receive monosynaptic input from local spinal neurons, motor- and sensory-associated brain areas and innocuous, proprioceptive, noxious and pruritic primary afferents. In paper II, global exonal deletion of the Vglut2 or Viaat locus in Glra3-Cre neurons did not affect the withdrawal response to interleukin 1 beta-induced thermal hypersensitivity. In paper III, single-cell RNA sequencing and bulk qRT-PCR analyses revealed widespread, but low Glra3 expression in both Slc17a6(+) and Slc32a1(+) neurons within the central nervous system. Males expressed higher levels in all investigated brain structures compared to females and RNAscope spatially validated Glra3 expression in Slc17a6(+) and Slc32a1(+) neurons. Urocortin 3 (UCN3) is a neuropeptide belonging to the corticotropin-releasing factor family. The spinal KF43 Ucn3-Cre neurons mediate mechanical itch and alloknesis. In paper IV, the lumbar KF31 Ucn3-Cre neurons were divided into two non-overlapping protein kinase C gamma(+) and calretinin(+) subpopulations. Activation evoked biting/licking and Cre-dependent exonal deletion of the Vglut2 locus removed this phenotype. The deletion did not affect the response to mechanical stimulation nor compound 48/80, however, these sensory-modality activated fos(+) cells co-expressed Ucn3. In rodents, the layer IV barrel field of S1 comprises of excitatory pyramidal and spiny stellate cells and this area receives sensory input from the whisker pad via the thalamic ventroposteromedial nucleus. Vesicular monoaminergic transporter 2 (VMAT2) sequesters monoamines into synaptic vesicles. Vmat2 is prominent in the developmental brain, while more sparsely detected in the adult brain. In paper V, a Vmat2-Cre mouse line labelled adult Vmat2(+) and Cre(+) layer IV S1 barrel neurons, which received monosynaptic thalamic input. These neurons displayed a homogenous intrinsically bursting firing pattern, indicative of excitatory neurons and shared the morphology of stellate spiny neurons. The Vmat2-Cre neurons also expressed excitatory and layer IV markers, and mainly cluster with layer IV neurons.