The impact of HCN4 channels on CNS brain networks as a new target in pain development

While it is well established that the isoform 2 of hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN2) plays an important role in development and maintenance pain, closely related HCN4 processing nociceptive signals not known. channels are highly expressed thalamus, a region for stimulus transmission information processing. We used brain-specific HCN4-knockout mouse line (HCN4-KO) to explore acute using several behavioral tests as multimodal magnetic resonance imaging (MRI) approach. Functional MRI (fMRI) brain responses were measured during peripheral thermal stimulation complemented by resting state (RS) before after stimulation. The data analyzed conventional graph-theoretical approaches. Finally, high-resolution anatomical acquired. HCN4-KO animals showed central thermal, but mechanical hypersensitivity experiments. open field analysis no significant differences motor readouts between controls uncovered increased anxiety mice. Thermal stimulus-driven fMRI (s-fMRI) revealed response volumes amplitudes HCN4-KO, most pronounced at lower temperatures subcortical input, amygdala limbic/hippocampal regions, cerebellum. These findings could be cross-validated analyses. Assessment short-term RS stimulation-related modulations functional connectivity only occurred control animals. This was consistent with finding hippocampus found smaller HCN4-KO. In summary, deletion impacts on nociception, which remarkably manifested hypersensitive phenotype. mediated key regions hypothalamus, somatosensory cortex, cerebellum amygdala. As consequence, mice more anxious, their brain-wide modulated