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Somatosensation is a complex sense mediated by more than a dozen distinct neural subtypes in the periphery. Although pressure and touch sensation have been mapped to primary somatosensory cortex in rodents, it has been controversial whether pain and temperature inputs are also directed to this area. Here we use a well-defined somatosensory modality, cool sensation mediated by peripheral TrpM8-receptors, to investigate the neural substrate for cool perception in the mouse neocortex. Using activation of cutaneous TrpM8 receptor-expressing neurons, we identify candidate neocortical areas responsive for cool sensation. Initially, we optimized TrpM8 stimulation and determined that menthol, a selective TrpM8 agonist, was more effective than cool stimulation at inducing expression of the immediate-early gene c-fos in the spinal cord. We developed a broad-scale brain survey method for identification of activated brain areas, using automated methods to quantify c-fos immunoreactivity (fos-IR) across animals. Brain areas corresponding to the posterior insular cortex and secondary somatosensory (S2) show elevated fos-IR after menthol stimulation, in contrast to weaker activation in primary somatosensory cortex (S1). In addition, menthol exposure triggered fos-IR in piriform cortex, the amygdala, and the hypothalamus. Menthol-mediated activation was absent in TrpM8-knock-out animals. Our results indicate that cool somatosensory input broadly drives neural activity across the mouse brain, with neocortical signal most elevated in the posterior insula, as well as S2 and S1. These findings are consistent with data from humans indicating that the posterior insula is specialized for somatosensory information encoding temperature, pain, and gentle touch.

Higher-order thalamic nuclei, such as the posterior medial nucleus (POm) in the somatosensory system or the pulvinar in the visual system, densely innervate the cortex and can influence perception and plasticity. To systematically evaluate how higher-order thalamic nuclei can drive cortical circuits, we investigated cell-type selective responses to POm stimulation in mouse primary somatosensory (barrel) cortex, using genetically targeted whole-cell recordings in acute brain slices. We find that ChR2-evoked thalamic input selectively targets specific cell types in the neocortex, revealing layer-specific modules for the summation and processing of POm input. Evoked activity in pyramidal neurons from deep layers is fast and synchronized by rapid feedforward inhibition from GABAergic parvalbumin-expressing neurons, and activity in superficial layers is weaker and prolonged, facilitated by slow inhibition from GABAergic neurons expressing the 5HT3a receptor. Somatostatin-expressing GABAergic neurons do not receive direct input in either layer and their spontaneous activity is suppressed during POm stimulation. This novel pattern of weak, delayed, thalamus-evoked inhibition in layer 2 suggests a longer integration window for incoming sensory information and may facilitate stimulus detection and plasticity in superficial pyramidal neurons.

The kappa opioid receptor (KOR) has numerous important roles in the nervous system including the modulation of mood, reward, pain, and itch. In addition, KOR is expressed in many non-neuronal tissues. However, the specific cell types that express KOR are poorly characterized. Here, we report the development of a KOR-Cre knockin allele, which provides genetic access to cells that express KOR. In this mouse, Cre recombinase (Cre) replaces the initial coding sequence of the Opkr1 gene (encoding the kappa opioid receptor). We demonstrate that the KOR-Cre allele mediates recombination by embryonic day 14.5 (E14.5). Within the brain, KOR-Cre shows expression in numerous areas including the cerebral cortex, nucleus accumbens and striatum. In addition, this allele is expressed in epithelium and throughout many regions of the body including the heart, lung, and liver. Finally, we reveal that KOR-Cre mediates recombination of a subset of bipolar and amacrine cells in the retina. Thus, the KOR-Cre mouse line is a valuable new tool for conditional gene manipulation to enable the study of KOR.