USH2A is a Meissner’s corpuscle protein necessary for normal vibration sensing in mice and humans

Fingertip mechanoreceptors comprise sensory neuron endings together with specialized skin cells that form the end-organ. Exquisitely sensitive, vibration-sensing neurons are associated with Meissner’s corpuscles in the skin. In the present study, we found that USH2A, a transmembrane protein with a very large extracellular domain, was found in terminal Schwann cells within Meissner’s corpuscles. Pathogenic USH2A mutations cause Usher’s syndrome, associated with hearing loss and visual impairment. We show that patients with biallelic pathogenic USH2A mutations also have clear and specific impairments in vibrotactile touch perception, as do mutant mice lacking USH2A. Forepaw rapidly adapting mechanoreceptors innervating Meissner’s corpuscles, recorded from Ush2a−/− mice, showed large reductions in vibration sensitivity. However, the USH2A protein was not found in sensory neurons. Thus, loss of USH2A in corpuscular end-organs reduced mechanoreceptor sensitivity as well as vibration perception. Thus, a tether-like protein is required to facilitate detection of small-amplitude vibrations essential for the perception of fine-grained tactile surfaces.The present study was funded by grants from the Deutsche Forschungsgemeinshaft (grant nos. SFB665-B6 to G.R.L., SFB1315 to J.F.A.P. and SFB1158-A01 to S.G.L.) and grants from the European Research Council (grant nos. 789128 to G.R.L. and ERC-2015-CoG-682422 to J.F.A.P.). Additional funding was from the Institute of Health Carlos III (Spanish Ministry of Science and Innovation, grant no. FIS PI16/00539 to J.M.).Peer reviewe

Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment

Sickness behavior and cognitive dysfunction occur frequently by unknown mechanisms in virus-infected individuals with malignancies treated with type I interferons (IFNs) and in patients with autoimmune disorders. We found that during sickness behavior, single-stranded RNA viruses, double-stranded RNA ligands, and IFNs shared pathways involving engagement of melanoma differentiation-associated protein 5 (MDA5), retinoic acid-inducible gene 1 (RIG-I), and mitochondrial antiviral signaling protein (MAVS), and subsequently induced IFN responses specifically in brain endothelia and epithelia of mice. Behavioral alterations were specifically dependent on brain endothelial and epithelial IFN receptor chain 1 (IFNAR). Using gene profiling, we identified that the endothelia-derived chemokine ligand CXCL10 mediated behavioral changes through impairment of synaptic plasticity. These results identified brain endothelial and epithelial cells as natural gatekeepers for virus-induced sickness behavior, demonstrated tissue specific IFNAR engagement, and established the CXCL10-CXCR3 axis as target for the treatment of behavioral changes during virus infection and type I IFN therapy

The Sensory Coding of Warm Perception

Animals continuously sense the temperature in their environment, which is crucial for survival and for maintaining an optimal energy expenditure. Thermal perception is enabled by sensory afferent neurons that innervate the skin and express molecules that transduce thermal stimuli into electrical signals, which are later processed by the nervous system. In the recent years, studies in genetically modified mice have found sensory afferents and ion channels that transduce cooling in mammals, but the perceptual ability of mice to sense warmth and the underlying encoding mechanisms remain unknown. In this work, I have investigated the neurobiological mechanisms that underlie the perception of warmth. To do so, I have employed the mouse (Mus musculus) as a model system due to both the phylogenetic proximity to humans and the availability of genetic tools for mechanistic studies. Using a sensory detection behavior, I first show that mice perceive tiny (0.5oC) changes in temperature of the forepaw. Like humans, mice are able to discriminate warming from cooling, they are less sensitive to warmth and the baseline temperature strongly impacts the perceptual saliency. Together, these data indicate that mice and humans share many features of thermal perception, suggesting common sensory coding mechanisms. Cooling perception in mice is known to require cool-activated sensory afferents that express the channel TRPM8, but the neurons encoding warmth are unknown. Here, warming recruited two polymodal afferent populations: one fired upon warming (warm-activated) and the other was both warm-silenced and cool-activated. To investigate their role in perception, I used gene knockouts and optogenetic afferent stimulation and found that mice sense and encode warming without the warm-activated ion channels TRPV1, TRPM3, TRPA1 and TRPM2. However, surprisingly, despite TRPM8+ afferent stimulation evoked a cooling percept, TRPM8-null mice cannot detect warming. Trpm8-/- mice possess warm-activated afferents but lack warm-silenced neurons, suggesting that cooling input from warm-inhibited fibers is required for warmth perception. In preliminary work I have also investigated the role of primary somatosensory cortex in warm perception. Using intrinsic optical imaging I observed that cooling and touch, but not warming, elicits robust responses; but silencing of this brain region impaired the perception of warming stimuli. Altogether, the data from my thesis suggest that warming perception is an integrative process and requires input from both warm- and cool-activated sensory pathways

Microglial CX(3)CR1 promotes adult neurogenesis by inhibiting Sirt 1/p65 signaling independent of CX(3)CL1

Homo and heterozygote cx3cr1 mutant mice, which harbor a green fluorescent protein (EGFP) in their cx3cr1 loci, represent a widely used animal model to study microglia and peripheral myeloid cells. Here we report that microglia in the dentate gyrus (DG) of cx3cr1(-/-) mice displayed elevated microglial sirtuin 1 (SIRT1) expression levels and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) p65 activation, despite unaltered morphology when compared to cx3cr1(+/-) or cx3cr1(+/+) controls. This phenotype was restricted to the DG and accompanied by reduced adult neurogenesis in cx3cr1(-/-) mice. Remarkably, adult neurogenesis was not affected by the lack of the CX(3)CR1-ligand, fractalkine (CX(3)CL1). Mechanistically, pharmacological activation of SIRT1 improved adult neurogenesis in the DG together with an enhanced performance of cx3cr1(-/-)mice in a hippocampusdependent learning and memory task. The reverse condition was induced when SIRT1 was inhibited in cx3cr1(-/-) mice, causing reduced adult neurogenesis and lowered hippocampal cognitive abilities. In conclusion, our data indicate that deletion of CX(3)CR1 from microglia under resting conditions modifies brain areas with elevated cellular turnover independent of CX(3)CL1

Sensory Schwann cells set perceptual thresholds for touch and selectively regulate mechanical nociception

Abstract Previous work identified nociceptive Schwann cells that can initiate pain. Consistent with the existence of inherently mechanosensitive sensory Schwann cells, we found that in mice, the mechanosensory function of almost all nociceptors, including those signaling fast pain, were dependent on sensory Schwann cells. In polymodal nociceptors, sensory Schwann cells signal mechanical, but not cold or heat pain. Terminal Schwann cells also surround mechanoreceptor nerve-endings within the Meissner’s corpuscle and in hair follicle lanceolate endings that both signal vibrotactile touch. Within Meissner´s corpuscles, two molecularly and functionally distinct sensory Schwann cells positive for Sox10 and Sox2 differentially modulate rapidly adapting mechanoreceptor function. Using optogenetics we show that Meissner’s corpuscle Schwann cells are necessary for the perception of low threshold vibrotactile stimuli. These results show that sensory Schwann cells within diverse glio-neural mechanosensory end-organs are sensors for mechanical pain as well as necessary for touch perception

The Sensory Coding of Warm Perception

Humans detect skin temperature changes that are perceived as warm or cool. Like humans, mice report forepaw skin warming with perceptual thresholds of less than 1°C and do not confuse warm with cool. We identify two populations of polymodal C-fibers that signal warm. Warm excites one population, whereas it suppresses the ongoing cool-driven firing of the other. In the absence of the thermosensitive TRPM2 or TRPV1 ion channels, warm perception was blunted, but not abolished. In addition, trpv1:trpa1:trpm3-/- triple-mutant mice that cannot sense noxious heat detected skin warming, albeit with reduced sensitivity. In contrast, loss or local pharmacological silencing of the cool-driven TRPM8 channel abolished the ability to detect warm. Our data are not reconcilable with a labeled line model for warm perception, with receptors firing only in response to warm stimuli, but instead support a conserved dual sensory model to unambiguously detect skin warming in vertebrates.status: publishe