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Specialized mechanosensory end organs within mammalian skin—hair follicle-associated lanceolate complexes, Meissner corpuscles, and Pacinian corpuscles—enable our perception of light, dynamic touch1. In each of these end organs, fast-conducting mechanically sensitive neurons, called Aβ low-threshold mechanoreceptors (Aβ LTMRs), associate with resident glial cells, known as terminal Schwann cells (TSCs) or lamellar cells, to form complex axon ending structures. Lanceolate-forming and corpuscle-innervating Aβ LTMRs share a low threshold for mechanical activation, a rapidly adapting (RA) response to force indentation, and high sensitivity to dynamic stimuli1–6. How mechanical stimuli lead to activation of the requisite mechanotransduction channel Piezo27–15and Aβ RA-LTMR excitation across the morphologically dissimilar mechanosensory end organ structures is not understood. Here, we report the precise subcellular distribution of Piezo2 and high-resolution, isotropic 3D reconstructions of all three end organs formed by Aβ RA-LTMRs determined by large volume enhanced Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) imaging. We found that within each end organ, Piezo2 is enriched along the sensory axon membrane and is minimally or not expressed in TSCs and lamellar cells. We also observed a large number of small cytoplasmic protrusions enriched along the Aβ RA-LTMR axon terminals associated with hair follicles, Meissner corpuscles, and Pacinian corpuscles. These axon protrusions reside within close proximity to axonal Piezo2, occasionally contain the channel, and often form adherens junctions with nearby non-neuronal cells. Our findings support a unified model for Aβ RA-LTMR activation in which axon protrusions anchor Aβ RA-LTMR axon terminals to specialized end organ cells, enabling mechanical stimuli to stretch the axon in hundreds to thousands of sites across an individual end organ and leading to activation of proximal Piezo2 channels and excitation of the neuron.

Low-threshold mechanoreceptors (LTMRs) and their cutaneous end organs convert light mechanical forces acting on the skin into electrical signals that propagate to the central nervous system. In mouse hairy skin, hair follicle-associated longitudinal lanceolate complexes, which are end organs comprising of LTMR axonal endings that intimately associate with terminal Schwann cell (TSC) processes, mediate LTMR responses to hair deflection and skin indentation. Here, we characterized developmental steps leading to the formation of Aβ RA-LTMR and Aδ-LTMR lanceolate complexes. During early postnatal development, Aβ RA-LTMRs and Aδ-LTMRs extend and prune cutaneous axonal branches in close association with nascent TSC processes. Netrin-G1 is expressed in these developing Aβ RA-LTMR and Aδ-LTMR lanceolate endings, and Ntng1 ablation experiments indicate that Netrin-G1 functions in sensory neurons to promote lanceolate ending elaboration around hair follicles. The Netrin-G ligand (NGL-1), encoded by Lrrc4c, is expressed in TSCs, and ablation of Lrrc4c phenocopies the lanceolate complex deficits observed in Ntng1 mutants. Moreover, NGL-1–Netrin-G1 signaling is a general mediator of LTMR end organ formation across diverse tissue types demonstrated by the fact that Aβ RA-LTMR endings associated with Meissner corpuscles and Pacinian corpuscles are also compromised in the Ntng1 and Lrrc4c mutant mice. Thus, axon-glia interactions mediated by NGL-1–Netrin-G1 signaling promote LTMR end organ formation.Significance statementOur sense of touch is essential for fundamental tasks ranging from object recognition to social exchange. Yet, touch remains one of the least understood senses at the developmental level. Here, we investigate the formation of lanceolate complexes, which are mechanosensory end organs associated with hair follicles. The axons of touch sensory neurons innervating hairy skin extend into the skin at late embryonic and neonatal times, prune excessive branches during early postnatal development, and closely associate with non-myelinating glial cells, called terminal Schwann cells (TSCs) during formation of mature endings around hair follicles. Moreover, NGL-1 and its receptor Netrin-G1 mediate a molecular dialogue between nascent TSCs and sensory neuron axonal endings to promote mechanosensory end organ formation in both hairy and non-hairy (glabrous) skin.

Our sense of touch emerges from an array of mechanosensory structures residing within the fabric of our skin. These tactile end organ structures convert innocuous forces acting on the skin into electrical signals that propagate to the CNS via the axons of low-threshold mechanoreceptors (LTMRs). Our rich capacity for tactile discrimination arises from the dissimilar intrinsic properties of the LTMR subtypes that innervate different regions of the skin and the structurally distinct end organ complexes with which they associate. These end organ structures comprise a range of non-neuronal cell types, which may themselves actively contribute to the transformation of tactile forces into neural impulses within the LTMR afferents. Although the mechanism and the site of transduction across end organs remain unclear, PIEZO2 has emerged as the principal mechanosensitive channel involved in light touch of the skin. Here we review the physiological properties of LTMR subtypes and discuss how features of their cutaneous end organ complexes shape subtype-specific tuning. Mammalian skin contains an array of specialized structures that transform mechanical forces into electrical signals. Handler and Ginty provide a comprehensive overview of the features of the skin’s mechanosensory end organs and the neurons with which they associate and consider how their diverse properties contribute to the sense of touch.

Commonly prescribed antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) take weeks to achieve therapeutic benefits1, 2. The underlying mechanisms of why antidepressants take weeks or months to reverse depressed mood are not understood. Using a single cell sequencing approach, we analyzed gene expression changes in mice subjected to stress-induced depression and determined their temporal response to antidepressant treatment in the cerebral cortex. We discovered that both glial and neuronal cell populations elicit gene expression changes in response to stress, and that these changes are reversed upon treatment with fluoxetine (Prozac), a widely prescribed selective serotonin reuptake inhibitor (SSRI). Upon reproducing the molecular signaling events regulated by fluoxetine3 in a cortical culture system, we found that these transcriptional changes are serotonin-dependent, require reciprocal neuron-glia communication, and involve temporally-specified sequences of autoregulation and cross-regulation between FGF2 and BDNF signaling pathways. Briefly, stimulation of Fgf2 synthesis and signaling directly regulates Bdnf synthesis and secretion cell-non-autonomously requiring neuron-glia interactions, which then activates neuronal BDNF-TrkB signaling to drive longer-term neuronal adaptations4–6 leading to improved mood. Our studies highlight temporal and cell type specific mechanisms promoting the onset of the antidepressant response, that we propose could offer novel avenues for mitigating delayed onset of antidepressant therapies.

Secrets of Meissner corpuscles The Meissner corpuscle, a mechanosensory end organ, was discovered more than 165 years ago and has since been found in the glabrous skin of all mammals, including that on human fingertips. Although prominently featured in textbooks, the function of the Meissner corpuscle is unknown. Neubarth et al. generated adult mice without Meissner corpuscles and used them to show that these corpuscles alone mediate behavioral responses to, and perception of, gentle forces (see the Perspective by Marshall and Patapoutian). Each Meissner corpuscle is innervated by two molecularly distinct, yet physiologically similar, mechanosensory neurons. These two neuronal subtypes are developmentally interdependent and their endings are intertwined within the corpuscle. Both Meissner mechanosensory neuron subtypes are homotypically tiled, ensuring uniform and complete coverage of the skin, yet their receptive fields are overlapping and offset with respect to each other. Science , this issue p. eabb2751 ; see also p. 1311

TRAAK is a membrane tension-activated K+channel that has been associated through behavioral studies to mechanical nociception. We used specific monoclonal antibodies in mice to show that TRAAK is localized exclusively to nodes of Ranvier, the action potential propagating elements of myelinated nerve fibers. Approximately 80 percent of myelinated nerve fibers throughout the central and peripheral nervous system contain TRAAK in an all-nodes or no-nodes per axon fashion. TRAAK is not observed at the axon initial segment where action potentials are first generated. We used polyclonal antibodies, the TRAAK inhibitor RU2 and node clamp amplifiers to demonstrate the presence and functional properties of TRAAK in rat nerve fibers. TRAAK contributes to the ‘leak’ K+current in mammalian nerve fiber conduction by hyperpolarizing the resting membrane potential, thereby increasing Na+channel availability for action potential propagation. Mechanical gating in TRAAK might serve a neuroprotective role by counteracting mechanically-induced ectopic action potentials. Alternatively, TRAAK may open in response to mechanical forces in the nodal membrane associated with depolarization during saltatory conduction and thereby contribute to repolarization of the node for subsequent spikes.

Animals rely on the relative timing of events in their environment to form and update predictive associations, but the molecular and circuit mechanisms for this temporal sensitivity remain incompletely understood. Here, we show that olfactory associations in Drosophila can be written and reversed on a trial-by-trial basis depending on the temporal relationship between an odor cue and dopaminergic reinforcement. Through the synchronous recording of neural activity and behavior, we show that reversals in learned odor attraction correlate with bidirectional neural plasticity in the mushroom body, the associative olfactory center of the fly. Two dopamine receptors, DopR1 and DopR2, contribute to this temporal sensitivity by coupling to distinct second messengers and directing either synaptic depression or potentiation. Our results reveal how dopamine-receptor signaling pathways can detect the order of events to instruct opposing forms of synaptic and behavioral plasticity, allowing animals to flexibly update their associations in a dynamic environment.

Not Too Much, Not Too Little The microRNA miR128 is expressed in brain neurons of the mouse. Lek Tan et al. (p. 1254 ) now find that miR128 is crucial to stable brain function. Mice deficient in miR128 developed hyperactivity and were susceptible to fatal seizures, whereas overexpression of miR128 correlated with reduced motor activity and reduced susceptibility to proconvulsive drugs. Experiments using ex vivo–isolated adult brain tissues suggested that miR-128 controlled motor activity by governing the signaling network that determines the intrinsic excitability and signal responsiveness of neurons.