Temperature is a universal cue and regulates many essential processes ranging from enzymatic reactions to species migration. Due to the profound impact of temperature on physiology and behavior, ...animals and humans have evolved sophisticated mechanisms to detect temperature changes. Studies from animal models, such as mouse,
, and
, have revealed many exciting principles of thermosensation. For example, conserved molecular thermosensors, including thermosensitive channels and receptors, act as the initial detectors of temperature changes across taxa. Additionally, thermosensory neurons and circuits in different species appear to adopt similar logic to transduce and process temperature information. Here, we present the current understanding of thermosensation at the molecular and cellular levels. We also discuss the fundamental coding strategies of thermosensation at the circuit level. A thorough understanding of thermosensation not only provides key insights into sensory biology but also builds a foundation for developing better treatments for various sensory disorders.
Cell-cell communication via ligand-receptor signaling is a fundamental feature of complex organs. Despite this, the global landscape of intercellular signaling in mammalian liver has not been ...elucidated. Here we perform single-cell RNA sequencing on non-parenchymal cells isolated from healthy and NASH mouse livers. Secretome gene analysis revealed a highly connected network of intrahepatic signaling and disruption of vascular signaling in NASH. We uncovered the emergence of NASH-associated macrophages (NAMs), which are marked by high expression of triggering receptors expressed on myeloid cells 2 (Trem2), as a feature of mouse and human NASH that is linked to disease severity and highly responsive to pharmacological and dietary interventions. Finally, hepatic stellate cells (HSCs) serve as a hub of intrahepatic signaling via HSC-derived stellakines and their responsiveness to vasoactive hormones. These results provide unprecedented insights into the landscape of intercellular crosstalk and reprogramming of liver cells in health and disease.
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•Heterogeneity and plasticity of non-parenchymal cells in healthy and NASH liver•Landscape of intrahepatic ligand-receptor signaling at single-cell resolution•Emergence of Trem2+ NASH-associated macrophages (NAMs) in mouse and human NASH•Stellakine secretion and contractile response to vasoactive hormones by HSCs
This work illustrates the heterogeneity of liver non-parenchymal cells (NPCs) and their reprogramming during NASH pathogenesis. Using single-cell RNA-sequencing analysis, the authors mapped the landscape of the intrahepatic ligand-receptor signaling network and revealed two fundamental aspects of HSC biology: stellakine secretion and contractile response to vasoactive hormones. Hepatic vascular dysfunction and emergence of Trem2+ NASH-associated macrophages (NAMs) are two conserved features of mouse and human NASH.
Lightly stroking the lips or gently poking some skin regions can evoke mechanical itch in healthy human subjects. Sensitization of mechanical itch and persistent spontaneous itch are intractable ...symptoms in chronic itch patients. However, the underlying neural circuits are not well defined. We identified a subpopulation of excitatory interneurons expressing Urocortin 3::Cre (Ucn3+) in the dorsal spinal cord as a central node in the pathway that transmits acute mechanical itch and mechanical itch sensitization as well as persistent spontaneous itch under chronic itch conditions. This population receives peripheral inputs from Toll-like receptor 5-positive (TLR5+) Aβ low-threshold mechanoreceptors and is directly innervated by inhibitory interneurons expressing neuropeptide Y::Cre (NPY+) in the dorsal spinal cord. Reduced synaptic inhibition and increased intrinsic excitability of Ucn3+ neurons lead to chronic itch sensitization. Our study sheds new light on the neural basis of chronic itch and unveils novel avenues for developing mechanism-specific therapeutic advancements.
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•Spinal Ucn3+ neurons transmit both mechanical itch and persistent spontaneous itch•Spinal Ucn3+ neurons receive inputs from TLR5+ LTMRs•Spinal NPY+ inhibitory interneurons gate Ucn3+ neurons•Sensitization of mechanical itch pathway contributes to chronic itch
Pan et al. identify a microcircuit in the dorsal spinal cord that transmit mechanically evoked itch. Sensitization of this pathway is required for chronic itch development.
As a universal mechanical cue, shear stress plays essential roles in many physiological processes, ranging from vascular morphogenesis and remodeling to renal transport and airway barrier function. ...Disrupted shear stress is commonly regarded as a major contributor to various human diseases such as atherosclerosis, hypertension, and chronic kidney disease. Despite the importance of shear stress in physiology and pathophysiology, our current understanding of mechanosensors that sense shear stress is far from complete. An increasing number of candidate mechanosensors have been proposed to mediate shear stress sensing in distinct cell types, including G protein-coupled receptors (GPCRs), G proteins, receptor tyrosine kinases, ion channels, glycocalyx proteins, and junctional proteins. Although multiple types of mechanosensors might be able to convert shear stress into downstream biochemical signaling events, in this review, we will focus on discussing the mechanosensitive GPCRs (angiotensin II type 1 receptor, GPR68, histamine H1 receptor, adhesion GPCRs) and ion channels (Piezo, TRP) that have been reported to be directly activated by shear stress.
Noxious pH triggers pungent taste and nocifensive behavior. While the mechanisms underlying acidic pH sensation have been extensively characterized, little is known about how animals sense alkaline ...pH in the environment. TMC genes encode a family of evolutionarily conserved membrane proteins whose functions are largely unknown. Here, we characterize C. elegans TMC-1, which was suggested to form a Na+-sensitive channel mediating salt chemosensation. Interestingly, we find that TMC-1 is required for worms to avoid noxious alkaline environment. Alkaline pH evokes an inward current in nociceptive neurons, which is primarily mediated by TMC-1 and to a lesser extent by the TRP channel OSM-9. However, unlike OSM-9, which is sensitive to both acidic and alkaline pH, TMC-1 is only required for alkali-activated current, revealing a specificity for alkaline sensation. Ectopic expression of TMC-1 confers alkaline sensitivity to alkali-insensitive cells. Our results identify an unexpected role for TMCs in alkaline sensation and nociception.
•Little is known about how animals sense alkaline pH in the environment•TMC-1 is required for C. elegans to avoid noxious alkaline environment•TMC-1 is required for alkali-activated currents in nociceptive neurons•Ectopic expression of TMC-1 confers alkaline sensitivity to alkali-insensitive cells
Little is known about how animals sense alkali in the environment. Wang et al. report that TMC-1, an evolutionarily conserved membrane protein, mediates alkaline sensation in C. elegans by functioning as an essential subunit of an alkali-activated channel.
Both poikilotherms and homeotherms live longer at lower body temperatures, highlighting a general role of temperature reduction in lifespan extension. However, the underlying mechanisms remain ...unclear. One prominent model is that cold temperatures reduce the rate of chemical reactions, thereby slowing the rate of aging. This view suggests that cold-dependent lifespan extension is simply a passive thermodynamic process. Here, we challenge this view in C. elegans by showing that genetic programs actively promote longevity at cold temperatures. We find that TRPA-1, a cold-sensitive TRP channel, detects temperature drop in the environment to extend lifespan. This effect requires cold-induced, TRPA-1-mediated calcium influx and a calcium-sensitive PKC that signals to the transcription factor DAF-16/FOXO. Human TRPA1 can functionally substitute for worm TRPA-1 in promoting longevity. Our results reveal a previously unrecognized function for TRP channels, link calcium signaling to longevity, and, importantly, demonstrate that genetic programs contribute to lifespan extension at cold temperatures.
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► Cold-dependent lifespan extension is not a passive thermodynamic process ► A genetic program actively contributes to lifespan extension at cold temperatures ► This program includes a cold-sensitive TRP channel, Ca2+ influx, PKC, SGK, and FOXO ► The intestine, a nonexcitable tissue, can also act as a cold receptor
A cold-sensitive ion channel detects temperature drops in the environment and actively promotes longevity in worms, suggesting that lifespan extension in response to cold temperatures is under genetic control.
Electroreception is employed by some fishes to locate prey or predators. However, why the nematode Caenorhabditis elegans senses electric fields is unclear. A new study shows that electroreception ...helps these microscopic worms to attach themselves to insects for transportation.
Electroreception is employed by some fishes to locate prey or predators. However, why the nematode Caenorhabditis elegans senses electric fields is unclear. A new study shows that electroreception helps these microscopic worms to attach themselves to insects for transportation.
Model organisms usually possess a small nervous system but nevertheless execute a large array of complex behaviors, suggesting that some neurons are likely multifunctional and may encode multiple ...behavioral outputs. Here, we show that the C. elegans interneuron AIY regulates two distinct behavioral outputs: locomotion speed and direction-switch by recruiting two different circuits. The "speed" circuit is excitatory with a wide dynamic range, which is well suited to encode speed, an analog-like output. The "direction-switch" circuit is inhibitory with a narrow dynamic range, which is ideal for encoding direction-switch, a digital-like output. Both circuits employ the neurotransmitter ACh but utilize distinct postsynaptic ACh receptors, whose distinct biophysical properties contribute to the distinct dynamic ranges of the two circuits. This mechanism enables graded C. elegans synapses to encode both analog- and digital-like outputs. Our studies illustrate how an interneuron in a simple organism encodes multiple behavioral outputs at the circuit, synaptic, and molecular levels.
Mechanotransduction channels mediate several common sensory modalities such as hearing, touch, and proprioception; however, very little is known about the molecular identities of these channels. Many ...TRP family channels have been implicated in mechanosensation, but none have been demonstrated to form a mechanotransduction channel, raising the question of whether TRP proteins simply play indirect roles in mechanosensation. Using
Caenorhabditis elegans as a model, here we have recorded a mechanosensitive conductance in a ciliated mechanosensory neuron in vivo. This conductance develops very rapidly upon mechanical stimulation with its latency and activation time constant reaching the range of microseconds, consistent with mechanical gating of the conductance. TRP-4, a TRPN (NOMPC) subfamily channel, is required for this conductance. Importantly, point mutations in the predicted pore region of TRP-4 alter the ion selectivity of the conductance. These results indicate that TRP-4 functions as an essential pore-forming subunit of a native mechanotransduction channel.
► The molecular identities of mechanotransduction channels remain largely elusive ► The activity of a mechanotransduction channel requires the TRP family channel TRP-4 ► TRP-4 is a pore-forming subunit of this mechanotransduction channel ► TRP-4 acts as a mechanotransduction channel in the TRP family
The nematode Caenorhabditis elegans is commonly used as a genetic model organism for dissecting integration of the sensory and motor systems. Despite extensive genetic and behavioural analyses that ...have led to the identification of many genes and neural circuits involved in regulating C. elegans locomotion behaviour, it remains unclear whether and how somatosensory feedback modulates motor output during locomotion. In particular, no stretch receptors have been identified in C. elegans, raising the issue of whether stretch-receptor-mediated proprioception is used by C. elegans to regulate its locomotion behaviour. Here we have characterized TRP-4, the C. elegans homologue of the mechanosensitive TRPN channel. We show that trp-4 mutant worms bend their body abnormally, exhibiting a body posture distinct from that of wild-type worms during locomotion, suggesting that TRP-4 is involved in stretch-receptor-mediated proprioception. We show that TRP-4 acts in a single neuron, DVA, to mediate its function in proprioception, and that the activity of DVA can be stimulated by body stretch. DVA both positively and negatively modulates locomotion, providing a unique mechanism whereby a single neuron can fine-tune motor activity. Thus, DVA represents a stretch receptor neuron that regulates sensory–motor integration during C. elegans locomotion.
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