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W4312912070 abstract "Article Figures and data Abstract Editor's evaluation eLife digest Introduction Results Discussion Materials and methods Data availability References Decision letter Author response Article and author information Metrics Abstract Mechanical nociception is an evolutionarily conserved sensory process required for the survival of living organisms. Previous studies have revealed much about the neural circuits and sensory molecules in mechanical nociception, but the cellular mechanisms adopted by nociceptors in force detection remain elusive. To address this issue, we study the mechanosensation of a fly larval nociceptor (class IV da neurons, c4da) using a customized mechanical device. We find that c4da are sensitive to mN-scale forces and make uniform responses to the forces applied at different dendritic regions. Moreover, c4da showed a greater sensitivity to localized forces, consistent with them being able to detect the poking of sharp objects, such as wasp ovipositor. Further analysis reveals that high morphological complexity, mechanosensitivity to lateral tension and possibly also active signal propagation in dendrites contribute to the sensory features of c4da. In particular, we discover that Piezo and Ppk1/Ppk26, two key mechanosensory molecules, make differential but additive contributions to the mechanosensitivity of c4da. In all, our results provide updates into understanding how c4da process mechanical signals at the cellular level and reveal the contributions of key molecules. Editor's evaluation Liu et al. present a fascinating study that significantly advances fundamental knowledge about the molecular and cellular pathways underlying mechanical nociception. The use of a combination of fine biophysics and neurogenetics provides unprecedented insight into mechanosensory functions in an intact tissue environment of the Drosophila larva. The results of this work have strong implications for our understanding of the sensation of acute pain. https://doi.org/10.7554/eLife.76574.sa0 Decision letter Reviews on Sciety eLife's review process eLife digest Being able to sense harm is essential for survival. Animals have to be able to tell the difference between a gentle touch and a dangerous pressure. They do this using nerve cells called mechanical nociceptors which switch on when the body feels a potentially painful pressure, such as a sharp object poking the skin. Once activated, the nerves send outputs to other parts of the central nervous system which coordinate the motions needed to escape the source of the pain. One popular model to understand harm-sensing is the larvae of fruit flies which automatically roll back and forth when they sense the pointy sting of a wasp. This process is initiated by sensory nerve cells called class IV dendritic arborization neurons (or c4da for short) which sit under the fly’s skin. However, it is still not fully understood how these mechanical nociceptors detect the poking forces of the wasp’s tail. To investigate, Liu, Wu et al. built a device that could poke sections of fly larvae under a microscope so they could see how different types of pressure affected the activity and shape of c4da cells. This revealed that c4da nerves were most sensitive to sharp objects that illicit a more localized force, which may explain why these cells are so good at responding to wasp attacks. Further analysis showed that this sensitivity was due to the high number of branches, or dendrites, protruding from the body of c4da nerves. Liu, Wu et al. discovered that the dendrites were coated in a touch-sensitive protein that can sense and amplify both squashing and pulling, resulting in a signal that activates c4da nerves to send outputs to other parts of the central nervous system. This mechanism increases the likelihood that a c4da cell will detect a mechanical pressure even if it is far away from the body of the nerve. These findings shed light on how sensory cells like c4da are optimized to carry out specific roles. This could be important for understanding other nerve systems which sense mechanical pressure, such as those involved in touch or auditory processes. However, further work is needed to see whether the molecules and mechanism identified by Liu, Wu et al. are also present in humans. Introduction Mechanosensation is a physiological process that transduces mechanical stimuli into neural signals (Chalfie, 2009). It underlies the perception of gentle touch, sound, acceleration and noxious force. To cope with manifold environmental forces, mechanoreceptor cells are diversified (Lumpkin et al., 2010; Zimmerman et al., 2014). Among different types of mechanoreceptor cells, those activated by noxious forces, that is mechanical nociceptors, are of particular importance because they are one of the sensory organs that are essential for the survival of living organisms (Lumpkin et al., 2010; Tracey, 2017). Much effort has been made to understand mechanical nociception in several model organisms. In mammals, free nerve endings of nociceptive neurons penetrate the keratinocyte layer of skin and serve as the primary nociceptors. The axons of these neurons output to neural circuits in the spinal cord, which then transmit pain signals to local interneurons or up to the brain to initiate neural reflexes (Tracey, 2017). At the molecular level, transient receptor potential (TRP) channels, Piezo and other channels are found to be involved in mechanical nociception (Kwan et al., 2006; Tracey, 2017; Murthy et al., 2018). In invertebrates (such as worms and flies), mechanical nociception has also been extensively studied (Chatzigeorgiou et al., 2010; Tracey, 2017). A widely used model is fly larval mechanical nociception mediated by class IV dendritic arborization neurons (c4da). C4da are polymodal nociceptors that can be activated by light, thermal and mechanical stimuli (Hwang et al., 2007; Xiang et al., 2010; Kim et al., 2012; Terada et al., 2016). The axon of c4da synapses to several targets in the ventral nerve cord, which then output signals to trigger the rolling behavior, a stereotyped locomotion in escaping from nociceptive stimuli (Grueber et al., 2007; Ohyama et al., 2015; Gerhard et al., 2017; Hu et al., 2017; Kaneko et al., 2017; Takagi et al., 2017; Yoshino et al., 2017; Burgos et al., 2018). Furthermore, two parallel molecular pathways in c4da, one mediated by Ppk1/Ppk26 and the other by Piezo, are proposed to be responsible for the behavioral responses in mechanical but not thermal nociception (Kim et al., 2012; Zhong et al., 2010; Gorczyca et al., 2014; Guo et al., 2014). An intriguing question is whether c4da neurons are optimized at the cellular level for its function as mechanical nociceptor? A recent study shows that the nociceptive response of c4da to thermal stimuli depends on the dendritic calcium influx through two TRPA channels and the L-type voltage-gated calcium channel, suggesting the presence of neuronal processing of heat-induced responses (Terada et al., 2016). In a more general sense, it is also intriguing how mechanoreceptor cells are optimized for their specific stimuli. An interesting study reports unique neuronal mechanisms in the mechanosensory neurons in tactile-foraging birds (Schneider et al., 2014), also demonstrating the presence of cellular mechanisms that facilitate the response to specific stimuli. So far, how c4da process mechanical inputs in nociception at the neuronal level remains unclear. To address this issue, we build a ‘mechanical-optical’ recording system that is able to measure the in vivo sensory response of c4da to controlled forces. We find that c4da are sensitive to mN-scale forces and use the entire dendritic territory (including the non-neuronal part of the epidermis) as the force-receptive field. In particular, c4da show greater responses to smaller probes, suggesting their sensory preference to localized forces. Further analysis reveals the cellular mechanisms that facilitate the sensory features of c4da and the contributions of key molecules. In all, these findings update the current model for the c4da-mediated mechanical nociception and provide novel insights into how mechano-nociceptor cells process force signals at the cellular level. Results Mechanical recording and the ‘sphere-surface’ contact model We set out by building a mechanical device that was able to exert and measure compressive forces onto fly larval fillets (Figure 1A). This device contained three parts: a piezo stack actuator, a metal beam coupled with a strain gauge and a glass force probe (Figure 1A and Figure 1—figure supplement 1). The whole device was mounted on the working stage of an inverted spinning-disk confocal microscope (Figure 1A and Figure 1—figure supplement 1). To record the force-evoked response of sensory neurons, freshly prepared larval fillet was spread and mounted on a polydimethylsiloxane (PDMS) pad (thickness: 1 mm) with the exterior surface of the cuticle accessible to the force probe and the interior surface visible to the confocal microscope (Figure 1A). When the force probe, driven by the piezo actuator, delivered compressive forces onto the larval fillet, the strain gauge converted the deflection of the metal beam into an electrical signal. The electrical signal could be translated into a force signal using the calibration curve (Figure 1B–C, see Materials and methods). By making spherical probes in different diameters (Figure 1D), we can study how mechanoreceptor cells respond to the probes of different sizes. In the meantime, we also monitored the position of force probes, dendritic morphology (membrane marker) and neuronal response (GCaMP6s) (Figure 1E). Figure 1 with 1 supplement see all Download asset Open asset The 'mechanical-optical' recording system. (A) The cartoon schematics for the ‘mechanical-optical’ recording system (left) and the contact model between a spherical probe and the larval fillet (right). Vin was the driving voltage of the piezo actuator. Vout was the readout voltage of the strain gauge. (B) The force calibration curve of the strain gauge. The data points were mean values from three measurements. (C) Representative traces for the input (driving voltage of the piezo actuator, upper panel) and the mechanical output (stimulating force, lower panel) of the recording system. (D) The scanning electron microscopy images of glass force probes of different sizes. Scale bar, 100 μm. (E) Left panel: a representative image of c4da (membrane, red channel), Middle panel: a bright field image of larval fillet. Right panel: two representative images showing the GCaMP6s signals in c4da at resting (left) and exciting (right) conditions. Yellow arrowhead: soma. White arrowhead: force probe. Scale bar, 100 μm. Genotype: uas-cd4-tdTom; ppk-gal4/20×uas-ivs-gcamp6s. (F) The mechanical schematics of the 'sphere-surface' model. Note that the contact interface had a spherical crown shape. The definitions of all model parameters were described in Materials and methods. (G) The cartoons schematics showing the relationship among indentation depth of the force probe (d) deflection of the beam (B) and stepping distance of the piezo (D). (H) The plots of D (red) and B (blue) versus the driving voltage of the piezo (Vin). (I) The comparison between the calculated (red and blue) and experimentally measured (black) contact forces. In our calculations, the maximal (4 MPa, red) and minimal (1.6 MPa, blue) values of the elastic modules of PDMS were from the literatures (Johnston et al., 2014; Vlassov et al., 2018). Data were presented as mean ± std (n=9 assays). Figure 1—source data 1 Numerical data for Figure 1. https://cdn.elifesciences.org/articles/76574/elife-76574-fig1-data1-v3.zip Download elife-76574-fig1-data1-v3.zip The contact mechanics between the force probe and fillet can be approximated using a classic ‘sphere-surface’ contact model (Johnson, 1985), which would allow us to separate the effects of different parameters, such as pressure and contact area. Note that to guarantee the accuracy of the contact model, the indentation depth (d) needs to be smaller than the radius of the spherical probe (r) (Figure 1F). This prerequisite is acceptable for our measurements because our pilot experiments showed that when the step distance (D) of the piezo actuator was greater than r, the force probe often penetrated the cuticle and caused tissue damage. The small deformation constraint would naturally minimize tissue damage (Figure 1—figure supplement 1) and allow us to focus on mechanical nociception (i.e. no major interference from chemo-nociception due to tissue damage). To confirm if the modeling approximation is valid, we calculated contact force (fmodel) from d (Equations 1 and 2, see Materials and methods), which could be obtained from the measured values of D and beam deflection (B) (Equation 3, see Materials and methods). fmodel was then compared to the experimentally measured forces (fexp) (Figure 1G–I). As shown in Figure 1I, the relationship between fexp and d fell in the range of model calculations, demonstrating that the model approximation is valid. Note that different values for the elastic modulus of PDMS (EPDMS) (Johnston et al., 2014; Vlassov et al., 2018) were used to calculate the upper and lower bounds of contact forces (Figure 1I). C4da are sensitive to mN-scale forces and more sensitive to small probes Using the customized mechanical device, we applied poking forces onto c4da at the positions of about 100 μm away from the soma (i.e. the ‘proximal’ region, denoted as p in the plots) (Figure 2A and Video 1). By simultaneously monitoring the position of the probes and neuronal morphology, we ensured that the probe made direct compression onto the dendrites. Force titration experiments using a 60 μm probe showed a half-activation force (f50) of ~3 mN and a full-activation force (f90) of ~4 mN, while those using a 30 μm probe showed a f50 of ~0.7 mN and a f90 of ~1.5 mN (Figure 2B–C). This observation suggests that the mechanosensitivity of c4da is dependent on probe size. To explore the role of the entire dendritic field in force detection, we compressed the dendrites of c4da at the positions of about 200 μm away from the soma (i.e. the ‘distal’ region, denoted as d in the figures) (Figure 2D). When the saturation force (4 mN) of the 60 μm probe was used, the responses of c4da were not significantly different from those to the proximal stimuli (Figure 2E). In the case of using a 30 μm probe and applying the saturation force (1.5 mN), the responses of c4da were to some extent weaker than those to the proximal stimuli, but most of the neurons still made clear responses (Figure 2E). Therefore, our results showed that c4da could respond to the forces applied onto any part of their dendritic arbors. Figure 2 with 3 supplements see all Download asset Open asset The mechanosensory features of c4da. (A) A representative image of c4da. The forces were applied at about 100 μm from the soma, i.e. along the green dashed circle. The representative force application points were marked using the filled circles (Green: 30 μm probe. Red: 60 μm probe). Genotype: uas-cd4-tdtom; ppk-gal4. (B) Representative responses of c4da (ΔF/F0, i.e. the change in calcium signal in the soma, unless otherwise stated hereinafter) to mN-scale forces delivered using the 30 μm (green) and 60 μm (red) probes. The black arrowhead indicated the defocused period of the soma caused by the stimulating force (2 s). Genotype: ppk-gal4/+; ppk-cd4-tdtom/20×uas-ivs-gcamp6s. (C) The force-response (ΔF/F0) plots of c4da (n=12 cells). The dashed lines were Boltzmann fitting. (D) The schematic showing the force application points (filled circles, green: 30 μm probe, red: 60 μm probe) of different stimuli. The dashed concentric circles were 100 and 200 μm in radius, respectively. (p) proximal dendrite. (d) distal dendrite. d-off: the ‘dendrite-off’ region. (E) The responses of c4da (ΔF/F0) to the proximal and distal stimuli using the 30 (1.5 mN) and 60 μm (4 mN) probes. Mann Whitney U test was used. *: p<0.05. ns: no significance. (F) The schematic showing the stimuli (filled circles, green: 30 μm probe, red: 60 μm probe, orange: 100 μm probe, blue: 200 μm probe) delivered using the probes of different sizes. The dashed circle was 200 μm in radius. (G) The responses of c4da (ΔF/F0, n=10 cells) to the forces applied on the distal dendrites using the probes of different sizes. (H) The plots of the responses of c4da (the same dataset as panel (G)) to distal stimuli versus central pressure (P0) (left panel) and contact areas (Ac) (right panel), respectively. Also see Figure 2—figure supplement 2 for the plots of the responses versus the pressures at other positions (Px μm). (I) The cartoon schematics of the modified behavior assay for mechanical nociception. VFF: Von Frey fiber, FP: force probe. (J) The behavioral responses of wild-type larvae to the mechanical poking stimuli using the probes of different sizes. The experiments were performed three times and the total numbers of larvae used for each type of probe were as following: 30 μm probe (n=92), 60 μm probe (n=67), 100 μm probe (n=69), 200 μm probe (n=70). One-way ANOVA test was used. **: p<0.01. ns: no significance. In panels (A), (D) and (F), scale bar: 100 μm. Asterisk: the soma. In panels (C), (G) and (H), data were presented as mean ± sem. In panel (E) and (J), data were presented as mean ± std and the numbers of cells were indicated below the scattered data points. Figure 2—source data 1 Numerical data for Figure 2. https://cdn.elifesciences.org/articles/76574/elife-76574-fig2-data1-v3.zip Download elife-76574-fig2-data1-v3.zip Video 1 Download asset This video cannot be played in place because your browser does support HTML5 video. You may still download the video for offline viewing. Download as MPEG-4 Download as WebM Download as Ogg The representative response of a c4da cell to the 4 mN force stimulus. The asterisk indicated the force application point and the white arrowhead indicated the soma. To further test the validity of this assay, we performed the same assay on c1da (class I da neuron) and c3da (class III da neuron). C1da showed no responses to compressive forces (Figure 2—figure supplement 1), consistent with their function being a proprioceptor rather than a tactile receptor (Hughes and Thomas, 2007; Guo et al., 2016; He et al., 2019). C3da showed a much smaller threshold of activation, suggesting a higher sensitivity in detecting tactile forces (using both 30 and 60 μm probes). This is consistent with their known function as a larval gentle touch receptor (Figure 2—figure supplement 1; Tsubouchi et al., 2012; Yan et al., 2013). The observation of different responses of c4da to the 30 and 60 μm probes suggests that c4da are more sensitive to smaller probes. To test this idea, we stimulated c4da using probes of different diameters (30, 60, 100, and 200 μm) at the distal regions (Figure 2F). We found that c4da made stronger responses (ΔF/F0) to smaller probes at the same force (Figure 2G). In addition, the slope of the force-ΔF/F0 curve increased as the probe became smaller (Figure 2G), reflecting an enhanced mechanosensitivity to the change in stimulating force. To further understand this result, we calculated central pressure (P0) and contact area (Ac) based on the ‘sphere-surface’ model (Equations 4–7, see Materials and methods), and then plotted the responses against these two parameters separately (Figure 2H). In the P0-ΔF/F0 plots (left panel in Figure 2H), we found that increasing contact area decreased the threshold of cell activation but had only a minor impact on the slopes of the curves, suggesting that c4da have a robust sensitivity to the change in pressure. Similar observations were obtained when the pressures at other positions (Px μm) were plotted against the responses (ΔF/F0) (Figure 2—figure supplement 2). In the Ac-ΔF/F0 plots (right panel in Figure 2H), when the contact area was the same, higher pressure led to stronger responses (Figure 2H), also consistent with c4da being a pressure sensor. The comparison of the ΔP (the change of pressure) and ΔAc (the change of contact area) of different probes showed that for a given change of forces, the smaller probes caused a smaller ΔAc but a greater ΔP in comparison to the larger probes (Figure 2H), explaining the higher sensitivity of c4da to the smaller probes. To further understand how the sensory preference of c4da to localized poking contributes to the behavioral response of larvae in nociception, we performed the behavior assay of mechanical nociception using a modified Von Frey fiber. To test the effect of different probe sizes, we attached the glass probes (shorter than 1 mm) of different diameters (from 30 to 200 μm) to the end of a Von Frey fiber (Figure 2I). Using these modified fibers, we were able to deliver poking forces of 15–20 mN to fly larvae. Note that mean value and variation of the stimulating forces were independent on the probe size (Figure 2—figure supplement 3). The defensive rolling behaviors were recorded and scored to reflect the sensory response of c4da. We found that fly larvae showed stronger behavioral responses to smaller probes (Figure 2J), in agreement with our observations on the cellular level. In summary, our results demonstrate that c4da are sensitive to mN-scale compressive forces applied onto their dendrites. In particular, c4da are more sensitive to smaller probes, consistent with c4da acting as a larval nociceptor to sense mechanical poking or sting from sharp objects, for example the wasp ovipositor (Hwang et al., 2007; Robertson et al., 2013; Cerkvenik et al., 2017). Morphological complexity likely contributes to the sensory features of c4da Having characterized the mechanosensory responses of c4da, we wondered what could be the cellular mechanisms underlying the sensory preference of c4da to small probes. The key thing is to ensure that an adequate number of mechanosensory molecules can be activated upon a localized force. Intuitively, a densely distributed dendritic arbor would be helpful. We tested this hypothesis by studying the sensory responses of a knock-down mutant of cut (cti), a key transcription factor underlying the high morphological complexity of c4da (Grueber et al., 2003; Jinushi-Nakao et al., 2007). C4da-cti neurons showed a sparser dendritic morphology than c4da-wt (Figure 3A). Modified Sholl analysis showed that the dendritic density of c4da-wt was uniform across almost the entire dendritic field, while that of c4da-cti was similar to c4da-wt in the proximal region but rapidly decreased towards the distal region (Figure 3B). In comparison to c4da-wt or c4da-scrambled RNAi, c4da-cti showed a similar response to the stimuli on the proximal dendrites, but a significantly weaker response to those on the distal dendrites (Figure 3C). We noted that the overall responses of c4da-cti to different probes were generally reduced and in particular, the responses to the 30 μm probe were reduced to the greatest extent (Figure 3D). Consistent with the cellular observations, the defensive rolling behaviors of c4da-cti in response to the mechanical poking of small probes (30 and 60 μm) were largely weakened in comparison to those of c4da-wt, while those to large probes (e.g. 100 μm) showed nearly no change (Figure 3E). Based on these observations, we conclude that the sensory preference of c4da to small probes was lost in c4da-cti. Figure 3 with 1 supplement see all Download asset Open asset The contribution of dendritic morphology to the sensory features of c4da. (A) The schematic showing the force application points (filled circles, green: 30 μm probe, red: 60 μm probe, orange: 100 μm probe) on c4da-cti. The dashed concentric circles were 100 and 200 μm in radius, respectively. (p) proximal dendrite. (d) distal dendrite. d-off: the ’dendrite-off’ region. Asterisk: the soma. Scale bar, 100 μm. Genotype: ppk-gal4/+, ppk-cd4-tdtom/uas-cti. (B) Modified Sholl analysis on the morphology of c4da-wt and c4da-cti. Note that there was a broad region in c4da-wt (red bar) in which the dendritic density was nearly constant. The shadow areas represented standard deviations. n=5 cells for each genotype. The black arrowhead indicated the regions of proximal dendrites. (C) The responses of c4da-cti (ΔF/F0) to the force stimuli (4 mN) applied onto the proximal and distal dendrites using a 60 μm probe. The numbers of cells were indicated below the scattered data points. Mann Whitney U test was used. *: p<0.05. ns: no significance. cti: ppk-gal4/20×uas-ivs-gcamp6s, ppk-cd4-tdtom/uas-cti. scrambledi: ppk-gal4/20×uas-ivs-gcamp6s, ppk-cd4-tdtom/uas-scrambledi. (D) The responses of c4da-cti (ΔF/F0) to the forces applied on the distal dendrites using the probes of different sizes. Data were presented as mean ± sem (n=10 cells). (E) The behavioral responses of cti larvae to mechanical poking using the probes of different sizes. wt: w1118. ppk-gal4: ppk-gal4; +/+. uas-cti: +/+; uas-cti. cti: ppk-gal4/+; uas-cti/+. ppk-gal4 larvae: 30 μm probe (n=63 larvae from three experiments), 60 μm probe (n=60 larvae from three experiments) and 100 μm probe (n=68 larvae from three experiments). uas-cti larvae: 30 μm probe (n=68 larvae from three experiments), 60 μm probe (n=72 larvae from three experiments) and 100 μm probe (n=63 larvae from three experiments). cti larvae: 30 μm probe (n=97 larvae from four experiments), 60 μm probe (n=91 larvae from four experiments) and 100 μm probe (n=91 larvae from four experiments). One-way ANOVA test was used. **: p<0.01. ns: no significance. In panels (C), (D) and (E), the corresponding data from c4da-wt were provided for comparison. In panel (C) and (E), data were presented as mean ± std. Figure 3—source data 1 Numerical data for Figure 3. https://cdn.elifesciences.org/articles/76574/elife-76574-fig3-data1-v3.zip Download elife-76574-fig3-data1-v3.zip Because Cut is a transcription factor, the reduction of its expression level might lead to other changes in addition to the disrupted morphology. To explore the effects of these potential factors, we performed several control experiments. First, we checked the expression level and subcellular localization of two mechanosensory molecules, that is Piezo and Ppk1/Ppk26, in c4da-cti. They showed similar expression and localization as in c4da-wt (Figure 3—figure supplement 1). Second, the changes in dendritic cytoskeleton might indirectly affect mechanosensation by altering the mechanical homeostasis of the dendrites, so we checked the dendritic signals of F-actin and microtubules. No significant difference was found (Figure 3—figure supplement 1). These two observations suggest that although the reduction in the expression level of Cut decreases the number of dendritic branches, the expression and localization of mechanosensory molecules and cytoskeletal elements are nearly unchanged in the existing dendrites of c4da-cti. Third, we also performed the same set of mechanical recording experiments on c3da-wt, in which there is no additional manipulation at the genetic level, but the dendritic density differs from that of c4da-wt in the way as in the case of c4da-cti (Figure 2—figure supplement 1). The responses of c3da-wt to the distal stimuli were significantly weaker than those to the proximal stimuli (Figure 2—figure supplement 1). In addition, no preference to small probes was found in c3da-wt (Figure 2—figure supplement 1). These sensory features were markedly different from those in c4da-wt, but similar to those in c4da-cti. In all, our observations are consistent with the dendritic morphology making a direct contribution in supporting the sensory features of c4da. Note that the potential contributions of other unknown factors cannot be absolutely excluded (see Discussion). Mechanosensitivity to lateral tension expands the force-receptive field An unexpected finding in studying c4da-cti, primarily due to the sparse dendritic morphology, was that when the force probe was not directly placed on a dendrite but on an adjacent region without any dendrite (i.e. the ‘dendrite-off’ mode, denoted as ‘d-off’ in the plots), the response of c4da was nearly unchanged, as if the force was directly applied on the dendrite (Figure 3C). We wondered if this reflects impalpable difference due to the overall reduction in the sensory response of c4da-cti or that the dendrites of c4da have an expanded force-receptive field. To verify this, we performed the same experiments on c4da-wt (d-off in Figure 2D). The responses of c4da-wt to the d-off stimuli were also unchanged from those to the distal stimuli (Figure 4A). Further experiments on c4da-wt showed that the responses kept nearly constant until the force was applied at least 40–60 μm away from a dendrite (Figure 4A). Based on these results, we conclude that the dendrites of c4da have an expanded force-receptive field. Figure 4 with 1 supplement see all Download asset Open asset The mechanosensitivity of c4da to lateral tension. (A) The responses of c4da (ΔF/F0) to the d-off stimuli (4 mN, 60 μm probe) applied at different positions.The numbers of cells were indicated below the scattered data points. Mann Whitney U test was used. **: p<0.01. *: p<0.05. ns: no significance. Genotype: ppk-gal4/+; ppk-cd4-tdtom/20×uas-ivs-gcamp6s. (B) Left panel: representative heat maps showing the 2D distributions of pressure perpendicular to the cuticle surface (PP) and tension parallel with the cuticle surface (TL) of the 30 μm (upper) and 60 (lower) μm probes. Scale bar, 30 μm. Right panels: representative line prof" @default.
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W4312912070 title "Decision letter: Drosophila mechanical nociceptors preferentially sense localized poking" @default.
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