Response properties of RAM-receptors A top: Schematic drawing of the predominant RAM anatomy in saphenous-nerve preparation (hair follicle receptor), tibial-nerve preparation (Meissner's corpuscle) and median/ulnar-nerve preparation (Meissner's corpuscle) Bottom: representative example traces of RAMs in response to a ramp and hold stimulation with a velocity of 0.45mm/s. B Minimal stimulation force needed to evoke an action potential in response to increasing amplitude vibrating stimuli (20 Hz); ANOVA: p>0.05; error bars represent SEM. C Average spike frequency in response to moving stimuli. Repeated measures ANOVA: p<0.0001; Bonferroni post-hoc tests are indicated; *** = p<0.001 ** p<0.01 * p<0.05; error bars represent SEM. 

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... was a quantitatively large difference in the way that RAMs in the glabrous forepaw skin coded moving stimuli compared to RAMs innervating hairy skin (Fig. 3C). Forepaw RAMs responded reliably with high firing rates to the slowest ramps used (0.075mm/s and 0.15mm/s), whereas hairy skin RAMs barely responded to the same stimuli (Fig. 3A,C) and these differences were statistically significant, (saphenous: n = 14; tibial: n = 14; median /ulnar: n = 21 repeated measure ANOVA F(2, 46) = 15.22, p< 0.0001). Thus RAMs in the forepaw glabrous skin are tuned to slower movements, but also have firing rates that were several fold higher than observed for afferents innervating hairy skin ( Fig 3A,C) 1.5mm/s (saphenous vs. median/ulnar) p<0.05. The vast majority of the forepaw RAMs had receptive fields clearly located in the glabrous skin and therefore likely innervate Meissner's corpuscles. It is possible that a very small number of receptors innervated hair follicles on the glabrous/hairy skin border, but due to the receptive field distributions ( Fig. 1) these afferents could not make up more than 10% of the total. The majority of RAMs in the tibial nerve also innervate glabrous skin and therefore also likely have Meissner's corpuscle ...

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... was a quantitatively large difference in the way that RAMs in the glabrous forepaw skin coded moving stimuli compared to RAMs innervating hairy skin (Fig. 3C). Forepaw RAMs responded reliably with high firing rates to the slowest ramps used (0.075mm/s and 0.15mm/s), whereas hairy skin RAMs barely responded to the same stimuli (Fig. 3A,C) and these differences were statistically significant, (saphenous: n = 14; tibial: n = 14; median /ulnar: n = 21 repeated measure ANOVA F(2, 46) = 15.22, p< 0.0001). Thus RAMs in the forepaw glabrous skin are tuned to slower movements, but also have firing rates that were several fold higher than observed for afferents innervating hairy skin ( Fig 3A,C) 1.5mm/s (saphenous vs. median/ulnar) p<0.05. The vast majority of the forepaw RAMs had receptive fields clearly located in the glabrous skin and therefore likely innervate Meissner's corpuscles. It is possible that a very small number of receptors innervated hair follicles on the glabrous/hairy skin border, but due to the receptive field distributions ( Fig. 1) these afferents could not make up more than 10% of the total. The majority of RAMs in the tibial nerve also innervate glabrous skin and therefore also likely have Meissner's corpuscle ...

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... was a quantitatively large difference in the way that RAMs in the glabrous forepaw skin coded moving stimuli compared to RAMs innervating hairy skin (Fig. 3C). Forepaw RAMs responded reliably with high firing rates to the slowest ramps used (0.075mm/s and 0.15mm/s), whereas hairy skin RAMs barely responded to the same stimuli (Fig. 3A,C) and these differences were statistically significant, (saphenous: n = 14; tibial: n = 14; median /ulnar: n = 21 repeated measure ANOVA F(2, 46) = 15.22, p< 0.0001). Thus RAMs in the forepaw glabrous skin are tuned to slower movements, but also have firing rates that were several fold higher than observed for afferents innervating hairy skin ( Fig 3A,C) 1.5mm/s (saphenous vs. median/ulnar) p<0.05. The vast majority of the forepaw RAMs had receptive fields clearly located in the glabrous skin and therefore likely innervate Meissner's corpuscles. It is possible that a very small number of receptors innervated hair follicles on the glabrous/hairy skin border, but due to the receptive field distributions ( Fig. 1) these afferents could not make up more than 10% of the total. The majority of RAMs in the tibial nerve also innervate glabrous skin and therefore also likely have Meissner's corpuscle ...

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... data suggests that the mouse has a highly developed forepaw tactile system adapted to manipulating objects and exploring their texture. The fact that myelinated sensory fiber receptor density was more than 3 fold higher than in the hind limb would enable much higher discriminative abilities using the forepaw. We calculated that the density of the myelinated sensory innervation was a striking 65 fibers/mm 2 . Analogously in humans tactile discrimination performance is clearly positively correlated with sensory innervation density . 5, 2018; which is highest on the finger tips and tongue (Van Boven and Johnson, 1994;Vallbo, 1979a, 1979b). Indeed mechanoreceptor density on the finger tips has been estimated to be ~240/cm 2 (Johansson and Vallbo, 1979c). We show here that Meissner's corpuscle density is not only very much higher in forepaw compared to hind paw glabrous skin, but also that each corpuscle receives around 25% more sensory endings compared to an equivalent corpuscle in the hind paw (Fig. 4). The anatomical adaptations that we have described in forepaw Meissner's corpuscles might underlie their functional specialization, including increased sensitivity to slower moving mechanical stimuli (Fig. 3). However, it is not clear why higher densities of sensory axons within a Meissner's corpuscle should increase the velocity sensitivity of the sensory unit. Mechanoreceptors including RAMs that innervate Meissner's corpuscles are thought to be equipped with a mechanotransduction apparatus that includes the mechanosensitive ion channel PIEZO2 and its modulator STOML3 ( Poole et al., 2014b;Ranade et al., 2014;Wetzel et al., 2017). Indeed small molecule inhibition of STOML3 in the mouse forepaw reversibly reduces the ability of the mouse to perceive mechanical stimuli ( Wetzel et al., 2017). It is known that the expression of mechanoreceptor specific potassium channels like KCNQ4 modulate the mechanoreceptor response to low frequency sinusoidal stimuli ( Heidenreich et al., 2012), so it is conceivable that mouse forepaw afferents express a different complement of potassium channels than mechanoreceptors innervating other skin regions. The high sensitivity of mouse ...

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... respond exclusively to moving stimuli, rapidly ceasing to fire after cessation of movement (Fig. 3A). Most RAMs in the hairy skin are associated with hair follicles, while the RAMs of the glabrous skin are associated with Meissner's corpuscles (Heidenreich et al., 2012;Lechner and Lewin, 2013;Poole et al., 2014a;Zimmerman et al., 2014). Forty-nine of the 111 Aβ-fibers recorded could be classified as RAMs and these receptors were equally sampled across hind paw hairy skin, hind paw glabrous skin and forepaw skin (Table 1). We used increasing amplitude vibration stimuli to assess the mean force threshold to activate all RAMs that innervate the different skin regions. The mean force thresholds were, as expected, very low with thresholds <3mN. There was a tendency for forepaw afferents (median and ulnar nerve) to be activated with smaller forces compared to afferents in hairy skin (saphenous nerve) or those innervating the hind paw glabrous skin (tibial nerve), but this difference was not statistically significant ( Fig. 3B; saphenous: n = 13; tibial: n = 13; median/ulnar: n = 21 Kruskal-Wallis test p = 0.6476). with increasing intensity. Right: Example trace of a receptor fiber responding to the vibrating stimulus. The force at the time of the first action potential was measured. C Left: schematic illustration of the ramp and hold stimulation. Four different velocities were used Right: Example trace of a receptor fiber responding to a ramp not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without ...

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... respond exclusively to moving stimuli, rapidly ceasing to fire after cessation of movement (Fig. 3A). Most RAMs in the hairy skin are associated with hair follicles, while the RAMs of the glabrous skin are associated with Meissner's corpuscles (Heidenreich et al., 2012;Lechner and Lewin, 2013;Poole et al., 2014a;Zimmerman et al., 2014). Forty-nine of the 111 Aβ-fibers recorded could be classified as RAMs and these receptors were equally sampled across hind paw hairy skin, hind paw glabrous skin and forepaw skin (Table 1). We used increasing amplitude vibration stimuli to assess the mean force threshold to activate all RAMs that innervate the different skin regions. The mean force thresholds were, as expected, very low with thresholds <3mN. There was a tendency for forepaw afferents (median and ulnar nerve) to be activated with smaller forces compared to afferents in hairy skin (saphenous nerve) or those innervating the hind paw glabrous skin (tibial nerve), but this difference was not statistically significant ( Fig. 3B; saphenous: n = 13; tibial: n = 13; median/ulnar: n = 21 Kruskal-Wallis test p = 0.6476). with increasing intensity. Right: Example trace of a receptor fiber responding to the vibrating stimulus. The force at the time of the first action potential was measured. C Left: schematic illustration of the ramp and hold stimulation. Four different velocities were used Right: Example trace of a receptor fiber responding to a ramp not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without ...

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... the sensitivity of RAMs found in the glabrous hind paw skin did not match that of the forepaw RAMs ( Glabrous hind paw RAMs were, however, capable of coding slower velocities than RAMs in hairy skin, but this was not statistically significant (Fig. ...

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... used the same protocols to test velocity sensitivity of D-hair receptors as we had used for RAMs. D-hair receptors are especially sensitive to fast moving stimuli (Fig. 6A,B) and had very low mechanical thresholds to vibration stimuli (Fig. 6C). There was no significant difference in the mean mechanical thresholds of D-hair receptors recorded across the three skin areas (Fig 6C saphenous: n = 13; tibial: n = 10; median/ulnar: n = 5, Kruskal-Wallis test p = 0.41). Importantly, the coding properties of all D-hair receptors recorded were almost identical across all three skin areas (Fig. 6B,C saphenous: n = 10; tibial: n = 18; median/ulnar: n = 7; repeated measures ANOVA F(2, 32) = 1.50; p = ...

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... was a quantitatively large difference in the way that RAMs in the glabrous forepaw skin coded moving stimuli compared to RAMs innervating hairy skin (Fig. 3C). Forepaw RAMs responded reliably with high firing rates to the slowest ramps used (0.075mm/s and 0.15mm/s), whereas hairy skin RAMs barely responded to the same stimuli (Fig. 3A,C) and these differences were statistically significant, (saphenous: n = 14; tibial: n = 14; median /ulnar: n = 21 repeated measure ANOVA F(2, 46) = 15.22, p< 0.0001). Thus RAMs in the forepaw glabrous skin are tuned to slower movements, but also have firing rates that were several fold higher than observed for afferents innervating hairy skin ( Fig 3A,C) 1.5mm/s (saphenous vs. median/ulnar) p<0.05. The vast majority of the forepaw RAMs had receptive fields clearly located in the glabrous skin and therefore likely innervate Meissner's corpuscles. It is possible that a very small number of receptors innervated hair follicles on the glabrous/hairy skin border, but due to the receptive field distributions ( Fig. 1) these afferents could not make up more than 10% of the total. The majority of RAMs in the tibial nerve also innervate glabrous skin and therefore also likely have Meissner's corpuscle ...

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... was a quantitatively large difference in the way that RAMs in the glabrous forepaw skin coded moving stimuli compared to RAMs innervating hairy skin (Fig. 3C). Forepaw RAMs responded reliably with high firing rates to the slowest ramps used (0.075mm/s and 0.15mm/s), whereas hairy skin RAMs barely responded to the same stimuli (Fig. 3A,C) and these differences were statistically significant, (saphenous: n = 14; tibial: n = 14; median /ulnar: n = 21 repeated measure ANOVA F(2, 46) = 15.22, p< 0.0001). Thus RAMs in the forepaw glabrous skin are tuned to slower movements, but also have firing rates that were several fold higher than observed for afferents innervating hairy skin ( Fig 3A,C) 1.5mm/s (saphenous vs. median/ulnar) p<0.05. The vast majority of the forepaw RAMs had receptive fields clearly located in the glabrous skin and therefore likely innervate Meissner's corpuscles. It is possible that a very small number of receptors innervated hair follicles on the glabrous/hairy skin border, but due to the receptive field distributions ( Fig. 1) these afferents could not make up more than 10% of the total. The majority of RAMs in the tibial nerve also innervate glabrous skin and therefore also likely have Meissner's corpuscle ...

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... was a quantitatively large difference in the way that RAMs in the glabrous forepaw skin coded moving stimuli compared to RAMs innervating hairy skin (Fig. 3C). Forepaw RAMs responded reliably with high firing rates to the slowest ramps used (0.075mm/s and 0.15mm/s), whereas hairy skin RAMs barely responded to the same stimuli (Fig. 3A,C) and these differences were statistically significant, (saphenous: n = 14; tibial: n = 14; median /ulnar: n = 21 repeated measure ANOVA F(2, 46) = 15.22, p< 0.0001). Thus RAMs in the forepaw glabrous skin are tuned to slower movements, but also have firing rates that were several fold higher than observed for afferents innervating hairy skin ( Fig 3A,C) 1.5mm/s (saphenous vs. median/ulnar) p<0.05. The vast majority of the forepaw RAMs had receptive fields clearly located in the glabrous skin and therefore likely innervate Meissner's corpuscles. It is possible that a very small number of receptors innervated hair follicles on the glabrous/hairy skin border, but due to the receptive field distributions ( Fig. 1) these afferents could not make up more than 10% of the total. The majority of RAMs in the tibial nerve also innervate glabrous skin and therefore also likely have Meissner's corpuscle ...

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... data suggests that the mouse has a highly developed forepaw tactile system adapted to manipulating objects and exploring their texture. The fact that myelinated sensory fiber receptor density was more than 3 fold higher than in the hind limb would enable much higher discriminative abilities using the forepaw. We calculated that the density of the myelinated sensory innervation was a striking 65 fibers/mm 2 . Analogously in humans tactile discrimination performance is clearly positively correlated with sensory innervation density . 5, 2018; which is highest on the finger tips and tongue (Van Boven and Johnson, 1994;Vallbo, 1979a, 1979b). Indeed mechanoreceptor density on the finger tips has been estimated to be ~240/cm 2 (Johansson and Vallbo, 1979c). We show here that Meissner's corpuscle density is not only very much higher in forepaw compared to hind paw glabrous skin, but also that each corpuscle receives around 25% more sensory endings compared to an equivalent corpuscle in the hind paw (Fig. 4). The anatomical adaptations that we have described in forepaw Meissner's corpuscles might underlie their functional specialization, including increased sensitivity to slower moving mechanical stimuli (Fig. 3). However, it is not clear why higher densities of sensory axons within a Meissner's corpuscle should increase the velocity sensitivity of the sensory unit. Mechanoreceptors including RAMs that innervate Meissner's corpuscles are thought to be equipped with a mechanotransduction apparatus that includes the mechanosensitive ion channel PIEZO2 and its modulator STOML3 ( Poole et al., 2014b;Ranade et al., 2014;Wetzel et al., 2017). Indeed small molecule inhibition of STOML3 in the mouse forepaw reversibly reduces the ability of the mouse to perceive mechanical stimuli ( Wetzel et al., 2017). It is known that the expression of mechanoreceptor specific potassium channels like KCNQ4 modulate the mechanoreceptor response to low frequency sinusoidal stimuli ( Heidenreich et al., 2012), so it is conceivable that mouse forepaw afferents express a different complement of potassium channels than mechanoreceptors innervating other skin regions. The high sensitivity of mouse ...

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... respond exclusively to moving stimuli, rapidly ceasing to fire after cessation of movement (Fig. 3A). Most RAMs in the hairy skin are associated with hair follicles, while the RAMs of the glabrous skin are associated with Meissner's corpuscles (Heidenreich et al., 2012;Lechner and Lewin, 2013;Poole et al., 2014a;Zimmerman et al., 2014). Forty-nine of the 111 Aβ-fibers recorded could be classified as RAMs and these receptors were equally sampled across hind paw hairy skin, hind paw glabrous skin and forepaw skin (Table 1). We used increasing amplitude vibration stimuli to assess the mean force threshold to activate all RAMs that innervate the different skin regions. The mean force thresholds were, as expected, very low with thresholds <3mN. There was a tendency for forepaw afferents (median and ulnar nerve) to be activated with smaller forces compared to afferents in hairy skin (saphenous nerve) or those innervating the hind paw glabrous skin (tibial nerve), but this difference was not statistically significant ( Fig. 3B; saphenous: n = 13; tibial: n = 13; median/ulnar: n = 21 Kruskal-Wallis test p = 0.6476). with increasing intensity. Right: Example trace of a receptor fiber responding to the vibrating stimulus. The force at the time of the first action potential was measured. C Left: schematic illustration of the ramp and hold stimulation. Four different velocities were used Right: Example trace of a receptor fiber responding to a ramp not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without ...

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... respond exclusively to moving stimuli, rapidly ceasing to fire after cessation of movement (Fig. 3A). Most RAMs in the hairy skin are associated with hair follicles, while the RAMs of the glabrous skin are associated with Meissner's corpuscles (Heidenreich et al., 2012;Lechner and Lewin, 2013;Poole et al., 2014a;Zimmerman et al., 2014). Forty-nine of the 111 Aβ-fibers recorded could be classified as RAMs and these receptors were equally sampled across hind paw hairy skin, hind paw glabrous skin and forepaw skin (Table 1). We used increasing amplitude vibration stimuli to assess the mean force threshold to activate all RAMs that innervate the different skin regions. The mean force thresholds were, as expected, very low with thresholds <3mN. There was a tendency for forepaw afferents (median and ulnar nerve) to be activated with smaller forces compared to afferents in hairy skin (saphenous nerve) or those innervating the hind paw glabrous skin (tibial nerve), but this difference was not statistically significant ( Fig. 3B; saphenous: n = 13; tibial: n = 13; median/ulnar: n = 21 Kruskal-Wallis test p = 0.6476). with increasing intensity. Right: Example trace of a receptor fiber responding to the vibrating stimulus. The force at the time of the first action potential was measured. C Left: schematic illustration of the ramp and hold stimulation. Four different velocities were used Right: Example trace of a receptor fiber responding to a ramp not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without ...

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... the sensitivity of RAMs found in the glabrous hind paw skin did not match that of the forepaw RAMs ( Glabrous hind paw RAMs were, however, capable of coding slower velocities than RAMs in hairy skin, but this was not statistically significant (Fig. ...

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... used the same protocols to test velocity sensitivity of D-hair receptors as we had used for RAMs. D-hair receptors are especially sensitive to fast moving stimuli (Fig. 6A,B) and had very low mechanical thresholds to vibration stimuli (Fig. 6C). There was no significant difference in the mean mechanical thresholds of D-hair receptors recorded across the three skin areas (Fig 6C saphenous: n = 13; tibial: n = 10; median/ulnar: n = 5, Kruskal-Wallis test p = 0.41). Importantly, the coding properties of all D-hair receptors recorded were almost identical across all three skin areas (Fig. 6B,C saphenous: n = 10; tibial: n = 18; median/ulnar: n = 7; repeated measures ANOVA F(2, 32) = 1.50; p = ...

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... respond exclusively to moving stimuli, rapidly ceasing to fire after cessation of movement (Fig. 3A). Most RAMs in the hairy skin are associated with hair follicles, while the RAMs of the glabrous skin are associated with Meissner's corpuscles (Heidenreich et al., 2012;Lechner and Lewin, 2013;Poole et al., 2014a;Zimmerman et al., 2014). Forty-nine of the 111 Aβ-fibers recorded could be classified as RAMs and these receptors were ...

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... force thresholds were, as expected, very low with thresholds <3mN. There was a tendency for forepaw afferents (median and ulnar nerve) to be activated with smaller forces compared to afferents in hairy skin (saphenous nerve) or those innervating the hind paw glabrous skin (tibial nerve), but this difference was not statistically significant ( Fig. 3B; saphenous: n = 13; tibial: n = 13; median/ulnar: n = 21 Kruskal-Wallis test p = 0.6476). with increasing intensity. Right: Example trace of a receptor fiber responding to the vibrating stimulus. The force at the time of the first action potential was measured. C Left: schematic illustration of the ramp and hold stimulation. Four ...

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... was a quantitatively large difference in the way that RAMs in the glabrous forepaw skin coded moving stimuli compared to RAMs innervating hairy skin (Fig. 3C). Forepaw RAMs responded reliably with high firing rates to the slowest ramps used (0.075mm/s and 0.15mm/s), whereas hairy skin RAMs barely responded to the same stimuli (Fig. 3A,C) and these differences were statistically significant, (saphenous: n = 14; tibial: n = 14; median /ulnar: n = 21 repeated measure ANOVA F(2, 46) = 15.22, p< ...

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... was a quantitatively large difference in the way that RAMs in the glabrous forepaw skin coded moving stimuli compared to RAMs innervating hairy skin (Fig. 3C). Forepaw RAMs responded reliably with high firing rates to the slowest ramps used (0.075mm/s and 0.15mm/s), whereas hairy skin RAMs barely responded to the same stimuli (Fig. 3A,C) and these differences were statistically significant, (saphenous: n = 14; tibial: n = 14; median /ulnar: n = 21 repeated measure ANOVA F(2, 46) = 15.22, p< 0.0001). Thus RAMs in the forepaw glabrous skin are tuned to slower movements, but also have firing rates that were several fold higher than observed for afferents innervating ...

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... 0.0001). Thus RAMs in the forepaw glabrous skin are tuned to slower movements, but also have firing rates that were several fold higher than observed for afferents innervating hairy skin ( Fig 3A,C) 1.5mm/s (saphenous vs. median/ulnar) p<0.05. The vast majority of the forepaw RAMs had receptive fields clearly located in the glabrous skin and therefore likely innervate Meissner's corpuscles. ...

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... the sensitivity of RAMs found in the glabrous hind paw skin did not match that of the forepaw RAMs ( Glabrous hind paw RAMs were, however, capable of coding slower velocities than RAMs in hairy skin, but this was not statistically significant (Fig. ...

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... receptors are especially sensitive to fast moving stimuli (Fig. 6A,B) and had very low mechanical thresholds to vibration stimuli (Fig. 6C). There was no significant difference in the mean mechanical thresholds of D-hair receptors recorded across the three skin areas (Fig 6C saphenous: n = 13; tibial: n = 10; median/ulnar: n = 5, Kruskal-Wallis test p = 0.41). Importantly, the coding properties of all D-hair receptors recorded were almost identical across all three skin areas (Fig. 6B,C saphenous: n = 10; tibial: n = 18; median/ulnar: n = 7; repeated measures ANOVA F(2, 32) = 1.50; p = 0.24). ...

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... glabrous skin, but also that each corpuscle receives around 25% more sensory endings compared to an equivalent corpuscle in the hind paw (Fig. 4). The anatomical adaptations that we have described in forepaw Meissner's corpuscles might underlie their functional specialization, including increased sensitivity to slower moving mechanical stimuli (Fig. 3). However, it is not clear why higher densities of sensory axons within a Meissner's corpuscle should increase the velocity sensitivity of the sensory unit. Mechanoreceptors including RAMs that innervate Meissner's corpuscles are thought to be equipped with a mechanotransduction apparatus that includes the mechanosensitive ion channel ...