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A Rapidly Adapting Understanding of Touch

A recent study shows that Meissner corpuscles mediate gentle touch perception and are innervated by molecularly distinct Aβ neuron types

by Melanie Schaffler


12 October 2020


PRF News

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A recent study shows that Meissner corpuscles mediate gentle touch perception and are innervated by molecularly distinct Aβ neuron types

Meissner corpuscles, receptors for vibration and pressure in the hairless skin of mammals, were first discovered over 165 years ago. However, the function of these structures in touch perception has remained relatively unclear. Now, using a new mouse model and modern genetic tools, a recent study provides an updated characterization of Meissner corpuscles and how they contribute to touch sensation.

 

Researchers led by David Ginty, Harvard Medical School, Boston, US, generated mice without Meissner corpuscles, and used the animals to show that these end organs mediate the perception of and behavioral responses to gentle force. They also found that each Meissner corpuscle was innervated by two physiologically and molecularly distinct mechanically sensitive neurons.

 

Together, the results reveal the requirement of Meissner corpuscles for gentle touch sensation and fine motor control, and the properties of the sensory neurons that innervate them.

 

This work “is really important because it shows that there is even greater heterogeneity and diversity in our sensory afferent endings than previously thought, on both a structural and a functional level –and that advances the field because it helps us understand how exactly we detect different textures,” said Cheryl Stucky, a touch and pain researcher at Medical College of Wisconsin, Milwaukee, US.

 

“These exciting findings pave the way for understanding the full complexity of touch receptor function,” wrote Kara Marshall and Ardem Patapoutian, The Scripps Research Institute, La Jolla, US, in an accompanying Perspective.

 

The research and Perspective were published June 19, 2020, in Science.

 

A characterization 165 years in the making

Work on Meissner corpuscles goes back all the way to the 1800s, and over the years research has shown that they play an important role in tactile sensation. Studies had also revealed that the afferents innervating Meissner corpuscles are Aβ rapidly adapting type I, low-threshold mechanoreceptors (RAI-LTMRs): neurons that are large in diameter, heavily myelinated, fire at the onset and offset of tactile stimuli, and respond to gentle force. Because rapidly adapting neurons respond at the onset and offset of sustained pressure on the skin, they are thought to convey information about dynamic (as opposed to static) tactile stimuli.

 

In short, Meissner corpuscles had been hypothesized as necessary for detecting moving tactile stimuli in glabrous (non-hairy) skin and for handling objects, but only now could this be confirmed because of the availability of the right tools.

 

“There’s always been these suggestions that Meissner corpuscle neurons are really important for detecting movement across the skin or detecting other aspects of our sensory environment, but that hasn’t really been tested until we had the genetic tools to do so,” said Alan Emanuel, Harvard Medical School, co-first author of the paper along with Nicole Neubarth, Two Six Labs, Arlington, Virginia, US, and Yin Liu, Stanford University, US. “Not until we had the genetic control and labeling [techniques] were we able to actually record from neurons that we knew innervated Meissner corpuscles.”

 

“We're excited to have a mouse model in which Meissner corpuscles are lacking, as well as new genetic tools to visualize and functionally manipulate Meissner corpuscle afferents, because this mechanosensory end organ was discovered in the 1850s, and its functions in tactile perception have remained unclear,” according to Ginty, expressing a similar sentiment.

 

The genetic tools Emanuel and Ginty were referring to were made possible by Liu’s graduate work. She found that brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, were required in primary sensory neurons for the development of Meissner corpuscles, a finding that allowed for the development of the genetic manipulations used in many of the key experiments in the current work.

 

Putting the new tools to the test: what the field has been waiting for

With the discovery that the development of Meissner corpuscles required the expression of TrkB in sensory neurons, the researchers characterized these structures more deeply than ever before, using behavioral, physiological, and computational modeling approaches.

 

As mice lacking BDNF or TrkB die neonatally, the authors created a conditional mouse model in which TrkB was knocked out exclusively in sensory neurons. These animals survive into adulthood and lack Meissner corpuscles. Electrophysiological recordings showed that the mice also lacked Aβ rapidly adapting responses, meaning that TrkB is needed for those responses, and not only for the development of Meissner corpuscles.

 

In the classic von Frey paw withdrawal test, the mice lacking Meissner corpuscles were unresponsive to the lightest forces applied to the hind paw, while controls responded to the full range of forces. A limitation of von Frey testing is that it is possible that a mouse senses a stimulus, but simply does not withdraw the paw. So the researchers used a unique operant behavioral assessment to address this drawback.

 

Here, the authors trained water-deprived mice to lick a spout for water when they detected stimulation of the paw. This paradigm therefore assesses tactile perception, rather than reflexive responses. Similar to the von Frey test results, the mice lacking Meissner corpuscles displayed higher tactile perception thresholds than controls, in this operant assay.

 

In another clever behavioral assessment of mice without Meissner corpuscles, the authors observed the ability of the animals to use their forepaws to eat sunflower seeds and how they did so. Though the amount of time required to deshell and eat the seeds was similar between controls and mice lacking Meissner corpuscles, the TrkB knockout mice tended to brace the seed on the floor while deshelling, rather than hold and rotate the seed like controls.

 

“It was really interesting to watch that experiment come together. There are all these intricate details about how they handle the seed in order to deshell it. And that seemed to be in line with the deficits in their ability to feel with their glabrous skin; they can make coarser manipulations but not the finer-scale ones,” explained Emanuel.

 

Stucky was particularly impressed by these behavioral assays. “I would like to develop even more clever behavioral assays [in my own lab]. There are so many different behaviors that we could observe that we haven’t yet, and this study makes me think we can be even more clever about designing really interesting behavioral paradigms.”

 

Two genetically distinct afferents

Having discovered that TrkB in sensory neurons was required for development of Meissner corpuscles, the authors went back to connect this finding to some previous work in the lab.

 

“A former postdoc in the lab [Wenqin Luo, now at the University of Pennsylvania, Philadelphia, US] had found that early Ret neurons [neurons that express the Ret tyrosine kinase earlier in development and express different relevant genes than those that express Ret later on] innervate Meissner corpuscles [Luo et al., 2009], so I always thought early Ret neurons were the only population that innervated Meissner corpuscles. I expected that ablating TrkB in early Ret neurons would create the same phenotype as ablating TrkB in all sensory neurons,” Liu said. Much to her confusion, she did not find a phenotype at all.

 

The researchers then asked if Ret+ afferents express TrkB at all. Genetic labeling experiments revealed that Meissner corpuscles are, in fact, innervated by two molecularly distinct Aβ neuron subtypes: one that expresses TrkB and another that expresses Ret.

 

Strikingly, these two neuron types also responded differently to mechanical stimuli. The TrkB+ afferents were more sensitive to indentation and responded at the onset and offset of stimuli, while the Ret+ afferents were less sensitive and responded at the onset, but rarely the offset of indentation. Some Ret+ afferents even had sustained firing during the duration of the stimulus, meaning that Meissner afferents are not always rapidly adapting. This raised the question of whether TrkB+ and Ret+ neurons form distinct endings within the corpuscle. The researchers therefore used electron microscopy to look at the fine structural properties of the axonal endings. They found that the axon terminals of TrkB+ Meissner afferents had a much more elaborate pattern of lamellar cell wrappings, or membranes, than the terminals of the Ret+ afferents.

 

The ends of the axons of these two afferent subtypes also appeared to be “homotypically tiled,” meaning that the receptive fields of neurons of the same type do not spatially overlap, and “heterotypically offset,” meaning that the two populations showed differences in their receptive field surface areas and the number of Meissner corpuscles innervated by individual neurons.

 

So what does all of this mean? Computational modeling suggested that the tiling pattern allows for better acuity and efficiency of tactile sensation. The heterotypic overlap of mechanoreceptors with different sensitivities and properties may allow for discrimination over a wider range of forces, as the TrkB+ afferents appear to encode very light forces, while both TrkB+ and Ret+ mechanoreceptors encode higher forces.

 

Time to revise the textbooks?

The researchers believe their study brings the field one step closer to understanding touch receptor function.

 

“From [this] work, we know that there are two genetically distinct Meissner corpuscle afferents. And this was really shocking because textbooks will tell you there’s only one. With the physiology, we discovered that there’s more diversity than people previously realized because they didn’t have the tools that we did. And with the behavior, we confirmed a lot of suspicions that people had about the properties of [Meissner corpuscles],” Neubarth said.

 

“These types of basic science studies like the one that we’ve published are really essential for laying the groundwork for what’s normal. And in a pathological state, you now might know what to look for. For example, now we know to confirm whether there are two neurons innervating a Meissner corpuscle if you see a deficit in tactile sensitivity,” said Emanuel.

 

As with many foundational studies, this work may raise even more questions than it answers.

 

“Unfortunately, I think we never really answered the question why there are two subtypes, and part of that is just that there are limitations in our ability to silence or ablate a single subtype. [That] would allow us to test the computational model [that the spatial orientation of the two Aβ subtypes is a way to enhance acuity], but we couldn’t test that yet. So in the future, it will be really valuable to look at the contributions of these two subtypes to behavior. But we need better tools,” explained Neubarth.

 

The accompanying Perspective raised several additional questions. For example, Marshall and Patapoutian wrote, “where does the mechanotransduction ion channel PIEZO2, which is necessary for touch sensation, sit in this structure?”

 

For her part, Stucky wondered how the physiology of the Meissner corpuscles and afferents might change with age. “Because with aging, you lose a lot of acuity and sensitivity in your fingertips, and people have a harder time grasping, sensing, and manipulating objects as they age. Is that in part because there are changes in the expression or function of these Meissner corpuscles?”

 

As for future work, Ginty said that “one current goal is to define the contributions of Meissner afferents to spinal cord and brain representation of touch signals. To this end, we're generating new tools that will enable acute and reversible silencing of Meissner afferents and other low-threshold mechanosensory neurons.”

 

They are also using mouse genetic tools, electron microscopy reconstructions, electrophysiology, and candidate gene manipulations to understand how forces acting on the skin trigger action potentials at the spike initiation site in Meissner corpuscle afferents.

 

The new findings may very well affect our understanding of other touch receptors in the skin. So maybe it’s time to revisit the function and innervation of Merkel cells and Pacinian corpuscles, too….

 

Melanie Schaffler is a PhD student at the University of Pennsylvania, Philadelphia, US.

 

Featured image: A Meissner corpuscle and its Aβafferents. Credit: From Neubarth et al., Science. 2020 Jun 19; 368(6497):eabb2751. Reprinted with permission from AAAS.

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