Scientists finally uncovered how the sixth sense works

[June 9, 2023: Staff Writer, The Brighter Side of News]

Sight, hearing, smell, taste, touch: We’re all familiar with the five senses that allow us to experience our surroundings. (CREDIT: Creative Commons)

In order to perform synchronized movements, our bodies depend on specific sensory neurons located in our muscles and joints. These neurons are crucial for the brain to be aware of the body's actions. A research group headed by Niccolò Zampieri has investigated the molecular markers of these neurons to gain deeper insight into their functioning and has published their findings in Nature Communications.

The five senses - vision, auditory, olfaction, gustation, and tactile perception - are well-known as the primary means by which we interact with and perceive our environment.

Of equal significance but not as widely recognized is the existence of a sixth sense. This sense is responsible for gathering data related to our movements, posture, and spatial positioning from our muscles and joints, and then transmitting this information to our central nervous system. Dr. Niccolò Zampieri, who leads the Development and Function of Neural Circuits Lab at the Max Delbrück Center in Berlin, explains this crucial function.

“This sense, known as proprioception, is what allows the central nervous system to send the right signals through motor neurons to muscles so that we can perform a specific movement.”

Precise connections are crucial

The cell bodies of the pSN are situated in the spinal cord's dorsal root ganglia. These cells are linked through extensive nerve fibers to muscle spindles and Golgi tendon organs, which continually monitor stretch and tension within all the body's muscles. The pSN transmits this data to the central nervous system, where it governs motor neuron activity, enabling us to execute various movements.

Different populations of sensory neurons cell bodies in a dorsal root ganglion (right) and their axons in the spinal cord (left): The cells in green detect proprioceptive information while the cells in red thermal and tactile information. (CREDIT: Stephan Dietrich, Zampieri Lab, Max Delbrück Center)

According to Dr. Stephan Dietrich, a member of Zampieri’s lab, “One prerequisite for this is that pSN precisely connect to different muscles in our bodies.” On the other hand, very little information was available about the molecular processes that facilitate these accurate connections and give the muscle-specific pSN their distinct characteristics.

“That’s why we used our study to look for molecular markers that differentiate the pSN for the abdominal, back and limb muscles in mice,” says Dietrich, lead author of the study, which was carried out at the Max Delbrück Center.

Guidance for nascent nerve fibers

Through single-cell sequencing, the researchers analyzed the genes in the pSN related to the abdominal, back, and leg muscles, determining which ones are transcribed into RNA. Dietrich notes that they discovered specific genes associated with each muscle group's pSN. Moreover, they demonstrated that these genes are active during embryonic development and continue to be active for some time after birth. According to Dietrich, this suggests that predetermined genetic programs dictate whether a proprioceptor will connect with the abdominal, back, or limb muscles.

Schematic illustrating central and peripheral connectivity of e15.5 proprioceptors at thoracic (left) and lumbar (right) spinal levels. (CREDIT: Nature Communications)

The Berlin-based scientists also identified multiple genes related to ephrins and their receptors in their findings. Dietrich explains that these proteins are known to play a role in directing developing nerve fibers toward their intended targets during nervous system development. The researchers observed that, in mice lacking the ability to produce ephrin-A5, the connections between proprioceptors and hind leg muscles were compromised.

One aim is better neuroprostheses

“The markers we identified should now help us further investigate the development and function of individual muscle-specific sensory networks,” says Dietrich. “With optogenetics, for instance, we can use light to turn proprioceptors on and off, either individually or in groups. This will allow us to reveal their specific role in our sixth sense,” adds Zampieri.

Representative image of tdTomato+ afferents in a lumbar spinal cord section from p7 Trpv1Cre; PvFlp; Ai65 mice. MMC, median motor column; LMC, lateral motor column. Scale bar: 100 µm. (CREDIT: Nature Communications)

In time, this knowledge should benefit patients, such as those with spinal cord injuries. “Once we better understand the details of proprioception, we’ll be able to optimize the design of neuroprostheses, which take over motor or sensory abilities that have been impaired by an injury,” says Zampieri.

Altered muscle tension causes a crooked spine

Moreover, he mentions that scientists in Israel have recently found that well-functioning proprioception is crucial for maintaining a robust skeletal structure. Scoliosis, a condition that occasionally emerges during growth in childhood, leads to a distorted and contorted spine.

Proprioceptors muscle-type identity emerges at early developmental stages. (CREDIT: Nature Communications)

“We suspect this is caused by dysfunctional proprioception, which alters the muscle tension in the back and distorts the spine,” says Zampieri.

Hip dysplasia, a malformation of the hip joint, could potentially be linked to improper proprioception. This possibility has inspired Zampieri to contemplate additional implications of the research: “If we can better understand our sixth sense, it will be possible to develop novel therapies that effectively counteract these and other types of skeletal damage.”

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