How is it that our brain and muscles can respond so quickly to tripping over a branch while hiking? Or while learning how to ride a bike? It’s mainly because of the cerebellum, an area of the brain responsible for muscle movement. Turns out, the cerebellum acts like a car and uses an “accelerating” system, as well as a “cruise control” system to keep itself moldable and adaptable. Unlike a car, though, the cerebellum’s “cruise control” is highly malleable but unknown. In an article by Alexander & Bowie investigated these mechanisms in the cerebellum and found that the cerebellum allows for fine-tune movement by changing sodium and calcium levels and then exciting other mechanisms that allow for cell functioning. This article explores the ways that our brains adapt for muscle movement and perhaps this research may help us find new treatment for movement and muscle disorders. 

Our world relies on muscle movement; how else would we make our morning coffee, jog on the treadmill, or drive to work? This muscle movement is regulated in the cerebellum area of the brain. This area of the brain is located at the base of your skull (as seen in the figure to the left) and is responsible for our everyday muscle movement. This area of the brain is flexible and malleable—just ask anyone who has drank too much alcohol. Drinking too much alcohol results in ataxia, where (at extreme levels) results in a lack of control for muscle movement². This is why someone may be stumbling around and can’t walk straight when intoxicated. How does the cerebellum regulate muscle movement if it is so easily malleable? 

The cerebellum is flexible and malleable, but how the cerebellum does that is still unknown. Alexander & Bowie investigate how these mechanisms work that keep the cerebellum flexible and adaptable. 

What we do know, though, is that the idea of flexibility (aka plasticity) can mainly be described as long-term potentiation and long-term depression. While those mechanisms of plasticity are involved in memory processing, the relationship to muscle movement is very important because these mechanisms change the level of plasticity that is exhibited by a certain area of the brain. Turns out, these processes can be regulated by calcium, sodium, and other processes. 

According to another study, the connections between certain cerebellar cells (stellate cells) and other cerebellar cells were found to have increased calcium levels only during certain motor movements³. In this case, the researchers looked at several mouse behaviors as their focus on motor movement and found that the act of licking was associated with these higher calcium levels, while the act of moving their whiskers was not associated with these higher calcium level³.  

Calcium is important for all cellular functioning, and in the case of the cerebellum, calcium modulates motor functioning by changing the amount of plasticity⁴. In the cerebellum, it can often be seen that the brain region undergoes a type of synaptic plasticity that is regulated by the increase in calcium levels and then excites other cells to open and release more calcium into the system⁴. Additionally, another study saw mice with altered calcium signaling showed muscle dysfunction⁵. This overall increase in calcium levels is part of what occurs when we make “muscle memories” in our brain⁵.

Both calcium and sodium have been shown to use certain channels to go in and out of the cell to make motor movement happen. One of these types of channels are called NMDA receptors⁶. It has been seen that increases in NMDA receptor activation has been linked to plasticity facilitation, learning and memory, as well as enhanced resistance to trauma and promote brain cell survival⁶. 

In this study, both male and female mice were used, and the age ranged from 18-30 days after birth¹. These mice were humanely sedated and then euthanized before taking out a chunk of their cerebellum¹. This chunk of tissue was rapidly removed and immediately put in an ice-cold cutting solution¹. The cerebellum was then cut up into thin slices for recording purposes.    

To record the electrical signal part of the experiment, the chunks were sliced down the middle so that two halves are created¹. Special recording pipettes were used to complete whole-cell patch recording in the cerebellar cells (stellate cells)¹. The recording apparatus was filled with the intracellular recording solution¹. The capacitance was then estimated. For the recordings, the voltage-gated responses and raw current traces were collected simultaneously¹. Since they were not able to measure the activity of sodium channels directly, the researchers adapted a protocol using a pulse to inactivate the sodium channels that were far away from the cell body followed by recording the sodium channels close to the cell body¹. 

To calculate the data, the voltage-dependence activation was analyzed by calculating the conductance from peak currents elicited by using a specific formula¹. Then, the researchers used statistical tests to compare the electrophysiological data recorded at rest and after 25 minutes¹. In some instances, the researchers also used other types of tests to compare the electrophysiological data between the controls and the experimental conditions¹.

Their results showed that the mechanisms that the cerebellum uses to keep itself young depends on several key players. These key players include receptors for glutamate that allow both sodium and calcium through its gates (the NMDA receptors), as well as calcium itself, and other more complicated processes, like the CaMKII pathway.  

The increases in calcium in the cell activate other pathways, such as the CaMKII pathway⁷. This pathway helps activate other processes in the body due to calcium increases within the cell⁷. Because of CaMKII’s large structure, this allows for CaMKII to stay activated and continue doing it’s thing (aka staying on cruise control), even after calcium levels have dropped⁷. 

The researchers also found that the calcium and the CaMKII pathways led to action potential threshold being lowered¹. This threshold lowering ultimately makes reaching the action potential easier and allows for more action potentials¹. Similar increases can also be seen for sodium, and other studies have seen that decreases in sodium increases the threshold⁸. This can be explained as the “acceleration” part of the car analogy. Let’s say if you’re getting onto the freeway and you begin to push the accelerator petal very quickly so that you can reach the appropriate speed limit. If the threshold (the speed limit) was higher, then you would have to push down harder on the accelerator, while if the threshold was lower, you would not have to press down as hard (it would be easier to reach the speed limit with less force from your foot). 

The researchers also found that NMDA receptors create a long-term increase in firing rates of inhibitory stellate cells, while also inducing plasticity through the calcium and CaMKII pathways that shift between activation and inactivation properties of certain sodium channels¹. These sodium channels are voltage gated, meaning that they open when certain electrical voltages are reached¹. They also found that these NMDA receptors also mediate plasticity in other cerebellar cells (not just in the stellate cells) that may result in the same shifts in voltage-gated sodium channels¹. 

These voltage-gated sodium channels open at certain voltages, so this means that they are not overly active and not super difficult to activate when necessary⁹. These can be seen as the police car behind you as you’re speeding up onto the freeway; the cop is only triggered to pull you over if you reach a certain speed (voltage). 

These mechanisms help us understand our cerebellum and perhaps in the future it may give us a better clue as to how to treat movement disorders. Targeting various aspects of this process can alter the plasticity mechanisms and ultimately lead to different outcomes. If we target the calcium and/or the CaMKII, we may see the action potential threshold being lowered so that we would be able to make our brains more excitable and perhaps help regulate muscle disorders. These mechanisms were found to operate in a “feedforward” mechanism, which is a mechanism that tries to act before something happens^10,11. This mechanism tries to prevent changes before they would occur, versus after they occur^10,11. This would be like putting on your seatbelt before beginning to drive, to prevent any accidents (or prevent the severity of the accidents). 

These research studies highlight the importance of studying the mechanism for motor functioning, so that we may be able to target and minimize the large impact of motor deficits. These motor movement preventions may aid and slow the steady muscle decline throughout life.

[+] References

[+] Other Work By Iris Gutierrez