In the playground, a popular game for kids of all ages is “Freeze.” The concept is rather simple. A leader tells the participants they are free to move around until everyone is told to freeze in place. Those who don’t suddenly stop are notified they are out and the game continues. It’s a great way to learn how to deal with environmental stimuli and also how to better control locomotor abilities. But most of all, it’s a great deal of fun.
For neuroscientists, understanding how we move in the environment – better known as locomotion – and freeze, also has been an enriching experience lasting well over half a century. Back in the 1940s, (1) researchers learned one of the headquarters for movement was in a region of the brain stem known as the reticular (literally networked) formation. Even closer examination in the 1960s revealed a specific area within this formation devoted to making us move. It was called the mesencephalic locomotor region or MLR for short.(2)
Finding the area was just the first step. Researchers still needed to learn how the cells in this region controlled running and walking. Unfortunately, due to the complexity of the human body, finding the answer to this question was simply not possible. To have a better idea, a much simpler nervous system was needed.
Routine go-to animals such as cats, rats, and mice were also too complex for this task. Researchers needed to go even further down the evolutionary tree. Eventually, the optimal animal was found in the form of the lamprey(3). It’s a small, jawless fish that visually appears to have no links to higher order animals including humans. But it has a fully functioning nervous system that appears to be an early ancestor of the human nervous system. It also has the MLR meaning it represented a good model for studies on locomotion.
The research took a few decades but in 2003, the laboratory of Dr. Réjean Dubuc at the Université du Québec in Montreal and Université de Montréal reached the point where he and his colleagues could provide (4) an understanding of how the lamprey starts to move, or in this case, swim. They found two different types of lamprey locomotion. The first, sensory-evoked locomotion, is based on a stimulus, such as touch. A sensory signal is integrated in the brainstem and then sent down to the spinal cord to produce movement. But, locomotion is often initiated in response to internal cues. This is where the MLR comes into focus. This area sends out signals to the spinal cord to initiate locomotion.
As for what controls the extent of movement, this responsibility falls on a group of cells known as reticulospinal (RS) cells. As the name implies, they link the reticular formation with the spinal cord. The MLR projects to these RS cells and sends them electrical signals. It’s up to them to determine how to translate this into action (5). Dubuc has found that much like a dimmer switch, the RS cells can interpret the intensity of the MLR signal and then control the intensity of the locomotor output.
While the results of Dubuc’s work provided an explanation of how we begin locomotion and also the type of movement we may choose, there was still one unanswered question: how do we freeze? Thankfully, that answer – at least in lampreys – has now been found. Last month, Dubuc’s team revealed (6) in the journal Cell Reports how a specific population of RS cells are responsible for slowing down and eventually coming to a stop.
When Dubuc’s team examined the population of RS cells, they realized there were three different types of activities upon MLR stimulation. These were conducted by separate groups of cells. One was activated at the start of movement in the form of a burst of discharge. Another set maintained movement continually responding to the MLR signal. Finally, there was a group activated – also in the form of a burst – to halt movement.
What intrigued Dubuc’s team was the burst occurring at the end of the stimulation, which seemed to indicate a ‘stop’ signal. When chemicals known to stimulate these now-named ‘stop cells’ were used, swimming was indeed halted suggesting they were responsible for a cessation of locomotion. But when other experiments following these ‘stop cells’ were performed, the results revealed much more than an ‘off’ switch.
The ‘stop cells’ conducted their burst during active swimming, meaning the stop signal was not immediately obeyed by the rest of the body. Time was needed to respond appropriately. In addition, the cells were not fundamental to stopping. When they were inactivated, the lampreys still managed to stop swimming although the ability was impaired. This latter observation suggested these cells were perhaps not the only ones to control stopping; rather they offered a signal to prompt more rapid stopping action.
The results of this study reveal a rather complex set off actions required to efficiently stop in place, particularly based on environmental cues. Yet, there is enough information to help provide anyone failing at the game of freeze with an excuse. Simply blame the RS cells for not properly listening to the MLR. Granted, it may not be enough to get back into the game, but it will definitely make for an interesting discussion as you sit with the others who also forgot to stand still.
- Sherman D, Fuller PM, Marcus J, Yu J, Zhang P, Chamberlin NL, et al. Anatomical Location of the Mesencephalic Locomotor Region and Its Possible Role in Locomotion, Posture, Cataplexy, and Parkinsonism. Frontiers in Neurology. 2015;6:140. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478394/
- Ryczko D, Dubuc R. The multifunctional mesencephalic locomotor region. Curr Pharm Des. 2013;19(24):4448-70. https://www.researchgate.net/profile/Dimitri_Ryczko/publication/235381670_The_Multifunctional_Mesencephalic_Locomotor_Region/links/56166fbf08ae73279641f221.pdf
- Shimeld SM, Donoghue PC. Evolutionary crossroads in developmental biology: cyclostomes (lamprey and hagfish). Development. 2012;139(12):2091-9. http://dev.biologists.org/content/139/12/2091.long
- Brocard F, Dubuc R. Differential contribution of reticulospinal cells to the control of locomotion induced by the mesencephalic locomotor region. J Neurophysiol. 2003;90(3):1714-27. http://jn.physiology.org/content/90/3/1714.short
- Dubuc R, Brocard F, Antri M, Fenelon K, Gariepy JF, Smetana R, et al. Initiation of locomotion in lampreys. Brain Res Rev. 2008;57(1):172-82. http://web2.uwindsor.ca/biology/zlab/Publications_files/Dubuc%20et%20al.%202008.pdf
- Juvin L, Gratsch S, Trillaud-Doppia E, Gariepy JF, Buschges A, Dubuc R. A Specific Population of Reticulospinal Neurons Controls the Termination of Locomotion. Cell Rep. 2016;15(11):2377-86. http://www.sciencedirect.com/science/article/pii/S221112471630612X
Text by Jason Tetro, for CAN-ACN