When the Brainstem Gets Excited About Walking

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Source: Dorothy Sherrill, from Wikimedia Commons.

Source: Dorothy Sherrill, from Wikimedia Commons.

When we’re walking from place to place, we have full control of when and how fast to go. But how does the brain tell the leg muscles to start walking? Speed up? Slow down?

To figure this out, we must identify which neurons are involved and how they are connected. Previous studies have done this by putting an electrode into locomotor regions in the mouse brain and electrically stimulating those areas to see if the mouse starts walking [1,2]. The area that causes mice to walk when stimulated is called the midbrain locomotor region (MLR). However, because of the limitations of microstimulation, it has been difficult to pinpoint the specific identities of neurons that control this process and the ways they are connected to the leg muscles.

Previous studies have suggested that the MLR controls locomotion by acting on parts of the brainstem, specifically an area called the lateral paragigantocellular nucleus (LPGi) [3]. However, when the LPGi is electrically stimulated in mice, there is no change in their walk. One possibility is that inhibitory and excitatory neurons are intermingled within those regions, and therefore microstimulation of the entire LPGi cancels itself out. If we could stimulate only the excitatory neurons or only the inhibitory neurons, we could see if there is an effect on locomotion. A recent study led by Paolo Capelli at the University of Basel used a tool called optogenetics to stimulate either excitatory or inhibitory neurons in the LPGi [4]. When the researchers stimulated excitatory neurons in the LPGi, they found that mice that were resting got up and walked, and mice that were already walking increased their walking speed! Conversely, mice stopped walking when they stimulated inhibitory neurons in the LPGi.

Optogenetics is a method that genetically alters specific types of neurons in specific locations so that they are activated when light is flashed onto them. In this case, light is flashed on the neurons through a tiny fiber-optic cable implanted into the mouse brain.

The study showed that excitatory and inhibitory neurons in the LPGi are sufficient for controlling walking. But is the MLR actually controlling locomotion through this pathway? To answer this question, the study began by using optogenetics to stimulate the excitatory neurons in the MLR and showed that this increased locomotion. Then they selectively destroyed the excitatory neurons in LPGi. Now when they tried to stimulate the excitatory neurons in the MLR, the effect on locomotion was greatly diminished, evidence that the MLR acts on excitatory neurons in the LPGi to control locomotion.

This study identified important aspects of neuronal circuitry in the locomotor system by showing where the neurons are, what controls them, and whether they are excitatory or inhibitory. By disentangling excitatory and inhibitory neurons, the study was able to identify neurons in the LPGi as an integral part of the locomotor circuit. Stimulating excitatory or inhibitory neurons in the LPGi was sufficient to change the locomotion pattern of the mouse significantly, meaning that these neurons are directly involved in the locomotion pathway. Finally, the study found LPGi to be the missing link between MLR and locomotor function. This opens more questions to be answered, like whether LPGi excitatory neurons talk to LPGi inhibitory neurons and what kinds of neurons are downstream of LPGi.

References

  1. Shik, Mark L., and Grigori N. Orlovsky. "Neurophysiology of locomotor automatism." Physiological reviews 56, no. 3 (1976): 465-501.

  2. Skinner, R. D., and E. Garcia-Rill. "The mesencephalic locomotor region (MLR) in the rat." Brain research 323, no. 2 (1984): 385-389.

  3. Noga, Brian R., Dean J. Kriellaars, Robert M. Brownstone, and Larry M. Jordan. "Mechanism for activation of locomotor centers in the spinal cord by stimulation of the mesencephalic locomotor region." Journal of neurophysiology 90, no. 3 (2003): 1464-1478.

  4. Capelli, Paolo, Chiara Pivetta, Maria Soledad Esposito, and Silvia Arber. "Locomotor speed control circuits in the caudal brainstem." Nature 551, no. 7680 (2017): 373.