On your marks; get set ... how the brain’s excitatory neurons start us walking – or running

Breaking new ground 8. feb 2018 3 min Professor Ole Kiehn Written by Morten Busch

Although both a sprint to catch a bus and a leisurely jaunt in the forest require movement, the initiating neuronal signals sent by the brain differ completely. A Danish-Swedish research group has investigated which parts of the brain control walking and running. The results, published in Nature, may help to provide more targeted treatment of the gait disorders associated with Parkinson’s disease for example.

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Locomotion is a fundamental motor function. Everyone knows how it feels to amble about, perhaps when getting a pair of socks from a drawer or putting a cup in the dishwasher. This happens almost automatically at a sedate tempo, but if something happens suddenly, we can change gear and get into running or escape mode. Researchers now know more about how the brain selects this change, since they have located the circuits in the brain that initiate walking and running and control the speed.

“The neuronal networks responsible for precisely coordinating locomotion are located in the spinal cord. These networks are very autonomous, but an initiation or start signal from the brain is required to recruit them. Previously, the initiation command was thought to originate from one neuronal circuit in the brain, but we discovered that, although two circuits can issue the command for slow walking, only one circuit sends the command for running,” explains the lead researcher, Ole Kiehn, Professor, Department of Neuroscience, University of Copenhagen and Mammalian Locomotor Laboratory, Department of Neuroscience, Karolinska Institutet, Stockholm.

Intermingled neurons

Almost 50 years ago, researchers demonstrated for the first time that electrically stimulating an area in the midbrain of animals could induce locomotion. This area is called the mesencephalic locomotor region (MLR). However, until a few years ago, researchers could not distinguish the contribution from different types of neurons in the MLR.

“There has been much debate about the extent to which the MLR comprises the cuneiform nucleus (CnF) or the pedunculopontine nucleus (PPN). We have now shown that the neurons in both the PPN and the CnF can initiate movement and maintain and regulate slow walking. However, only the CnF can initiate high-speed running like gallop and bound, and the PPN is more involved in slow and exploratory walking,” says Ole Kiehn.

The researchers used optogenetic and chemogenetic tools in experiments on mice to manipulate various types of neurons with either light or specific drugs. This advanced technique enabled researchers to distinguish the contribution from different types of neurons..

The PPN and CnF contain different types of neurons that are intermingled, so electrical stimulation cannot be used to differentiate one type from another. Today, we can activate or deactivate specific populations of neurons using optogenetics and chemogenetics. We can thus show that only the neurons containing the neurotransmitter glutamate in the PPN and CnF contribute to initiating locomotion and regulating the speed.

When the researchers stimulated the PPN neurons, the mice walked and trotted. However, when they stimulated the CnF neurons, the mice walked or trotted but also ran rapidly if the frequency of light-stimulation was increased.

“Conversely, if we inhibited the CnF neurons, the mice could no longer run rapidly but surprisingly could still walk or trot. This therefore shows that the initiation or start neurons in the PPN and CnF not only work together but also individually regulate either slow explorative walking (PPN) or fast running (CnF).”

Like heat-seeking missiles

The same research group has previously shown that the brainstem contains stop neurons whose activity halts locomotion. These new studies of start neurons have given the researchers a much more comprehensive sense of how the brain controls locomotion.

“Together, the start and stop neurons define the episodic nature of locomotion, and although the experiments were performed on mice, we believe that people use similar mechanisms. We therefore also think that our discovery can help people who have impaired ability to walk, either because of damage to the spinal cord or the degeneration of neurons in the brain, such as in Parkinson’s disease,” says Ole Kiehn.

The researchers are therefore planning to investigate in mouse models of Parkinson’s disease, if PPN and CnF activity is affected. The disease affects the dopamine-producing neurons in the substantia nigra and thereby the functioning of the basal ganglia that transmit signals onwards to the PPN.

“Deep brain stimulation is used today to treat some symptoms of Parkinson’s disease. Tiny electrodes are implanted in the brain to electrically stimulate various regions. Our new knowledge may be used to target the important circuits very precisely, almost like a heat-seeking missile, and thereby possibly use deep brain stimulation in a better way to improve walking. The same method may also be used for people who have injuries to the spinal cord that severely affect their walking,” concludes Ole Kiehn.

Midbrain circuits that set locomotor speed and gait selection” has been published in Nature. The Novo Nordisk Foundation awarded the article’s main author, Ole Kiehn, a Laureate Research Grant in 2016 for the project Functional Organization of Large-scale Integrated Neuronal Networks Controlling Locomotion in Mammals and Mechanisms for Development of Impaired Motor Function in the Diseased Brain. A European Research Council Advanced Grant, the United States National Institute of Neurological Disorders and Stroke and the Swedish Research Council have also supported the research.

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