Discovery May Explain Conflicting DBS Results

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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The mesencephalic locomotor region, a brain region previously thought to control only walking and other forms of locomotion in vertebrates, also regulates postural changes and other movements, according to a study in mice.

“It was surprising that within this region, which everybody has linked to locomotion, many of the neurons are not actually tuned to locomotion,” Silvia Arber, PhD, the study’s senior author, said in a press release. Arber is a group leader at the Friedrich Miescher Institut for Biomedical Research and the Biozentrum of the University of Basel, in Switzerland,

These findings may explain why deep brain stimulation (DBS) of this region has led to inconsistent results in people with Parkinson’s disease. DBS in this brain area likely influences the activity of distinct neuronal populations that control different movements, which may suppress the activity of one another, the researchers noted.

“Therapeutic approaches that target and activate specific neurons could be very successful,” Arber said.

The study, “Functional diversity for body actions in the mesencephalic locomotor region,” was published in the journal Cell.

Locomotion (movement from one place to another) in vertebrates, particularly those moving with two or four limbs on land, is the result of postural control, coordinated limb recruitment and movement, and efficient block of other motor programs not compatible with locomotion.

“These behavioral observations raise the question of the underlying neuronal circuit mechanisms involved in the selection and regulation of locomotion and other forms of body movements,” the researchers wrote.

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The mesencephalic locomotor region, as the name suggests, has been known for decades for its role in controlling walking and other forms of locomotion in several vertebrates. Previous work from Arber’s team showed that neurons from this region connecting to the medulla, an area of the brainstem, are involved in locomotion. The brainstem is the most posterior part of the brain, connecting it to the spinal cord.

However, several studies have suggested that this region may contain neuronal populations with distinct functions.

Now, using cutting-edge techniques to label, activate, and suppress specific populations of neurons in mice’s brains, Arber and her team provided evidence of the existence of functionally distinct populations of neurons that control different body movements besides locomotion.

They identified, for the first time, two intermingled neuronal populations in the mesencephalic locomotor region: one connecting to the spinal cord, and the other to a brain area involved in movement control called the basal ganglia.

Neurons connecting to spinal cord were highly activated as mice reared up, while those connecting to the basal ganglia were strongly recruited for forelimb behaviors such as grooming and object handling. Notably, only a few of these neurons switched on during locomotion.

To further confirm the function of these neuronal populations, the team specifically switched on or off each of these populations using a technique called optogenetics, in which brain cells are genetically modified to respond to light.

Light-induced activation of the spinal cord-connected neurons stopped the mice’s movement and led to a forward extension of their head and forelimbs, while their block resulted in body shortening while rearing and reduced locomotion speed, likely due to postural impairment.

Notably, when conditions favored mice’s transition to locomotion, activation of these neurons “induced body stretching transitioning into at least one full stepping cycle in a fraction of trials, suggesting that body stretching may facilitate the transition to locomotion,” the researchers wrote.

These findings support a model in which mesencephalic locomotor region neurons connecting to the spinal cord are “required for postural body adjustments needed for full-body exploratory behaviors,” while locomotion-promoting effects rely on interaction with neurons connecting with the medulla, they added.

When neurons connecting to the basal ganglia were switched on, all body movements stalled, while uncoordinated full body movements were observed following the neuron’s suppression.

These observations suggest that basal ganglia-connecting neurons in the mesencephalic locomotor region may “play a more holistic modulatory role to orchestrate body movements,” and that they may be involved in “the selection of desired and the [suppression] of nonselected motor programs,” the team wrote.

They also noted that, interestingly, the stalling of ongoing movements induced by the activation of these neurons resembled the freezing episodes of Parkinson’s patients, which may prompt new research on whether the disease affects this neuronal population.

Still, the precise impact of these basal ganglia-connecting neurons during behavior cannot be accurately assessed from this type of whole-population approaches, the team noted, as each of them showed variable activation during natural behavior and were never modulated as an entire neuronal population.

The fact that the mesencephalic locomotor region controls movements and behaviors other than locomotion also may help explain the inconsistent, small benefits and many side effects observed when DBS — electrical stimulation of target brain regions — was applied to this region in Parkinson’s patients.

“Our work suggests that targeting spinally projecting [mesencephalic locomotor region] neurons might be beneficial for postural stabilization, whereas promoting limb stepping might need targeting of medulla-projecting populations,” the researchers wrote. They noted, however, that current DBS technology cannot efficiently target only such specific populations.

Next, the team plans to determine the role of the mesencephalic locomotor region in action selection, a process through which the brain chooses to perform a particular movement and suppresses conflicting motor programs.

“It’s exciting that this region controls more than locomotion, so it will be interesting to understand how the neurons we identified interact with other brain regions involved in movement control,” Arber said.

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