Vagus nerve stimulation enhances motor learning in animal husbandry…: Neuroscience Today

Article in brief

In a study in mice, researchers found that vagus nerve stimulation, which is approved by the U.S. Food and Drug Administration to help stroke patients recover locomotor, can enhance adaptive locomotor behavior by releasing cholinergic signals in the basal forebrain.

To understand how the VNS can modulate specific circuits, the researchers used optogenetics and calcium imaging in mice that learn the skilled reaching task. They found that VNS enhanced skilled motor learning in healthy animals via a cholinergic reinforcing mechanism. Reinforcement motor learning relies on cholinergic neuronal activity in the primary forebrain, and in the primary motor cortex, the VNS modulates neurons that specifically activate outcomes.

Stimulating the vagus nerve (VNS) can enhance adaptive motor behavior in mice and do so by stimulating cholinergic signals in the basal forebrain, according to a study published online July 19. neuron.

This finding reinforces the rationale for using VNS to restore motor ability in stroke, which was recently approved by the US Food and Drug Administration for patients who have reached a stabilization stage in their rehabilitation.

Jesse Dawson, Professor of Stroke Medicine in the School of Veterinary Medicine and Life Sciences at the University of Glasgow. Dr. Dawson was the principal investigator for the clinical trial of VNS at scalpel Which led to her consent to having a stroke and not participating in neuron study.

“This new study consolidates the main hypothesis of the effect of the VNS on neuroplasticity, which is mediated through the activation of cholinergic neuroregulatory networks.”

Study details

VNS is used to treat epilepsy and depression. Either way, the stimulation is constant, said study lead author Kristen Weil, PhD, associate professor and vice president of research in the departments of neurosurgery, physiology, and biophysics at the University of Colorado School of Medicine in Aurora.

While the stimulation device was essentially the same in her study (although much smaller) and similarly implanted on the left side of the cervical vagus nerve, the stimulation protocol was significantly different, based on evidence that stimulation is precisely timed. , rather than constant stimulation can drive circuit plasticity and promote the acquisition of new behaviors.

“We applied stimulation in a temporally accurate manner, paired with specific behaviors,” she said. “We were interested at what point in the learning process the VNS was effective in healthy animals, and seeing what specific circuits acted by stimulation.”

Mice with VNS devices in place were trained to reach through an incision to grab food pellets from a column where they were balanced, a task that required precise movements. Dr. Welle and her team provided vagus nerve stimulation at one of three different time points: randomly during the 20-minute training session, during pellet access or after successful retrieval.

“When the animal grabs the granules and puts them back in the mouth, we stimulate the vagus nerve,” she said. “This was the only time we found that stimulation enhanced motor learning.”

Using a placebo VNS, with the stimulus implanted but not triggered, the mice had success 46 percent of the time. After training with VNS delivered after recovery, they were successful 59 percent of the time.

In another experiment, designed to demonstrate that the VNS itself was neither intrinsically rewarding nor aversive, Dr. Philae found that rats neither preferred visiting the room in which the stimulus was initially applied, nor preferably avoiding it. Instead, she said, “We think we’re taking advantage of the brain’s reinforcement system. It makes the animal more receptive to feedback about whether or not its actions were successful,” and thus leads to faster learning.

It is not yet clear whether VNS will also accelerate aversive learning, or whether it is specifically related to enhancing the desired outcome.

To determine the mechanism of reinforcement, Dr. Wille’s team placed electrodes in the basal forebrain, a source of projecting cortical cholinergic neurons. The reinforcement in motor learning has been shown to depend on cholinergic neuromodulation, and the team showed that the VNS modulates the firing rate of these neurons. When these cholinergic neurons were inhibited, that is, they used light to modulate cell activity, the VNS could no longer enhance learning.

Figure 2

We know that when we stimulate the vagus, we also turn on this system, along with other centers in the brain. What we don’t know is whether other parts of the brain also contribute to the learning effect, and if they are required as well, in addition to the cholinergic system.” — Dr. Christine Wylie

Dr. Welle noted that the VNS also activates other types of neuromodulatory systems, including the noradrenaline system, which is thought to be partly responsible for the anticonvulsant effects of the VNS.

“We know that when we stimulate the vagus, we also turn on this system, along with other centers in the brain. What we don’t know is whether other parts of the brain also contribute to the learning effect, and if they are needed as well, in addition to the cholinergic system. Important details that you will need to work on in future experiments.

It is also not yet clear whether the VNS mimics some of the self-reinforcement normally made by the vagus nerve. Dr Philae said: “I would say the science is still researching this question, but there is promising work being done by other groups, which suggests that ambiguity may be required for things like spatial learning, as well as to represent rewards from the gut, so there are hints “.

Expert Comment

“This is an impressive set of experiments because it provides very clear evidence that the VNS, which acts by affecting cholinergic networks, can cause a reorganization of the motor cortex and neuroplasticity,” said Dr. Dawson.

“We know from our study that VNS has a modest but significant effect in improving upper extremity function in people after stroke, beyond what we see with physical therapy alone.”

In their randomized, placebo-controlled study of 106 stroke patients with moderate to severe upper extremity impairment, Dr. Dawson and colleagues demonstrated that six weeks of VNS combined with rehabilitation led to a clinically meaningful improvement in an upper limb Fugl-Meyer score in 47 percent of VNS patients, versus 24 percent in controls.

“This study sheds important light on the mechanism of VNS in the brain,” said David M. Labener, MD, professor and chair of the department of neurology at the University of Arizona School of Medicine in Tucson.

He noted that “stimulating the vagus nerve does many things, including altering blood flow and affecting neurotransmitters in the brain,” none of which are linked to seizure control. “Therefore, it does not surprise me that VNS also has the effect observed in this paper” on cholinergic neuromodulation. The benefit shown on motor learning is “a fairly exciting advance, if it holds up and can be shown to be beneficial to a large number of people.”

Cost may be an issue, he added, noting that external stimulation may be a more practical treatment for the large number of stroke patients who may benefit from it.

“Despite the number of years it’s been used clinically, it’s been difficult to know how vagus nerve stimulation works in the brain,” Stephen Schachter, MD, professor of neuroscience at Harvard Medical School, noted. “This study brings us very close to understanding at least one way it works in the brain.”

While the relevance of cholinergic facilitation revealed in this study to effects beyond motor learning is uncertain, “it clearly gives researchers direction to pursue new hypotheses.”

He added that if the VNS can facilitate non-motor learning as well, it may become attractive for treating other types of learning deficits, such as poor reading skills, and for cognitive enhancement. For both stroke rehabilitation and other, more meditative applications, a non-invasive method of vagus nerve stimulation may be preferable, particularly because the need for stimulation is likely to be short-lived rather than chronic.

Disclosures

Dr. Philae had no disclosures. Dr. Dawson revealed that MicroTransponder Inc. Conference expenses paid to present VNS-related study results in early 2020.