Targeting Brain’s ‘Go’ Pathway Might Help Relieve Parkinson’s Symptoms
Parkinson’s disease affects the brain’s motor control circuitry, causing rigidity, slowed movement and poor balance. In a study published in Nature,* researchers have teased apart this circuitry, confirming that it contains two distinct pathways – a “go” pathway that tells the body to move and a “stop” pathway that suppresses movement. Tipping the balance in favor of the go pathway might help treat patients.
People with Parkinson’s disease lose cells in a part of the brain called the basal ganglia, which helps control motor functions. As those neurons degenerate and stop producing an essential brain chemical called dopamine, Parkinson’s symptoms set in. Scientists have long believed that the circuitry within the basal ganglia can be separated into a go pathway and a stop pathway that becomes dominant in Parkinson’s. However, until now no one had tested this theory directly.
The new study was led by Anatol Kreitzer, Ph.D., an investigator at the Gladstone Institute of Neurological Disease (GIND) in San Francisco, CA.
To selectively target the go and stop pathways in the mouse brain, Dr. Kreitzer and his team collaborated with Karl Deisseroth, M.D, Ph.D., a bioengineer at Stanford University, in Palo Alto, CA. Dr. Deisseroth is the developer of a technology called optogenetics, through which select neurons can be genetically engineered to respond to pulses of light in the same way they might respond to an electrical shock.
To make the theoretical go and stop neurons in mice responsive to light, the researchers used two genetic switches. One switch was the gene for channelrhodopsin-2 (ChR2), a light-sensitive protein from green algae that helps the algae move toward sunlight. The ChR2 gene was delivered to neurons within the mouse brain using a virus. Meanwhile, a gene-splicing enzyme called Cre recombinase was used to restrict expression of the ChR2 gene to either the go or the stop neurons. A laser-coupled probe was implanted in the animals’ brains, and turned on at controlled times, while the researchers observed the behavior of the mice in a chamber. Turning on the laser activated the neurons expressing ChR2.
The team found that turning on the go neurons in mice increased the amount of time the mice spent moving. Meanwhile, activating neurons in the stop pathway caused periods of immobility called freezing, a symptom similar to that experienced by patients with Parkinson’s. When the mice did move during stop pathway activation, their movements became slower and shorter.
“We found that by activating the stop pathway we could mimic Parkinson’s disease. But what we really wanted was a strategy to treat the disease symptoms,” Dr. Kreitzer said in a statement from GIND.
To that end, the researchers tested the effects of activating the go pathway in a mouse model of Parkinson’s disease. Prior to the test, the mice were given a toxin called 6-OHDA, which destroys the same dopamine-producing neurons lost in Parkinson’s. Five days later, the mice showed the rigidity and slowed movement that are characteristic of the disease. Stimulating the go pathway restored their mobility to pre-toxin levels.
Finding a way to stimulate the go pathway in patients would be a new approach to treating the symptoms of Parkinson's. Current treatments include L-dopa and other dopamine-related drugs, as well as deep brain stimulation, a surgical intervention believed to target the stop pathway.
Dr. Kreitzer’s study was funded by the Gladstone Institutes, the W.M. Keck Foundation, the Pew Scholars Program in the Biomedical Sciences, the McKnight Foundation, and the National Institutes of Health. The Cre recombinase-producing mice used in the study were provided by the Gene Expression Nervous System Atlas (GENSAT), a resource supported by the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Mental Health (NIMH) and the NIH Neuroscience Blueprint.
-By Daniel Stimson, Ph.D.
Parkinson’s disease affects the brain’s motor control circuitry, causing rigidity, slowed movement and poor balance. In a study published in Nature,* researchers have teased apart this circuitry, confirming that it contains two distinct pathways – a “go” pathway that tells the body to move and a “stop” pathway that suppresses movement. Tipping the balance in favor of the go pathway might help treat patients. People with Parkinson’s disease lose cells in a part of the brain called the basal ganglia, which helps control motor functions. As those neurons degenerate and stop producing an essential brain chemical called dopamine, Parkinson’s symptoms set in. Scientists have long believed that the circuitry within the basal ganglia can be separated into a go pathway and a stop pathway that becomes dominant in Parkinson’s. However, until now no one had tested this theory directly.
The new study was led by Anatol Kreitzer, Ph.D., an investigator at the Gladstone Institute of Neurological Disease (GIND) in San Francisco, CA.
To selectively target the go and stop pathways in the mouse brain, Dr. Kreitzer and his team collaborated with Karl Deisseroth, M.D, Ph.D., a bioengineer at Stanford University, in Palo Alto, CA. Dr. Deisseroth is the developer of a technology called optogenetics, through which select neurons can be genetically engineered to respond to pulses of light in the same way they might respond to an electrical shock.
To make the theoretical go and stop neurons in mice responsive to light, the researchers used two genetic switches. One switch was the gene for channelrhodopsin-2 (ChR2), a light-sensitive protein from green algae that helps the algae move toward sunlight. The ChR2 gene was delivered to neurons within the mouse brain using a virus. Meanwhile, a gene-splicing enzyme called Cre recombinase was used to restrict expression of the ChR2 gene to either the go or the stop neurons. A laser-coupled probe was implanted in the animals’ brains, and turned on at controlled times, while the researchers observed the behavior of the mice in a chamber. Turning on the laser activated the neurons expressing ChR2.
The team found that turning on the go neurons in mice increased the amount of time the mice spent moving. Meanwhile, activating neurons in the stop pathway caused periods of immobility called freezing, a symptom similar to that experienced by patients with Parkinson’s. When the mice did move during stop pathway activation, their movements became slower and shorter.
“We found that by activating the stop pathway we could mimic Parkinson’s disease. But what we really wanted was a strategy to treat the disease symptoms,” Dr. Kreitzer said in a statement from GIND.
To that end, the researchers tested the effects of activating the go pathway in a mouse model of Parkinson’s disease. Prior to the test, the mice were given a toxin called 6-OHDA, which destroys the same dopamine-producing neurons lost in Parkinson’s. Five days later, the mice showed the rigidity and slowed movement that are characteristic of the disease. Stimulating the go pathway restored their mobility to pre-toxin levels.
Finding a way to stimulate the go pathway in patients would be a new approach to treating the symptoms of Parkinson's. Current treatments include L-dopa and other dopamine-related drugs, as well as deep brain stimulation, a surgical intervention believed to target the stop pathway.
Dr. Kreitzer’s study was funded by the Gladstone Institutes, the W.M. Keck Foundation, the Pew Scholars Program in the Biomedical Sciences, the McKnight Foundation, and the National Institutes of Health. The Cre recombinase-producing mice used in the study were provided by the Gene Expression Nervous System Atlas (GENSAT), a resource supported by the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Mental Health (NIMH) and the NIH Neuroscience Blueprint.
-By Daniel Stimson, Ph.D.
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