These are neurons in the brainstem involved in walking are lit up using optogenetics. [Roseberry et al., Cell]
Credit: Tom Roseberry, Gladstone Institutes
Two secrets of one of the brain's most
enigmatic regions have finally been revealed. In a pair of new studies,
scientists from the Gladstone Institutes have discovered a specific
neural circuit that controls walking, and they found that input to this
circuit is disrupted in Parkinson's disease.
Walking becomes a major challenge for people afflicted by Parkinson's
disease. Parkinson's is caused by a depletion of dopamine--an important
neurochemical--in the basal ganglia (BG), a brain region involved in
fundamental behaviors like movement, learning, reward, and motivation.
In Parkinson's, an imbalance arises between two pathways in the BG: the
direct or "go" pathway and the indirect or "stop" pathway. Ordinarily,
these pathways work together seamlessly to control locomotion, but in
Parkinson's the stop pathway overpowers the go pathway, making it
difficult to initiate movement. How the imbalance between these two
pathways developed remained a mystery--until now.
Correcting an Imbalance in the Brain
Published in Neuron, scientists led by Gladstone associate
investigator Anatol Kreitzer, PhD, discovered that dopamine depletion
causes a miscommunication between the BG and another region called the
thalamus, an area thought to relay sensory information to the brain.
This miscommunication results in a loss of input to the go pathway from
the thalamus, which consequently disrupts movement. Blocking the
connection between the two regions reversed the imbalance between the
stop and go pathways and restored normal behavior in a mouse model of
Parkinson's.
"This study provides strong evidence for a mechanism by which the
stop pathway overcomes the go pathway in Parkinson's disease," says
first author Philip Parker, PhD, a former graduate student in Dr.
Kreitzer's lab at the Gladstone Institutes and the University of
California, San Francisco (UCSF). "Our findings implicate the thalamus
in the development of the disease, an area of the brain that has
received relatively little attention in Parkinson's research."
"Several studies have targeted the thalamus with deep brain
stimulation to treat Parkinson's, but the region's role in the disease
was not well established," adds Dr. Kreitzer, who is also an associate
professor of physiology and neurology at UCSF. "Our findings finally
provide a clear picture of how the thalamus can imbalance neural
circuits and suppress movement in this condition."
Discovering How the Brain Controls Walking
In the second study, published in Cell, the scientists
discovered that the go and stop pathways from the BG control locomotion
by regulating a group of nerve cells in the brainstem that connects the
brain to the spinal cord. The researchers revealed that the go pathway
selectively activates a type of neuron in the brainstem that releases
the neurochemical glutamate, and these neurons are responsible for
triggering locomotion.
The scientists used optogenetics--an innovative research tool that
uses light to activate or inhibit select cells in the brain--to
stimulate either the go or the stop pathway in mice that were running on
a tiny treadmill, while recording neural activity in the brainstem.
They discovered that the go pathway selectively activated glutamate
neurons, causing the mice to move, whereas the stop pathway inhibited
these neurons and made the mice stop.
"This is the first time we have been able to demonstrate how the go
and stop pathways regulate locomotion," says Tom Roseberry, a graduate
student in the lab of Dr. Kreitzer. "We show a very precise connection
from the basal ganglia to the brainstem that controls movement."
Remarkably, the researchers discovered that the brainstem neurons can
overpower the signals from the BG--that is, if glutamate neurons were
turned on, the animal moved even if the stop pathway is activated.
"In order to understand why walking is particularly disrupted in
Parkinson's disease, we need to map out the circuitry that controls
locomotion," says Dr. Kreitzer. "Our study shows that a specific set of
neurons in the brainstem are both necessary and sufficient to initiate
locomotion. This finding could open the door for new treatment targets
to help Parkinson's patients walk more easily."
Story Source:
The above post is reprinted from
materials provided by
Gladstone Institutes. The original item was written by Dana G. Smith, PhD.
Note: Materials may be edited for content and length.
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