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Editor-in-charge | Xi
Behind every seemingly simple action in our lives, we rely on the precise regulation
of the central nervous system motor system.
In humans and other mammals, the striatum in the brain is a key part
of controlling movement.
For a long time, it has been believed that motor control and other functions of the striatum rely on the real-time regulation
of neural circuits in the striatum by dopamine and other neuromodulatory transmitters.
In Parkinson's, striatal dysfunction due to the loss of dopamine-making cells is a recognized primary cause
.
Current classical theory holds that the main nerve cell types of the striatum are spiny projection neurons divided into two types
.
One is a "direct pathway" to neurons that promote movement
.
The other is "indirect pathway" neurons that inhibit movement
.
During exercise, dopamine exerts opposite functional modulations
on these two neurons through different dopamine receptors specifically expressed on these two neurons.
Specifically, dopamine upregulates intracellular protein kinase A (protein kinase A; PKA), thereby enhancing the signaling propagation function of such neurons and further promoting movement
.
At the same time, dopamine downregulates the activity of protein kinase A on neurons that inhibit the "indirect pathway" of movement, thereby reducing the function of such neurons and reducing their inhibition of movement, achieving the effect
of "negative negative to positive".
So the role of dopamine in both types of neurons is to promote movement, like the throttle
of a car.
This is also why dopamine neurons are damaged in Parkinson's disease, and the reduction of dopamine release can cause significant movement disorders
.
If there is a throttle, there should be a brake
.
However, the vast majority of research has focused on the role
of dopamine in promoting exercise.
Little is known about whether there is a "brake" mechanism to fight dopamine in the striatum
.
On November 9, 2022, the team of Haining Zhong at the Vollum Institute of Health and Science University of Oregon published an article in Nature magazine, Locomotion activates PKA through dopamine and adenosine in striatal neurons , revealing a new "brake" mechanism in motor control in the striatum of the brain, opening new avenues
for the treatment of Parkinson's and other diseases associated with the striatum.
In 2018, Zhong Haining's group and Mao Tianyi's group of the Vollum Research Institute cooperated to publish a report entitled A Highly Sensitive A-Kinase Activity Reporter for Imaging in the journal Neuron Neuromodulatory Events in Awake Mice, a novel protein kinase A activity probe
.
This probe combines two-photon fluorescence lifetime imaging microscopy; 2pFLIM), which can monitor protein kinase A activity in neurons in the cerebral cortex of mice in real time during behavioral processes (see BioArt report: NeuronHaining Zhong/Mao Tianyi collaboration group achieves the first in vivo monitoring of neuromodulated subcellular signaling).
In this Nature, Ma Lei, a postdoc in Zhong's team, with the help of Ding Jun's lab at Stanford University, measured protein kinase A activity in neurons of the striatum at the single-cell level by further combining tiny "gradient index lenses" like needles
.
The study found that, contrary to classical theory, protein kinase A activity during exercise was increased
in both types of striatal neurons that promoted and inhibited movement.
Further study surfaces, dopamine does upregulate protein kinase A activity
in "direct pathway" neurons that promote movement.
However, to the researchers' surprise, exercise also led to the release
of another neurotransmitter, adenosine.
Adenosine upregulates protein kinase A activity in neurons of the "indirect pathway" that inhibits movement, thereby enhancing the function of these neurons and inhibiting the movement
of animals.
Its ultimate role is to enhance the inhibition of exercise, playing an antagonistic role in dopamine function
.
So adenosine is the "brake" corresponding to the "throttle"
of dopamine.
Just as the accelerator and brake together provide precise control of the car's movement in a car, dopamine and adenosine can work together to maintain the striatal neurons that promote and inhibit movement in a relatively balanced state, and work together to control the motor system more
accurately.
As mentioned earlier, an imbalance in the activity of two neurons in the striatum can lead to various motor disorder diseases
.
The striatum also has other important functions such as regulating learning and receiving rewards, and its functional imbalance is associated
with numerous psychiatric disorders.
In the past, almost all drug research on related diseases has focused on the regulation of dopamine or dopamine receptors
.
The results of this article may now help devise new strategies
to treat striatal dysfunction by modulating adenosine or adenosine receptors.
It is worth mentioning that the receptor of adenosine is also a major site of action of the familiar caffeine: caffeine inhibits the function of
adenosine receptors.
Drinking coffee is also similar to temporarily lifting the brakes
applied by adenosine.
Figure: (left) Schematic
diagram of the experiment.
(middle) In animal voluntary locomotion, protein kinase A (PKA) activity is elevated in both striatal spiny projection neurons that promote (dSPN) and inhibit (iSPN) movement
.
(Right) Using the adenosine probe developed by Li Yulong's research group at Peking University, it was directly detected that movement in the striatum led to an increase
in adenosine levels.
Postdoctoral fellow Ma Lei is the first author, and Zhong Haining is the corresponding author
.
Other collaborators include Maozhen Qin, Julian Day-Cooney and Michael A.
Muniak, postdocs in the Mao Tianyi team at the Vollum Institute at Oregon Health & Science University, and Omar Jaidar Benavides
, a postdoc in Ding's team at Stanford University.
Original link: https://doi.
org/10.
1038/s41586-022-05407-4
Platemaker: Eleven
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