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Written by Han Xu Linzi, edited by Han Xu Linzi, Wang Sizhen In Parkinson's disease (PD), the loss of midbrain dopaminergic cells can lead to dyskinesias, such as gait freezing, slowed movement and falls
.
More and more evidence shows that these motor deficits can be partly attributed to changes in the mesencephalic locomotor region (MLR), which plays a key role in the control of vertebrate movement through the downstream reticulospinal tract.
[1]
.
Dopaminergic neurons in the substantia nigra pars compacta (SNc) indirectly control MLR activity through the basal ganglia.
At the same time, MLR also receives direct projections from SNc and zona incerta dopaminergic neurons
.
Studies have shown that in the PD monkey model, the dopaminergic innervation of MLR degenerates [2]
.
Therefore, the loss of dopaminergic neurons in PD has an important impact on MLR activity
.
The loss of MLR neurons, abnormal neural activity, changes in connectivity and metabolic defects may lead to the disappearance of motor command amplification, resulting in dyskinesia
.
Dyskinesia and frozen gait in PD may be related to decreased MLR neuronal activity [3]
.
Increasing the activity of MLR neurons, such as levodopa treatment, may be a potential method to improve the motor symptoms of PD [4]
.
The improvement of motion by deep brain stimulation (DBS) of the subthalamic nucleus is also believed to be related to MLR, because there are direct and indirect projections between the subthalamic nucleus and MLR
.
However, the efficacy of levodopa and DBS in the subthalamic nucleus may diminish over time, which forces us to find new treatments [5]
.
Since 2005, MLR has been studied as a potential target of DBS, but the results of the study are mixed [6, 7]
.
MLR is a heterogeneous structure containing multiple regions.
The cuneiform nucleus (CnF) controls the range of motion speed, while the pedunculopontine nucleus (PPN) controls slow motion, posture, and in some cases.
Movement inhibition [8]
.
Human DBS targets PPN
.
However, it is not clear which cell type in MLR is the best target for improving motor function in PD
.
Optogenetic studies have found that CnF glutamatergic neurons play a key role in regulating wider movement speeds, while PPN glutamatergic neurons control slower speeds
.
GABAergic neurons in CnF and PPN may stop movement by inhibiting glutamatergic neurons
.
The role of cholinergic neurons in PPN is uncertain, because their activation increases or decreases movement [8]
.
Clinically, DBS may stimulate all neurons around the electrode, including GABAergic neurons that stop movement, which has led to inconsistent research results
.
On October 20, 2021, the Dimitri Ryczko research group of the University of Sherbrooke, Canada, published the (First release) titled "Optogenetic stimulation of glutamatergic neurons in the cuneiform nucleus controls locomotion in a mouse model of Parkinson's disease" on PNAS.
Research papers
.
Stimulating PD mice by optogenetics revealed the improvement effect of glutamatergic neurons in CnF on dyskinesia, and provided a basis for CnF as a PD treatment target
.
The authors used bilateral striatal injections of 6-hydroxydopamine (6-OHDA) to construct a PD mouse model in Vglut2-ChR2-EYFP mice, and used a high-speed camera combined with DeepLabCut Networks to evaluate the performance of the mice in the mine experiment.
Exercise function, set injection of saline as a control group
.
Striatum injection of 6-OHDA can cause striatal dopaminergic neurodegeneration and SNc dopaminergic cell damage, resulting in damage to the substantia nigra-striatum pathway, which induces obvious PD motor deficits, including the total length of exercise in mice, The number of starting times, speed and rounds are all reduced, and the time of stationary movement increases
.
The above sports indexes of the control group remained unchanged
.
In order to explore the effect of activating glutamatergic (Vglut2+) neurons in CnF on the motor function of PD mice, the authors used optogenetics and patch clamp recording methods
.
It was found that after optogenetic activation of glutamatergic neurons in the CnF of PD mice, the total length of exercise, the number of starts, and the speed of PD mice’s exercise increased, and the resting time was reduced.
Light stimulation of control mice can get the same Function (Figure 1)
.
These results suggest that optogenetic activation of glutamatergic neurons in CnF can improve dyskinesia in PD mice
.
Figure 1 Optogenetic activation of glutamatergic neurons in CnF of Vglut2-ChR2-EYFP mice modeled by 6-OHDA improves the motor function of mice (Source: Fougère, Maxime et al.
, PNAS, 2021) The main role of CnF It controls movement, so the authors then explored whether CnF still has this regulatory function in PD mice
.
The PD mice were stimulated with different laser powers and the movement speed changes were observed.
It was found that the movement speed of the mice showed an "S"-like trend with the increase of laser function (Figure 2), and this trend was also observed in the control group of mice.
Exist
.
This shows that the damage of the substantia nigra-dopaminergic pathway caused by 6-OHDA does not affect the regulating effect of CnF on movement speed
.
Figure 2.
The mouse's movement speed is proportional to the stimulated laser power (Source: Fougère, Maxime et al.
, PNAS, 2021) Next, the author explored whether optogenetic activation of glutamatergic neurons in CnF can induce normal Movement, the author used DeepLabCut Networks to analyze the movement of 6 points (iliac bone, hip joint, knee joint, ankle joint, metatarsophalangeal toe and toe) of mouse hind limbs in a high-speed camera video
.
(I) Compared with the spontaneous movement before the injection, the angle of the hip, ankle and metatarsophalangeal joints in the control group after the injection of normal saline changed similarly over time, but the amplitude of the knee joint angle increased slightly after the injection (+ 7%); (II) In the experimental group, the angles of the knee, ankle and metatarsophalangeal joints were similar after optogenetic stimulation after 6-OHDA injection and the spontaneous movement before modeling, but the hip joint angle was lower after 6-OHDA injection Shows a higher amplitude (+38%); (III) In the spontaneous movement before intracerebral injection, compared with the control group, only the knee angle of the 6-OHDA injection group showed higher amplitude (+16%) (IV) During the exercise of light-stimulated mice, there was no difference in the movement of the limbs (buttocks, knees, ankles and metatarsal toes) between the control group and the 6-OHDA injection laboratory group (Figure 3)
.
These results comprehensively indicate that the limb movement disorder in Parkinson's disease can be improved by light stimulation of CnF Vglut2+ neurons, and the limb movement is basically similar to the spontaneous movement before the injury (modeling)
.
Figure 3.
Optogenetic stimulation of CnF glutamatergic neurons can induce normal limb movements in PD mice (Source: Fougère, Maxime et al.
, PNAS, 2021).
Conclusion and discussion of the article, inspiration and prospects for the above experiments The results show that activating glutamatergic (Vglut2+) neurons in CnF can improve dyskinesia in PD mice [9]
.
Therefore, Vglut2+ neurons in CnF are potential therapeutic targets for PD
.
At present, clinical deep brain stimulation therapy focuses on the PPN in MLR, while ignoring CnF.
At present, the first clinical trial on CnF deep brain stimulation therapy has been carried out
.
How to selectively stimulate the Vglut2+ neurons in CnF is the key to future research, which can be tried by adjusting the stimulation frequency and pharmacological assistance [10]
.
Autopsy found that the cholinergic neurons in the PPN of PD patients had degeneration, but whether the state of glutamatergic neurons in CnF also changed, there are few studies
.
There have been clinical trials trying to use CnF deep brain stimulation to treat progressive supranuclear palsy (a non-classical PD) movement disorder (such as frozen gait)
.
In short, increasing the activity of glutamatergic neurons in CnF is a way to improve the motor function of PD
.
Future research should focus on improving the dyskinesia of PD patients by regulating these neurons through drug treatment, optimizing deep brain stimulation schemes, optogenetic or chemical genetic tools
.
Original link: https:// selection of previous articles [1] PNAS︱ Tan Hongtao/Chen Peng's research group collaborated to reveal that dopaminergic neurons regulate chronic stress-induced effects Fly memory disorders [2] Mol Psychiatry | Gao Tianming's research team reveals the local neural network mechanism of fear memory fading [3] Nat Commun | Working memory representation of the visual cortex regulates the effect of distracting attention [4] Science | Breakthrough! Immune CD4+ T cells are involved in the disease process of Lewy body dementia [5] Cell Rep︱ New research reveals the role of hypothalamic neuronal calcium homeostasis regulators in the formation of obesity [6] Science︱ first confirmed in humans: multiple neurodegeneration Sexual diseases can affect the neurogenesis of the hippocampal dentate gyrus [7] Neuron︱ new discovery! The hippocampus playback in the awake state promotes memory function by storing and updating specific past experiences [8] Mol Psychiatry︱ A new discovery of biomarkers for depression-mitochondrial proteins in exosomes [9] Science | Breakthrough! Astrocyte Ca2+ induces ATP release to regulate myelin axon excitability and conduction velocity [10] Neurosci Bull︱Shen Ying’s team reveals the three-dimensional spatial heterogeneity of the cerebellar nucleus to the thalamus.
Recommended training courses for high-quality scientific research [1] discount Countdown ︱ EEG data analysis introductory class (online: 2021.
12.
4~12.
16) [2] Discount countdown︱ Near-infrared brain function data processing class (online: 11.
1~11.
14) [3] Data graph help guide! How good is it to learn these software? 【4】JAMA Neurol︱Attention! Young people are more likely to suffer from "Alzheimer's disease"? References (slide up and down to view) [1] A.
Demain et al.
, High-level gait and balance disorders in the elderly: A midbrain dis- ease? J.
Neurol.
261, 196–206 (2014)[2] A .
-S.
Rolland et al.
,
.
More and more evidence shows that these motor deficits can be partly attributed to changes in the mesencephalic locomotor region (MLR), which plays a key role in the control of vertebrate movement through the downstream reticulospinal tract.
[1]
.
Dopaminergic neurons in the substantia nigra pars compacta (SNc) indirectly control MLR activity through the basal ganglia.
At the same time, MLR also receives direct projections from SNc and zona incerta dopaminergic neurons
.
Studies have shown that in the PD monkey model, the dopaminergic innervation of MLR degenerates [2]
.
Therefore, the loss of dopaminergic neurons in PD has an important impact on MLR activity
.
The loss of MLR neurons, abnormal neural activity, changes in connectivity and metabolic defects may lead to the disappearance of motor command amplification, resulting in dyskinesia
.
Dyskinesia and frozen gait in PD may be related to decreased MLR neuronal activity [3]
.
Increasing the activity of MLR neurons, such as levodopa treatment, may be a potential method to improve the motor symptoms of PD [4]
.
The improvement of motion by deep brain stimulation (DBS) of the subthalamic nucleus is also believed to be related to MLR, because there are direct and indirect projections between the subthalamic nucleus and MLR
.
However, the efficacy of levodopa and DBS in the subthalamic nucleus may diminish over time, which forces us to find new treatments [5]
.
Since 2005, MLR has been studied as a potential target of DBS, but the results of the study are mixed [6, 7]
.
MLR is a heterogeneous structure containing multiple regions.
The cuneiform nucleus (CnF) controls the range of motion speed, while the pedunculopontine nucleus (PPN) controls slow motion, posture, and in some cases.
Movement inhibition [8]
.
Human DBS targets PPN
.
However, it is not clear which cell type in MLR is the best target for improving motor function in PD
.
Optogenetic studies have found that CnF glutamatergic neurons play a key role in regulating wider movement speeds, while PPN glutamatergic neurons control slower speeds
.
GABAergic neurons in CnF and PPN may stop movement by inhibiting glutamatergic neurons
.
The role of cholinergic neurons in PPN is uncertain, because their activation increases or decreases movement [8]
.
Clinically, DBS may stimulate all neurons around the electrode, including GABAergic neurons that stop movement, which has led to inconsistent research results
.
On October 20, 2021, the Dimitri Ryczko research group of the University of Sherbrooke, Canada, published the (First release) titled "Optogenetic stimulation of glutamatergic neurons in the cuneiform nucleus controls locomotion in a mouse model of Parkinson's disease" on PNAS.
Research papers
.
Stimulating PD mice by optogenetics revealed the improvement effect of glutamatergic neurons in CnF on dyskinesia, and provided a basis for CnF as a PD treatment target
.
The authors used bilateral striatal injections of 6-hydroxydopamine (6-OHDA) to construct a PD mouse model in Vglut2-ChR2-EYFP mice, and used a high-speed camera combined with DeepLabCut Networks to evaluate the performance of the mice in the mine experiment.
Exercise function, set injection of saline as a control group
.
Striatum injection of 6-OHDA can cause striatal dopaminergic neurodegeneration and SNc dopaminergic cell damage, resulting in damage to the substantia nigra-striatum pathway, which induces obvious PD motor deficits, including the total length of exercise in mice, The number of starting times, speed and rounds are all reduced, and the time of stationary movement increases
.
The above sports indexes of the control group remained unchanged
.
In order to explore the effect of activating glutamatergic (Vglut2+) neurons in CnF on the motor function of PD mice, the authors used optogenetics and patch clamp recording methods
.
It was found that after optogenetic activation of glutamatergic neurons in the CnF of PD mice, the total length of exercise, the number of starts, and the speed of PD mice’s exercise increased, and the resting time was reduced.
Light stimulation of control mice can get the same Function (Figure 1)
.
These results suggest that optogenetic activation of glutamatergic neurons in CnF can improve dyskinesia in PD mice
.
Figure 1 Optogenetic activation of glutamatergic neurons in CnF of Vglut2-ChR2-EYFP mice modeled by 6-OHDA improves the motor function of mice (Source: Fougère, Maxime et al.
, PNAS, 2021) The main role of CnF It controls movement, so the authors then explored whether CnF still has this regulatory function in PD mice
.
The PD mice were stimulated with different laser powers and the movement speed changes were observed.
It was found that the movement speed of the mice showed an "S"-like trend with the increase of laser function (Figure 2), and this trend was also observed in the control group of mice.
Exist
.
This shows that the damage of the substantia nigra-dopaminergic pathway caused by 6-OHDA does not affect the regulating effect of CnF on movement speed
.
Figure 2.
The mouse's movement speed is proportional to the stimulated laser power (Source: Fougère, Maxime et al.
, PNAS, 2021) Next, the author explored whether optogenetic activation of glutamatergic neurons in CnF can induce normal Movement, the author used DeepLabCut Networks to analyze the movement of 6 points (iliac bone, hip joint, knee joint, ankle joint, metatarsophalangeal toe and toe) of mouse hind limbs in a high-speed camera video
.
(I) Compared with the spontaneous movement before the injection, the angle of the hip, ankle and metatarsophalangeal joints in the control group after the injection of normal saline changed similarly over time, but the amplitude of the knee joint angle increased slightly after the injection (+ 7%); (II) In the experimental group, the angles of the knee, ankle and metatarsophalangeal joints were similar after optogenetic stimulation after 6-OHDA injection and the spontaneous movement before modeling, but the hip joint angle was lower after 6-OHDA injection Shows a higher amplitude (+38%); (III) In the spontaneous movement before intracerebral injection, compared with the control group, only the knee angle of the 6-OHDA injection group showed higher amplitude (+16%) (IV) During the exercise of light-stimulated mice, there was no difference in the movement of the limbs (buttocks, knees, ankles and metatarsal toes) between the control group and the 6-OHDA injection laboratory group (Figure 3)
.
These results comprehensively indicate that the limb movement disorder in Parkinson's disease can be improved by light stimulation of CnF Vglut2+ neurons, and the limb movement is basically similar to the spontaneous movement before the injury (modeling)
.
Figure 3.
Optogenetic stimulation of CnF glutamatergic neurons can induce normal limb movements in PD mice (Source: Fougère, Maxime et al.
, PNAS, 2021).
Conclusion and discussion of the article, inspiration and prospects for the above experiments The results show that activating glutamatergic (Vglut2+) neurons in CnF can improve dyskinesia in PD mice [9]
.
Therefore, Vglut2+ neurons in CnF are potential therapeutic targets for PD
.
At present, clinical deep brain stimulation therapy focuses on the PPN in MLR, while ignoring CnF.
At present, the first clinical trial on CnF deep brain stimulation therapy has been carried out
.
How to selectively stimulate the Vglut2+ neurons in CnF is the key to future research, which can be tried by adjusting the stimulation frequency and pharmacological assistance [10]
.
Autopsy found that the cholinergic neurons in the PPN of PD patients had degeneration, but whether the state of glutamatergic neurons in CnF also changed, there are few studies
.
There have been clinical trials trying to use CnF deep brain stimulation to treat progressive supranuclear palsy (a non-classical PD) movement disorder (such as frozen gait)
.
In short, increasing the activity of glutamatergic neurons in CnF is a way to improve the motor function of PD
.
Future research should focus on improving the dyskinesia of PD patients by regulating these neurons through drug treatment, optimizing deep brain stimulation schemes, optogenetic or chemical genetic tools
.
Original link: https:// selection of previous articles [1] PNAS︱ Tan Hongtao/Chen Peng's research group collaborated to reveal that dopaminergic neurons regulate chronic stress-induced effects Fly memory disorders [2] Mol Psychiatry | Gao Tianming's research team reveals the local neural network mechanism of fear memory fading [3] Nat Commun | Working memory representation of the visual cortex regulates the effect of distracting attention [4] Science | Breakthrough! Immune CD4+ T cells are involved in the disease process of Lewy body dementia [5] Cell Rep︱ New research reveals the role of hypothalamic neuronal calcium homeostasis regulators in the formation of obesity [6] Science︱ first confirmed in humans: multiple neurodegeneration Sexual diseases can affect the neurogenesis of the hippocampal dentate gyrus [7] Neuron︱ new discovery! The hippocampus playback in the awake state promotes memory function by storing and updating specific past experiences [8] Mol Psychiatry︱ A new discovery of biomarkers for depression-mitochondrial proteins in exosomes [9] Science | Breakthrough! Astrocyte Ca2+ induces ATP release to regulate myelin axon excitability and conduction velocity [10] Neurosci Bull︱Shen Ying’s team reveals the three-dimensional spatial heterogeneity of the cerebellar nucleus to the thalamus.
Recommended training courses for high-quality scientific research [1] discount Countdown ︱ EEG data analysis introductory class (online: 2021.
12.
4~12.
16) [2] Discount countdown︱ Near-infrared brain function data processing class (online: 11.
1~11.
14) [3] Data graph help guide! How good is it to learn these software? 【4】JAMA Neurol︱Attention! Young people are more likely to suffer from "Alzheimer's disease"? References (slide up and down to view) [1] A.
Demain et al.
, High-level gait and balance disorders in the elderly: A midbrain dis- ease? J.
Neurol.
261, 196–206 (2014)[2] A .
-S.
Rolland et al.
,
