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On October 19, the journal Cell Reports published an online research paper entitled "The direct and indirect pathway neurons of the ventrolateral striatum play different roles in regulating licking movement and substantia nigra neuron activity".
Completed by Yao Haishan's research group at the Center for Excellence in Brain Science and Intelligent Technology of the Chinese Academy of Sciences (Institute of Neuroscience), the State Key Laboratory of Neuroscience, and the Shanghai Center for Brain Science and Brain-inspired Research
.
The study found that the direct and indirect pathways of striatal neurons have different regulatory effects on movement on the second and hundred millisecond time scales, providing new clues for understanding the mechanism of basal ganglia regulating movement
.
The basal ganglia are found in all vertebrates and consist of a series of nuclei extending from the forebrain to the midbrain.
They play an important role in motor control and decision-making behavior
.
The nuclei of the basal ganglia include the striatum, lateral globus pallidus (GPe), medial globus pallidus (GPi), subthalamic nucleus (STN), substantia nigra reticulum (SNr), and substantia nigra compaction (SNc)
.
Striatum, GPe, GPi and SNr are mainly composed of gamma-aminobutyric acid (GABA) neurons, STN is mainly composed of excitatory neurons, and SNc is composed of dopaminergic neurons
.
The striatum is the main input nucleus of the basal ganglia and receives excitatory input from the cortex and thalamus, as well as dopaminergic input from SNc
.
In neurodegenerative diseases (such as Parkinson's disease and Huntington's disease), the loss of SNc dopaminergic neurons or striatal GABAergic neurons causes damage to the function of the basal ganglia circuit, leading to dyskinesia
.
Therefore, in-depth study of the loop mechanism of the basal ganglia regulating movement is of great significance for guiding the treatment of movement disorders in neurodegenerative diseases
.
The vast majority of neurons in the striatum are medium spiny neurons (MSN), which can be divided into two categories according to dopamine receptor subtypes, namely D1-MSNs that express D1 dopamine receptors and D2- that express D2 dopamine receptors.
MSNs
.
D1-MSNs of the striatum are directly projected to the export nucleus SNr and GPi of the basal ganglia, forming a direct pathway; D2-MSNs indirectly projected to the export nucleus of the basal ganglia through GPe and STN, forming an indirect pathway
.
When the activity of GABAergic neurons in the output nucleus of the basal ganglia increases, it can inhibit the activity of the thalamus or brainstem neurons downstream of it
.
According to the classic model of the basal ganglia, the direct pathway promotes movement by inhibiting the output nucleus of the basal ganglia, and the indirect pathway prevents movement by inhibiting the output nucleus
.
Cell-type-specific optogenetic experiments found that D1-MSNs (D2-MSNs) that activate the striatum can indeed promote (inhibit) movement
.
However, the cell type-specific records found that D1-MSNs and D2-MSNs are active at the same time during autonomous movement
.
Recent studies have also found that there are differences in the activities of D1-MSNs and D2-MSNs on the sub-second time scale, and the activities at different moments of the motion sequence are also different
.
These studies show that the direct and indirect pathways of striatal neurons to encode motor information are more complicated than those described by the classic model
.
Some unresolved questions include: What are the characteristics of the activities of the striatal neurons in the direct and indirect pathways on the fine time scale? How does activity on sub-second time scales regulate fine movement? During exercise, how does the activity of striatal neurons in the direct and indirect pathways affect the activity of different neuronal subgroups of SNr? Because licking is a rhythmic fine movement with a time accuracy of 100 milliseconds, in order to explore the above problems, Yao Haishan's research team trained head-fixed mice to perform autonomous licking behavioral tasks, combined with optogenetic manipulation and electrophysiology Record and study the activity characteristics and functions of D1-MSNs and D2-MSNs in the ventrolateral striatum (VLS) in this behavior, and how their activities regulate the firing rate of SNr neurons
.
The research team found that suppressing VLS on the second-level time scale reduced the number of licks in the licking sequence and the rate of licking, but did not change the licking rhythm
.
Inhibition of D1-MSNs can reduce the rate of licking, and inhibition of D2-MSNs can increase the rate of licking
.
Through optogenetic marker recording in VLS, it was found that most of the activities of D1-MSNs and D2-MSNs were related to licking behavior, but the two showed activity differences in the beginning and execution stages of the licking sequence
.
On the one-hundred-millisecond time scale of a single licking cycle, the phases of the oscillations triggered by the licking of D1-MSNs and D2-MSNs are significantly different
.
The licking trigger activity of D1-MSNs reached a peak when the mouse tongue touched the water outlet, which was different from the activity pattern of D2-MSNs
.
In the tongue-out phase of a single licking cycle, instantaneous inhibition of D1-MSNs can reduce the probability of this licking action, while instantaneous inhibition of D2-MSNs has no effect on licking behavior
.
The experiment of electrophysiological recording while optogenetic manipulation found that in the two cases of D1-MSNs that inhibit VLS and D2-MSNs that inhibit VLS, the activities of SNr neurons with inhibitory or sustained response types are both present.
Opposite change
.
The study shows that the direct and indirect pathways of striatal neurons have different regulatory effects on movement on the second and hundred millisecond time scales, and they also antagonistically regulate the activity of the basal ganglia output nucleus neurons.
It provides a reference basis for further understanding of the loop mechanism of the basal ganglia regulating movement
.
This work was funded by the National Natural Science Foundation of China, the Chinese Academy of Sciences and the Shanghai Municipal Government
.
A.
Optogenetic manipulation of the ventrolateral striatum of mice with licking behavior
.
B.
D1-MSNs and D2-MSNs have different phase characteristics in the licking-triggered oscillation activity
.
C.
In the tongue-out phase of licking motion, instantaneous inhibition of D1-MSNs can reduce the probability of a single licking motion
.
D.
The D1-MSNs and D2-MSNs of VLS antagonistically regulate the activity of SNr neurons in the output nucleus of the basal ganglia
.
Source: Center for Excellence in Brain Science and Intelligent Technology, Chinese Academy of Sciences
Completed by Yao Haishan's research group at the Center for Excellence in Brain Science and Intelligent Technology of the Chinese Academy of Sciences (Institute of Neuroscience), the State Key Laboratory of Neuroscience, and the Shanghai Center for Brain Science and Brain-inspired Research
.
The study found that the direct and indirect pathways of striatal neurons have different regulatory effects on movement on the second and hundred millisecond time scales, providing new clues for understanding the mechanism of basal ganglia regulating movement
.
The basal ganglia are found in all vertebrates and consist of a series of nuclei extending from the forebrain to the midbrain.
They play an important role in motor control and decision-making behavior
.
The nuclei of the basal ganglia include the striatum, lateral globus pallidus (GPe), medial globus pallidus (GPi), subthalamic nucleus (STN), substantia nigra reticulum (SNr), and substantia nigra compaction (SNc)
.
Striatum, GPe, GPi and SNr are mainly composed of gamma-aminobutyric acid (GABA) neurons, STN is mainly composed of excitatory neurons, and SNc is composed of dopaminergic neurons
.
The striatum is the main input nucleus of the basal ganglia and receives excitatory input from the cortex and thalamus, as well as dopaminergic input from SNc
.
In neurodegenerative diseases (such as Parkinson's disease and Huntington's disease), the loss of SNc dopaminergic neurons or striatal GABAergic neurons causes damage to the function of the basal ganglia circuit, leading to dyskinesia
.
Therefore, in-depth study of the loop mechanism of the basal ganglia regulating movement is of great significance for guiding the treatment of movement disorders in neurodegenerative diseases
.
The vast majority of neurons in the striatum are medium spiny neurons (MSN), which can be divided into two categories according to dopamine receptor subtypes, namely D1-MSNs that express D1 dopamine receptors and D2- that express D2 dopamine receptors.
MSNs
.
D1-MSNs of the striatum are directly projected to the export nucleus SNr and GPi of the basal ganglia, forming a direct pathway; D2-MSNs indirectly projected to the export nucleus of the basal ganglia through GPe and STN, forming an indirect pathway
.
When the activity of GABAergic neurons in the output nucleus of the basal ganglia increases, it can inhibit the activity of the thalamus or brainstem neurons downstream of it
.
According to the classic model of the basal ganglia, the direct pathway promotes movement by inhibiting the output nucleus of the basal ganglia, and the indirect pathway prevents movement by inhibiting the output nucleus
.
Cell-type-specific optogenetic experiments found that D1-MSNs (D2-MSNs) that activate the striatum can indeed promote (inhibit) movement
.
However, the cell type-specific records found that D1-MSNs and D2-MSNs are active at the same time during autonomous movement
.
Recent studies have also found that there are differences in the activities of D1-MSNs and D2-MSNs on the sub-second time scale, and the activities at different moments of the motion sequence are also different
.
These studies show that the direct and indirect pathways of striatal neurons to encode motor information are more complicated than those described by the classic model
.
Some unresolved questions include: What are the characteristics of the activities of the striatal neurons in the direct and indirect pathways on the fine time scale? How does activity on sub-second time scales regulate fine movement? During exercise, how does the activity of striatal neurons in the direct and indirect pathways affect the activity of different neuronal subgroups of SNr? Because licking is a rhythmic fine movement with a time accuracy of 100 milliseconds, in order to explore the above problems, Yao Haishan's research team trained head-fixed mice to perform autonomous licking behavioral tasks, combined with optogenetic manipulation and electrophysiology Record and study the activity characteristics and functions of D1-MSNs and D2-MSNs in the ventrolateral striatum (VLS) in this behavior, and how their activities regulate the firing rate of SNr neurons
.
The research team found that suppressing VLS on the second-level time scale reduced the number of licks in the licking sequence and the rate of licking, but did not change the licking rhythm
.
Inhibition of D1-MSNs can reduce the rate of licking, and inhibition of D2-MSNs can increase the rate of licking
.
Through optogenetic marker recording in VLS, it was found that most of the activities of D1-MSNs and D2-MSNs were related to licking behavior, but the two showed activity differences in the beginning and execution stages of the licking sequence
.
On the one-hundred-millisecond time scale of a single licking cycle, the phases of the oscillations triggered by the licking of D1-MSNs and D2-MSNs are significantly different
.
The licking trigger activity of D1-MSNs reached a peak when the mouse tongue touched the water outlet, which was different from the activity pattern of D2-MSNs
.
In the tongue-out phase of a single licking cycle, instantaneous inhibition of D1-MSNs can reduce the probability of this licking action, while instantaneous inhibition of D2-MSNs has no effect on licking behavior
.
The experiment of electrophysiological recording while optogenetic manipulation found that in the two cases of D1-MSNs that inhibit VLS and D2-MSNs that inhibit VLS, the activities of SNr neurons with inhibitory or sustained response types are both present.
Opposite change
.
The study shows that the direct and indirect pathways of striatal neurons have different regulatory effects on movement on the second and hundred millisecond time scales, and they also antagonistically regulate the activity of the basal ganglia output nucleus neurons.
It provides a reference basis for further understanding of the loop mechanism of the basal ganglia regulating movement
.
This work was funded by the National Natural Science Foundation of China, the Chinese Academy of Sciences and the Shanghai Municipal Government
.
A.
Optogenetic manipulation of the ventrolateral striatum of mice with licking behavior
.
B.
D1-MSNs and D2-MSNs have different phase characteristics in the licking-triggered oscillation activity
.
C.
In the tongue-out phase of licking motion, instantaneous inhibition of D1-MSNs can reduce the probability of a single licking motion
.
D.
The D1-MSNs and D2-MSNs of VLS antagonistically regulate the activity of SNr neurons in the output nucleus of the basal ganglia
.
Source: Center for Excellence in Brain Science and Intelligent Technology, Chinese Academy of Sciences
