Nature︱ Breakthrough! How astrocytes close the critical period of motor neuron circuits

And explore the mysteries of neuroscience with rigorous academic and logical thinking.
Written by Wang Sizhen, edited by Wang Sizhen, critical periods, also known as critical periods, refer to the short time intervals in the process of neural activity modifying neural circuits.

In the critical period, neural activity can modify the morphological attributes of neurons, thereby permanently changing the structure and function of neural circuits [1-2].

The critical period is necessary for the assembly of neural circuits.
The extension of the critical period or the failure of the critical period to be terminated in time is related to some neurodevelopmental disorders, such as autism and epilepsy [1-2].

However, what mechanism controls the timely end of the critical period? We still know very little.

 Previous studies have shown that the critical period can integrate various forms of plasticity to modify neural circuits, such as homeostasis plasticity, which includes changes in the number, structure and function of synapses in the entire neuron, as well as changes in remote connections [1] .

 Researcher Chris Q.
Doe’s research group at the Howard Hughes Medical Institute Institute of Neuroscience at the University of Oregon has long used Drosophila as the research object to study the development of the central nervous system (CNS), especially: How Drosophila neural progenitor cells generate nerve The diversity of cells, and how different neurons build precise neural circuits to produce motor behavior.

On April 7, 2021, the research group published the latest research paper titled Astrocytes close a motor circuit critical period online on Nature (the research group’s Dr.
Sarah D.
Ackerman contributed the first article and joint communication), and found fruit flies.
The duration of the critical period in the development of the motor circuit (that is, the timely closure of the critical period) depends on the neuron-neurotransmitter signaling pathway from astrocytes to motor neurons.At present, it is known to everyone that the critical phase disorder will manifest as motor deficits, but related research focuses on sensory neural circuits.

However, in the developing motor neural circuit, what kind of state will it be in the critical period? This research aims to answer this scientific question.

 In this work, the researchers selected two representative Drosophila motor neurons, aCC and RP2, for research, and expressed GtACR2 (an anion light-sensitive channel protein).
Neuron optogenetic silencing will cause a significant increase in the volume of motor neuron dendrites, and rapid activation with Chrimson (a light-sensitive channel protein) for 1 hour will cause significant loss of motor neurons, including loss of dendritic volume, and removal Activation for 22 hours can save the loss of dendritic volume.

This indicates that the activity induces the plasticity of motor neuron dendrites, rather than excitotoxicity (Figure 1).

So far, the researchers have defined a critical period of activity-dependent motor nerve dendritic plasticity.

 Figure 1 defines the critical period of the plasticity of the motor nerve circuit (picture quoted from: Sckerman, SD, Perez-Catalan, NA, Freeman, MR et al.
.
Nature, 2021).
Then, the author found that in the later stage of embryo formation, more Long-term (1 and 4 hours) GtACR2 silenced neurons will increase the size and complexity of dendrites, increase the number of excitatory synapses, and decrease the number of inhibitory synapses.

The short-term Chrimson activation (15 minutes) will have the opposite result.

Subsequently, the authors proved that these morphological changes of neurons are related to excitability and inhibitory synaptic input: reduced neuronal activity will lead to a decrease in the compensatory nature of inhibitory synaptic input, resulting in compensatory excitatory synaptic input.
Increase, thereby rebalancing neural network activity (Figure 2).

The author also proved that during the critical period of neurons, neurons will proportionally allocate two synaptic inputs to match the level of neuron activity (Figure 2).

Figure 2 The length of neuron dendrites and the time scale of synaptic input (picture quoted from: Sckerman, SD, Perez-Catalan, NA, Freeman, MR et al.
.
Nature, 2021) Then, next, the end of the critical period is Who controls it? What is the mechanism? First, the author observed that in the late stage of Drosophila embryo formation, astrocytes will penetrate the end of the nerve fiber network and gradually envelop the motor neuron synapses.
At this time, the critical period is closed.

This suggests that astrocytes have some connection with the end of the critical period.

Indeed, the authors found that astrocytes control the end of the critical period; and for the dynamic changes of neuronal dendritic pseudopods (dynamic transition to a stable state), and at the same time for the closure of the critical period, astrocytes are necessary of.

Secondly, the authors discovered four genes that control the end of the critical period in astrocytes, namely gat, chpf, Neuroligins (Nlg) 2 and 4 (Figure 3).

Neuroligins, or neural junction proteins, are a type of cell adhesion proteins that regulate the morphogenesis of astrocytes [4], and Neurexin 1 (Nrx-1 for short) is a transmembrane synaptic adhesion molecule.
Regulate the synaptic structure and function of the brain and neuromuscular junctions [5].

Neuronectin can bind to axon protein.

The authors found that: Nlg2-Nrx-1 ligand receptor signal transduction between astrocytes and motor neurons is necessary for timely shutdown at critical times, that is, signal transduction between these two cells Will limit dendritic plasticity (Figure 3).

Figure 3 Astrocytes end the critical period (picture quoted from: Sckerman, SD, Perez-Catalan, NA, Freeman, MR et al.
.
Nature, 2021) So how is the Nlg2-Nrx-1 ligand receptor signaling pathway? The one that is closed when the key is adjusted? Further results show that the closure of the critical period does not depend on the excitatory-inhibitory synaptic balance mediated by Nlg2, but Nlg2 in astrocytes combines with Nrx-1 in motor neurons to stabilize the tree.
The protruding microtubules are stable and shut down during a critical period (Figure 4).

Figure 4 Signal transduction of astrocytes and motor neurons will limit dendritic plasticity and end the critical period (picture quoted from: Sckerman, SD, Perez-Catalan, NA, Freeman, MR et al.
.
Nature, 2021) In mammals, inappropriate prolongation of the critical period has long-term effects on nervous system function [2].

Here, the authors observed that, at the end of the critical period, after at least 24 hours of acute activation of Drosophila motor neurons, the neuronal connections undergo long-lasting changes (Figure 5).

Furthermore, healthy drosophila larvae show continuous linear movement, while the movement behavior of larvae that prolong the critical period shows excessive turning, leading to abnormal spiral behavior.

And the larvae knocked out astrocyte genes (chpf, Nlg2, Nlg4) also had similar but lesser effects (Figure 5).

These results indicate that, under certain circumstances, an appropriate extension of the critical period can lead to long-term changes in sports behavior.

 Figure 5 Prolonging the critical period to change sports behavior (picture quoted from: Sckerman, SD, Perez-Catalan, NA, Freeman, MR et al.
.
Nature, 2021) Conclusion and discussion The critical period is necessary for the assembly of neural circuits, the key The prolongation of the period, or the failure of the critical period to be terminated in time, is related to neurodevelopmental disorders.

Astrocytes regulate synapseogenesis, synaptic pruning, and synaptic effects.

During the critical period, astrocyte signaling can regulate the plasticity of neurons, but its role in shutting down during the critical period is unclear.

 This study: defines a critical period in the development of the motor neural circuit in Drosophila, and determines that astrocytes can promote the timely closure of the critical period of movement, and reveals a series of astrocyte-motor neuron signaling pathways.
How to regulate the closure of this critical period. Original link: https://doi.
org/10.
1038/s41586-021-03441-2 Recommended high-quality scientific research training courses [1] Medicine plus patch clamp and optogenetic and calcium imaging technology seminar (April 24-25, 2 days and 1 night) [2] Online ︱Single Cell Sequencing Data Analysis and Research Thinking Seminar (January 16-17, 21) (courses can be booked from April to May 2021) [3] Multimodal Brain Image data processing analysis/machine learning application online training brain image: 17-18 Machine learning: 23-24 reference (slide up and down to view) [1] Keck, T.
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[5] Xing, G.
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