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There are some controversies about adult nerve regeneration, but more evidence supports the existence of nerve regeneration in the hippocampal DG area after adulthood.
These adult neurons are integrated into the existing neural circuits after maturation, and participate in hippocampal-related memory behaviors and emotions.
However, under pathological conditions such as depression, anxiety, and Alzheimer's disease, the "ecological environment" of nerve regeneration in the hippocampal DG area becomes disordered, which directly causes a decrease in the number of new neurons.
In the brain, there is a group of immune cells-microglia that dynamically monitor neurons in real time.
Under physiological conditions, these immune cells secrete factors that can regulate the neurogenic microenvironment and positively regulate nerve regeneration.
In pathological conditions, microglia secrete inflammatory factors to destroy nerve regeneration.
On March 17, 2021, the research team of You Zili, College of Life Science and Technology, Chengdu University of Electronic Technology published an article in Science Advances, and found that IL4-driven microglia depend on brain-derived neurotrophic factor (BDNF) signals to promote neurogenesis effect.
Researchers used sugar water preference, tail suspension experiments, forced swimming and other experiments to evaluate depression-like behaviors to screen out hypersensitive mice and hyposensitive mice after chronic restraint stress.
In behavior, hypersensitive mice showed more obvious depression-like behavioral symptoms.
At the molecular level, the levels of IL-4 and its receptor IL4Rα in the hippocampus of highly sensitive mice decreased, while the levels of IL-4 and IL4Rα in hyposensitive mice increased.
In addition, the number of Arg1-positive microglia with neuroprotective effects increased in hyposensitive mice and decreased in highly sensitive mice.
After stress, the number of new neurons in the hippocampus decreases.
The number of neural precursor cells in the hippocampal DG area of hypersensitive mice decreases, cell proliferation is impaired, and the Notch and Wnt signaling pathways related to nerve regeneration are also disordered.Because the molecular weight of IL4 cannot pass through the blood-brain barrier, the researchers used viral vector tools to effectively and specifically increase the level of IL4 in the hippocampus through AAV-IL4.
Gene overexpression | AAV customized services can promote the differentiation, survival and maturation of neural precursor cells in the hippocampus through IL4 overexpression, and "repair" the nerve regeneration disorder caused by chronic stress.
The number of Arg1-positive microglia increases.
Relieve depression-like behaviors.
At the same time, the researchers used a similar virus interference technology combined with Cx3CR1-cre mice to specifically knock down IL4Rα on microglia.
It was found that after knocking down IL4Rα, mice were more sensitive to stress, exhibited depression-like behavior, and the number of neuroprotective microglia was also reduced.
To further confirm that IL4Rα signaling plays a key role in stress-induced neurogenesis, they used a dual virus strategy to perform chronic stress after knocking down IL4Rα, and then overexpress IL4 in the hippocampus.
The mice still showed depression-like behaviors.
, Nerve regeneration still has obstacles.
This indicates that knocking down IL4Rα cancels the therapeutic effect of IL4 overexpression.
In transcriptomics analysis, it was found that BDNF increased significantly after IL4 was overexpressed in the hippocampus, while the expression of BDNF decreased during chronic stress.
Through immunofluorescence experiments, it was found that IL-4 mediated BDNF was widely distributed on Arg1 positive microglia.
BDNF neutralizing antibody or BDNF receptor antagonist blocked BDNF signal, and found that the neurogenesis effect of Arg1-positive microglia can be effectively blocked.
These results indicate that IL-4 promotes the secretion of BDNF by inducing Arg1 microglia, thereby promoting neurogenesis and antidepressant effects.
In summary, this article reveals that IL-4 driven neuroprotective phenotype of microglia exerts antidepressant effects through BDNF signal-mediated promotion of nerve regeneration.
[References] 1.
Zhang et al.
, Sci.
Adv.
2021; 7: eabb9888, IL4-driven microglia modulate stress resilience through BDNF-dependent neurogenesis The pictures in the article are all from the references
There are some controversies about adult nerve regeneration, but more evidence supports the existence of nerve regeneration in the hippocampal DG area after adulthood.
These adult neurons are integrated into the existing neural circuits after maturation, and participate in hippocampal-related memory behaviors and emotions.
However, under pathological conditions such as depression, anxiety, and Alzheimer's disease, the "ecological environment" of nerve regeneration in the hippocampal DG area becomes disordered, which directly causes a decrease in the number of new neurons.
In the brain, there is a group of immune cells-microglia that dynamically monitor neurons in real time.
Under physiological conditions, these immune cells secrete factors that can regulate the neurogenic microenvironment and positively regulate nerve regeneration.
In pathological conditions, microglia secrete inflammatory factors to destroy nerve regeneration.
On March 17, 2021, the research team of You Zili, College of Life Science and Technology, Chengdu University of Electronic Technology published an article in Science Advances, and found that IL4-driven microglia depend on brain-derived neurotrophic factor (BDNF) signals to promote neurogenesis effect.
Researchers used sugar water preference, tail suspension experiments, forced swimming and other experiments to evaluate depression-like behaviors to screen out hypersensitive mice and hyposensitive mice after chronic restraint stress.
In behavior, hypersensitive mice showed more obvious depression-like behavioral symptoms.
At the molecular level, the levels of IL-4 and its receptor IL4Rα in the hippocampus of highly sensitive mice decreased, while the levels of IL-4 and IL4Rα in hyposensitive mice increased.
In addition, the number of Arg1-positive microglia with neuroprotective effects increased in hyposensitive mice and decreased in highly sensitive mice.
After stress, the number of new neurons in the hippocampus decreases.
The number of neural precursor cells in the hippocampal DG area of hypersensitive mice decreases, cell proliferation is impaired, and the Notch and Wnt signaling pathways related to nerve regeneration are also disordered.Because the molecular weight of IL4 cannot pass through the blood-brain barrier, the researchers used viral vector tools to effectively and specifically increase the level of IL4 in the hippocampus through AAV-IL4.
Gene overexpression | AAV customized services can promote the differentiation, survival and maturation of neural precursor cells in the hippocampus through IL4 overexpression, and "repair" the nerve regeneration disorder caused by chronic stress.
The number of Arg1-positive microglia increases.
Relieve depression-like behaviors.
At the same time, the researchers used a similar virus interference technology combined with Cx3CR1-cre mice to specifically knock down IL4Rα on microglia.
It was found that after knocking down IL4Rα, mice were more sensitive to stress, exhibited depression-like behavior, and the number of neuroprotective microglia was also reduced.
To further confirm that IL4Rα signaling plays a key role in stress-induced neurogenesis, they used a dual virus strategy to perform chronic stress after knocking down IL4Rα, and then overexpress IL4 in the hippocampus.
The mice still showed depression-like behaviors.
, Nerve regeneration still has obstacles.
This indicates that knocking down IL4Rα cancels the therapeutic effect of IL4 overexpression.
In transcriptomics analysis, it was found that BDNF increased significantly after IL4 was overexpressed in the hippocampus, while the expression of BDNF decreased during chronic stress.
Through immunofluorescence experiments, it was found that IL-4 mediated BDNF was widely distributed on Arg1 positive microglia.
BDNF neutralizing antibody or BDNF receptor antagonist blocked BDNF signal, and found that the neurogenesis effect of Arg1-positive microglia can be effectively blocked.
These results indicate that IL-4 promotes the secretion of BDNF by inducing Arg1 microglia, thereby promoting neurogenesis and antidepressant effects.
In summary, this article reveals that IL-4 driven neuroprotective phenotype of microglia exerts antidepressant effects through BDNF signal-mediated promotion of nerve regeneration.
[References] 1.
Zhang et al.
, Sci.
Adv.
2021; 7: eabb9888, IL4-driven microglia modulate stress resilience through BDNF-dependent neurogenesis The pictures in the article are all from the references
