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Click on the blue letters to follow us Alfred G.
Knudson put forward the famous second-hit hypothesis of tumorigenesis in 1971.
He believed that the first mutation occurred in germ cells, and the second mutation occurred in somatic cells after birth
.
The second-strike hypothesis is also applicable to neuropsychiatric diseases such as depression and autism
.
Early inflammation has a lasting and profound impact on the development of the central nervous system, and there may be behavioral changes in adulthood
.
The model can be simplified as follows: the first blow: inflammatory damage in the early developmental stage may cause abnormal neuronal plasticity through excessive synaptic pruning or microglia activation; the second blow: stress can promote or inhibit this effect.
Resulting in changes in behavior
.
On July 7, 2021, the joint research team of Zhang Zhi, Jin Yan and Xu Lin of the Department of Life Sciences and Medicine of the University of Science and Technology of China and Xu Lin of the Chinese Academy of Sciences revealed the mechanism of adolescent depression caused by early inflammation activation
.
Mice on the 14th day after birth (the critical period of development, P14) were injected with LPS to simulate an early inflammatory response, and they exhibited depression-like behavior during adolescence (day 45)
.
Immunofluorescence showed that the number and activity of microglia in the cingulate cortex (ACC) brain area increased after LPS stimulation
.
After the injection of LPS during the critical period of development, the colony-stimulating factor receptor inhibitor (to clear microglia) was injected intraperitoneally on the 21st day after birth, and it was found that these adolescent mice that experienced early inflammatory stimulation did not develop depression-like behaviors
.
This indicates that the inflammatory response mediated by microglia mediates depression-like behavior in adolescent mice
.
Immunofluorescence experiments further found that the activation of glutamatergic neurons in the ACC brain area of adolescent mice after early LPS stress was reduced.
Fiber-optic calcium imaging records also found that the calcium ion activity of glutamatergic neurons in the ACC brain area was also reduced.
Photon calcium imaging also further confirmed the reduction of the above-mentioned neuronal activity in young mice after early inflammatory stress
.
Researchers found that activating glutamatergic neurons in the ACC brain region did not exhibit depression-like behavior in adolescent mice even if they experienced inflammatory activation during development
.
Normal mice also showed depression-like behavior after inhibiting this type of neuron
.
These results indicate that the low activity of glutamatergic neurons in the ACC brain region is the key basis for causing depressive behavior in adolescent mice
.
The dendritic spine density in the ACC brain area of the adolescent mice after early LPS stress decreased, and the small excitatory postsynaptic current decreased
.
Two-photon microscopy found that the rate of disappearance and formation of dendritic spines in this brain area were more than three times that of the control group
.
These results indicate that the early LPS stress causes the disorder of synaptic plasticity in the ACC brain area, and this disorder can exist for a long time
.
In addition, the contact between microglia and neuron dendrites increased after early LPS stress, and more specifically, the phagocytic synapses of microglia increased
.
After selectively inhibiting the activity of microglial cells, the above-mentioned phagocytic function is weakened
.
Single-cell sequencing technology found that the expression of Cx3cr1 was significantly increased in LPS-stressed mice
.
Previous studies have shown that after knocking out Cx3cr1, mice have abnormal synaptic pruning, functional connectivity disorders, and social disorders
.
The researchers used the AAV virus in combination with Cx3cr1-cre mice to specifically knock out Cx3cr1 on microglia and can reverse the depression-like behavior disorder caused by LPS, accompanied by the restoration of neuronal function and morphology: ACC brain neuronal activity Increase, dendritic spine density, small excitatory postsynaptic current increase
.
After the mice were overexpressed Cx3cr1 through the virus-specific overexpression of Cx3cr1 just after birth, the mice showed depression-like behavior on the 45th day.
At the same time, the activity of neurons in the ACC brain area decreased, the activity of microglia increased, and the phagocytic synapses increased.
Dendritic spine density decreases, and tiny excitatory postsynaptic currents decrease
.
This means that early inflammatory stress promotes Cx3cr1-mediated microglia to phagocytize synapses and cause depression-like behaviors
.
In summary, this article reveals that the activation of inflammation in the developmental phase leads to low neuronal activity in the ACC brain region, increased synapses in the brain region phagocytosed by microglia, and eventually depression-like behaviors
.
[References] 1.
https://doi.
org/10.
1016/j.
neuron.
2021.
06.
012 The pictures in the article are all from the references
Knudson put forward the famous second-hit hypothesis of tumorigenesis in 1971.
He believed that the first mutation occurred in germ cells, and the second mutation occurred in somatic cells after birth
.
The second-strike hypothesis is also applicable to neuropsychiatric diseases such as depression and autism
.
Early inflammation has a lasting and profound impact on the development of the central nervous system, and there may be behavioral changes in adulthood
.
The model can be simplified as follows: the first blow: inflammatory damage in the early developmental stage may cause abnormal neuronal plasticity through excessive synaptic pruning or microglia activation; the second blow: stress can promote or inhibit this effect.
Resulting in changes in behavior
.
On July 7, 2021, the joint research team of Zhang Zhi, Jin Yan and Xu Lin of the Department of Life Sciences and Medicine of the University of Science and Technology of China and Xu Lin of the Chinese Academy of Sciences revealed the mechanism of adolescent depression caused by early inflammation activation
.
Mice on the 14th day after birth (the critical period of development, P14) were injected with LPS to simulate an early inflammatory response, and they exhibited depression-like behavior during adolescence (day 45)
.
Immunofluorescence showed that the number and activity of microglia in the cingulate cortex (ACC) brain area increased after LPS stimulation
.
After the injection of LPS during the critical period of development, the colony-stimulating factor receptor inhibitor (to clear microglia) was injected intraperitoneally on the 21st day after birth, and it was found that these adolescent mice that experienced early inflammatory stimulation did not develop depression-like behaviors
.
This indicates that the inflammatory response mediated by microglia mediates depression-like behavior in adolescent mice
.
Immunofluorescence experiments further found that the activation of glutamatergic neurons in the ACC brain area of adolescent mice after early LPS stress was reduced.
Fiber-optic calcium imaging records also found that the calcium ion activity of glutamatergic neurons in the ACC brain area was also reduced.
Photon calcium imaging also further confirmed the reduction of the above-mentioned neuronal activity in young mice after early inflammatory stress
.
Researchers found that activating glutamatergic neurons in the ACC brain region did not exhibit depression-like behavior in adolescent mice even if they experienced inflammatory activation during development
.
Normal mice also showed depression-like behavior after inhibiting this type of neuron
.
These results indicate that the low activity of glutamatergic neurons in the ACC brain region is the key basis for causing depressive behavior in adolescent mice
.
The dendritic spine density in the ACC brain area of the adolescent mice after early LPS stress decreased, and the small excitatory postsynaptic current decreased
.
Two-photon microscopy found that the rate of disappearance and formation of dendritic spines in this brain area were more than three times that of the control group
.
These results indicate that the early LPS stress causes the disorder of synaptic plasticity in the ACC brain area, and this disorder can exist for a long time
.
In addition, the contact between microglia and neuron dendrites increased after early LPS stress, and more specifically, the phagocytic synapses of microglia increased
.
After selectively inhibiting the activity of microglial cells, the above-mentioned phagocytic function is weakened
.
Single-cell sequencing technology found that the expression of Cx3cr1 was significantly increased in LPS-stressed mice
.
Previous studies have shown that after knocking out Cx3cr1, mice have abnormal synaptic pruning, functional connectivity disorders, and social disorders
.
The researchers used the AAV virus in combination with Cx3cr1-cre mice to specifically knock out Cx3cr1 on microglia and can reverse the depression-like behavior disorder caused by LPS, accompanied by the restoration of neuronal function and morphology: ACC brain neuronal activity Increase, dendritic spine density, small excitatory postsynaptic current increase
.
After the mice were overexpressed Cx3cr1 through the virus-specific overexpression of Cx3cr1 just after birth, the mice showed depression-like behavior on the 45th day.
At the same time, the activity of neurons in the ACC brain area decreased, the activity of microglia increased, and the phagocytic synapses increased.
Dendritic spine density decreases, and tiny excitatory postsynaptic currents decrease
.
This means that early inflammatory stress promotes Cx3cr1-mediated microglia to phagocytize synapses and cause depression-like behaviors
.
In summary, this article reveals that the activation of inflammation in the developmental phase leads to low neuronal activity in the ACC brain region, increased synapses in the brain region phagocytosed by microglia, and eventually depression-like behaviors
.
[References] 1.
https://doi.
org/10.
1016/j.
neuron.
2021.
06.
012 The pictures in the article are all from the references
