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The integrated stress response (ISR) is a highly conservative biological process that regulates protein synthesis and participates in the process of long-term memory by regulating synaptic plasticity.
Animal experiments have shown that ISR inhibitors can enhance learning and memory.
Under healthy conditions, the ISR signal is activated by the phosphorylation state of eukaryotic initiating factor 2α (eIF2a), which has the effect of promoting survival and development.
Because eIF2a phosphorylation itself is short-lived, it is difficult to quickly capture ISR signaling events in a very short time.
On April 23, 2021, the Nicole Calakos research team of the Department of Neurology of Duke University Medical Center published an article in Science and developed a two-color ISR signal reporting system SPOTlight: red when the ISR is activated, and green when the ISR is inactive.
The technology revealed the existence of high levels of ISR in striatal cholinergic neurons.
Schematic diagram of SPOTlight reporting system.
Researchers insert green and red fluorophores into different but overlapping reading frames (part of DNA or RNA), and fused the red fluorescent protein into the start codon of activating transcription factor 4 (ATF4).
When ISR When activated, the protein begins to be transcribed and expressed after a high degree of eIF2a phosphorylation; fusion of green fluorescent protein in the upstream open reading frame (uORF2), the protein begins to be transcribed and expressed when the level of eIF2a phosphorylation is low.
Through such conversion of red and green fluorescent proteins, the state of ISR activation can be observed in real time, which is called SPOTlight reporting system.
They further encapsulated the SPOTlight plasmid in the AAV viral vector.
The distribution of ISR responses in the whole brain.
Researchers have found that green fluorescent protein is more expressed in the whole brain of mice, and red fluorescence is slightly expressed in hippocampal pyramidal neurons, cerebellar Purkinje cells, and striatal cholinergic neurons.
protein.This indicates that ISR has occurred in these areas.
In addition, striatal cholinergic neurons expressing red fluorescent protein are not randomly distributed.
The typical feature of striatal cholinergic neurons is tonic action potential discharge.
In order to further confirm whether the discharge activity of cholinergic neurons in the striatum is a molecular event that induces ISR, they injected the chemo-suppressive virus AAV-hM4Di-mCherry into the striatum of ChAT-Cre mice and found that the chronically inhibited The phosphorylation level of eIF2a is significantly reduced after type neurons, which indicates that striatal cholinergic neurons are involved in the activation of ISR.
Previous studies have shown that ISR is involved in the long-term inhibitory effect of striatal projection neurons, and dopamine type 2 receptor signaling (D2R) can instantaneously reduce the action potential of cholinergic neurons.
In vitro brain slice experiments found that the incubation of ISR inhibitors can significantly reverse the inhibitory effect of D2R on the tonic action potential discharge activity of cholinergic neurons.
The reduction of CReP (the regulatory subunit in the eIF2a phosphatase complex) causes the continuous phosphorylation of eIF2a.
In order to achieve ISR that specifically affects cholinergic neurons in the striatum, the researchers constructed the AAV-DIO-CReP virus to specifically promote the expression of CReP on cholinergic neurons in the striatum, and the ISR is inactivated and destroyed.
The physiological regulation of D2R on cholinergic neurons.
This further indicates that the activation state of ISR of cholinergic neurons in the striatum can change the function of D2R on the discharge activity of cholinergic neurons.
After the researchers inhibited the ISR of cholinergic neurons in the striatum, the mice found the hidden platform faster in the water maze experiment.
In the experiment of training pressing levers to obtain food rewards, after inhibiting ISR, mice pressed the levers more times and obtained more food.
These behavioral experiments show that the inhibition of ISR of cholinergic neurons in the striatum can enhance learning and memory.
In general, this article uses SPOTlight technology to find that there is a stable ISR activation state in the striatum of the brain.
After inhibiting ISR, it can eliminate the inhibitory effect of D2R on the discharge activity of cholinergic neurons and enhance the learning and memory function.
[References] 1.
https://doi.
org/10.
1126/science.
abe1931 The pictures in the article are all from the references
The integrated stress response (ISR) is a highly conservative biological process that regulates protein synthesis and participates in the process of long-term memory by regulating synaptic plasticity.
Animal experiments have shown that ISR inhibitors can enhance learning and memory.
Under healthy conditions, the ISR signal is activated by the phosphorylation state of eukaryotic initiating factor 2α (eIF2a), which has the effect of promoting survival and development.
Because eIF2a phosphorylation itself is short-lived, it is difficult to quickly capture ISR signaling events in a very short time.
On April 23, 2021, the Nicole Calakos research team of the Department of Neurology of Duke University Medical Center published an article in Science and developed a two-color ISR signal reporting system SPOTlight: red when the ISR is activated, and green when the ISR is inactive.
The technology revealed the existence of high levels of ISR in striatal cholinergic neurons.
Schematic diagram of SPOTlight reporting system.
Researchers insert green and red fluorophores into different but overlapping reading frames (part of DNA or RNA), and fused the red fluorescent protein into the start codon of activating transcription factor 4 (ATF4).
When ISR When activated, the protein begins to be transcribed and expressed after a high degree of eIF2a phosphorylation; fusion of green fluorescent protein in the upstream open reading frame (uORF2), the protein begins to be transcribed and expressed when the level of eIF2a phosphorylation is low.
Through such conversion of red and green fluorescent proteins, the state of ISR activation can be observed in real time, which is called SPOTlight reporting system.
They further encapsulated the SPOTlight plasmid in the AAV viral vector.
The distribution of ISR responses in the whole brain.
Researchers have found that green fluorescent protein is more expressed in the whole brain of mice, and red fluorescence is slightly expressed in hippocampal pyramidal neurons, cerebellar Purkinje cells, and striatal cholinergic neurons.
protein.This indicates that ISR has occurred in these areas.
In addition, striatal cholinergic neurons expressing red fluorescent protein are not randomly distributed.
The typical feature of striatal cholinergic neurons is tonic action potential discharge.
In order to further confirm whether the discharge activity of cholinergic neurons in the striatum is a molecular event that induces ISR, they injected the chemo-suppressive virus AAV-hM4Di-mCherry into the striatum of ChAT-Cre mice and found that the chronically inhibited The phosphorylation level of eIF2a is significantly reduced after type neurons, which indicates that striatal cholinergic neurons are involved in the activation of ISR.
Previous studies have shown that ISR is involved in the long-term inhibitory effect of striatal projection neurons, and dopamine type 2 receptor signaling (D2R) can instantaneously reduce the action potential of cholinergic neurons.
In vitro brain slice experiments found that the incubation of ISR inhibitors can significantly reverse the inhibitory effect of D2R on the tonic action potential discharge activity of cholinergic neurons.
The reduction of CReP (the regulatory subunit in the eIF2a phosphatase complex) causes the continuous phosphorylation of eIF2a.
In order to achieve ISR that specifically affects cholinergic neurons in the striatum, the researchers constructed the AAV-DIO-CReP virus to specifically promote the expression of CReP on cholinergic neurons in the striatum, and the ISR is inactivated and destroyed.
The physiological regulation of D2R on cholinergic neurons.
This further indicates that the activation state of ISR of cholinergic neurons in the striatum can change the function of D2R on the discharge activity of cholinergic neurons.
After the researchers inhibited the ISR of cholinergic neurons in the striatum, the mice found the hidden platform faster in the water maze experiment.
In the experiment of training pressing levers to obtain food rewards, after inhibiting ISR, mice pressed the levers more times and obtained more food.
These behavioral experiments show that the inhibition of ISR of cholinergic neurons in the striatum can enhance learning and memory.
In general, this article uses SPOTlight technology to find that there is a stable ISR activation state in the striatum of the brain.
After inhibiting ISR, it can eliminate the inhibitory effect of D2R on the discharge activity of cholinergic neurons and enhance the learning and memory function.
[References] 1.
https://doi.
org/10.
1126/science.
abe1931 The pictures in the article are all from the references
