Mol Psychiatry Gao Tianming's group reveals the local neural network mechanism of fear memory fading

Written by Chen Yihua, edited by Chen Yihua, Wang Sizhen Posttraumatic Stress Disorder (PTSD) is an individual suffering from a severe traumatic event that causes long-term and persistent physical and mental disorders [1]
.

Epidemiological studies have found that the lifetime prevalence of PTSD in the general population is 5.
9%-14.
8%[2], and the incidence rate after natural disasters such as earthquakes is as high as 23.
66%[3]
.

In addition, the proportion of patients with comorbid other mental diseases such as depression, drug addiction, and sleep disorders is as high as 80% [4]
.

The main clinical manifestations of PTSD are repeated recurrence of traumatic memories, continuous avoidance of trauma-related clues, negative changes in cognition and mood, and increased alertness [5]; most patients lose their ability to work and live, and give patients themselves and their families , The society has caused a great burden
.

Exposure therapy based on the principle of regression is commonly used clinically to treat PTSD [6], which is a type of treatment that allows patients to be repeatedly exposed to traumatic situations to gradually weaken the traumatic memory
.

However, this treatment method only produces a good effect on 30-70% of PTSD patients [7]
.

Therefore, it is necessary to study the mechanism of traumatic memory loss in PTSD in order to discover new treatment methods
.

 Fear conditioned memory is a classic animal model used to study PTSD
.

In this model, after a non-harmful conditioned stimulus (CS, such as environmental cues or sound cues) is associated with a noxious unconditioned stimulus (US, such as plantar electric shock), CS can induce The body reacts with fear
.

After the establishment of conditioned fear, if only CS is repeatedly presented without presenting US, the ability of CS to cause the body's conditioned fear response will gradually weaken or even be lost.
This process is called the disappearance of fear memory [8]
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This model is often used to explore the biological mechanism of the maintenance and disappearance of fear memories, and provide clues for the elimination of pathological traumatic memories
.

 A large number of studies from animals and humans have consistently confirmed that the medial prefrontal cortex (mPFC) is an important brain area that regulates the loss of fear memory[9,10]
.

The brain, including the emotional and memory systems, is always integrating a large amount of incoming information and making appropriate output.
The function of this complex system depends on the maintenance of the dynamic balance of different neural circuits and networks [11]
.

The neural network is formed by numerous neurons connected through synapses, and the information flow is mainly transmitted by pyramidal neurons in the brain area
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Local inhibitory interneurons, mainly GABAergic neurons, participate in the integration and processing of information by regulating the firing pattern, firing timing, synchronization activity and output of pyramidal neurons [12-16]
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In animal models of conditioned fear memory, mPFC's inhibitory synaptic plasticity changes are involved in regulating the long-term storage of fear memory [17]
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However, the local neural network mechanism of mPFC regulating the fade of fear memory is still unclear
.

 Paralbumin (PV) positive neurons are an important type of GABAergic interneurons[18]
.

In the early stages of development, PV neurons are mainly composed of neurons with low expression of PV protein (low-PV neurons); as the development progresses, low-PV neurons gradually differentiate into neurons with high expression of PV protein (high-PV neurons).
Neuron) [19-21]
.

The latest research has found that in the learning process of adult animals, the local neural network composed of PV neurons in the hippocampus shows obvious changes in plasticity
.

Moreover, participating in the process of regulating learning and memory is a brand-new model of neuroplasticity [22]
.

 On October 26, 2021, Tianming Gao's team from Southern Medical University published a research paper titled "PV Network Plasticity Mediated by Neuregulin1-ErbB4 Signalling Controls Fear Extinction" in Molecular Psychiatry
.

Dr.
Chen Yihua and Dr.
Hu Nengyuan are the co-first authors
.

Research work innovatively found that the local PV neuron network mediated by the neurotonin-1 (NRG1)-ErbB4 signaling pathway in mPFC has long-term plasticity (lasting> 48 h), breaking the traditional belief that the NRG1-ErbB4 pathway The old view that the regulation of neuronal activity only has an acute effect (lasting <a few minutes) reveals the new function of the NRG1-ErbB4 pathway; further analyzes the plastic changes of the PV neuron network through the mPFC long-projection neural circuit (mPFC- The basal medial amygdala circuit) regulates the fading of fear memories
.

This study reveals the local molecular network mechanism of mPFC-mediated "top-down" regulation of fear memory fading
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(Extended reading: The latest research of Gao Tianming's group, see "Logical Neuroscience" report for details: Mol Psychiatry︱ Gao Tianming's group reveals the different roles of astrocytes and neurons in synaptic plasticity and memory; JCI︱Tianming’s research team revealed that the prefrontal cortex has an opposite role in regulating anxiety and fear.
The mPFC is composed of the prelimbic cortex (PL) and the infralimbic cortex (IL)
.

The researchers found that the disappearance of fear memory can induce the PV neuron network in the IL brain area of ​​adult mice to shift to a pattern of increased low-PV and reduced high-PV; but it does not affect the composition of the PV neuron network in the PL brain area
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Glutamate decarboxylase 67 (GAD67) is a key enzyme in GABA synthesis, and its expression level affects the level of GABA synthesis
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The results of the study show that the PV fluorescence intensity of a single PV neuron is highly positively correlated with the GAD67 fluorescence intensity, suggesting that the plasticity change of the PV neuron network in the IL brain area is a functional change
.

Further research found that although fear memory fading training does not change the total number of PV neurons, it leads to long-term plasticity changes in the PV neuron network, which is manifested in the fact that the PV neuron network goes high and low- from the second to the sixth day of the fading training.
PV, low high-PV conversion (Figure 1)
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Figure 1 Fear memory fading induces changes in low-PV network plasticity in IL brain regions (Source: Chen et al.
, Molecular Psychiatry, 2021) Manipulating PV neuron network plasticity through chemical genetics and pharmacological methods can regulate the fading of fear memory Process (Figure 2)
.

These results suggest that changes in the plasticity of the PV neuron network in the IL brain area may be a key neural network mechanism that regulates the decline of fear memory
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Figure 2 Continuous low-PV plasticity changes in the IL brain area are necessary for the disappearance of fear memories (Source: Chen et al.
, Molecular Psychiatry, 2021) In order to detect the molecular mechanism that the disappearance of fear memories induces changes in the plasticity of PV neuronal networks The researchers tested 8 molecules that regulate the differentiation and maturation of PV neurons, and found that the expression level of NRG1 increased during the fading process of fear memory, and the time window was consistent with the changes in the plasticity of the PV neural network; the mouse IL brain area was given Exogenous NRG1 can induce the transformation of PV neuron network to high low-PV, while giving ecto-ErbB4 to neutralize endogenous NRG1 has the opposite effect
.

Previous studies have shown that NRG1 mainly acts on PV neurons through ErbB4 receptors [23-25]
.

Therefore, the researchers further knocked out the ErbB4 receptor on PV neurons, and the results showed that the high-PV ratio of PV-Cre; ErbB4f/f mice increased significantly (Figure 3)
.

These results indicate that NRG1-ErbB4 can regulate the plasticity of the PV neuron network in the IL brain area
.

Figure 3 The NRG1-ErbB4 signaling pathway regulates changes in PV neural network plasticity (Source: Chen et al.
, Molecular Psychiatry, 2021).
Researchers have further found that the brain area NRG1 is neutralized or knocked down on IL and knocked down or knocked down on PV neurons.
The ErbB4 receptor impairs the disappearance of fear memories; the exogenous increase of IL NRG1 facilitates the disappearance of fear memories
.

These results indicate that the IL brain area NRG1-ErbB4 can regulate the fade of fear memory (Figure 4)
.

Figure 4 The NRG1-ErbB4 signaling pathway regulates the fading of fear memory (Source: Chen et al.
, Molecular Psychiatry, 2021) So does NRG1 signal regulate the fading of fear memory by regulating the plasticity of the PV neuron network? While giving exogenous NRG1 to the IL brain area, the researchers used chemical genetics to interfere with the transformation of local PV neuronal network plasticity to low-PV mode, and found that NRG1's regulatory effect on PV neural network plasticity was blocked, and at the same time The facilitating effect on the fading of fear memories is also blocked
.

In the same way, the combined use of ecto-ErbB4 and chemical genetics method for reverse verification further confirmed that the NRG1 signal regulates the decline of fear memory by regulating the plasticity of the PV neuron network (Figure 5)
.

Figure 5 NRG1 signal regulates the decline of fear memory by adjusting the plasticity of PV neural network (source: Chen et al.
, Molecular Psychiatry, 2021).
According to the literature, the basal medial amygdala (BMA) is the downstream target brain of mPFC Area, activating the mPFC neurons projected to the BMA facilitates the disappearance of fear memories [26]
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Therefore, the researchers further explored whether IL neurons projected to BMA depend on PV neuron plasticity to regulate the fading of fear memories
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The researchers found that at 1.
5 h and 10 h after the fear memory faded, the IL neurons projected to the BMA were activated, which was consistent with the change in the plasticity of the PV neural network after the fade
.

Using chemical genetics, it was found that after the fear memory fades, the transformation of the plasticity of the PV neuron network is prevented, the IL neurons projected to the BMA are no longer activated, and the fear memory does not fade further
.

These results indicate that the long-term plasticity of the local PV neuron network of mPFC affects the fading of fear memory by regulating the long-projection neural circuit (Figure 6)
.

Figure 6 The long-term plasticity of the local PV neuron network of mPFC affects the fading of fear memory by regulating the long-projection neural circuit (Source: Chen et al.
, Molecular Psychiatry, 2021).
Conclusion and discussion of the article, inspiration and prospects for this research The findings are consistent with earlier reports that the plasticity of IL brain regions is important for the disappearance of fear memories [27,28]
.

In order to clarify the local neural network mechanism of IL brain area regulating the loss of fear memory, the researchers used the method of 24 hours between two subsidence trainings and found that the PV neural network was reconstructed after the subsidence training, and this change was dependent on the NRG1-ErbB4 signal.
Access
.

The reconstruction of PV neural network can be observed 6 hours after subtraction, and this change lasts to 48 hours.
This is the time window of the memory consolidation process, which is consistent with the view that memory consolidation may involve local neural network activities[29,30]
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 It is worth noting that through the analysis of previous single-cell sequencing data, it is found that the differentially expressed genes of high-PV neurons are involved in ion transport, vesicle-mediated transport, and GABAergic synaptic transmission; and low-PV neurons Differentially expressed genes are involved in the transport of calcium ions across the membrane and the development of the nervous system, indicating that high-PV neurons are mature cells, while low-PV neurons are immature cells [31,32]
.

The researchers analyzed the gene expression in PV neurons of control mice and regression mice.
Neurons in the regression group contained a greater proportion of low-PV neurons and showed molecular characteristics consistent with low-PV neurons
.

Since the neurons in the regression group are still a mixed population of low-PV neurons and high-PV neurons, the genes changed during the regression learning may also be related to processes other than the plasticity of low-PV neurons
.

This requires further development of new technologies to separate low-PV neurons and high-PV neurons to confirm this conclusion
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 The expression of NRG1 is regulated by neuronal activity [33-35]
.

The increased neuronal activity (1.
5 h c-Fos peak) in IL induced by the disappearance of fear memory may stimulate the expression of NRG1
.

NRG1 is widely expressed in pyramidal neurons, interneurons, astrocytes and microglia [36-38]
.

At the same time, NRG1 has different regions, including hippocampus and amygdala [39-41], these two brain regions are the input regions of mPFC [42,43]
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It is worth noting that the input of the hippocampus or amygdala to mPFC is essential for fear-related behaviors [44-46]
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Future research needs to explore whether the plasticity of the PV network depends on the endogenous NRG1 in the IL cortex or its input at the loop level
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 Previous work has shown that neutralizing NRG1 and inhibiting or knocking out ErbB4 receptors can reduce GABAergic transmission [47]
.

NRG1 activates ErbB4, increases GABAA receptor-mediated synaptic current [48] and enhances depolarization-induced GABA release [40]
.

These results indicate that NRG1-ErbB4 signaling plays a role in the acute enhancement of GABAergic activity
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Interestingly, the study found that NRG1 induced a sustained low-PV mode, while neutralizing endogenous NRG1, knocking down NRG1, or knocking out ErbB4 in PV neurons produced the opposite transition
.

Low-PV neurons represent the immature state of PV neurons and exhibit diminished functional output
.

Therefore, this study is the first to prove that the NRG1-ErbB4 pathway has a lasting effect (at least 48 hours), which can continuously regulate local GABAergic activity, revealing the new role of NRG1-ErbB4 signaling in the mature brain.
In short, the study found that the previously unknown The molecular and local neural network mechanisms of mPFC-mediated top-down regulation of fear subsidence
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The study found that the continuous plasticity of the local PV neuron network in IL is necessary for the fear subsidence of adult mice, which is mediated by the NRG1-ErbB4 signal
.

In addition, the adjustment of the IL neurons that project BMA to fear subsidence depends on the composition of the PV neuron network.
These findings provide a new theoretical basis for the treatment of mental diseases such as PTSD
.

Original link: https://doi.
org/10.
1038/s41380-021-01355-z Selected previous articles [1] Nat Commun | Working memory representation of the visual cortex regulates the effect of distracting attention [2] Science | Breakthrough! Immune CD4+ T cells are involved in the disease process of Lewy body dementia [3] Cell Rep︱ new research reveals the role of hypothalamic neuronal calcium homeostasis regulators in the formation of obesity [4] Science︱ first confirmed in humans: multiple neurodegeneration Sexual diseases can affect the neurogenesis of the hippocampal dentate gyrus [5] Neuron︱ new discovery! The hippocampus playback in the awake state promotes memory function by storing and updating specific past experiences [6] Mol Psychiatry︱ A new discovery of biomarkers for depression-mitochondrial proteins in exosomes [7] Science | Breakthrough! Astrocyte Ca2+ induces ATP release to regulate myelin axon excitability and conduction velocity [8] Neurosci Bull︱Shen Ying’s team reveals the three-dimensional heterogeneity of the cerebellar nucleus to thalamus projection [9] J Neurosci︱ Cao Junli’s group Revealing the loop mechanism of the anterior cingulate gyrus to regulate mirror pain [10] Nat Commun︱Non-human primate (monkey marmoset) autism model Revealing biological abnormalities in the early development of human diseases High-quality scientific research training courses recommended [1] Discount Countdown ︱ EEG data analysis introductory class (online: 2021.
12.
4~12.
16) [2] Discount countdown︱ Near-infrared brain function data processing class (online: 11.
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Arlington, V.
271-280 (American Psychiatric Publishing, 2013) 2.
Atwoli, L.
, Stein, DJ, Koenen, KC & McLaughlin, KA Epidemiology of posttraumatic stress disorder: prevalence, correlates and consequences.