Nat Commun—Xu Tianle/Li Weiguang/Zhang Siyu teamwork reveals the neuronal cluster organization patterns in which fear and regression memory compete with each other

Written by Wang Qi, Li Weiguang

Responsible editor - Wang Sizhen

Editor—Natsuba

As a basic, stable, cross-species conserved emotional memory, fear memory is the memory of an organism's experience of reacting violently defensively to danger or threats, and is necessary for early warning of threats and adaptation to the environment[1].

However, dangers or threats do not always exist, and the physiological process of an organism inhibiting the regulation of pre-existing fear memories to achieve benefits and avoidance is called fear regression
.
A new memory formed in the process of fear fading against and confrontation with inherent fear memory, called regression memory, and the balance and coordinated expression between fear memory and fear memory are the fundamental guarantee for the body to maintain moderate vigilance and respond to changes in the surrounding complex environment according to local conditions[2].

In terms of neural mechanism, fear regression is an ideal research model
for characterizing the dynamic regulation of fear memory and the interaction between different memories.
In terms of translational applications, fear regression is an effective treatment for
correcting affective disorders at the cognitive level.
Exposure therapy for post-traumatic stress disorder (PTSD) and anxiety disorders, commonly used in clinical treatment, is a vivid example of the theory of fear regression in medical practice, with some patients showing a significant reduction in pathological emotional symptoms after treatment [3].

。 By focusing on the neurobiological mechanisms of fear regression, Xu Tianle's team in 2018 characterized the dynamic adaptability of long-range neural loop projection synapses accompanied by regression learning from the ventral hippocampus (vHPC) to the medial prefrontal cortex (mPFC), and identified its molecular driving mechanism[4].
In 2021, in response to the major "pain point" problem of the refractory and recurrence of fear affective disorder, Xu Tianle's team revealed the key neural mechanisms of recurrence after fear memory fading, and revealed the scene dependence of fear regression-reproduction transformation and the synaptic integration law of sensory input union in the fear memory center, the amygdala[5]; In 2022, for the blotting basis of regressive memory, a regressing memory imprinting neural network centered on mPFC was discovered, revealing the dynamic change of imprinted neural connection strength across brain regions, and providing neurobiological evidence for understanding the behavioral characteristics of regressive memory vulnerability[6].

However, in terms of neural circuit organization rules, how the body chooses fear memory and regression memory to express[7], in other words, the neuronal cluster organization law of the competition between fear and regression memory is still an unresolved key scientific question
.

According to the basic law of distributed split storage of the whole brain [8], although fear memory and regressive memory have high overlap in storing brain regions and neural circuits, due to the completely different behavioral performance of triggering clues for the same dangerous event, it shows that the two use unique clusters of neurons to encode and process
completely opposite behaviors respectively 。 In past studies, taking the fear center-amygdala as an example, two types of neurons, namely "fear neuron" and "extinction
neuron," have been defined based on the different responses of basal-lateral amygdala (BLA) neurons to conditional sound cues during fear memory and fear regression 。 Among them, "fear neurons" respond to conditioned stimulus (CS) that does not subside, corresponding to the fear behavior caused by CS; "Regression neurons," on the other hand, respond to regressed CS, corresponding to the "no fear" (i.
e.
, regression) behavior triggered by CS [8].

Further studies have found that the two types of neurons in BLA have different functional and anatomical projections [10].

The researchers also used memory-blotting cell labeling methods based on neuroactive cell populations (TRAP) to identify clusters of "regressing neurons" with specific molecular markers in the BLAs [11].

Unfortunately, there is no direct evidence of a correspondence between these two clusters of fear-regressing neurons that rely on neural loop projection and molecular marker definitions, respectively, and further research
is needed.
These studies conceptually demonstrate that fear memory and regressive memory use unique clusters of neurons to encode and process completely opposite behaviors, respectively, but these characteristic clusters of neurons still need to be carefully and adequately identified
.
Therefore, unbiased labeling, identification, and analysis of the function and mechanism of action of these neuronal clusters on a brain-wide scale is an important way to understand the interaction between fear and regressive memory competition to
reveal the mechanism of complex cognitive function in the brain.

The insular cortex (IC), which is essential for handling disgusting and rewarding stimuli and coordinating adaptive behavioral responses, is a potential regulatory center for fear memory and regressive memory [12].

Compared to the function of the amygdala, it has been proposed that ICs play a key role in regulating the introduction of subjective sensations into cognition and motivation [13], but their role in fear memory and regression memory remains controversial [14].

Notably, a recent study showed that ICs maintain a balance of fear by integrating information from the body to regulate fear emotions in both directions [15].

However, at the level of neuronal clusters characteristic of memory, the rules of neural circuit organization of ICs encoding fear memory and regressive memory, respectively, are unclear
.

On September 21, 2022, the team of Professor Xu Tianle and Zhang Siyu of the School of Basic Medical Sciences of Shanghai Jiao Tong University and the Children's Brain Science Center of the National Children's Medical Center (Shanghai) cooperated with Li Weiguang, a researcher at the Institute of Brain Science Transformation of Fudan University, to publish an executive gateway to decipher online in Nature Communications threat or extinction memory via distinct subcortical pathways" research paper
.
Dr.
Qi Wang and Jiajie Zhu of Shanghai Jiao Tong University School of Basic Medicine are co-first authors
.
In this study, using a variety of technical means such as behavior, neural loop tracing, neural activity capture in situ markers, optogenetics, electrophysiology, and in vivo optical fiber recording, the neuronal clusters that characterize fear memory and regression memory are found in the insular cortex of the brain to characterize fear memory and regression memory in a variety of technical means, and to illustrate the neural circuit organization rules of the two memory neuron clusters at different levels such as "intercortical - intracortical - subcortic".
In order to understand the one-click switch between fear memory and regressive memory, improve the understanding of the nature of memory complexity, and also lay a theoretical foundation
for the development of new strategies for precise intervention in mental disorders such as anxiety disorders and post-traumatic stress disorder.
(Further reading: The latest research results of the Xu Tianle / Li Weiguang team, see the "Logical Neuroscience" report (click to read): Mol Psychiatry - Li Weiguang/Xu Tianle / Jiang Fan teamwork to reveal the dynamic imprinting network mechanism of fear fading to form new memories )

To identify whether ICs are distributed with clusters of neurons with fear memory and regressed memories, the researchers used TRAP2 transgenic mice to inject Cre-dependent adeno-associated virus (AAV) AAV-DIO-mCherry at the IC site to achieve memory neuron markers
in this brain region.
After the virus is fully expressed, the mice are trained to have conditioned fear learning or regression to mark fear memory or regression memory neurons
, respectively.
When tagging fear memory neurons, after conditional fear training, intraperitoneal injection of 4-hydroxytamoxifen (4-OHT) was injected to mark IC neurons activated during fear memory acquisition, control mice only received sound stimulation and injected 4-OHT, and the two groups of mice perfused c-fos after memory extraction to observe the number and distribution
of IC-activated neurons 。 When labeling regressive memory neurons, mice in the regression memory group were injected intraperitoneally with 4-OHT after the end of the second day of regression training, mice in the fear extraction group as a control were injected with 4-OHT intraperitoneally after only two sound stimulations, and the sound cue group as another control received only sound stimulation and 4-OHT throughout the whole process, and after memory retrieval, the number and distribution
of IC-activated neurons were observed.
The researchers found that IC neurons activated during fear memory acquisition were reactivated during fear memory retrieval, and that fear memory-related IC neurons were mainly distributed in the anterior island cortex
.
In addition, regressive memory-activated IC neurons are reactivated during regressive memory retrieval, and regression memory-related IC neurons are also concentrated in the anterior island cortex (Figure 1
).
These results suggest that ICs are the potential storage center
for fear and regression memories.

Figure 1 Localization distribution of fear memory and regression memory neurons in the insecticular cortex

(Source: Wang, et al.
, Nat Commun, 2022)

The researchers examined whether ICs were necessary
to extract fear memories or fade memories by inhibiting the function of these underlying memory neurons during memory retrieval.
Using the memory neuron labeling strategy described earlier, the researchers expressed Cre-dependent NPHR in ICs and then performed optogenetic inhibition experiments
.
Studies have found that optogenetics inhibits fear memory neurons in ICs, significantly reducing fear responses during the fear memory retrieval phase; In contrast, regressive memory neurons that inhibit ICs significantly impair the extraction of regressive memory, which is manifested by an increase in fear response after regression (Figure 2
).
The results showed that TRAP-tagged IC fear memory and regressive memory neurons played a necessary role
in fear memory and regressive memory retrieval, respectively.

Fig.
2 Functional identification of fear memory and regression memory neurons in the insula cortex (Source: Wang, et al.
, Nat Commun, 2022)
In order to identify the physical distribution of fear memory and regression memory neuron clusters in IC, researchers compared the co-standard of
fear neurons and regressive memory neurons.
Using the memory neuron labeling strategy described earlier, the researchers expressed mCherry in IC neurons activated during the fear memory acquisition phase, perfusion staining c-fos
after fear memory or regression memory extraction.
It was found that fear memory-related IC neurons were reactivated during the fear memory retrieval phase; Conversely, the fear memory-related IC neurons and the regressive memory retrieval activated IC neurons do not overlap to a large extent, indicating that the two are independent clusters
of neurons.
In addition, with the help of fluorescently labeled viruses with axon-enhanced expression, the researchers found that fear memory-related IC neurons were more directed towards the central amygdala (CeA) brain region, while regressive memory-related IC neurons were more directed towards the nucleus accumbens (NAc) brain region (Figure 3).

。 Based on the characteristic neural projection patterns of IC memory neurons, the researchers used neural projection loop tracing techniques to identify IC neurons projected to CeA or NAc, respectively, as two isolated clusters (i.
e.
, clusters of IC-CeA and IC-NAc-projected neurons), consistent
with previous reports [14].
To this end, the researchers further analyzed the role
of these two groups of neurons in fear memory and regression memory.

Fig.
3 Anatomical separation of insula cortex fear memory and regressive memory neurons (Source: Wang, et al.
, Nat Commun, 2022)
To study the function of IC-CeA and IC-NAc projection neuron clusters, researchers monitored the activity changes of
these neurons in fear and regression memory-related behaviors by in-vivo fiber recording 。 The study found that for IC-CeA projection neurons, the response of mice to sound cues gradually increased during fear memory acquisition; After regression training, the response of IC-CeA projected neurons to sound cues was also weakened after the mice had a reduced fear of sound cues, suggesting that IC-CeA projected neurons encoded fear memories
.
For IC-NAc-projected neurons, there was no significant change in the response of mice to sound cues during fear memory acquisition, whereas after mice acquired regressive memory, the response of IC-NAc projected neurons to sound cues was enhanced (Figure 4), indicating that IC-NAc projected neuron encoding regression memory
.

Fig.
4 Activity characteristics of two groups of projected neurons in the insula cortex in the stages of fear memory and regression memory (Source: Wang, et al.
, Nat Commun, 2022)
In order to clarify the behavioral significance of the two groups of IC-projected neurons, the researchers conducted functional loss and functional acquisition experiments
。 The researchers projected neuronal clusters in IC-CeA and IC-NAc, expressing Cre-dependent tetanus toxin (TetTox), respectively, to deactivate the transmitter release ability of specific IC neuron clusters, and found that the inactivated IC-CeA projected neuron clusters blocked the learning process of fear memory, which was manifested as fear memory being difficult to form and less fear in the memory extraction stage; The inactivation IC-NAc projected a cluster of neurons, which did not affect the learning process of fear memory, but significantly hindered the regression memory, which was manifested as a decrease in the conditional fear response caused by regression training
.
Instead, the researchers found that the activation of IC-CeA projected neurons using moderate shock intensity as an unconditioned stimulus (US) stage of fear memory learning promotes the formation of fear memories by using moderate shock intensity as an unconditioned stimulus (US); Activating IC-NAc-projected neurons during the regression training phase significantly promotes the formation of regressive memory (Figure 5
).
These experimental results suggest that IC-CeA and IC-NAc projected neurons play a key role
in fear memory and regressive memory, respectively.

Figure 5 Effects of bidirectional manipulation of two groups of projection neurons in the insula cortex on fear memory and regression memory (Source: Wang, et al.
, Nat Commun, 2022)
In order to further understand how fear memory and regression memory specifically recruit different projection neurons of ICs, The researchers went on to identify the intrinsic electrophysiological properties of IC-CeA and IC-NAc projected neurons and the potential role
of microloops between them in the regulation of memory-dependent behavior.
In terms of intrinsic physiological properties, the researchers found that IC-CeA responsible for fear memory projected higher excitability in the basal state of neurons, providing supporting evidence
for understanding the firmness of negative emotions associated with fear memories.
More interestingly, there is also a memory-behavior-dependent interaction between IC-CeA and IC-NAc projected neuron clusters
.
Specifically, in the internal IC loop, after mice learned fear memories, the intensity of excitatory synaptic links projected from IC-CeA to IC-NAc projected neurons was weakened, which was manifested by a significant increase in paired-pulse ratio (PPR) reflecting the ability of presynaptic transmitter release[17].
In addition, the feed-forward inhibition intensity (i.
e.
, IPSC/EPSC ratio) of neurons projected from IC-CeA projection neurons to IC-NAc was significantly increased, which overall indicates that IC-CeA projection neurons responsible for fear memory have increased inhibitory input regulation
on IC-NAc projection neurons responsible for regressing memory.
Instead, after mice underwent regression training, IC-NAc-projected neurons responsible for regressing memory increased inhibitory input regulation to IC-CeA-projected neurons responsible for fear memory (Figure 6).

These results suggest that there is a memory-behavior-dependent interaction inhibition between IC-CeA and IC-NAc projected neuron clusters, which may constitute a neural loop mechanism
for the body to switch positive and negative emotions.

Fig.
6 The internal microloop plasticity mechanism of two groups of projected neurons in the insular cortex to regulate fear memory and regression memory (Source: Wang, et al.
, Nat Commun, 2022)
In order to understand the multi-stage loop regulation law of two groups of projection neurons encoding different memories in the IC cortex, researchers tracked the upper level neurons of the two groups of IC projected neuron clusters in the whole brain with the help of reverse transsingle synaptic tracing technology
。 Studies have found that the frontal cortex responsible for advanced cognitive function (eg, orbitofrontal cortex, OFC)[18] has a stronger
synaptic afferent to IC-NAc responsible for regressing memory by projecting synapses.
Selective activation of OFC→IC neural projection or OFC →IC→ NAc neural circuits, specifically promotes regressive memory (Figure 7).

These results suggest that OFC performs top-down bias control over clusters of IC-specific memory neurons, thereby selectively driving the expression
of specific memories.

Fig.
7 Upstream long-range loop mechanism of insular cortex projection neurons regulating fear-regressing memory (Source: Wang, et al.
, Nat Commun, 2022)

Figure 8 Work summary figure: "Intercortic-intracortic-subcortical" loop organization of
fear and regression memory distributed storage.

(Source: Wang, et al.
, Nat Commun, 2022)

Conclusion and discussion, inspiration and prospects

Through the comprehensive use of cutting-edge techniques in neuroscience, aiming at the neural mechanism of threatening fear memory and safe regression memory coordination and balanced expression, this study found neuronal clusters responsible for characterizing these two opposite memories in the insular cortex of the brain, and explained the neural circuit organization rules of the two memory neuron clusters at different levels such as "intercortical - intracortical - subcortical", in order to understand the interaction and dynamic transformation between different emotional memories.
Raising awareness of the complex nature of emotional memory provides an important theoretical basis
.
Based on this, the researchers propose a working model (Figure 8) to conceptualize the organizing principles of different clusters of memory neurons, wherein "top-down" neural loop connections act as multi-level switches
for continuous processing of memory information along the "intercortic-intracortical-subcortic" region.
This neural loop organization architecture of memory discrimination and processing is expected to stimulate the study of recognizing more intercortical memory neuron clusters long-range loops throughout the brain, providing material for a more comprehensive outline of the fundamental mechanisms of memory and cognitive regulation, and inspiring new precision intervention strategies
for related affective disorders.

How to carry out distributed storage of memory is a cutting-edge scientific problem
in the field of learning and memory at present.
The study identified novel neural circuit mechanisms that regulate fear memory and regressive memory, and found in the island cortex two groups of neurons that do not overlap each other that can be used to encode fear memory and regressive memory
, respectively.
As we all know, fear memory is necessary for the survival of the body, and regression memory is a necessary factor
for the organism to adapt to different changing environments.
Correspondingly, the body's ability to identify the threat of a particular stimulus and then coordinate the processing of coexisting, competing fearful memories and regressive memories is critical
.
This disruption of cognitive abilities is the pathological basis
of a variety of neuropsychiatric disorders.
Therefore, the new laws of memory storage and extraction revealed by the study may provide a new perspective
for understanding the threatening recognition ability and even the emotion regulation ability of individuals under physiological and pathological conditions.

This study provides new materials for understanding the laws of memory distributed storage, but also raises new scientific questions
.
For example, it is unclear
whether the neural connections between the orbitofrontal cortex and the different subgroups of the insula cortex identified here use a "one-to-one" or "one-to-many" connection model.
In addition, the precise cell type-specific connections and their functions from the insula cortex to the downstream central amygdala or nucleus have not been adequately identified
.
Of particular importance is whether the two groups of projected neurons identified within the insula cortex have different molecular expression profiles or whether they have molecular targets that can be specifically targeted
.
In addition, for fear memory and regression memory, how is the division of labor between the multi-level neural circuits centered on the island cortex and the previously identified amygdala-hippocampus-prefrontal neural circuit[7]? These issues all require further in-depth study
.

In summary, by revealing competing interoperable neuronal clusters responsible for fear memory and regressive memory within the island cortex, this study establishes the organizational rules of multiple interacting loops within the cortex that rely on different subcortical pathways and are simultaneously controlled by the frontal cortex "top-down", which provides a new understanding for understanding
the loop calculation principle of the same clue driving the opposite memory behavior.
At the same time, the study is expected to inspire more and more in-depth research to reveal the fundamental laws
of multi-memory collaborative co-coding.

Original link: https://doi.
org/10.
1038/s41467-022-33241-9

Introduction to the Author's Research Group (Swipe Up and Down to Read)

Professor Xu Tianle's team at Shanghai Jiao Tong University School of Medicine has long been committed to the analysis
of brain cognitive principles and clinical translation.
At the microscopic level, with the goal of elaborating the signal transduction mechanism of nerve cells and its physiological function, the role and mechanism of novel ion channels - acid-sensing ion channel (ASIC) in synaptic plasticity and learning and memory are studied.
To explore the abnormal regulation of ion channels and neural signals in stroke, chronic pain and related affective disorders and novel interventions
.
At the mesoscopic level, from the perspective of memory, "emotions (such as fear, happiness)-emotion-empathy" and its long-range and local loop mechanisms of interaction with memory, attention, and social behavior are studied, and new technologies
for precise neuroregulation are inspired.

Focusing on the general direction of "Memory Principle and Application Research", the research team of Li Weiguang of the Institute of Brain Science Transformation of Fudan University selects different memory models such as emotional memory, feeding memory, and sports memory, analyzes the basic characteristics of memory imprint in multiple dimensions, and reconstructs and synthesizes the goal to portray the physiological nature of normal life activities such as emotional emotion, nutritional metabolism, and exercise behavior and the development of obstacles.
Pioneer the application of memory principles in brain-body interaction regulation, and examine the symptom evolution and rehabilitation of chronic neuropsychiatric diseases from the perspective of memory; Explore the new patterns and plasticity mechanisms of long-term changes in brain activity caused by peripheral or central regular stimulation, develop new strategies for disease intervention based on memory principles, and promote clinical translational applications
.

Shanghai Jiao Tong University School of Medicine researcher Zhang Siyu team is good at the use of tool viruses to study the cell type-specific and dominant target-specific neuronal subsets of neural circuits, has self-developed high-throughput anatomical data analysis software, through the combination of optogenetics, neurophysiology, optical imaging and animal behavior and other technical means, from the perspective of anatomical and functional joint groups to analyze the composition and hierarchical structure of the relevant brain network.
Studying how neural circuits associated with selective attention process information deepens the understanding of how components interact with cognitive behavioral neural circuits in order to help optimize cognitive behavior and treat
cognitive deficits 。 Selected articles from previous issues[1] Prog Neurobiol Frontier ThinkingEffects of genetic factors, aging and intestinal microbial disorders on immune responses in "dry" and "wet" retinal degenerative degeneration[2] Sci Adv-Xi Zhengxiong's team discovered a new mechanism of sports reward: midbrain red nucleus - ventral covered area glutamate neural pathway [3] Mol Psychiatry - Niu Jianqin / Xiao Lan's team found that the oligodendroglial precursor cell DISC-Δ3 variable shear inhibits excitatory synaptic growth leading to schizophrenia [4] PNAS | Sun Bo's research group and collaborators found that time signals are the main factors regulating multicellular information networks[5] Cell Reports—Liu Sheng/Liu Yizhi's team mapped mammalian retinal ganglion cell multimodal maps[6] Cereb Cortex - default mode network brain imprint in patients treated with depression with electrical shock [7] Mol Psychiatry - Xiong Wei's research group to analyze the neural loop mechanism of fear enhancing shock reflex [8] Transl Psychiatry—Early Damage to Cortical Circuit Plasticity and Connectivity in Mouse Models of Alzheimer's Disease[9] J Neurosci—Li Shao/Ma Tonghui's team revealed the orthogonal array structure of AQP4 in mouse with aquaporin point mutation and depolymerization of mice and reduced its polarity distribution at the astrocyte endpodia [10] Cereb Cortex - Yu Yuguo team worked together to build a human brain energy and activity map to reveal the law of energy distribution Quality scientific research training course recommendation [1] Symposium on Patch Clamp and Optogenetics and Calcium Imaging Technology (October 15-16, 2022, Tencent Conference)【2】R Language Clinical Prediction Biomedical Statistics Special Training (October 15-16, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing) Conference/Forum Preview & Review

[1] Trailer | Conference on Neuromodulation and Brain-Computer Interface (U.
S.
Pacific Time: October 12-13), Beijing Time[
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Welcome to "Logical Neuroscience" [1] Talent Recruitment - "Logical Neuroscience" Recruitment Article Interpretation/Writing Position (Network Part-time, Online Office) References (Swipe Up and Down)

1.
Izquierdo I, Furini CR, Myskiw JC.
Fear memory.
Physiol Rev.
2016; 96(2): 695-750.

2.
Bouton ME, Maren S, McNally GP.
Behavioral and neurobiological mechanisms of Pavlovian and instrumental extinction learning.
Physiol Rev.
2021; 101(2): 611-81.

3.
Ressler KJ, Berretta S, Bolshakov VY, Rosso IM, Meloni EG, Rauch SL, Carlezon WA Jr.
Post-traumatic stress disorder: clinical and translational neuroscience from cells to circuits.
Nat Rev Neurol.
2022; 18(5): 273-88.

4.
Wang Q, Wang Q, Song XL, Jiang Q, Wu YJ, Li Y, Yuan TF, Zhang S, Xu NJ, Zhu MX, Li WG, Xu TL.
Fear extinction requires ASIC1a-dependent regulation of hippocampal-prefrontal correlates.
Sci Adv.
2018; 4(10): eaau3075.

5.
Li WG, Wu YJ, Gu X, Fan HR, Wang Q, Zhu JJ, Yi X, Wang Q, Jiang Q, Li Y, Yuan TF, Xu H, Lu J, Xu NJ, Zhu MX, Xu TL.
Input associativity underlies fear memory renewal.
Natl Sci Rev.
2021; 8(9): nwab004.

6.
Gu X, Wu YJ, Zhang Z, Zhu JJ, Wu XR, Wang Q, Yi X, Lin ZJ, Jiao ZH, Xu M, Jiang Q, Li Y, Xu NJ, Zhu MX, Wang LY, Jiang F, Xu TL, Li WG.
Dynamic tripartite construct of interregional engram circuits underlies forgetting of extinction memory.
Mol Psychiatry.
2022; doi:10.
1038/s41380-022-01684-7.

7.
Marek R, Sun Y, Sah P.
Neural circuits for a top-down control of fear and extinction.
Psychopharmacology (Berl).
2019; 236(1): 313-20.

8.
Roy DS, Park YG, Kim ME, Zhang Y, Ogawa SK, DiNapoli N, Gu X, Cho JH, Choi H, Kamentsky L, Martin J, Mosto O, Aida T, Chung K, Tonegawa S.
Brain-wide mapping reveals that engrams for a single memory are distributed across multiple brain regions.
Nat Commun.
2022; 13(1): 1799.

9.
Herry C, Ciocchi S, Senn V, Demmou L, Müller C, Lüthi A.
Switching on and off fear by distinct neuronal circuits.
Nature.
2008; 454(7204): 600-6.

10.
Senn V, Wolff SB, Herry C, Grenier F, Ehrlich I, Gründemann J, Fadok JP, Müller C, Letzkus JJ, Lüthi A.
Long-range connectivity defines behavioral specificity of amygdala neurons.
Neuron.
2014; 81(2): 428-37.

11 .
Zhang X, Kim J, Tonegawa S.
Amygdala reward neurons form and store fear extinction memory.
Neuron.
2020; 105(6): 1077-93.

12.
Gogolla N.
The insular cortex.
Curr Biol.
2017; 27(12): R580-6.

13.
Gehrlach DA, Dolensek N, Klein AS, Roy Chowdhury R, Matthys A, Junghänel M, Gaitanos TN, Podgornik A, Black TD, Reddy Vaka N, Conzelmann KK, Gogolla N.
Aversive state processing in the posterior insular cortex.
Nat Neurosci.
2019; 22(9): 1424-37.

14.
Dolan RJ.
Emotion, cognition, and behavior.
Science.
2002; 298(5596): 1191-4.

15.
Klein AS, Dolensek N, Weiand C, Gogolla N.
Fear balance is maintained by bodily feedback to the insular cortex in mice.
Science.
2021; 374(6570): 1010-5.

16.
Wang Q, Zhu JJ, Wang L, Kan YP, Liu YM, Wu YJ, Gu X, Yi X, Lin ZJ, Wang Q, Lu JF, Jiang Q, Li Y, Liu MG, Xu NJ, Zhu MX, Wang LY, Zhang S, Li WG, Xu TL.
Insular cortical circuits as an executive gateway to decipher threat or extinction memory via distinct subcortical pathways.
Nat Commun.
2022; 13(1): 5540.

17.
Zucker RS, Regehr WG.
Short-term synaptic plasticity.
Annu Rev Physiol.
2002; 64: 355-405.

18.
Schoenbaum G, Roesch MR, Stalnaker TA, Takahashi YK.
A new perspective on the role of the orbitofrontal cortex in adaptive behaviour.
Nat Rev Neurosci.
2009; 10(12): 885-92.

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