The paraventricular nucleus of the thalamus(PVT),which serves as a hub,receives dense projections from the medial prefrontal cortex(mPFC)and projects to the lateral division of central amygdala(CeL).The infralimbic(IL...The paraventricular nucleus of the thalamus(PVT),which serves as a hub,receives dense projections from the medial prefrontal cortex(mPFC)and projects to the lateral division of central amygdala(CeL).The infralimbic(IL)cortex plays a crucial role in encoding and recalling fear extinction memory.Here,we found that neurons in the PVT and IL were strongly activated during fear extinction retrieval.Silencing PVT neurons inhibited extinction retrieval at recent time point(24 h after extinction),while activating them promoted extinction retrieval at remote time point(7 d after extinction),suggesting a critical role of the PVT in extinction retrieval.In the mPFC-PVT circuit,projections from IL rather than prelimbic cortex to the PVT were dominant,and disrupting the IL-PVT projection suppressed extinction retrieval.Moreover,the axons of PVT neurons preferentially projected to the CeL.Silencing the PVT-CeL circuit also suppressed extinction retrieval.Together,our findings reveal a new neural circuit for fear extinction retrieval outside the classical IL-amygdala circuit.展开更多
Fear extinction is a biological process in which learned fear behavior diminishes without anticipated reinforcement,allowing the organism to re-adapt to ever-changing situations.Based on the behavioral hypothesis that...Fear extinction is a biological process in which learned fear behavior diminishes without anticipated reinforcement,allowing the organism to re-adapt to ever-changing situations.Based on the behavioral hypothesis that extinction is new learning and forms an extinction memory,this new memory is more readily forgettable than the original fear memory.The brain’s cellular and synaptic traces underpinning this inherently fragile yet reinforceable extinction memory remain unclear.Intriguing questions are about the whereabouts of the engram neurons that emerged during extinction learning and how they constitute a dynamically evolving functional construct that works in concert to store and express the extinction memory.In this review,we discuss recent advances in the engram circuits and their neural connectivity plasticity for fear extinction,aiming to establish a conceptual framework for understanding the dynamic competition between fear and extinction memories in adaptive control of conditioned fear responses.展开更多
We recently reported two novel breeding lines of rats known as Carioca High- and Low-conditioned Freezing (CHF and CLF), based on defensive freezing responses to contextual cues previously associated with electric foo...We recently reported two novel breeding lines of rats known as Carioca High- and Low-conditioned Freezing (CHF and CLF), based on defensive freezing responses to contextual cues previously associated with electric footshock. The present study used animals of the 8th generation of our selective breeding program to investigate both contextual fear extinction and re-extinction. The results consistently showed that CHF animals froze more than CLF animals. Long extinction training was able to extinguish phenotypic differences between lines, but the divergence was restored after just one fear reacquisition training session. These differences disappeared again during re-extinction training. The possible neural mechanisms involved in these two types of learning are discussed.展开更多
In the contemporary research landscape of mental illness treatment,fear-related disorders such as post-traumatic stress disorder continue to pose significant challenges.Although exposure therapy remains a fundamental ...In the contemporary research landscape of mental illness treatment,fear-related disorders such as post-traumatic stress disorder continue to pose significant challenges.Although exposure therapy remains a fundamental component of treatment,its efficacy varies considerably among individuals.DNA methylation plays a pivotal role in the extinction of fear memories,providing a promising molecular mechanism that could enhance the success of exposure-based interventions.Extensive studies have consistently demonstrated a substantial association between DNA methylation and neuronal plasticity.While DNA methylation holds potential regulatory effects on the effectiveness of exposure therapy,the bidirectional regulatory relationship between it and neuronal activity necessitates addressing several challenges before its widespread clinical application for mental disorders.First,excessive DNA methylation may suppress neural function,and non-selective enhancement of methylation could be counterproductive.Furthermore,due to potential systemic side effects,the use of methylation-modulating agents might disrupt the physiological balance and functionality of other organs and systems.Despite the dynamic interplay between DNA methylation and neuronal activity offering novel insights into the treatment of mental disorders, the strict consideration of target specificity and an appropriate dosing window requirescautious implementation in clinical practice.展开更多
Fear memory underlies anxiety-related disorders, including posttraumatic stress disorder(PTSD). PTSD is a fear-based disorder,characterized by difficulties in extinguishing the learned fear response and maintaining ex...Fear memory underlies anxiety-related disorders, including posttraumatic stress disorder(PTSD). PTSD is a fear-based disorder,characterized by difficulties in extinguishing the learned fear response and maintaining extinction. Currently, the first-line treatment for PTSD is exposure therapy, which forms an extinction memory to compete with the original fear memory. However,the extinguished fear often returns under numerous circumstances, suggesting that novel methods are needed to eliminate fear memory or facilitate extinction memory. This review discusses research that targeted extinction and reconsolidation to manipulate fear memory. Recent studies indicate that sleep is an active state that can regulate memory processes. We also discuss the influence of sleep on fear memory. For each manipulation, we briefly summarize the neural mechanisms that have been identified in human studies. Finally, we highlight potential limitations and future directions in the field to better translate existing interventions to clinical settings.展开更多
基金This work was supported by the National Natural Science Foundation of China(31530091 and 81870912)the National Key Research and Development Program of China(2016YFC1306703)+1 种基金the Science and Technology Program of Guangdong Province,China(2018B030334001)the Collaborative Innovation Center for Cardiovascular Disease Translational Medicine,China.
文摘The paraventricular nucleus of the thalamus(PVT),which serves as a hub,receives dense projections from the medial prefrontal cortex(mPFC)and projects to the lateral division of central amygdala(CeL).The infralimbic(IL)cortex plays a crucial role in encoding and recalling fear extinction memory.Here,we found that neurons in the PVT and IL were strongly activated during fear extinction retrieval.Silencing PVT neurons inhibited extinction retrieval at recent time point(24 h after extinction),while activating them promoted extinction retrieval at remote time point(7 d after extinction),suggesting a critical role of the PVT in extinction retrieval.In the mPFC-PVT circuit,projections from IL rather than prelimbic cortex to the PVT were dominant,and disrupting the IL-PVT projection suppressed extinction retrieval.Moreover,the axons of PVT neurons preferentially projected to the CeL.Silencing the PVT-CeL circuit also suppressed extinction retrieval.Together,our findings reveal a new neural circuit for fear extinction retrieval outside the classical IL-amygdala circuit.
基金supported by grants from the STI2030-Major Projects(2021ZD0202800)the National Natural Science Foundation of China(32071023 and 32371078)+2 种基金the Program of Shanghai Academic/Technology Research Leader(22XD1420700)the Shanghai Municipal Health Commission(2022XD046)Innovative Research Team of High-Level Local Universities in Shanghai.
文摘Fear extinction is a biological process in which learned fear behavior diminishes without anticipated reinforcement,allowing the organism to re-adapt to ever-changing situations.Based on the behavioral hypothesis that extinction is new learning and forms an extinction memory,this new memory is more readily forgettable than the original fear memory.The brain’s cellular and synaptic traces underpinning this inherently fragile yet reinforceable extinction memory remain unclear.Intriguing questions are about the whereabouts of the engram neurons that emerged during extinction learning and how they constitute a dynamically evolving functional construct that works in concert to store and express the extinction memory.In this review,we discuss recent advances in the engram circuits and their neural connectivity plasticity for fear extinction,aiming to establish a conceptual framework for understanding the dynamic competition between fear and extinction memories in adaptive control of conditioned fear responses.
基金supported by the Secretary for Science and Technology of Brazil(CNPq)and Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro(FAPERJ).
文摘We recently reported two novel breeding lines of rats known as Carioca High- and Low-conditioned Freezing (CHF and CLF), based on defensive freezing responses to contextual cues previously associated with electric footshock. The present study used animals of the 8th generation of our selective breeding program to investigate both contextual fear extinction and re-extinction. The results consistently showed that CHF animals froze more than CLF animals. Long extinction training was able to extinguish phenotypic differences between lines, but the divergence was restored after just one fear reacquisition training session. These differences disappeared again during re-extinction training. The possible neural mechanisms involved in these two types of learning are discussed.
基金Supported by the General Program of the Joint Fund Project Under the Liaoning Provincial Science and Technology Plan,No.2024-MSLH-104Research Project Plan of the Qingpu Branch of Zhongshan Hospital,No.QYT2023-02Research Topic of the Shanghai Qingpu District Health Commission,No.QWJ2024-10.
文摘In the contemporary research landscape of mental illness treatment,fear-related disorders such as post-traumatic stress disorder continue to pose significant challenges.Although exposure therapy remains a fundamental component of treatment,its efficacy varies considerably among individuals.DNA methylation plays a pivotal role in the extinction of fear memories,providing a promising molecular mechanism that could enhance the success of exposure-based interventions.Extensive studies have consistently demonstrated a substantial association between DNA methylation and neuronal plasticity.While DNA methylation holds potential regulatory effects on the effectiveness of exposure therapy,the bidirectional regulatory relationship between it and neuronal activity necessitates addressing several challenges before its widespread clinical application for mental disorders.First,excessive DNA methylation may suppress neural function,and non-selective enhancement of methylation could be counterproductive.Furthermore,due to potential systemic side effects,the use of methylation-modulating agents might disrupt the physiological balance and functionality of other organs and systems.Despite the dynamic interplay between DNA methylation and neuronal activity offering novel insights into the treatment of mental disorders, the strict consideration of target specificity and an appropriate dosing window requirescautious implementation in clinical practice.
基金supported by the National Key Technology Research and Development Program of the Ministry of Science and Technology of China(2015BAI13B01)
文摘Fear memory underlies anxiety-related disorders, including posttraumatic stress disorder(PTSD). PTSD is a fear-based disorder,characterized by difficulties in extinguishing the learned fear response and maintaining extinction. Currently, the first-line treatment for PTSD is exposure therapy, which forms an extinction memory to compete with the original fear memory. However,the extinguished fear often returns under numerous circumstances, suggesting that novel methods are needed to eliminate fear memory or facilitate extinction memory. This review discusses research that targeted extinction and reconsolidation to manipulate fear memory. Recent studies indicate that sleep is an active state that can regulate memory processes. We also discuss the influence of sleep on fear memory. For each manipulation, we briefly summarize the neural mechanisms that have been identified in human studies. Finally, we highlight potential limitations and future directions in the field to better translate existing interventions to clinical settings.
