Post-traumatic stress disorder(PTSD)is a psychiatric disorder caused by traumatic past experiences,rooted in the neurocircuits of fear memory formation.Memory processes include encoding,storing,and recalling to forget...Post-traumatic stress disorder(PTSD)is a psychiatric disorder caused by traumatic past experiences,rooted in the neurocircuits of fear memory formation.Memory processes include encoding,storing,and recalling to forgetting,suggesting the potential to erase fear memories through timely interventions.Conventional strategies such as medications or electroconvulsive therapy often fail to provide permanent relief and come with significant side-effects.This review explores how fear memory may be erased,particularly focusing on the mnemonic phases of reconsolidation and extinction.Reconsolidation strengthens memory,while extinction weakens it.Interfering with memory reconsolidation could diminish the fear response.Alternatively,the extinction of acquired memory could reduce the fear memory response.This review summarizes experimental animal models of PTSD,examines the nature and epidemiology of reconsolidation to extinction,and discusses current behavioral therapy aimed at transforming fear memories to treat PTSD.In sum,understanding how fear memory updates holds significant promise for PTSD treatment.展开更多
BACKGROUND Fear-related disorders,such as post-traumatic stress disorder(PTSD),significantly impact patients and families.Exposure therapy is a common treatment,but imp-roving its effectiveness remains a key challenge...BACKGROUND Fear-related disorders,such as post-traumatic stress disorder(PTSD),significantly impact patients and families.Exposure therapy is a common treatment,but imp-roving its effectiveness remains a key challenge.Fear conditioning and extinction in animal models offer insights into its mechanisms.Our previous research indi-cates that DNA methyltransferases play a role in fear memory renewal.AIM To investigate the role of DNA methylation in the extinction of fear memory,with the goal of identifying potential strategies to enhance the efficacy of exposure therapy for fear-related disorders.METHODS This study investigated the role of DNA methylation in fear memory extinction in mice.DNA methylation was manipulated using N-phthalyl-L-tryptophan(RG108)to reduce methylation and L-methionine injections to enhance it.Neuronal activity,and dendritic spine density was measured following extinction training.RESULTS RG108 suppressed extinction,reduced spine density,and inhibited neuronal activity.Methionine injections facilitated extinction.CONCLUSION DNA methylation is crucial for fear memory extinction.Enhancing methylation may improve the efficacy of exposure therapy,offering a potential strategy to treat fear-related disorders.展开更多
Numerous studies on the formation and consolidation of memory have shown that memory processes are characterized by phase-dependent and dynamic regulation.Memory retrieval,as the only representation of memory content ...Numerous studies on the formation and consolidation of memory have shown that memory processes are characterized by phase-dependent and dynamic regulation.Memory retrieval,as the only representation of memory content and an active form of memory processing that induces memory reconsolidation,has attracted increasing attention in recent years.Although the molecular mechanisms specifc to memory retrievalinduced reconsolidation have been gradually revealed,an understanding of the time-dependent regulatory mechanisms of this process is still lacking.In this study,we applied a transcriptome analysis of memory retrieval at diferent time points in the recent memory stage.Diferential expression analysis and Short Time-series Expression Miner(STEM)depicting temporal gene expression patterns indicated that most diferential gene expression occurred at 48 h,and the STEM cluster showing the greatest transcriptional upregulation at 48 h demonstrated the most significant diference.We then screened the diferentially-expressed genes associated with that met the expression patterns of those cluster-identifed genes that have been reported to be involved in learning and memory processes in addition to dipeptidyl peptidase 9(DPP9).Further quantitative polymerase chain reaction verifcation and pharmacological intervention suggested that DPP9 is involved in 48-h fear memory retrieval and viral vector-mediated overexpression of DPP9 countered the 48-h retrieval-induced attenuation of fear memory.Taken together,our fndings suggest that temporal gene expression patterns are induced by recent memory retrieval and provide hitherto undocumented evidence of the role of DPP9 in the retrieval-induced reconsolidation of fear memory.展开更多
The importance of astrocytes in behavior control is increasingly appreciated,but little is known about the effects of their dynamic activity in regulating learning and memory.In the present study,we constructed AAVs o...The importance of astrocytes in behavior control is increasingly appreciated,but little is known about the effects of their dynamic activity in regulating learning and memory.In the present study,we constructed AAVs of photoactivatable and photoinactivatable Ras-related C3 botulinum toxin substrate 1(Rac1)under the mGFAP promoter,which enabled the manipulation of Rac1 activity in astrocytes by optical stimulation in free-moving mice.We found that both up-regulation and down-regulation of astrocytic Rac1 activity in the basolateral amygdala(BLA)attenuated memory acquisition in a fear conditioning mouse model.Meanwhile,neuronal activation in the BLA induced by memory acquisition was inhibited under both the up-and down-regulation of astrocytic Rac1 activity during training.In terms of the impact on fear memory retrieval,we found both up-and down-regulation of BLA astrocytic Rac1 activity impaired memory retrieval of fear conditioning and memory retrieval-induced neuronal activation.Notably,the effect of astrocytic Rac1 on memory retrieval was reversible.Our results demonstrate that the normal activity of astrocytic Rac1 is necessary for the activation of neurons and memory formation.Both activation and inactivation of astrocytic Rac1 activity in the BLA reduced the excitability of neurons,and thereby impaired fear memory acquisition and retrieval.展开更多
OBJECTIVE Post-traumatic stress disorder(PTSD)is characterized by poor adapta⁃tion to a traumatic experience and disturbances in fear memory regulation,and currently lacks effective medication.Cannabidiol(CBD)is the p...OBJECTIVE Post-traumatic stress disorder(PTSD)is characterized by poor adapta⁃tion to a traumatic experience and disturbances in fear memory regulation,and currently lacks effective medication.Cannabidiol(CBD)is the primary component of the Cannabis sativa plant;it does not have any psychoactive effects and has been implicated in modulating fear learning in mammals.The present study investigated the effect of CBD on PTSD-like behaviors in a mouse pre-shock model,the effect of CBD in the modulation of trauma-related fear memory,a crucial process leading to core symptoms of PTSD.METHODS Pre-shock model was applied in which mice were submitted to training with two days of 0.8 mA×12 times of foot-shock,and PTSD-like behaviors was evaluated during 3 and 26 d,including freezing time to the conditioned context,open field test,elevated plus maze test and social interaction test.RESULTS CBD(10 mg·kg^(-1))administration alleviated main PTSD-like symptoms in the mouse pre-shock model by attenuating trauma-related fear memory,decreasing anxiety-like behavior,and increasing social interaction behavior.However,sertraline(15 mg·kg^(-1))was only effective when adminis⁃tered throughout the test period.Furthermore,CBD reduced the formation,retrieval,and recon⁃solidation of trauma-related fear memory,whereas sertraline only reduced fear-memory retrieval.Neither CBD nor sertraline influenced the acquisi⁃tion of trauma-related fear memory.CONCLU⁃SION CBD produced anti-PTSD-like actions in mice,and could disrupt trauma-related fear mem⁃ory by interfering with multiple aspects of fear memory processing in mice.These findings indi⁃cate that CBD may be a promising candidate for treating PTSD.展开更多
To the Editor:Posttraumatic stress disorder(PTSD),a severe psychiatric disorder post-trauma,is closely linked to fear memory.[1]Current treatments like selective serotonin reuptake inhibitors have limited effectivenes...To the Editor:Posttraumatic stress disorder(PTSD),a severe psychiatric disorder post-trauma,is closely linked to fear memory.[1]Current treatments like selective serotonin reuptake inhibitors have limited effectiveness and side effects,necessitating new non-invasive approaches.PTSD often co-occurs with depression,and both are connected to inflammatory system disruptions,with increased proinflammatory cytokines in patients.[2,3]Transcutaneous auricular vagus nerve stimulation(taVNS)shows promise for treating depression by reducing neuroinflammation.[4]taVNS combines auricular acupuncture(a technique in Traditional Chinese Medicine)and neuroanatomy,targeting the auricular branch of the vagus nerve to influence brain regions like the thalamus and hippocampus.This study hypothesizes that taVNS may reduce fear memory among fear-conditioned mice through the modulation of inflammatory responses.We utilized a fear-conditioning mouse model to evaluate the impact on freezing behavior and quantify inflammatory markers,including corticosterone,interleukin-10(IL-10)and interleukin-1β(IL-1β),within both serum and brain regions.展开更多
Post-traumatic stress disorder(PTSD)is a severe neuropsychiatric disorder characterised by reexperiencing,avoidance and hyperarousal.Memory abnormalities manifested as intrusive thoughts and prolonged distressful emot...Post-traumatic stress disorder(PTSD)is a severe neuropsychiatric disorder characterised by reexperiencing,avoidance and hyperarousal.Memory abnormalities manifested as intrusive thoughts and prolonged distressful emotions are postulated as key roles in PTSD development and persistence.Over the past decades,convergent results from human and animal studies have systematically investigated contributions of the amygdala,hippocampus and medial prefrontal cortex(mPFC)in fear memory processes,including fear acquisition,storage,reconsolidation and extinction.These findings provide mechanistic insights for cognitive-behavioural therapy and aid in developing pathological region-targeted neuromodulation treatment for PTSD.Taking advantage of advances in cell-type selective labelling and manipulation technologies,recent studies have focused on the spatiotemporal regulation of neural circuits underlying distinct phases of fear memory processes.These findings have revealed that multiple distributed brain areas participate in the fear memory encoding network.Moreover,the functional role of distinct neuronal ensembles within the amygdala-hippocampus-mPFC pathway,identified by genetic markers and projection profiles,has been assigned to temporally separate features of fear processing,demonstrating the sophistication of the fear encoding circuit.These results provide mechanistic insights into PTSD pathology and might shed light on aetiology-based clinical interventions for PTSD.Therefore,the present review will mainly focus on the recent progress in elucidating neural circuit mechanisms underlying the dynamic regulation of fear memory,with an emphasis on the spatial distribution of fear memory encoding neural networks and the temporal coherence between neuronal ensemble activity and fear expression.展开更多
Fear memory is crucial for survival and adaptation in complex and dynamically changing environments that enables individuals to avoid or escape from potentially dangerous situations.However,excessive fear memories can...Fear memory is crucial for survival and adaptation in complex and dynamically changing environments that enables individuals to avoid or escape from potentially dangerous situations.However,excessive fear memories can significantly contribute to emotional disabilities and mental disorders,including panic disorder,phobias,social anxiety disorder,and post-traumatic stress disorder(PTSD).展开更多
Fear memory,a predictive and protective mechanism in potentially hostile environments,elicits defensive behavioral responses that have evolved to help organisms avoid harm and ensure survival.However,excessive fear me...Fear memory,a predictive and protective mechanism in potentially hostile environments,elicits defensive behavioral responses that have evolved to help organisms avoid harm and ensure survival.However,excessive fear memories may contribute to the onset of various psychological disorders,such as panic disorder,phobias,and post-traumatic stress disorder(PTSD).展开更多
The phenomenon of fear memory generalization can be defined as the expansion of an individual's originally specific fear responses to a similar yet genuinely harmless stimulus or situation subsequent to the occurr...The phenomenon of fear memory generalization can be defined as the expansion of an individual's originally specific fear responses to a similar yet genuinely harmless stimulus or situation subsequent to the occurrence of a traumatic event[1].Fear generalization within the normal range represents an adaptive evolutionary mechanism to facilitate prompt reactions to potential threats and to enhance the likelihood of survival.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
Clustered protocadherins(Pcdhs)are a large family of cadherin-like cell adhesion proteins that are central for neurite selfavoidance and neuronal connectivity in the brain.Their downstream nonreceptor tyrosine kinase ...Clustered protocadherins(Pcdhs)are a large family of cadherin-like cell adhesion proteins that are central for neurite selfavoidance and neuronal connectivity in the brain.Their downstream nonreceptor tyrosine kinase Pyk2(proline-rich tyrosine kinase 2,also known as Ptk2b,Cakb,Raftk,Fak2,and Cadtk)is predominantly expressed in the hippocampus.We constructed Pyk2-null mouse lines and found that these mutant mice showed enhancement in contextual fear memory,without significant change in auditory-cued and spatial-referenced learning and memory.In addition,by preparing Y402F mutant mice,we observed that Pyk2 suppressed contextual fear memory in an autophosphorylation-independent manner.Moreover,using high-throughput RNA sequencing,we found that immediate early genes,such as Npas4,cFos,Zif268/Egr1,Arc,and Nr4a1,were enhanced in Pyk2-null mice.We further showed that Pyk2 disruption affected pyramidal neuronal complexity and spine dynamics.Thus,we demonstrated that Pyk2 is a novel fear memory suppressor molecule and Pyk2-null mice provide a model for understanding fearrelated disorders.These findings have interesting implications regarding dysregulation of the Pcdh–Pyk2 axis in neuropsychiatric disorders.展开更多
The psychostimulant methylphenidate (MPD; also called Ritalin) is a blocker of dopamine and norepi-nephrine transporter. It has been clinically used for treatment of Attention Deficit and Hyperactivity Disorder (ADHD)...The psychostimulant methylphenidate (MPD; also called Ritalin) is a blocker of dopamine and norepi-nephrine transporter. It has been clinically used for treatment of Attention Deficit and Hyperactivity Disorder (ADHD). There have been inconsistent reports regarding the effects of systemically adminis-tered MPD on learning and memory, either in animals or humans. In the present study, we investigated the effect of direct infusion of MPD into the basolateral nucleus of amygdala (BLA) or the anterior cin-gulate cortex (ACC) on conditioned fear memory. Rats were trained on a one-trial step-through inhibi-tory avoidance task. MPD was infused bilaterally into the BLA or the ACC, either at ‘0’ or 6 h post-training. Saline was administered as control. Memory retention was tested 48 h post-training. In-tra-BLA or intra-ACC infusion of MPD ‘0’ h but not 6 h post-training significantly improved 48-h memory retention: the MPD-treated rats had significant longer step-through latency than controls. The present results indicate that action of MPD in the BLA or the ACC produces a beneficial effect on the consoli-dation of inhibitory avoidance memory.展开更多
In anticipation of the massive burden of neurodegenerative disease within super-aged societies, great efforts have been made to utilize neural stem and progenitor cells for regenerative medicine. The capacity of intri...In anticipation of the massive burden of neurodegenerative disease within super-aged societies, great efforts have been made to utilize neural stem and progenitor cells for regenerative medicine. The capacity of intrinsic neural stem and progenitor cells to regenerate damaged brain tissue remains unclear, due in part to the lack of knowledge about how these newly born neurons integrate into functional circuitry. As sizable integration of adult-born neurons naturally occurs in the dentate gyrus region of the hippocampus, clarifying the mechanisms of this process could provide insights for applying neural stem and progenitor cells in clinical settings. There is convincing evidence of functional correlations between adult-born neurons and memory consolidation and sleep; therefore, we describe some new advances that were left untouched in our recent review.展开更多
Lesions and temporary inactivation of the hippocampus (HPC) in rodents occasionally lead to discrepant amnesic effects. We directly compared and contrasted the retrograde amnesic effects that small HPC lesions (~50% d...Lesions and temporary inactivation of the hippocampus (HPC) in rodents occasionally lead to discrepant amnesic effects. We directly compared and contrasted the retrograde amnesic effects that small HPC lesions (~50% damage), large HPC lesions (~80% damage), and combined dorsal and ventral HPC inactivation using the sodium channel blocker tetrodotoxin (TTX) had on contextual fear conditioning. Compared to control rats, large HPC lesions significantly reduced freezing during retention testing, a behaviour consistent with retrograde amnesia. In contrast, neither the small lesions nor the TTX inactivation significantly reduced freezing. The extent of damage was significantly and negatively correlated with retention performance (r<sub>(9)</sub> = -0.896, p < 0.001), suggesting that 70% or more of the HPC needed to be damaged to observe deficits. Importantly, TTX inactivation disrupted spatial memory in the Morris Water Task, confirming that our inactivation procedure did impair one form of HPC-dependent memory. To assess the extent of the TTX inactivation, immediate early gene expression was quantified in the HPC following the Morris Water Task. However, despite the behavioural impairment, we did not find a significant reduction in expression. We conclude that temporary inactivation of the HPC may fail to impair context fear memory because this technique does not sufficiently disrupt the HPC.展开更多
Posttraumatic stress disorder(PTSD)is a complex mental disorder notable for traumatic experience memory.Although current first-line treatments are linked with clinically important symptom reduction,a large proportion ...Posttraumatic stress disorder(PTSD)is a complex mental disorder notable for traumatic experience memory.Although current first-line treatments are linked with clinically important symptom reduction,a large proportion of patients retained to experience considerable residual symptoms,indicating pathogenic mechanism should be illustrated further.Recent studies reported that newly formed myelin could shape neural circuit function and be implicated in fear memory preservation.However,its role in PTSD remains to be elucidated.In this study,we adopted a restraint stress-induced PTSD mouse model and found that PTSD-related neuropsychiatric symptoms were accompanied by increased myelination in the posterior parietal cortex and hippocampus.Fluoxetine,but not risperidone or sertraline,has a more profound rescue effect on neuropsychological behaviors and myelin abnormalities.Further mechanistic experiments revealed that fluoxetine could directly interfere with oligodendroglial differentiation by upregulating Wnt signaling.Our data demonstrated the correlation between PTSD and abnormal myelination,suggesting that the oligodendroglial lineage could be a target for PTSD treatment.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supported by the National Key Research and Development Project of China(2021ZD0202800)the National Natural Science Foundation of China(U21A20418,82003727).
文摘Post-traumatic stress disorder(PTSD)is a psychiatric disorder caused by traumatic past experiences,rooted in the neurocircuits of fear memory formation.Memory processes include encoding,storing,and recalling to forgetting,suggesting the potential to erase fear memories through timely interventions.Conventional strategies such as medications or electroconvulsive therapy often fail to provide permanent relief and come with significant side-effects.This review explores how fear memory may be erased,particularly focusing on the mnemonic phases of reconsolidation and extinction.Reconsolidation strengthens memory,while extinction weakens it.Interfering with memory reconsolidation could diminish the fear response.Alternatively,the extinction of acquired memory could reduce the fear memory response.This review summarizes experimental animal models of PTSD,examines the nature and epidemiology of reconsolidation to extinction,and discusses current behavioral therapy aimed at transforming fear memories to treat PTSD.In sum,understanding how fear memory updates holds significant promise for PTSD treatment.
基金Supported by National Natural Science Foundation of China,No.82360231Yunnan Basic Research Program General Project,No.202401AT070075+1 种基金Dali Basic Research Program Key Project,No.202301A020021Youth Special Project for Basic Research of Local Universities in Yunnan Province,No.202301BA070001-127.
文摘BACKGROUND Fear-related disorders,such as post-traumatic stress disorder(PTSD),significantly impact patients and families.Exposure therapy is a common treatment,but imp-roving its effectiveness remains a key challenge.Fear conditioning and extinction in animal models offer insights into its mechanisms.Our previous research indi-cates that DNA methyltransferases play a role in fear memory renewal.AIM To investigate the role of DNA methylation in the extinction of fear memory,with the goal of identifying potential strategies to enhance the efficacy of exposure therapy for fear-related disorders.METHODS This study investigated the role of DNA methylation in fear memory extinction in mice.DNA methylation was manipulated using N-phthalyl-L-tryptophan(RG108)to reduce methylation and L-methionine injections to enhance it.Neuronal activity,and dendritic spine density was measured following extinction training.RESULTS RG108 suppressed extinction,reduced spine density,and inhibited neuronal activity.Methionine injections facilitated extinction.CONCLUSION DNA methylation is crucial for fear memory extinction.Enhancing methylation may improve the efficacy of exposure therapy,offering a potential strategy to treat fear-related disorders.
基金supported by the STI2030-Major Projects(2022ZD0204900)the National Natural Science Foundation of China(32071029 and 32271080)+1 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB32020200)the Yunnan Provincial Science and Technology Department(202402AA310014).
文摘Numerous studies on the formation and consolidation of memory have shown that memory processes are characterized by phase-dependent and dynamic regulation.Memory retrieval,as the only representation of memory content and an active form of memory processing that induces memory reconsolidation,has attracted increasing attention in recent years.Although the molecular mechanisms specifc to memory retrievalinduced reconsolidation have been gradually revealed,an understanding of the time-dependent regulatory mechanisms of this process is still lacking.In this study,we applied a transcriptome analysis of memory retrieval at diferent time points in the recent memory stage.Diferential expression analysis and Short Time-series Expression Miner(STEM)depicting temporal gene expression patterns indicated that most diferential gene expression occurred at 48 h,and the STEM cluster showing the greatest transcriptional upregulation at 48 h demonstrated the most significant diference.We then screened the diferentially-expressed genes associated with that met the expression patterns of those cluster-identifed genes that have been reported to be involved in learning and memory processes in addition to dipeptidyl peptidase 9(DPP9).Further quantitative polymerase chain reaction verifcation and pharmacological intervention suggested that DPP9 is involved in 48-h fear memory retrieval and viral vector-mediated overexpression of DPP9 countered the 48-h retrieval-induced attenuation of fear memory.Taken together,our fndings suggest that temporal gene expression patterns are induced by recent memory retrieval and provide hitherto undocumented evidence of the role of DPP9 in the retrieval-induced reconsolidation of fear memory.
基金the China Postdoctoral Science Foundation(BX20180070 and 2019M661347)the National Natural Science Foundation of China(31930046 and 31771176).
文摘The importance of astrocytes in behavior control is increasingly appreciated,but little is known about the effects of their dynamic activity in regulating learning and memory.In the present study,we constructed AAVs of photoactivatable and photoinactivatable Ras-related C3 botulinum toxin substrate 1(Rac1)under the mGFAP promoter,which enabled the manipulation of Rac1 activity in astrocytes by optical stimulation in free-moving mice.We found that both up-regulation and down-regulation of astrocytic Rac1 activity in the basolateral amygdala(BLA)attenuated memory acquisition in a fear conditioning mouse model.Meanwhile,neuronal activation in the BLA induced by memory acquisition was inhibited under both the up-and down-regulation of astrocytic Rac1 activity during training.In terms of the impact on fear memory retrieval,we found both up-and down-regulation of BLA astrocytic Rac1 activity impaired memory retrieval of fear conditioning and memory retrieval-induced neuronal activation.Notably,the effect of astrocytic Rac1 on memory retrieval was reversible.Our results demonstrate that the normal activity of astrocytic Rac1 is necessary for the activation of neurons and memory formation.Both activation and inactivation of astrocytic Rac1 activity in the BLA reduced the excitability of neurons,and thereby impaired fear memory acquisition and retrieval.
文摘OBJECTIVE Post-traumatic stress disorder(PTSD)is characterized by poor adapta⁃tion to a traumatic experience and disturbances in fear memory regulation,and currently lacks effective medication.Cannabidiol(CBD)is the primary component of the Cannabis sativa plant;it does not have any psychoactive effects and has been implicated in modulating fear learning in mammals.The present study investigated the effect of CBD on PTSD-like behaviors in a mouse pre-shock model,the effect of CBD in the modulation of trauma-related fear memory,a crucial process leading to core symptoms of PTSD.METHODS Pre-shock model was applied in which mice were submitted to training with two days of 0.8 mA×12 times of foot-shock,and PTSD-like behaviors was evaluated during 3 and 26 d,including freezing time to the conditioned context,open field test,elevated plus maze test and social interaction test.RESULTS CBD(10 mg·kg^(-1))administration alleviated main PTSD-like symptoms in the mouse pre-shock model by attenuating trauma-related fear memory,decreasing anxiety-like behavior,and increasing social interaction behavior.However,sertraline(15 mg·kg^(-1))was only effective when adminis⁃tered throughout the test period.Furthermore,CBD reduced the formation,retrieval,and recon⁃solidation of trauma-related fear memory,whereas sertraline only reduced fear-memory retrieval.Neither CBD nor sertraline influenced the acquisi⁃tion of trauma-related fear memory.CONCLU⁃SION CBD produced anti-PTSD-like actions in mice,and could disrupt trauma-related fear mem⁃ory by interfering with multiple aspects of fear memory processing in mice.These findings indi⁃cate that CBD may be a promising candidate for treating PTSD.
基金supported by grants from the priming scientific research foundation for the junior researcher in Beijing Tongren Hospital,Capital Medical University(No.2023-YJJ-ZZL-018)the National Natural Science Foundation of China(No.82270411)+1 种基金the Beijing Hospitals Authority’s Ascent Plan(No.DFL20220203)the Capital’s Funds for Health Improvement and Research(No.CFH2024-2-2058).
文摘To the Editor:Posttraumatic stress disorder(PTSD),a severe psychiatric disorder post-trauma,is closely linked to fear memory.[1]Current treatments like selective serotonin reuptake inhibitors have limited effectiveness and side effects,necessitating new non-invasive approaches.PTSD often co-occurs with depression,and both are connected to inflammatory system disruptions,with increased proinflammatory cytokines in patients.[2,3]Transcutaneous auricular vagus nerve stimulation(taVNS)shows promise for treating depression by reducing neuroinflammation.[4]taVNS combines auricular acupuncture(a technique in Traditional Chinese Medicine)and neuroanatomy,targeting the auricular branch of the vagus nerve to influence brain regions like the thalamus and hippocampus.This study hypothesizes that taVNS may reduce fear memory among fear-conditioned mice through the modulation of inflammatory responses.We utilized a fear-conditioning mouse model to evaluate the impact on freezing behavior and quantify inflammatory markers,including corticosterone,interleukin-10(IL-10)and interleukin-1β(IL-1β),within both serum and brain regions.
基金supported by the National Natural Science Foundation of China(82401772)the Shanghai Municipal Education Commission(2021-01-07-00-02-E0086).
文摘Post-traumatic stress disorder(PTSD)is a severe neuropsychiatric disorder characterised by reexperiencing,avoidance and hyperarousal.Memory abnormalities manifested as intrusive thoughts and prolonged distressful emotions are postulated as key roles in PTSD development and persistence.Over the past decades,convergent results from human and animal studies have systematically investigated contributions of the amygdala,hippocampus and medial prefrontal cortex(mPFC)in fear memory processes,including fear acquisition,storage,reconsolidation and extinction.These findings provide mechanistic insights for cognitive-behavioural therapy and aid in developing pathological region-targeted neuromodulation treatment for PTSD.Taking advantage of advances in cell-type selective labelling and manipulation technologies,recent studies have focused on the spatiotemporal regulation of neural circuits underlying distinct phases of fear memory processes.These findings have revealed that multiple distributed brain areas participate in the fear memory encoding network.Moreover,the functional role of distinct neuronal ensembles within the amygdala-hippocampus-mPFC pathway,identified by genetic markers and projection profiles,has been assigned to temporally separate features of fear processing,demonstrating the sophistication of the fear encoding circuit.These results provide mechanistic insights into PTSD pathology and might shed light on aetiology-based clinical interventions for PTSD.Therefore,the present review will mainly focus on the recent progress in elucidating neural circuit mechanisms underlying the dynamic regulation of fear memory,with an emphasis on the spatial distribution of fear memory encoding neural networks and the temporal coherence between neuronal ensemble activity and fear expression.
文摘Fear memory is crucial for survival and adaptation in complex and dynamically changing environments that enables individuals to avoid or escape from potentially dangerous situations.However,excessive fear memories can significantly contribute to emotional disabilities and mental disorders,including panic disorder,phobias,social anxiety disorder,and post-traumatic stress disorder(PTSD).
基金supported by the National Natural Science Foundation of China(82104138)the Zhejiang Provincial Natural Science Foundation of China(LY24H310003).
文摘Fear memory,a predictive and protective mechanism in potentially hostile environments,elicits defensive behavioral responses that have evolved to help organisms avoid harm and ensure survival.However,excessive fear memories may contribute to the onset of various psychological disorders,such as panic disorder,phobias,and post-traumatic stress disorder(PTSD).
基金supported by the Shandong Provincial Natural Science Foundation(ZR2022QH144).
文摘The phenomenon of fear memory generalization can be defined as the expansion of an individual's originally specific fear responses to a similar yet genuinely harmless stimulus or situation subsequent to the occurrence of a traumatic event[1].Fear generalization within the normal range represents an adaptive evolutionary mechanism to facilitate prompt reactions to potential threats and to enhance the likelihood of survival.
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 grants from the National Natural Science Foundation of China(31200825 to L.S.and 31630039 to Q.W.)the Ministry of Science and Technology of China(2017YFA0504203 and 2018YFC1004504)+2 种基金the Science and Technology Commission of Shanghai Municipality(19JC1412500 and 21DZ2210200 to Q.W.)Shanghai Jiao Tong University Scientific and Technological Innovation Funds(17JCYB12 to L.S.)Q.W.is a Shanghai Subject Chief Scientist.
文摘Clustered protocadherins(Pcdhs)are a large family of cadherin-like cell adhesion proteins that are central for neurite selfavoidance and neuronal connectivity in the brain.Their downstream nonreceptor tyrosine kinase Pyk2(proline-rich tyrosine kinase 2,also known as Ptk2b,Cakb,Raftk,Fak2,and Cadtk)is predominantly expressed in the hippocampus.We constructed Pyk2-null mouse lines and found that these mutant mice showed enhancement in contextual fear memory,without significant change in auditory-cued and spatial-referenced learning and memory.In addition,by preparing Y402F mutant mice,we observed that Pyk2 suppressed contextual fear memory in an autophosphorylation-independent manner.Moreover,using high-throughput RNA sequencing,we found that immediate early genes,such as Npas4,cFos,Zif268/Egr1,Arc,and Nr4a1,were enhanced in Pyk2-null mice.We further showed that Pyk2 disruption affected pyramidal neuronal complexity and spine dynamics.Thus,we demonstrated that Pyk2 is a novel fear memory suppressor molecule and Pyk2-null mice provide a model for understanding fearrelated disorders.These findings have interesting implications regarding dysregulation of the Pcdh–Pyk2 axis in neuropsychiatric disorders.
基金Supported by the Ministry of Science and Technology of China(Grant Nos.2006CB500807 and 2006AA02Z199)the Ministry of Education of China(Program for Changjiang Scholars and Innovative Research Team in University)the National Natural Science Foundation of China(Grant Nos.30225023,30430240 and 30611120530)
文摘The psychostimulant methylphenidate (MPD; also called Ritalin) is a blocker of dopamine and norepi-nephrine transporter. It has been clinically used for treatment of Attention Deficit and Hyperactivity Disorder (ADHD). There have been inconsistent reports regarding the effects of systemically adminis-tered MPD on learning and memory, either in animals or humans. In the present study, we investigated the effect of direct infusion of MPD into the basolateral nucleus of amygdala (BLA) or the anterior cin-gulate cortex (ACC) on conditioned fear memory. Rats were trained on a one-trial step-through inhibi-tory avoidance task. MPD was infused bilaterally into the BLA or the ACC, either at ‘0’ or 6 h post-training. Saline was administered as control. Memory retention was tested 48 h post-training. In-tra-BLA or intra-ACC infusion of MPD ‘0’ h but not 6 h post-training significantly improved 48-h memory retention: the MPD-treated rats had significant longer step-through latency than controls. The present results indicate that action of MPD in the BLA or the ACC produces a beneficial effect on the consoli-dation of inhibitory avoidance memory.
基金partially supported by the MEXT World Premier International Research Center Initiative,CREST JST,MEXT KAKENHI for Scientific Research on Innovative Areas "Microendophenotype"(25116530)and "Memory Dynamism"(26115502)JSPS KAKENHI Grants(16K18359,15F15408)+12 种基金Research Foundation for Opto-Science and TechnologyKato Memorial Bioscience FoundationJapan Foundation for Applied EnzymologyUehara Memorial Foundation2016 Inamori Research Grants ProgramIchiro Kanehara Foundation for the Promotion of Medical Sciences and Medical CareLife Science Foundation of JapanKowa Life Science Foundation Research GrantGSK Japan Research GrantKANAE Foundation for the Promotion of Medical ScienceShimadzu Foundation for the Promotion of Science and TechnologyTakeda Science Foundation to MSThe Tokyo Biochemical Research Foundation to SS
文摘In anticipation of the massive burden of neurodegenerative disease within super-aged societies, great efforts have been made to utilize neural stem and progenitor cells for regenerative medicine. The capacity of intrinsic neural stem and progenitor cells to regenerate damaged brain tissue remains unclear, due in part to the lack of knowledge about how these newly born neurons integrate into functional circuitry. As sizable integration of adult-born neurons naturally occurs in the dentate gyrus region of the hippocampus, clarifying the mechanisms of this process could provide insights for applying neural stem and progenitor cells in clinical settings. There is convincing evidence of functional correlations between adult-born neurons and memory consolidation and sleep; therefore, we describe some new advances that were left untouched in our recent review.
文摘Lesions and temporary inactivation of the hippocampus (HPC) in rodents occasionally lead to discrepant amnesic effects. We directly compared and contrasted the retrograde amnesic effects that small HPC lesions (~50% damage), large HPC lesions (~80% damage), and combined dorsal and ventral HPC inactivation using the sodium channel blocker tetrodotoxin (TTX) had on contextual fear conditioning. Compared to control rats, large HPC lesions significantly reduced freezing during retention testing, a behaviour consistent with retrograde amnesia. In contrast, neither the small lesions nor the TTX inactivation significantly reduced freezing. The extent of damage was significantly and negatively correlated with retention performance (r<sub>(9)</sub> = -0.896, p < 0.001), suggesting that 70% or more of the HPC needed to be damaged to observe deficits. Importantly, TTX inactivation disrupted spatial memory in the Morris Water Task, confirming that our inactivation procedure did impair one form of HPC-dependent memory. To assess the extent of the TTX inactivation, immediate early gene expression was quantified in the HPC following the Morris Water Task. However, despite the behavioural impairment, we did not find a significant reduction in expression. We conclude that temporary inactivation of the HPC may fail to impair context fear memory because this technique does not sufficiently disrupt the HPC.
基金supported by grants from the National Nature Science Foundation of China(32271034,32070964,82301703,32300791,and 81901378)Science and Technology Innovation Enhancement Project of Army Medical University(2022XQN40)+4 种基金National Key Research and Development Program of China(2021ZD0201703)Chongqing Natural Science Fund for Distinguished Young Scholars(CSTB2023NSCQ-JQX0030)Undergraduate Research Cultivation Project of Army Medical University(2020XBK16)Guangdong Basic and Applied Basic Research Foundation(2021A1515110268 and 2023A1515010651)Shenzhen Fundamental Research Program(RCBS20210706092411028 and JCYJ20210324121214039).
文摘Posttraumatic stress disorder(PTSD)is a complex mental disorder notable for traumatic experience memory.Although current first-line treatments are linked with clinically important symptom reduction,a large proportion of patients retained to experience considerable residual symptoms,indicating pathogenic mechanism should be illustrated further.Recent studies reported that newly formed myelin could shape neural circuit function and be implicated in fear memory preservation.However,its role in PTSD remains to be elucidated.In this study,we adopted a restraint stress-induced PTSD mouse model and found that PTSD-related neuropsychiatric symptoms were accompanied by increased myelination in the posterior parietal cortex and hippocampus.Fluoxetine,but not risperidone or sertraline,has a more profound rescue effect on neuropsychological behaviors and myelin abnormalities.Further mechanistic experiments revealed that fluoxetine could directly interfere with oligodendroglial differentiation by upregulating Wnt signaling.Our data demonstrated the correlation between PTSD and abnormal myelination,suggesting that the oligodendroglial lineage could be a target for PTSD treatment.
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.
