Neurobiological mechanisms in the regulation of conditioned fear memory by the retrieval-extinction paradigm / 中华行为医学与脑科学杂志

Fear memories are temporarily suppressed after repeated retrieval, a phenomenon known as memory extinction.How to reduce or even eliminate fear memory is the key to the treatment of fear related diseases such as post-traumatic stress disorder(PTSD). A single extinction training based on Pavlov's fear regulation task could only inhibit the expression of conditioned fear memory traces, but it could not eliminate the acquired conditioned fear memory. However, according to the reconsolidation theory based on memory, the retrieval-extinction paradigm has a more lasting effect on the erasure and rewriting of fear memory, and can effectively prevent the return of fear memory. Studies have shown that extraction-regression is closely related to a variety of neurotransmitter receptors such as glutamate receptor(GluR), dopamine receptor(DAR), L-type voltage-gated calcium channels(LVGCs) and cannabinoid. Moreover, its effect is closely related with factors such as retrieval-extinction memory stage. At present, most of the researches on extracted boundary conditions only stay at the level of behavior, with little understanding and exploration on the level of molecular mechanism. From the perspective of molecular neurobiology, with different stages of memory and different types of receptors and molecular mechanisms, this research reviewed the mechanisms of retrieval-extinction in recent years.It provided valuable signaling pathways, molecular targets and research directions for the treatment of fear-related diseases such as PTSD.

Rac1 Signaling in Amygdala Astrocytes Regulates Fear Memory Acquisition and Retrieval / 神经科学通报·英文版

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.

Altered expression of AMPAR and NMDAR subunits in hippocampal CA1 area with contextual fear memory generalization in mice / 中华行为医学与脑科学杂志

Objective To investigate the alteration of subunit expression of AMPAR and NMDAR in hippocampal CA1 area of mice with contextual fear memory generalization.Methods 35 male C57BL/6 mice,aged 8 weeks,were involved in the experiment.Seven mice were randomly selected as the naive group, which didn't receive the behavioral training.28 mice experienced the context fear conditioning and contextual shift task were divided into generalization group and non generalization group according to the result.Then Western blot was used to measure the expression of AMPAR and NMDAR subunits in CA1 in the naive group,non generalization group and generalization group.Results (1)Seven mice(discrimination ratio:0.52±0.08)showed contextual generalization when undergoing the same stress level,while the other 21 mice (discrimination ratio:0.75±0.07)didn't(P<0.01),however,these two group showed similar freezing(%) in the memory acquisition process.(2)The subunit composition of AMPA receptors had no significant differ-ence in CA1 area among the Naive group,non generalization group and generalization group(P>0.05).(3) NR1 subunit was similar in the three groups(P>0.05).NR2A expression was significantly increased in the non generalization group(1.11±0.20)and generalization group(1.09±0.20)compared with that in the na-ive group(0.95±0.17)(both P<0.05).The expression of NR2B was significantly increased in generalization group(1.05±0.17)compared with that in the naive group(0.83±0.19)and non generalization group(0.80± 0.14)(both P<0.05).The ratio of NR2A/NR2B was significantly increased in non generalization group (1.23±0.25)compared with that in the naive group(0.89±0.31)and generalization group(0.86±0.17) (both P<0.05).Conclusion (1)Only part of the individuals show contextual fear memory generalization after the same stress,and this contextual generalization progress is not related to the acquisition of context fear memory.(2)There is no significant change in expression of AMPAR subunits in CA1 of mice with the contextual generalization.The rise of NR2B and the decline of ratio of NR2A/NR2B are the main changes, suggesting that consequently the alternation of synaptic plasticity maybe one of the mechanisms of contextual fear memory generalization.

Fear memory and heart rate and blood pressure during conditioned fear in rats with hippocampal lesion or fimbria-fornix transection / 中华行为医学与脑科学杂志

Objective To investigate the effects of dorsal hippocampal lesions (DH) or fimbria-fornix transection (FF) on the learning and memory of conditioned fear and the heart rate and blood pressure in rats.Methods Nineteen male adult Wistar rats were used in this experiment.They were implanted telemetry sensors in their abdominal aortas.Two week later,six of the rats were subjected to permanent NMDA-induced neurotoxic lesions to the dorsal hippocampus (DH) and seven for the fimbria-fornix transection (FF)through stereotactic brain surgery,the left six were treated with saline as the control (Sham).All rats were subjected to a conditioned fear experiment.Meanwhile,changes in heart rate and blood pressure were measured.Results There was no significant difference in heart rate and blood pressure among the rats with the hippocampal operation or fimbria-fornix transection.In the acquisition of conditioned fear,there were significant difference in freezing time among the three group in both inter-trial-interval (ITI) and conditioned stimulus (CS) process (all P＜0.05).The freezing time of the FF group showed significantly lower than that of the Sham group (P＜0.05).There was no significant difference in heart rate and blood pressure among the three group(P＞0.05).In the test of conditioned contextual fear memory,the freezing time percentage in the FF group ((0.31±0.16) ％) significantly lower than that in the Sham group ((2.78± 1.23) ％) (P＜0.05)at the first 3 min of the test.There was a significant difference in heart rate among the three group.The heart rate of FF group ((436.42± 10.16) times/min) was significantly lower than that of the Sham group ((472.48±4.43) times/min,P＜0.01) and the DH group ((469.94 ±7.36)times/min,P＜0.01).In the test of conditioned tone fear memory.The freezing time percentage in FF group ((18.78±6.29) ％) was significantly lower than that in the Sham ((51.77±9.33)％,P＜0.01) and DH group ((59.19±8.13)％,P＜0.01),but the freezing time percentage between the later two groups had no difference (P=0.52).The synchronous telemetry measurement showed there was no significant difference both in the heart rate and the blood pressure among the groups (all P＞0.05) during the conditioned tone test.Conclusion The dorsal hippocampal lesions and fimbria-fornix transection in rats can significantly reduce the learning and memory ability in conditioned fear and scene fear in rats,and the effect of fimbria-fornix transection is more obvious.The decrease in,fear memory is not synchronously reflected in heart rate and blood pressure in rats.

Differential Histone Acetylation in Sub-Regions of Bed Nucleus of the Stria Terminalis Underlies Fear Consolidation and Extinction

OBJECTIVE: The hallmark of anxiety disorders is excessive fear. Previous studies have suggested that selective neural projections from Basal nucleus of stria terminalis (BNST) to amygdala and vice-versa precisely control the fear learning process. However the exact mechanism how the BNST controls fear consolidation and its extinction is largely unknown. In the present study we observed the changes in the BNST sub-regions following fear conditioning and its extinction. METHODS: The change in the number of positive neurons was determined by immunohistochemistry for Acetyl H3 (Histone 3), Acetyl H4 (Histone 4), cAMP response element binding Protein (CBP) and c-fos in three sub-regions of the BNST namely the anterio-lateral BNST (STLP) and anterio-medial BNST (STMA), and lateral-ventral BNST (STLV) of rats subjected to auditory fear conditioning and extinction. RESULTS: We found significant increase in the number of CBP, acetyl H3 and acetyl H4 positive neurons in the STMA and STLV but not in the STLP after fear conditioning. However, following fear extinction the number of CBP, acetyl H3 and acetyl H4 positive neurons increased significantly in the STLP but not in the STMA and STLV. Similar changes were observed in the number of c-fos positive neurons after fear consolidation and extinction. CONCLUSION: The results from this study suggest that the differential histone acetylation in the different sub-regions of the BNST following fear learning and its extinction may be responsible for changes in the neuronal activation patterns resulting in either fear or less fear.

Novel therapeutic targets for post-traumatic stress disorder:endocannabinoid system / 中国病理生理杂志

Post-traumatic stress disorder (PTSD) is a kind of mental disorder that usually occurs after life-threatening and strong mental traumas .Clinical studies showed that the PTSD patients are 3 times more likely to have can-nabis as compared with the healthy people .The use of cannabinoids has a close relationship with the occurrence and clini-cal manifestations of PTSD .Experimental studies revealed that endocannabinoid ( eCB) signal alterations in animal models of PTSD influenced fear memory of the animals , suggesting a close correlation between the eCB system and the pathogenesis of PTSD.Given that the eCB system was reported to regulate affective states and participate in memory consolidation , re-trieval and extinction , targeting the eCB system may improve the emotional and cognitive features of PTSD , thereby holding out great promise for the development of novel approaches for clinical treatment of PTSD .

Neurobiological mechanisms of conditioned fear memory reconsolidation / 中国病理生理杂志

Post-traumatic stress disorder (PTSD) is a reactive mental disorder that occurs after an individual was exposed to a traumatic event,and the core of the treatment is the extinction of conditioned fear memory caused by stress.Fear memory is an incentive mechanism based on external stimuli that occupy a central position in the defense system.Traditional memory concept convinced that the original memory traces were in an unstable state when the memory was activated.This process is called memory reconsolidation.The research has proved the existence of the fear memory reconsolidation,but the specific mechanism of reconsolidation has not been clarified.The animal studies show that many brain sites and molecular mechanisms are involved in the process of fear memory reconsolidation.Understanding the underlying mechanisms of fear memory reconsolidation is conducive to the treatment of specific phobias and PTSD.This review summarized the brain structure and molecular mechanism of conditioned fear memory reconsolidation,providing a new direction for the in-depth study of conditioned fear memory reconsolidation and PTSD.

Neurobiological mechanisms of conditioned fear memory reconsolidation / 中国病理生理杂志

Post-traumatic stress disorder (PTSD) is a reactive mental disorder that occurs after an individual was exposed to a traumatic event,and the core of the treatment is the extinction of conditioned fear memory caused by stress.Fear memory is an incentive mechanism based on external stimuli that occupy a central position in the defense system.Traditional memory concept convinced that the original memory traces were in an unstable state when the memory was activated.This process is called memory reconsolidation.The research has proved the existence of the fear memory reconsolidation,but the specific mechanism of reconsolidation has not been clarified.The animal studies show that many brain sites and molecular mechanisms are involved in the process of fear memory reconsolidation.Understanding the underlying mechanisms of fear memory reconsolidation is conducive to the treatment of specific phobias and PTSD.This review summarized the brain structure and molecular mechanism of conditioned fear memory reconsolidation,providing a new direction for the in-depth study of conditioned fear memory reconsolidation and PTSD.

Effect and mechanism of dexmedetomidine and mifepristone on fear memory in rats with PTSD / 中华行为医学与脑科学杂志

Objective To investigate the effect and mechanism of dexmedetomidine, mifepristone and dexmedetomidine plus mifepristone on the fear memory in rats with post?traumatic stress disorder ( PTSD) . Methods 40 male SD rats were randomly divided into five groups with 8 in each group:control group (group C),PTSD model group (group P),dexmedetomidine group (group D),mifepristone group ( group M) and dexmedetomidine plus mifepristone group ( group U) . Fear memory in rats was evaluated by fear conditioning test ( FC) . Anxiety?like behavior was assessed by the elevated plus?maze test ( EPM) . Ex?pressions of BDNF and its receptor TrkB in the hippocampus of rats after fear condition were detected using Western blot ( WB) and CORT level in the serum was detected using enzyme?linked immunosorbent assay (ELISA). Results Compared with group P,the freezing scores in the FC in group D((32.29±8.09) %), M((33.33±8.21) %),and U((9.38±3.31) %) were significantly decreased (P<0.05). The times and en?tries in the open arms of the EPM were significantly increased (P<0.05) . The expressions of BDNF in group D(0.65±0.04),M(0.71±0.04),U(0.79±0.07) and TrkB in group D(0.66±0.04),M(0.71±0.04),U (0.86±0.03) were obviously rescued in hippocampus of rats (P<0.05). The CORT level in serum in group D ((37.65±12.37)μg/L) and U((59.10±5.23)μg/L) was decreased (P<0.05). There was no difference be?tween group P and M. Conclusion These results suggest that dexmedetomidine, mifepristone and dexme?detomidine plus mifepristone can significantly enhance fear extinction and improve anxiety?like behaviors in rats with PTSD. The mechanism may be that dexmedetomidine and mifepristone could enhance the expres? sions of BDNF and TrkB in the hippocampus.

Interactional effects of corticosterone and stress in the formation of PTSD-like memory impairment rats / 中华行为医学与脑科学杂志

Objective To investigate the interactional roles corticosterone and stress played during the PTSD-Like memory impairment.Methods First we established the model of PTSD-like memory using three levels of electric shock:0 mA,0.8 mA and 1.4 mA.The freezing time percent of each group were calculated 24 hours later in order to find which group of rats obtained the PTSD-like memory,and generalizing tests was used to verify it.After the model was established,rats received adrenalectomy (ADX) were operated bilaterally in order to investigate the effect of corticosterone and fed with corticosterone in the drinking water 7 days before fear conditioning.These rats were divided into four groups:control group (no corticosterone supplement,0 mA shock),Cort group (corticosterone supplement,0 mA shock),shock group (no corticosterone supplement,1.4 mA shock),Cort-shock group (corticosterone supplement,1.4 mA shock).A two-way factorial analysis of variance was used to determine whether there was a significant interaction between corticosterone and shock.Results The freezing time percent of group 0.8 mA raised compared with the group 0 mA,whereas the freezing time percent of group 1.4 mA showed reversely and the generalizing effects appeared,compared with group 0.8 mA.In two-way factorial analysis design,the freezing time percent of Cort-shock group significantly increased (P＜0.05) compared with other groups,and there was no significant variance among the other groups.Corticosterone (F=6.464,P＜0.05) and stress (F=53.419,P ＜0.01) played parts in the formation of PTSD-like memory impairment,and they interacted with each other (F=11.580,P＜0.05).Conclusion PTSD-like memory impairment can be induced on rats with high (1.4 mA) electrical shock,and they have interactional effect with each other in the process.

What ethologically based models have taught us about the neural systems underlying fear and anxiety

Classical Pavlovian fear conditioning to painful stimuli has provided the generally accepted view of a core system centered in the central amygdala to organize fear responses. Ethologically based models using other sources of threat likely to be expected in a natural environment, such as predators or aggressive dominant conspecifics, have challenged this concept of a unitary core circuit for fear processing. We discuss here what the ethologically based models have told us about the neural systems organizing fear responses. We explored the concept that parallel paths process different classes of threats, and that these different paths influence distinct regions in the periaqueductal gray - a critical element for the organization of all kinds of fear responses. Despite this parallel processing of different kinds of threats, we have discussed an interesting emerging view that common cortical-hippocampal-amygdalar paths seem to be engaged in fear conditioning to painful stimuli, to predators and, perhaps, to aggressive dominant conspecifics as well. Overall, the aim of this review is to bring into focus a more global and comprehensive view of the systems organizing fear responses.

Effects of 6-OHDA lesion of hippocampal CA3 dopaminergic system on conditioned fear memory in rats / 中华行为医学与脑科学杂志

ObjectiveTo investigate the effects of hippocampal CA3 dopaminergic system in acquisition and consolidation of Pavlovian fear conditioning,and expression of GluR1 and NR2B in medial prefrontal cortex (mPFC),CA1 and basolateral amygdala (BLA) after fear conditioning training.MethodsBilateral injection 6-OHDA into hippocampal CA3 to lesion dopaminergic fibers 2 weeks before fear conditioning training.The change of GluR1 and NR2B were analyzed by western blot after training.ResultsCompared with the saline group ( (66.44 ± 16.58)％ ),there were significant decreases ( (39.24 ± 12.83)％,(31.15 ±6.51 )％ ) in the consolidation of short- and long- term fear memory (P ＜ 0.05 ) but not the acquisition ( ( 65.58 ± 5.33 ) ％,P ＞ 0.05).The expression of GluR1 protein was significantly increased in BLA (P＜0.01 ) but not the mPFC or hippocampal CA1 (P＞1.05 ),compared with the saline group.In addition,the expression of NR2B protein was significantly increased in the mPFC and decreased in BLA (P＜0.01) but not the hippocampal CA1 (P＞0.05),compared with the saline group.ConclusionDown-regulation of dopaminergic system in hippocampal CA3 may impair the consolidation but not the acquisition of fear memory,and also regulate the expression of GluR1,NR2B protein related to fear memory in other brain regions.

Effect of Intensity of Unconditional Stimulus on Reconsolidation of Contextual Fear Memory

Memory reconsolidation is ubiquitous across species and various memory tasks. It is a dynamic process in which memory is modified and/or updated. In experimental conditions, memory reconsolidation is usually characterized by the fact that the consolidated memory is disrupted by a combination of memory reactivation and inhibition of protein synthesis. However, under some experimental conditions, the reactivated memory is not disrupted by inhibition of protein synthesis. This so called "boundary condition" of reconsolidation may be related to memory strength. In Pavlovian fear conditioning, the intensity of unconditional stimulus (US) determines the strength of the fear memory. In this study, we examined the effect of the intensity of US on the reconsolidation of contextual fear memory. Strong contextual fear memory, which is conditioned with strong US, is not disrupted by inhibition of protein synthesis after its reactivation; however, a weak fear memory is often disrupted. This suggests that a US of strong intensity can inhibit reconsolidation of contextual fear memory.

The effects of venlafaxine on the extinction of fear memory in rat / 中华行为医学与脑科学杂志

ObjectiveTo identify the effects of venlafaxiue on the acquisition and consolidation of fear extinction memory in conditioning fear memory extinction model.MethodsMale Sprague-Dawley rats were treated with fear conditioning training in the A environment.Before the extinction training,all the experimental rats were given different doses of venlafaxine intraperitoneal injection.After 24 hours,all the rats test in the B environment.ResultsRepeated-measures ANOVA were conducted on the percent of freezing time for between-session extinction,test condition (F2,44 =458.958,P＜0.001 ) and VEN dose(F2,22 =43.026,P＜0.001 ) and a Test condition * Treatment interaction (F4,44 =31.363,P ＜ 0.001 ).For the within-session,post hoc comparisons indicated that the three groups that received different dose of VEN (0,20 and 40 mg/kg) did not differ from each other (P ＞ 0.05 ),indicating similar extinction following the post-conditioning.The rats injected with high-dose venlafaxine (40 mg/kg) intraperitoneally before extinction training showed pro,motion of between-subjects extinction of fear memory,but does not affect the within-subjects extinction.There was no significant catabolism in the rats injected with middle-dose (20 mg/kg).ConclusionThe available date indicate that venlafaxine could promote the extinction of fear memory and there is a dose-dependent relationship of venlafaxine in the facilitation of fear memory.Our results could provide some clinical guidance for the treatment of post-traumatic stress disorder and panic disorder.