Comparison between cannabidiol and sertra⁃line in modulation of post-traumatic stress dis⁃order-like behaviors and fear memory in mice

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.

Rac1 Signaling in Amygdala Astrocytes Regulates Fear Memory Acquisition and Retrieval

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.

Pyk2 suppresses contextual fear memory in an autophosphorylation-independent manner

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.

Infusion of methylphenidate into the basolateral nucleus of amygdala or anterior cingulate cortex enhances fear memory consolidation in rats

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.

Contrasting the Amnesic Effects of Temporary Inactivation with Lesions of the Hippocampus on Context Memory

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(9) = -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.

Memory Trace for Fear Extinction:Fragile yet Reinforceable

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.

luoxetine Rescues Excessive Myelin Formation and Psychological Behaviors in a Murine PTSD Model

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.