Vibration-reduced anxiety-like behavior relies on ameliorating abnormalities of the somatosensory cortex and medial prefrontal cortex

Tibetan singing bowls emit low-frequency sounds and produce perceptible harmonic tones and vibrations through manual tapping.The sounds the singing bowls produce have been shown to enhance relaxation and reduce anxiety.However,the underlying mechanism remains unclear.In this study,we used chronic restraint stress or sleep deprivation to establish mouse models of anxiety that exhibit anxiety-like behaviors.We then supplied treatment with singing bowls in a bottomless cage placed on the top of a cushion.We found that unlike in humans,the combination of harmonic tones and vibrations did not improve anxietylike behaviors in mice,while individual vibration components did.Additionally,the vibration of singing bowls increased the level of N-methyl-D-aspartate receptor 1 in the somatosensory cortex and prefrontal cortex of the mice,decreased the level ofγ-aminobutyric acid A(GABA)receptorα1 subtype,reduced the level of CaMKII in the prefrontal cortex,and increased the number of GABAergic interneurons.At the same time,electrophysiological tests showed that the vibration of singing bowls significantly reduced the abnormal low-frequency gamma oscillation peak frequency in the medial prefrontal cortex caused by stress restraint pressure and sleep deprivation.Results from this study indicate that the vibration of singing bowls can alleviate anxiety-like behaviors by reducing abnormal molecular and electrophysiological events in somatosensory and medial prefrontal cortex.

The selective 5-HTIA receptor antagonist WAY-100635 inhibits neuronal activity of the ventromedial prefrontal cortex in a rodent model of Parkinson's disease

Objective The ventral part of the medial prefrontal cortex（mPFC）plays an important role in initiation and control of voluntary movement,mood and cognition.However,after the degeneration of the nigrostriatal pathway,the neuronal activity of the ventral mPFC and the role of serotonin1A（5-hydroxytryptamine,5-HT1A）receptors in the firing of the neurons are still unknown.The present study is to investigate the change of neuronal activity in the ventral mPFC and the effect of systemic administration of the selective 5-HT1Areceptor antagonist WAY-100635 on the activity of the neurons in normal and 6-hydroxydopamine（6-OHDA）-lesioned rats.Methods Single unit responses were recorded extracellularly with glass microelectrodes from ventral mPFC neurons in normal rats and 6-OHDA unilaterally lesiond rats in vivo.Results 6-OHDA lesion of the substantia nigra pars compacta（SNc）significantly increased the firing rate with no change in the firing pattern of neurons of the ventral mPFC in rats.Systemic administration of WAY-100635（0.1 mg/kg,i.v.）did not change the mean firing rate and firing pattern of ventral mPFC neurons in normal rats.In contrast,WAY-100635 signifi- cantly decreased the mean firing rate of the neurons in rats with 6-OHDA lesion of the SNc.Conclusion These data suggest that the degeneration of the nigrostriatal pathway results in an increase of neuronal activity of ventral mPFC and dysfunction of 5-HT1Areceptor.

Neurochemical metabolites in the medial prefrontal cortex in bipolar disorder A proton magnetic resonance spectroscopy study

The aim of this study was to investigate proton magnetic resonance spectroscopy metabolite values in the medial prefrontal cortex of individuals with euthymic bipolar disorder. The subjects consisted of 15 patients with euthymic bipolar disorder type I and 15 healthy controls. We performed proton magnetic resonance spectroscopy of the bilateral medial prefrontal cortex and measured levels of N-acetyl aspartate, choline and creatine. Levels of these three metabolites in the medial prefrontal cortex were found to be lower in patients with bipolar disorder compared with healthy controls. A positive correlation was found between illness duration and choline levels in the right medial prefrontal cortex. Our study suggests that during the euthymic period, there are abnormalities in cellular energy and membrane phospholipid metabolism in the medial prefrontal cortex, and that this may impair neuronal activity and integrity.

Distinct neuronal excitability alterations of medial prefrontal cortex in early-life neglect model of rats

Object:Early-life neglect has irreversible emotional effects on the central nervous system.In this work,we aimed to elucidate distinct functional neural changes in me-dial prefrontal cortex(mPFC)of model rats.Methods:Maternal separation with early weaning was used as a rat model of early-life neglect.The excitation of glutamatergic and GABAergic neurons in rat mPFC was recorded and analyzed by whole-cell patch clamp.Results:Glutamatergic and GABAergic neurons of mPFC were distinguished by typi-cal electrophysiological properties.The excitation of mPFC glutamatergic neurons was significantly increased in male groups,while the excitation of mPFC GABAergic neurons was significant in both female and male groups,but mainly in terms of rest membrane potential and amplitude,respectively.Conclusions:Glutamatergic and GABAergic neurons in medial prefrontal cortex showed different excitability changes in a rat model of early-life neglect,which can contribute to distinct mechanisms for emotional and cognitive manifestations.

High frequency heart rate variability evoked by repetitive transcranial magnetic stimulation over the medial prefrontal cortex: A preliminary investigation on brain processing of acute stressor-evoked cardiovascular reactivity

Introduction: Transcranial Magnetic Stimulation (TMS) is a non-invasive technique for brain stimulation. Repetitive TMS (rTMS) over the medial Prefrontal Cortex (mPFC), Broadman Area 10 (BA10) may stimulate transynaptically perigenual Anterior Cingulate Cortex (pACC, BA 33), insula, amigdala, hypothalamus and connected branches of the Autonomic Nervous System (ANS) involved in stressorevoked cardiovascular reactivity. Stressors are associated with an increase in sympathetic cardiac control, a decrease in parasympathetic control, or both, and, consequently, an increase in systolic/stroke volume, total vascular impedance/resistance and heart rate, a decrease of baroreflex sensitivity, i.e., an increase in blood pressure/arterial tension. Objectives and Aims: The present work aims, using TMS and accordingly to Gianaros modeling, based on functional neuroimaging studies and previous neuroanatomical data from animal models, to probe the connectivity of brain systems involved in stressor-evoked cardiovascular reactivity and to explore TMS potential as a tool for detection and stratification of individual differences concerning this reactivity and hemorreological risk factors correlated with the development of Coronary Heart Disease (CHD). Methods: Both subjects, a 52 years old male and a 40 years old female with previous increased Low Frequency (LF)/High Frequency (HF) Heart Rate Variability (HRV) ratios (respectively, 4.209/3.028) without decompensated cardiorespiratory symptoms, gave informed consent, and ethico-legal issues have been observed. Electroencephalographic (EEG) monitoring has been performed for safety purposes. Immediately after administration, over the mPFC, of 15 pulses of rTMS, during 60 second, with an inductive electrical current, at the stimulating coil, of 85.9 Ampère per μsecond and 66 Ampère per μsecond, respectively, for male and female subjects (a “figure-of-eight” coil and magnetic stimulator MagLite, Dantec/Medtronic, have been used), HRV spectrum analysis (cStress software) has been performed (during 5 minutes, in supine position). Results: In both subjects, LF power, HF power and LF/HF ratio results, before and after rTMS administration, pointed towards sympathetic attenuation and parasympathetic augmentation (respectively, in male/female subject: decreased LF power—65.1 nu/69.3 nu, before rTMS;56.1 nu/41.6 nu, after rTMS;increased HF power—15.5 nu/22.9 nu, before rTMS;30.9 nu/45.5 nu, after rTMS). Conclusions: In this preliminary investigation, the existence of a link between “mind” and heart’s function has been put in evidence, through a reversible “virtual” lesion, of brain systems involved in cardiovascular control, caused by TMS. Repetitive TMS over mPFC decreased brain function involved in stressorevoked cardiovascular reactivity, suggesting the importance of TMS in the management of stress-related cardiovascular disorders.

Dopamine D2 receptors in the dorsomedial prefrontal cortex modulate social hierarchy in male mice

Social hierarchy greatly influences behavior and health.Both human and animal studies have signaled the medial prefrontal cortex(mPFC)as specifically related to social hierarchy.Dopamine D1 receptors(D1Rs)and D2 receptors(D2Rs)are abundantly expressed in the mPFC,modulat-ing its functions.However,it is unclear how DR-expressing neurons in the mPFC regulate social hierarchy.Here,using a confrontation tube test,we found that most adult C57BL/6J male mice could establish a linear social rank after 1 week of cohabitation.Lower rank individuals showed social anxiety together with decreased serum testosterone levels.D2R expression was significantly downregulated in the dorsal part of mPFC(dmPFC)in lower rank individuals,whereas D1R expression showed no significant difference among the rank groups in the whole mPFC.Virus knockdown of D2Rs in the dmPFC led to mice being particularly prone to lose the contests in the confrontation tube test.Finally,simultaneous D2R activation in the subordinates and D2R inhibition in the dominants in a pair switched their dominant-subordinate relationship.The above results indicate that D2Rs in the dmPFC play an important role in social dominance.Our findings provide novel insights into the divergent func-tions of prefrontal D1Rs and D2Rs in social dominance,which may contribute to ameliorating social dysfunctions along with abnormal social hierarchy.

Effects of Melatonin Levels on Neurotoxicity of the Medial Prefrontal Cortex in a Rat Model of Parkinson＇s Disease

Background： Damage of the medial prefrontal cortex （mPFC） results in similar characteristics to the cognitive deficiency seen with the progress of Parkinson＇s disease （PD）. Since the course of mPFC damage is still unclear, our study aimed to investigate the effects of melatonin （MT） on neurotoxicity in the mPFC of a rat model of PD. Methods： One hundred and fifty-four normal, male Wistar rats were randomly divided into the following five groups： normal ＋ normal saline （NS）, normal ＋ 6-hydroxydopamine （6-OHDA）, sham pinealectomy （PX） ＋ 6-OHDA, PX ＋ 6-OHDA, and MT ＋ 6-OHDA. 6-OHDA was injected into the right substantia nigra pars compacta （SNc） and ventral tegmental area （VTA） of each group, except normal ＋ NS, 60 days after the PX. In the MT treatment group, MT was administered immediately after the intraperitoneal injection at 4 p.m. every day, for 14 days. Neuronal apoptosis in the mPFC was exalnined using the TUNEL method, while the expression oftyrosine hydroxylase （TH）, Bax, and Bcl-2 in this region was measured using immunohistochemistry. The concentration of malondialdehyde （MDA） in the mPFC was examined using the thioharbituric acid method. Results： Rats in the normal ＋ 6-OHDA and sham PX ＋ 6-OHDA groups were combined into one group （Group N ＋ 6-OHDA） since there was no significant discrepancy between the groups for all the detected parameters. Apoptosis of cells in the NS, MT ＋ 6-OHDA, N ＋ 6-OH DA, and PX ＋ 6-OHDA groups was successively significantly increased （Hc = 256.25, P 〈 0.001 ）. The gray value of TH （＋） fibers in the NS, MT ＋ 6-OHDA, N ＋ 6-OHDA, and PX ＋ 6-OHDA groups was also successively significantly increased （F= 99.33, P 〈 0.001 ）. The staining intensities of Bax and Bcl-2 were as follows： Group NS ＋/＋, Group MT ＋ 6-OHDA ＋＋/＋, Group N ＋ 6-OHDA ＋＋/＋, and PX ＋ 6-OHDA ＋＋＋/＋. The concentrations of MDA in the NS, MT ＋ 6-OHDA, N ＋ 6-OHDA, and PX ＋ 6-OHDA groups were significantly increased in sequence （Hc = 296.309, P 〈 0.001 ）. Conclusions： Neuronal damage of the VTA by 6-OHDA might induce VTA-mPFC nerve fibers to undergo anterograde nerve damage, in turn inducing transneuronal damage of the mPFC. PX significantly exacerbated the neurotoxicity in the mPFC, which was induced by the neuronal injury of the VTA. However, MT replacement therapy significantly alleviated the neurotoxicity in the mPFC.

Anticipatory activity in rat medial prefrontal cortex during a working memory task

Objective Working memory is a key cognitive function in which the prefrontal cortex plays a crucial role. This study aimed to show the firing patterns of a neuronal population in the prefrontal cortex of the rat in a working memory task and to explore how a neuronal ensemble encodes a working memory event. Methods Sprague-Dawley rats were trained in a Y-maze until they reached an 80% correct rate in a working memory task. Then a 16-channel microelectrode array was implanted in the prefrontal cortex. After recovery, neuronal population activity was recorded during the task, using the Cerebus data-acquisition system. Spatio-temporal trains of action potentials were obtained from the original neuronal population signals. Results During the Y-maze working memory task, some neurons showed significantly in- creased firing rates and evident neuronal ensemble activity. Moreover, the anticipatory activity was associated with the delayed alternate choice of the upcoming movement. In correct trials, the averaged pre-event firing rate （10.86 ± 1.82 spikes/ bin） was higher than the post-event rate （8.17 ± 1.15 spikes/bin） （P 〈0.05）. However, in incorrect trials, the rates did not differ. Conclusion The results indicate that the anticipatory activity of a neuronal ensemble in the prefrontal cortex may play a role in encoding working memory events.

Reversal of Social Recognition Deficit in Adult Mice with MECP2 Duplication via Normalization of MeCP2 in the Medial Prefrontal Cortex

Methyl-CpG binding protein 2(MeCP2) is a basic nuclear protein involved in the regulation of gene expression and microRNA processing.Duplication of MECP2-containing genomic segments causes MECP2 duplication syndrome,a severe neurodevelopmental disorder characterized by intellectual disability,motor dysfunction,heightened anxiety,epilepsy,autistic phenotypes,and early death.Reversal of the abnormal phenotypes in adult mice with MECP2 duplication(MECP2-TG) by normalizing the MeCP2 levels across the whole brain has been demonstrated.However,whether different brain areas or neural circuits contribute to different aspects of the behavioral deficits is still unknown.Here,we found that MECP2-TG mice showed a significant social recognition deficit,and were prone to display aversive-like behaviors,including heightened anxiety-like behaviors and a fear generalization phenotype.In addition,reduced locomotor activity was observed in MECP2-TG mice.However,appetitive behaviors and learning and memory were comparable in MECP2-TG and wild-type mice.Functional magnetic resonance imaging illustrated that the differences between MECP2-TG and wild-type mice were mainly concentrated in brain areas regulating emotion and social behaviors.We used the CRISPR-Cas9 method to restore normal MeCP2 levels in the medial prefrontal cortex(mPFC) and bed nuclei of the stria terminalis(BST) of adult MECP2-TG mice,and found that normalization of MeCP2 levels in the mPFC but not in the BST reversed the social recognition deficit.These data indicate that the mPFC is responsible for the social recognition deficit in the transgenic mice,and provide new insight into potential therapies for MECP2 duplication syndrome.

Effect of reward alteration following acupuncture for morphine withdrawal rats on neuronal discharges in the ventral medial prefrontal cortex

Objective：To observe the effect of reward alteration following acupuncture for morphine withdrawal rats on the behavior and neuronal discharges in the medial prefrontal cortex （mPFC）. Methods：The Sprague-Dawley （SD） rats were randomly allocated into a model group, a confinement group, an electroacupuncture （EA） group, and a control group. Rats with morphine addiction were made by intraperitoneal injection of naloxone （same dose injection of saline for rats in the control group）, followed by a 2-week morphine withdrawal. Acupuncture and confinement were completed during the morphine withdrawal period. Upon withdrawal, the rats received conditioned place preference （CPP） training and open field test. The multi-channel neural signal processor was used in the electrophysiological experiment to measure the neuronal discharges in different subareas of prefrontal cortex in CPP box and aversion box. Results：Rats in the model group and the confinement group spent longer period of time in CPP box than those in the EA group and the control group （allP〈0.01）; there was no statistically significant difference between the EA group and the control group. The total distances of movement by rats in the model group and the confinement group were longer than those in the EA group and the control group （allP〈0.01）. The mPFC neuronal discharge frequencies were compared between morphine preference box and aversion box. The mPFC neuronal discharge frequencies in the model group and the confinement group were higher than those in the EA group and the control group （allP〈0.05）; there was no statistically significant difference between the EA group and the control group. Conclusion：Acupuncture can effectively interfere with the reward alteration following morphine withdrawal, possibly because of its involvement with the mPFC neuronal discharges.

Brain region-specific roles of brain-derived neurotrophic factor in social stress-induced depressive-like behavior

Brain-derived neurotrophic factor is a key factor in stress adaptation and avoidance of a social stress behavioral response.Recent studies have shown that brain-derived neurotrophic factor expression in stressed mice is brain region–specific,particularly involving the corticolimbic system,including the ventral tegmental area,nucleus accumbens,prefrontal cortex,amygdala,and hippocampus.Determining how brain-derived neurotrophic factor participates in stress processing in different brain regions will deepen our understanding of social stress psychopathology.In this review,we discuss the expression and regulation of brain-derived neurotrophic factor in stress-sensitive brain regions closely related to the pathophysiology of depression.We focused on associated molecular pathways and neural circuits,with special attention to the brain-derived neurotrophic factor–tropomyosin receptor kinase B signaling pathway and the ventral tegmental area–nucleus accumbens dopamine circuit.We determined that stress-induced alterations in brain-derived neurotrophic factor levels are likely related to the nature,severity,and duration of stress,especially in the above-mentioned brain regions of the corticolimbic system.Therefore,BDNF might be a biological indicator regulating stress-related processes in various brain regions.

In vivo imaging reveals a synchronized correlation among neurotransmitter dynamics during propofol and sevoflurane anesthesia

General anesthesia is widely applied in clinical practice.However,the precise mechanism of loss of consciousness induced by general anesthetics remains unknown.Here,we measured the dynamics of five neurotransmitters,includingγ-aminobutyric acid,glutamate,norepinephrine,acetylcholine,and dopamine,in the medial prefrontal cortex and primary visual cortex of C57BL/6 mice through in vivo fiber photometry and genetically encoded neurotransmitter sensors under anesthesia to reveal the mechanism of general anesthesia from a neurotransmitter perspective.Results revealed that the concentrations of γ-aminobutyric acid,glutamate,norepinephrine,and acetylcholine increased in the cortex during propofol-induced loss of consciousness.Dopamine levels did not change following the hypnotic dose of propofol but increased significantly following surgical doses of propofol anesthesia.Notably,the concentrations of the five neurotransmitters generally decreased during sevoflurane-induced loss of consciousness.Furthermore,the neurotransmitter dynamic networks were not synchronized in the non-anesthesia groups but were highly synchronized in the anesthetic groups.These findings suggest that neurotransmitter dynamic network synchronization may cause anesthetic-induced loss of consciousness.

Merits and demerits of administering esketamine in preventing postpartum depression following cesarean section

Emergency cesarean section is associated with the development of postpartum depression.Esketamine has been demonstrated to have a rapid onset of antide-pressant effects.Randomized controlled trials and meta-analyses have demon-strated the efficacy of esketamine in preventing postpartum depression after ce-ssarean section.However,the data included in these analyses were derived from elective cesarean sections and differed in the dose and timing of esketamine ad-ministration.Esketamine is a dissociative anesthetic with a dose-dependent risk of inducing psychotic symptoms,including hallucinations.In the setting of cesarean section,esketamine should be administered with caution and only if the potential benefits outweigh the risks.

Ventral medial prefrontal functional connectivity and emotion regulation in chronic schizophrenia: A pilot study

People with schizophrenia exhibit impaired social cognitive functions, particularly emotion regulation. Abnormal activations of the ventral medial prefrontal cortex （vMPFC） during emotional tasks have been demonstrated in schizophrenia, suggesting its important role in emotion processing in patients. We used the resting-state functional connectivity approach, setting a functionally relevant region, the vMPFC, as a seed region to examine the intrinsic functional interactions and communication between the vMPFC and other brain regions in schizophrenic patients. We found hypo-connectivity between the vMPFC and the medial frontal cortex, right middle temporal lobe （MTL）, right hippocampus, parahippocampal cortex （PHC） and amygdala. Further, there was a decreased strength of the negative connectivity （or anticorrelation） between the vMPFC and the bilateral dorsal lateral prefrontal cortex （DLPFC） and pre-supplementary motor areas. Among these connectivity alterations, reduced vMPFC-DLPFC connectivity was positively correlated with positive symptoms on the Positive and Negative Syndrome Scale, while vMPFC-right MTL/PHC/amygdala functional connectivity was positively correlated with the performance of emotional regulation in patients. These findings imply that communication and coordination throughout the brain networks are disrupted in schizophrenia. The emotional correlates of vMPFC connectivity suggest a role of the hypo-connectivity between these regions in the neuropathology of abnormal social cognition in chronic schizophrenia.

Adolescent social isolation influences cognitive function in adult rats

Adolescence is a critical period for neurodevelopment. Evidence from animal studies suggests that isolated rearing can exert negative effects on behavioral and brain development. The present study aimed to investigate the effects of adolescent social isolation on latent inhibition and brain-derived neurotrophic factor levels in the forebrain of adult rats. Male Wistar rats were randomly divided into adolescent isolation （isolated housing, 38-51 days of age） and social groups. Latent inhibition was tested at adulthood. Brain-derived neurotrophic factor levels were measured in the medial prefrontal cortex and nucleus accumbens by an enzyme-linked immunosorbent assay. Adolescent social isolation impaired latent inhibition and increased brain-derived neurotrophic factor levels in the medial prefrontal cortex of young adult rats. These data suggest that adolescent social isolation has a profound effect on cognitive function and neurotrophin levels in adult rats and may be used as an animal model of neurodevelopmental disorders.

Chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway

Ketamine, a rapid-acting antidepressant drug, has been used to treat major depressive disorder and bipolar disorder(BD). Recent studies have shown that ketamine may increase the potential risk of treatment-induced mania in patients. Ketamine has also been applied to establish animal models of mania. At present, however, the underlying mechanism is still unclear. In the current study, we found that chronic lithium exposure attenuated ketamine-induced mania-like behavior and c-Fos expression in the medial prefrontal cortex(mPFC) of adult male mice. Transcriptome sequencing was performed to determine the effect of lithium administration on the transcriptome of the PFC in ketamine-treated mice, showing inactivation of the phosphoinositide 3-kinase(PI3K)-protein kinase B(AKT) signaling pathway. Pharmacological inhibition of AKT signaling by MK2206(40 mg/kg), a selective AKT inhibitor, reversed ketamine-induced mania.Furthermore, selective knockdown of AKT via AAVAKT-sh RNA-EGFP in the mPFC also reversed ketamine-induced mania-like behavior. Importantly,pharmacological activation of AKT signaling by SC79(40 mg/kg), an AKT activator, contributed to mania in low-dose ketamine-treated mice. Inhibition of PI3K signaling by LY294002(25 mg/kg), a specific PI3K inhibitor, reversed the mania-like behavior in ketamine-treated mice. However, pharmacological inhibition of mammalian target of rapamycin(mTOR)signaling with rapamycin(10 mg/kg), a specific mTOR inhibitor, had no effect on ketamine-induced mania-like behavior. These results suggest that chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway, which may be a novel target for the development of BD treatment.

Role of 5-hydroxytryptamine type 3 receptors in the regulation of anxiety reactions

5-Hydroxytryptamine(5-HT)type 3 receptor(5-HT_(3)R)is the only type of ligand-gated ion channel in the 5-HT receptor family.Through the high permeability of Na+,K+,and Ca2+and activation of subsequent voltage-gated calcium channels(VGCCs),5-HT_(3)R induces a rapid increase of neuronal excitability or the release of neurotransmitters from axon terminals in the central nervous system(CNS).5-HT_(3)Rs are widely expressed in the medial prefrontal cortex(mPFC),amygdala(AMYG),hippocampus(HIP),periaqueductal gray(PAG),and other brain regions closely associated with anxiety reactions.They have a bidirectional regulatory effect on anxiety reactions by acting on different types of cells in different brain regions.5-HT_(3)Rs mediate the activation of the cholecystokinin(CCK)system in the AMYG,and theγ-aminobutyric acid(GABA)“disinhibition”mechanism in the prelimbic area of the mPFC promotes anxiety by the activation of GABAergic intermediate inhibitory neurons(IINs).In contrast,a 5-HT_(3)R-induced GABA“disinhibition”mechanism in the infralimbic area of the mPFC and the ventral HIP produces anxiolytic effects.5-HT_(2)R-mediated regulation of anxiety reactions are also activated by 5-HT_(3)R-activated 5-HT release in the HIP and PAG.This provides a theoretical basis for the treatment of anxiety disorders or the production of anxiolytic drugs by targeting 5-HT_(3)Rs.However,given the circuit specific modulation of 5-HT_(3)Rs on emotion,systemic use of 5-HT_(3)R agonism or antagonism alone seems unlikely to remedy anxiety,which deeply hinders the current clinical application of 5-HT_(3)R drugs.Therefore,the exploitation of circuit targeting methods or a combined drug strategy might be a useful developmental approach in the future.

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.

Projections from Infralimbic Cortex to Paraventricular Thalamus Mediate Fear Extinction Retrieval

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.

Chronic Oral Administration of Magnesium-L-Threonate Prevents Oxaliplatin-Induced Memory and Emotional Deficits by Normalization of TNF-a/NF-j B Signaling in Rats

Antineoplastic drugs such as oxaliplatin(OXA)often induce memory and emotional deficits.At present,the mechanisms underlying these side-effects are not fully understood,and no effective treatment is available.Here,we show that the short-term memory deficits and anxietylike and depression-like behaviors induced by intraperitoneal injections of OXA(4 mg/kg per day for 5 consecutive days) were accompanied by synaptic dysfunction and downregulation of the NR2 B subunit of N-methyl-Daspartate receptors in the hippocampus,which is critically involved in memory and emotion.The OXA-induced behavioral and synaptic changes were prevented by chronic oral administration of magnesium-L-threonate(L-TAMS,604 mg/kg per day,from 2 days before until the end of experiments).We found that OXA injections significantly reduced the free Mg~(2+) in serum and cerebrospinal fluid(from ~0.8 mmol/L to ~ 0.6 mmol/L).The Mg~(2+) deficiency(0.6 mmol/L) upregulated tumor necrosis factor(TNF-α) and phospho-p65(p-p65),an active form of nuclear factor-kappaB(NF-κB),and downregulated the NR2 B subunit in cultured hippocampal slices.Oral L-TAMS prevented the OXA-induced upregulation of TNF-α and p-p65,as well as microglial activation in the hippocampus and the medial prefrontal cortex.Finally,similar to oral L-TAMS,intracerebroventricular injection of PDTC,an NF-κB inhibitor,also prevented the OXAinduced memory/emotional deficits and the changes in TNF-α,p-p65,and microglia.Taken together,the activation of TNF-α/NF-κB signaling resulting from reduced brain Mg~(2+) is responsible for the memory/emotional deficits induced by OXA.Chronic oral L-TAMS may be a novel approach to treating chemotherapy-induced memory/emotional deficits.