Microglial activation in the medial prefrontal cortex after remote fear recall participates in the regulation of auditory fear extinction.

Excessive or inappropriate fear responses can lead to anxiety-related disorders, such as post-traumatic stress disorder (PTSD). Studies have shown that microglial activation occurs after fear conditioning and that microglial inhibition impacts fear memory. However, the role of microglia in fear memory recall remains unclear. In this study, we investigated the activated profiles of microglia after the recall of remote-cued fear memory and the role of activated microglia in the extinction of remote-cued fear in adult male C57BL/6 mice. The results revealed that the expression of the microglia marker Iba1 increased in the medial prefrontal cortex (mPFC) at 10 min and 1 h following remote-cued fear recall, which was accompanied by amoeboid morphology. Inhibiting microglial activation through PLX3397 treatment before remote fear recall did not affect recall, reconsolidation, or regular extinction but facilitated recall-extinction and mitigated spontaneous recovery. Moreover, our results demonstrated reduced co-expression of Iba1 and postsynaptic density protein 95 (PSD95) in the mPFC, along with decreases in the p-PI3K/PI3K ratio, p-Akt/Akt ratio, and KLF4 expression after PLX3397 treatment. Our results suggest that microglial activation after remote fear recall impedes fear extinction through the pruning of synapses in the mPFC, accompanied by alterations in the expression of the PI3K/AKT/KLF4 pathway. This finding can help elucidate the mechanism involved in remote fear extinction, contributing to the theoretical foundation for the intervention and treatment of PTSD.

CK2 negatively regulates the extinction of remote fear memory.

Cognitive behavioral therapy, rooted in exposure therapy, is currently the primary approach employed in the treatment of anxiety-related conditions, including post-traumatic stress disorder (PTSD). In laboratory settings, fear extinction in animals is a commonly employed technique to investigate exposure therapy; however, the precise mechanisms underlying fear extinction remain elusive. Casein kinase 2 (CK2), which regulates neuroplasticity via phosphorylation of its substrates, has a significant influence in various neurological disorders, such as Alzheimer's disease and Parkinson's disease, as well as in the process of learning and memory. In this study, we adopted a classical Pavlovian fear conditioning model to investigate the involvement of CK2 in remote fear memory extinction and its underlying mechanisms. The results indicated that the activity of CK2 in the medial prefrontal cortex (mPFC) of mice was significantly upregulated after extinction training of remote cued fear memory. Notably, administration of the CK2 inhibitor CX-4945 prior to extinction training facilitated the extinction of remote fear memory. In addition, CX-4945 significantly upregulated the expression of p-ERK1/2 and p-CREB in the mPFC. Our results suggest that CK2 negatively regulates remote fear memory extinction, at least in part, by inhibiting the ERK-CREB pathway. These findings contribute to our understanding of the underlying mechanisms of remote cued fear extinction, thereby offering a theoretical foundation and identifying potential targets for the intervention and treatment of PTSD.

Decarbonization potentials of the embodied energy use and operational process in buildings: A review from the life-cycle perspective.

Accounting for one third of global energy-related carbon emissions, the construction and operation of buildings are crucial for mitigating climate change. Decarbonization potentials of embodied and operational energy use in buildings are worth exploring from a life-cycle perspective. This paper focuses on the individual building level and collects the latest cases, to offer a comprehensive and timely understanding of the assessment and reduction of building life cycle carbon emissions (LCCEs). As for the collected cases, the operational process accounts for the largest share of building LCCEs, averaging 67%, followed by the production and construction phase, averaging 31%. Carbon emissions from the demolition process are relatively low, averaging 2%. The most commonly used method for assessing LCCEs is process-based, combining the activity level and carbon emission factors. Advanced technologies such as building information modelling and building performance simulation have been employed in recent years to assess embodied and operational carbon emissions effectively. Different approaches are proposed for the decarbonization of each stage in the building life cycle. In the production stage, the effective approaches could be optimizing the building structure, improving the material performance, and using bio-based materials, etc. Prefabrication technology is helpful to decarbonize the construction process. Energy conservation and electrification, renewable energy integration, and smart energy management can effectively reduce the building's operational carbon emissions. Beyond the life cycle, recycling waste materials is proven to have great environmental benefits. Further studies are suggested to trade off the embodied and operational carbon, to fully explore building life-cycle decarbonization potentials.

Female rats prefer to forage food from males, an effect that is not influenced by stress.

As social beings, animals and humans alike make real life decisions that are often influenced by other members. Most current research has focused on the influence of same-sex peers on individual decision-making, with potential opposite sex effect scarcely explored. Here, we developed a behavioral model to observe food foraging decision-making in female rats under various social situations. We found that female rats preferred to forage food from male over female rats or from the no-rat storage side. Female rats were more likely to forage food from familiar males than from unfamiliar. This opposite-sex preference was not altered by the lure of sweet food, or with estrous cycle, nor under stress conditions. These results suggest that the opposite sex influences food foraging decision-making in female rats. The behavioral model established could facilitate future investigation into the underlying neurobiological mechanisms.

CNTN1 Aggravates Neuroinflammation and Triggers Cognitive Deficits in Male Mice by Boosting Crosstalk between Microglia and Astrocytes.

A wealth of knowledge regarding glial cell-mediated neuroinflammation, which contributes to cognitive deficits in Alzheimer's disease (AD) has emerged in recent years. Contactin 1(CNTN1), a member of the cell adhesion molecule and immunoglobulin supergene family, is centrally involved in axonal growth regulation and is also a key player in inflammation-associated disorders. However, whether CNTN1 plays a role in inflammation-related cognitive deficits and how this process is triggered and orchestrated remain to be fully elucidated. In this study, we examined postmortem brains with AD. CNTN1 immunoreactivity was markedly increased, particularly in the CA3 subregion, as compared with non-AD brains. Furthermore, by applying an adeno-associated virus-based approach to overexpress CNTN1 directly via stereotactic injection in mice, we demonstrated that hippocampal CNTN1 overexpression triggered cognitive deficits detected by novel object-recognition, novel place-recognition and social cognition tests. The mechanisms underlying these cognitive deficits could be attributed to hippocampal microglia and astrocyte activation, which led to aberrant expression of excitatory amino acid transporters (EAAT)1/EAAT2. This resulted in long-term potentiation (LTP) impairment that could be reversed by minocyline, an antibiotic and the best-known inhibitor of microglial activation. Taken together, our results identified Cntn1 as a susceptibility factor involved in regulating cognitive deficits via functional actions in the hippocampus. This factor correlated with microglial activation and triggered astrocyte activation with abnormal EAAT1/EAAT2 expression and LTP impairment. Overall, these findings may significantly advance our understanding of the pathophysiological mechanisms underlying the risk of neuroinflammation related cognitive deficits.

CNTN1 in the Nucleus Accumbens is Involved in Methamphetamine-Induced Conditioned Place Preference in Mice.

Methamphetamine (Meth), a commonly used central nervous system stimulant, is highly addictive. Currently, there is no effective treatment for Meth dependence and abuse, although cell adhesion molecules (CAMs) have been shown to play an important role in the formation and remodeling of synapses in the nervous system while also being involved in addictive behavior. Contactin 1 (CNTN1) is a CAM that is widely expressed in the brain; nevertheless, its role in Meth addiction remains unclear. Therefore, in the present study, we established mouse models of single and repeated Meth exposure and subsequently determined that CNTN1 expression in the nucleus accumbens (NAc) was upregulated in mice following single or repeated Meth exposure, whereas CNTN1 expression in the hippocampus was not significantly altered. Intraperitoneal injection of the dopamine receptor 2 antagonist haloperidol reversed Meth-induced hyperlocomotion and upregulation of CNTN1 expression in the NAc. Additionally, repeated Meth exposure also induced conditioned place preference (CPP) in mice and upregulated the expression levels of CNTN1, NR2A, NR2B, and PSD95 in the NAc. Using an AAV-shRNA-based approach to specifically silence CNTN1 expression in the NAc via brain stereotaxis reversed Meth-induced CPP and decreased the expression levels of NR2A, NR2B, and PSD95 in the NAc. These findings suggest that CNTN1 expression in the NAc plays an important role in Meth-induced addiction, and the underlying mechanism may be related to the expression of synapse-associated proteins in the NAc. The results of this study improved our understanding of the role of cell adhesion molecules in Meth addiction.

RBM3 suppresses stemness remodeling of prostate cancer in bone microenvironment by modulating N6-methyladenosine on CTNNB1 mRNA.

Bone metastasis is the most happened metastatic event in prostate cancer (PCa) and needs a large effort in treatment. When PCa metastasizes to the bone, the new microenvironment can induce the epigenome reprogramming and stemness remodeling of cancer cells, thereby increasing the adaptability of cancer cells to the bone microenvironment, and this even leads to the occurrence of secondary tumor metastasis. Our group has previously found that RNA binding motif 3 (RBM3) affects the stem cell-like properties of PCa by interfering with alternative splicing of CD44. However, whether RBM3, as a stress-response protein, can resist microenvironmental remodeling of PCa particularly in bone metastasis remains unknown. By co-culturing PCa cells with osteoblasts to mimic PCa bone metastases, we found that RBM3 upregulates the N6-methyladenosine (m6A) methylation on the mRNA of catenin beta 1 (CTNNB1) in a manner dependent on methyltransferase 3 (METTL3), an N6-adenosine-methyltransferase complex catalytic subunit. Consequently, this modification results in a decreased stability of CTNNB1 mRNA and a followed inactivation of Wnt signaling, which ultimately inhibits the stemness remodeling of PCa cells by osteoblasts. Thus, the present study may extend our understanding of the inhibitory role of RBM3 on particularly bone metastasis of PCa.

Infralimbic YTHDF1 is necessary for the beneficial effects of acute mild exercise on auditory fear extinction retention.

Exposure therapy is the most effective approach of behavioral therapy for anxiety and post-traumatic stress disorder (PTSD). But fear is easy to reappear even after successful extinction. So, identifying novel strategies for augmenting exposure therapy is rather important. It was reported that exercise had beneficial effects on cognitive and memory deficits. However, whether exercise could affect fear memory, especially for fear extinction remained elusive. Here, our results showed that exposure to acute mild exercise 1 or 2 h before extinction training can augment recent fear extinction retention and 2 h for the remote fear extinction retention. These beneficial effects could be attributed to increased YTHDF1 expression in medial prefrontal cortex (mPFC). Furthermore, by using an AAV-shRNA-based approach to silence YTHDF1 expression via stereotactic injection in prelimbic cortex (PL) or infralimbic cortex (IL), respectively, we demonstrated that silence YTHDF1 in IL, but not in PL, blunted augmentation of exposure therapy induced by acute mild exercise and accompanied with decreased NR2B and GluR1 expression. Moreover, YTHDF1 modulated dendritic spines remodeling of pyramidal neuron in IL. Collectively, our findings suggested that acute mild exercise acted as an effective strategy in augmenting exposure therapy with possible implications for understanding new treatment underlying PTSD.

Environmental enrichment ameliorates high-fat diet induced olfactory deficit and decrease of parvalbumin neurons in the olfactory bulb in mice.

Overweight induced by high-fat diet (HFD) represents one of the major health concerns in modern societies, which can cause lasting peripheral and central metabolic disorders in all age groups. Specifically, childhood obesity could lead to life-long impact on brain development and functioning. On the other hand, environmental enrichment (EE) has been demonstrated to be beneficial for learning and memory. Here, we explored the impact of high-fat diet on olfaction and organization of olfactory bulb cells in adolescent mice, and the effect of EE intervention thereon. Puberty mice (3-week-old) fed with HFD for 10 weeks exhibited poorer odor sensitivity and olfactory memory relative to controls consuming standard chows. The behavioral deficits were rescued in the HFD group with EE intervention. Neuroanatomically, parvalbumin (PV) interneurons in the olfactory bulb (OB) were reduced in the HFD-fed animals relative to control, while EE intervention also normalized this alteration. In contrast, cells expressing calbindin (CB), doublecortin (DCX) in the OB were not altered. Our findings suggest that PV interneurons may play a crucial role in mediating the HFD-induced olfactory deficit in adolescent mice, and can also serve a protective effect of EE against the functional deficit.

Injection of Anti-proBDNF Attenuates Hippocampal-Dependent Learning and Memory Dysfunction in Mice With Sepsis-Associated Encephalopathy.

Sepsis-associated encephalopathy (SAE) is a risk factor for cognitive and memory dysfunction; however, the mechanism remains unclear. Brain-derived neurotrophic factor (BDNF) was reported to have a positive effect on cognition and emotion regulation, but the study of its precursor, proBDNF, has been limited. This study aimed to elucidate the effects and associated mechanisms of hippocampal proBDNF in a lipopolysaccharide (LPS)-induced SAE mouse model. In this study, we found that the mice exhibited cognitive dysfunction on day 7 after LPS injection. The expression of proBDNF and its receptor, p75 NTR , was also increased in the hippocampus, while the levels of BDNF and its receptor, TrkB, were decreased. A co-localization study showed that proBDNF and p75 NTR were mainly co-localized with neurons. Furthermore, LPS treatment reduced the expression of NeuN, Nissl bodies, GluR4, NR1, NR2A, and NR2B in the hippocampus of SAE mice. Furthermore, an intrahippocampal or intraperitoneal injection of anti-proBDNF antibody was able to ameliorate LPS-induced cognitive dysfunction and restore the expression of NeuN, Nissl bodies, GluR4, NR1, NR2A, NR2B, and PSD95. These results indicated that treatment with brain delivery by an intrahippocampal and systemic injection of mAb-proBDNF may represent a potential therapeutic strategy for treating patients with SAE.

Expression of Cntn1 is regulated by stress and associated with anxiety and depression phenotypes.

In recent years, our understanding of neural circuits associated with depression has increased. Although inherited factors are known to influence individual differences in the risk for this disorder, it has been difficult to identify specific genes that moderate circuit functions affecting depression. Genome-wide association studies have identified genetic variants of Cntn1 that are linked to major depressive disorders. Cntn1, a subset of the neural cell adhesion protein and immunoglobulin supergene family, participates in cell contact formation and axonal growth control and plays a role in degenerative and inflammatory disorders. However, neuronal substrates that mediate Cntn1 action on depression-like phenotypes and involved mechanisms are unclear. Here, we exploited chronic unpredictable stress (CUS) exposure and found that CUS treatment significantly increased hippocampal Cntn1 messenger RNA and protein expression in both mice and rats, but not in the medial prefrontal cortex, which presented a region-specific regulation. Using an adeno-associated virus-based approach to directly overexpress Cntn1 via stereotactic injection, we demonstrated that Cntn1 overexpression in the hippocampus triggered anxiety- and depression-like phenotypes in addition to microglia activation or phagocytosis in the hippocampus, resulting in upregulation of pro-inflammatory cytokine (IL1α, IL6, and Ccl2) mRNA expression and downregulation of anti-inflammatory cytokine (IL4 and CD206) mRNA expression, determined using real-time quantitative PCR, thus impairing hippocampal immature neurons in the dentate gyrus, determined using immunohistochemical staining for doublecortin, a specific marker for immature neurons. Collectively, our results identified Cntn1 as a novel risk gene involved in regulating anxiety and depression via functional actions in the hippocampus that is correlated with microglial activation or phagocytosis and reduced hippocampal immature neurons. These results may provide a better understanding of the pathophysiological mechanisms underlying the risk of depression-related disorders.

Brd4 participates in epigenetic regulation of the extinction of remote auditory fear memory.

BACKGROUND: Inaccurate fear memories can be maladaptive and potentially portrait a core symptomatic dimension of fear adaptive disorders such as post-traumatic stress disorder (PTSD), which is generally characterized by an intense and enduring memory for the traumatic events. Evidence exists in support of epigenetic regulation of fear behavior. Brd4, a member of the bromodomain and extra-terminal domain (BET) protein family, serves as a chromatin "reader" by binding to histones in acetylated lysine residues, and hence promotes transcriptional activities. However, less is known whether Brd4 participates in modulating cognitive activities especially memory formation and extinction. Here we provide evidence for a role of Brd4 in modulation of auditory fear memory. Auditory fear conditioning resulted in a biphasic Brd4 activation in the anterior cingulate cortex (ACC) and hippocampus of adult mice. Thus, Brd4 phosphorylation occurred 6 h and 3-14 days, respectively, after auditory fear conditioning. Systemic inhibition of Brd4 with a BET inhibitor, JQ1, impaired the extinction of remote (i.e., 14 days after conditioning) fear memory. Further, conditional Brd4 knockout in excitatory neurons of the forebrain impaired remote fear extinction as observed in the JQ1-treated mice. Herein, we identified that Brd4 is essential for extinction of remote fear in rodents. These results thus indicate that Brd4 potentially plays a role in the pathogenesis of PTSD.

Brain-derived neurotrophic factor precursor in the immune system is a novel target for treating multiple sclerosis.

Rationale: Brain-derived neurotrophic factor precursor (proBDNF) is expressed in the central nervous system (CNS) and the immune system. However, the role of proBDNF in the pathogenesis of multiple sclerosis (MS) is unknown. Methods: Peripheral blood and post-mortem brain and spinal cord specimens were obtained from multiple sclerosis patients to analyze proBDNF expression in peripheral lymphocytes and infiltrating immune cells in the lesion site. The proBDNF expression profile was also examined in the experimental autoimmune encephalomyelitis (EAE) mouse model, and polyclonal and monoclonal anti-proBDNF antibodies were used to explore their therapeutic effect in EAE. Finally, the role of proBDNF in the inflammatory immune activity of peripheral blood mononuclear cells (PBMCs) was verified in vitro experiments. Results: High proBDNF expression was detected in the circulating lymphocytes and infiltrated inflammatory cells at the lesion sites of the brain and spinal cord in MS patients. In the EAE mouse model, proBDNF was upregulated in CNS and in circulating and splenic lymphocytes. Systemic but not intracranial administration of anti-proBDNF blocking antibodies attenuated clinical scores, limited demyelination, and inhibited proinflammatory cytokines in EAE mice. Immuno-stimulants treatment increased the proBDNF release and upregulated the expression of p75 neurotrophic receptors (p75NTR) in lymphocytes. The monoclonal antibody against proBDNF inhibited the inflammatory response of PBMCs upon stimulations. Conclusion: The findings suggest that proBDNF from immune cells promotes the immunopathogenesis of MS. Monoclonal Ab-proB may be a promising therapeutic agent for treating MS.

Hippocampal LASP1 ameliorates chronic stress-mediated behavioral responses in a mouse model of unpredictable chronic mild stress.

Substantial evidence has revealed that abnormalities in synaptic plasticity play important roles during the process of depression. LASP1 (LIM and SH3 domain protein 1), a member of actin-binding proteins, has been shown to be associated with the regulation of synaptic plasticity. However, the role of LASP1 in the regulation of mood is still unclear. Here, using an unpredictable chronic mild stress (UCMS) paradigm, we found that the mRNA and protein levels of LASP1 were decreased in the hippocampus of stressed mice and that UCMS-induced down-regulation of LASP1 was abolished by chronic administration of fluoxetine. Adenosine-associated virus-mediated hippocampal LASP1 overexpression alleviated the UCMS-induced behavioral results of forced swimming test and sucrose preference test in stressed mice. It also restored the dendritic spine density, elevated the levels of AKT (a serine/threonine protein kinase), phosphorylated-AKT, insulin-like growth factor 2, and postsynaptic density protein 95. These findings suggest that LASP1 alleviates UCMS-provoked behavioral defects, which may be mediated by an enhanced dendritic spine density and more activated AKT-dependent LASP1 signaling, pointing to the antidepressant role of LASP1.

The Retrotransposition of L1 is Involved in the Reconsolidation of Contextual Fear Memory in Mice.

BACKGROUND: The long interspersed element-1 (L1) participates in memory formation, and DNA methylation patterns of L1 may suggest resilience or vulnerability factors for Post-Traumatic Stress Disorder (PTSD), of which the principal manifestation is a pathological exacerbation of fear memory. However, the unique roles of L1 in the reconsolidation of fear memory remain poorly understood. OBJECTIVE: The study aimed to investigate the role of L1 in the reconsolidation of context-dependent fear memory. METHODS: Mice underwent fear conditioning and fear recall in the observation chambers. Fear memory was assessed by calculating the percentage of time spent freezing in 5 min. The medial prefrontal cortex (mPFC) and hippocampus were removed for further analysis. Open Reading Frame 1 (ORF1) mRNA and ORF2 mRNA of L1 were analyzed by real-time quantitative polymerase chain reaction. After reactivation of fear memory, lamivudine was administered and its effects on fear memory reconsolidation were observed. RESULTS: ORF1 and ORF2 mRNA expressions in the mPFC and hippocampus after recent (24 h) and remote (14 days) fear memory recall exhibited augmentation via different temporal and spatial patterns. Reconsolidation of fear memory was markedly inhibited in mice treated with lamivudine, which could block L1. DNA methyltransferase mRNA expression declined following lamivudine treatment in remote fear memory recall. CONCLUSION: The retrotransposition of L1 participated in the reconsolidation of fear memory after reactivation of fear memory, and with lamivudine treatment, spontaneous recovery decreased with time after recent and remote fear memory recall, providing clues for understanding the roles of L1 in fear memory.

Detecting urine metabolites of bladder cancer by surface-enhanced Raman spectroscopy.

AIM: Metabolites present in urine reflect the current phenotype of the cancer state. Surface-enhanced Raman spectroscopy (SERS) can be used in urine supernatant or sediment to largely reflect the metabolic status of the body. MATERIALS & METHODS: SERS was performed to detect bladder cancer (BCa) and predict tumour grade from urine supernatant, which contains various system metabolites, as well as from urine sediment, which contains exfoliated tumour cells. RESULTS & DISCUSSION: Upon combining the urinary supernatant and sediment results, the total diagnostic sensitivity and specificity of SERS were 100% and 98.85%, respectively, for high-grade tumours and 97.53% and 90.80%, respectively, for low-grade tumours. CONCLUSION: The present results suggest high potential for SERS to detect BCa from urine, especially when combining both urinary supernatant and sediment results.

Effects of environmental enrichment on cognitive behavior and the expression of adenosine triphosphate binding cassette transporter A7 in hippocampus of adolescent mice with high fat diet. / ä¸°å¯ŒçŽ¯å¢ƒå¯¹é’æ˜¥æœŸé«˜è„‚é¥®é£Ÿå°é¼ è®¤çŸ¥è¡Œä¸ºå’Œæµ·é©¬ä¸‰ç£·é ¸è ºè‹·ç»“åˆç›’è½¬è¿å­A7表达的影响.

OBJECTIVES: To investigate the effects of environmental enrichment on cognitive behavior and the expression of adenosine triphosphate binding cassette transporter A7 (ABCA7) in hippocampus of the adolescent mice with high fat diet. METHODS: A total of healthy 3-week-old male C57BL/6J mice were randomly divided into 3 groups: a control (Con) group, a high fat diet (HFD) group, and a high fat diet+environmental enrichment (HFD+EE) group, with 10 mice in each group. The Con group was given normal diet. The HFD group was given high fat diet. The HFD+EE group was given high fat diet; at the same time, they treated by environmental enrichment. After 10 weeks, open field test was used to detect activity. Novel object recognition test and Y maze test were used to detect cognitive behavior. After the test, the brain was collected and used to detect the protein expression of ABCA7 in the hippocampus by immunohistochemistry and Western blotting. And quantitative RT-PCR (RT-qPCR) was used to detect the ABCA7 mRNA expression level in the hippocampus. RESULTS: There was no significant difference in the total movement distance in the mice among the 3 groups (P>0.05). In the novel object recognition test, the discrimination index of the HFD group was much lower than that of the Con group, and the difference was significant (P<0.01). The discrimination index of the HFD+EE group was higher than that of the HFD group, and the difference was significant (P<0.01). In the Y maze test, there was no significant difference in the percentage of time spent on the new arm among the mice in the 3 groups (P=0.1279). The percentage of entries in new arm in the HFD group was much lower than that in the Con group, and the difference was significant (P<0.01). The percentage of the entries in new arm in the HFD+EE group was significantly higher than that in the HFD group (P<0.05). The results of immunohistochemistry showed that ABCA7 was positively expressed in the cytoplasm of hippocampal neurons in the mice from these 3 groups, and the expression of ABCA7 in the hippocampus of the HFD group was lower than that of the Con group (CA1: P<0.01, CA3: P=0.06), while the expression of ABCA7 in hippocampus of HFD+EE group was higher than that of HFD group (CA1: P=0.23, CA3: P<0.05). Western blotting results showed that compared with the Con group, the protein level of ABCA7 in the hippocampus of the HFD group was significantly reduced (P<0.05), while compared with the Con group, the protein level of ABCA7 in the hippocampus of the HFD+EE group showed an upward trend (P=0.06). The results of RT-qPCR showed that the mRNA level of ABCA7 in the hippocampus of HFD group was significantly lower than that of the Con group (P<0.01), while the mRNA level of ABCA7 in the hippocampus of HFD+EE group was significantly higher than that of the HFD group (P<0.01). CONCLUSIONS: High fat diet in adolescent can impair cognitive function with a decrease in the expression of ABCA7 in hippocampus, which can be ameliorate by environmental enrichment.

Correction to: Involvement of proBDNF in Monocytes/Macrophages with Gastrointestinal Disorders in Depressive Mice.

Dr. Chang-Qi Li should be added as co-author because Fig. 1 originated from him.

BET proteins inhibitor JQ-1 impaired the extinction of remote auditory fear memory: An effect mediated by insulin like growth factor 2.

Fear extinction is an important preclinical model for behavior therapy in human anxiety disorders, such as post-traumatic stress disorder (PTSD). Histone acetylation is involved in the extinction of fear memory. As the "readers" of histone acetylation markers, the role of the bromodomain and extraterminal domain (BET) proteins in fear extinction is still unclear. In the present study, we found that suppression of BET proteins using small molecule JQ-1 had no effects on the acquisition of auditory fear or on the extinction of recent auditory fear, but it impaired the extinction of remote auditory fear. We found that insulin like growth factor 2 (IGF-2) mRNA and protein were up-regulated in the anterior cingulate cortex (ACC) after the extinction training of remote fear memory, and that this effect was inhibited by JQ-1 administration. Further, the local delivery of IGF-2 protein to the ACC region rescued the impaired extinction of remote memory caused by JQ-1 administration, which suggesting IGF-2 mediates the effects of JQ-1 on remote memory extinction. Gene expression profiling analysis demonstrated that JQ-1 treatment inhibited the up-regulated expression of a key set of neuroplasticity-related genes following remote memory extinction. Together, these findings establish BET proteins as epigenetic mediator for the extinction of remote fear memory. In particular, the findings of this study imply that as a prospective preclinical cancer drug, JQ-1 (or other BET bromodomain inhibitors) should be modified to prevent it from crossing the blood brain barrier and causing neurological side effects.

Corticosterone Induced the Increase of proBDNF in Primary Hippocampal Neurons Via Endoplasmic Reticulum Stress.

Major depression disorder is one of the most common psychiatric disorders that greatly threaten the mental health of a large population worldwide. Previous studies have shown that endoplasmic reticulum (ER) stress plays an important role in the pathophysiology of depression, and current research suggests that brain-derived neurotrophic factor precursor (proBDNF) is involved in the development of depression. However, the relationship between ER and proBDNF in the pathophysiology of depression is not well elucidated. Here, we treated primary hippocampal neurons of mice with corticosterone (CORT) and evaluated the relationship between proBDNF and ERS. Our results showed that CORT induced ERS and upregulated the expression of proBDNF and its receptor, Follistatin-like protein 4 (FSTL4), which contributed to significantly decreased neuronal viability and expression of synaptic-related proteins including NR2A, PSD95, and SYN. Anti-proBDNF neutralization and ISRIB (an inhibitor of the ERS) treatment, respective ly, protected neuronal viabilities and increased the expression of synaptic-related proteins in corticosterone-exposed neurons. ISRIB treatment reduced the expression of proBDNF and FSTL4, whereas anti-proBDNF treatment did not affect ERS markers (Grp78, p-PERK, ATF4) expression. Our study presented evidence that CORT-induced ERS negatively regulated the neuronal viability and the level of synaptic-related protein of primary neurons via the proBDNF/FSTL4 pathway.