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Posttraumatic stress disorder (PTSD), a psychiatric disorder caused by stressful events, is characterized by long-lasting fear memory. The nucleus accumbens shell (NAcS) is a key brain region that regulates fear-associated behavior. Small-conductance calcium-activated potassium channels (SK channels) play a key role in regulating the excitability of NAcS medium spiny neurons (MSNs) but their mechanisms of action in fear freezing are unclear. We established an animal model of traumatic memory using conditioned fear freezing paradigm, and investigated the alterations in SK channels of NAc MSNs subsequent to fear conditioning in mice. We then utilized an adeno-associated virus (AAV) transfection system to overexpress the SK3 subunit and explore the function of the NAcS MSNs SK3 channel in conditioned fear freezing. Fear conditioning activated NAcS MSNs with enhanced excitability and reduced the SK channel-mediated medium after-hyperpolarization (mAHP) amplitude. The expression of NAcS SK3 were also reduced time-dependently. The overexpression of NAcS SK3 impaired conditioned fear consolidation without affecting conditioned fear expression, and blocked fear conditioning-induced alterations in NAcS MSNs excitability and mAHP amplitude. Additionally, the amplitudes of mEPSC, AMPAR/NMDAR ratio, and membrane surface GluA1/A2 expression in NAcS MSNs was increased by fear conditioning and returned to normal levels upon SK3 overexpression, indicating that fear conditioning-induced decrease of SK3 expression caused postsynaptic excitation by facilitating AMPAR transmission to the membrane. These findings show that the NAcS MSNs SK3 channel plays a critical role in conditioned fear consolidation and that it may influence PTSD pathogenesis, making it a potential therapeutic target against PTSD. [Display omitted] [ABSTRACT FROM AUTHOR]

Recent studies found that non‐coding RNAs (ncRNAs) played crucial roles in drug addiction through epigenetic regulation of gene expression and underlying drug‐induced neuroadaptations. In this study, we characterized lncRNA transcriptome profiles in the nucleus accumbens (NAc) of mice exhibiting morphine‐conditioned place preference (CPP) and explored the prospective roles of novel differentially expressed lncRNA, lncLingo2 and its derived miR‐876‐5p in the acquisition of opioids‐associated behaviours. We found that the lncLingo2 was downregulated within the NAc core (NAcC) but not in the NAc shell (NAcS). This downregulation was found to be associated with the development of morphine CPP and heroin intravenous self‐administration (IVSA). As Mfold software revealed that the secondary structures of lncLingo2 contained the sequence of pre‐miR‐876, transfection of LV‐lncLingo2 into HEK293 cells significantly upregulated miR‐876 expression and the changes of mature miR‐876 are positively correlated with lncLingo2 expression in NAcC of morphine CPP trained mice. Delivering miR‐876‐5p mimics into NAcC also inhibited the acquisition of morphine CPP. Furthermore, bioinformatics analysis and dual‐luciferase assay confirmed that miR‐876‐5p binds to its target gene, Kcnn3, selectively and regulates morphine CPP training‐induced alteration of Kcnn3 expression. Lastly, the electrophysiological analysis indicated that the currents of small conductance calcium‐activated potassium (SK) channel was increased, which led to low neuronal excitability in NAcC after CPP training, and these changes were reversed by lncLingo2 overexpression. Collectively, lncLingo2 may function as a precursor of miR‐876‐5p in NAcC, hence modulating the development of opioid‐associated behaviours in mice, which may serve as an underlying biomarker and therapeutic target of opioid addiction. [ABSTRACT FROM AUTHOR]

Introduction: Several studies have linked inflammation and oxidative stress with the pathogenesis of depression. Artesunate is a commonly used medication to treat malaria and has been shown to produce antioxidant, anti‐inflammatory, and immunomodulatory effects. However, its prophylactic effects on depression and depression‐related brain pathology are unknown. Methods: In Experiment 1, using a PC12 cell line, we investigated whether artesunate can prevent hydrogen peroxide (H2O2)‐induced oxidative injury that mimics oxidative stress commonly observed in the depressed brain. Next, using lipopolysaccharide (LPS)‐induced mouse model of depression, we investigated whether artesunate can prevent behavioral deficits observed in the open field test, novelty‐suppressed feeding test, sucrose preference test, forced swimming test, and tail suspension procedure. Results: We found that artesunate significantly prevented a H2O2‐induced reduction in PC12 cell activity, suggesting its antioxidant potential. We also found that mice pretreated with artesunate (5, 15 mg/kg) intraperitoneally (i.p.) prior to the LPS (.8 mg/kg, i.p.) treatment showed fewer and less severe depression‐ and anxiety‐like behaviors than the LPS‐treated control mice. Conclusion: Our findings indicate that artesunate produces antioxidant effect, as well as antidepressant and anxiolytic effects. Importantly, our findings first demonstrate that artesunate can prevent LPS‐induced depression‐ and anxiety‐like symptoms, strongly suggesting its prophylactic potential in the treatment of depression and, perhaps, other psychiatric disorders associated with inflammation and oxidative stress. [ABSTRACT FROM AUTHOR]

• Atractylenolide III produces antidepressant- and anxiolytic-like effects in rat models. Atractylenolide III, a major component of the atractylodes macrocephala Koidz, derived from the rhizoma atractylodes , has been reported to produce various pharmacological effects including anti-aging, anti-inflammation, anti-tumor, and other effects. Growing evidence suggests that proinflammatory cytokines, such as interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-α, are increased in depressed patients. The present study was aimed at investigating the antidepressant- and anxiolytic-like effects of atractylenolide III in lipopolysaccharide (LPS) challenge and chronic unpredictable mild stress (CUMS) rat model. We found that 30 mg/kg of atractylenolide III administered by oral gavage for 14 days, significantly reduced the immobility time in a forced swimming test (FST), but did not alter the number of crossings in an open field test (OFT), respectively. The results indicated that atractylenolide III has an antidepressant-like effect without affecting locomotor activity. We then used the LPS-induced depression model to assess the effects of atractylenolide III on behaviors in FST, sucrose preference test (SPT), and novelty-suppressed feeding test (NSFT). Interestingly, in addition to the antidepressant-like effects, 30 mg/kg of atractylenolide III also produced an anxiolytic-like effect. To further identify the antidepressant- and anxiolytic-like effects of atractylenolide III, we used the CUMS model with 28 consecutive days of the atractylenolide III treatment, followed by the SPT, FST, and NSFT. Atractylenolide III prevented CUMS-induced depressive- and anxiety-like behaviors in rats. To illustrate the underlying possible mechanisms of action of atractylenolide III, we measured the proinflammatory cytokines levels. The results showed that atractylenolide III decreased the proinflammatory cytokines levels in the hippocampus of CUMS exposed rats. In summary, our findings demonstrated that atractylenolide III produces antidepressant- and anxiolytic-like effects in rats, and these effects appear to be mediated by inhibition of hippocampal neuronal inflammation. [ABSTRACT FROM AUTHOR]

A progressive increase in drug craving following drug exposure is an important trigger of relapse. CircularRNAs (CircRNAs), key regulators of gene expression, play an important role in neurological diseases. However, the role of circRNAs in drug craving is unclear. In the present study, we trained mice to morphine conditioned place preference (CPP) and collected the nucleus accumbens (NAc) sections on abstinence day 1 (AD1) and day 14 (AD14) for RNA-sequencing. CircTmeff-1, which was highly expressed in the NAc core, was associated with incubation of context-induced morphine craving. The gain- and loss- of function showed that circTmeff-1 was a positive regulator of incubation. Simultaneously, the expression of miR-541–5p and miR-6934–3p were down-regulated in the NAc core during the incubation period. The dual luciferase reporter, RNA pulldown, and fluorescence insitu hybridization assays confirmed that miR-541–5p and miR-6934–3p bind to circTmeff-1 selectively. Furthermore, bioinformatics and western blot analysis suggested that vesicle-associated membrane protein 1 (VAMP1) and neurofascin (NFASC), both overlapping targets of miR-541–5p and miR-6934–3p, were highly expressed during incubation. Lastly, AAV-induced down-regulation of circTmeff-1 decreased VAMP1 and NFASC expression and incubation of morphine craving. These findings suggested that circTmeff-1, a novel circRNA, promotes incubation of context-induced morphine craving by sponging miR-541/miR-6934 in the NAc core. Thus, circTmeff-1 represents a potential therapeutic target for context-induced opioid craving, following prolonged abstinence. [Display omitted] [ABSTRACT FROM AUTHOR]