Correlation between immune-related genes and depression-like features in an animal model and in humans.

A growing body of evidence suggests that immune-related genes play pivotal roles in the pathophysiology of depression. In the present study, we investigated a plausible connection between gene expression, DNA methylation, and brain structural changes in the pathophysiology of depression using a combined approach of murine and human studies. We ranked the immobility behaviors of 30 outbred Crl:CD1 (ICR) mice in the forced swim test (FST) and harvested their prefrontal cortices for RNA sequencing. Of the 24,532 analyzed genes, 141 showed significant correlations with FST immobility time, as determined through linear regression analysis with p ≤ 0.01. The identified genes were mostly involved in immune responses, especially interferon signaling pathways. Moreover, induction of virus-like neuroinflammation in the brains of two separate mouse cohorts (n = 30 each) using intracerebroventricular polyinosinic:polycytidylic acid injection resulted in increased immobility during FST and similar expression of top immobility-correlated genes. In human blood samples, candidate gene (top 5%) expression profiling using DNA methylation analysis found the interferon-related USP18 (cg25484698, p = 7.04 × 10-11, Δß = 1.57 × 10-2; cg02518889, p = 2.92 × 10-3, Δß =  - 8.20 × 10-3) and IFI44 (cg07107453, p = 3.76 × 10-3, Δß =  - 4.94 × 10-3) genes to be differentially methylated between patients with major depressive disorder (n = 350) and healthy controls (n = 161). Furthermore, cortical thickness analyses using T1-weighted images revealed that the DNA methylation scores for USP18 were negatively correlated with the thicknesses of several cortical regions, including the prefrontal cortex. Our results reveal the important role of the interferon pathway in depression and suggest USP18 as a potential candidate target. The results of the correlation analysis between transcriptomic data and animal behavior carried out in this study provide insights that could enhance our understanding of depression in humans.

Temperature Compensation of Fiber Bragg Grating Sensors in Smart Strand.

Compared to other types of sensors, fiber optic sensors have improved accuracy and durability. Recently, the Smart Strand was developed to maximize the advantages of fiber optic sensors for measuring the cable forces in prestressed concrete structures or cable-supported bridges. The Smart Strand has fiber Bragg gratings (FBGs) embedded in a core wire of the seven-wire strand. Similar to other sensors, the strain measured at an FBG is affected by temperature; therefore, the temperature effect that is not related to the mechanical strain should be compensated for or corrected in the long-term measurement subjected to temperature variation. However, a temperature compensation procedure for the FBG has yet to be established, and relevant studies have used different formulas for the compensation. Moreover, when the FBG sensors are packaged with a certain material-such as fiber reinforced polymer-for protection, it is important to consider the interaction between the FBG, packaging material, and host material during thermal behavior. Therefore, this study proposed a reasonable procedure for temperature compensation for the FBG sensors embedded in packaging material and host material. In particular, the thermal sensitivity of the Smart Strand was intensively investigated. The proposed theoretical formulas were validated through comparison with data obtained from various specimens in a temperature-controlled chamber. Finally, the procedure was applied to correct the data measured using the Smart Strands in a 20-m-long full-scale specimen for about a year, thus resulting in a realistic trend of the long-term prestressing force.

Tyrosine kinase Fyn regulates iNOS expression in LPS-stimulated astrocytes via modulation of ERK phosphorylation.

The high concentrations of nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) in activated glial cells in response to neuroinflammatory stimuli have neurotoxic effects on the brain. At basal levels, iNOS expression is low, and proinflammatory stimuli induce iNOS expression in astrocytes, microglia, and oligodendrocytes. Fyn, a non-receptor tyrosine kinase, regulates iNOS expression in several types of immune cells. However, its role in stimulated astrocytes is less clear. In this study, we investigated the role of Fyn in the regulation of lipopolysaccharide (LPS)-induced iNOS expression in astrocytes from mice and rats. Intracerebroventricular LPS injections in cortical regions enhanced iNOS mRNA and protein levels, which were increased in Fyn-deficient mice. Accordingly, LPS-induced nitrite production was enhanced in primary astrocytes cultured from Fyn-deficient mice or rats. Similar results were observed in cultured astrocytes after the siRNA-induced knockdown of Fyn expression. Finally, we observed increased LPS-induced extracellular signal-regulated protein kinase (ERK) activation in Fyn-deficient astrocytes. These results suggested that Fyn has a regulatory role in iNOS expression in astrocytes during neuroinflammatory responses.

Activation of the dopamine D1 receptor can extend long-term spatial memory persistence via PKA signaling in mice.

Many works have been performed to understand the mechanisms of the formation and persistence of memory. However, it is not fully understood whether the decay of long-term memory can be modulated by the activation of dopamine D1 receptor. A Barnes maze task was employed to measure long-term spatial memory. We observed that the spatial memory acquired through 3 trials per session for 4 days had begun to fade out by the 14th day and had completely disappeared by 21 days after the first probe test. The intraperitoneal administration of SKF 38393 (a dopamine D1 receptor agonist) for 7 days beginning on the 14th day after the first probe test prevented natural memory forgetting, and the intraperitoneal administration of SCH 23390 (a dopamine D1 receptor antagonist) prevented this memory persistence. In the Western blotting, the administration of SKF 38393 increased the phosphorylation levels of PKA, ERK1/2, CaMKII, and CREB in the hippocampus. In addition, such increased levels were decreased by the corresponding antagonist (SCH 23390). Moreover, the inhibition of PKA could completely reverse the preservation of spatial memory induced by dopamine D1 receptor activation. These results suggest that the activation of the dopamine D1 receptor plays a critical role in the persistence of long-term spatial memory through the PKA signaling pathway.

Eclalbasaponin II Ameliorates the Cognitive Impairment Induced by Cholinergic Blockade in Mice.

Eclalbasaponin II derived from Eclipta prostrata L. (Asteraceae) has been reported to have anti-fibrotic, anti-bacterial and autophagic activities, but its effect on cognitive function has not been investigated. We studied the effect of eclalbasaponin II on cholinergic blockade-induced memory impairment in mice using the passive avoidance, Y-maze, and Morris water maze tasks. Eclalbasaponin II (10 or 20 mg/kg, p.o.) significantly ameliorated the cognitive dysfunction induced by scopolamine in the passive avoidance, Y-maze, and the Morris water maze tasks. To identify the mechanism of the memory-ameliorating effect of eclalbasaponin II, acetylcholinesterase (AChE) activity assay, Western blot analysis and electrophysiology were conducted. Eclalbasaponin II inhibited the AChE activity in ex vivo study, and the administration of eclalbasaponin II and its metabolite, echinocystic acid, increased the phosphorylation levels of memory-related signaling molecules, including protein kinase B (Akt) and glycogen synthase kinase-3ß (GSK-3ß), in the hippocampus. Although eclalbasaponin II did not affect hippocampal long term potentiation (LTP), echinocystic acid significantly enhanced hippocampal LTP formation (30 µM). These results suggest that eclalbasaponin II ameliorates cholinergic blockade-induced cognitive impairment via AChE inhibition, LTP formation and the activation of Akt-GSK-3ß signaling, and that eclalbasaponin II may be a useful to treat cognitive impairment derived from cholinergic dysfunction.

Cognitive Ameliorating Effect of Acanthopanax koreanum Against Scopolamine-Induced Memory Impairment in Mice.

Acanthopanax koreanum Nakai (Araliaceae) is one of the most widely cultivated medicinal plants in Jeju Island, Korea, and the roots and stem bark of A. koreanum have been traditionally used as a tonic agent for general weakness. However, the use of A. koreanum for general weakness observed in the elderly, including those with declined cognitive function, has not been intensively investigated. This study was performed to investigate the effect of the ethanol extract of A. koreanum (EEAK) on cholinergic blockade-induced memory impairment in mice. To evaluate the ameliorating effects of EEAK against scopolamine-induced memory impairment, mice were orally administered EEAK (25, 50, 100, or 200 mg/kg), and several behavioral tasks, including a passive avoidance task, the Y-maze, and a novel object recognition task, were employed. Besides, western blot analysis was conducted to examine whether EEAK affected memory-associated signaling molecules, such as protein kinase B (Akt), Ca2+ /calmodulin-dependent protein kinase II (CaMKII), and cAMP response element-binding protein (CREB). The administration of EEAK (100 or 200 mg/kg, p.o.) significantly ameliorated the scopolamine-induced cognitive impairment in the passive avoidance task, the Y-maze, and the novel object recognition task. The phosphorylation levels of both Akt and CaMKII were significantly increased by approximately two-fold compared with the control group because of the administration of EEAK (100 or 200 mg/kg) (p < 0.05). Moreover, the phosphorylation level of CREB was also significantly increased compared with the control group by the administration of EEAK (200 mg/kg) (p < 0.05). The present study suggests that EEAK ameliorates the cognitive dysfunction induced by the cholinergic blockade, in part, via several memory-associated signaling molecules and may hold therapeutic potential against cognitive dysfunction, such as that presented in neurodegenerative diseases, for example, Alzheimer's disease. Copyright © 2017 John Wiley & Sons, Ltd.

4-Hydroxybenzyl methyl ether improves learning and memory in mice via the activation of dopamine D1 receptor signaling.

The phenolic compound 4-hydroxybenzyl methyl ether (HBME) is isolated from Gastrodia elata Blume (Orchidaceae). In the present study, we investigated the effect of HBME on three stages of memory (acquisition, consolidation, and retrieval) using the step-through passive avoidance task. HBME was administered at 3 time points; 1 h before the acquisition trial, immediately after the acquisition trial, and 1h before the retention trial, respectively. HBME (10 mg/kg, p.o.) markedly increased the step-through latency compared with the vehicle-treated control at all stages of memory. To clarify the mechanism of the memory-enhancing effect of HBME, an antagonism study and Western blot analysis were performed. The enhancing effects of HBME on each phase were reversed by the sub-effective dose of the dopamine D1 receptor antagonist SCH23390 (0.0125 mg/kg, s.c.), or the protein kinase A (PKA) antagonist H-89 (0.25 mg/kg, i.p.). In addition, the administration of HBME (10 mg/kg, p.o.) significantly increased the phosphorylation of the cortical and hippocampal PKA/cAMP response element-binding protein (CREB), and was reversed by the co-administration of SCH23390. HBME (10 mg/kg, p.o.) also ameliorated the memory impairment induced by SCH23390 or scopolamine. Taken together, these results suggest that the effect of HBME on cognitive functions may be partly involved in dopaminergic neurotransmitter signaling and that HBME could be a potential therapeutic agent for treating the cognitive dysfunction induced by dopaminergic or cholinergic neurotransmitter system deficits.

The Epigenetic Reader BRD2 as a Specific Modulator of PAI-1 Expression in Lipopolysaccharide-Stimulated Mouse Primary Astrocytes.

The post translational modification of lysine acetylation is a key mechanism that regulates chromatin structure. Epigenetic readers, such as the BET domains, are responsible for reading histone lysine acetylation which is a hallmark of open chromatin structure, further providing a scaffold that can be accessed by RNA polymerases as well as transcription factors. Recently, several reports have assessed and highlighted the roles of epigenetic readers in various cellular contexts. However, little is known about their role in the regulation of inflammatory genes, which is critical in exquisitely tuning inflammatory responses to a variety of immune stimuli. In this study, we investigated the role of epigenetic readers BRD2 and BRD4 in the lipopolysaccharide (LPS)-induced immune responses in mouse primary astrocytes. Inflammatory stimulation by LPS showed that the levels of Brd2 mRNA and protein were increased, while Brd4 mRNA levels did not change. Knocking down of Brd2 mRNA using specific small interfering RNA (siRNA) in cultured mouse primary astrocytes inhibited LPS-induced mRNA expression and secretion of plasminogen activator inhibitor-1 (PAI-1). However, no other pro-inflammatory cytokines, such as Il-6, Il-1ß and Tnf-α, were affected. Indeed, treatment with bromodomain-containing protein inhibitor, JQ1, blocked Pai-1 mRNA expression through the inhibition of direct BRD2 protein-binding and active histone modification on Pai-1 promoter. Taken together, our data suggest that BRD2 is involved in the modulation of neuroinflammatory responses through PAI-1 and via the regulation of epigenetic reader BET protein, further providing a potential novel therapeutic strategy in neuroinflammatory diseases.

Nodakenin Enhances Cognitive Function and Adult Hippocampal Neurogenesis in Mice.

In our previous study, we demonstrated that nodakenin, a coumarin compound isolated from Angelica decursiva, ameliorates learning and memory impairments induced by scopolamine. In the present study, we investigated the effects of nodakenin on the cognitive function in the normal naïve mice in a passive avoidance task, and the results showed that nodakenin significantly increased the latency time in normal naïve mice. In addition, sub-chronic administration of nodakenin increased the number of 5-bromo-2-deoxyuridine (BrdU)-positive cells in the hippocampal dentate gyrus (DG) region. The percentage of BrdU and NeuN (neuronal cell marker)-immunopositive cells was also significantly increased by the nodakenin administration. Western blotting results showed that the expression levels of phosphorylated protein kinase B (Akt) and phosphorylated glycogen synthase kinase-3ß (GSK-3ß) were significantly increased in hippocampal tissue by sub-chronic nodakenin administration. These findings suggest that the sub-chronic administration of nodakenin enhances adult hippocampal neurogenesis in the DG region via Akt-GSK-3ß signaling and this increase may be associated with nodakenin's positive effect on cognitive processing.

Chronic exposure to ethanol of male mice before mating produces attention deficit hyperactivity disorder-like phenotype along with epigenetic dysregulation of dopamine transporter expression in mouse offspring.

Preconception exposure to EtOH through the paternal route may affect neurobehavioral and developmental features of offspring. This study investigates the effects of paternal exposure to EtOH before conception on the hyperactivity, inattention, and impulsivity behavior of male offspring in mice. Sire mice were treated with EtOH in a concentration range approximating human binge drinking (0-4 g/kg/day EtOH) for 7 weeks and mated with untreated females mice to produce offspring. EtOH exposure to sire mice induced attention deficit hyperactivity disorder (ADHD)-like hyperactive, inattentive, and impulsive behaviors in offspring. As a mechanistic link, both protein and mRNA expression of dopamine transporter (DAT), a key determinant of ADHD-like phenotypes in experimental animals and humans, were significantly decreased by paternal EtOH exposure in cerebral cortex and striatum of offspring mice along with increased methylation of a CpG region of the DAT gene promoter. The increase in methylation of DAT gene promoter was also observed in the sperm of sire mice, suggesting germline changes in the epigenetic methylation signature of DAT gene by EtOH exposure. In addition, the expression of two key regulators of methylation-dependent epigenetic regulation of functional gene expression, namely, MeCP2 and DNMT1, was markedly decreased in offspring cortex and striatum sired by EtOH-exposed mice. These results suggest that preconceptional exposure to EtOH through the paternal route induces behavioral changes in offspring, possibly via epigenetic changes in gene expression, which is essential for the regulation of ADHD-like behaviors.

Translational regulation of NeuroD1 expression by FMRP: involvement in glutamatergic neuronal differentiation of cultured rat primary neural progenitor cells.

Fragile X mental retardation protein (FMRP) is encoded by Fmr1 gene in which mutation is known to cause fragile X syndrome characterized by mental impairment and other psychiatric symptoms similar to autism spectrum disorders. FMRP plays important roles in cellular mRNA biology such as transport, stability, and translation as an RNA-binding protein. In the present study, we identified potential role of FMRP in the neural differentiation, using cortical neural progenitor cells from Sprague-Dawley rat. We newly found NeuroD1, an essential regulator of glutamatergic neuronal differentiation, as a new mRNA target interacting with FMRP in co-immunoprecipitation experiments. We also identified FMRP as a regulator of neuronal differentiation by modulating NeuroD1 expression. Down-regulation of FMRP by siRNA also increased NeuroD1 expression along with increased pre- and post-synaptic development of glutamatergic neuron, as evidenced by Western blot and immunocytochemistry. On the contrary, cells harboring FMRP over-expression construct showed decreased NeuroD1 expression. Treatment of cultured neural precursor cells with a histone deacetylase inhibitor, valproic acid known as an inducer of hyper-glutamatergic neuronal differentiation, down-regulated the expression of FMRP, and induced NeuroD1 expression. Our study suggests that modulation of FMRP expression regulates neuronal differentiation by interaction with its binding target mRNA, and provides an example of the gene and environmental interaction regulating glutamatergic neuronal differentiation.

Neonatal dysregulation of 2-arachidonoylglycerol induces impaired brain function in adult mice.

The endocannabinoid system (ECS) regulates neurotransmission linked to synaptic plasticity, cognition, and emotion. While it has been demonstrated that dysregulation of the ECS in adulthood is relevant not only to central nervous system (CNS) disorders such as autism spectrum disorder, cognitive dysfunction, and depression but also to brain function, there are few studies on how dysregulation of the ECS in the neonatal period affects the manifestation and pathophysiology of CNS disorders later in life. In this study, DO34, a diacylglycerol lipase alpha (DAGLα) inhibitor affecting endocannabinoid 2-AG production, was injected into C57BL/6N male mice from postnatal day (PND) 7 to PND 10, inducing dysregulation of the ECS in the neonatal period. Subsequently, we examined whether it affects neuronal function in adulthood through electrophysiological and behavioral evaluation. DO34-injected mice showed significantly decreased cognitive functions, attributed to impairment of hippocampal synaptic plasticity. The findings suggest that regulation of ECS activity in the neonatal period may induce enduring effects on adult brain function.

Heukharang (Lactuca sativa L.) extracts enhanced the sleep behavior of mice: potential involvement of adenosine A1 and A2A receptors.

A significant proportion of the world's population suffers from insomnia, a disorder characterized by complications in initiating and maintaining sleep. Many medications used to treat insomnia target the γ-aminobutyric acid (GABA) neurotransmitter system. However, these substances, such as benzodiazepines, induce significant adverse consequences, including dependence and memory impairment, after prolonged use. Thus, current studies are aimed at developing therapeutic hypnotics derived from natural sources that may cause less severe side effects. Heukharang is a variety of lettuce from Korea that was discovered to contain sleep-promoting compounds. Therefore, we investigated the potential effects of sub-chronic administration of Heukharang extract (FSD-LS) on sleep behavior (pentobarbital-induced sleeping test), brain wave activity and sleep architecture (electroencephalography), and physiological behavior (open-field test and rota-rod) in mice, along with radioligand binding assays (GABAA, adenosine A1 and A2A receptors). We found that FSD-LS prolonged the total sleep duration and reduced the onset time of sleep, and enhanced delta wave power and non-rapid eye movement (NREM) sleep duration, all indicating persistent sleep-enhancing effects. FSD-LS lacked adverse effects on the spontaneous locomotor activity and motor coordination of mice, unlike diazepam. Pharmacological blocking using caffeine and bicuculline supported the possible involvement of adenosine receptors in the sleep-promoting effects of FSD-LS, with partial contribution from GABA receptor activity. Overall, our study recommends FSD-LS as a potential source for the development of sleep-aiding therapeutics.

Impact and Interrelationships of Striatal Proteins, EPHB2, OPRM1, and PER2 on Mild Cognitive Impairment.

With the global increase in life expectancy, there has been a rise in the incidence of cognitive impairments attributed to diverse etiologies. Notably, approximately 50% of individuals diagnosed with mild cognitive impairment (MCI) progress to dementia within 3 years. However, the precise mechanisms underlying MCI remain elusive. Therefore, this study aimed to elucidate potential mechanisms implicated in MCI utilizing Per2 knockout (KO) mice, which have previously been shown to have cognitive deficits. Behavioral (Y-maze, Barnes maze) and molecular (electrophysiology, RNA sequencing, western blot, and immunofluorescence) experiments were conducted in Per2 KO and wild-type (WT) mice. Per2 KO mice exhibited impaired spatial working memory in the Y-maze and Barnes maze. However, there were no significant group differences in hippocampal long-term potentiation (LTP) between Per2 KO and WT mice, whereas striatal LTP in Per2 KO mice was lower compared to WT mice. In RNA sequencing analysis, 58 genes were downregulated and 64 genes were upregulated in the striatum of Per2 KO mice compared to WT mice. Among the differentially expressed genes, four genes (Chrm2, EphB2, Htr1b, Oprm1) were identified. Optimal expression levels of EPHB2 and OPRM1 were found to significantly enhance cognitive performance in mice. Additionally, Per2 KO mice exhibited reduced EPHB2-NMDAR-LTP and OPRM-mTOR signaling, along with elevated amyloid beta (Aß) levels, when compared to WT mice. However, these alterations were reversed upon administration of morphine treatment. Striatal OPRM1-mTOR signaling, EPHB2-NMDAR-LTP signaling, and Aß expression levels may exert a combined effect on MCI under the control of Per2 expression.

Valproic acid induces astrocyte-dependent neurite outgrowth from cultured rat primary cortical neuron via modulation of tPA/PAI-1 activity.

Tissue plasminogen activator (tPA) is expressed in several regions of brain and plays regulatory roles such as neurite outgrowth, synaptic plasticity and long term potentiation. The activity of tPA is regulated by an endogenous inhibitor plasminogen activator inhibitor-1 (PAI-1), which is expressed mainly in astrocytes. Valproic acid (VPA), a histone deacetylase inhibitor that is used for the treatment of epilepsy and bipolar disorders, promotes neurite extension, neuronal growth and has neuroprotective effect in neurodegenerative diseases. In this study, we examined whether the neurite extension effects of VPA is mediated by modulating tPA/PAI-1 system. VPA dose-dependently increased tPA activity and decreased PAI-1 activity in rat primary astrocytes but not in neurons. PAI-1 protein level secreted into the culture medium but not tPA per se was decreased by VPA. In co-culture system or in neuronal culture stimulated with astrocyte conditioned media but not in pure neuronal cell culture, VPA induced neurite outgrowth via increased tPA activity due to the decreased PAI-1 activity in astrocytes. The decrease in PAI-1 activity and increased neurite extension was regulated via JNK mediated post-transcriptional pathway. The essential role of tPA/PAI-1 system in the regulation of VPA-mediated neurite extension was further demonstrated by experiments using astrocyte conditioned media obtained from tPA or PAI-1 knockout mice. Regulation of PAI-1 activity in astrocyte by VPA may affect both physiological and pathological processes in brain by upregulating tPA activity.

Male-specific alteration in excitatory post-synaptic development and social interaction in pre-natal valproic acid exposure model of autism spectrum disorder.

Autism spectrum disorder (ASD) is a pervasive developmental disorder characterized by three main behavioral symptoms including social deficits, impaired communication, and stereotyped and repetitive behaviors. ASD prevalence shows gender bias to male. Prenatal exposure to valproic acid (VPA), a drug used in epilepsy and bipolar disorder, induces autistic symptoms in both human and rodents. As we reported previously, prenatally VPA-exposed animals at E12 showed impairment in social behavior without any overt reproductive toxicity. Social interactions were not significantly different between male and female rats in control condition. However, VPA-exposed male offspring showed significantly impaired social interaction while female offspring showed only marginal deficits in social interaction. Similar male inclination was observed in hyperactivity behavior induced by VPA. In addition to the ASD-like behavioral phenotype, prenatally VPA-exposed rat offspring shows crooked tail phenotype, which was not different between male and female groups. Both male and female rat showed reduced GABAergic neuronal marker GAD and increased glutamatergic neuronal marker vGluT1 expression. Interestingly, despite of the similar increased expression of vGluT1, post-synaptic marker proteins such as PSD-95 and α-CAMKII expression was significantly elevated only in male offspring. Electron microscopy showed increased number of post-synapse in male but not in female at 4 weeks of age. These results might suggest that the altered glutamatergic neuronal differentiation leads to deranged post-synaptic maturation only in male offspring prenatally exposed to VPA. Consistent with the increased post-synaptic compartment, VPA-exposed male rats showed higher sensitivity to electric shock than VPA-exposed female rats. These results suggest that prenatally VPA-exposed rats show the male preponderance of ASD-like behaviors including defective social interaction similar to human autistic patients, which might be caused by ectopic increase in glutamatergic synapses in male rats.

Prunella vulgaris attenuates prepulse inhibition deficit and attention disruption induced by MK-801 in mice.

Prunella vulgaris var. lilacina is widely distributed in Korea, Japan, China, and Europe, and it has been traditionally used to treat inflammation or hypertension. In the present study, we investigated the effects of the ethanolic extract of the spikes of Prunella vulgaris var. lilacina (EEPV) on dizocilpine (MK-801)-induced schizophrenia-like phenotype behaviors such as the disruption of prepulse inhibition and attention deficits in mice. We also determined the effect of EEPV on MK-801-induced alterations in phosphorylated extracellular signal-regulated kinase, phosphorylated protein kinase B, phospho-glycogen synthase kinase 3-ß, and phosphorylated cAMP response element-binding protein levels in the cortex and hippocampus of mice. MK-801-induced prepulse inhibition deficits were ameliorated by the administration of EEPV, as shown in the acoustic startle response test. Furthermore, EEPV attenuated the MK-801-induced attention deficits in the water finding test. We also found that EEPV attenuated the increased phosphorylated extracellular signal-regulated kinase, phosphorylated protein kinase B, or phospho-glycogen synthase kinase 3-ß levels induced by MK-801 in the cortex but not in the hippocampus. These results suggest that EEPV could be useful for treating schizophrenia because EEPV ameliorates prepulse inhibition disruption and attention deficits induced by MK-801.

Augmented impulsive behavior in febrile seizure-induced mice.

Febrile seizure (FS) is one of the most prevalent etiological events in childhood affecting 2-5% of children from 3 months to 5 years old. Debates on whether neurodevelopmental consequences rise in later life following a febrile seizure or not are still ongoing however there is limited evidence of its effect, especially in a laboratory setting. Moreover, the comparative study using both male and female animal models is sparse. To examine the effect of FS on the behavioral features of mice, both sexes of ICR mice were induced with hyperthermic seizures through exposure to an infrared heat lamp. The mice were divided into two groups, one receiving a single febrile seizure at postnatal day 11 (P11) and one receiving three FS at P11, P13, and P15. Starting at P30 the FS-induced mice were subjected to a series of behavioral tests. Mice with seizures showed no locomotor and motor coordination deficits, repetitive, and depressive-like behavior. However, the FS-induced mice showed impulsive-like behavior in both elevated plus maze and cliff avoidance tests, which is more prominent in male mice. A greater number of mice displayed impaired CAT in both males and females in the three-time FS-induced group compared to the single induction group. These results demonstrate that after induction of FS, male mice have a higher susceptibility to consequences of febrile seizure than female mice and recurrent febrile seizure has a higher chance of subsequent disorders associated with decreased anxiety and increased impulsivity. We confirmed the dysregulated expression of impulsivity-related genes such as 5-HT1A and tryptophan hydroxylase 2 from the prefrontal cortices of FS-induced mice implying that the 5-HT system would be one of the mechanisms underlying the increased impulsivity after FS. Taken together, these findings are useful in unveiling future discoveries about the effect of childhood febrile seizure and the mechanism behind it.

Hycanthone Inhibits Inflammasome Activation and Neuroinflammation-Induced Depression-Like Behaviors in Mice.

Despite the various medications used in clinics, the efforts to develop more effective treatments for depression continue to increase in the past decades mainly because of the treatment-resistant population, and the testing of several hypotheses- and target-based treatments. Undesirable side effects and unresponsiveness to current medications fuel the drive to solve this top global health problem. In this study, we focused on neuroinflammatory response-mediated depression which represents a cluster of depression etiology both in animal models and humans. Several meta-analyses reported that proinflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) were increased in major depressive disorder patients. Inflammatory mediators implicated in depression include type-I interferon and inflammasome pathways. To elucidate the molecular mechanisms of neuroinflammatory cascades underlying the pathophysiology of depression, we introduced hycanthone, an antischistosomal drug, to check whether it can counteract depressive-like behaviors in vivo and normalize the inflammation-induced changes in vitro. Lipopolysaccharide (LPS) treatment increased proinflammatory cytokine expression in the murine microglial cells as well as the stimulation of type I interferon-related pathways that are directly or indirectly regulated by Janus kinase-signal transducer and activator of transcription (JAK-STAT) activation. Hycanthone treatment attenuated those changes possibly by inhibiting the JAK-STAT pathway and inflammasome activation. Hycanthone also ameliorated depressive-like behaviors by LPS. Taken together, we suggest that the inhibitory action of hycanthone against the interferon pathway leading to attenuation of depressive-like behaviors can be a novel therapeutic mechanism for treating depression.

Effect of temporal interference electrical stimulation on phasic dopamine release in the striatum.

BACKGROUND: Temporal interference stimulation (TIS) is a neuromodulation technique that could stimulate deep brain regions by inducing interfering electrical signals based on high-frequency electrical stimulations of multiple electrode pairs from outside the brain. Despite numerous TIS studies, however, there has been limited investigation into the neurochemical effects of TIS. OBJECTIVE: We performed two experiments to investigate the effect of TIS on the medial forebrain bundle (MFB)-evoked phasic dopamine (DA) response. METHODS: In the first experiment, we applied TIS next to a carbon fiber microelectrode (CFM) to examine the modulation of the MFB-evoked phasic DA response in the striatum (STr). Beat frequencies and intensities of TIS were 0, 2, 6, 10, 20, 60, 130 Hz and 0, 100, 200, 300, 400, 500 µA. In the second experiment, we examined the effect of TIS with a 2 Hz beat frequency (based on the first experiment) on MFB-evoked phasic DA release when applied above the cortex (with a simulation-based stimulation site targeting the striatum). We employed 0 Hz and 2 Hz beat frequencies and a control condition without stimulation. RESULTS: In the first experiment, TIS with a beat frequency of 2 Hz and an intensity of 400 µA or greater decreased MFB-evoked phasic DA release by roughly 40%, which continued until the experiment's end. In contrast, TIS at beat frequencies other than 2 Hz and intensities less than 400 µA did not affect MFB-evoked phasic DA release. In the second experiment, TIS with a 2 Hz beat frequency decreased only the MFB-evoked phasic DA response, but the reduction in DA release was not sustained. CONCLUSIONS: STr-applied and cortex-applied TIS with delta frequency dampens evoked phasic DA release in the STr. These findings demonstrate that TIS could influence the neurochemical modulation of the brain.