Chronic social stress in early life can predispose mice to antisocial maltreating behavior

Purpose In our previous study, we developed an assay system to evaluate antisocial maltreating behavior of conspecific mice using a perpetrator–victim paradigm. We also generated a mouse model for the maltreating behavior by mimicking child maltreatment or abuse. Here, we further investigate the antisocial behavior using anti-aggressive and antipsychotic drugs. Methods Model mice sequentially subjected to maternal separation (MS), social defeat (SD), and social isolation (SI) in that order (MS/SD/SI model) were subjected to a maltreating behavioral task. The MS/SD/SI mice were treated with oxytocin (OXY), clozapine (CLZ), haloperidol (HAL), and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Western blotting and enzyme-linked immunosorbent assay were used for protein analysis. Results A substantial portion of the MS/SD/SI model mice (46% of males and 40% of females) showed a higher number of nose pokes than the control. OXY or 8-OH-DPAT treatment reduced the high number of nose pokes by the MS/SD/SI mice, whereas HAL increased it. CLZ did not affect the number of nose pokes by the MS/SD/SI mice. Interestingly, although the OXY level in the MS/SD/SI mice was similar to that in the control, the amount of OXY receptor was lower in the MS/SD/SI mice. The amount of 5-HT1A receptor was also decreased in the MS/SD/SI mice. Conclusion Chronic social stress in childhood might predispose a mouse to antisocial behavior. Our maltreating behavior assay system, including the MS/SD/SI model, is a good animal system for research on and drug screening for brain disorders associated with antisocial or psychotic behavior

Gamma oscillation in functional brain networks is involved in the spontaneous remission of depressive behavior induced by chronic restraint stress in mice

Additional file 1: Table S1. Statistical results of the cross-correlation in Fig. 2c

Direct Generation of Neurosphere-Like Cells from Human Dermal Fibroblasts

Neural stem cell (NSC) transplantation replaces damaged brain cells and provides disease-modifying effects in many neurological disorders. However, there has been no efficient way to obtain autologous NSCs in patients. Given that ectopic factors can reprogram somatic cells to be pluripotent, we attempted to generate human NSC-like cells by reprograming human fibroblasts. Fibroblasts were transfected with NSC line-derived cellular extracts and grown in neurosphere culture conditions. The cells were then analyzed for NSC characteristics, including neurosphere formation, gene expression patterns, and ability to differentiate. The obtained induced neurosphere-like cells (iNS), which formed daughter neurospheres after serial passaging, expressed neural stem cell markers, and had demethylated SOX2 regulatory regions, all characteristics of human NSCs. The iNS had gene expression patterns that were a combination of the patterns of NSCs and fibroblasts, but they could be differentiated to express neuroglial markers and neuronal sodium channels. These results show for the first time that iNS can be directly generated from human fibroblasts. Further studies on their application in neurological diseases are warranted

Profiles of Multidrug Resistance Protein-1 in the Peripheral Blood Mononuclear Cells of Patients with Refractory Epilepsy

BACKGROUND: About one third of patients with epilepsy become refractory to therapy despite receiving adequate medical treatment, possibly from multidrug resistance. P-glycoprotein, encoded by multidrug resistance protein-1 (MDR1) gene, at the blood brain barrier is considered as a major factor mediating drug efflux and contributing to resistance. Given that peripheral blood mononuclear cells (PBMNCs) express MDR1, we investigated a MDR1 status of PBMNCs in various subsets of epilepsy patients and demonstrated their association with clinical characteristics. METHODOLOGY/PRINCIPAL FINDINGS: Clinical and MDR1 data were collected from 140 patients with epilepsy, 30 healthy volunteers, and 20 control patients taking anti-epileptic drugs. PBMNCs were isolated, and basal MDR1 levels and MDR1 conformational change levels were measured by flow cytometry. MDR1 profiles were analyzed according to various clinical parameters, including seizure frequency and number of medications used in epilepsy patients. Epilepsy patients had a higher basal MDR1 level than non-epilepsy groups (p<0.01). Among epilepsy patients, there is a tendency for higher seizure frequency group to have higher basal MDR1 level (p = 0.059). The MDR1 conformational change level was significantly higher in the high-medication-use group than the low-use group (p = 0.028). Basal MDR1 (OR = 1.16 [95% CI: 1.060-1.268]) and conformational change level (OR = 1.11 [95% CI: 1.02-1.20]) were independent predictors for seizure frequency and number of medications, respectively. CONCLUSIONS/SIGNIFICANCE: The MDR1 profile of PBMNCs is associated with seizure frequency and medication conditions in patients with epilepsy

Design of Large-Scale Microwave Cavity for Uniform and Efficient Plastic Heating

To reduce carbon emissions during heating in the manufacturing processes, microwave technology has attracted significant attention. Microwaves have considerable advantages over traditional heating methods, including more rapid heating, lower thermal damage, and eco-friendly processes. To apply microwaves to the manufacturing process, uniform and efficient heating is required. We analyzed the effect of various design parameters for uniform and efficient heating by changing the cavity heights, application of the reflector, and number and positions of waveguides. We conducted a numerical simulation and verified the findings by experiments. The results showed that a slight change in the cavity height altered the electromagnetic field distribution and heating parameters, such as the coefficient of variance and power absorption efficiency. With reflectors installed, 66% of cases exhibited better comprehensive evaluation coefficient (CEC) with consideration of uniform heating and power absorption. The spherical reflector showed 81% of cases, better than those of the ordinary model without a reflector. Furthermore, when double waveguides were installed, the average coefficient of variance (COV) was improved by 22%, and power absorption efficiency was increased by 53% compared to the single waveguide case. When the power applied to the waveguides was doubled, the average COV values improved by 18%. This large-scale analysis will be helpful in applying microwaves to actual industrial sites

Direct lineage reprogramming of mouse fibroblasts to functional midbrain dopaminergic neuronal progenitors

AbstractThe direct lineage reprogramming of somatic cells to other lineages by defined factors has led to innovative cell-fate-change approaches for providing patient-specific cells. Recent reports have demonstrated that four pluripotency factors (Oct4, Sox2, Klf4, and c-Myc) are sufficient to directly reprogram fibroblasts to other specific cells, including induced neural stem cells (iNSCs). Here, we show that mouse fibroblasts can be directly reprogrammed into midbrain dopaminergic neuronal progenitors (DPs) by temporal expression of the pluripotency factors and environment containing sonic hedgehog and fibroblast growth factor 8. Within thirteen days, self-renewing and functional induced DPs (iDPs) were generated. Interestingly, the inhibition of both Jak and Gsk3β notably enhanced the iDP reprogramming efficiency. We confirmed the functionality of the iDPs by showing that the dopaminergic neurons generated from iDPs express midbrain markers, release dopamine, and show typical electrophysiological profiles. Our results demonstrate that the pluripotency factors-mediated direct reprogramming is an invaluable strategy for supplying functional and proliferating iDPs and may be useful for other neural progenitors required for disease modeling and cell therapies for neurodegenerative disorders

Preliminary Observations on Sensitivity and Specificity of Magnetization Transfer Asymmetry for Imaging Myelin of Rat Brain at High Field

Magnetization transfer ratio (MTR) has been often used for imaging myelination. Despite its high sensitivity, the specificity of MTR to myelination is not high because tissues with no myelin such as muscle can also show high MTR. In this study, we propose a new magnetization transfer (MT) indicator, MT asymmetry (MTA), as a new method of myelin imaging. The experiments were performed on rat brain at 9.4 T. MTA revealed high signals in white matter and significantly low signals in gray matter and muscle, indicating that MTA has higher specificity than MTR. Demyelination and remyelination studies demonstrated that the sensitivity of MTA to myelination was as high as that of MTR. These experimental results indicate that MTA can be a good biomarker for imaging myelination. In addition, MTA images can be efficiently acquired with an interslice MTA method, which may accelerate clinical application of myelin imaging

Intracellular gold nanoparticles increase neuronal excitability and aggravate seizure activity in the mouse brain.

Due to their inert property, gold nanoparticles (AuNPs) have drawn considerable attention; their biological application has recently expanded to include nanomedicine and neuroscience. However, the effect of AuNPs on the bioelectrical properties of a single neuron remains unknown. Here we present the effect of AuNPs on a single neuron under physiological and pathological conditions in vitro. AuNPs were intracellularly applied to hippocampal CA1 neurons from the mouse brain. The electrophysiological property of CA1 neurons treated with 5- or 40-nm AuNPs was assessed using the whole-cell patch-clamp technique. Intracellular application of AuNPs increased both the number of action potentials (APs) and input resistance. The threshold and duration of APs and the after hyperpolarization (AHP) were decreased by the intracellular AuNPs. In addition, intracellular AuNPs elicited paroxysmal depolarizing shift-like firing patterns during sustained repetitive firings (SRF) induced by prolonged depolarization (10 sec). Furthermore, low Mg2+-induced epileptiform activity was aggravated by the intracellular AuNPs. In this study, we demonstrated that intracellular AuNPs alter the intrinsic properties of neurons toward increasing their excitability, and may have deleterious effects on neurons under pathological conditions, such as seizure. These results provide some considerable direction on application of AuNPs into central nervous system (CNS)

Differential regulation of observational fear and neural oscillations by serotonin and dopamine in the mouse anterior cingulate cortex

Rationale The aberrant regulation of serotonin (5-HT) and dopamine (DA) in the brain has been implicated in neuropsychiatric disorders associated with marked impairments in empathy, such as schizophrenia and autism. Many psychiatric drugs bind to both types of receptors, and the anterior cingulate cortex (ACC) is known to be centrally involved with empathy. However, the relationship between the 5-HT/DA system in the ACC and empathic behavior is not yet well known. Objectives We investigated the role of 5-HT/DA in empathylike behavior and in the regulation of ACC neural activity. Methods An observational fear learning task was conducted following microinjections of 5-HT, DA, 5-HT and DA, methysergide (5-HT receptor antagonist), SCH-23390 (DA D1 receptor antagonist), or haloperidol (DA D2 receptor antagonist) into the mouse ACC. The ACC neural activity influenced by 5-HT and DA was electrophysiologically characterized in vitro and in vivo. Results The microinjection of haloperidol, but not methysergide or SCH-23390, decreased the fear response of observing mice. The administration of 5-HTand 5-HT and DA together, but not DA alone, reduced the freezing response of observing mice. 5-HT enhanced delta-band activity and reduced alphaand gamma-band activities in the ACC, whereas DA reduced only alpha-band activity. Based on entropy, reduced complexity of ACC neural activity was observed with 5-HT treatment. Conclusions The current results demonstrated that DA D2 receptors in the ACC are required for observational fear learning, whereas increased 5-HT levels disrupt observational fear and alter the regularity of ACC neural oscillations.141711Nsciescopu