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Neurofibromatosis 1 (NF1) is a multisymptomatic disorder with highly variable presentations, which include short stature, susceptibility to formation of the characteristic benign tumors known as neurofibromas, intense freckling and skin discoloration, and cognitive deficits, which characterize most children with the condition. Attention deficits and Autism Spectrum manifestations augment the compromised learning presented by most patients, leading to behavioral problems and school failure, while fragmented sleep contributes to chronic fatigue and poor quality of life. Neurofibromin (Nf1) is present ubiquitously during human development and postnatally in most neuronal, oligodendrocyte, and Schwann cells. Evidence largely from animal models including Drosophila suggests that the symptomatic variability may reflect distinct cell-type-specific functions of the protein, which emerge upon its loss, or mutations affecting the different functional domains of the protein. This review summarizes the contributions of Drosophila in modeling multiple NF1 manifestations, addressing hypotheses regarding the cell-type-specific functions of the protein and exploring the molecular pathways affected upon loss of the highly conserved fly homolog dNf1. Collectively, work in this model not only has efficiently and expediently modelled multiple aspects of the condition and increased understanding of its behavioral manifestations, but also has led to pharmaceutical strategies towards their amelioration. [ABSTRACT FROM AUTHOR]

Global health efforts have increased against infectious diseases, but issues persist with pathogens like Group B Streptococcus (GBS). Preclinical studies have elaborated on the mechanistic process of GBS-induced chorioamnionitis and its impact on the fetal programming of chronic neuropsychiatric diseases. GBS inoculation in rodents demonstrated the following: (i) silent and self-limited placental infection, similar to human chorioamnionitis; (ii) placental expression of chemokines attracting polymorphonuclear (PMN) cells; (iii) in vitro cytokine production; (iv) PMN infiltration in the placenta (histologic hallmark of human chorioamnionitis), linked to neurobehavioral impairments like cerebral palsy and autism spectrum disorders (ASD); (v) upregulation of interleukin-1β (IL-1β) in the placenta and fetal blood, associated with higher ASD risk in humans; (vi) sex-specific effects, with higher IL-1β release and PMN recruitment in male placenta; (vii) male offspring exhibiting ASD-like traits, while female offspring displayed attention deficit and hyperactivity disorder (ADHD)-like traits; (viii) IL-1 and/or NF-kB blockade alleviate placental and fetal inflammation, as well as subsequent neurobehavioral impairments. These findings offer potential therapeutic avenues, including sex-adapted anti-inflammatory treatment (e.g., blocking IL-1; repurposing of FDA-approved IL-1 receptor antagonist (IL-1Ra) treatment). Blocking the IL-1 pathway offers therapeutic potential to alleviate chorioamnionitis-related disabilities, presenting an opportunity for a human phase II RCT that uses IL-1 blockade added to the classic antibiotic treatment of chorioamnionitis. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation has been identified as one of the primary pathogenic factors of neuropsychiatric systemic lupus erythematosus (NPSLE). However, there are no dedicated treatments available in clinics to alleviate neuroinflammation in NPSLE. It has been proposed that stimulating basal forebrain (BF) cholinergic neurons may provide potent anti-inflammatory effects in several inflammatory diseases, but its potential role in NPSLE remains unexplored. This study aims to investigate whether and how stimulating BF cholinergic neurons has a protective effect on NPSLE. Results: Optogenetic stimulation of BF cholinergic neurons significantly ameliorated olfactory dysfunction and anxiety- and depression-like phenotype in pristane induced lupus (PIL) mice. The increased expression of adhesion molecules (P-selectin and vascular cell adhesion molecule-1 (VCAM-1)), leukocyte recruitment, blood-brain barrier (BBB) leakage were significantly decreased. Notably, the brain histopathological changes, including the elevated levels of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β), IgG deposition in the choroid plexus and lateral ventricle wall and lipofuscin accumulation in the cortical and hippocampal neurons, were also significantly attenuated. Furthermore, we confirmed the colocalization between the BF cholinergic projections and the cerebral vessels, and the expression of α7-nicotinic acetylcholine receptor (α7nAChR) on the cerebral vessels. Conclusion: Our data indicate that stimulation of BF cholinergic neurons could play a neuroprotective role in the brain through its cholinergic anti-inflammatory effects on cerebral vessels. Therefore, this may be a promising preventive target for NPSLE. [ABSTRACT FROM AUTHOR]

Background: The continuously increasing association of Alzheimer's disease (AD) with increased mortality rates indicates an unmet medical need and the critical need for establishing novel molecular targets for therapeutic potential. Agonists for peroxisomal proliferator activating receptors (PPAR) are known to regulate energy in the body and have shown positive effects against Alzheimer's disease. There are three members of this class (delta, gamma, and alpha), with PPAR-gamma being the most studied, as these pharmaceutical agonists offer promise for AD because they reduce amyloid beta and tau pathologies, display anti-inflammatory properties, and improve cognition. However, they display poor brain bioavailability and are associated with several adverse side effects on human health, thus limiting their clinical application. Methods: We have developed a novel series of PPAR-delta and PPAR-gamma agonists in silico with AU9 as our lead compound that displays selective amino acid interactions focused upon avoiding the Tyr-473 epitope in the PPAR-gamma AF2 ligand binding domain. Results: This design helps to avoid the unwanted side effects of current PPAR-gamma agonists and improve behavioral deficits and synaptic plasticity while reducing amyloid-beta levels and inflammation in 3xTgAD animals. Conclusions: Our innovative in silico design of PPAR-delta/gamma agonists may offer new perspectives for this class of agonists for AD. [ABSTRACT FROM AUTHOR]

L-Cysteine (L-Cys) is a semi-essential amino acid. It serves as a substrate for enzyme cystathionine-β-synthase in the central nervous system (CNS). L-Cys showed various antioxidant characteristics. Though, studies on the effect of free L-Cys administration to evaluate the CNS functioning is very limited. Therefore, we assessed the effects of L-Cys on corticosterone (CORT) induced oxidative stress, behavioral deficits and memory impairment in male rats. L-Cys (150 mg/kg/ml) administered to vehicle and CORT (20 mg/kg/ml) treated rats orally for 28 days. Behavioral activities were conducted after treatment period. Subsequently, rats were sacrificed, blood and brain were removed. Hippocampus was isolated from brain and then hippocampus and plasma were collected for oxidative, biochemical and neurochemical analysis. Results showed that repeated treatment of L-Cys produced antidepressant, anxiolytic and memory-improving effects which may be ascribed to the enhanced antioxidant profile, normalized cholinergic, serotonergic neurotransmission in brain (hippocampus) following CORT administration. Increased plasma CORT by CORT administration was also normalized by L-Cys. The current study concluded that administration of free L-Cys improved the behavioral, biochemical, neurochemical and redox status of CNS. Hence, L-Cys could be protective therapeutic modulator against stress induced neurological ailments. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is a progressive form of dementia that results in problems with memory, thinking, and behavior. It often starts with abnormal aggregation and deposition of β amyloid and tau, followed by neuronal damage such as atrophy of the hippocampi, leading to Alzheimer's disease (AD). The aim of this article is to map the genetic-imaging-clinical pathway for AD in order to delineate the genetically-regulated brain changes that drive disease progression based on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. We develop a novel two-step approach to delineate the association between high-dimensional 2D hippocampal surface exposures and the Alzheimer's Disease Assessment Scale (ADAS) cognitive score, while taking into account the ultra-high dimensional clinical and genetic covariates at baseline. Analysis results suggest that the radial distance of each pixel of both hippocampi is negatively associated with the severity of behavioral deficits conditional on observed clinical and genetic covariates. These associations are stronger in Cornu Ammonis region 1 (CA1) and subiculum subregions compared to Cornu Ammonis region 2 (CA2) and Cornu Ammonis region 3 (CA3) subregions. for this article, including a standardized description of the materials available for reproducing the work, are available as an online supplement. [ABSTRACT FROM AUTHOR]

Background: Preclinical rodent models for Parkinson's disease (PD) based on viral human alpha-synuclein (h-αSyn) overexpression recapitulate some of the pathological hallmarks as it presents in humans, such as progressive cell loss and additional synucleinopathy in cortical and subcortical structures. Recent studies have combined viral vector-based overexpression of human wild-type αSyn with the sequential or simultaneous inoculation of preformed fibrils (PFFs) derived from human αSyn. Objective: The goal of the study was to investigate whether sequential or combined delivery of the AAV vector and the PFFs are equipotent in inducing stable neurodegeneration and behavioral deficits. Methods: Here we compare between four experimental paradigms (PFFs only, AAV-h-αSyn only, AAV-h-αSyn with simultaneous PFFs, and AAV-h-αSyn with sequential PFFs) and their respective GFP control groups. Results: We observed reduction of TH expression and loss of neurons in the midbrain in all AAV (h-αSyn or GFP) injected groups, with or without additional PFFs inoculation. The overexpression of either h-αSyn or GFP alone induced motor deficits and dysfunctional dopamine release/reuptake in electrochemical recordings in the ipsilateral striatum. However, we observed a substantial formation of insoluble h-αSyn aggregates and inflammatory response only when h-αSyn and PFFs were combined. Moreover, the presence of h-αSyn induced higher axonal pathology compared to control groups. Conclusion: Simultaneous AAV and PFFs injections are equipotent in the presented experimental setup in inducing histopathological and behavioral changes. This model provides new and interesting possibilities for characterizing PD pathology in preclinical models and means to assess future therapeutic interventions. [ABSTRACT FROM AUTHOR]

A maternal high-fat diet affects offspring neurodevelopment with long-term consequences on their brain health and behavior. During the past three decades, obesity has rapidly increased in the whole human population worldwide, including women of reproductive age. It is known that maternal obesity caused by a high-fat diet may lead to neurodevelopmental disorders in their offspring, such as autism spectrum disorder, attention deficit hyperactivity disorder, anxiety, depression, and schizophrenia. A maternal high-fat diet can affect offspring neurodevelopment due to inflammatory activation of the maternal gut, adipose tissue, and placenta, mirrored by increased levels of pro-inflammatory cytokines in both maternal and fetal circulation. Furthermore, a maternal high fat diet causes gut microbial dysbiosis further contributing to increased inflammatory milieu during pregnancy and lactation, thus disturbing both prenatal and postnatal neurodevelopment of the offspring. In addition, global molecular and cellular changes in the offspring's brain may occur due to epigenetic modifications including the downregulation of brain-derived neurotrophic factor (BDNF) expression and the activation of the endocannabinoid system. These neurodevelopmental aberrations are reflected in behavioral deficits observed in animals, corresponding to behavioral phenotypes of certain neurodevelopmental disorders in humans. Here we reviewed recent findings from rodent models and from human studies to reveal potential mechanisms by which a maternal high-fat diet interferes with the neurodevelopment of the offspring. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a common complex neurodegenerative disease, and aerobic exercise (EX) has potential to improve motor dysfunction. This study aimed to explore whether EX acts on PD in mice mode. Mice were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and subjected to a 4-week physical exercise regimen (EX-PD group) and underwent RNA-Seq. Here, MPTP caused PD, which was characterized by neuron shrinkage and behavioral deficits, whereas EX improved PD by rescuing neuronal survival and motor function in mice. Moreover, circRNA expression profiles identified a total of 142 differentially expressed circRNAs (DEcircRNAs) between PD and EX-PD group. These DEcircRNAs were mainly involved in PD, dopaminergic synapses, and calcium signaling pathways. The expression of circZfp827 and circTshz2 were significantly elevated in PD group while reduced owing to EX intervention. In contrast, EX intervention significantly restored decline in circHivep2 expression due to PD. The circRNA-miRNAmRNA network suggested that circZfp827, circHivep2, and circTshz2 were involved in ceRNA mechanism of EX to improve PD, and their target genes were significantly decreased after interference. The directly binding regulation relationship of circTshz2-mmu-miR-326-3p-Th was verified by double luciferase reporter assay. Our research revealed that EX improved motor behavioral deficits and pathological features of PD mice, and circRNA-based signatures are potential candidates for further assessment as PD biomarkers for improvement by EX. [ABSTRACT FROM AUTHOR]

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Clinical and experimental evidences reveal that excess exposure to manganese is neurotoxic and leads to cellular damage. However, the mechanism underlying manganese neurotoxicity remains poorly understood but oxidative stress has been implicated to be one of the key pathophysiological features related to it. The present study investigates the effects associated with manganese induced toxicity in rats and further to combat these alterations with a well-known antioxidant N-acetylcysteine which is being used in mitigating the damage by its radical scavenging activity. The study was designed to note the sequential changes along with the motor and memory dysfunction associated with biochemical and histo-pathological alterations following exposure and treatment for 2 weeks. The results so obtained showed decrease in the body weights, behavioral deficits with increased stress markers and also neuronal degeneration in histo-pathological examination after manganese intoxication in rats. To overcome the neurotoxic effects of manganese, N-acetylcysteine was used in the current study due to its pleiotropic potential in several pathological ailments. Taken together, N-acetylcysteine helped in ameliorating manganese induced neurotoxic effects by diminishing the behavioral deficits, normalizing acetylcholinesterase activity, and augmentation of redox status. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is characterized by protein inclusions and loss of striatal neurons which result from expanded CAG repeats in the poly-glutamine (polyQ) region of the huntingtin (HTT) gene. Both polyQ expansion and loss of HTT have been shown to cause axonal transport defects. While studies show that HTT is important for vesicular transport within axons, the cargo that HTT transports to/from synapses remain elusive. Here, we show that HTT is present with a class of Rab4-containing vesicles within axons in vivo. Reduction of HTT perturbs the bi-directional motility of Rab4, causing axonal and synaptic accumulations. In-vivo dual-color imaging reveal that HTT and Rab4 move together on a unique putative vesicle that may also contain synaptotagmin, synaptobrevin, and Rab11. The moving HTT-Rab4 vesicle uses kinesin-1 and dynein motors for its bi-directional movement within axons, as well as the accessory protein HIP1 (HTT-interacting protein 1). Pathogenic HTT disrupts the motility of HTT-Rab4 and results in larval locomotion defects, aberrant synaptic morphology, and decreased lifespan, which are rescued by excess Rab4. Consistent with these observations, Rab4 motility is perturbed in iNeurons derived from human Huntington's Disease (HD) patients, likely due to disrupted associations between the polyQ-HTT-Rab4 vesicle complex, accessory proteins, and molecular motors. Together, our observations suggest the existence of a putative moving HTT-Rab4 vesicle, and that the axonal motility of this vesicle is disrupted in HD causing synaptic and behavioral dysfunction. These data highlight Rab4 as a potential novel therapeutic target that could be explored for early intervention prior to neuronal loss and behavioral defects observed in HD. [ABSTRACT FROM AUTHOR]

Rationale: Cortical and hippocampal neuronal apoptosis and neuroinflammation are associated with behavioral deficits following traumatic brain injury (TBI). Objectives: The present study was designed to investigate the potential protective effects of flavonoid chrysin against TBI-induced vestibulomotor impairment, exploratory/locomotor dysfunctions, recognition memory decline, and anxiety/depression-like behaviors, as well as the verified possible involved mechanisms. Methods: Chrysin (25, 50, or 100 mg/kg/day; P.O.) was administered to rats immediately after diffuse TBI induction, and it was continued for 3 or 14 days. Behavioral functions were assessed by employing standard behavioral paradigms at scheduled points in time. Three days post-TBI, inflammation status was assayed in both cerebral cortex and hippocampus using ELISA kits. Moreover, apoptosis and expression of Bcl-2 family proteins were examined by TUNEL staining and immunohistochemistry, respectively. Results: The results indicated that treatment with chrysin improved vestibulomotor dysfunction, ameliorated recognition memory deficit, and attenuated anxiety/depression-like behaviors in the rats with TBI. Chrysin treatment also modulated inflammation status, reduced apoptotic index, and regulated Bcl-2 family proteins expression in the brains of rats with TBI. Conclusions: In conclusion, the results suggest that chrysin could be beneficial for protection against TBI-associated behavioral deficits, owing to its anti-apoptotic and anti-inflammatory properties. [ABSTRACT FROM AUTHOR]

Taurine, an essential neutraceutical, has been reported to exhibit antioxidant and anti-inflammatory properties. Substantial evidence indicates that prolonged stress is one of the leading causes of psychological and physiological anomalies. Restraint stress (RS) rat model is the most widely used experimental model for the induction of chronic psycho-emotional stress. In the present study, Swiss albino male mice were restrained for 6 h/day for 28 consecutive days. Animals were divided into four groups: control, RS, RS + taurine, and taurine control group. Taurine, a potent antioxidant, was administered (200 mg/kg) orally along with RS for 28 days. The taurine intervention significantly restored the RS-induced neurobehavioral alterations evident by the elevated plus-maze, Morris water maze test, forced swim test, tail suspension test, and a sucrose preference test. Moreover, taurine significantly prevented hippocampal oxidative stress (lipid peroxidation, reduced glutathione, and nitrite) and other neurochemical (acetylcholinesterase, and IL-1β) anomalies. Using western blotting analyses, we demonstrate that taurine treatment significantly ameliorated the alterations in Brain-derived neurotrophic factor, caspase-3, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) level in the hippocampus. Thus, Taurine effectively inhibited RS-induced oxidative stress, neuroinflammation, and apoptosis via a mechanism involving the inhibition of the NF-κB signaling pathway. In summary, our study is the first to demonstrate that NF-κB and caspase-3 inhibition, as well as BDNF augmentation, was involved in neuroprotective potential of taurine against RS-induced behavioural anomalies. [ABSTRACT FROM AUTHOR]

Autophagy is crucial for cell survival, development, division, and homeostasis. The mammalian target of rapamycin (mTOR), which is the foremost negative controller of autophagy, plays a key role in many endogenous processes. The present study investigated whether rapamycin can ameliorate surgery—induced cognitive deficits by inhibiting mTOR and activating autophagy in the hippocampus. Both adult and aged C57BL/6J mice received an intraperitoneal injection of rapamycin (10 mg/kg/day) for 5 days per week for one and a half months. Mice were then subjected to partial hepatectomy under general anesthesia. Behavioral performance was assessed on postoperative days 3, 7, and 14. Hippocampal autophagy-related (Atg)-5, phosphorylated mTOR, and phosphorylated p70S6K were examined at each time point. Brain derived neurotrophic factor (BDNF), synaptophysin, and tau hyperphosphorylation (T396) in the hippocampus were also examined. Surgical trauma and anesthesia exacerbated spatial learning and memory impairment in aged mice on postoperative days 3 and 7. Following partial hepatectomy, the levels of phosphorylated mTOR, phosphorylated 70S6K, and phosphorylated tau were all increased in the hippocampus. A corresponding decline in BDNF and synaptophysin were observed. Rapamycin treatment restored autophagy function, attenuated phosphorylation of tau protein, and increased BDNF and synaptophysin expression in the hippocampus of surgical mice. Furthermore, surgery and anesthesia induced spatial learning and memory impairments were also reversed by rapamycin treatment. Autophagy impairments and mTOR hyperactivation were detected along with surgery—induced behavioral deficits. Inhibiting the mTOR signaling pathway with rapamycin successfully ameliorated surgery-related cognitive impairments by sustaining autophagic degradation, inhibiting tau hyperphosphorylation, and increasing synaptophysin and BDNF expression. [ABSTRACT FROM AUTHOR]

Exposure of the developing fetus to Zika virus (ZIKV) results in a set of brain abnormalities described as the congenital Zika syndrome. Although microcephaly is the most obvious outcome, neuropathologies, such as intracranial calcifications and polymicrogyria, can occur in the absence of microcephaly. Moreover, the full impact of exposure on motor, social, and cognitive skills during development remains uncharacterized. We examined the long-term neurobehavioral consequences of neonatal ZIKV exposure in four genetically divergent inbred mouse strains (C57BL/6J, 129Sl/SvImJ, FVB/NJ, and DBA/2J). Male and female mice were infected on postnatal day 1, considered comparable with exposure late in the second trimester of humans. We demonstrate strain differences in early susceptibility to the virus and the time course of glial reaction in the brain. These changes were associated with strain- and sex-dependent differences in long-term behavioral abnormalities that include hyperactivity, impulsiveness, and motor incoordination. In addition, the adult brains of susceptible mice exhibited widespread calcifications that may underlie the behavioral deficits observed. Characterization of the neuropathological sequelae of developmental exposure to the Zika virus in different immunocompetent mouse strains provides a foundation for identifying genetic and immune factors that contribute to long-term neurobehavioral consequences in susceptible individuals. [ABSTRACT FROM AUTHOR]

Nanomaterials of graphene and its derivatives have been widely applied in recent years, but whose impacts on the environment and health are still not well understood. In the present study, the potential adverse effects of graphite (G), graphite oxide nanoplatelets (GO) and graphene quantum dots (GQDs) on the motor nervous system were investigated using nematode Caenorhabditis elegans as the assay system. After being characterized using TEM, SEM, XPS and PLE, three nanomaterials were chronically exposed to C. elegans for 6 days. In total, 50-100 mg l−1 GO caused a significant reduction in the survival rate, but G and GDDs showed low lethality on nematodes. After chronic exposure of sub-lethal dosages, three nanomaterials were observed to distribute primarily in the pharynx and intestine; but GQDs were widespread in nematode body. Three graphene-based nanomaterials resulted in significant declines in locomotor frequency of body bending, head thrashing and pharynx pumping. In addition, mean speed, bending angle-frequency and wavelength of the crawling movement were significantly reduced after exposure. Using transgenic nematodes, we found high concentrations of graphene-based nanomaterials induced down-expression of dat-1::GFP and eat-4::GFP, but no significant changes in unc-47::GFP. This indicates that graphene-based nanomaterials can lead to damages in the dopaminergic and glutamatergic neurons. The present data suggest that chronic exposure of graphene-based nanomaterials may cause neurotoxicity risks of inducing behavioral deficits and neural damage. These findings provide useful information to understand the toxicity and safe application of graphene-based nanomaterials. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Current clinical research into mild traumatic brain injury (mTBI) has focused on white matter changes as identified by advanced MRI based imaging techniques. However, perivascular tau accumulation in the brains of individuals diagnosed with mTBI suggests that the vasculature plays a key role in the pathology. This study used a rat model to examine whether the endothelial glycocalyx, a layer of the vasculature responsible for sensing luminal shear forces, is damaged by exposure to repeated low intensity blast, and whether this layer is associated with observed behavioral deficits. The blast exposure used consisted of 12, 40 kPa blast exposures conducted with a minimum of 24 h between blasts. We found that repeated blast exposure reduced glycocalyx length and density in various brain regions indicating damage. This blast exposure paradigm was associated with a mild performance decrement in the Morris water maze (MWM) which assesses learning and memory. Administration of hyaluronidase, an enzyme that binds to and degrades hyaluronan (a major structural component of the glycocalyx) prior to blast exposure reduced the observed behavioral deficits and induced a thickening of the glycocalyx layer. Taken together these findings demonstrate that the endothelial glycocalyx degradation following repeated blast is associated with behavioral decrements which can be prevented by treatment with hyaluronidase. [ABSTRACT FROM AUTHOR]

Single nucleotide polymorphisms ( SNPs) in the human type A gamma-aminobutyric acid ( GABA) receptor β2 subunit gene ( GABRB2) have been associated with schizophrenia and quantitatively correlated with mRNA expression in the postmortem brain tissue of patients with schizophrenia. l-Methionine ( MET) administration has been reported to cause a recrudescence of psychotic symptoms in patients with schizophrenia, and similar symptoms have been generated in MET-induced mice. In this study, a zebrafish animal model was used to evaluate the relationship between the gabrb2 mRNA expression and its promoter DNA methylation in developmental and MET-induced schizophrenia-like zebrafish. The results indicated developmental increases in global DNA methylation and decreases in gabrb2 promoter methylation in zebrafish. A significant increase in gabrb2 mRNA levels was observed after GABA was synthesized. Additionally, the MET-triggered schizophrenia-like symptoms in adult zebrafish, involving social withdrawal and cognitive dysfunction analyzed with social interaction and T-maze behavioral tests, were accompanied by significantly increased DNA methylation levels in the global genome and the gabrb2 promoter. Furthermore, the significant correlation between gabrb2 mRNA expression and gabrb2 promoter methylation observed in the developmental stages became non-significant in MET-triggered adult zebrafish. These findings demonstrate that gabrb2 mRNA expression is associated with DNA methylation varies by developmental stage and show that these epigenetic association mechanisms are disrupted in MET-triggered adult zebrafish with schizophrenia-like symptoms. In conclusion, these results provide plausible epigenetic evidence of the GABAA receptor β2 subunit involvement in the schizophrenia-like behaviors and demonstrate the potential use of zebrafish models in neuropsychiatric research. [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder (PTSD) is a severe psychiatric condition. The allopregnanolone biosynthesis has been implicated as one of the possible contributors to PTSD. Inulin-type oligosaccharides of morinda officinalis (IOMO) had been shown to be effective in the therapy of depression. However, few studies concern the anti-PTSD-like effects of IOMO. To evaluate this, the single prolonged stress (SPS) model was used in the present study. It had been shown that the behavioral deficits of SPS-treated rats were reversed by IOMO (25.0 and 50.0 mg/kg, i.p.), which reversed the increased freezing time in contextual fear paradigm (CFP) and the decreased time and entries in open arms in the elevated plus maze (EPM) test without affecting the locomotor activity in the open field (OF) test. In addition, the decreased allopregnanolone in the prefrontal cortex, hippocampus, and amygdala was reversed by IOMO (25.0 and 50.0 mg/kg, i.p.), respectively. In summary, the present study indicated that the IOMO exert anti-PTSD-like behaviors, which maybe associated with the brain allopregnanolone biosynthesis. [ABSTRACT FROM AUTHOR]

Background: Souvenaid™ is a nutraceutical compound thought to positively enhance synaptic function. In line with this mechanism of action, Souvenaid™ has been shown to improve cognitive function in subjects with mild Alzheimer's disease in randomized clinical trials. To date, however, the potential of Souvenaid™ to improve cognitive functioning in subjects with other neurodegenerative conditions also characterized by synaptic loss has not been explored. Objective: To evaluate the impact of Souvenaid™ on executive functions, social cognition and behavioral disturbances in subjects with the behavioral variant of frontotemporal dementia (bv-FTD). Methods: Twenty-six subjects with bv-FTD were enrolled in the study and randomized to Souvenaid™ (125 ml/day) or placebo groups. After 12 weeks, subjects were switched between the two groups. All subjects, blinded to treatment, underwent clinical and cognitive evaluations at enrollment, after 12 weeks and after 24 weeks. Results: Treatment with Souvenaid™ was associated with a significant reduction of behavioral symptoms and an increase in Theory of Mind skills compared to placebo, which both returned to baseline when Souvenaid™ was discontinued. Souvenaid™ did not have an effect on executive functions. Conclusions: Our results provide evidence of the potential of Souvenaid™ therapy for the treatment of behavioral disturbances and social cognition skills in FTD. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Temporal lobe epilepsy is characterized by spontaneous recurrent seizures (SRS) and associated with behavioral problems. However, the molecular mechanisms underlying these problems are not yet clear. In this study, kainic acid (KA) was systemically administered to immature male Wistar rats to induce SRS. The behavior of the immature rats was evaluated with a water maze, elevated-plus mazes, and open field tests. The expression patterns of synaptophysin, SNAP-25, and synaptotagmin 1 (Syt 1) were examined by reverse-transcriptase polymerase chain reaction (RT-PCR) and Western blot analysis. KA-treated rats with SRS demonstrated learning and memory deficits, reduced anxiety, and increased locomotor activity, compared with placebo-treated rats and KA-treated rats without SRS. No neuronal cell loss was observed in the hippocampus 6 weeks after exposure to KA. However, RT-PCR and Western blot analyses revealed decreased synaptophysin, SNAP-25, and Syt 1 expression in KA-treated rats with SRS. Synaptophysin, SNAP-25, and Syt1 expression levels were found to be positively correlated with learning and memory but negatively correlated with anxiety and locomotor activity. These data suggested that SRS may induce changes in synaptophysin, SNAP-25, and Syt1 expression and may be functionally related to SRS-induced behavioral deficits. [ABSTRACT FROM AUTHOR]

Background Following the onset of focal ischemic stroke, the brain experiences a series of alterations including infarct evolvement, cellular proliferation in the penumbra, and behavioral deficits. However, systematic study on the temporal and spatial dependence of these alterations has not been provided. Results Using multiple approaches, we assessed stroke outcomes by measuring brain injury, dynamic cellular and glial proliferation, and functional deficits at different times up to two weeks after photothrombosis (PT)-induced ischemic stroke in adult mice. Results from magnetic resonance imaging (MRI) and Nissl staining showed a maximal infarction, and brain edema and swelling 1-3 days after PT. The rate of Bromodeoxyuridine (Brdu)-labeled proliferating cell generation is spatiotemporal dependent in the penumbra, with the highest rate in post ischemic days 3-4, and higher rate of proliferation in the region immediate to the ischemic core than in the distant region. Similar time-dependent generation of proliferating GFAP+ astrocytes and Iba1+ microglia/macrophage were observed in the penumbra. Using behavioral tests, we showed that PT resulted in the largest functional deficits during post ischemic days 2-4. Conclusion Our study demonstrated that first a few days is a critical period that causes brain expansion, cellular proliferation and behavioral deficits in photothrombosis-induced ischemic model, and proliferating astrocytes only have a small contribution to the pools of proliferating cells and reactive astrocytes. [ABSTRACT FROM AUTHOR]

Natural leaching processes and/or anthropogenic contamination can result in ground water concentrations of the essential metal manganese (Mn) that far exceed the current regulatory standards. Neurological consequences of Mn drinking water (DW) overexposure to experimental animals, i.e., mice, including its brain deposition/distribution and behavioral effects are understudied. Adult male C57BL/6 mice were exposed to Mn via the DW for 8 weeks. After 5 weeks of Mn exposure, magnetic resonance imaging revealed significant Mn deposition in all examined brain regions; the degree of Mn deposition did not increase further a week later. Behaviorally, early hyperactivity and more time spent in the center of the arenas in an open field test, decreased forelimb grip strength and less time swimming in a forced swim test were observed after 6 weeks of Mn DW exposure. Eight-week Mn DW exposure did not alter striatal dopamine, its metabolites, or the expression of key dopamine homeostatic proteins, but it significantly increased striatal 5-hydroxyindoleacetic acid (a serotonin metabolite) levels, without affecting the levels of serotonin itself. Increased expression (mRNA) of glial fibrillary acidic protein (GFAP, an astrocyte activation marker), heme oxygenase-1 and inducible nitric oxide synthase (oxidative and nitrosative stress markers, respectively) were observed 8 weeks post-Mn DW exposure in the substantia nigra. Besides mRNA increases, GFAP protein expression was increased in the substantia nigra pars reticulata. In summary, the neurobehavioral deficits, characterized by locomotor and emotional perturbations, and nigral glial activation associated with significant brain Mn deposition are among the early signs of Mn neurotoxicity caused by DW overexposure. [ABSTRACT FROM AUTHOR]

Exposure to alcohol has serious consequences for the developing fetus, leading to a range of conditions collectively known as fetal alcohol spectrum disorders (FASD). Most importantly, alcohol exposure affects the development of the brain during critical periods of differentiation and growth, leading to cognitive and behavioral deficits. The molecular mechanisms and processes underlying the teratogenic effects of alcohol exposure remain poorly understood and are complex, because the specific effects depend on the timing, amount, and duration of exposure as well as genetic susceptibility. Accumulating evidence from studies on DNA methylation and histone modification that affect chromatin structure, as well as on the role of microRNAs in regulating mRNA levels supports the contribution of epigenetic mechanisms to the development of FASD. These epigenetic effects are difficult to study, however, because they often are cell-type specific and transient in nature. Rodent models play an important role in FASD research. Although recent studies using these models have yielded some insight into epigenetic mechanisms affecting brain development, they have generated more questions than they have provided definitive answers. Researchers are just beginning to explore the intertwined roles of different epigenetic mechanisms in neurogenesis and how this process is affected by exposure to alcohol, causing FASD. [ABSTRACT FROM AUTHOR]

Biomarkers represent a promising tool as 'early-indicators' of potential pollutant impacts, providing the link between individuals' responses and higher hierarchical levels, such as populations and communities. In this study we use alteration of escape behavior, caused by exposure to typical agrochemicals, as a biomarker of wetland pollution. Tadpoles from three different Iberian anuran species were exposed to sublethal concentrations of copper sulfate and ammonium nitrate for 96 h. Different behavioral indicators were then monitored: number of stimuli to provoke a displacement, distance moved, and nature of escape movement. All species showed similar behavioral alterations. The endpoints of all the three behavioral indices showed deficits leading to a reduction in the capacity and efficiency of escape. The recovery when larvae were moved to clean water was surprisingly fast. After 96 h in recovery, almost all larvae showed normal escape behavior. This indicates that this larval behavioral biomarker can be used as a warning tool in wetland biomonitoring programs in a continuous runoff or spill pollution context. [ABSTRACT FROM AUTHOR]

8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a selective 5-hydroxy-tryptamine (5-HT; serotonin)-1A agonist was used to evaluate the role 5-HT-1 A receptors in restraint-induced behavioral deficits and adaptation to repeated restraint stress in rats. Animals were injected with 8-OH-DPAT at a dose of 0.25 mg/kg 1 h before exposing to an episode of 2 h/day restraint stress daily for 5 days. Effects of drug administration and restraint stress on 24 h cumulative food intakes were monitored daily. Intensity of 8-OH-DPAT-induced serotonin syndrome was also monitored each day before submitting animals to the episode of stress. Exposure to the first episode of 2 h restraint stress resulted in a decrease in 24 h cumulative food intake and an attenuation of 8-OH-DPAT-induced serotonin syndrome monitored next day. The deficits attenuated following 2nd and 3rd 2 h/day restraint were not observed following the 4th and 5th 2 h/day restraint. The decreases of food intake following 1st and 2nd day restraint sessions were smaller in 8-OH-DPAT than saline-injected animals. Administration of 8-OH-DPAT on day 6 elicited comparable serotonin syndrome in unrestrained and repeatedly restrained groups. Brain 5-HT metabolism decreased in unrestrained but not repeatedly restrained animals. The results suggest that a decrease in serotonergic neurotransmission is involved in restraint-induced behavioral deficits while a normalization of serotonin neurotransmission due to desensitization of somatodendritic 5-HT-1A receptors may help cope with the stress demand to produce adaptation to stress. [ABSTRACT FROM AUTHOR]

Developmental exposure to chlorpyrifos (CPF) causes persistent changes in serotonergic (5HT) systems. We administered 1 mg/kg/day CPF to rats on postnatal days 1-4, a regimen below the threshold for systemic toxicity. When tested in adulthood, CPF-exposed animals showed abnormalities in behavioral tests that involve 5HT mechanisms. In the elevated plus maze, males treated with CPF spent more time in the open arms, an effect seen with 5HT deficiencies in animal models of depression. Similarly, in an anhedonia test, the CPF-exposed group showed a decreased preference for chocolate milk versus water. Developmental CPF exposure also has lasting effects on cognitive function. We replicated our earlier finding that developmental CPF exposure ablates the normal sex differences in 16-arm radial maze learning and memory: during acquisition training, control male rats typically perform more accurately than do control females, but CPF treatment eliminated this normal sex difference. Females exposed to CPF showed a reduction in working and reference memory errors down to the rate of control males. Conversely, CPF-exposed males exhibited an increase in working and reference memory errors. After radial-arm acquisition training, we assessed the role of 5HT by challenging the animals with the 5HT2 receptor antagonist ketanserin. Ketanserin did not affect performance in controls but elicited dose-dependent increases in working and reference memory errors in the CPF group, indicating an abnormal dependence on 5HT systems. Our results indicate that neonatal CPF exposures, classically thought to be subtoxic, produce lasting changes in 5HT-related behaviors that resemble animal models of depression. [ABSTRACT FROM AUTHOR]

Recommendations from experts and recently established guidelines on how to improve the face and predictive validity of animal models of stroke have stressed the importance of using older animals and long-term behavioral-functional endpoints rather than relying almost exclusively on acute measures of infarct volume in young animals. The objective of the present study was to determine whether we could produce occlusions in older rats with an acceptable mortality rate and then detect reliable, long-lasting functional deficits. A reversible intraluminar suture middle cerebral artery occlusion (MCAO) procedure was used to produce small infarcts in middle-aged rats. This resulted in an acceptable mortality rate, and robust disabilities were detected in functional assays, although the degree of total tissue loss measured 90 d after MCAO was quite modest. Infarcted animals were functionally impaired relative to sham control animals even 90 d after the occlusions, and when animals were subgrouped based on amount of tissue loss, MCAO animals with only 4% tissue loss exhibited enduring neurological-behavioral impairments relative to sham-operated controls, and the functional impairments in the group with the largest infarcts (20% tissue loss) were more severe than the functional impairments in the rats with 4% tissue loss. These results suggest that this model, using reversible MCAO to produce small infarcts and long-lasting functional-behavioral deficits in older rats, may represent an advance in the relatively higher-throughput modeling of stroke and its recovery in rodents and may be useful in the development and characterization of future stroke therapies. [ABSTRACT FROM AUTHOR]

This paper does not reflect official EPA policy. Epidemiological studies on the neurodevelopmental effects of exposure to PCBs initiated in the last decade have had the opportunity to take advantage of modern methodologies for the analysis of congeners of PCBs, dioxins, and related orga-nochlorine compounds. Each of these studies is a longitudinal prospective study, in which women were recruited during pregnancy and the children are being followed for at least several years after birth. The study from which the largest body of data has been published to date is being performed in the Netherlands, in which exposure to PCBs and related compounds is through the general food supply. Mother-infant pairs were recruited in two cities. Half of the infants were bottle-fed and half breast-fed in each city. Four PCB congeners (118, 138, 153, 180) were assessed in maternal and cord plasma, breast milk, and plasma of the child at 3.5 years. TEQ in breast milk was calculated based on PCDDs/PCDFs and dioxin-like PCBs. Various measures ofin uteroexposure were associated with suboptimal neurological status during infancy, whereas maternal plasma PCB concentration was associated with cognitive deficits (Kaufman scores) at 3.5 years of age. The child's concurrent plasma PCB levels and maternal PCB plasma levels independently predicted performance on various aspects of a vigilance task, and maternal and cord plasma levels predicted impairment of complex play behavior. Poor scores on behavioral ratings were associated with concurrent blood PCB concentrations in the child. A study in Oswego in Lake Ontario fish eaters includes mothers who never ate Great Lakes fish and mothers who consumed greater than 40 PCB-equivalent pounds of Lake Ontario fish over their lifetime. Sixty-eight PCB congeners were measured in cord blood. Suboptimal neurological status during infancy was associated with maternal fish consumption and highly chlorinated cord PCB levels, whereas deficits in short-term memory at 6 months and 1 year of age were associated with total chlorinated cord PCB levels. In a study in Germany of 171 mother-infant pairs, PCB congeners 138, 153, and 180 were measured in cord plasma and milk 2 weeks after birth; both measures are considered markers of in utero exposure. Suboptimal neurological status during infancy, decrements in Bayley scores at 30 months and Kaufman scores at 42 months were associated with PCBs in milk but not cord plasma. These studies, combined with data from previous studies, reveal a consistent relationship between PCB exposure and suboptimal neurological status during infancy, and cognitive deficits associated within uteroexposure. Data from the Dutch study revealed effects on other behavioral domains associated with concurrent (postnatal) exposure. Although it is not possible to identify specific congeners or groups of congeners that may be responsible for the neurotoxic effects observed in these studies, the TEQ approach was not particularly predictive for neurotoxic outcomes. [ABSTRACT FROM PUBLISHER]

The effect of ischemia/reperfusion-induced neuronal damage on the memory impairment were investigated using active avoidance and Morris water maze tasks in Wistar rats. Focal ischemia was induced by 1 h occlusion of the right middle cerebral artery (MCA) of Wistar male rats. Reperfusion was induced by releasing the occlusion and restoring the blood circulation for 24 h. The acquisition and preservation memory tested by active avoidance showed a significant difference between the sham and ischemia/reperfusion group. The water maze acquisition performance was also significant difference between sham and ischemia/reperfusion groups in both latency and moving distance. The infarction volume was increased by the ischemia/reperfusion. Furthermore, the cresyl violet staining of the ischemia/reperfusion brain showed severe neuronal damage (pyramidal cell loss) in the cortex in addition to the striatum lesion of brain. This study shows that pyramidal cell damage in the cortex lesion may be partially related to memorial disturbance in the ischemia/reperfusion brain injury. [ABSTRACT FROM AUTHOR]

Schizophrenia is a neurodevelopmental disorder whose etiopathogenesis includes changes in cellular as well as extracellular structures. Perineuronal nets (PNNs) associated with parvalbumin-positive interneurons (PVs) in the prefrontal cortex (PFC) are dysregulated in schizophrenia. However, the postnatal development of these structures along with their associated neurons in the PFC is unexplored, as is their effects on behavior and neural activity. Therefore, in this study, we employed a DISC1 (Disruption in Schizophrenia) mutation mouse model of schizophrenia to assess these developmental changes and tested whether enzymatic digestion of PNNs in the PFC affected schizophrenia-like behaviors and neural activity. Developmentally, we found that the normal formation of PNNs, PVs, and colocalization of these two in the PFC, peaked around PND 22 (postnatal day 22). However, in DISC1, mutation animals from PND 0 to PND 60, both PNNs and PVs were significantly reduced. After enzymatic digestion of PNNs with chondroitinase in adult animals, the behavioral pattern of control animals mimicked that of DISC1 mutation animals, exhibiting reduced sociability, novelty and increased ultrasonic vocalizations, while there was very little change in other behaviors, such as working memory (Y-maze task involving medial temporal lobe) or depression-like behavior (tail-suspension test involving processing via the hypothalamic pituitary adrenal (HPA) axis). Moreover, following chondroitinase treatment, electrophysiological recordings from the PFC exhibited a reduced proportion of spontaneous, high-frequency firing neurons, and an increased proportion of irregularly firing neurons, with increased spike count and reduced inter-spike intervals in control animals. These results support the proposition that the aberrant development of PNNs and PVs affects normal neural operations in the PFC and contributes to the emergence of some of the behavioral phenotypes observed in the DISC1 mutation model of schizophrenia. [ABSTRACT FROM AUTHOR]

The functional consequences following methamphetamine-induced neuronal damage were evaluated under several different conditions known to affect the magnitude of the lesion. It was found that methamphetamine (6.25 mg/kg administered SC, four times at 2-h intervals) caused long-lasting depletions of striatal dopamine and serotonin and that pretreatment with the antioxidant, ascorbic acid (100 mg/kg), attenuated these depletions, whereas pretreatment with the superoxide dismutase inhibitor diethyldithiocarbamate (200 mg/kg) exacerbated these depletions. The dopamine depletions resulting from the repeated administration of methamphetamine under these various conditions did not result in any alteration in the consumption of a sweetened-condensed milk solution under baseline conditions. However, when these lesioned animals were challenged with acutely administered methamphetamine, it was observed that there was an altered sensitivity to the milk intake decreasing effects of this compound. That is, the degree to which the acutely administered methamphetamine reduced the intake of sweetened-condensed milk was highly correlated with the magnitude of the methamphetamine-induced dopamine and serotonin depletions. These observations support the hypothesis that methamphetamine-induced neuronal damage is mediated by free radical formation and indicate that behavioral measures may be employed to assess neuronal damage. [ABSTRACT FROM AUTHOR]

Changes with time after injury in behavioral deficits, as determined by the Morris swim test, and the in vivo specific binding of HEAT, a selective α-adrenoreceptor ligand, were compared with the time-course of development of cortical hypometabolism in rats with focal freezing lesions. In our trauma model, cortical hypometabolism was detectable in the lesioned hemisphere at 4 hr, became maximal (50% of normal) at 3 days and diminished towards normal on days 5 and 10 post-injury. Progressive impairment of acquisition of the Morris water maze task was demonstrated up to day 3 post-lesion with improvement thereafter. On day 3 the latency to reach criterion was 60% longer in lesioned animals than in corresponding sham-operated ones. An increase in the volume of distribution of HEAT, limited to cortical areas of the lesioned hemisphere, was demonstrable at 4 hr post-lesion and reached its maximum on day 3 (200% of normal) with subsequent return toward normal on days 5 and 10. Several types of drugs were shown previously to modify the cortical hypometabolism associated with cerebral injury. The present data indicate that the same drugs also modify the in vivo binding of HEAT and the behavioral deficits induced by brain lesions. Ibuprofen, a non-steroidal anti-inflammatory drug, p-chlorophenylalanine, an inhibitor of serotonin synthesis, ketanserin, a specific 5HT-receptor antagonist, and prazosin, an α-adrenergic receptor blocker all normalized the in vivo binding of HEAT in the cortical areas of the lesioned hemisphere. All groups of animals treated with these drugs also showed subtle, but statistically highly significant improvements in latency to locate the platform in the Morris water maze. Taken together these results show good correlation between behavioral deficits, changes in α-noradrenergic receptor binding and cortical hypometabolism in injured brain. This supports the hypothesis that post-injury cortical hypometabolism is a reflection of cortical functional depression in which both the serotonergic and noradrenergic neurotransmitter systems play a role, compatible with their inhibitory effects in the cortex and their postulated involvement in cortical information processing. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD), characterized by dopaminergic neuron degeneration in the substantia nigra and dopamine depletion in the striatum, affects up to 1% of the global population over 50 years of age. Our previous study found that a heteropolysaccharide from Saccharina japonica exhibits neuroprotective effects through antioxidative stress. In view of its high molecular weight and complex structure, we degraded the polysaccharide and subsequently obtained four oligosaccharides. In this study, we aimed to further detect the neuroprotective mechanism of the oligosaccharides. We applied MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) to induce PD, and glucuronomannan oligosaccharides (GMn) was subsequently administered. Results showed that GMn ameliorated behavioral deficits in Parkinsonism mice. Furthermore, we observed that glucuronomannan oligosaccharides contributed to down-regulating the apoptotic signaling pathway through enhancing the expression of tyrosine hydroxylase (TH) in dopaminergic neurons. These results suggest that glucuronomannan oligosaccharides protect dopaminergic neurons from apoptosis in PD mice. [ABSTRACT FROM AUTHOR]