Early life exposure to sevoflurane impairs adulthood spatial memory in the rat

Sevoflurane is a general anesthetic commonly used in the pediatric setting because it is sweet-smelling, nonflammable, fast acting and has a very short recovery time. Although recent clinical data suggest that early anesthesia exposure is associated with subsequent learning and memory problems, it is difficult to determine the exact scope of developmental neurotoxicity associated with exposure to specific anesthetics such as sevoflurane. This is largely due to inconsistencies in the literature. Thus, in the present studies we evaluated the effect of early life exposure to sevoflurane (1%, 2%, 3% or 4%) on adulthood memory impairment in Sprague-Dawley rats. Animals were exposed to different regimens of sevoflurane anesthesia on postnatal days (PNDs) 3, 7, or 14 or at 7 weeks (P7W) of age and spatial memory performance was assessed in adulthood using the Morris Water Maze (MWM). Rats exposed to sevoflurane exhibited significant memory impairment which was concentration and exposure duration dependent. Disruption of MWM performance was more severe in animals exposed on both PNDs 3 and 7 than in animals exposed on both PNDs 3 and 14. The younger the animal's age at the time of exposure, the more significant the effect on later MWM performance. Compared to the neonates, animals exposed at P7W were relatively insensitive to sevoflurane: memory was impaired in this group only after repeated exposures to low doses or single exposures to high doses. Early life exposure to sevoflurane can result in spatial memory impairments in adulthood and the shorter the interval between exposures, the greater the deficit.     

Epigenetics of stress adaptations in the brain

Recent findings in epigenetics shed new light on the regulation of gene expression in the central nervous system (CNS) during stress. The most frequently studied epigenetic mechanisms are DNA methylation, histone modifications and microRNA activity. These mechanisms stably determine cell phenotype but can also be responsible for dynamic molecular adaptations of the CNS to stressors. The limbic–hypothalamic–pituitary–adrenal axis (LHPA) is the primary circuit that initiates, regulates and terminates a stress response. The same brain areas that control stress also react to stress dynamically and with long-term consequences. One of the biological processes evoking potent adaptive changes in the CNS such as changes in behavior, gene activity or synaptic plasticity in the hippocampus is psychogenic stress. This review summarizes the current data regarding the epigenetic basis of molecular adaptations in the brain including genome-wide epigenetic changes of DNA methylation and particular genes involved in epigenetic responses that participate in the brain response to chronic psychogenic stressors. It is concluded that specific epigenetic mechanisms in the CNS are involved in the stress response.     

Zinc transporter 3 (ZnT3) and vesicular zinc in central nervous system function

Zinc transporter 3 (ZnT3) is the sole mechanism responsible for concentrating zinc ions within synaptic vesicles in a subset of the brain’s glutamatergic neurons. This vesicular zinc can then be released into the synaptic cleft in an activity-dependent fashion, where it can exert many signaling functions. This review provides a comprehensive discussion of the localization and function of ZnT3 and vesicular zinc in the central nervous system. We begin by reviewing the fundamentals of zinc homeostasis and transport, and the discovery of ZnT3. We then focus on four main topics. I) The anatomy of the zincergic system, including its development and its modulation through experience-dependent plasticity. II) The role of zinc in intracellular signaling, with a focus on how zinc affects neurotransmitter receptors and synaptic plasticity. III) The behavioural characterization of the ZnT3 KO mouse, which lacks ZnT3 and, therefore, vesicular zinc. IV) The roles of ZnT3 and vesicular zinc in health and disease.     

Clinical correlates of graph theory findings in temporal lobe epilepsy

PurposeTemporal lobe epilepsy (TLE) is considered a brain network disorder, additionally representing the most common form of pharmaco-resistant epilepsy in adults. There is increasing evidence that seizures in TLE arise from abnormal epileptogenic networks, which extend beyond the clinico-radiologically determined epileptogenic zone and may contribute to the failure rate of 30–50% following epilepsy surgery. Graph theory allows for a network-based representation of TLE brain networks using several neuroimaging and electrophysiologic modalities, and has potential to provide clinicians with clinically useful biomarkers for diagnostic and prognostic purposes.MethodsWe performed a review of the current state of graph theory findings in TLE as they pertain to localization of the epileptogenic zone, prediction of pre- and post-surgical seizure frequency and cognitive performance, and monitoring cognitive decline in TLE.ResultsAlthough different neuroimaging and electrophysiologic modalities have yielded occasionally conflicting results, several potential biomarkers have been characterized for identifying the epileptogenic zone, pre-/post-surgical seizure prediction, and assessing cognitive performance. For localization, graph theory measures of centrality have shown the most potential, including betweenness centrality, outdegree, and graph index complexity, whereas for prediction of seizure frequency, measures of synchronizability have shown the most potential. The utility of clustering coefficient and characteristic path length for assessing cognitive performance in TLE is also discussed.ConclusionsFuture studies integrating data from multiple modalities and testing predictive models are needed to clarify findings and develop graph theory for its clinical utility.     

Associations between anxiety disorders,suicide ideation,and age in nationally representative samples of Canadian and American adults

Suicidal behaviors are of significant concern for the individuals displaying such behavior and for service providers who encounter them. Using nationally representative samples of Canadian and American adults, we aimed to examine: whether age moderates the relationship between having any anxiety disorder and suicide ideation (SI), the prevalence of SI among younger and older adults, and whether age and individual anxiety disorders were differentially associated with SI. Age moderated the relationship between any anxiety disorder and SI among Americans only. Past-year SI was less prevalent among older, compared to younger, adults; though, nearly every anxiety disorder was associated with increased odds of SI among younger and older Canadian and American adults after controlling for covariates. Effect sizes were particularly large for older American adults, but were coupled with large confidence intervals. Findings contribute to a growing literature suggesting that SI in the context of anxiety is a highly prevalent and complex mental health problem across the adult lifespan.     

Diffusion alterations associated with Parkinson's disease symptomatology: A review of the literature

Parkinson's disease (PD) is a heterogeneous neurological disorder with a variety of motor and non-motor symptoms. The underlying mechanisms of these symptoms are not fully understood. An increased interest in structural connectivity analyses using diffusion tensor imaging (DTI) in PD has led to an expansion of our understanding of the impact of abnormalities in diffusivity on phenotype. This review outlines the contribution of these abnormalities to symptoms of PD including bradykinesia, tremor and non-tremor phenotypes, freezing of gait, cognitive impairment, mood, sleep disturbances, visual hallucinations and olfactory dysfunction. Studies have shown that impairments in cognitive functioning are related to diffusion abnormalities in frontal and parietal regions, as well as in the corpus callosum and major fibres connecting midbrain and subcortical structures with the neocortex. However, the impact of diffusion alterations on motor, mood and other symptoms of PD are less well understood. The findings presented here highlight the challenges faced and the potential areas of future research avenues where DTI may be beneficial. Larger cohort studies and standardized imaging protocols are required to investigate current promising preliminary findings.     

Diet,behavior and immunity across the lifespan

It is increasingly appreciated that perinatal events can set an organism on a life-long trajectory for either health or disease, resilience or risk. One early life variable that has proven critical for optimal development is the nutritional environment in which the organism develops. Extensive research has documented the effects of both undernutrition and overnutrition, with strong links evident for an increased risk for obesity and metabolic disorders, as well as adverse mental health outcomes. Recent work has highlighted a critical role of the immune system, in linking diet with long term health and behavioral outcomes. The present review will summarize the recent literature regarding the interactions of diet, immunity, and behavior.     

Maternal separation induces alterations of serotonergic system in different aged rats

Maternal separation (MS) induces profound behavioral and neurochemical dysregulations in adult rodents. In the present longitudinal study, we investigated the effects of repeated (4 h/day) maternal separation during postnatal days 1–21 on serotonergic synthesis and activity in the prefrontal cortex (PFC), nucleus accumbens (NAc) and hippocampus of juvenile (post-natal day 21, PND 21), adolescent (PND 35) and early adult (PND 56) male Wistar rats. We found that MS increased 5-HT levels in the PFC of juvenile rats, and although MS increased 5-HT and 5-HIAA levels in the NAc of adolescent rats, the ratio between 5-HIAA and 5-HT decreased in the PFC. In addition, MS-treated adult rats showed increased levels of 5-HT in the PFC as well as 5-HT and 5-HIAA in the NAc. These data provided evidence that MS leads to profound and age-specific changes in serotonergic synthesis and activity in rodents. Our study also found that there are U-shaped and inverted U-shaped patterns for serotonergic synthesis and serotonergic activity from younger rats to adults, respectively. Together, our findings support the use of maternal separation as an animal model for studying the neurobiological pathogenesis of neurodevelopmental diseases.     

Long term retention of retigabine in a cohort of people with drug resistant epilepsy

PurposeTo assess the utility of retigabine (RTG) for epilepsy in clinical practice at a single UK tertiary centre.MethodsWe identified all individuals who were offered RTG from April 2011 to May 2013. We collected demographics, seizure types, previous and current antiepileptic drugs (AEDs), starting and maximum attained daily dose of RTG, clinical benefits, side effects, and reason to discontinue RTG from in- and outpatient encounters until February 28, 2014.Results145 people who had failed a median of 11 AEDs took at least one dose of RTG. One year retention was 32% and decreased following the safety alert by the US Federal Drug Administration (FDA) in April 2013. None became seizure free. 34 people (24%) reported a benefit that was ongoing at last assessment in five (3%). The most relevant benefit was the significant reduction or cessation of drop attacks or seizure-related falls in four women, this persisted at last assessment in two. The presence of simple partial seizures was associated with longer retention, as was a higher attained dose of RTG. Adverse effects were seen in 74% and largely CNS-related or nonspecific and affected the genitourinary system in 13%.ConclusionRetention of RTG was less favourable compared to data from open label extension studies of the regulatory trials. In comparison with historical data on similar retention audits retention of RTG at one year appears to be less than lamotrigine, topiramate, levetiracetam, pregabalin, zonisamide, and lacosamide, and slightly higher than gabapentin.     

Tissue oxidative stress induced by patulin and protective effect of crocin

Patulin (PAT) is a secondary toxic metabolite produced principally by Penicillium expansum. This mycotoxin is known to be teratogenic, mutagenic, immunotoxic and neurotoxic, and it has been shown to cause damage in several organs in laboratory animals. This study focuses on the prevention of experimental murine PAT-induced nephrotoxicity and hepatotoxicity. We investigate the ability of a natural product, crocin (CRO), to counteract the toxic effects of PAT. Pre-treatment of mice with CRO prevented PAT-induced oxidative damage in both liver and kidney. CRO reduced lipid peroxidation, protein oxidation and restored redox status by regulating the endogenous antioxidant enzymatic system. These data corroborate and extend findings in PAT-induced nephrotoxicity and hepatotoxicity, and further suggest that preventive effect of CRO towards other forms of PAT toxicity, including neurotoxicity, may be warranted.     

Molecular regulation of dendritic spine dynamics and their potential impact on synaptic plasticity and neurological diseases

The structure and dynamics of dendritic spines reflect the strength of synapses, which are severely affected in different brain diseases. Therefore, understanding the ultra-structure, molecular signaling mechanism(s) regulating dendritic spine dynamics is crucial. Although, since last century, dynamics of spine have been explored by several investigators in different neurological diseases, but despite countless efforts, a comprehensive understanding of the fundamental etiology and molecular signaling pathways involved in spine pathology is lacking. The purpose of this review is to provide a contextual framework of our current understanding of the molecular mechanisms of dendritic spine signaling, as well as their potential impact on different neurodegenerative and psychiatric diseases, as a format for highlighting some commonalities in function, as well as providing a format for new insights and perspectives into this critical area of research. Additionally, the potential strategies to restore spine structure–function in different diseases are also pointed out. Overall, these informations should help researchers to design new drugs to restore the structure–function of dendritic spine, a “hot site” of synaptic plasticity.     

Effects of methylmercury on spinal cord afferents and efferents—A review

Methylmercury (MeHg) is an environmental neurotoxicant of public health concern. It readily accumulates in exposed humans, primarily in neuronal tissue. Exposure to MeHg, either acutely or chronically, causes severe neuronal dysfunction in the central nervous system and spinal neurons; dysfunction of susceptible neuronal populations results in neurodegeneration, at least in part through Ca²⁺-mediated pathways. Biochemical and morphologic changes in peripheral neurons precede those in central brain regions, despite the fact that MeHg readily crosses the blood-brain barrier. Consequently, it is suggested that unique characteristics of spinal cord afferents and efferents could heighten their susceptibility to MeHg toxicity. Transient receptor potential (TRP) ion channels are a class of Ca²⁺-permeable cation channels that are highly expressed in spinal afferents, among other sensory and visceral organs. These channels can be activated in numerous ways, including directly via chemical irritants or indirectly via Ca²⁺ release from intracellular storage organelles. Early studies demonstrated that MeHg interacts with heterologous TRP channels, though definitive mechanisms of MeHg toxicity on sensory neurons may involve more complex interaction with, and among, differentially-expressed TRP populations. In spinal efferents, glutamate receptors of the N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and possibly kainic acid (KA) classes are thought to play a major role in MeHg-induced neurotoxicity. Specifically, the Ca²⁺-permeable AMPA receptors, which are abundant in motor neurons, have been identified as being involved in MeHg-induced neurotoxicity. In this review, we will describe the mechanisms that could contribute to MeHg-induced spinal cord afferent and efferent neuronal degeneration, including the possible mediators, such as uniquely expressed Ca²⁺-permeable ion channels.     

Extinction of avoidance behavior by safety learning depends on endocannabinoid signaling in the hippocampus

The development of exaggerated avoidance behavior is largely responsible for the decreased quality of life in patients suffering from anxiety disorders. Studies using animal models have contributed to the understanding of the neural mechanisms underlying the acquisition of avoidance responses. However, much less is known about its extinction. Here we provide evidence in mice that learning about the safety of an environment (i.e., safety learning) rather than repeated execution of the avoided response in absence of negative consequences (i.e., response extinction) allowed the animals to overcome their avoidance behavior in a step-down avoidance task. This process was context-dependent and could be blocked by pharmacological (3 mg/kg, s.c.; SR141716) or genetic (lack of cannabinoid CB1 receptors in neurons expressing dopamine D1 receptors) inactivation of CB1 receptors. In turn, the endocannabinoid reuptake inhibitor AM404 (3 mg/kg, i.p.) facilitated safety learning in a CB1-dependent manner and attenuated the relapse of avoidance behavior 28 days after conditioning. Safety learning crucially depended on endocannabinoid signaling at level of the hippocampus, since intrahippocampal SR141716 treatment impaired, whereas AM404 facilitated safety learning. Other than AM404, treatment with diazepam (1 mg/kg, i.p.) impaired safety learning. Drug effects on behavior were directly mirrored by drug effects on evoked activity propagation through the hippocampal trisynaptic circuit in brain slices: As revealed by voltage-sensitive dye imaging, diazepam impaired whereas AM404 facilitated activity propagation to CA1 in a CB1-dependent manner. In line with this, systemic AM404 enhanced safety learning-induced expression of Egr1 at level of CA1. Together, our data render it likely that AM404 promotes safety learning by enhancing information flow through the trisynaptic circuit to CA1.     

High-mobility group box-1 was released actively and involved in LPS induced depressive-like behavior

Depression disorder is a common mental illness, of which the pathogenesis is not well understood. Studies suggest that immunity imbalance and up-regulation of pro-inflammatory cytokines may be associated with the pathogenesis of depression. High-mobility group box 1 protein (HMGB1) has gained much attention as an important player in innate immune responses and an modulating factor in several inflammatory diseases. Here we sought to explore the role of HMGB1 in the development of depression. Depression model was established with low dose of lipopolysaccharide (LPS) administration. Depressive behavior was reflected with increased immobility time in tail suspension test. Accompanying with depressive-like behavior, translocation of HMGB1 from nuclei to cytoplasm was observed by immunofluorescence assays. Meanwhile, no significant necrosis was observed evaluated by hematoxylin-eosin staining. These data indicated that HMGB1 was released actively in the central nervous system. In addition, treating the mice with human recombinant HMGB1 (rHMGB1) could induce the development of depressive-like behavior. Blockage of HMGB1 with GZA abrogated the depressive-like behavior induced by LPS or rHMGB1. These results implicated that HMGB1 was involved in LPS-induced depressive-like behavior.     

A systematic review of mirror neuron system function in developmental coordination disorder: Imitation,motor imagery,and neuroimaging evidence

PURPOSEThe aim of this systematic review was to investigate the evidence of abnormal functioning of the mirror neuron system (MNS) in children and adults with developmental coordination disorder (DCD), through examination of imitation, motor imagery, and neuroimaging literature.METHODSThe following databases were comprehensively searched for relevant articles: CINAHL Plus, Embase, MEDLINE, PsycINFO, Pubmed, and Web of Science. Full-text articles of all potentially relevant citations were obtained and assessed for eligibility by two authors. Outcome measures of interest at a motor behaviour level were any measures of imitation or motor imagery proficiency and, at a neurological level, were any measures of neural activity in MNS brain regions. Due to differences in outcome measures between studies and the variables reported, a narrative review was undertaken to synthesise findings from the studies.RESULTSOverall, 31 articles met the inclusion criteria. Children and adults with DCD display deficits imitating meaningful and novel gestures and demonstrate different response patterns to controls when undertaking complex motor imagery tasks. Children with DCD present reduced activation and connectivity of frontal, parietal, and temporal MNS regions.CONCLUSIONSPreliminary evidence indicates some deficit in the functioning of the MNS at a motor behaviour and neurological level. As no published neuroimaging studies have been designed specifically to explore MNS function, these results must be interpreted with caution. Further research to explore the MNS hypothesis in greater detail, particularly from a neuroimaging perspective, has the potential to provide information on the underlying mechanisms of DCD, inform future research into the aetiology of this disorder, and inform intervention approaches.     

Levetiracetam but not valproate inhibits function of CD8+ T lymphocytes

PurposeTo further elucidate possible immune-modulatory effects of valproate (VPA) or levetiracetam (LEV), we investigated their influence on apoptosis and cytotoxic function of CD8⁺ T lymphocytes in humans.MethodsIn 15 healthy subjects (9 female (60%), 35.7 ± 12.1 years), apoptosis and cytotoxic function of CD8⁺ T lymphocytes were measured using flow cytometry following in vitro exposure to LEV (5 mg/L and 50 mg/L) and VPA (10 mg/L and 100 mg/L). Apoptosis rates were determined after incubation with LEV or VPA for 1 h or 24 h. Cytotoxic function was assessed following 2 h stimulation with mixed virus peptides, using perforin release, CD107a/b expression and proliferation. The presence of synaptic vesicle protein 2A (SV2A) was investigated in human CD8⁺ T lymphocytes by flow cytometry analysis, Western blot and real time polymerase chain reaction (rtPCR).ResultsHigh concentration of LEV decreased perforin release of CD8⁺ T lymphocytes (LEV 50 mg/L vs. CEF only: 21.4% (interquartile range (IQR) 16.5–35.9%) vs. 16.6% (IQR 12–24.9%), p = 0.002). LEV had no influence on apoptosis and proliferation (p > 0.05). VPA (100 mg/L) slowed apoptosis of CD8⁺ T lymphocytes after 24 h (VPA 100 mg/L vs. control: 7.3% (IQR 5.4–9.5%) vs. 11.3% (IQR 8.2–15.1%), p < 0.001), but had no effects on perforin release (p > 0.05). SV2A protein was detected in CD8⁺ T lymphocytes.ConclusionLEV decreased degranulation of CD8⁺ T lymphocytes which may contribute to the increased incidence of upper respiratory tract infections in LEV treated patients. Inhibition of SV2A may be responsible for this effect.     

Responses to voluntary hyperventilation in children with separation anxiety disorder: Implications for the link to panic disorder

BackgroundBiological theories on respiratory regulation have linked separation anxiety disorder (SAD) to panic disorder (PD). We tested if SAD children show similarly increased anxious and psychophysiological responding to voluntary hyperventilation and compromised recovery thereafter as has been observed in PD patients.MethodsParticipants were 49 children (5–14 years old) with SAD, 21 clinical controls with other anxiety disorders, and 39 healthy controls. We assessed cardiac sympathetic and parasympathetic, respiratory (including pCO₂), electrodermal, electromyographic, and self-report variables during baseline, paced hyperventilation, and recovery.ResultsSAD children did not react with increased anxiety or panic symptoms and did not show signs of slowed recovery. However, during hyperventilation they exhibited elevated reactivity in respiratory variability, heart rate, and musculus corrugator supercilii activity indicating difficulty with respiratory regulation.ConclusionsReactions to hyperventilation are much less pronounced in children with SAD than in PD patients. SAD children showed voluntary breathing regulation deficits.     

Sleep and memory in mammals,birds and invertebrates

Sleep supports memory consolidation. Based on studies in mammals, sleep-dependent consolidation has been conceptualized as ‘active system consolidation’. During waking, information is encoded into an initial store (hippocampus). During subsequent sleep, some of the newly encoded memories are selected to be reactivated and redistributed toward networks serving as long-term store (e.g., neocortex), whereby memories become transformed into more general, schema-like representations. Here we asked whether sleep in non-mammalian species might play a comparable role for memory. The literature review revealed that sleep produces enhancing effects on memory in all non-mammalian species studied. Furthermore, across species some of the hallmarking features of active system consolidation were identified: Studies of filial imprinting in chicks suggest that a redistribution of imprinting memory toward long-term storage sites occurs during sleep; song learning in birds appears to be driven by reactivations of song representations during sleep; studies of bees demonstrated the selectivity of sleep-dependent consolidation, benefiting extinction but not original classical conditioning. Although overall fragmentary, first evidence in non-mammalian species suggests active system consolidation might be an evolutionary conserved function of sleep.