Late Prenatal Immune Activation in Mice Leads to Behavioral and Neurochemical Abnormalities Relevant to the Negative Symptoms of Schizophrenia

Based on the human epidemiological association between prenatal infection and higher risk of schizophrenia, a number of animal models have been established to explore the long-term brain and behavioral consequences of prenatal immune challenge. Accumulating evidence suggests that the vulnerability to specific forms of schizophrenia-related abnormalities is critically influenced by the precise timing of the prenatal immunological insult. In the present study, we tested the hypothesis whether late prenatal immune challenge in mice may induce long-term behavioral and neurochemical dysfunctions primarily associated with the negative symptoms of schizophrenia. We found that prenatal exposure to the viral mimic polyriboinosinic-polyribocytidilic acid (Poly-I:C; 5 mg/kg, i.v.) on gestation day (GD) 17 led to significant deficits in social interaction, anhedonic behavior, and alterations in the locomotor and stereotyped behavioral responses to acute apomorphine (APO) treatment in both male and female offspring. In addition, male but not female offspring born to immune challenged mothers displayed behavioral/cognitive inflexibility as indexed by the presence of an abnormally enhanced latent inhibition (LI) effect. Prenatal immune activation in late gestation also led to numerous, partly sex-specific changes in basal neurotransmitter levels, including reduced dopamine (DA) and glutamate contents in the prefrontal cortex and hippocampus, as well as reduced γ-aminobutyric acid (GABA) and glycine contents in the hippocampus and prefrontal cortex, respectively. The constellation of behavioral and neurochemical abnormalities emerging after late prenatal Poly-I:C exposure in mice leads us to conclude that this immune-based experimental model provides a powerful neurodevelopmental animal model especially for (but not limited to) the negative symptoms of schizophrenia.     

Attentional functioning in children with ADHD – predominantly hyperactive-impulsive type and children with ADHD – combined type

Summary. Although particular importance has been attributed to attention deficits in attention deficit hyperactivity disorder (ADHD), there is no consensus as to the exact nature of inattention in ADHD or which components of attention are affected. The present study was based on a neuropsychological model of attention and assessed various components of attention in 23 children with ADHD/predominantly hyperactive-impulsive type (ADHD-H), 32 children with ADHD/combined type (ADHD-C) and healthy children (N₁ = 23 and N₂ = 32). A computerized test battery consisting of reaction time tasks of low complexity was used for the assessment of attention (alertness task, vigilance task, divided attention task, visual scanning task, incompatibility task, test of crossmodal integration, flexibility task). In comparison to healthy participants, patient groups were impaired in measures of vigilance, divided attention, selective attention and flexibility but not in measures of alertness. Analysis of the test performance of patient groups revealed no differences between children with ADHD-H and children with ADHD-C. The results of the present study suggest that both children with ADHD-H and children with ADHD-C are seriously impaired in attentional functioning. Children with ADHD-H and children with ADHD-C produced comparable results in measures of attention.     

Too Much of a Good Thing: Blocking Noradrenergic Facilitation in Medial Prefrontal Cortex Prevents the Detrimental Effects of Chronic Stress on Cognition

Cognitive impairments associated with dysfunction of the medial prefrontal cortex (mPFC) are prominent in stress-related psychiatric disorders. We have shown that enhancing noradrenergic tone acutely in the rat mPFC facilitated extra-dimensional (ED) set-shifting on the attentional set-shifting test (AST), whereas chronic unpredictable stress (CUS) impaired ED. In this study, we tested the hypothesis that the acute facilitatory effect of norepinephrine (NE) in mPFC becomes detrimental when activated repeatedly during CUS. Using microdialysis, we showed that the release of NE evoked in mPFC by acute stress was unchanged at the end of CUS treatment. Thus, to then determine if repeated elicitation of this NE activity in mPFC during CUS may have contributed to the ED deficit, we infused a cocktail of α₁-, β₁-, and β₂-adrenergic receptor antagonists into the mPFC prior to each CUS session, then tested animals drug free on the AST. Antagonist treatment prevented the CUS-induced ED deficit, suggesting that NE signaling during CUS compromised mPFC function. We confirmed that this was not attributable to sensitization of adrenergic receptor function following chronic antagonist treatment, by administering an additional microinjection into the mPFC immediately prior to ED testing. Acute antagonist treatment did not reverse the beneficial effects of chronic drug treatment during CUS, nor have any effect on baseline ED performance in chronic vehicle controls. Thus, we conclude that blockade of noradrenergic receptors in mPFC protected against the detrimental cognitive effects of CUS, and that repeated elicitation of noradrenergic facilitatory activity is one mechanism by which chronic stress may promote mPFC cognitive dysfunction.     

Disruption of Long-Term Depression Potentiates Latent Inhibition: Key Role for Central Nucleus of the Amygdala

BackgroundLatent inhibition (LI) reflects an adaptive form of learning impaired in certain forms of mental illness. Glutamate receptor activity is linked to LI, but the potential role of synaptic plasticity remains unspecified.MethodsAccordingly, the present study examined the possible role of long-term depression (LTD) in LI induced by prior exposure of rats to an auditory stimulus used subsequently as a conditional stimulus to signal a pending footshock. We employed 2 mechanistically distinct LTD inhibitors, the Tat-GluA2_3Y peptide that blocks endocytosis of the GluA2-containing glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, or the selective glutamate n-methyl-d-aspartate receptor 2B antagonist, Ro25-6981, administered prior to the acquisition of 2-way conditioned avoidance with or without tone pre-exposure.ResultsSystemic LTD blockade with the Tat-GluA2_3Y peptide strengthened the LI effect by further impairing acquisition of conditioned avoidance in conditional stimulus-preexposed rats compared with normal conditioning in non-preexposed controls. Systemic Ro25-6981 had no significant effects. Brain region–specific microinjections of the Tat-GluA2_3Y peptide into the nucleus accumbens, medial prefrontal cortex, or central or basolateral amygdala demonstrated that disruption of glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor endocytosis in the central amygdala also potentiated the LI effect.ConclusionsThese data revealed a previously unknown role for central amygdala LTD in LI as a key mediator of cognitive flexibility required to respond to previously irrelevant stimuli that acquire significance through reinforcement. The findings may have relevance both for our mechanistic understanding of LI and its alteration in disease states such as schizophrenia, while further elucidating the role of LTD in learning and memory.     

The immediate effect of unilateral lumbar Z-joint mobilisation on posterior chain neurodynamics: a randomised controlled study

Hamstring strain (HS) is a common musculoskeletal condition and abnormal neurodynamics has been shown to influence HS and delay recovery. The efficacy of stretching for preventing and treating HS remains uncertain despite extensive research and wide-spread use. The effects of cervical spine mobilisation on peripheral nervous system function, neurodynamics and muscle force in the upper limb have been reported. Very few studies have reported effects of lumbar spine mobilisation on these variables in the lower limb. This study aimed to determine immediate effects of either a unilateral zygopophyseal joint posteroanterior mobilisation or a static posterior chain muscle stretch on the range of passive straight leg raise (SLR) in comparison to a non-treatment control. Using a single-blinded, randomised controlled study design, 36 healthy participants were allocated into one of three groups (control; mobilisation; static posterior chain muscle stretch). Measures of SLR were taken before and after intervention for each group on the day of testing. A General Linear Model (GLM) and a paired sample t-test showed a significant difference between base line and post-intervention for the mobilisation group only (p < 0.001), and suggests that unilateral lumbar spine zygopophyseal joint mobilisation can immediately restore posterior chain neurodynamics.     

Binding of blood proteins to carbon nanotubes reduces cytotoxicity

With the potential wide uses of nanoparticles such as carbon nanotubes in biomedical applications, and the growing concerns of nanotoxicity of these engineered nanoparticles, the importance of nanoparticle-protein interactions cannot be stressed enough. In this study, we use both experimental and theoretical approaches, including atomic force microscope images, fluorescence spectroscopy, CD, SDS-PAGE, and molecular dynamics simulations, to investigate the interactions of single-wall carbon nanotubes (SWCNTs) with human serum proteins, and find a competitive binding of these proteins with different adsorption capacity and packing modes. The π-π stacking interactions between SWCNTs and aromatic residues (Trp, Phe, Tyr) are found to play a critical role in determining their adsorption capacity. Additional cellular cytotoxicity assays, with human acute monocytic leukemia cell line and human umbilical vein endothelial cells, reveal that the competitive bindings of blood proteins on the SWCNT surface can greatly alter their cellular interaction pathways and result in much reduced cytotoxicity for these protein-coated SWCNTs, according to their respective adsorption capacity. These findings have shed light toward the design of safe carbon nanotube nanomaterials by comprehensive preconsideration of their interactions with human serum proteins.     

Dimensions of executive functioning in schizophrenia and their relationship with processing speed

Context: The nature of executive dysfunction in schizophrenia is nebulous, due to inconsistencies in conceptualizing and operationalizing the construct, and the broader question of whether schizophrenia is best characterized in terms of specific vs generalized cognitive deficits. The current study aimed to determine whether executive functions represent unitary vs diverse constructs in schizophrenia.Methods: Participants included 145 community-dwelling individuals with schizophrenia. Executive functions were measured with the Delis-Kaplan Executive Functioning System (D-KEFS). We conducted an exploratory factor analysis (EFA) with principal axis factoring, as well as parallel analyses to examine the latent constructs underlying the D-KEFS tasks, a second EFA on weighted residuals of the D-KEFS tasks (after accounting for processing speed measured with the Digit Symbol task), and bivariate correlations to examine relationships between the D-KEFS components and relevant demographic and clinical variables, crystallized verbal knowledge, and functional capacity.Results: EFA of the D-KEFS tasks yielded 2 factors (cognitive flexibility/timed tests and abstraction). EFA of the processing speed-weighted D-KEFS residuals also yielded 2 factors (cognitive flexibility and abstraction). Cognitive flexibility was negatively correlated with psychopathology. Better abstraction was associated with higher education, shorter illness duration, and better functional capacity. Both factors were positively correlated with crystallized verbal knowledge.Conclusions: Executive functions in schizophrenia could be parsed into 2 partially related but separable subconstructs. Future efforts to elucidate functional outcomes as well as neurobiological underpinnings of schizophrenia may be facilitated by attending to the distinction between cognitive flexibility and abstraction.     

两种慢性应激诱导的抑郁模型大鼠前额叶认知功能的比较研究

目的本研究旨在比较两种慢性应激诱导的抑郁模型大鼠前额叶介导的认知灵活性损伤特征。方法分别给予应激组大鼠(n=8只/组)两周慢性不可预期性应激(chronic unpredictable stress,CUS)或社会挫败(social defeat,SD)应激。应激结束后采用糖水偏好测试检测快感缺失(一种典型抑郁样行为),采用注意定势转移任务(attentional set-shifting task,AST)检测认知灵活性改变,主要包括逆反学习(reversal learning,REL)和外维度定势转移(extra-dimensional set-shifting,EDS)能力。结果与相应对照组相比,CUS组大鼠的糖水消耗量降低[(7.24±1.64)vs(13.83±1.50),P0.05]。SD组大鼠的糖水消耗量和糖水偏好指数较相应对照组降低[(4.28±1.96)vs(13.17±2.79),P0.01;(27.96±11.64)vs(82.97±16.13),P0.05]。在AST测试中,CUS诱导以EDS损害为特征的认知灵活性缺失,表现在CUS组大鼠在EDS阶段的训练达标次数较相应对照组增加[(15.57±1.53)vs(10.50±1.41),P0.05],而社会挫败应激诱导以REL和EDS损害为特征的认知灵活性缺失,表现在SD组大鼠在REL和EDS阶段的训练达标次数均较相应对照组增加[REL:(17.30±0.76)vs(14.00±0.97),P0.01);EDS:(15.80±1.72)vs(9.33±0.80),P0.01]。结论慢性不可预期性应激和社会挫败应激诱导的抑郁模型大鼠表现出认知灵活性不同成分的损害,为进一步研究抑郁症不同认知表型障碍的神经生物学机理提供了实验基础。     

Coping with negative life events in old age: the role of tenacious goal pursuit and flexible goal adjustment

Objective: This study examines the relationships between negative life events and tenacious goal pursuit (TGP) and flexible goal adjustment (FGA), two fundamental modes of self-regulation suggested by Brandtstädter, and their effects on mental health.

Methods: TGP/FGA, negative life events and depression were assessed in 670 elderly people living in the community. Hierarchical regressions were carried out to examine the effects of the two self-regulation modes and negative life events on depression.

Results: Findings demonstrate the role of TGP and FGA in coping with negative life events. While both FGA and TGP were related to depression, FGA was found to have beneficial effects for the participants who had encountered negative life events. With age, people become less tenacious, but no conclusive relationship was found between flexibility and age.

Discussion: Our findings support the importance of both modes of coping for the mental health of older adults. In particular, the ability to adjust goals was shown to be critical as a way of preventing the development of depressive symptoms following negative life events.     

Child sleep and mother labour market outcomes

We show that sleep deprivation exerts strong negative effects on mothers’ labour market performance. To isolate variations in maternal sleep, we exploit unique variations in child sleep disruption using a UK panel dataset that follows mother-child pairs through time. We find that sleeping one hour less per night on average significantly decreases maternal labour force participation, the number of hours worked and household income. We identify one mechanism driving the effects, namely the influence of maternal sleep on selection into full-time versus part-time work. Increased schedule flexibility for mothers with sufficient tenure mitigates the negative effects of sleep deprivation.