Intrauterine position effects in a mouse model of maternal immune activation.

Rodent models of maternal immune activation (MIA) are increasingly used as experimental tools in preclinical research of immune-mediated neurodevelopmental disorders and mental illnesses. Using a viral-like MIA model that is based on prenatal poly(I:C) exposure in mice, we have recently identified the existence of subgroups of MIA-exposed offspring that show dissociable behavioral, transcriptional, brain network and inflammatory profiles even under conditions of genetic homogeneity and identical MIA. Here, we tested the hypothesis that the intrauterine positions of fetuses, which are known to shape individual variability in litter-bearing mammals through variations in fetal hormone exposure, may contribute to the variable outcomes of MIA in mice.

Prefrontal microglia deficiency during adolescence disrupts adult cognitive functions and synaptic structures: A follow-up study in female mice.

The prefrontal cortex (PFC) provides executive top-down control of a variety of cognitive processes. A distinctive feature of the PFC is its protracted structural and functional maturation throughout adolescence to early adulthood, which is necessary for acquiring mature cognitive abilities. Using a mouse model of cell-specific, transient and local depletion of microglia, which is based on intracerebral injection of clodronate disodium salt (CDS) into the PFC of adolescent male mice, we recently demonstrated that microglia contribute to the functional and structural maturation of the PFC in males.

Deficient DNA base-excision repair in the forebrain leads to a sex-specific anxiety-like phenotype in mice.

Background: Neuropsychiatric disorders, such as schizophrenia (SZ) and autism spectrum disorder (ASD), are common, multi-factorial and multi-symptomatic disorders. Ample evidence implicates oxidative stress, deficient repair of oxidative DNA lesions and DNA damage in the development of these disorders. However, it remains unclear whether insufficient DNA repair and resulting DNA damage are causally connected to their aetiopathology, or if increased levels of DNA damage observed in patient tissues merely accumulate as a consequence of cellular dysfunction.

Adolescence is a sensitive period for prefrontal microglia to act on cognitive development.

The prefrontal cortex (PFC) is a cortical brain region that regulates various cognitive functions. One distinctive feature of the PFC is its protracted adolescent maturation, which is necessary for acquiring mature cognitive abilities in adulthood. Here, we show that microglia, the brain's resident immune cells, contribute to this maturational process.

Astrocytes in schizophrenia.

Schizophrenia is a severe and clinically heterogenous mental disorder affecting approximately 1% of the population worldwide. Despite tremendous achievements in the field of schizophrenia research, its precise aetiology remains elusive. Besides dysfunctional neuronal signalling, the pathophysiology of schizophrenia appears to involve molecular and functional abnormalities in glial cells, including astrocytes.

Oral application of clozapine-N-oxide using the micropipette-guided drug administration (MDA) method in mouse DREADD systems.

The designer receptor exclusively activated by designer drugs (DREADD) system is one of the most widely used chemogenetic techniques to modulate the activity of cell populations in the brains of behaving animals. DREADDs are activated by acute or chronic administration of their ligand, clozapine-N-oxide (CNO). There is, however, a current lack of a non-invasive CNO administration technique that can control for drug timing and dosing without inducing substantial distress for the animals.

Neuronal activity increases translocator protein (TSPO) levels.

The mitochondrial protein, translocator protein (TSPO), is a widely used biomarker of neuroinflammation, but its non-selective cellular expression pattern implies roles beyond inflammatory processes. In the present study, we investigated whether neuronal activity modifies TSPO levels in the adult central nervous system. First, we used single-cell RNA sequencing to generate a cellular landscape of basal TSPO gene expression in the hippocampus of adult (12 weeks old) C57BL6/N mice, followed by confocal laser scanning microscopy to verify TSPO protein in neuronal and non-neuronal cell populations.

Basic Concept of Microglia Biology and Neuroinflammation in Relation to Psychiatry.

The hypothesis that the neuroimmune system plays a role in the pathogenesis of different psychiatric disorders, including schizophrenia, depression, and bipolar disease, has attained increasing interest over the past years. Previously thought to have the sole purpose of protecting the central nervous system (CNS) from harmful stimuli, it is now known that the central immune system is critically involved in regulating physiological processes including neurodevelopment, synaptic plasticity, and circuit maintenance. Hence, alterations in microglia - the main immune cell of the CNS - and/or inflammatory factors do not unequivocally connote ongoing neuroinflammation or neuroinflammatory processes per se but rather might signify changes in brain homoeostasis.

Prenatal exposure to TiO nanoparticles in mice causes behavioral deficits with relevance to autism spectrum disorder and beyond.

Environmental factors are involved in the etiology of autism spectrum disorder (ASD) and may contribute to the raise in its incidence rate. It is currently unknown whether the increasing use of nanoparticles such as titanium dioxide (TiO NPs) in consumer products and biomedical applications may play a role in these associations. While nano-sized TiO is generally regarded as safe and non-toxic, excessive exposure to TiO NPs may be associated with negative health consequences especially when occurring during sensitive developmental periods.

Controversies and prospects about microglia in maternal immune activation models for neurodevelopmental disorders.

Activation of the maternal immune system during pregnancy is a well-established risk factor for neuropsychiatric disease in the offspring, yet, the underlying mechanisms leading to altered brain function remain largely undefined. Microglia, the resident immune cells of the brain, are key to adequate development of the central nervous system (CNS), and are prime candidates to mediate maternal immune activation (MIA)-induced brain abnormalities. As such, the effects of MIA on the immunological phenotype of microglia has been widely investigated.

Critical review of the safety assessment of titanium dioxide additives in food.

Nanomaterial engineering provides an important technological advance that offers substantial benefits for applications not only in the production and processing, but also in the packaging and storage of food. An expanding commercialization of nanomaterials as part of the modern diet will substantially increase their oral intake worldwide. While the risk of particle inhalation received much attention, gaps of knowledge exist regarding possible adverse health effects due to gastrointestinal exposure.

Immunological Processes in Schizophrenia Pathology: Potential Biomarkers?

Accumulating evidence suggests that the pathophysiology or schizophrenia involves alterations in immune functions, both peripherally and centrally. Immunopsychiatric research has provided a number of candidate biomarkers that could aid estimating the risk of developing schizophrenia and/or predicting its clinical course or outcomes. This chapter summarizes the findings of immune dysfunctions along the clinical course of schizophrenia and discusses their potential value as predictive, trait or state biomarkers.

Reconceptualization of translocator protein as a biomarker of neuroinflammation in psychiatry.

A great deal of interest in psychiatric research is currently centered upon the pathogenic role of inflammatory processes. Positron emission tomography (PET) using radiolabeled ligands selective for the 18 kDa translocator protein (TSPO) has become the most widely used technique to assess putative neuroimmune abnormalities in vivo. Originally used to detect discrete neurotoxic damages, TSPO has generally turned into a biomarker of 'neuroinflammation' or 'microglial activation'.

Translational evaluation of translocator protein as a marker of neuroinflammation in schizophrenia.

Positron emission tomography (PET) imaging with radiotracers that target translocator protein 18 kDa (TSPO) has become a popular approach to assess putative neuroinflammatory processes and associated microglia activation in psychotic illnesses. It remains unclear, however, whether TSPO imaging can accurately capture low-grade inflammatory processes such as those present in schizophrenia and related disorders. Therefore, we evaluated the validity of TSPO as a disease-relevant marker of inflammation using a translational approach, which combined neurodevelopmental and neurodegenerative mouse models with PET imaging in patients with recent-onset schizophrenia and matched controls.

Hypervulnerability of the adolescent prefrontal cortex to nutritional stress via reelin deficiency.

Overconsumption of high-fat diets (HFDs) can critically affect synaptic and cognitive functions within telencephalic structures such as the medial prefrontal cortex (mPFC). The underlying mechanisms, however, remain largely unknown. Here we show that adolescence is a sensitive period for the emergence of prefrontal cognitive deficits in response to HFD.

Late prenatal immune activation causes hippocampal deficits in the absence of persistent inflammation across aging.

Background: Prenatal exposure to infection and/or inflammation is increasingly recognized to play an important role in neurodevelopmental brain disorders. It has recently been postulated that prenatal immune activation, especially when occurring during late gestational stages, may also induce pathological brain aging via sustained effects on systemic and central inflammation. Here, we tested this hypothesis using an established mouse model of exposure to viral-like immune activation in late pregnancy.

A protocol for concurrent high-quality immunohistochemical and biochemical analyses in adult mouse central nervous system.

Biochemical analysis of central nervous system proteins and nucleic acids requires fresh-tissue homogenates, whereas immunohistochemistry usually is performed in sections prepared from perfusion-fixed tissue. Post-mortem immersion-fixation is possible, but largely impairs morphological preservation and protein antigenicity. Here, we present a simple, fast and versatile protocol allowing concurrent biochemical and immunohistochemical analysis, including pre-embedding immunoelectron microscopy, using tissue from the same animal.

Reelin immunoreactivity in neuritic varicosities in the human hippocampal formation of non-demented subjects and Alzheimer's disease patients.

Background: Reelin and its downstream signaling members are important modulators of actin and microtubule cytoskeleton dynamics, a fundamental prerequisite for proper neurodevelopment and adult neuronal functions. Reductions in Reelin levels have been suggested to contribute to Alzheimer's disease (AD) pathophysiology. We have previously reported an age-related reduction in Reelin levels and its accumulation in neuritic varicosities along the olfactory-limbic tracts, which correlated with cognitive impairments in aged mice.

Decisive role of Reelin signaling during early stages of Alzheimer's disease.

Alzheimer's disease (AD) is one of the largest unmet medical concerns of our society. Around 25 million patients worldwide together with their families are still waiting for an effective treatment. We have recently initiated a re-evaluation of our knowledge of the molecular and cellular mechanisms underlying sporadic AD.

Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice.

Background: Alzheimer's disease (AD) is the most prevalent form of age-related dementia, and its effect on society increases exponentially as the population ages. Accumulating evidence suggests that neuroinflammation, mediated by the brain's innate immune system, contributes to AD neuropathology and exacerbates the course of the disease. However, there is no experimental evidence for a causal link between systemic inflammation or neuroinflammation and the onset of the disease.

Long-term effects of darusentan on left-ventricular remodelling and clinical outcomes in the EndothelinA Receptor Antagonist Trial in Heart Failure (EARTH): randomised, double-blind, placebo-controlled trial.

Background: Endothelin-receptor blockade provides haemodynamic benefit in experimental and clinical heart failure. We aimed to measure the effects of long-term endothelin-blockade on left-ventricular (LV) remodelling and clinical outcomes in patients with chronic heart failure.

Methods: 642 patients with chronic heart failure were assigned the oral endothelin(A)-antagonist darusentan at 10, 25, 50, 100, or 300 mg daily or placebo for 24 weeks in addition to standard therapy in a randomised, double-blind, placebo-controlled trial.

Hemodynamic and neurohumoral effects of selective endothelin A (ET(A)) receptor blockade in chronic heart failure: the Heart Failure ET(A) Receptor Blockade Trial (HEAT).

Background: The endothelin (ET-1) system is activated in chronic heart failure (CHF). Whether, what type, and what degree of selective ET blockade is clinically beneficial is unknown. We investigated hemodynamic and neurohumoral effects of 3 weeks of treatment with various dosages of the orally available ET(A) antagonist darusentan in addition to modern standard therapy in patients with CHF.