Electroconvulsive seizures (ECS) do not prevent LPS-induced behavioral alterations and microglial activation

Background: Long-term neuroimmune activation is a common finding in major depressive disorder (MDD). Literature suggests a dual effect of electroconvulsive therapy (ECT), a highly effective treatment strategy for MDD, on neuroimmune parameters: while ECT acutely increases inflammatory parameters, such as serum levels of pro-inflammatory cytokines, there is evidence to suggest that repeated ECT sessions eventually result in downregulation of the inflammatory response. We hypothesized that this might be due to ECT-induced attenuation of microglial activity upon inflammatory stimuli in the brain. Methods: Adult male C57Bl/6J mice received a series of ten electroconvulsive seizures (ECS) or sham shocks, followed by an intracerebroventricular (i.c.v.) lipopolysaccharide (LPS) or phosphate-buffered saline (PBS) injection. Brains were extracted and immunohistochemically stained for the microglial marker ionized calcium-binding adaptor molecule 1 (Iba1). In addition, a sucrose preference test and an open-field test were performed to quantify behavioral alterations. Results: LPS induced a short-term reduction in sucrose preference, which normalized within 3 days. In addition, LPS reduced the distance walked in the open field and induced alterations in grooming and rearing behavior. ECS did not affect any of these parameters. Phenotypical analysis of microglia demonstrated an LPS-induced increase in microglial activity ranging from 84 to 213 % in different hippocampal regions (CA3 213 %; CA1 84 %; dentate gyrus 131 %; and hilus 123 %). ECS-induced alterations in microglial activity were insignificant, ranging from -2.6 to 14.3 % in PBS-injected mice and from -20.2 to 6.6 % in LPS-injected mice. Conclusions: We were unable to demonstrate an effect of ECS on LPS-induced microglial activity or behavioral alterations

The effects of social environment on AD-related pathology in hAPP-J20 mice and tau-P301L mice

In humans, social factors (e.g., loneliness) have been linked to the risk of developing Alzheimer's Disease (AD). To date, AD pathology is primarily characterized by amyloid-β plaques and tau tangles. We aimed to assess the effect of single- and group-housing on AD-related pathology in a mouse model for amyloid pathology (J20, and WT controls) and a mouse model for tau pathology (P301L) with and without seeding of synthetic human tau fragments (K18). Female mice were either single housed (SH) or group housed (GH) from the age of 6-7 weeks onwards. In 12-week-old P301L mice, tau pathology was induced through seeding by injecting K18 into the dorsal hippocampus (P301L K18), while control mice received a PBS injection (P301L PBS). P301L mice were sacrificed at 4 months of age and J20 mice at 10 months of age. In all mice brain pathology was histologically assessed by examining microglia, the CA1 pyramidal cell layer and specific AD pathology: analysis of plaques in J20 mice and tau hyperphosphorylation in P301L mice. Contrary to our expectation, SH-J20 mice interestingly displayed fewer plaques in the hippocampus compared to GH-J20 mice. However, housing did not affect tau hyperphosphorylation at Ser202/Thr205 of P301L mice, nor neuronal cell death in the CA1 region in any of the mice. The number of microglia was increased by the J20 genotype, and their activation (based on cell body to cell size ratio) in the CA1 was affected by genotype and housing condition (interaction effect). Single housing of P301L mice was linked to the development of stereotypic behavior (i.e. somersaulting and circling behavior). In P301L K18 mice, an increased number of microglia were observed, among which were rod microglia. Taken together, our findings point to a significant effect of social housing conditions on amyloid plaques and microglia in J20 mice and on the development of stereotypic behavior in P301L mice, indicating that the social environment can modulate AD-related pathology. </p

Immune and neurotrophin stimulation by electroconvulsive therapy:is some inflammation needed after all?

A low-grade inflammatory response is commonly seen in the peripheral blood of major depressive disorder (MDD) patients, especially those with refractory and chronic disease courses. However, electroconvulsive therapy (ECT), the most drastic intervention reserved for these patients, is closely associated with an enhanced haematogenous as well as neuroinflammatory immune response, as evidenced by both human and animal studies. A related line of experimental evidence further shows that inflammatory stimulation reinforces neurotrophin expression and may even mediate dramatic neurogenic and antidepressant- like effects following exposure to chronic stress. The current review therefore attempts a synthesis of our knowledge on the neurotrophic and immunological aspects of ECT and other electrically based treatments in psychiatry. Perhaps contrary to contemporary views, we conclude that targeted potentiation, rather than suppression, of inflammatory responses may be of therapeutic relevance to chronically depressed patients or a subgroup thereof

Measuring the free fall of antihydrogen

After the first production of cold antihydrogen by the ATHENA and ATRAP experiments ten years ago, new second-generation experiments are aimed at measuring the fundamental properties of this anti-atom. The goal of AEGIS (Antimatter Experiment: Gravity, Interferometry, Spectroscopy) is to test the weak equivalence principle by studying the gravitational interaction between matter and antimatter with a pulsed, cold antihydrogen beam. The experiment is currently being assembled at CERN's Antiproton Decelerator. In AEGIS, antihydrogen will be produced by charge exchange of cold antiprotons with positronium excited to a high Rydberg state (n > 20). An antihydrogen beam will be produced by controlled acceleration in an electric-field gradient (Stark acceleration). The deflection of the horizontal beam due to its free fall in the gravitational field of the earth will be measured with a moire deflectometer. Initially, the gravitational acceleration will be determined to a precision of 1%, requiring the detection of about 105 antihydrogen atoms. In this paper, after a general description, the present status of the experiment will be reviewed

Effects of selective TNFR1 inhibition or TNFR2 stimulation, compared to non-selective TNF inhibition, on (neuro)inflammation and behavior after myocardial infarction in male mice

BACKGROUND: Myocardial infarction (MI) coinciding with depression worsens prognosis. Although Tumor Necrosis Factor alpha (TNF) is recognized to play a role in both conditions, the therapeutic potential of TNF inhibition is disappointing. TNF activates two receptors, TNFR1 and TNFR2, associated with opposite effects. Therefore, anti-inflammatory treatment with specific TNF receptor interference was compared to non-specific TNF inhibition regarding effects on heart, (neuro)inflammation, brain and behavior in mice with MI. METHODS: Male C57BL/6 mice were subjected to MI or sham surgery. One hour later, MI mice were randomized to either non-specific TNF inhibition by Enbrel, specific TNFR1 antagonist-, or specific TNFR2 agonist treatment until the end of the protocol. Control sham and MI mice received saline. Behavioral evaluation was obtained day 10-14 after surgery. Eighteen days post-surgery, cardiac function was measured and mice were sacrificed. Blood and tissue samples were collected for analyses of (neuro)inflammation. RESULTS: MI mice displayed left ventricular dysfunction, without heart failure, (neuro) inflammation or depressive-like behavior. Both receptor-specific interventions, but not Enbrel, doubled early post-MI mortality. TNFR2 agonist treatment improved left ventricular function and caused hyper-ramification of microglia, with no effect on depressive-like behavior. In contrast, TNFR1 antagonist treatment was associated with enhanced (neuro)inflammation: more plasma eosinophils and monocytes; increased plasma Lcn2 and hippocampal microglia and astrocyte activation. Moreover, increased baseline heart rate, with reduced beta-adrenergic responsiveness indicated sympathetic activation, and coincided with reduced exploratory behavior in the open field. Enbrel did not affect neuroinflammation nor behavior. CONCLUSION: Early receptor interventions, but not non-specific TNF inhibition, increased mortality. Apart from this undesired effect, the general beneficial profile after TNFR2 stimulation, rather than the unfavourable effects of TNFR1 inhibition, would render TNFR2 stimulation preferable over non-specific TNF inhibition in MI with comorbid depression. However, follow-up studies regarding optimal timing and dosing are needed

The combination of vitamins and omega-3 fatty acids has an enhanced anti-inflammatory effect on microglia

Neuroinflammation is a common phenomenon in the pathology of many brain diseases. In this paper we explore whether selected vitamins and fatty acids known to modulate inflammation exert an effect on microglia, the key cell type involved in neuroinflammation. Previously these nutrients have been shown to exert anti-inflammatory properties acting on specific inflammatory pathways. We hypothesized that combining nutrients acting on converging anti-inflammatory pathways may lead to enhanced anti-inflammatory properties as compared to the action of a single nutrient. In this study, we investigated the anti-inflammatory effect of combinations of nutrients based on the ability to inhibit the LPS-induced release of nitric oxide and interleukin-6 from BV-2 cells. Results show that omega-3 fatty acids, vitamins A and D can individually reduce the LPS-induced secretion of the pro-inflammatory cytokines by By 2 cells. Moreover, we show that vitamins A, D and omega-3 fatty acids (docosahexaenoic and eicosapentaenoic) at concentrations where they individually had little effect, significantly reduced the secretion of the inflammatory mediator, nitric oxide, when they were combined. The conclusion of this study is that combining different nutrients acting on convergent anti-inflammatory pathways may result in an increased anti-inflammatory efficacy. (C) 2016 Elsevier Ltd. All rights reserved

Evaluating [C-11]PBR28 PET for Monitoring Gut and Brain Inflammation in a Rat Model of Chemically Induced Colitis

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon that affects an increasing number of patients. High comorbidity is observed between UC and other diseases in which inflammation may be involved, including brain diseases such as cognitive impairment, mental disorders, anxiety, and depression. To investigate the increased occurrence of these brain diseases in patients with UC, non-invasive methods for monitoring peripheral and central inflammation could be applied. Therefore, the goal of this study is to assess the feasibility of monitoring gut and brain inflammation in a rat model of chemically induced colitis by positron emission tomography (PET) with [C-11]PBR28, a tracer targeting the translocator protein (TSPO), which is upregulated when microglia and macrophages are activated. Colitis was induced in rats by intra-rectal injection of 2,4,6-trinitrobenzenesulfonic acid (TNBS). Rats with colitis and healthy control animals were subjected to [C-11]PBR28 PET of the abdomen followed by ex vivo biodistribution in order to assess whether inflammation in the gut could be detected. Another group of rats with colitis underwent repetitive [C-11]PBR28 PET imaging of the brain to investigate the development of neuroinflammation. Eleven days after TNBS injection, ex vivo biodistribution studies demonstrated increased [C-11]PBR28 uptake in the inflamed cecum and colon of rats with colitis as compared to healthy controls, whereas PET imaging did not show any difference between groups at any time. Similarly, repetitive PET imaging of the brain did not reveal any neuroinflammation induced by the TNBS administration in the colon. In contrast, significantly increased [C-11]PBR28 uptake in cerebellum could be detected in ex vivo biodistribution studies on day 11. Inflammation in both the gut and the brain of rats with chemically induced colitis was observed by ex vivo biodistribution. However, these effects could not be detected by [C-11]PBR28 PET imaging in our colitis model, which is likely due to spill-over effects and insufficient resolution of the PET camera