The 7q11.23 Protein DNAJC30 Interacts with ATP Synthase and Links Mitochondria to Brain Development.

Despite the known causality of copy-number variations (CNVs) to human neurodevelopmental disorders, the mechanisms behind each gene's contribution to the constellation of neural phenotypes remain elusive. Here, we investigated the 7q11.23 CNV, whose hemideletion causes Williams syndrome (WS), and uncovered that mitochondrial dysfunction participates in WS pathogenesis. Dysfunction is facilitated in part by the 7q11.23 protein DNAJC30, which interacts with mitochondrial ATP-synthase machinery. Removal of Dnajc30 in mice resulted in hypofunctional mitochondria, diminished morphological features of neocortical pyramidal neurons, and altered behaviors reminiscent of WS. The mitochondrial features are consistent with our observations of decreased integrity of oxidative phosphorylation supercomplexes and ATP-synthase dimers in WS. Thus, we identify DNAJC30 as an auxiliary component of ATP-synthase machinery and reveal mitochondrial maladies as underlying certain defects in brain development and function associated with WS.

Predictive factors for infection after osteosynthesis of tibial plateau fractures: a retrospective study of 314 patients.

INTRODUCTION: The reported incidence of infection related with tibial plateau fractures (IRTPF) ranges from 2 to 23%. This complication can result in catastrophic consequences such as deformity, post-traumatic osteoarthritis, chronic pain, loss of function, and substantial economic burdens on healthcare systems due to extended hospital stays and the resources required for treatment. Consequently, it is imperative to emphasize the identification of infection risk factors. METHODS: A retrospective case-control study was designed, encompassing patients who underwent surgery for tibial plateau fractures between 2015 and 2020. Frequencies and measures of central tendency were compared between infected patients (cases) and non-infected patients (controls) using rank-based statistical tests. Subsequently, two logistic regression models were employed to control for potential confounding variables. RESULTS: A total of 314 patients were included, predominantly male (71.15%). Average age of 44.41 years. IRTPF were observed in 7.64% of the patients. In the univariate inferential statistical analysis, high-energy fractures (OR 6.35, p < 0.001), fractures with compartment syndrome (OR 7.10, p < 0.001), two-stage management with temporary external fixation (OR 8.18, p < 0.001), the use of 2 or more approaches in definitive surgery (OR 2.93, p = 0.011), and the use of two or more plates (OR 9.17, p < 0.001) were identified as risk factors for infection. On average, the duration of surgery in infected patients was 201.2 min, compared to 148.4 min in non-infected patients (p < 0.001). When performing two logistic regression models, the following independent risk factors were identified: high-energy fractures (OR 5.04, p = 0.012), the presence of compartment syndrome (OR 4.53, p = 0.007), and the use of two or more plates in definitive surgery (OR 5.04, p = 0.023). CONCLUSIONS: High-energy tibial plateau fractures (Schatzker IV, V, and VI), the presence of concomitant compartment syndrome, and the use of 2 or more plates in definitive surgery are associated with a higher risk of infection related to fracture following open reduction and osteosynthesis treatment. LEVEL OF EVIDENCE: Case-Control Study.

ALDH1A1 and ALDH1A3 paralogues of aldehyde dehydrogenase 1 control myogenic differentiation of skeletal muscle satellite cells by retinoic acid-dependent and -independent mechanisms.

ALDH1A1 and ALDH1A3 paralogues of aldehyde dehydrogenase 1 (ALDH1) control myogenic differentiation of skeletal muscle satellite cells (SC) by formation of retinoic acid (RA) and subsequent cell cycle adjustments. The respective relevance of each paralogue for myogenic differentiation and the mechanistic interaction of each paralogue within RA-dependent and RA-independent pathways remain elusive.We analysed the impact of ALDH1A1 and ALDH1A3 activity on myogenesis of murine C2C12 myoblasts. Both paralogues are pivotal factors in myogenic differentiation, since CRISPR/Cas9-edited single paralogue knock-out impaired serum withdrawal-induced myogenic differentiation, while successive recombinant re-expression of ALDH1A1 or ALDH1A3, respectively, in the corresponding ALDH1 paralogue single knock-out cell lines, recovered the differentiation potential. Loss of differentiation in single knock-out cell lines was restored by treatment with RA-analogue TTNPB, while RA-receptor antagonization by AGN 193109 inhibited differentiation of wildtype cell lines, supporting the idea that RA-dependent pathway is pivotal for myogenic differentiation which is accomplished by both paralogues.However, overexpression of ALDH1-paralogues or disulfiram-mediated inhibition of ALDH1 enzymatic activity not only increased ALDH1A1 and ALDH1A3 protein levels but also induced subsequent differentiation of C2C12 myoblasts independently from serum withdrawal, indicating that ALDH1-dependent myogenic differentiation relies on different cellular conditions. Remarkably, ALDH1-paralogue knock-out impaired the autophagic flux, namely autophagosome cargo protein p62 formation and LC3B-I to LC3B-II conversion, demonstrating that ALDH1-paralogues interact with autophagy in myogenesis. Together, ALDH1 paralogues play a crucial role in myogenesis by orchestration of complex RA-dependent and RA-independent pathways.

Distinct Firing Activities of the Hypothalamic Arcuate Nucleus Neurons to Appetite Hormones.

The hypothalamic arcuate nucleus (Arc) is a central unit that controls the appetite through the integration of metabolic, hormonal, and neuronal afferent inputs. Agouti-related protein (AgRP), proopiomelanocortin (POMC), and dopaminergic neurons in the Arc differentially regulate feeding behaviors in response to hunger, satiety, and appetite, respectively. At the time of writing, the anatomical and electrophysiological characterization of these three neurons has not yet been intensively explored. Here, we interrogated the overall characterization of AgRP, POMC, and dopaminergic neurons using genetic mouse models, immunohistochemistry, and whole-cell patch recordings. We identified the distinct geographical location and intrinsic properties of each neuron in the Arc with the transgenic lines labelled with cell-specific reporter proteins. Moreover, AgRP, POMC, and dopaminergic neurons had different firing activities to ghrelin and leptin treatments. Ghrelin led to the increased firing rate of dopaminergic and AgRP neurons, and the decreased firing rate of POMC. In sharp contrast, leptin resulted in the decreased firing rate of AgRP neurons and the increased firing rate of POMC neurons, while it did not change the firing rate of dopaminergic neurons in Arc. These findings demonstrate the anatomical and physiological uniqueness of three hypothalamic Arc neurons to appetite control.

Hypothalamic POMC neurons promote cannabinoid-induced feeding.

Hypothalamic pro-opiomelanocortin (POMC) neurons promote satiety. Cannabinoid receptor 1 (CB1R) is critical for the central regulation of food intake. Here we test whether CB1R-controlled feeding in sated mice is paralleled by decreased activity of POMC neurons. We show that chemical promotion of CB1R activity increases feeding, and notably, CB1R activation also promotes neuronal activity of POMC cells. This paradoxical increase in POMC activity was crucial for CB1R-induced feeding, because designer-receptors-exclusively-activated-by-designer-drugs (DREADD)-mediated inhibition of POMC neurons diminishes, whereas DREADD-mediated activation of POMC neurons enhances CB1R-driven feeding. The Pomc gene encodes both the anorexigenic peptide α-melanocyte-stimulating hormone, and the opioid peptide ß-endorphin. CB1R activation selectively increases ß-endorphin but not α-melanocyte-stimulating hormone release in the hypothalamus, and systemic or hypothalamic administration of the opioid receptor antagonist naloxone blocks acute CB1R-induced feeding. These processes involve mitochondrial adaptations that, when blocked, abolish CB1R-induced cellular responses and feeding. Together, these results uncover a previously unsuspected role of POMC neurons in the promotion of feeding by cannabinoids.

Characteristics and health burden of the undiagnosed population at risk of chronic obstructive pulmonary disease in China.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality in China. However, identifying patients has proved challenging, resulting in widespread under-diagnosis of the condition. We examined the prevalence of COPD diagnosis and COPD risk among adults in urban mainland China, the factors associated with having a COPD diagnosis or COPD risk, and the healthcare resource use and health outcomes of these groups compared with controls. METHODS: Respondents to the 2017 National Health and Wellness Survey in China (n = 19,994) were classified into three groups: 'COPD Diagnosed', 'COPD Risk (undiagnosed)', and Control (unaffected), based on their self-reported diagnosis and Lung Function Questionnaire (LFQ) score. The groups were characterised by sociodemographic, health-related quality of life (HRQoL), productivity impairment, and healthcare resource use. Pairwise comparisons (t tests and chi-squared tests) and multivariable regression analyses were used to investigate factors associated with being at risk of, or diagnosed with, COPD. RESULTS: 3320 (16.6%) respondents had a suspected risk of COPD but did not report receiving a diagnosis. This was projected to 105.3 million people, or 16.9% of adult urban Chinese. Of these respondents with an identified risk, only 554 (16.7%) were aware of COPD by name. Relative to those without COPD, those with a risk of COPD (undiagnosed) had significantly greater healthcare resource use, lower productivity and lower HRQoL not only compared to those without COPD, but also compared to people with a COPD diagnosis. Factors associated with increased odds of being at risk of COPD were older age, smoking, alcohol consumption, overweight BMI, occasional exercise, higher comorbidities, asthma diagnosis, being female, lower education, not being employed, and living in a high pollution province (p < 0.05). CONCLUSIONS: There is a substantial group of individuals, undiagnosed, but living with a risk of COPD, who have impaired HRQoL, lower productivity and elevated healthcare resource use patterns. Case-detection tools such as the LFQ may prove a quick and cost-effective approach for identifying these at-risk individuals for further definitive testing and appropriate treatment in China.

The G protein-coupled receptor 55 ligand l-α-lysophosphatidylinositol exerts microglia-dependent neuroprotection after excitotoxic lesion.

Searching for chemical agents and molecular targets protecting against secondary neuronal damage reflects one major issue in neuroscience. Cannabinoids limit neurodegeneration by activation of neuronal G protein-coupled cannabinoid receptor 1 (CB1 ) and microglial G protein-coupled cannabinoid receptor 2 (CB2 ). However, pharmacological experiments with CB1 /CB2 -deficient mice unraveled the existence of further, so-called non-CB1 /non-CB2 G protein-coupled receptor (GPR) subtypes. GPR55, whose function in the brain is still poorly understood, represents a novel target for various cannabinoids. Here, we investigated whether GPR55 reflects a potential beneficial target in neurodegeneration by using the excitotoxicity in vitro model of rat organotypic hippocampal slice cultures (OHSC). l-α-Lysophosphatidylinositol (LPI), so far representing the most selective agonist for GPR55, protected dentate gyrus granule cells and reduced the number of activated microglia after NMDA (50 µM) induced lesions. The relevance of GPR55 activation for LPI-mediated neuroprotection was determined by using Gpr55 siRNA. Microglia seems to mediate the observed neuroprotection since their depletion in OHSC attenuated the beneficial effects of LPI. Moreover, LPI alone induced microglia chemotaxis but conversely significantly attenuated ATP triggered microglia migration. These effects seemed to be independent from intracellular Ca(2+) and p38 or p44/p42 MAPK phosphorylation. In conclusion, this study unmasked a yet unknown role for GPR55 in neuroprotection driven by LPI-mediated modulation of microglia function.

Antibodies to cannabinoid type 1 receptor co-react with stomatin-like protein 2 in mouse brain mitochondria.

Anti-cannabinoid type 1 receptor (CB1 ) polyclonal antibodies are widely used to detect the presence of CB1 in a variety of brain cells and their organelles, including neuronal mitochondria. Surprisingly, we found that anti-CB1 sera, in parallel with CB1 , also recognize the mitochondrial protein stomatin-like protein 2. In addition, we show that the previously reported effect of synthetic cannabinoid WIN 55,212-2 on mitochondrial complex III respiration is not detectable in purified mitochondrial preparations. Thus, our study indicates that a direct relationship between endocannabinoid signaling and mitochondrial functions in the cerebral cortex seems unlikely, and that caution should be taken interpreting findings obtained using anti-CB1 antibodies.

Testing Replicability and Generalizability of the Time on Task Effect.

The time on task (ToT) effect describes the relationship of the time spent on a cognitive task and the probability of successful task completion. The effect has been shown to vary in size and direction across tests and even within tests, depending on the test taker and item characteristics. Specifically, investing more time has a positive effect on response accuracy for difficult items and low ability test-takers, but a negative effect for easy items and high ability test-takers. The present study sought to test the replicability of this result pattern of the ToT effect across samples independently drawn from the same populations of persons and items. Furthermore, its generalizability was tested in terms of differential correlations across ability tests. To this end, ToT effects were estimated for three different reasoning tests and one test measuring natural sciences knowledge in 10 comparable subsamples with a total N = 2640. Results for the subsamples were highly similar, demonstrating that ToT effects are estimated with sufficient reliability. Generally, faster answers tended to be more accurate, suggesting a relatively effortless processing style. However, with increasing item difficulty and decreasing person ability, the effect flipped to the opposite direction, i.e., higher accuracy with longer processing times. The within-task moderation of the ToT effect can be reconciled with an account on effortful processing or cognitive load. By contrast, the generalizability of the ToT effect across different tests was only moderate. Cross-test relations were stronger in relative terms if performance in the respective tasks was more strongly related. This suggests that individual differences in the ToT effect depend on test characteristics such as their reliabilities but also similarities and differences of their processing requirements.

Time dependent neuroprotection of mycophenolate mofetil: effects on temporal dynamics in glial proliferation, apoptosis, and scar formation.

BACKGROUND: Immunosuppressants such as mycophenolate mofetil (MMF) have the capacity to inhibit microglial and astrocytic activation and to reduce the extent of cell death after neuronal injury. This study was designed to determine the effective neuroprotective time frame in which MMF elicits its beneficial effects, by analyzing glial cell proliferation, migration, and apoptosis. METHODS: Using organotypic hippocampal slice cultures (OHSCs), temporal dynamics of proliferation and apoptosis after N-methyl-D-aspartate (NMDA)-mediated excitotoxicity were analyzed by quantitative morphometry of Ki-67 or cleaved caspase-3 immunoreactive glial cells. Treatment on NMDA-lesioned OHSCs with mycophenolate mofetil (MMF)100 µg/mL was started at different time points after injury or performed within specific time frames, and the numbers of propidium iodide (PI)+ degenerating neurons and isolectin (I)B(4)(+) microglial cells were determined. Pre-treatment with guanosine 100 µmol/l was performed to counteract MMF-induced effects. The effects of MMF on reactive astrocytic scar formation were investigated in the scratch-wound model of astrocyte monolayers. RESULTS: Excitotoxic lesion induction led to significant increases in glial proliferation rates between 12 and 36 hours after injury and to increased levels of apoptotic cells between 24 and 72 hours after injury. MMF treatment significantly reduced glial proliferation rates without affecting apoptosis. Continuous MMF treatment potently reduced the extent of neuronal cell demise when started within the first 12 hours after injury. A crucial time-frame of significant neuroprotection was identified between 12 and 36 hours after injury. Pre-treatment with the neuroprotective nucleoside guanosine reversed MMF-induced antiproliferative effects on glial cells. In the scratch-wound model, gap closure was reached within 48 hours in controls, and was potently inhibited by MMF. CONCLUSIONS: Our data indicate that immunosuppression by MMF significantly attenuates the extent of neuronal cell death when administered within a crucial time frame after injury. Moreover, long-lasting immunosuppression, as required after solid-organ transplantation, does not seem to be necessary. Targeting inosine 5-monophosphate dehydrogenase, the rate-limiting enzyme of purine synthesis, is an effective strategy to modulate the temporal dynamics of proliferation and migration of microglia and astrocytes, and thus to reduce the extent of secondary neuronal damage and scar formation.

Development and Validation of the Open Matrices Item Bank.

Figural matrices tasks are one of the most prominent item formats used in intelligence tests, and their relevance for the assessment of cognitive abilities is unquestionable. However, despite endeavors of the open science movement to make scientific research accessible on all levels, there is a lack of royalty-free figural matrices tests. The Open Matrices Item Bank (OMIB) closes this gap by providing free and unlimited access (GPLv3 license) to a large set of empirically validated figural matrices items. We developed a set of 220 figural matrices based on well-established construction principles commonly used in matrices tests and administered them to a sample of N = 2572 applicants to medical schools. The results of item response models and reliability analyses demonstrate the excellent psychometric properties of the items. In the discussion, we elucidate how researchers can already use the OMIB to gain access to high-quality matrices tests for their studies. Furthermore, we provide perspectives for features that could additionally improve the utility of the OMIB.

Do Grittier People Have Greater Subjective Well-Being? A Meta-Analysis.

The present study conducted a meta-analysis to examine the relation between grit and subjective well-being (SWB). The association between grit (i.e., overall grit, perseverance of effort, and consistency of interest) and SWB (i.e., positive affect, negative affect, happiness, depression, life satisfaction, job satisfaction, and school satisfaction) were synthesized across 83 studies and 66,518 participants. The results based on a random-effects model showed a substantial correlation between overall grit and SWB (ρ = .46, 95% confidence interval [CI] = [.43, .48]), followed by perseverance of effort (ρ = .38, 95% CI = [.33, .43]) and consistency of interest (ρ = .23, 95% CI = [.17, .28]). The moderator analysis indicated that the correlations between overall grit/consistency of effort and SWB become weaker as age increased, and these links were stronger in affective well-being than in cognitive well-being. Moreover, grit explained unique variance in SWB even after controlling for conscientiousness. Implications and directions for further research are discussed.

The long-term buffering effect of sense of coherence on psychopathological symptoms during the first year of the COVID-19 pandemic: A prospective observational study.

The COVID-19 pandemic is a major chronic stressor affecting all societies and almost all individuals. Consequently, research demonstrated a negative impact of COVID-19 on mental health in parts of the general population. However, not all people are affected equally thus making the identification of resilience factors modulating the pandemic's impact on mental health an important research agenda. One of these factors is sense of coherence (SOC), the key component of the salutogenesis framework. The current study aimed at investigating the long-term relationship between SOC and psychopathological symptoms, and the impact of COVID-19-related rumination as its moderator. The prospective observational study assessed psychopathological symptoms and SOC before the COVID-19 outbreak in Germany (February 2020) and at six critical time points during the pandemic in an online panel (n = 1,479). Bivariate latent change score models and latent growth mixture modeling were used to analyze changes in psychopathological symptoms and SOC along with their interaction and to differentiate trajectories of COVID-19-related rumination. A model allowing for unidirectional coupling from SOC to psychopathological symptoms demonstrated best fit. In the total sample, psychopathological symptoms increased significantly over time. Previous SOC predicted later changes in psychopathological symptoms, whereby a stronger SOC was associated with a decrease in symptoms over time. The same pattern of results was evident in the high-rumination (17.2%) but not in the low-rumination group (82.8%). Our findings demonstrate that SOC is an important predictor and modulator of psychopathological symptoms during the COVID-19 pandemic, particularly in those respondents that ruminate about the pandemic.

The cannabinoid WIN 55,212-2-mediated protection of dentate gyrus granule cells is driven by CB1 receptors and modulated by TRPA1 and Cav 2.2 channels.

Cannabinoids regulate numerous physiological and pathological events like inflammation or neurodegeneration via CB(1) and CB(2) receptors. The mechanisms behind cannabinoid effects show a high variability and may also involve transient receptor potential channels (TRP) and N-type voltage-gated Ca(2+) channels (Ca(v) 2.2). In the present study we investigated the neuroprotective effects of the synthetic cannabinoid WIN 55,212-2 (WIN) on dentate gyrus (DG) granule cells and elucidated the involvement of TRP and Ca(v) 2.2 that are shown to participate in inflammatory processes. Organotypic hippocampal slice cultures were excitotoxically lesioned using NMDA and subsequently incubated with different WIN concentrations (0.001-10 µM). WIN showed neuroprotective properties in an inverse concentration-dependent manner, most effectively at 0.01 µM. The CB(1) receptor antagonist AM251 blocked neuroprotection mediated by WIN whereas the CB(2) receptor antagonist AM630 showed no effects. Application of the TRPA1 blocker HC-030031 enhanced the neuroprotective efficacy of high (10 µM) WIN concentrations and the number of degenerating neurons became equal to that seen after application of the most effective WIN dose (0.01 µM). In contrast, the application of TRPA1 agonist icilin or allyl isothiocyanate (AITC) led to a stronger neurodegeneration. The use of TRPV1 blocker 6-iodo-nordihydrocapsaicin did not affect WIN-mediated neuroprotection. The selective Ca(v) 2.2 blocker ω-conotoxin (GVIA) completely blocked neuroprotection shown by 10 µM WIN. GVIA and HC-030031 exerted no effects at WIN concentrations lower than 10 µM. Our data show that WIN protects dentate gyrus granule cells in a concentration dependent manner by acting upon CB(1) receptors. At high (10 µM) concentrations WIN additionally activates TRPA1 and Ca(v) 2.2 within the hippocampal formation that both interfere with CB(1) receptor-mediated neuroprotection. This leads to the conclusion that physiological and pharmacological effects of cannabinoids strongly depend on their concentration and the neuroprotective efficacy of cannabinoids may be determined by interaction of activated CB(1) receptor, TRPA1, and Ca(v) 2.2.

Treatment options for subjective tinnitus: self reports from a sample of general practitioners and ENT physicians within Europe and the USA.

BACKGROUND: Tinnitus affects about 10-15% of the general population and risks for developing tinnitus are rising through increased exposure to leisure noise through listening to personal music players at high volume. The disorder has a considerable heterogeneity and so no single mechanism is likely to explain the presence of tinnitus in all those affected. As such there is no standardized management pathway nor singly effective treatment for the condition. Choice of clinical intervention is a multi-factorial decision based on many factors, including assessment of patient needs and the healthcare context. The present research surveyed clinicians working in six Westernized countries with the aims: a) to establish the range of referral pathways, b) to evaluate the typical treatment options for categories of subjective tinnitus defined as acute or chronic, and c) to seek clinical opinion about levels of satisfaction with current standards of practice. METHODS: A structured online questionnaire was conducted with 712 physicians who reported seeing at least one tinnitus patients in the previous three months. They were 370 general practitioners (GPs) and 365 ear-nose-throat specialists (ENTs) from the US, Germany, UK, France, Italy and Spain. RESULTS: Our international comparison of health systems for tinnitus revealed that although the characteristics of tinnitus appeared broadly similar across countries, the patient's experience of clinical services differed widely. GPs and ENTs were always involved in referral and management to some degree, but multi-disciplinary teams engaged either neurology (Germany, Italy and Spain) or audiology (UK and US) professionals. For acute subjective tinnitus, pharmacological prescriptions were common, while audiological and psychological approaches were more typical for chronic subjective tinnitus; with several specific treatment options being highly country specific. All therapy options were associated with low levels of satisfaction. CONCLUSIONS: Despite a large variety of treatment options, the low success rates of tinnitus therapy lead to frustration of physicians and patients alike. For subjective tinnitus in particular, effective therapeutic options with guidelines about key diagnostic criteria are urgently needed.

Test Preparation in Figural Matrices Tests: Focus on the Difficult Rules.

It is well documented that training the rules employed in figural matrices tests enhances test performance. Previous studies only compare experimental conditions in which all or no rules were trained and therefore ignore the particular influence of knowledge about the easy and difficult rules. With the current study, we wanted to provide some first insights into this topic. Respondents were assigned to four groups that received training for no rules, only the easy rules, only the difficult rules, or for all rules. The results show that a training only for the difficult rules was more effective than the other trainings. This applies also to performance in the easy rules that were actually not part of the training. A possible explanation for this finding is a facilitation of the solution process that is primarily driven by knowledge about the difficult rules. In conclusion, our results demonstrate that taking differences between the rules into account may provide a deeper understanding of the effects of trainings for figural matrices tests.

An endocannabinoid system is localized to the hypophysial pars tuberalis of Syrian hamsters and responds to photoperiodic changes.

The hypophysial pars tuberalis (PT), an important interface between neuroendocrine brain centers (hypothalamus, pineal organ) and the pars distalis (PD) of the hypophysis, plays a central role in regulating seasonal reproduction and prolactin release. However, the signaling molecules that transmit photoperiodic information from the PT to the PD and control prolactin release (the so-called "tuberalins") have not yet been identified, despite an intense search for more than three decades. Here, we demonstrate an endocannabinoid system in the PT of the Syrian hamster, a photoperiodic species. By means of in situ hybrization, the PT was found to express N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD), fatty acid amide hydrolase (FAAH), sn-1-selective diacylglycerol lipases (DAGLalpha and DAGLbeta), and monoacylglycerol lipase (MAGL), enzymes involved in endocannabinoid synthesis and degradation. The expression of NAPE-PLD, FAAH, and DAGLalpha was confirmed by immunohistochemistry. Expression and protein levels of DAGLs controlling the synthesis of 2-arachidonoyl glycerol (2-AG), a major endocannabinoid, were upregulated in the PT of Syrian hamsters kept under long-day conditions. Consequently, 2-AG levels were increased in the PT of these hamsters. A primary target of 2-AG, the cannabinoid receptor 1 (CB1), was expressed in the PD. Double-immunolabeling revealed that most of the CB1-immunoreactive cells in the PD were folliculostellate cells that were also immunoreactive for S-100 protein. Thus, the PT comprises an endocannabinoid system, and 2-AG may act as a photoperiodic messenger from the PT to the PD for the regulation of hypophysial hormonal secretion.

2-Arachidonoylglycerol elicits neuroprotective effects on excitotoxically lesioned dentate gyrus granule cells via abnormal-cannabidiol-sensitive receptors on microglial cells.

Endocannabinoids like 2-arachidonoylglycerol (2-AG) exert neuroprotective effects after brain injuries. According to current concepts, these neuroprotective effects are due to interactions between 2-AG and cannabinoid (CB)1 receptors on neurons. Moreover, 2-AG modulates migration and proliferation of microglial cells which are rapidly activated after brain lesion. This effect is mediated via CB2- and abnormal-cannabidiol (abn-CBD)-sensitive receptors. In the present study, we investigated whether the abn-CBD-sensitive receptor on microglial cells contributes to 2-AG-mediated neuroprotection in organotypic hippocampal slice cultures (OHSCs) after excitotoxic lesion induced by NMDA (50 microM) application for 4 h. This lesion caused neuronal damage and accumulation of microglial cells within the granule cell layer. To analyze the role of abn-CBD-sensitive receptors for neuroprotection and microglial cell accumulation, two agonists of the abn-CBD-sensitive receptor, abn-CBD or 2-AG, two antagonists, 1,3-dimethoxy-5-methyl-2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen1-yl]-benzene (O-1918) or cannabidiol (CBD), and the CB1 receptor antagonist AM251, were applied to NMDA-lesioned OHSC. Propidium iodide (PI) labeling was used as a marker of degenerating neurons and isolectin B(4) (IB(4)) as a marker of microglial cells. Application of both, abn-CBD or 2-AG to lesioned OHSC significantly decreased the number of IB(4)(+) microglial cells and PI(+) neurons in the dentate gyrus. In contrast to AM251, application of O-1918 or CBD antagonized these effects. When microglial cells were depleted by preincubation of OHSC with the bisphosphonate clodronate (100 microg/mL) for 5 days before excitotoxic lesion, 2-AG and abn-CBD lost their neuroprotective effects. We therefore propose that the endocannabinoid 2-AG exerts its neuroprotective effects via activation of abn-CBD-sensitive receptors on microglial cells.

Macrophages protect against loss of adipose tissue during cancer cachexia.

BACKGROUND: Cancer cachexia represents a central obstacle in medical oncology as it is associated with poor therapy response and reduced overall survival. Systemic inflammation is considered to be a key driver of cancer cachexia; however, clinical studies with anti-inflammatory drugs failed to show distinct cachexia-inhibiting effects. To address this contradiction, we investigated the functional importance of innate immune cells for hepatocellular carcinoma (HCC)-associated cachexia. METHODS: A transgenic HCC mouse model was intercrossed with mice harbouring a defect in myeloid cell-mediated inflammation. Body composition of mice was analysed via nuclear magnetic resonance spectroscopy and microcomputed tomography. Quantitative PCR was used to determine adipose tissue browning and polarization of adipose tissue macrophages. The activation state of distinct areas of the hypothalamus was analysed via immunofluorescence. Multispectral immunofluorescence imaging and immunoblot were applied to characterize sympathetic neurons and macrophages in visceral adipose tissue. Quantification of pro-inflammatory cytokines in mouse serum was performed with a multiplex immunoassay. Visceral adipose tissue of HCC patients was quantified via the L3 index of computed tomography scans obtained during routine clinical care. RESULTS: We identified robust cachexia in the HCC mouse model as evidenced by a marked loss of visceral fat and lean mass. Computed tomography-based analyses demonstrated that a subgroup of human HCC patients displays reduced visceral fat mass, complementing the murine data. While the myeloid cell-mediated inflammation defect resulted in reduced expression of pro-inflammatory cytokines in the serum of HCC-bearing mice, this unexpectedly did not translate into diminished but rather enhanced cachexia-associated fat loss. Defective myeloid cell-mediated inflammation was associated with decreased macrophage abundance in visceral adipose tissue, suggesting a role for local macrophages in the regulation of cancer-induced fat loss. CONCLUSIONS: Myeloid cell-mediated inflammation displays a rather unexpected beneficial function in a murine HCC model. These results demonstrate that immune cells are capable of protecting the host against cancer-induced tissue wasting, adding a further layer of complexity to the pathogenesis of cachexia and providing a potential explanation for the contradictory results of clinical studies with anti-inflammatory drugs.

Role of astrocytes, microglia, and tanycytes in brain control of systemic metabolism.

Astrocytes, microglia, and tanycytes play active roles in the regulation of hypothalamic feeding circuits. These non-neuronal cells are crucial in determining the functional interactions of specific neuronal subpopulations involved in the control of metabolism. Recent advances in biology, optics, genetics, and pharmacology have resulted in the emergence of novel and highly sophisticated approaches for studying hypothalamic neuronal-glial networks. Here we summarize the progress in the field and argue that glial-neuronal interactions provide a core hub integrating food-related cues, interoceptive signals, and internal states to adapt a complex set of physiological responses operating on different timescales to finely tune behavior and metabolism according to metabolic status. This expanding knowledge helps to redefine our understanding of the physiology of food intake and energy metabolism.