G-CSF increases calprotectin expression, liver damage and neuroinflammation in a murine model of alcohol-induced ACLF.

Background and aims: Granulocyte colony-stimulating factor (G-CSF) has been proposed as a therapeutic option for patients with ACLF, however clinical outcomes are controversial. We aimed at dissecting the role of G-CSF in an alcohol-induced murine model of ACLF. Methods: ACLF was triggered by a single alcohol binge (5 g/kg) in a bile duct ligation (BDL) liver fibrosis model. A subgroup of mice received two G-CSF (200 µg/kg) or vehicle injections prior to acute decompensation with alcohol. Liver, blood and brain tissues were assessed. Results: Alcohol binge administered to BDL-fibrotic mice resulted in features of ACLF indicated by a significant increase in liver damage and systemic inflammation compared to BDL alone. G-CSF treatment in ACLF mice induced an increase in liver regeneration and neutrophil infiltration in the liver compared to vehicle-treated ACLF mice. Moreover, liver-infiltrating neutrophils in G-CSF-treated mice exhibited an activated phenotype indicated by increased expression of CXC motif chemokine receptor 2, leukotriene B4 receptor 1, and calprotectin. In the liver, G-CSF triggered increased oxidative stress, type I interferon response, extracellular matrix remodeling and inflammasome activation. Circulating IL-1ß was also increased after G-CSF treatment. In the cerebellum, G-CSF increased neutrophil infiltration and S100a8/9 expression, induced microglia proliferation and reactive astrocytes, which was accompanied by oxidative stress, and inflammasome activation compared to vehicle-treated ACLF mice. Conclusion: In our novel ACLF model triggered by alcohol binge that mimics ACLF pathophysiology, neutrophil infiltration and S100a8/9 expression in the liver and brain indicate increased tissue damage, accompanied by oxidative stress and inflammasome activation after G-CSF treatment.

Innate immune activation: Parallels in alcohol use disorder and Alzheimer's disease.

Alcohol use disorder is associated with systemic inflammation and organ dysfunction especially in the liver and the brain. For more than a decade, studies have highlighted alcohol abuse-mediated impairment of brain function and acceleration of neurodegeneration through inflammatory mechanisms that directly involve innate immune cells. Furthermore, recent studies indicate overlapping genetic risk factors between alcohol use and neurodegenerative disorders, specifically regarding the role of innate immunity in the pathomechanisms of both areas. Considering the pressing need for a better understanding of the relevance of alcohol abuse in dementia progression, here we summarize the molecular mechanisms of neuroinflammation observed in alcohol abuse and Alzheimer's disease, the most common cause of dementia. In addition, we highlight mechanisms that are already established in the field of Alzheimer's disease that may be relevant to explore in alcoholism to better understand alcohol mediated neurodegeneration and dementia, including the relevance of the liver-brain axis.

Identifying the In Vivo Cellular Correlates of Antipsychotic Drugs.

GPCRs such as 5-HT2A and D2 are implicated in the therapeutic and the side effects of antipsychotics. However, the pattern of brain activity that leads to the behavioral effects of antipsychotics is poorly understood. To address this question, we used the transgenic 'FosTRAP' mice (Mus musculus), where a fluorescent reporter marks the cells responsive to the stimulus of interest. Here, the stimulus was an administration of various antipsychotic drugs. In case of typical antipsychotics such as Haloperidol, the c-fos active cells were predominantly found in the striatum, whereas in case of the atypical antipsychotics (Clozapine and Olanzapine), c-fos-induced cells were more numerous in the cortical regions, e.g., orbital cortex, piriform cortex. Curiously, we also observed ependymal cells to be a novel cellular target of atypical antipsychotics. 5-HT2A is considered to be a major target for atypical antipsychotics. Therefore, we bred 'FosTRAP' mice with 5-HT2A knock-out (KO) mice and tested their response to the prototype of atypical antipsychotics, Clozapine. Interestingly, the absence of 5-HT2A did not significantly affect the number of c-fos-induced cells in the cortical regions. However, the ependymal cells showed a dramatically reduced response to Clozapine in the absence of 5-HT2A. In summary, the TRAP system has allowed us to identify various region-specific activity induced by antipsychotics and novel cellular targets of the antipsychotics. These results serve as a "proof of principle" study that can be extended to explore the biochemical and physiological changes brought about by antipsychotics and specifically identify antipsychotic-responsive cells in the live tissue.

Sedative effect of Clozapine is a function of 5-HT2A and environmental novelty.

Antipsychotic drugs are the mainstay in the treatment of schizophrenia and bipolar disorder. However, antipsychotics often exhibit sedation or activity suppression among many other side effects, and the factors that influence them remain poorly understood. We now show, using a 5-HT2A knockout (Htr2a-/-) mouse, that environmental circumstances can affect suppression of activity induced by the atypical antipsychotic- Clozapine. We observed that Htr2a-/- mice were more resistant to Clozapine-induced suppression of activity (CISA) and this behaviour was dependent on the environment being 'novel'. In their 'home' environment, at identical doses the mice exhibited CISA. Interestingly, the effect of genotype and environmental novelty on CISA could not be extended to the other antipsychotics that were tested, i.e. Haloperidol and Risperidone. Haloperidol-induced activity suppression was independent of context and genotype. Whereas context affected Risperidone-induced activity suppression only in the Htr2a+/+ mice. Furthermore, we observed that caffeine, a stimulant, elicited resistance to CISA similar to that seen in the 'novel' context. Our study establishes a previously unknown interaction between the environmental context, 5-HT2A and CISA and emphasises the role of non-pharmacological factors such as environment on the effects of the drug, which seem antipsychotic-specific. Our findings should advance the understanding of the side effects of individual antipsychotics and the role of environment to overcome side effects such as sedation.

Obesity as a perceived social signal.

Fat accumulation has been classically considered as a means of energy storage. Obese people are theorized as metabolically 'thrifty', saving energy during times of food abundance. However, recent research has highlighted many neuro-behavioral and social aspects of obesity, with a suggestion that obesity, abdominal obesity in particular, may have evolved as a social signal. We tested here whether body proportions, and abdominal obesity in particular, are perceived as signals revealing personality traits. Faceless drawings of three male body forms namely lean, muscular and feminine, each with and without abdominal obesity were shown in a randomized order to a group of 222 respondents. A list of 30 different adjectives or short descriptions of personality traits was given to each respondent and they were asked to allocate the most appropriate figure to each of them independently. The traits included those directly related to physique, those related to nature, attitude and moral character and also those related to social status. For 29 out of the 30 adjectives people consistently attributed specific body forms. Based on common choices, the 30 traits could be clustered into distinct 'personalities' which were strongly associated with particular body forms. A centrally obese figure was perceived as "lethargic, greedy, political, money-minded, selfish and rich". The results show that body proportions are perceived to reflect personality traits and this raises the possibility that in addition to energy storage, social selection may have played some role in shaping the biology of obesity.