The metabolic regulator USF-1 is involved in the control of affective behaviour in mice.

Epidemiological studies indicate a bidirectional association between metabolic disturbances, including obesity and related pathological states, and mood disorders, most prominently major depression. However, the biological mechanisms mediating the comorbid relationship between the deranged metabolic and mood states remain incompletely understood. Here, we tested the hypothesis that the enhanced activation of brown fat tissue (BAT), known to beneficially regulate obesity and accompanying dysfunctional metabolic states, is also paralleled by an alteration of affective behaviour. We used upstream stimulatory factor 1 (USF-1) knock-out (KO) mice as a genetic model of constitutively activated BAT and positive cardiometabolic traits and found a reduction of depression-like and anxiety-like behaviours associated with USF-1 deficiency. Surgical removal of interscapular BAT did not impact the behavioural phenotype of USF-1 KO mice. Further, the absence of USF-1 did not lead to alterations of adult hippocampal neural progenitor cell proliferation, differentiation, or survival. RNA-seq analysis characterised the molecular signature of USF-1 deficiency in the hippocampus and revealed a significant increase in the expression of several members of the X-linked lymphocyte-regulated (xlr) genes, including xlr3b and xlr4b. Xlr genes are the mouse orthologues of the human FAM9 gene family and are implicated in the regulation of dendritic branching, dendritic spine number and morphology. The transcriptional changes were associated with morphological alterations in hippocampal neurons, manifested in reduced dendritic length and complexity in USF-1 KO mice. Collectively these data suggest that the metabolic regulator USF-1 is involved in the control of affective behaviour in mice and that this modulation of mood states is unrelated to USF-1-dependent BAT activation, but reflected in structural changes in the brain.

Uncoupling Protein-1 Modulates Anxiety-Like Behavior in a Temperature-Dependent Manner.

A strong bidirectional link between metabolic and psychiatric disorders exists; yet, the molecular basis underlying this interaction remains unresolved. Here we explored the role of the brown adipose tissue (BAT) as modulatory interface, focusing on the involvement of uncoupling protein 1 (UCP-1), a key metabolic regulator highly expressed in BAT, in the control of emotional behavior. Male and female constitutive UCP-1 knock-out (KO) mice were used to investigate the consequences of UCP-1 deficiency on anxiety-related and depression-related behaviors under mild thermogenic (23°C) and thermoneutral (29°C) conditions. UCP-1 KO mice displayed a selective enhancement of anxiety-related behavior exclusively under thermogenic conditions, but not at thermoneutrality. Neural and endocrine stress mediators were not affected in UCP-1 KO mice, which showed an activation of the integrated stress response alongside enhanced fibroblast-growth factor-21 (FGF-21) levels. However, viral-mediated overexpression of FGF-21 did not phenocopy the behavioral alterations of UCP-1 KO mice and blocking FGF-21 activity did not rescue the anxiogenic phenotype of UCP-1 KO mice. No effects of surgical removal of the intrascapular BAT on anxiety-like behavior or FGF-21 levels were observed in either UCP-1 KO or WT mice. We provide evidence for a novel role of UCP-1 in the regulation of emotions that manifests as inhibitory constraint on anxiety-related behavior, exclusively under thermogenic conditions. We propose this function of UCP-1 to be independent of its activity in the BAT and likely mediated through a central role of UCP-1 in brain regions with converging involvement in energy and emotional control.SIGNIFICANCE STATEMENT In this first description of a temperature-dependent phenotype of emotional behavior, we propose uncoupling protein-1 (UCP-1), the key component of the thermogenic function of the brown adipose tissue, as molecular break controlling anxiety-related behavior in mice. We suggest the involvement of UCP-1 in fear regulation to be mediated through its expression in brain regions with converging roles in energy and emotional control. These data are important and relevant in light of the largely unexplored bidirectional link between metabolic and psychiatric disorders, which has the potential for providing insight into novel therapeutic strategies for the management of both conditions.

Ag/Au Bimetallic Nanoparticles Trigger Different Cell Death Pathways and Affect Damage Associated Molecular Pattern Release in Human Cell Lines.

Apoptosis induction is a common therapeutic approach. However, many cancer cells are resistant to apoptotic death and alternative cell death pathways including pyroptosis and necroptosis need to be triggered. At the same time, danger signals that include HMGB1 and HSP70 can be secreted/released by damaged cancer cells that boost antitumor immunity. We studied the cytotoxic effects of AgAu NPs, Ag NPs and Au NPs with regard to the programmed cell death (apoptosis, necroptosis, pyroptosis) and the secretion/release of HSP70 and HMGB1. Cancer cell lines were incubated with 30, 40 and 50 µg/mL of AgAu NPs, Ag NPs and Au NPs. Cytotoxicity was estimated using the MTS assay, and mRNA fold change of CASP1, CASP3, BCL-2, ZPB1, HMGB1, HSP70, CXCL8, CSF1, CCL20, NLRP3, IL-1ß and IL-18 was used to investigate the associated programmed cell death. Extracellular levels of HMGB1 and IL-1ß were investigated using the ELISA technique. The nanoparticles showed a dose dependent toxicity. Pyroptosis was triggered for LNCaP and MDA-MB-231 cells, and necroptosis for MDA-MB-231 cells. HCT116 cells experience apoptotic death and show increased levels of extracellular HMGB1. Our results suggest that in a manner dependent of the cellular microenvironment, AgAu NPs trigger mixed programmed cell death in P53 deficient MDA-MB-231 cells, while they also trigger IL-1ß release in MDA-MB-231 and LNCaP cells and release of HMGB1 in HCT116 cells.

Unlocking the Memory Component of Alzheimer's Disease: Biological Processes and Pathways across Brain Regions.

Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by a progressive loss of memory and a general cognitive decline leading to dementia. AD is characterized by changes in the behavior of the genome and can be traced across multiple brain regions and cell types. It is mainly associated with ß-amyloid deposits and tau protein misfolding, leading to neurofibrillary tangles. In recent years, however, research has shown that there is a high complexity of mechanisms involved in AD neurophysiology and functional decline enabling its diverse presentation and allowing more questions to arise. In this study, we present a computational approach to facilitate brain region-specific analysis of genes and biological processes involved in the memory process in AD. Utilizing current genetic knowledge we provide a gene set of 265 memory-associated genes in AD, combinations of which can be found co-expressed in 11 different brain regions along with their functional role. The identified genes participate in a spectrum of biological processes ranging from structural and neuronal communication to epigenetic alterations and immune system responses. These findings provide new insights into the molecular background of AD and can be used to bridge the genotype-phenotype gap and allow for new therapeutic hypotheses.

Western diet-induced fear memory impairment is attenuated by 6-shogaol in C57BL/6N mice.

Dementia is a progressive cognitive diminution impeding with normal daily activities that is constantly on the increase. Currently, the estimated prevalence is 50 million affected people worldwide, a figure expected to triple within the next 30 years. While the pathophysiology of the different types of dementia is complex, likely involving the interplay between multiple genetic and environmental factors, strong evidence points towards an important link between diet and cognitive health. Here we examined the consequences of high-fat, high-sugar Western diet (HFSD)-induced obesity on cognitive performance in the fear conditioning task in mice and explored a possible beneficial effect of 6-shogaol (6S), an active constituent of ginger, in this model. Chronic exposure to HFSD significantly enhanced body weight gain in C57BL/6N mice and this effect was prevented by treatment with 6S. HFSD + vehicle-treated mice presented with a selective deficit in cued fear memory, which was not observed in HFSD + 6S-treated animals. The findings of this study provide first evidence for a beneficial effect of 6S on HFSD-induced obesity and emotional memory deficit in mice.

Cognitive-Linguistic Performance and Quality of Life in Healthy Aging.

BACKGROUND/AIMS: This study investigated quality of life (QoL) in relation to cognitive-linguistic performance and demographic characteristics (age, education and gender) in a large cohort of cognitively healthy older adults. METHOD: A total of 578 Greek-Cypriots aged 60-91 years were recruited from the Neurocognitive Study on Aging. Of those, 395 healthy participants (171 males and 224 females) who met all study criteria were retained. They completed measures of executive functioning, working memory, receptive vocabulary and confrontational naming in addition to the WHOQOL-BREF (brief version of the WHO QoL questionnaire). RESULTS: There were modest but significant relationships between executive functioning, working memory, vocabulary measures and the WHOQOL-BREF (p < 0.01). MANOVA yielded significant gender and education effects on QoL. Sequential stepwise regression confirmed that gender, depression scores and years of education made significant contributions to predicting the total score on WHOQOL-BREF and accounted for 31% of the variance (R² = 0.310). CONCLUSION: Self-reports of QoL remain stable in older adulthood. Demographic variables such as gender and years of education affected several domains of QoL, and, along with depression symptomatology, accounted for a significant part of the WHOQOL-BREF variance. Cognitive-linguistic measures correlated on the physical and psychological health domains of the WHOQOL-BREF in healthy older adults.