Social isolation stress and chronic glutathione deficiency have a common effect on the glutamine-to-glutamate ratio and myo-inositol concentration in the mouse frontal cortex.

Environmental stress can interact with genetic predisposition to increase the risk of developing psychopathology. In this work, we tested the hypothesis that social isolation stress interacts with impaired glutathione synthesis and have cumulative effects on the neurochemical profile of the frontal cortex. A mouse model with chronic glutathione deficit induced by knockout (-/-) of the glutamate-cysteine ligase modulatory subunit (Gclm) was exposed to social isolation stress from weaning to post-natal day 65. Using magnetic resonance methods at high-field (14.1 T), we analysed the neurochemical profile in the frontal cortex, brain size and ventricular volume of adult animals. Glutathione deficit was accompanied by elevated concentrations of N-acetylaspartate, alanine, and glutamine, as well as the ratio of glutamine-to-glutamate (Gln/Glu), and by a reduction in levels of myo-inositol and choline-containing compounds in the frontal cortex of -/- animals with respect to wild-type littermates. Although there was no significant interaction between social isolation stress and glutathione deficiency, mice reared in isolation displayed lower myo-inositol concentration (-8.4%, p < 0.05) and larger Gln/Glu (+7.6%, p < 0.05), relative to those in group housing. Furthermore, glutathione deficiency caused a reduction in whole brain volume and enlargement of ventricles, but social isolation had no effect on these parameters. We conclude that social isolation caused neurochemical alterations that may add to those associated to impaired glutathione synthesis

Impact of Caffeine Consumption on Type 2 Diabetes-Induced Spatial Memory Impairment and Neurochemical Alterations in the Hippocampus.

Diabetes affects the morphology and plasticity of the hippocampus, and leads to learning and memory deficits. Caffeine has been proposed to prevent memory impairment upon multiple chronic disorders with neurological involvement. We tested whether long-term caffeine consumption prevents type 2 diabetes (T2D)-induced spatial memory impairment and hippocampal alterations, including synaptic degeneration, astrogliosis, and metabolic modifications. Control Wistar rats and Goto-Kakizaki (GK) rats that develop T2D were treated with caffeine (1 g/L in drinking water) for 4 months. Spatial memory was evaluated in a Y-maze. Hippocampal metabolic profile and glucose homeostasis were investigated by <sup>1</sup> H magnetic resonance spectroscopy. The density of neuronal, synaptic, and glial-specific markers was evaluated by Western blot analysis. GK rats displayed reduced Y-maze spontaneous alternation and a lower amplitude of hippocampal long-term potentiation when compared to controls, suggesting impaired hippocampal-dependent spatial memory. Diabetes did not impact the relation of hippocampal to plasma glucose concentrations, but altered the neurochemical profile of the hippocampus, such as increased in levels of the osmolites taurine (P < 0.001) and myo-inositol (P < 0.05). The diabetic hippocampus showed decreased density of the presynaptic proteins synaptophysin (P < 0.05) and SNAP25 (P < 0.05), suggesting synaptic degeneration, and increased GFAP (P < 0.001) and vimentin (P < 0.05) immunoreactivities that are indicative of astrogliosis. The effects of caffeine intake on hippocampal metabolism added to those of T2D, namely reducing myo-inositol levels (P < 0.001) and further increasing taurine levels (P < 0.05). Caffeine prevented T2D-induced alterations of GFAP, vimentin and SNAP25, and improved memory deficits. We conclude that caffeine consumption has beneficial effects counteracting alterations in the hippocampus of GK rats, leading to the improvement of T2D-associated memory impairment

Caffeine Consumption Prevents Diabetes-Induced Memory Impairment and Synaptotoxicity in the Hippocampus of NONcZNO10/LTJ Mice

Diabetic conditions are associated with modified brain function, namely with cognitive deficits, through largely undetermined processes. More than understanding the underlying mechanism, it is important to devise novel strategies to alleviate diabetes-induced cognitive deficits. Caffeine (a mixed antagonist of adenosine A1 and A2A receptors) emerges as a promising candidate since caffeine consumption reduces the risk of diabetes and effectively prevents memory deficits caused by different noxious stimuli. Thus, we took advantage of a novel animal model of type 2 diabetes to investigate the behavioural, neurochemical and morphological modifications present in the hippocampus and tested if caffeine consumption might prevent these changes. We used a model closely mimicking the human type 2 diabetes condition, NONcNZO10/LtJ mice, which become diabetic at 7–11 months when kept under an 11% fat diet. Caffeine (1 g/l) was applied in the drinking water from 7 months onwards. Diabetic mice displayed a decreased spontaneous alternation in the Y-maze accompanied by a decreased density of nerve terminal markers (synaptophysin, SNAP25), mainly glutamatergic (vesicular glutamate transporters), and increased astrogliosis (GFAP immunoreactivity) compared to their wild type littermates kept under the same diet. Furthermore, diabetic mice displayed up-regulated A2A receptors and down-regulated A1 receptors in the hippocampus. Caffeine consumption restored memory performance and abrogated the diabetes-induced loss of nerve terminals and astrogliosis. These results provide the first evidence that type 2 diabetic mice display a loss of nerve terminal markers and astrogliosis, which is associated with memory impairment; furthermore, caffeine consumption prevents synaptic dysfunction and astrogliosis as well as memory impairment in type 2 diabetes

Regional mitochondrial DNA and cell-type changes in post-mortem brains of non-diabetic Alzheimer’s disease are not present in diabetic Alzheimer’s disease

Background: Mitochondrial dysfunction is implicated in both diabetes and Alzheimer’s disease (AD), and diabetes also increases the risk of AD, however the combined impact of AD and diabetes on brain mitochondria is unknown. The purpose of this study was to test the hypothesis that the combination of both diabetes and AD exacerbates mitochondrial dysfunction. Methods: Post-mortem human brains (n=74), were used to determine mitochondrial DNA (mtDNA) content of cerebellum, frontal cortex and parietal cortex by quantifying absolute mtDNA copy number/cell using real time qPCR. mtDNA content was compared between diabetic and non-diabetic cases representing non-cognitively impaired controls (NCI), mildly cognitively impaired (MCI) and AD. A subset of parietal cortex samples was used to quantify mRNAs corresponding to cell types and mitochondrial function. Immune-staining of parietal cortex sections followed by semi-automated stereological assessment was performed to assess cell types. Results. Using mtDNA as an indicator of mitochondrial content, we observed significant regional variation, being highest in the parietal cortex, and lowest in the cerebellum. In the absence of diabetes, AD cases had decreased parietal cortex mtDNA, reduced MAP2 (neuronal) mRNA and increased GFAP (astrocyte) mRNA, relative to NCI. However, in the presence of both diabetes and AD, we did not observe these changes in the parietal cortex. Irrespective of cognitive status, all 3 brain regions in diabetic cases had significantly higher mtDNA than the non-diabetic cases. Conclusion. Our data show that the parietal cortex has the highest mitochondrial content but is also the most vulnerable to changes in AD, as shown by reduced mtDNA and neurones in this region. In contrast, when patients have both diabetes and AD, the AD associated parietal cortex changes are no longer seen, suggesting that the pathology observed in diabetic AD may be different to that seen in non-diabetic AD. The lack of clear functional changes in mitochondrial parameters in diabetic AD suggest that there may be different mechanisms contributing to cognitive impairment in diabetes and their impact on the respective disease neuro-pathologies remain to be fully understood

Increased hepatic fatty acid polyunsaturation precedes ectopic lipid deposition in the liver in adaptation to high-fat diets in mice.

We monitored hepatic lipid content (HLC) and fatty acid (FA) composition in the context of enhanced lipid handling induced by a metabolic high-fat diet (HFD) challenge and fasting. Mice received a control diet (10% of kilocalories from fat, N = 14) or an HFD (45% or 60% of kilocalories from fat, N = 10 and N = 16, respectively) for 26 weeks. A subset of five mice receiving an HFD (60% of kilocalories from fat) were switched to the control diet for the final 7 weeks. At nine time points, magnetic resonance spectroscopy was performed in vivo at 14.1 T, interleaved with glucose tolerance tests. Glucose intolerance promptly developed with the HFD, followed by a progressive increase of fasting insulin level, simultaneously with that of HLC. These metabolic defects were normalized by dietary reversal. HFD feeding immediately increased polyunsaturation of hepatic FA, before lipid accumulation. Fasting-induced changes in hepatic lipids (increased HLC and FA polyunsaturation, decreased FA monounsaturation) in control-diet-fed mice were not completely reproduced in HFD-fed mice, not even after dietary reversal. A similar adaptation of hepatic lipids to both fasting and an HFD suggests common mechanisms of lipid trafficking from adipose tissue to the liver. Altered hepatic lipid handling with fasting indicates imperfect metabolic recovery from HFD exposure