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Chronic alcohol consumption from adolescence-to-adulthood in mice — Effect on gene expression in the hypothalamus

ABSTRACT: We employed a paradigm of chronic moderate alcohol intake from adolescence-to-adulthood in mice, and analyzed the alcohol effect on both behavioral and hypothalamic gene expression changes.

ORGANISM(S): Mus musculus

PROVIDER: GSE42770 | GEO | 2013/06/30

SECONDARY ACCESSION(S): PRJNA183191

REPOSITORIES: GEO

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Project description:The crucial role of nutrition for cerebral health and the impact of dietary habits on brain structure and function have been long far recognized. To date a major health concern is associated with the increased consumption of fructose as added sugar in many types of drinks and processed foods, especially among young people. High-fructose intake has been pointed out as the possible culprit for the raised incidence of chronic diseases, such as obesity, cardiovascular disease, nonalcoholic fatty liver disease, and type 2 diabete. Further, it has been reported that high-fructose intake is associated with the over-activation of its cerebral metabolism, which was proposed to negatively impact on whole brain physiology and cognitive function. Notably, we previously reported that short-term fructose-rich diet induces mitochondrial dysfunction, oxidative stress, and neuroinflammation in hippocampus of young rats, as well as the imbalance of redox homeostasis, autophagic mechanisms and representation of synaptic markers in frontal cortex of both adult and young rats. Animal studies have also revealed the damaging effect of high-fructose diets on hippocampal functions during periods of neurocognitive development, such as childhood and adolescence. Hypothalamus plays a crucial role in maintaining whole body homeostasis. Long-term fructose overfeeding was reported to alter hypothalamic-pituitary-adrenal axis, leading to elevations in glucocorticoids in peri-adolescent rats [22]. Further, fructose overconsumption was associated with impairment of hypothalamic insulin signalling, oxidative stress and inflammation , and it was proposed that fructose-driven perturbations of hypothalamic function may compromise the potential for satiety, thereby increasing the prospect of developing obesity. Data currently available on hypothalamic dysfunctions related to a high-fructose diet essentially refer to the effects of long-term sugar feeding, while information on corresponding alterations associated with a short-term dietary treatment, particularly in the critical period of adolescence, is still lacking. Due to complexity and multiplicity of hypothalamic functions, there is also the need for a holistic characterization aimed at unveiling the general picture of hypothalamic dysfunctions associated with a high-fructose diet. To fill this gap, we investigated adolescent rats fed a fructose-rich or control diet, for 3 weeks. To verify whether the fructose-driven changes are rescued after the switch to a control diet, half of the rats from both animal groups were then fed a control diet for additional 3 weeks until young adulthood phase. Quantitative proteomics on hypothalamic extracts of all animal groups was used to identify molecular alterations triggered by fructose-rich diet and to obtain insights into the relationship between sugar feeding and possible dysfunctions of hypothalamus.

Project description:Adolescent binge alcohol exposure has been previously shown to have long-lasting effects on the expression of hypothalamic genes that regulate the stress response, even in the absence of subsequent adult alcohol exposure. Those data suggested that alcohol can induce permanent gene expression changes, potentially through epigenetic modifications. Importantly, epigenetic modifications can be transmitted to future generations therefore, in these studies we investigated the effects of adolescent binge alcohol exposure on hypothalamic gene expression patterns in the F1 generation offspring. It has been well documented that maternal alcohol exposure during fetal development can have devastating neurological consequences. However, less is known about the consequences of maternal and/or paternal alcohol exposure outside of the gestational time frame. Here, we exposed adolescent male and female rats to a repeated binge EtOH exposure paradigm and then mated them in adulthood. Hypothalamic samples were taken from the offspring of these animals at postnatal day (PND) 7 and subjected to a genome-wide microarray analysis followed by qRT-PCR for selected genes. Importantly, the parents were not intoxicated at the time of mating and were not exposed to EtOH at any time during gestation therefore, the offspring were never directly exposed to EtOH. Our results showed that the offspring of alcohol-exposed parents had significant differences in the expression of hypothalamic genes that mediate neurogenesis and synaptic plasticity during neurodevelopment, genes important for directing chromatin remodeling, posttranslational modifications or transcription regulation, as well as genes involved in regulation of obesity and reproductive function. These data demonstrate that repeated binge alcohol exposure during pubertal development can potentially have detrimental effects on future offspring even in the absence of direct fetal alcohol exposure. Male and female Wistar rats were purchased from Charles River Laboratories (Wilmington, MA) at weaning (postnatal day (PND) 23) and allowed to acclimate for 7 days after arrival. Animals were handled for 5 min./once/day beginning at PND 30. Pubertal EtOH exposure began on PND 37, which is defined as peri-puberty. Animals were undisturbed following the first exposure of our binge EtOH exposure paradigm until PND 68 (late puberty/early adult) at which time they received a second exposure to the same treatment paradigm. During the duration of the experiment, males and females were separately housed in pairs on a 12:12 light/dark cycle with lights on at 0700 h with food and water available ad libitum. Binge Exposure Paradigm and Treatment Design. Rats were handled 5min./once/day for 7 d prior to treatment to control for nonspecific stress responses. At 37 d, animals were given 3 g/kg EtOH (20% v/v in tap water; N = 3/sex), or tap water alone (N = 3/sex), once/day via oral gavage at 10:00 AM to avoid disrupting normal feeding patterns. This process was repeated according to the following schedule for a total duration of 8 consecutive days: 3 d EtOH, 2 d tap water, 3 d EtOH. Control animals were given tap water alone once/day for 8 consecutive days. Our previous studies showed that this repeated binge-pattern EtOH paradigm does not affect body weight/growth curves and consistently results in blood alcohol concentrations (BAC) of 150-180 mg/dl in males and 210-240 mg/dl in females. We and others have previously used this paradigm as a model for the pattern of binge alcohol consumption observed in adolescents and BAC achieved are similar to those observed in humans following a binge drinking episode . After peri-pubertal treatments, animals were left undisturbed in their home cage until PND 68 when each group was again exposed to their respective treatment (i.e. control or binge EtOH. We waited 24 hours after the last dose of EtOH to ensure that blood alcohol concentrations in the parents were undetectable at the time of mating (data not shown). Animals were grouped into mating pairs: binge male + binge female (N = 3 pairs); water male + water female (N = 3 pairs). All of the females gave birth to 12-16 pups approximately 28 d after being housed with a male, indicating that conception took place approximately 6 d after pairing; therefore, the pups were never directly exposed to alcohol at any time. At PND 7 pups were deeply anesthetized on ice and sacrificed. Brains were rapidly removed, the hypothalamus microdissected on ice, and then stored in -80ºC until further processing for a genome-wide analysis on hypothalamic total RNA samples using a chip-based microarray (Southern California Genotyping Consortium, SCGC, Illumina Rat Ref-12). The PND 7 time point was chosen because the extent of rat neurodevelopment at PND 7 is roughly equivalent to that of a human infant at birth

Project description:Action of alcohol on synaptic mRNA in the amygdala of mice Chronic alcohol consumption induces changes in gene expression, causing persistent long-term neuro-adaptations and the remodeling of synaptic structures. These alcohol-induced synaptic changes may rely specifically on the local translation of mRNAs in the synaptic compartments of the cell. We profiled the transcriptome from synaptoneurosomes (SN) and paired total homogenates (TH) of amygdala to analyze the synaptic adaptations induced by chronic voluntary alcohol consumption in mice. In the SN both the number of alcohol-responsive mRNAs and the magnitude of fold-change were greater than in the TH. Accordingly, the SN detected many genes with coordinated patterns of expression producing a highly connected mRNA network in gene co-expression analysis. The greater sensitivity of the SN preparation allowed for improved cell-type specificity analysis, revealing an up-regulation of alcohol-responsive astrocytic and microglial modules that correlated with alcohol consumption. Alcohol was found to induce changes in the SN functionally important biological pathways, including long-term potentiation, long-term potentiation depression, glutamate pathway, neuro-immune, RNA-processing and translational machineries and provided overlap with changes seen in human alcoholic brain. Transposable elements were responsive to alcohol and found in the down-regulated neuronal mRNA module, which may underlie some of the coordinated gene expression changes associated with alcohol. We provide evidence that enrichment of synaptic components reveals a more intricate network of coordinated gene expression. Increased resolution captures the molecular effects of synaptic manipulations and provides an improved technique for identifying therapeutic targets for alcohol abuse. Synaptoneurosomes (SN) and Paired total homogenates (TH) were prepared from the same homogenate. 42 microarrays were used in total for the alcohol-control analysis (8 alcohol treated mice and 13 controls), 21 SN and 21 paired TH. 2 TH (control) samples were found outliers and were removed from the analysis. For the SN vs. TH analysis, the 2 TH samples found outliers were removed with the 2 paired SN samples.