scholarly journals Acamprosate-responsive brain sites for suppression of ethanol intake and preference

2011 ◽  
Vol 301 (4) ◽  
pp. R1032-R1043 ◽  
Author(s):  
Allison Brager ◽  
Rebecca A. Prosser ◽  
J. David Glass
Keyword(s):  
Alcohol Intake ◽  
Free Choice ◽  
Clock Gene ◽  
Brain Regions ◽  
Ethanol Intake ◽  
Mutant Mice ◽  
Wild Type ◽  
Circadian Clock Gene ◽  
Recovering Alcoholics ◽  
Brain Reward

Acamprosate suppresses alcohol intake and craving in recovering alcoholics; however, the central sites of its action are unclear. To approach this question, brain regions responsive to acamprosate were mapped using acamprosate microimplants targeted to brain reward and circadian areas implicated in alcohol dependence. mPer2 mutant mice with nonfunctional mPer2, a circadian clock gene that gates endogenous timekeeping, were included, owing to their high levels of ethanol intake and preference. Male wild-type (WT) and mPer2 mutant mice received free-choice (15%) ethanol/water for 3 wk. The ethanol was withdrawn for 3 wk and then reintroduced to facilitate relapse. Four days before ethanol reintroduction, mice received bilateral blank or acamprosate-containing microimplants releasing ∼50 ng/day into reward [ventral tegmental (VTA), peduculopontine tegmentum (PPT), and nucleus accumbens (NA)] and circadian [intergeniculate leaflet (IGL) and suprachiasmatic nucleus (SCN)] areas. The hippocampus was also targeted. Circadian locomotor activity was measured throughout. Ethanol intake and preference were greater in mPer2 mutants than in wild-type (WT) mice (27 g·kg−1·day−1 vs. 13 g·kg−1·day−1 and 70% vs. 50%, respectively; both, P < 0.05). In WTs, acamprosate in all areas, except hippocampus, suppressed ethanol intake and preference (by 40–60%) during ethanol reintroduction. In mPer2 mutants, acamprosate in the VTA, PPT, and SCN suppressed ethanol intake and preference by 20–30%. These data are evidence that acamprosate's suppression of ethanol intake and preference are manifest through actions within major reward and circadian sites.

scholarly journals The clock gene Period1 regulates innate routine behaviour in mice

2014 ◽  
Vol 281 (1781) ◽  
pp. 20140034 ◽  
Author(s):  
Philipp Bechstein ◽  
Nils-Jörn Rehbach ◽  
Gowzekan Yuhasingham ◽  
Christoph Schürmann ◽  
Melanie Göpfert ◽  
...  
Keyword(s):  
Clock Gene ◽  
Memory Deficits ◽  
Nest Building ◽  
Partner Choice ◽  
Mutant Mice ◽  
Spatial Learning And Memory ◽  
Wild Type ◽  
Circadian Clock Gene ◽  
Deficient Mice

Laboratory mice are well capable of performing innate routine behaviour programmes necessary for courtship, nest-building and exploratory activities although housed for decades in animal facilities. We found that in mice inactivation of the clock gene Period1 profoundly changes innate routine behaviour programmes like those necessary for courtship, nest building, exploration and learning. These results in wild-type and Period1 mutant mice, together with earlier findings on courtship behaviour in wild-type and period -mutant Drosophila melanogaster , suggest a conserved role of Period- genes on innate routine behaviour. Additionally, both per -mutant flies and Period1 -mutant mice display spatial learning and memory deficits. The profound influence of Period1 on routine behaviour programmes in mice, including female partner choice, may be independent of its function as a circadian clock gene, since Period1 -deficient mice display normal circadian behaviour.

scholarly journals Diurnal Amplitudes of Arterial Pressure and Heart Rate Are Dampened in Clock Mutant Mice and Adrenalectomized Mice

Endocrinology ◽  
2008 ◽  
Vol 149 (7) ◽  
pp. 3576-3580 ◽  
Author(s):  
Hiroyoshi Sei ◽  
Katsutaka Oishi ◽  
Sachiko Chikahisa ◽  
Kazuyoshi Kitaoka ◽  
Eiji Takeda ◽  
...  
Keyword(s):  
Heart Rate ◽  
Arterial Pressure ◽  
Clock Gene ◽  
Clock Genes ◽  
Plasma Aldosterone ◽  
Mutant Mice ◽  
Wild Type ◽  
Clock Mutant ◽  
Wild Type Control

Arterial pressure (AP), heart rate (HR), and cardiovascular diseases, including ischemic heart attack and cerebrovascular accident, show diurnal variation. Evidence that circadian-related genes contribute to cardiovascular control has been accumulated. In this study, we measured the AP and HR of Clock mutant mice on the Jcl/ICR background to determine the role of the Clock gene in cardiovascular function. Mice with mutated Clock genes had a dampened diurnal rhythm of AP and HR, compared with wild-type control mice, and this difference disappeared after adrenalectomy. The diurnal acrophase in both mean arterial pressure and HR was delayed significantly in Clock mutant mice, compared with wild-type mice, and this difference remained after adrenalectomy. Clock mutant mice had a lower concentration of plasma aldosterone, compared with wild-type mice. Our data suggest that the adrenal gland is involved in the diurnal amplitude, but not the acrophase, of AP and HR, and that the function of the Clock gene may be related to the nondipping type of AP elevation.

Circadian Clock Gene Expression in Brain Regions of Alzheimer ’s Disease Patients and Control Subjects

2011 ◽  
Vol 26 (2) ◽  
pp. 160-170 ◽  
Author(s):  
Nicolas Cermakian ◽  
Elaine Waddington Lamont ◽  
Philippe Boudreau ◽  
Diane B. Boivin
Keyword(s):  
Gene Expression ◽  
Circadian Clock ◽  
Clock Gene ◽  
Brain Regions ◽  
Circadian Clock Gene ◽  
Control Subjects ◽  
Clock Gene Expression ◽  
And Control

scholarly journals gcProfileMakeR: An R Package for Automatic Classification of Constitutive and Non-Constitutive Metabolites

Metabolites ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 211
Author(s):  
Fernando Perez-Sanz ◽  
Victoria Ruiz-Hernández ◽  
Marta I. Terry ◽  
Sara Arce-Gallego ◽  
Julia Weiss ◽  
...  
Keyword(s):  
Clock Gene ◽  
Floral Scent ◽  
R Package ◽  
Large Datasets ◽  
Wild Type ◽  
Circadian Clock Gene ◽  
Automatic Data ◽  
The Third ◽  
Automatic Data Analysis

Metabolomes comprise constitutive and non-constitutive metabolites produced due to physiological, genetic or environmental effects. However, finding constitutive metabolites and non-constitutive metabolites in large datasets is technically challenging. We developed gcProfileMakeR, an R package using standard Excel output files from an Agilent Chemstation GC-MS for automatic data analysis using CAS numbers. gcProfileMakeR has two filters for data preprocessing removing contaminants and low-quality peaks. The first function NormalizeWithinFiles, samples assigning retention times to CAS. The second function NormalizeBetweenFiles, reaches a consensus between files where compounds in close retention times are grouped together. The third function getGroups, establishes what is considered as Constitutive Profile, Non-constitutive by Frequency i.e., not present in all samples and Non-constitutive by Quality. Results can be plotted with the plotGroup function. We used it to analyse floral scent emissions in four snapdragon genotypes. These included a wild type, Deficiens nicotianoides and compacta affecting floral identity and RNAi:AmLHY targeting a circadian clock gene. We identified differences in scent constitutive and non-constitutive profiles as well as in timing of emission. gcProfileMakeR is a very useful tool to define constitutive and non-constitutive scent profiles. It also allows to analyse genotypes and circadian datasets to identify differing metabolites.

scholarly journals Circadian- and sex-dependent increases in intravenous cocaine self-administration in Npas2 mutant mice

2019 ◽  
Author(s):  
Lauren M. DePoy ◽  
Darius D. Becker-Krail ◽  
Wei Zong ◽  
Kaitlyn Petersen ◽  
Neha M. Shah ◽  
...  
Keyword(s):  
Substance Use ◽  
Drugs Of Abuse ◽  
Active Phase ◽  
Brain Regions ◽  
Mutant Mice ◽  
Wild Type ◽  
Self Administration ◽  
Circadian Transcription ◽  
Intravenous Cocaine

AbstractSubstance use disorder is associated with disruptions in circadian rhythms. The circadian transcription factor neuronal PAS domain protein 2 (NPAS2) is enriched in reward-related brain regions and regulates reward, but its role in substance use is unclear. To examine the role of NPAS2 in drug taking, we measured intravenous cocaine self-administration (acquisition, dose-response, progressive ratio, extinction, cue-induced reinstatement) in wild-type (WT) and Npas2 mutant mice at different times of day. In the light (inactive) phase, cocaine reinforcement was increased in all Npas2 mutants, while self-administration and motivation were affected sex-dependently. These sex differences were amplified during the dark (active) phase with Npas2 mutation increasing self-administration, reinforcement, motivation, extinction responding and reinstatement in females, but only reinforcement in males. To determine whether circulating hormones are driving these sex differences, we ovariectomized WT and Npas2 mutant females and confirmed that unlike sham controls, ovariectomized mutant mice showed no increase in self-administration. To identify whether striatal brain regions are activated in Npas2 mutant females, we measured cocaine-induced ΔFosB expression. Relative to WT, ΔFosB expression was increased in D1+ neurons in the nucleus accumbens core and dorsolateral striatum in Npas2 mutant females after dark phase self-administration. We also identified potential target genes that may underlie the behavioral responses to cocaine in Npas2 mutant females. These results suggest NPAS2 regulates reward and activity in specific striatal regions in a sex and time of day specific manner. Striatal activation could be augmented by circulating sex hormones, leading to an increased effect of Npas2 mutation in females.Significance StatementCircadian disruptions are a common symptom of substance use disorders and chronic exposure to drugs of abuse alters circadian rhythms, which may contribute to subsequent substance use. Diurnal rhythms are commonly found in behavioral responses to drugs of abuse with drug sensitivity and motivation peaking during the dark (active) phase in nocturnal rodents. Emerging evidence links disrupted circadian genes to substance use vulnerability and drug-induced alterations to these genes may augment drug-seeking. The circadian transcription factor NPAS2 is enriched in reward-related brain regions and regulates reward, but its role in substance use is unclear. To examine the role of NPAS2 in drug taking, we measured intravenous cocaine self-administration in wild-type and Npas2 mutant mice at different times of day.

scholarly journals Alopecia in Harlequin mutant mice is associated with reduced AIF protein levels and expression of retroviral elements

2020 ◽  
Author(s):  
Maik Hintze ◽  
Sebastian Griesing ◽  
Marion Michels ◽  
Birgit Blanck ◽  
Lena Wischhof ◽  
...  
Keyword(s):  
Hair Growth ◽  
Transcriptional Regulators ◽  
Mutant Mice ◽  
Wild Type ◽  
Protein Levels ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Keratinocyte Cell ◽  
Apoptosis Inducing Factor ◽  
Hair Cortex

AbstractWe investigated the contribution of apoptosis-inducing factor (AIF), a key regulator of mitochondrial biogenesis, in supporting hair growth. We report that pelage abnormalities developed during hair follicle (HF) morphogenesis in Harlequin (Hq) mutant mice. Fragility of the hair cortex was associated with decreased expression of genes encoding structural hair proteins, though key transcriptional regulators of HF development were expressed at normal levels. Notably, Aifm1 (R200 del) knockin males and Aifm1(R200 del)/Hq females showed minor hair defects, despite substantially reduced AIF levels. Furthermore, we cloned the integrated ecotropic provirus of the Aifm1Hq allele. We found that its overexpression in wild-type keratinocyte cell lines led to down-regulation of HF-specific Krt84 and Krtap3-3 genes without altering Aifm1 or epidermal Krt5 expression. Together, our findings imply that pelage paucity in Hq mutant mice is mechanistically linked to severe AIF deficiency and is associated with the expression of retroviral elements that might potentially influence the transcriptional regulation of structural hair proteins.

scholarly journals Moderate alcohol intake promotes pancreatic ductal adenocarcinoma development in mice expressing oncogenic Kras

2020 ◽  
Vol 318 (2) ◽  
pp. G265-G276
Author(s):  
Kinji Asahina ◽  
Steven Balog ◽  
Edward Hwang ◽  
Eugene Moon ◽  
Emily Wan ◽  
...  
Keyword(s):  
Risk Factors ◽  
Risk Factor ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Alcohol Drinking ◽  
Calcium Binding ◽  
Alcohol Intake ◽  
Western Diet ◽  
Mutant Mice ◽  
Ductal Adenocarcinoma ◽  
Moderate Alcohol Intake

Kras mutations are associated with pancreatic ductal adenocarcinoma (PDAC). Although tobacco smoking, pancreatitis, and obesity are known environmental risk factors for PDAC, the contribution of moderate alcohol intake to PDAC remains elusive. In the present study, we tested whether a combination of risk factors or moderate alcohol intake induces PDAC development in mice. Control Pdx1Cre and Pdx1Cre;LSL- KrasG12D mutant mice were fed a Western alcohol diet containing high levels of cholesterol and saturated fat, 3.5% alcohol, and lipopolysaccharide for 5 mo. In addition, mice were treated with cerulein, for induction of pancreatitis, and nicotine every month. Treatment with all of these risk factors promoted development of advanced pancreatic neoplasia and PDAC in the Pdx1Cre;LSL- KrasG12D mice but not in the control Pdx1Cre mice. Moderate alcohol intake or Western diet feeding also significantly promoted advanced neoplasia and PDAC development in Pdx1Cre;LSL- KrasG12D mice compared with mice fed a regular chow. Alcohol, but not Western diet, increased tumor development in the liver in the Pdx1Cre;LSL- KrasG12D mice, but its origin remained elusive due to leakiness of Pdx1Cre in hepatocytes. RNA-seq analysis revealed that alcohol feeding increases expression of markers for tumors ( Epcam, Krt19, Prom1, Wt1, and Wwtr1), stroma ( Dcn, Fn1, and Tnc), and cytokines ( Tgfb1 and Tnf) and decreases expression of Fgf21 and Il6 in the pancreatic tumor tissues. Immunostaining showed heterogeneous expression of nephronectin, S100 calcium-binding protein A6, and vascular cell adhesion molecule 1 in pancreatic tumors surrounded by podoplanin-positive stromal cells. Our data indicate that moderate alcohol drinking is a risk factor for development of PDAC. NEW & NOTEWORTHY Heavy alcohol intake has been suspected to be a risk factor of pancreatic ductal adenocarcinoma (PDAC) in humans. However, the contribution of moderate alcohol intake to PDAC development remains elusive. In the present study, we experimentally show that moderate alcohol feeding significantly induces advanced stages of pancreatic intraepithelial neoplasia development and invasive PDAC in Pdx1Cre;LSL- KrasG12D mutant mice. Our data indicate that moderate alcohol drinking is a risk factor for PDAC.

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