Quantitative trait loci for sensitivity to ethanol intoxication in a C57BL/6J × 129S1/SvImJ inbred mouse cross

Individual variation in sensitivity to acute ethanol (EtOH) challenge is associated with alcohol drinking and is a predictor of alcohol abuse. Previous studies have shown that the C57BL/6J (B6) and 129S1/SvImJ (S1) inbred mouse strains differ in responses on certain measures of acute EtOH intoxication. To gain insight into genetic factors contributing to these differences, we performed quantitative trait locus (QTL) analysis of measures of EtOH-induced ataxia (accelerating rotarod), hypothermia, and loss of righting reflex (LORR) duration in a B6 × S1 F2 population. We confirmed that S1 showed greater EtOH-induced hypothermia (specifically at a high dose) and longer LORR compared to B6. QTL analysis revealed several additive and interacting loci for various phenotypes, as well as examples of genotype interactions with sex. QTLs for different EtOH phenotypes were largely non-overlapping, suggesting separable genetic influences on these behaviors. The most compelling main-effect QTLs were for hypothermia on chromosome 16 and for LORR on chromosomes 4 and 6. Several QTLs overlapped with loci repeatedly linked to EtOH drinking in previous mouse studies. The architecture of the traits we examined was complex but clearly amenable to dissection in future studies. Using integrative genomics strategies, plausible functional and positional candidates may be found. Uncovering candidate genes associated with variation in these phenotypes in this population could ultimately shed light on genetic factors underlying sensitivity to EtOH intoxication and risk for alcoholism in humans

Genetic Dissection of Acute Ethanol Responsive Gene Networks in Prefrontal Cortex: Functional and Mechanistic Implications

Background Individual differences in initial sensitivity to ethanol are strongly related to the heritable risk of alcoholism in humans. To elucidate key molecular networks that modulate ethanol sensitivity we performed the first systems genetics analysis of ethanol-responsive gene expression in brain regions of the mesocorticolimbic reward circuit (prefrontal cortex, nucleus accumbens, and ventral midbrain) across a highly diverse family of 27 isogenic mouse strains (BXD panel) before and after treatment with ethanol. Results Acute ethanol altered the expression of ~2,750 genes in one or more regions and 400 transcripts were jointly modulated in all three. Ethanol-responsive gene networks were extracted with a powerful graph theoretical method that efficiently summarized ethanol\u27s effects. These networks correlated with acute behavioral responses to ethanol and other drugs of abuse. As predicted, networks were heavily populated by genes controlling synaptic transmission and neuroplasticity. Several of the most densely interconnected network hubs, including Kcnma1 and Gsk3β, are known to influence behavioral or physiological responses to ethanol, validating our overall approach. Other major hub genes like Grm3, Pten and Nrg3 represent novel targets of ethanol effects. Networks were under strong genetic control by variants that we mapped to a small number of chromosomal loci. Using a novel combination of genetic, bioinformatic and network-based approaches, we identified high priority cis-regulatory candidate genes, including Scn1b,Gria1, Sncb and Nell2. Conclusions The ethanol-responsive gene networks identified here represent a previously uncharacterized intermediate phenotype between DNA variation and ethanol sensitivity in mice. Networks involved in synaptic transmission were strongly regulated by ethanol and could contribute to behavioral plasticity seen with chronic ethanol. Our novel finding that hub genes and a small number of loci exert major influence over the ethanol response of gene networks could have important implications for future studies regarding the mechanisms and treatment of alcohol use disorders

search of a better mouse test

Abstract: To elucidate pathways from specific genes to complex behaviors, assays of mouse behavior need to be valid, reliable and replicable across laboratories. Behavioral assays are proving to be as complex as the intricate cellular and molecular pathways that are the main interest of many mouse users. There is no perfect behavioral test, but we propose some aphorisms to stimulate discussion that is necessary for continued progress in task development. For maximal utility, a behavioral test should yield valid data for most of the commonly used inbred mouse strains. Tests of simple, ubiquitous behaviors usually yield meaningful data for most mice, especially when based on automated scoring or on simple physical measures that are likely to be replicable across laboratories. Extreme test scores resulting from non-performance on a task can inflate the apparent reliability of a test, and devious adaptations to a task can undermine its validity. The optimal apparatus configuration for certain genetic or pharmacological analyses might depend on the particular laboratory environment. Despite our best efforts, the mice will continue to win some innings. Article: Many genetic mutations in mice alter the nervous system and thereby change behavior. Consequently, mouse behavior is a phenotype of considerable interest in neuroscience, and comprehensive assessment of a mutation must involve assays of behavior. Although numerous tests of behavior are available [1], we believe that some of the popular tests can be made more reliable, valid and replicable across laboratories. Here, we discuss criteria for building better mouse tests. Behavioral testing should be viewed as a work in progress -an enterprise made more challenging by the daunting complexity of behavior and its sensitivity to factors that are quite subtl

Tracking consolidant penetration into fossil bone using neutron radiography

In the conservation of fragile fossil bone material, impregnation by solvent-borne consolidant is often required. Understanding the mode of penetration of consolidants into fossil bone is of crucial importance. It is governed by a variety of factors; neutron imaging is a powerful tool to monitor and visualise this penetration (non-destructively). The consolidation of a vertebrate fossil from the Maastrichtian of the southeast Netherlands was imaged at the High Flux Reactor facility at Petten, the Netherlands. The analysis shows current conservation practice to result in a sufficiently deep and isotropic penetration.JRC.F.4-Nuclear Reactor Integrity Assessment and Knowledge Managemen

Tracking consolidant penetration into fossil bone using neutron radiography

In the conservation of fragile fossil bone material impregnation by solvent-borne consolidant is often required. Understanding the mode of penetration of consolidants into fossil bone is of crucial importance. It is governed by a variety of factors; neutron imaging is a powerful tool to monitor and visualise this penetration (non-destructively). The consolidation of a vertebrate fossil from the Maastrichtian of the southeast Netherlands was imaged at the High Flux Reactor facility at Petten, the Netherlands. The analysis shows current conservation practice to result in a sufficiently deep and isotropic penetration

Tetracycline derivatives reduce binge alcohol consumption in High Drinking in the Dark mice

Alcohol use disorders (AUDs) are prevalent, and are characterized by binge-like drinking, defined by patterns of focused drinking where dosages ingested in 2–4 ​h reach intoxicating blood alcohol levels (BALs). Current medications are few and compliance with the relatively rare prescribed usage is low. Hence, novel and more effective medications are needed. We developed a mouse model of genetic risk for binge drinking (HDID: High Drinking in the Dark mice) by selectively breeding for high BALs after binge drinking. A transcriptional analysis of HDID brain tissue with RNA-Seq implicated neuroinflammatory mechanisms, and, more specifically extracellular matrix genes, including those encoding matrix metalloproteinases (MMPs). Prior experiments from other groups have shown that the tetracycline derivatives doxycycline, minocycline, and tigecycline, reduce binge drinking in inbred C57BL/6J mice. We tested these three compounds in female and male HDID mice and found that all three reduced DID and BAL. They had drug-specific effects on intake of water or saccharin in the DID assay. Thus, our results show that the effectiveness of synthetic tetracycline derivatives as potential therapeutic agents for AUDs is not limited to the single C57BL/6J genotype previously targeted, but extends to a mouse model of a population at high risk for AUDs