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

Visualizing Topical Quotations Over Time to Understand News Discourse

We present the PICTOR browser, a visualization designed to facilitate the analysis of quotations about userspecified topics in large collections of news text. PICTOR focuses on quotations because they are a major vehicle of communication in the news genre. It extracts quotes from articles that match a user’s text query, and groups these quotes into “threads” that illustrate the development of subtopics over time. It allows users to rapidly explore the space of relevant quotes by viewing their content and speakers, to examine the contexts in which quotes appear, and to tune how threads are constructed. We offer two case studies demonstrating how PICTOR can support a richer understanding of news events.</p