The role of the type 7 adenylyl cyclase isoform in alcohol use disorder and depression.

The translation of extracellular signals to intracellular responses involves a number of signal transduction molecules. A major component of this signal transducing function is adenylyl cyclase, which produces the intracellular "second messenger," cyclic AMP. What was initially considered as a single enzyme for cyclic AMP generation is now known to be a family of nine membrane-bound enzymes, and one cytosolic enzyme.

Evaluation and characterization of expression quantitative trait analysis methods in the Hybrid Rat Diversity Panel.

The Hybrid Rat Diversity Panel (HRDP) is a stable and well-characterized set of more than 90 inbred rat strains that can be leveraged for systems genetics approaches to understanding the genetic and genomic variation associated with complex disease. The HRDP exhibits substantial between-strain diversity while retaining substantial within-strain isogenicity, allowing for the precise mapping of genetic variation associated with complex phenotypes and providing statistical power to identify associated variants. In order to robustly identify associated genetic variants, it is important to account for the population structure induced by inbreeding.

Beyond Genes: Inclusion of Alternative Splicing and Alternative Polyadenylation to Assess the Genetic Architecture of Predisposition to Voluntary Alcohol Consumption in Brain of the HXB/BXH Recombinant Inbred Rat Panel.

Post transcriptional modifications of RNA are powerful mechanisms by which eukaryotes expand their genetic diversity. For instance, researchers estimate that most transcripts in humans undergo alternative splicing and alternative polyadenylation. These splicing events produce distinct RNA molecules, which in turn yield distinct protein isoforms and/or influence RNA stability, translation, nuclear export, and RNA/protein cellular localization.

Sex Differences in the Brain Transcriptome Related to Alcohol Effects and Alcohol Use Disorder.

There is compelling evidence that sex and gender have crucial roles in excessive alcohol (ethanol) consumption. Here, we review some of the data from the perspective of brain transcriptional differences between males and females, focusing on rodent animal models. A key emerging transcriptional feature is the role of neuroimmune processes.

Effects of acetate on cerebral blood flow, systemic inflammation, and behavior in alcohol use disorder.

Background: Alcohol use disorders (AUDs) are associated with altered regulation of physiological processes in the brain. Acetate, a metabolite of ethanol, has been implicated in several processes that are disrupted in AUDs including transcriptional regulation, metabolism, inflammation, and neurotransmission. To further understand the effects of acetate on brain function in AUDs, we investigated the effects of acetate on cerebral blood flow (CBF), systemic inflammatory cytokines, and behavior in AUD.

Controlling the "Opioid Epidemic": A Novel Chemical Entity (NCE) to Reduce or Supplant Opiate Use for Chronic Pain.

We report on the ongoing project "A Novel Therapeutic to Ameliorate Chronic Pain and Reduce Opiate Use." Over 100 million adults in the U.S.

A long non-coding RNA (Lrap) modulates brain gene expression and levels of alcohol consumption in rats.

LncRNAs are important regulators of quantitative and qualitative features of the transcriptome. We have used QTL and other statistical analyses to identify a gene coexpression module associated with alcohol consumption. The "hub gene" of this module, Lrap (Long non-coding RNA for alcohol preference), was an unannotated transcript resembling a lncRNA.

Alcoholic-Hepatitis, Links to Brain and Microbiome: Mechanisms, Clinical and Experimental Research.

The following review article presents clinical and experimental features of alcohol-induced liver disease (ALD). Basic aspects of alcohol metabolism leading to the development of liver hepatotoxicity are discussed. ALD includes fatty liver, acute alcoholic hepatitis with or without liver failure, alcoholic steatohepatitis (ASH) leading to fibrosis and cirrhosis, and hepatocellular cancer (HCC).

Effects of Alcohol and Acetate on Cerebral Blood Flow: A Pilot Study.

Background: Acute alcohol produces effects on cerebral metabolism and blood flow. Alcohol is converted to acetate, which serves as a source of energy for the brain and is an agonist at G protein-coupled receptors distributed in different cell types in the body including neurons. Acetate has been hypothesized to play a role in the cerebral blood flow (CBF) response after alcohol ingestion.

Networking in Biology: The Hybrid Rat Diversity Panel.

One of the most fruitful resources for systems genetic studies of nonhuman mammals is a panel of inbred strains that exhibits significant genetic diversity between strains but genetic stability (isogenicity) within strains. These characteristics allow for fine mapping of complex phenotypes (QTLs) and provide statistical power to identify loci which contribute nominally to the phenotype. This type of resource also allows the planning and performance of investigations using the same genetic backgrounds over several generations of the test animals.

Predictive modeling of miRNA-mediated predisposition to alcohol-related phenotypes in mouse.

Background: MicroRNAs (miRNAs) are small non-coding RNAs that bind messenger RNAs and promote their degradation or repress their translation. There is increasing evidence of miRNAs playing an important role in alcohol related disorders. However, the role of miRNAs as mediators of the genetic effect on alcohol phenotypes is not fully understood.

Unsupervised, Statistically Based Systems Biology Approach for Unraveling the Genetics of Complex Traits: A Demonstration with Ethanol Metabolism.

Background: A statistical pipeline was developed and used for determining candidate genes and candidate gene coexpression networks involved in 2 alcohol (i.e., ethanol [EtOH]) metabolism phenotypes, namely alcohol clearance and acetate area under the curve in a recombinant inbred (RI) (HXB/BXH) rat panel.

Voluntary exposure to a toxin: the genetic influence on ethanol consumption.

Ethyl alcohol is a toxin that, when consumed at high levels, produces organ damage and death. One way to prevent or ameliorate this damage in humans is to reduce the exposure of organs to alcohol by reducing alcohol ingestion. Both the propensity to consume large volumes of alcohol and the susceptibility of human organs to alcohol-induced damage exhibit a strong genetic influence.

Novel Molecule Exhibiting Selective Affinity for GABA Receptor Subtypes.

Aminoquinoline derivatives were evaluated against a panel of receptors/channels/transporters in radioligand binding experiments. One of these derivatives (DCUK-OEt) displayed micromolar affinity for brain γ-aminobutyric acid type A (GABA) receptors. DCUK-OEt was shown to be a positive allosteric modulator (PAM) of GABA currents with α1β2γ2, α1β3γ2, α5β3γ2 and α1β3δ GABA receptors, while having no significant PAM effect on αβ receptors or α1β1γ2, α1β2γ1, α4β3γ2 or α4β3δ receptors.

Using Baseline Transcriptional Connectomes in Rat to Identify Genetic Pathways Associated with Predisposition to Complex Traits.

Although rat is a critical model organism in preclinical medications development, its use in systems genetics studies remains sparse. The PhenoGen database and website contain detailed information on the qualitative and quantitative aspects of the rat brain, liver, heart, and brown adipose transcriptome. This database has been generated using the HXB/BXH recombinant inbred panel and is being expanded to a hybrid rat diversity panel that includes many common inbred strains as well.

Uncovering the liver's role in immunity through RNA co-expression networks.

Gene co-expression analysis has proven to be a powerful tool for ascertaining the organization of gene products into networks that are important for organ function. An organ, such as the liver, engages in a multitude of functions important for the survival of humans, rats, and other animals; these liver functions include energy metabolism, metabolism of xenobiotics, immune system function, and hormonal homeostasis. With the availability of organ-specific transcriptomes, we can now examine the role of RNA transcripts (both protein-coding and non-coding) in these functions.

A novel substituted aminoquinoline selectively targets voltage-sensitive sodium channel isoforms and NMDA receptor subtypes and alleviates chronic inflammatory and neuropathic pain.

Recent understanding of the systems that mediate complex disease states, has generated a search for molecules that simultaneously modulate more than one component of a pathologic pathway. Chronic pain syndromes are etiologically connected to functional changes (sensitization) in both peripheral sensory neurons and in the central nervous system (CNS). These functional changes involve modifications of a significant number of components of signal generating, signal transducing and signal propagating pathways.

The sequenced rat brain transcriptome--its use in identifying networks predisposing alcohol consumption.

Unlabelled: A quantitative genetic approach, which involves correlation of transcriptional networks with the phenotype in a recombinant inbred (RI) population and in selectively bred lines of rats, and determination of coinciding quantitative trait loci for gene expression and the trait of interest, has been applied in the present study. In this analysis, a novel approach was used that combined DNA-Seq data, data from brain exon array analysis of HXB/BXH RI rat strains and six pairs of rat lines selectively bred for high and low alcohol preference, and RNA-Seq data (including rat brain transcriptome reconstruction) to quantify transcript expression levels, generate co-expression modules and identify biological functions that contribute to the predisposition of consuming varying amounts of alcohol. A gene co-expression module was identified in the RI rat strains that contained both annotated and unannotated transcripts expressed in the brain, and was associated with alcohol consumption in the RI panel.

Influence of sex on genetic regulation of "drinking in the dark" alcohol consumption.

The ILSXISS (LXS) recombinant inbred (RI) panel of mice is a valuable resource for genetic mapping studies of complex traits, due to its genetic diversity and large number of strains. Male and female mice from this panel were used to investigate genetic influences on alcohol consumption in the "drinking in the dark" (DID) model. Male mice (38 strains) and female mice (36 strains) were given access to 20% ethanol during the early phase of their circadian dark cycle for four consecutive days.

The multiMiR R package and database: integration of microRNA-target interactions along with their disease and drug associations.

microRNAs (miRNAs) regulate expression by promoting degradation or repressing translation of target transcripts. miRNA target sites have been catalogued in databases based on experimental validation and computational prediction using various algorithms. Several online resources provide collections of multiple databases but need to be imported into other software, such as R, for processing, tabulation, graphing and computation.

Is the alcohol deprivation effect genetically mediated? Studies with HXB/BXH recombinant inbred rat strains.

Background: Two features of alcohol addiction that have been widely studied in animal models are relapse drinking following periods of alcohol abstinence and the escalation of alcohol consumption after chronic continuous or intermittent alcohol exposure. The genetic contribution to these phenotypes has not been systematically investigated.

Methods: HXB/BXH recombinant inbred (RI) rat strains were given access to alcohol sequentially as follows: alcohol (10%) as the only fluid for 1 week; alcohol (10%) and water in a 2-bottle choice paradigm for 7 weeks ("pre-alcohol deprivation effect [ADE] alcohol consumption"); 2 weeks of access to water only (alcohol deprivation); and 2 weeks of reaccess to 10% alcohol and water ("post-ADE alcohol consumption").

The neurobiology of alcohol consumption and alcoholism: an integrative history.

Studies of the neurobiological predisposition to consume alcohol (ethanol) and to transition to uncontrolled drinking behavior (alcoholism), as well as studies of the effects of alcohol on brain function, started a logarithmic growth phase after the repeal of the 18th Amendment to the United States Constitution. Although the early studies were primitive by current technological standards, they clearly demonstrated the effects of alcohol on brain structure and function, and by the end of the 20th century left little doubt that alcoholism is a "disease" of the brain. This review traces the history of developments in the understanding of ethanol's effects on the most prominent inhibitory and excitatory systems of brain (GABA and glutamate neurotransmission).

Whole brain and brain regional coexpression network interactions associated with predisposition to alcohol consumption.

To identify brain transcriptional networks that may predispose an animal to consume alcohol, we used weighted gene coexpression network analysis (WGCNA). Candidate coexpression modules are those with an eigengene expression level that correlates significantly with the level of alcohol consumption across a panel of BXD recombinant inbred mouse strains, and that share a genomic region that regulates the module transcript expression levels (mQTL) with a genomic region that regulates alcohol consumption (bQTL). To address a controversy regarding utility of gene expression profiles from whole brain, vs specific brain regions, as indicators of the relationship of gene expression to phenotype, we compared candidate coexpression modules from whole brain gene expression data (gathered with Affymetrix 430 v2 arrays in the Colorado laboratories) and from gene expression data from 6 brain regions (nucleus accumbens (NA); prefrontal cortex (PFC); ventral tegmental area (VTA); striatum (ST); hippocampus (HP); cerebellum (CB)) available from GeneNetwork.