Murine Warriors or Worriers: The Saga of Comt1, B2 SINE Elements, and the Future of Translational Genetics

Catechol-O-methyltransferase (COMT) is an extremely well characterized enzyme that degrades catecholamines. A common coding polymorphism (rs4680; Val158Met) in the human COMT gene has been associated with a diverse array of phenotypes including personality, cognition, pain sensitivity, and risk for psychiatric disorders (Tunbridg

Dark Matter: Are Mice the Solution to Missing Heritability?

Genome-wide association studies (GWAS) in humans have identified hundreds of single nucleotide polymorphisms associated with complex traits, yet for most traits studied, the sum total of all these identified variants fail to explain a significant portion of the heritable variation. Reasons for this “missing heritability” are thought to include the existence of rare causative variants not captured by current genotyping arrays, structural variants that go undetected by existing technology, insufficient power to identify multi-gene interactions, small sample sizes, and the influence of environmental and epigenetic effects. As genotyping technologies have evolved it has become inexpensive and relatively straightforward to perform GWAS in mice. Mice offer a powerful tool for elucidating the genetic architecture of behavioral and physiological traits, and are complementary to human studies. Unlike F2 crosses of inbred strains, advanced intercross lines, heterogeneous stocks, outbred, and wild-caught mice have more rapid breakdown of linkage disequilibrium which allow for increasingly high resolution mapping. Because some of these populations are created using a small number of founder chromosomes they are not expected to harbor rare alleles. We discuss the differences between these mouse populations and examine their potential to overcome some of the pitfalls that have plagued human GWAS studies

Assessing the motivational effects of ethanol in mice using a discrete-trial current-intensity intracranial self-stimulation procedure.

BackgroundAlcohol (ethanol) produces both rewarding and aversive effects, and sensitivity to these effects is associated with risk for an alcohol use disorder (AUD). Measurement of these motivational effects in animal models is an important but challenging aspect of preclinical research into the neurobiology of AUD. Here, we evaluated whether a discrete-trial current-intensity intracranial self-stimulation (ICSS) procedure can be used to assess both reward-enhancing and aversive responses to ethanol in mice.MethodsMale and female C57BL/6J mice were surgically implanted with bipolar stimulating electrodes targeting the medial forebrain bundle and trained on a discrete-trial current-intensity ICSS procedure. Mice were tested for changes in response thresholds after various doses of ethanol (0.5 g/kg-1.75 g/kg; n = 5-7 per dose), using a Latin square design.ResultsA 1 g/kg dose of ethanol produced a significant reward-enhancement (i.e., lowered response thresholds), whereas a 1.75 g/kg dose produced an aversive effect (elevated response thresholds). Ethanol doses from 1 to 1.75 g/kg increased response latencies as compared to saline treatment.ConclusionsThe discrete-trial current-intensity ICSS procedure is an effective assay for measuring both reward-enhancing responses to ethanol as well as aversive responses in the same animal. This should prove to be a useful tool for assessing the effects of experimental manipulations on the motivational effects of ethanol in mice

Role of Glyoxalase 1 (Glo1) and methylglyoxal (MG) in behavior: recent advances and mechanistic insights

Glyoxalase 1 (GLO1) is a ubiquitous cellular enzyme that participates in the detoxification of methylglyoxal (MG), a cytotoxic byproduct of glycolysis that induces protein modification (advanced glycation end-products, AGEs), oxidative stress, and apoptosis. The concentration of MG is elevated under high-glucose conditions, such as diabetes. As such, GLO1 and MG have been implicated in the pathogenesis of diabetic complications. Recently, findings have linked GLO1 to numerous behavioral phenotypes, including psychiatric diseases (anxiety, depression, schizophrenia, and autism) and pain. This review highlights GLO1's association with behavioral phenotypes, describes recent discoveries that have elucidated the underlying mechanisms, and identifies opportunities for future research

QTL analysis of type I and type IIA fibers in soleus muscle in a cross between LG/J and SM/J mouse strains

Peer reviewedPublisher PD

Genome-wide association study in two cohorts from a multi-generational mouse advanced intercross line highlights the difficulty of replication due to study-specific heterogeneity

There has been extensive discussion of the Replication Crisis in many fields, including genome-wide association studies

Nociceptin attenuates the escalation of oxycodone self-administration by normalizing CeA-GABA transmission in highly addicted rats.

Approximately 25% of patients who are prescribed opioids for chronic pain misuse them, and 5 to 10% develop an opioid use disorder. Although the neurobiological target of opioids is well known, the molecular mechanisms that are responsible for the development of addiction-like behaviors in some but not all individuals are poorly known. To address this issue, we used a unique outbred rat population (heterogeneous stock) that better models the behavioral and genetic diversity that is found in humans. We characterized individual differences in addiction-like behaviors using an addiction index that incorporates the key criteria of opioid use disorder: escalated intake, highly motivated responding, and hyperalgesia. Using in vitro electrophysiological recordings in the central nucleus of the amygdala (CeA), we found that rats with high addiction-like behaviors (HA) exhibited a significant increase in γ-aminobutyric acid (GABA) transmission compared with rats with low addiction-like behaviors (LA) and naive rats. The superfusion of CeA slices with nociceptin/orphanin FQ peptide (N/OFQ; 500 nM), an endogenous opioid-like peptide, normalized GABA transmission in HA rats. Intra-CeA levels of N/OFQ were lower in HA rats than in LA rats. Intra-CeA infusions of N/OFQ (1 μg per site) reversed the escalation of oxycodone self-administration in HA rats but not in LA rats. These results demonstrate that the downregulation of N/OFQ levels in the CeA may be responsible for hyper-GABAergic tone in the CeA that is observed in individuals who develop addiction-like behaviors. Based on these results, we hypothesize that small molecules that target the N/OFQ system might be useful for the treatment of opioid use disorder

QTLRel: an R Package for Genome-wide Association Studies in which Relatedness is a Concern

BACKGROUND Existing software for quantitative trait mapping is either not able to model polygenic variation or does not allow incorporation of more than one genetic variance component. Improperly modeling the genetic relatedness among subjects can result in excessive false positives. We have developed an R package, QTLRel, to enable more flexible modeling of genetic relatedness as well as covariates and non-genetic variance components. RESULTS We have successfully used the package to analyze many datasets, including F₃₄ body weight data that contains 688 individuals genotyped at 3105 SNP markers and identified 11 QTL. It took 295 seconds to estimate variance components and 70 seconds to perform the genome scan on an Linux machine equipped with a 2.40GHz Intel(R) Core(TM)2 Quad CPU. CONCLUSIONS QTLRel provides a toolkit for genome-wide association studies that is capable of calculating genetic incidence matrices from pedigrees, estimating variance components, performing genome scans, incorporating interactive covariates and genetic and non-genetic variance components, as well as other functionalities such as multiple-QTL mapping and genome-wide epistasis.This project was supported by NIH grants R01DA021336, R01MH079103 and R21DA024845