Biology subjects

Bagley, J. R.

Publications and source records attributed to Bagley, J. R..

10 recordsLinked to original sources

bioRxiv2024

Differing genetics of saline and cocaine self administration in the hybrid mouse diversity panel

To identify genes that regulate the response to the potentially addictive drug cocaine, we performed a control experiment using genome-wide association studies (GWASs) and RNA-Seq of a panel of inbred and recombinant inbred mice undergoing intravenous self-administration of saline. A linear mixed model increased statistical power for analysis of the longitudinal behavioral data, which was acquired over 10 days. A total of 145 loci were identified for saline compared to 17 for the corresponding cocaine GWAS. Only one locus overlapped. Transcriptome-wide association studies (TWASs) using RNA-Seq data from the nucleus accumbens and medial frontal cortex identified 5031434O11Rik and Zfp60 as significant for saline self-administration. Two other genes, Myh4 and Npc1, were nominated based on proximity to loci for multiple endpoints or a cis locus regulating expression. All four genes have previously been implicated in locomotor activity, despite the absence of a strong relationship between saline taking and distance traveled in the open field. Our results indicate a distinct genetic basis for saline and cocaine self-administration, and suggest some common genes for saline self-administration and locomotor activity.

genetics↗

bioRxiv2022

Neuron Navigator 1 Regulates Learning, Memory, and the Response to Multiple Potentially Addictive Drugs

Genetic variation accounts for much of the risk for developing a substance use disorder (SUD). Inbred mouse strains exhibit substantial and heritable differences in the extent of voluntary cocaine intravenous self-administration (IVSA). Computational genetic analysis of IVSA data obtained from an inbred strain panel identified Nav1, a member of the neuron navigator family that regulates dendrite formation and axonal guidance, as a candidate gene. To test this hypothesis, we generated and characterized Nav1 knockout (KO) mice. Nav1 KO mice exhibited increased cocaine intake during IVSA testing. Surprisingly, Nav1 KO mice also displayed a reduced susceptibility to become opioid dependent or develop opioid-induced hyperalgesia after chronic morphine administration, and had impaired spatial learning/memory. Immunohistochemistry and electrophysiology studies revealed that inhibitory synapse density in the cortex of Nav1 KO mice was reduced, and excitatory synaptic transmission was increased in the Nav1 KO cortex and hippocampus. Transcriptomic analysis revealed that Nav1 KO mice had a marked increase in excitatory neurons in a deep cortical layer. Collectively, our results indicate that Nav1 regulates learning, memory, and the response to multiple addictive drugs, and that changes in the excitatory and inhibitory synaptic balance in the cortex and hippocampus could possibly mediate these phenotypic effects.

genetics↗

bioRxiv2022

Genetic pathways regulating the longitudinal acquisition of cocaine self administration in mice

To identify genetic pathways for addiction, we analyzed intravenous self-administration of cocaine or saline in a panel of 84 inbred and recombinant inbred mouse strains over 10 days. We integrated the behavior data with RNA-Seq data from the medial frontal cortex and nucleus accumbens from 41 strains. The self-administration of cocaine and saline showed distinct genetic bases. We maximized power to map loci for cocaine intake by using a linear mixed model to account for this longitudinal phenotype while correcting for population structure. A total of 15 unique significant loci were identified in the genome-wide association study (GWAS). A transcriptome-wide association study (TWAS) highlighted the Trpv2 ion channel as a key locus for cocaine self-administration from the GWAS. In addition, 17 genes supplementary to the GWAS were identified including Arhgef26, Slc18b1 and Slco5a1. We found numerous instances where alternate splice site selection or RNA editing altered transcript abundance. Our work emphasizes the importance of Trpv2, a known cannabinoid receptor, for the response to cocaine as well as identifying further relevant loci.

genetics↗

bioRxiv2022

Gonadal Sex and Sex-Chromosome Complement Interact to Affect Ethanol Consumption in Adolescent Four Core Genotypes Mice

BackgroundSex differences in ethanol consumption have been reported in both humans and laboratory rodents, but the independent/dependent contributions of genetic and hormonal sex{square}biasing mechanisms to these phenotypes have not yet been fully explored. MethodsTo examine the contributions of sex-chromosome complement (SCC) and gonadal sex (GS) to ethanol consumption, we studied adolescent (28-32 days old) four core genotypes (FCG) mice (C57BL/6J background; FCG model allows for independent assortment of GS and SCC) using a modified drinking-in-the-dark (DID) procedure. Mice were offered concurrent access to 20%, 10% and 0% ethanol (in water) in four daily 2-hour sessions. Consumption at the level of individual bouts was recorded. ResultsAlthough all four genotype groups preferred the 20% ethanol over 10% and 0%, and showed similar consumption of the 10% and 0% solutions, the group rankings for consumption of the 20% ethanol solution were XX+testes > XY+testes > XY+ovaries > XX+ovaries. Thus, an interaction was observed between SCC and GS for which the simple effect of SCC was greatest in mice with ovaries (XY > XX) and the simple effect of GS was greatest in XX mice (testes > ovaries). Moreover, these effects varied in magnitude across and within drinking sessions. The behavioral microstructure of ethanol consumption (i.e., parameterization of within-session discriminable drinking bouts) support the validity of our 3-bottle modification of the DID procedure as a model of binge-like consumption as: (1) the consumption rate of the 20% ethanol solution was ~80 g EtOH/kg/h within a bout (~12 s/bout, ~3 bouts/session), (2) most of this ethanol consumption was completed in a single bout and (3) within-session ethanol consumption was greater earlier than later, indicating "front loading." ConclusionsThese results indicate that SCC and GS interact on ethanol consumption in adolescent FCG mice on a C57BL/6J background to affect binge-like consumption from the very initiation of access and that these effects are dynamic as they varied both across and within sessions. HighlightsO_LIGonadal sex and sex-chromosome complement interact on ethanol consumption in adolescent four core genotypes mice C_LIO_LIIn adolescent four core genotypes mice, mice with testes drink more ethanol than mice with ovaries, particularly in the presence of an XX karyotype C_LIO_LIIn adolescent four core genotypes mice, XY mice drink more ethanol than XX mice, but only in mice with ovaries C_LIO_LIThe effects of sex-biasing biological factors on the patterns of ethanol consumption by adolescent four core genotypes mice that we observed in our 3-bottle Drinking-in-the-Dark procedure showed face validity with some of the sex/gender differences observed in human adolescents C_LI

animal behavior and cognition↗

bioRxiv2022

Reversal Learning Phenotypes are Linked with Novel Genetic Loci in Diversity Outbred Mice

Impulsive behavior and impulsivity are heritable phenotypes that are strongly associated with risk for substance use disorders in human subjects. Consequently, identifying the neurogenetic mechanisms that influence impulsivity may also reveal novel biological insights into addiction vulnerability. Past studies from our laboratory using the BXD and Collaborative Cross (CC) recombinant inbred mouse panels have revealed that behavioral indicators of impulsivity measured in a reversal learning task are heritable and are genetically correlated with aspects of intravenous cocaine self-administration. Genome wide linkage studies in the BXD panel revealed a quantitative trait locus (QTL) on chromosome 10, but the specific genes affecting this trait remain elusive. To achieve greater precision in our mapping efforts, we have turned to Diversity Outbred (DO) mice. A total of 392 DO mice (230 males, 295 females) were successfully phenotyped using the same reversal learning test utilized in our earlier studies. Our primary indicator of impulsive responding, a measure that isolates the relative difficulty mice have with reaching performance criteria under reversal conditions, revealed a genome wide significant QTL on chromosome 7 (max LOD score = 8.73, p<0.05). A measure of premature responding akin to that implemented in the 5-choice serial reaction time task yielded a suggestive QTL on chromosome 17 (max LOD score = 9.14, p<0.1). Positional candidate genes were prioritized (2900076A07Rik, Wdr73 and Zscan2) based upon expression QTL data we collected in DO and CC mice and analyses using publicly available gene expression and phenotype databases. These findings may advance understanding of the genetics that drive impulsive behavior and enhance risk for substance use disorders.

genetics↗

bioRxiv2021

Extreme Phenotypic Diversity in Operant Responding for an Intravenous Cocaine or Saline Infusion in the Hybrid Mouse Diversity Panel

Cocaine self-administration is complexly determined trait, and a substantial proportion of individual differences in cocaine use is determined by genetic variation. Cocaine intravenous self-administration (IVSA) procedures in laboratory animals provide opportunities to prospectively investigate neurogenetic influences on the acquisition of voluntary cocaine use. Large and genetically diverse mouse populations, including the Hybrid Mouse Diversity Panel (HMDP), have been developed for forward genetic approaches that can reveal genetic variants that influence traits like cocaine IVSA. This population enables high resolution and well-powered genome wide association studies, as well as the discovery of genetic correlations. Here, we provide information on cocaine (or saline - as a control) IVSA in 65 strains of the HMDP. We found cocaine IVSA to be substantially heritable in this population, with strain-level intake ranging for near zero to >25 mg/kg/session. Though saline IVSA was also found to be heritable, a very modest genetic correlation between cocaine and saline IVSA indicates that operant responding for the cocaine reinforcer was influenced by a substantial proportion of unique genetic variants. These data indicate that the HMDP is suitable for forward genetic approaches for the analysis of cocaine IVSA, and this project has also led to the discovery of reference strains with extreme cocaine IVSA phenotypes, revealing them as polygenic models of risk and resilience to cocaine reinforcement. This is part of an ongoing effort to characterize genetic and genomic variation that moderates cocaine IVSA, which may, in turn, provide a more comprehensive understanding of cocaine risk genetics and neurobiology.

animal behavior and cognition↗

bioRxiv2020

Heritability of ethanol consumption and pharmacokinetics in a genetically diverse panel of Collaborative Cross mouse strains and their inbred founder lines

BackgroundInter-individual variation in voluntary ethanol consumption and ethanol response is partially influenced by genetic variation. Discovery of the genes and allelic variants that affect these phenotypes may clarify the etiology and pathophysiology of problematic alcohol use, including alcohol use disorder. Genetically diverse mouse populations also demonstrate heritable variation in ethanol consumption and can be utilized to discover the genes and gene networks that influence this trait. The Collaborative Cross (CC) recombinant inbred strains, Diversity Outbred (DO) population and their eight founder strains are complementary mouse resources that capture substantial genetic diversity and can demonstrate expansive phenotypic variation in heritable traits. These populations may be utilized to discover candidate genes and gene networks that moderate ethanol consumption and other ethanol-related traits. MethodsWe characterized ethanol consumption, preference and pharmacokinetics in the eight founder strains and ten CC strains in 12-hour drinking sessions during the dark phase of the circadian cycle. ResultsEthanol consumption was found to be substantially heritable, both early in ethanol access and over a chronic intermittent access schedule. Ethanol pharmacokinetics were also found to be heritable; however, no association between strain-level ethanol consumption and pharmacokinetics was detected. The PWK/PhJ strain was found to be the highest drinking strain, with consumption substantially exceeding C57BL/6J, a strain commonly used as a model of "high" or "binge" drinking. Notably, we found strong evidence that sex moderated genetic effects on voluntary ethanol drinking. ConclusionsCollectively, this research may serve as a foundation for expanded genetic study of ethanol consumption in the CC/DO and related populations; moreover, we have identified reference strains with extreme consumption phenotypes that effectively represent polygenic models of hazardous ethanol use.

genetics↗

bioRxiv2020

Validity of the Lumen(R) hand-held metabolic device to measure fuel utilization in healthy young adults

BackgroundMetabolic carts measure the carbon dioxide produced and oxygen consumed from the breath in order to assess metabolic fuel usage (carbohydrates vs. fats). However, these systems are expensive, time-consuming, and only available in the clinic. A small hand-held device capable of measuring metabolic fuel via CO2 from exhaled air has been developed ObjectiveTo evaluate the validity of a novel hand-held device (Lumen(R)) for measuring metabolic fuel utilization in healthy young adults MethodsMetabolic fuel usage was assessed in healthy participants (n = 33; age: 23.1 {+/-} 3.9 y) via respiratory exchange ratio (RER) values from the "gold-standard" metabolic cart as well as %CO2 from the Lumen device. Measurements were performed at rest in two conditions, fasting, and after consuming 150 grams of glucose in order to determine changes in metabolic fuel. Reduced major axis regression was performed as well as Bland-Altman plots and linear regressions to test for agreement between RER and Lumen %CO2. ResultsBoth RER and Lumen %CO2 significantly increased after glucose intake compared with fasting conditions (P < .0001). Regression analyses and Bland-Altman plots revealed an agreement between the two measurements with a systematic bias resulting from the nature of the different units. ConclusionsThis study shows the validity of Lumen(R) to estimate metabolic fuel utilization in a comparable manner with the "gold-standard" metabolic cart, providing the ability for real-time metabolic information for users under any circumstances.

physiology↗

bioRxiv2020

Genetic variation and sex differences are missed opportunities for addiction biology.

Concerns about external validity of rodent models and translation of findings across species are often based on narrow investigations of populations with limited diversity. Sources of individual variation - including genetics and sex - are only infrequently encompassed in model organism studies. As with most complex diseases, risk for cocaine use disorder is subject to considerable inter-individual variation. Explicit inclusion of individual differences in rodent research may reveal conserved phenotypes and molecular systems relevant to human addiction. We surveyed cocaine-related traits in both males and females of eight inbred mouse strains whose genomes collectively capture 90% of the genetic diversity of the mouse species. Across these strains, individual differences explained a substantial proportion of variance in cocaine-responsive or cocaine response-predictive behavioral and physiological phenotypes. Wild-derived mouse strains often extended the phenotypic ranges of these behaviors beyond what is observed in conventional laboratory strains. Striatum transcriptional responses to cocaine were also highly dependent upon strain and sex differences; most cocaine-responsive genes were differentially expressed in a manner moderated by strain, sex, or their combination. We compared the strain- and sex-mediated transcriptional responses to cocaine in mice to transcriptomic analysis of people with cocaine use disorder and found that mouse similarity to humans was highly dependent upon mouse genetic background and sex. Specifically, male WSB/EiJ mice and female NOD/ShiLtJ mice exhibited the greatest degree of neural transcriptional consilience with humans with cocaine use disorder. Model organism diversity thus represents a crucial source of biological information that can substantially improve external validity of neuropsychiatric research. Significance StatementLaboratory mice are widely used in research on neurobiological mechanisms of addiction, but most studies use a single strain and often sex of mice. To assess how individual differences in mice modulate addiction-related traits and how this impacts comparative analysis with humans, we studied cocaine-relevant behaviors and brain molecular correlates in both males and females of genetically diverse mouse strains. In this population, individual differences related to sex and/or genetics explain large proportions of differences in cocaine-related traits. Importantly, brain gene expression data demonstrated that some strains mimic human genomic states more readily than others. Individual differences thus represent a crucial and underdeveloped source of biological information about addiction mechanisms that may influence the translational utility of such studies.

neuroscience↗

bioRxiv2018

Extraordinary Fast-Twitch Fiber Abundance Elite Weightlifters

Human skeletal muscle fibers exist across a continuum of slow [->] fast-twitch. The amount of each fiber type (FT) influences muscle performance but remains largely unexplored in elite athletes, particularly from strength/power sports. To address this nescience, vastus lateralis (VL) biopsies were performed on World/Olympic (female, n=6, \"WCF\") and National-caliber (female, n=9, \"NCF\"; and male, n=6, \"NCM\") American weightlifters. Participant accolades included 3 Olympic Games, 19 World Championships, 25 National records, and >170 National/International medals. Samples were analyzed for myosin heavy chain (MHC) content via SDS-PAGE using two distinct techniques: single fiber (SF) distribution (%) and homogenate (HG) composition. These athletes displayed the highest MHC IIa concentrations ever reported in healthy VL (23{+/-}9% I, 5{+/-}3% I/IIa, 67{+/-}13% IIa, and 6{+/-}10% IIa/IIx), with WCF expressing a notable 71{+/-}17% (NCF=67{+/-}8%, NCM=63{+/-}16%). The heavyweights accounted for 91% of the MHC IIa/IIx fibers. When compared to SF, HG overestimated MHC I (23{+/-}9 vs. 31{+/-}9%) and IIx (0{+/-}0 vs. 3{+/-}6%) by misclassifying I/IIa fibers as I and IIa/IIx fibers as IIx. These findings suggest athlete caliber (World vs. National), training experience, and body mass determine FT% more than sex and refutes the common pronouncement that women possess more slow and fewer fast-twitch fibers than men. Our results also show the abundance of pure MHC IIa and rarity of IIx in elite strength/power-trained athletes, indicate a potential link between MHC IIa/IIx frequency and body mass, and question the fidelity of HG as a measure of FT% distribution. The extreme fast-twitch abundance partially explains how elite weightlifters generate high forces in rapid time-frames. These data highlight the need for more cellular and molecular muscle research on elite anaerobic athletes.

physiology↗