Cocaine-induced locomotor activation differs across six sets of inbred mouse substrains

Cocaine use disorders (CUD) are devastating for affected individuals and impose a significant burden on society, but there are currently no FDA-approved therapies. The development of novel and effective treatments has been hindered by substantial gaps in our knowledge about the etiology of these disorders. The risk for developing a CUD is influenced by genetics, the environment and complex interactions between the two. Identifying specific genes and environmental risk factors that increase CUD risk would provide an avenue for the development of novel treatments. Rodent models of addiction-relevant behaviors have been a valuable tool for studying the genetics of response to drugs of abuse. Traditional genetic mapping using genetically and phenotypically divergent inbred mice has been successful in identifying numerous chromosomal regions that influence addiction-relevant behaviors, but these strategies rarely result in identification of the causal gene or genetic variant. To overcome this challenge, reduced complexity crosses (RCC) between closely related inbred mouse substrains have been proposed as a method for rapidly identifying and validating functional variants. The RCC approach is dependent on identifying phenotypic differences between substrains. To date, however, the study of addiction-relevant behaviors has been limited to very few sets of substrains, mostly comprising the C57BL/6 lineage. The present study expands upon the current literature to assess cocaine-induced locomotor activation in 20 inbred mouse substrains representing six inbred strain lineages (A/J, BALB/c, FVB/N, C3H/He, DBA/2 and NOD) that were either bred in-house or supplied directly by a commercial vendor. To our knowledge, we are the first to identify significant differences in cocaine-induced locomotor response in several of these inbred substrains. The identification of substrain differences allows for the initiation of RCC populations to more rapidly identify specific genetic variants associated with acute cocaine response. The observation of behavioral profiles that differ between mice generated in-house and those that are vendor-supplied also presents an opportunity to investigate the influence of environmental factors on cocaine-induced locomotor activity.

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Genetic modulation of initial sensitivity to Δ9-tetrahydrocannabinol (THC) among the BXD family of mice

10.1101/2021.01.08.425948 ◽

2021 ◽

Author(s):

Cory Parks ◽

Chris M Rogers ◽

J. Pjotr Prins ◽

Robert W. Williams ◽

Hao Chen ◽

...

Keyword(s):

Single Dose ◽

Drugs Of Abuse ◽

Cannabinoid Receptor ◽

Inbred Mice ◽

Strain Differences ◽

Inbred Strains ◽

Thermal Stimulus ◽

Motor Impairments ◽

Initial Sensitivity ◽

Acute Responses

Cannabinoid receptor 1 activation by the major psychoactive component in cannabis, Δ9-tetrahydrocannabinol (THC), produces motor impairments, hypothermia, and analgesia upon acute exposure. In previous work, we demonstrated significant sex and strain differences in acute responses to THC following administration of a single dose (10 mg/kg, i.p.) in C57BL/6J (B6) and DBA/2J (D2) inbred mice. To determine the extent to which these differences are heritable, we quantified acute responses to a single dose of THC (10 mg/kg, i.p.) in males and females from 20 members of the BXD family of inbred strains derived by crossing and inbreeding B6 and D2 mice. Acute THC responses (initial sensitivity) were quantified as changes from baseline for: 1. spontaneous activity in the open field (mobility), 2. body temperature (hypothermia), and 3. tail withdrawal latency to a thermal stimulus (analgesia/antinociception). Initial sensitivity to the immobilizing, hypothermic, and antinociceptive effects of THC varied substantially across the BXD family. Heritability was highest for mobility and hypothermia traits, indicating that segregating genetic variants modulate initial sensitivity to THC. We identified genomic loci and candidate genes, including Ndufs2, Scp2, Rps6kb1 or P70S6K, Pde4d, and Pten, that may control variation in THC initial sensitivity. We also detected strong correlations between initial responses to THC and legacy phenotypes related to intake or response to other drugs of abuse (cocaine, ethanol, and morphine). Our study demonstrates the feasibility of mapping genes and variants modulating THC responses in the BXDs to systematically define biological processes and liabilities associated with drug use and abuse.

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Terc Gene Cluster Variants Predict Liver Telomere Length in Mice

Cells ◽

10.3390/cells10102623 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2623

Author(s):

Dana Zeid ◽

Sean Mooney-Leber ◽

Laurel R. Seemiller ◽

Lisa R. Goldberg ◽

Thomas J. Gould

Keyword(s):

Linkage Disequilibrium ◽

Telomere Length ◽

Gene Cluster ◽

Inbred Mice ◽

Inbred Mouse ◽

Mouse Strains ◽

Chromosome 3 ◽

Human Populations ◽

Nucleotide Polymorphisms ◽

Initial Finding

Variants in a gene cluster upstream-adjacent to TERC on human chromosome 3, which includes genes APRM, LRRC31, LRRC34 and MYNN, have been associated with telomere length in several human populations. Currently, the mechanism by which variants in the TERC gene cluster influence telomere length in humans is unknown. Given the proximity between the TERC gene cluster and TERC (~0.05 Mb) in humans, it is speculated that cluster variants are in linkage disequilibrium with a TERC causal variant. In mice, the Terc gene/Terc gene cluster are also located on chromosome 3; however, the Terc gene cluster is located distantly downstream of Terc (~60 Mb). Here, we initially aim to investigate the interactions between genotype and nicotine exposure on absolute liver telomere length (aTL) in a panel of eight inbred mouse strains. Although we found no significant impact of nicotine on liver aTL, this first experiment identified candidate single nucleotide polymorphisms (SNPs) in the murine Terc gene cluster (within genes Lrrc31, Lrriq4 and Mynn) co-varying with aTL in our panel. In a second experiment, we tested the association of these Terc gene cluster variants with liver aTL in an independent panel of eight inbred mice selected based on candidate SNP genotype. This supported our initial finding that Terc gene cluster polymorphisms impact aTL in mice, consistent with data in human populations. This provides support for mice as a model for telomere dynamics, especially for studying mechanisms underlying the association between Terc cluster variants and telomere length. Finally, these data suggest that mechanisms independent of linkage disequilibrium between the Terc/TERC gene cluster and the Terc/TERC gene mediate the cluster’s regulation of telomere length.

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Etiology and Risk Factors for Rheumatoid Arthritis: A State-of-the-Art Review

Frontiers in Medicine ◽

10.3389/fmed.2021.689698 ◽

2021 ◽

Vol 8 ◽

Author(s):

Vasco C. Romão ◽

João Eurico Fonseca

Keyword(s):

Rheumatoid Arthritis ◽

Risk Factors ◽

Disease Risk ◽

State Of The Art ◽

Current Knowledge ◽

Epidemiological Studies ◽

Complex Interactions ◽

Significant Burden ◽

Risk Of Disease ◽

Societal Level

Rheumatoid arthritis (RA) is the most common systemic inflammatory rheumatic disease. It is associated with significant burden at the patient and societal level. Extensive efforts have been devoted to identifying a potential cause for the development of RA. Epidemiological studies have thoroughly investigated the association of several factors with the risk and course of RA. Although a precise etiology remains elusive, the current understanding is that RA is a multifactorial disease, wherein complex interactions between host and environmental factors determine the overall risk of disease susceptibility, persistence and severity. Risk factors related to the host that have been associated with RA development may be divided into genetic; epigenetic; hormonal, reproductive and neuroendocrine; and comorbid host factors. In turn, environmental risk factors include smoking and other airborne exposures; microbiota and infectious agents; diet; and socioeconomic factors. In the present narrative review, aimed at clinicians and researchers in the field of RA, we provide a state-of-the-art overview of the current knowledge on this topic, focusing on recent progresses that have improved our comprehension of disease risk and development.

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Role of Genetic Resistance in Invasive Pneumococcal Infection: Identification and Study of Susceptibility and Resistance in Inbred Mouse Strains

Infection and Immunity ◽

10.1128/iai.69.1.426-434.2001 ◽

2001 ◽

Vol 69 (1) ◽

pp. 426-434 ◽

Cited By ~ 90

Author(s):

Neill A. Gingles ◽

Janet E. Alexander ◽

Aras Kadioglu ◽

Peter W. Andrew ◽

Alison Kerr ◽

...

Keyword(s):

Inbred Mice ◽

Inbred Mouse ◽

Genetic Resistance ◽

Pneumococcal Infection ◽

Mouse Strains ◽

Inflammatory Lesions ◽

Invasive Pneumococcal Infection ◽

Susceptibility And Resistance

ABSTRACT From a panel of nine inbred mice strains intranasally infected withStreptococcus pneumoniae type 2 strain, BALB/c mice were resistant and CBA/Ca and SJL mice were susceptible to infection. Further investigation revealed that BALB/c mice were able to prevent proliferation of pneumococci in the lungs and blood, whereas CBA/Ca mice showed no bacterial clearance. Rapidly increasing numbers of bacteria in the blood was a feature of CBA/Ca but not BALB/c mice. In the lungs, BALB/c mice recruited significantly more neutrophils than CBA/Ca mice at 12 and 24 h postinfection. Inflammatory lesions in BALB/c mice were visible much earlier than in CBA/Ca mice, and there was a greater cellular infiltration into the lung tissue of BALB/c mice at the earlier time points. Our data suggest that resistance or susceptibility to intranasal pneumococci may have an association with recruitment and/or function of neutrophils.

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Laboratory Strains of Murine Cytomegalovirus Are Genetically Similar to but Phenotypically Distinct from Wild Strains of Virus

Journal of Virology ◽

10.1128/jvi.00160-08 ◽

2008 ◽

Vol 82 (13) ◽

pp. 6689-6696 ◽

Cited By ~ 46

Author(s):

L. M. Smith ◽

A. R. McWhorter ◽

L. L. Masters ◽

G. R. Shellam ◽

A. J. Redwood

Keyword(s):

Inbred Mice ◽

Laboratory Strain ◽

Murine Cytomegalovirus ◽

Phenotypic Characteristics ◽

Phenotypic Differences ◽

Resistance Patterns ◽

Wild Strains ◽

Clinical Models ◽

Low Passage

ABSTRACT Murine cytomegalovirus (MCMV) is widely used to model human cytomegalovirus (HCMV) infection. However, it is known that serially passaged laboratory strains of HCMV differ significantly from recently isolated clinical strains of HCMV. It is therefore axiomatic that clinical models of HCMV using serially passaged strains of MCMV may not be able to fully represent the complexities of the system they are attempting to model and may not fully represent the complex biology of MCMV. To determine whether genotypic and phenotypic differences also exist between laboratory strains of MCMV and wild derived strains of MCMV, we sequenced the genomes of three low-passage strains of MCMV, plus the laboratory strain, K181. We coupled this genetic characterization to their phenotypic characteristics. In contrast to what is seen with HCMV (and rhesus CMV), there were no major genomic rearrangements in the MCMV genomes. In addition, the genome size was remarkably conserved between MCMV strains with no major insertions or deletions. There was, however, significant sequence variation between strains of MCMV, particularly at the genomic termini. These more subtle genetic differences led to considerable differences in in vivo replication with some strains of MCMV, such as WP15B, replicating preferentially in otherwise-MCMV-resistant C57BL/6 mice. CBA mice were no more resistant to MCMV than C57BL/6 mice and for some MCMV strains appeared to control infection less well than C57BL/6 mice. It is apparent that the previously described host resistance patterns of inbred mice and MCMV are not consistently applicable for all MCMV strains.

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Genetic Modulation of Initial Sensitivity to Δ9-Tetrahydrocannabinol (THC) Among the BXD Family of Mice

Frontiers in Genetics ◽

10.3389/fgene.2021.659012 ◽

2021 ◽

Vol 12 ◽

Author(s):

Cory Parks ◽

Chris M. Rogers ◽

Pjotr Prins ◽

Robert W. Williams ◽

Hao Chen ◽

...

Keyword(s):

Single Dose ◽

Drugs Of Abuse ◽

Cannabinoid Receptor ◽

Inbred Mice ◽

Strain Differences ◽

Inbred Strains ◽

Thermal Stimulus ◽

Motor Impairments ◽

Initial Sensitivity ◽

Acute Responses

Cannabinoid receptor 1 activation by the major psychoactive component in cannabis, Δ9-tetrahydrocannabinol (THC), produces motor impairments, hypothermia, and analgesia upon acute exposure. In previous work, we demonstrated significant sex and strain differences in acute responses to THC following administration of a single dose (10 mg/kg, i.p.) in C57BL/6J (B6) and DBA/2J (D2) inbred mice. To determine the extent to which these differences are heritable, we quantified acute responses to a single dose of THC (10 mg/kg, i.p.) in males and females from 20 members of the BXD family of inbred strains derived by crossing and inbreeding B6 and D2 mice. Acute THC responses (initial sensitivity) were quantified as changes from baseline for: 1. spontaneous activity in the open field (mobility), 2. body temperature (hypothermia), and 3. tail withdrawal latency to a thermal stimulus (antinociception). Initial sensitivity to the immobilizing, hypothermic, and antinociceptive effects of THC varied substantially across the BXD family. Heritability was highest for mobility and hypothermia traits, indicating that segregating genetic variants modulate initial sensitivity to THC. We identified genomic loci and candidate genes, including Ndufs2, Scp2, Rps6kb1 or P70S6K, Pde4d, and Pten, that may control variation in THC initial sensitivity. We also detected strong correlations between initial responses to THC and legacy phenotypes related to intake or response to other drugs of abuse (cocaine, ethanol, and morphine). Our study demonstrates the feasibility of mapping genes and variants modulating THC responses in the BXDs to systematically define biological processes and liabilities associated with drug use and abuse.

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Differential Maintenance and Frequency-Dependent Tuning of LTP at Hippocampal Synapses of Specific Strains of Inbred Mice

Journal of Neurophysiology ◽

10.1152/jn.2000.84.5.2484 ◽

2000 ◽

Vol 84 (5) ◽

pp. 2484-2493 ◽

Cited By ~ 57

Author(s):

Peter V. Nguyen ◽

Steven N. Duffy ◽

Jennie Z. Young

Keyword(s):

Genetic Background ◽

Pyramidal Neurons ◽

Inbred Mice ◽

Inbred Mouse ◽

Mouse Strains ◽

Synaptic Facilitation ◽

Ca1 Pyramidal Neurons ◽

Hippocampal Synapses ◽

Strain Dependent

Transgenic and knockout mice are used extensively to elucidate the molecular mechanisms of hippocampal synaptic plasticity. However, genetic and phenotypic variations between inbred mouse strains that are used to construct genetic models may confound the interpretation of cellular neurophysiological data derived from these models. Using in vitro slice stimulation and recording methods, we compared the membrane biophysical, cellular electrophysiological, and synaptoplastic properties of hippocampal CA1 neurons in four specific strains of inbred mice: C57BL/6J, CBA/J, DBA/2J, and 129/SvEms/J. Hippocampal long-term potentiation (LTP) induced by theta-pattern stimulation, and by repeated multi-burst 100-Hz stimulation at various interburst intervals, was better maintained in area CA1 of slices from BL/6J mice than in slices from CBA and DBA mice. At an interburst interval of 20 s, maintenance of LTP was impaired in CBA and DBA slices, as compared with BL/6J slices. When the interburst interval was reduced to 3 s, induction of LTP was significantly enhanced in129/SvEms slices, but not in DBA and CBA slices. Long-term depression (LTD) was not significantly different between slices from these four strains. For the four strains examined, CA1 pyramidal neurons showed no significant differences in spike-frequency accommodation, membrane input resistance, and number of spikes elicited by current injection. Synaptically-evoked glutamatergic postsynaptic currents did not significantly differ among CA1 pyramidal neurons in these four strains. Since the observed LTP deficits resembled those previously seen in transgenic mice with reduced hippocampal cAMP-dependent protein kinase (PKA) activity, we searched for possible strain-dependent differences in cAMP-dependent synaptic facilitation induced by forskolin (an activator of adenylate cyclase) and IBMX (a phosphodiesterase inhibitor). We found that forskolin/IBMX-induced synaptic facilitation was deficient in area CA1 of DBA/2J and CBA/J slices, but not in BL/6J and 129/SvEms/J slices. These defects in cAMP-induced synaptic facilitation may underlie the deficits in memory, observed in CBA/J and DBA/2J mice, that have been previously reported. We conclude that hippocampal LTP is influenced by genetic background and by the temporal characteristics of the stimulation protocol. The plasticity of hippocampal synapses in some inbred mouse strains may be “tuned” to particular temporal patterns of synaptic activity. From a broader perspective, our data support the notion that strain-dependent variation in genetic background is an important factor that can influence the synaptoplastic phenotypes observed in studies that use genetically modified mice to explore the molecular bases of synaptic plasticity.

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Strain variation in spermatozoal glycosidases in inbred mice

Genetics Research ◽

10.1017/s0016672300018668 ◽

1978 ◽

Vol 32 (2) ◽

pp. 183-193 ◽

Cited By ~ 4

Author(s):

Steven J. Self ◽

Bryan G. Winchester ◽

James R. Archer

Keyword(s):

Significant Variation ◽

Inbred Mice ◽

Inbred Mouse ◽

Mouse Strains ◽

Sperm Cells ◽

Inbred Mouse Strains ◽

Strain Variation ◽

Genetic Studies ◽

Optimal Activity ◽

Genetical Variation

SUMMARYTen glycosidases were measured in suspensions of spermatozoa from the vasa deferentia of two inbred mouse strains and their intercrosses. Eight of these glycosidases were associated with the sperm cells and all of these showed genetical variation between the strains except α-l-fucosidase with optimal activity at pH 5·4. In contrast liver enzyme activities showed no significant variation except α-l-fucosidase. Genetic studies indicated that the variation of spermatozoal β-d-hexosaminidase, α-d-mannosidase, α-l-fucosidase and β-d-galactosidase are inherited at autosomal loci and α-d-galactosidase variation shows X-linked inheritance. We propose a new provisional gene symbol (Afuc-2) for a spermatozoal variant of α-l-fucosidase.

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Substrains of Inbred Mice Differ in Their Physical Activity as a Behavior

The Scientific World JOURNAL ◽

10.1155/2013/237260 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 12

Author(s):

Dario Coletti ◽

Emanuele Berardi ◽

Paola Aulino ◽

Eleonora Rossi ◽

Viviana Moresi ◽

...

Keyword(s):

Physical Activity ◽

Wheel Running ◽

Average Distance ◽

Inbred Mice ◽

Inbred Mouse ◽

Inbred Mouse Strain ◽

Time Frame ◽

Mouse Strains ◽

Muscle Adaptation ◽

Voluntary Activity

Recent studies strengthen the belief that physical activity as a behavior has a genetic basis. Screening wheel-running behavior in inbred mouse strains highlighted differences among strains, showing that even very limited genetic differences deeply affect mouse behavior. We extended this observation to substrains of the same inbred mouse strain, that is, BALB/c mice. We found that only a minority of the population of one of these substrains, the BALB/c J, performs spontaneous physical activity. In addition, the runners of this substrain cover a significantly smaller distance than the average runners of two other substrains, namely, the BALB/c ByJ and the BALB/c AnNCrl. The latter shows a striking level of voluntary activity, with the average distance run/day reaching up to about 12 kilometers. These runners are not outstanders, but they represent the majority of the population, with important scientific and economic fallouts to be taken into account during experimental planning. Spontaneous activity persists in pathological conditions, such as cancer-associated cachexia. This important amount of physical activity results in a minor muscle adaptation to endurance exercise over a three-week period; indeed, only a nonsignificant increase in NADH transferase+ fibers occurs in this time frame.

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Enhanced VWF biosynthesis and elevated plasma VWF due to a natural variant in the murine Vwf gene

Blood ◽

10.1182/blood-2006-04-014688 ◽

2006 ◽

Vol 108 (9) ◽

pp. 3061-3067 ◽

Cited By ~ 17

Author(s):

Heidi L. Lemmerhirt ◽

Jordan A. Shavit ◽

Gallia G. Levy ◽

Suzanne M. Cole ◽

Jeffrey C. Long ◽

...

Keyword(s):

Genetic Variation ◽

Inbred Mice ◽

Inbred Mouse ◽

Mouse Strains ◽

Genetic Modifiers ◽

Wide Range ◽

Natural Variant ◽

Vitro Analysis

Abstract Both genetic and environmental influences contribute to the wide variation in plasma von Willebrand factor (VWF) levels observed in humans. Inbred mouse strains also have highly variable plasma VWF levels, providing a convenient model in which to study genetic modifiers of VWF. Previously, we identified a major modifier of VWF levels in the mouse (Mvwf1) as a regulatory mutation in murine Galgt2. We now report the identification of an additional murine VWF modifier (Mvwf2). Mvwf2 accounts for approximately 16% of the 8-fold plasma VWF variation (or ∼ 25% of the genetic variation) observed between the A/J and CASA/RkJ strains and maps to the murine Vwf gene itself. Twenty SNPs were identified within the coding regions of the A/J and CASA/RkJ Vwf alleles, and in vitro analysis of recombinant VWF demonstrated that a single SNP (+7970G>A) and the associated nonsynonymous amino acid change (R2657Q) confers a significant increase in VWF biosynthesis from the CASA/RkJ Vwf allele. This change appears to represent a unique gain of function that likely explains the mechanism of Mvwf2 in vivo. The identification of a natural Vwf gene variant among inbred mice affecting biosynthesis suggests that similar genetic variation may contribute to the wide range of VWF levels observed in humans.

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