Sexually Dimorphic, Developmental, and Chronobiological Behavioral Profiles of a Mouse Mania Model

Saul, Michael C.; Stevenson, Sharon A.; Gammie, Stephen C.

doi:10.1371/journal.pone.0072125

Cited by 10 publications

(10 citation statements)

References 69 publications

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“…Although neither disorder has overall sex prevalence differences, we observed similar AH SNP enrichment for BIP ( P all < 0.01), but not for the well-powered SCZ dataset. Previous work has revealed sexual dimorphism in onset, course, and co-morbidities of BIP[61] and in animal models, and suggested that it may be driven by endocrine systems[62]; thus the AH SNP enrichment in ASD is not unique but is also unlikely to be an artifact manifest in all GWAS data.…”

Section: Resultsmentioning

confidence: 99%

Pleiotropic Mechanisms Indicated for Sex Differences in Autism

et al. 2016

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Sexual dimorphism in common disease is pervasive, including a dramatic male preponderance in autism spectrum disorders (ASDs). Potential genetic explanations include a liability threshold model requiring increased polymorphism risk in females, sex-limited X-chromosome contribution, gene-environment interaction driven by differences in hormonal milieu, risk influenced by genes sex-differentially expressed in early brain development, or contribution from general mechanisms of sexual dimorphism shared with secondary sex characteristics. Utilizing a large single nucleotide polymorphism (SNP) dataset, we identify distinct sex-specific genome-wide significant loci. We investigate genetic hypotheses and find no evidence for increased genetic risk load in females, but evidence for sex heterogeneity on the X chromosome, and contribution of sex-heterogeneous SNPs for anthropometric traits to ASD risk. Thus, our results support pleiotropy between secondary sex characteristic determination and ASDs, providing a biological basis for sex differences in ASDs and implicating non brain-limited mechanisms.

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Section: Resultsmentioning

confidence: 99%

Pleiotropic Mechanisms Indicated for Sex Differences in Autism

et al. 2016

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“…MSN mice display reduced anxiety and depression, increased sexual behavior, hyperactivity, and circadian abnormalities (Scotti et al, 2011, Saul et al, 2012, Saul et al, 2013). Lithium and olanzapine, an atypical antipsychotic, only reduced hyperactivity, with no changes observed for anxiety behavior in these mice (Scotti et al, 2011).…”

Section: Mouse Models Amenable To Systems Neuroscience and Functionalmentioning

confidence: 99%

Animal models of bipolar mania: The past, present and future

2016

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Bipolar disorder (BD) is the sixth leading cause of disability in the world according to the World Health Organization and affects nearly 6 million (~2.5% of the population) adults in the United State alone each year. BD is primarily characterized by mood cycling of depressive (e.g., helplessness, reduced energy and activity, and anhedonia) and manic (e.g., increased energy and hyperactivity, reduced need for sleep, impulsivity, reduced anxiety and depression), episodes. The following review describes several animal models of bipolar mania with a focus on more recent findings using genetically modified mice, including several with the potential of investigating the mechanisms underlying ‘mood’ cycling (or behavioral switching in rodents). We discuss whether each of these models satisfy criteria of validity (i.e., face, predictive, and construct), while highlighting their strengths and limitations. Animal models are helping to address critical questions related to pathophysiology of bipolar mania, in an effort to more clearly define necessary targets of first-line medications, lithium and valproic acid, and to discover novel mechanisms with the hope of developing more effective therapeutics. Future studies will leverage new technologies and strategies for integrating animal and human data to reveal important insights into the etiology, pathophysiology, and treatment of BD.

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“…Based upon previous behavioral work demonstrating alterations in seasonality in MSN mice [ 15 ], a variant in Npas2 interested us greatly due to that gene’s involvement in seasonal affective disorder [ 19 ]. Brain gene expression work on MSN animals implicated transcriptional regulation as an important system dysregulated in the MSN brain [ 16 ], so we were particularly motivated to examine variants in Hltf ( Smarca3 ), Cp , Polr3c , and Smarca4 .…”

Section: Resultsmentioning

confidence: 99%

“…The Madison (MSN) mouse strain is an inbred strain derived from the outbred Hsd:ICR (ICR) founder population over the course of 15 years. MSN mice are a face-valid mania model displaying a suite of behaviors associated with a manic endophenotype including locomotor hyperactivity, decreased swim immobility, increased sexual behavior, advanced diurnal rhythm, and seasonal-like alterations in locomotor hyperactivity relative to control strains [ 14 , 15 ]. MSN animals are consistent with a predictively valid mania model, showing the expected attenuation of mania when treated with lithium chloride or the atypical antipsychotic olanzapine [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…Here, we report the results of a small-scale whole exome resequencing study on MSN mice to identify potential candidate alleles, then validate a small subset of these candidate alleles in a large population using a low-throughput genotyping method. Based upon our previous gene expression and behavioral work, we predicted variants unique to the MSN strain in purinergic reception related genes, molecular clock genes, and chromatin remodeling genes [ 15 , 16 ]. Genomic enrichment of our gene expression work predicted that MSN animals would show perturbations in genomic regions sharing synteny with human loci linked to bipolar disorder and related mental health disorders [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

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Genomic variants in an inbred mouse model predict mania-like behaviors

et al. 2018

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Contemporary rodent models for bipolar disorders split the bipolar spectrum into complimentary behavioral endophenotypes representing mania and depression. Widely accepted mania models typically utilize single gene transgenics or pharmacological manipulations, but inbred rodent strains show great potential as mania models. Their acceptance is often limited by the lack of genotypic data needed to establish construct validity. In this study, we used a unique strategy to inexpensively explore and confirm population allele differences in naturally occurring candidate variants in a manic rodent strain, the Madison (MSN) mouse strain. Variants were identified using whole exome resequencing on a small population of animals. Interesting candidate variants were confirmed in a larger population with genotyping. We enriched these results with observations of locomotor behavior from a previous study. Resequencing identified 447 structural variants that are mostly fixed in the MSN strain relative to control strains. After filtering and annotation, we found 11 non-synonymous MSN variants that we believe alter protein function. The allele frequencies for 6 of these variants were consistent with explanatory variants for the Madison strain’s phenotype. The variants are in the Npas2, Cp, Polr3c, Smarca4, Trpv1, and Slc5a7 genes, and many of these genes’ products are in pathways implicated in human bipolar disorders. Variants in Smarca4 and Polr3c together explained over 40% of the variance in locomotor behavior in the Hsd:ICR founder strain. These results enhance the MSN strain’s construct validity and implicate altered nucleosome structure and transcriptional regulation as a chief molecular system underpinning behavior.

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Sexually Dimorphic, Developmental, and Chronobiological Behavioral Profiles of a Mouse Mania Model

Cited by 10 publications

References 69 publications

Pleiotropic Mechanisms Indicated for Sex Differences in Autism

Pleiotropic Mechanisms Indicated for Sex Differences in Autism

Animal models of bipolar mania: The past, present and future

Genomic variants in an inbred mouse model predict mania-like behaviors

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