Ovariectomy results in inbred strain-specific increases in anxiety-like behavior in mice

Women are at an increased risk for developing affective disorders during times of hormonal flux, including menopause when the ovaries cease production of estrogen. However, while all women undergo menopause, not all develop an affective disorder. Increased vulnerability can result from genetic predisposition, environmental factors and gene by environment interactions. In order to investigate interactions between genetic background and estrogen depletion, we performed bilateral ovariectomy, a surgical procedure that results in estrogen depletion and is thought to model the post-menopausal state, in a genetically defined panel of 37 inbred mouse strains. Seventeen days post-ovariectomy, we assessed behavior in two standard rodent assays of anxiety- and depressive-like behavior, the open field and forced swim tests. We detected a significant interaction between ovariectomy and genetic background on anxiety-like behavior in the open field. No strain specific effects of ovariectomy were observed in the forced swim assay. However, we did observe significant strain effects for all behaviors in both the open field and forced swim tests. This study is the largest to date to look at the effects of ovariectomy on behavior and provides evidence that ovariectomy interacts with genetic background to alter anxiety-like behavior in an animal model of menopause.

[1]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[2]  L. Melton,et al.  Long-term risk of depressive and anxiety symptoms after early bilateral oophorectomy , 2008, Menopause.

[3]  P. Kandi,et al.  Nicotine and 17β-estradiol produce an antidepressant-like effect in female ovariectomized rats , 2011, Brain Research Bulletin.

[4]  John W. Tukey,et al.  Exploratory Data Analysis. , 1979 .

[5]  C. Belzung,et al.  Correlations between behaviours in the elevated plus-maze and sensitivity to unpredictable subchronic mild stress: evidence from inbred strains of mice , 2005, Behavioural Brain Research.

[6]  R. Kessler,et al.  Twelve‐month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States , 2012, International journal of methods in psychiatric research.

[7]  D. Pfaff,et al.  Estrogen's effects on activity, anxiety, and fear in two mouse strains , 2002, Behavioural Brain Research.

[8]  D. Pfaff,et al.  Estrogen increases locomotor activity in mice through estrogen receptor alpha: specificity for the type of activity. , 2003, Endocrinology.

[9]  P. Heydarpour,et al.  Estradiol reduces depressive-like behavior through inhibiting nitric oxide/cyclic GMP pathway in ovariectomized mice , 2013, Hormones and Behavior.

[10]  Michel Bourin,et al.  Forced swimming test in mice: a review of antidepressant activity , 2004, Psychopharmacology.

[11]  Chung-Hey Chen,et al.  Depressive symptoms in Taiwanese women during the peri- and post-menopause years: associations with demographic, health, and psychosocial characteristics. , 2013, Maturitas.

[12]  J. Becker,et al.  Female rats are not more variable than male rats: a meta-analysis of neuroscience studies , 2016, Biology of Sex Differences.

[13]  D. Rubinow,et al.  Estrogen effects on the forced swim test differ in two outbred rat strains , 2012, Physiology & Behavior.

[14]  A. Rodrigues,et al.  Acute treatments with GMP produce antidepressant‐like effects in mice , 2000, Neuroreport.

[15]  L. Dennerstein,et al.  Neurobehavioral impact of menopause on mood , 2007, Expert review of neurotherapeutics.

[16]  I. Lucki,et al.  Sensitivity to the effects of pharmacologically selective antidepressants in different strains of mice , 2001, Psychopharmacology.

[17]  L. Tarantino,et al.  Prototypical anxiolytics do not reduce anxiety-like behavior in the open field in C57BL/6J mice , 2015, Pharmacology Biochemistry and Behavior.

[18]  P. Skolnick,et al.  Intra- and interstrain differences in models of “behavioral despair” , 2001, Pharmacology Biochemistry and Behavior.

[19]  L. Tarantino,et al.  Comt1 genotype and expression predicts anxiety and nociceptive sensitivity in inbred strains of mice , 2010, Genes, brain, and behavior.

[20]  H. Yoshimura,et al.  Animal model of menopausal depressive-like state in female mice: prolongation of immobility time in the forced swimming test following ovariectomy , 2005, Psychopharmacology.

[21]  K. Svenson,et al.  A General Bayesian Approach to Analyzing Diallel Crosses of Inbred Strains , 2012, Genetics.

[22]  H. Gershenfeld,et al.  Genetic differences in the tail-suspension test and its relationship to imipramine response among 11 inbred strains of mice , 2001, Biological Psychiatry.

[23]  Florian Holsboer,et al.  Behavioural performance in three substrains of mouse strain 129 , 1997, Brain Research.

[24]  P. Skolnick,et al.  Genetic differences in a tail suspension test for evaluating antidepressant activity , 2004, Psychopharmacology.

[25]  Takeo Yoshikawa,et al.  Identification of multiple genetic loci linked to the propensity for "behavioral despair" in mice. , 2002, Genome research.

[26]  Andrew I. Su,et al.  Phenotypic Characterization of a Genetically Diverse Panel of Mice for Behavioral Despair and Anxiety , 2010, PloS one.

[27]  R. Pero,et al.  Non-specific steroidal esterase activity and distribution in human and other mammalian tissues. , 1994, Clinica chimica acta; international journal of clinical chemistry.

[28]  Joseph G Ibrahim,et al.  A Note on Permutation Tests for Variance Components in Multilevel Generalized Linear Mixed Models , 2007, Biometrics.

[29]  A. Fernández-Guasti,et al.  Antidepressant-Like Effect of Different Estrogenic Compounds in the Forced Swimming Test , 2003, Neuropsychopharmacology.

[30]  D. Spiegelman,et al.  Prevalence and predictors of depressive symptoms in older premenopausal women: the Harvard Study of Moods and Cycles. , 1999, Archives of general psychiatry.

[31]  N. Popova,et al.  Role of genotype and dopamine receptors in behaviour of inbred mice in a forced swimming test , 1991, Psychopharmacology.

[32]  Richard E Brown,et al.  What are We Measuring When We Test Strain Differences in Anxiety in Mice? , 2013, Behavior Genetics.

[33]  D. David,et al.  Antidepressant-like effects in various mice strains in the forced swimming test , 2003, Psychopharmacology.

[34]  M. Dubocovich,et al.  Antidepressant-like activity of the melatonin receptor antagonist, luzindole (N-0774), in the mouse behavioral despair test. , 1990, European journal of pharmacology.

[35]  D. Bates,et al.  Fitting Linear Mixed-Effects Models Using lme4 , 2014, 1406.5823.

[36]  D. Pfaff,et al.  Effects of Estrogen on Activity and Fear-Related Behaviors in Mice , 2001, Hormones and Behavior.

[37]  E. Simpson.  Sources of estrogen and their importance , 2003, The Journal of Steroid Biochemistry and Molecular Biology.

[38]  Douglas Wahlsten,et al.  Survey of 21 inbred mouse strains in two laboratories reveals that BTBR T/+ tf/tf has severely reduced hippocampal commissure and absent corpus callosum , 2003, Brain Research.

[39]  N. Moore,et al.  Animal models of depression: are there any? , 2003, Human psychopharmacology.

[40]  P. Schmidt,et al.  Sex Hormones and Mood in the Perimenopause , 2009, Annals of the New York Academy of Sciences.

[41]  S. Kõks,et al.  Strain and gender differences in the behavior of mouse lines commonly used in transgenic studies , 2001, Physiology & Behavior.

[42]  K. Ritchie,et al.  Lifetime hormonal factors may predict late-life depression in women , 2008, International Psychogeriatrics.

[43]  L. Garcia-Segura,et al.  Long-term ovariectomy enhances anxiety and depressive-like behaviors in mice submitted to chronic unpredictable stress , 2010, Hormones and Behavior.

[44]  H. Yamashita,et al.  Higher incidence of hysterectomy and oophorectomy in women suffering from clinical depression: Retrospective chart review , 2010, Psychiatry and clinical neurosciences.

[45]  J. Hutchison,et al.  Localisation of aromatase activity in androgen target areas of the mouse brain , 1992, Neuroscience Letters.

[46]  A. Ramos,et al.  Stress and emotionality: a multidimensional and genetic approach , 1997, Neuroscience & Biobehavioral Reviews.

[47]  T. Gould,et al.  Antidepressant‐like responses to lithium in genetically diverse mouse strains , 2011, Genes, brain, and behavior.

[48]  D. David,et al.  Antidepressant-like effects in various mice strains in the tail suspension test , 2003, Behavioural Brain Research.

[49]  H. Gershenfeld,et al.  An exploratory factor analysis of the Tail Suspension Test in 12 inbred strains of mice and an F2 intercross , 2003, Brain Research Bulletin.

[50]  C. S. Hall,et al.  Emotional behavior in the rat. I. Defecation and urination as measures of individual differences in emotionality. , 1934 .

[51]  G. Forloni,et al.  Genotype-Dependent Activity of Tryptophan Hydroxylase-2 Determines the Response to Citalopram in a Mouse Model of Depression , 2005, The Journal of Neuroscience.

[52]  F. Clavel-Chapelon,et al.  Lifetime endogenous reproductive factors and severe depressive symptoms in postmenopausal women: findings from the E3N cohort , 2013, Menopause.

[53]  G. Wegener,et al.  Female Flinders Sensitive Line rats show estrous cycle-independent depression-like behavior and altered tryptophan metabolism , 2016, Neuroscience.

[54]  Daniel E. Adkins,et al.  Genetics of Adverse Reactions to Haloperidol in a Mouse Diallel: A Drug–Placebo Experiment and Bayesian Causal Analysis , 2013, Genetics.

[55]  I. Zucker,et al.  Female mice liberated for inclusion in neuroscience and biomedical research , 2014, Neuroscience & Biobehavioral Reviews.

[56]  Martyn Plummer,et al.  Bayesian Graphical Models using MCMC , 2016 .

[57]  J. Crabbe,et al.  Genetics of mouse behavior: interactions with laboratory environment. , 1999, Science.

[58]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[59]  A. Rodrigues,et al.  Agmatine produces antidepressant-like effects in two models of depression in mice , 2002, Neuroreport.

[60]  H. Araki,et al.  Factors producing a menopausal depressive-like state in mice following ovariectomy , 2006, Psychopharmacology.

[61]  Tian Xu,et al.  The expanding role of mouse genetics for understanding human biology and disease , 2008, Disease Models & Mechanisms.

[62]  E. Freeman.  Associations of depression with the transition to menopause , 2010, Menopause.

[63]  D. Pfaff,et al.  Estrogen alters behavior and forebrain c-fos expression in ovariectomized rats subjected to the forced swim test. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[64]  A. R. Massensini,et al.  Object recognition memory deficit and depressive-like behavior caused by chronic ovariectomy can be transitorialy recovered by the acute activation of hippocampal estrogen receptors , 2015, Psychoneuroendocrinology.

[65]  Patrick F. Sullivan,et al.  ANTIPSYCHOTIC-INDUCED VACUOUS CHEWING MOVEMENTS AND EXTRAPYRAMIDAL SIDE-EFFECTS ARE HIGHLY HERITABLE IN MICE , 2010, The Pharmacogenomics Journal.

[66]  J. Domingo,et al.  Assessing anxiety in C57BL/6J mice: a pharmacological characterization of the open-field and light/dark tests. , 2014, Journal of pharmacological and toxicological methods.

[67]  Andrew Gelman,et al.  Data Analysis Using Regression and Multilevel/Hierarchical Models , 2006 .

[68]  C. Belzung,et al.  The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. , 2003, European journal of pharmacology.

[69]  S. Yamada,et al.  Mouse strain differences in immobility and sensitivity to fluvoxamine and desipramine in the forced swimming test: analysis of serotonin and noradrenaline transporter binding. , 2008, European journal of pharmacology.

[70]  L. Tarantino,et al.  Forward genetic approaches to understanding complex behaviors. , 2012, Current topics in behavioral neurosciences.

[71]  M. Okada,et al.  Influences of ovariectomy and continuous replacement of 17beta-estradiol on the tail skin temperature and behavior in the forced swimming test in rats. , 1997, Japanese journal of pharmacology.

[72]  J. Crabbe,et al.  Stability of inbred mouse strain differences in behavior and brain size between laboratories and across decades , 2006, Proceedings of the National Academy of Sciences.

[73]  M. Marván,et al.  Clomipramine modifies fluctuations of forced swimming immobility in different phases of the rat estrous cycle. , 1996, Archives of medical research.

[74]  L. Tarantino,et al.  Initial locomotor sensitivity to cocaine varies widely among inbred mouse strains , 2015, Genes, brain, and behavior.

[75]  S. Crawford,et al.  Longitudinal study of hormone levels and depression among women transitioning through menopause , 2001, Climacteric.

[76]  B. H. Miller,et al.  Evaluating genetic markers and neurobiochemical analytes for fluoxetine response using a panel of mouse inbred strains , 2011, Psychopharmacology.

[77]  M. Altemus.  Sex differences in depression and anxiety disorders: Potential biological determinants , 2006, Hormones and Behavior.

[78]  J. Quevedo,et al.  Effects of long-term ovariectomy on anxiety and behavioral despair in rats , 2009, Physiology & Behavior.

[79]  A. Rodrigues,et al.  Involvement of NMDA receptors and l-arginine-nitric oxide pathway in the antidepressant-like effects of zinc in mice , 2003, Behavioural Brain Research.

[80]  C. Soares.  Mood disorders in midlife women: understanding the critical window and its clinical implications , 2014, Menopause.

[81]  L. Schalkwyk,et al.  Behavioural battery testing: Evaluation and behavioural outcomes in 8 inbred mouse strains , 2010, Physiology & Behavior.

[82]  A. Walf,et al.  Estradiol reduces anxiety- and depression-like behavior of aged female mice , 2010, Physiology & Behavior.

[83]  N. Kokras,et al.  Forced swim test: What about females? , 2015, Neuropharmacology.