Selective Breeding for Divergence in Novelty-seeking Traits: Heritability and Enrichment in Spontaneous Anxiety-related Behaviors

Outbred Sprague–Dawley rats can be classified as high responders (HR) or low responders (LR) based on their levels of exploratory locomotion in a novel environment. While this novelty-seeking dimension was originally related to differential vulnerability to substance abuse, behavioral, neuroendocrine and gene expression studies suggest a fundamental difference in emotional reactivity between these animals. Here, we report the first study to selectively breed rats based on this novelty-seeking dimension. Response to novelty was clearly heritable, with a >2-fold difference in behavior seen after eight generations of selection. Three tests of anxiety-like behavior consistently showed significantly greater anxiety in LR-bred rats compared to HR-bred animals, and this difference was diminished in the open field test by administration of the anxiolytic benzodiazepine drug, chlordiazepoxide. Cross-fostering revealed that responses to novelty were largely unaffected by maternal interactions, though there was an effect on anxiety-like behavior. These selected lines will enable future research on the interplay of genetic, environmental and developmental variables in controlling drug seeking behavior, stress and emotional reactivity.

[1]  D. Abrous,et al.  Behavioural trait of reactivity to novelty is related to hippocampal neurogenesis , 1999, The European journal of neuroscience.

[2]  T. Steimer,et al.  Divergent Stress Responses and Coping Styles in Psychogenetically Selected Roman High-(RHA) and Low-(RLA) Avoidance Rats: Behavioural, Neuroendocrine and Developmental Aspects , 2003, Stress.

[3]  P. Piazza,et al.  Dopaminergic activity is reduced in the prefrontal cortex and increased in the nucleus accumbens of rats predisposed to develop amphetamine self-administration , 1991, Brain Research.

[4]  J. B. Justice,et al.  Response to novelty predicts the locomotor and nucleus accumbens dopamine response to cocaine , 1991, Synapse.

[5]  M. Marinelli,et al.  Interaction between glucocorticoid hormones, stress and psychostimulant drugs * , 2002, The European journal of neuroscience.

[6]  H. Akil,et al.  Individual differences in novelty-seeking behavior in rats: a c-fos study , 2001, Neuroscience.

[7]  H. Akil,et al.  Social defeat alters the acquisition of cocaine self-administration in rats: role of individual differences in cocaine-taking behavior , 2001, Psychopharmacology.

[8]  B. Woodside,et al.  Mother to infant or infant to mother? Reciprocal regulation of responsiveness to stress in rodents and the implications for humans. , 2004, Journal of psychiatry & neuroscience : JPN.

[9]  E. Abercrombie,et al.  Individual differences in behavioral reactivity: correlation with stress-induced norepinephrine efflux in the hippocampus of Sprague-Dawley rats , 1999, Brain Research Bulletin.

[10]  S. Levine,et al.  Developmental determinants of sensitivity and resistance to stress , 2005, Psychoneuroendocrinology.

[11]  T. Steimer,et al.  Inter-individual vs line/strain differences in psychogenetically selected Roman High-(RHA) and Low-(RLA) Avoidance rats: neuroendocrine and behavioural aspects , 2005, Neuroscience & Biobehavioral Reviews.

[12]  F. Holsboer,et al.  Behavioural profiles of two Wistar rat lines selectively bred for high or low anxiety-related behaviour , 1998, Behavioural Brain Research.

[13]  D. Falconer,et al.  Introduction to Quantitative Genetics. , 1961 .

[14]  M. Meaney,et al.  Variations in Maternal Care Alter GABAA Receptor Subunit Expression in Brain Regions Associated with Fear , 2003, Neuropsychopharmacology.

[15]  Shakti Sharma,et al.  Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[16]  J. B. Justice,et al.  Individual differences in basal and cocaine-stimulated extracellular dopamine in the nucleus accumbens using quantitative microdialysis , 1992, Brain Research.

[17]  M. Zuckerman,et al.  Sensation seeking and psychopathology , 1979, Psychiatry Research.

[18]  M. Kalinichev,et al.  Individual differences in locomotor reactivity to a novel environment and sensitivity to opioid drugs in the rat. I. Expression of morphine-induced locomotor sensitization , 2004, Psychopharmacology.

[19]  H. Akil,et al.  Neurobiological Correlates of Individual Differences in Novelty-Seeking Behavior in the Rat: Differential Expression of Stress-Related Molecules , 2000, The Journal of Neuroscience.

[20]  J. Bouyer,et al.  Reaction of sleep–wakefulness cycle to stress is related to differences in hypothalamo–pituitary–adrenal axis reactivity in rat , 1998, Brain Research.

[21]  R. Landgraf,et al.  High vs Low Anxiety-Related Behavior Rats: An Animal Model of Extremes in Trait Anxiety , 2002, Behavior genetics.

[22]  D. Falconer.  Introduction to quantitative genetics. 1. ed. , 1984 .

[23]  J. Crabbe.  Genetic contributions to addiction. , 2002, Annual review of psychology.

[24]  M. Le Moal,et al.  Vertical Shifts in Self-Administration Dose–Response Functions Predict a Drug-Vulnerable Phenotype Predisposed to Addiction , 2000, The Journal of Neuroscience.

[25]  I. Weaver,et al.  Maternal Programming of Individual Differences in Defensive Responses in the Rat , 2004, Annals of the New York Academy of Sciences.

[26]  H. Akil,et al.  The search for the neurobiological basis of vulnerability to drug abuse: using microarrays to investigate the role of stress and individual differences , 2004, Neuropharmacology.

[27]  M. Le Moal,et al.  Factors that predict individual vulnerability to amphetamine self-administration. , 1989, Science.

[28]  M. Le Moal,et al.  Novelty-seeking in rats--biobehavioral characteristics and possible relationship with the sensation-seeking trait in man. , 1996, Neuropsychobiology.

[29]  M. Le Moal,et al.  Corticosterone levels determine individual vulnerability to amphetamine self-administration. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[30]  M. Kabbaj.  Neurobiological bases of individual differences in emotional and stress responsiveness: high responders-low responders model. , 2004, Archives of neurology.

[31]  P. Piazza,et al.  Glucocorticoids as a biological substrate of reward: physiological and pathophysiological implications , 1997, Brain Research Reviews.

[32]  A. Caspi,et al.  Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene , 2003, Science.

[33]  D. Blizard,et al.  The Maudsley Reactive and Nonreactive Strains: A New Perspective , 2002, Behavior genetics.

[34]  S. L. Sell,et al.  Estrous cycle influence on individual differences in the response to novelty and cocaine in female rats , 2005, Behavioural Brain Research.

[35]  G. A. Rowan,et al.  Selective breeding for negative contrast in consummatory behavior. , 1994, Journal of experimental psychology. Animal behavior processes.

[36]  W. P. Smotherman,et al.  Pituitary--adrenal responsiveness of rat mothers to noxious stimuli and stimuli produced by pups. , 1976, Ciba Foundation symposium.