Hybridizing behavioral models: A possible solution to some problems in neurophenotyping research?

The use of batteries of single-domain tests for neurophenotyping research is a common strategy to achieve higher data density and explore different behavioral domains. This approach, however, is accompanied by several methodological challenges, briefly discussed here. As an alternative, this paper advocates the wider use of extensive "hybrid" protocols that assess multiple domains in parallel, or logically/logistically combine experimental paradigms, in a way that disproportionately maximizes the number of tested phenotypes per experimental manipulation. Several examples of this approach are given in this paper, demonstrating the potential to reduce time, cost and subject requirements for the experiments. Offering behavioral analyses that are lacking in the standard single-domain tests, such "hybrid" models enable innovative modeling of neuropsychiatric disorders by more thorough and broader investigation of complex phenotypical characteristics.

[1]  R. Quirion,et al.  Characterization of neuropeptide Y, Y2 receptor knockout mice in two animal models of learning and memory processing , 2007, Journal of Molecular Neuroscience.

[2]  R. Mechoulam,et al.  Differential response to acute and repeated stress in cannabinoid CB1 receptor knockout newborn and adult mice , 2005, Behavioural pharmacology.

[3]  R. Paylor,et al.  The use of behavioral test batteries, II: Effect of test interval , 2006, Physiology & Behavior.

[4]  A. Griffith,et al.  Anxiety and otovestibular disorders: Linking behavioral phenotypes in men and mice , 2008, Behavioural Brain Research.

[5]  Xia Li,et al.  Decreases in nestlet shredding of mice by serotonin uptake inhibitors: comparison with marble burying. , 2006, Life sciences.

[6]  Roger M. Nitsch,et al.  Laboratory animal welfare: Cage enrichment and mouse behaviour , 2004, Nature.

[7]  M. El Yacoubi,et al.  Genetic rodent models of depression. , 2007, Current opinion in pharmacology.

[8]  D. Murphy,et al.  The regular and light–dark Suok tests of anxiety and sensorimotor integration: utility for behavioral characterization in laboratory rodents , 2008, Nature Protocols.

[9]  R. Lathe,et al.  The individuality of mice , 2004, Genes, brain, and behavior.

[10]  J. Delacour,et al.  A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data , 1988, Behavioural Brain Research.

[11]  J. Crawley.  Behavioral Phenotyping of Transgenic and Knockout Mice , 1999 .

[12]  H. Akiskal,et al.  Toward an integrative model of the spectrum of mood, behavioral and personality disorders based on fear and anger traits: II. Implications for neurobiology, genetics and psychopharmacological treatment. , 2006, Journal of affective disorders.

[13]  R. Wicks,et al.  Modeling anxiety-like states: pharmacological characterization of the chick separation stress paradigm , 2006, Behavioural pharmacology.

[14]  Alan Mackay-Sim,et al.  Swimming behaviour and post-swimming activity in Vitamin D receptor knockout mice , 2006, Brain Research Bulletin.

[15]  P M Nolan,et al.  Generation of mouse mutants as a tool for functional genomics. , 2000, Pharmacogenomics.

[16]  D. Murphy,et al.  Effects of serotonergic agents on food-restriction-induced hyperactivity , 1996, Pharmacology Biochemistry and Behavior.

[17]  L. Spear,et al.  Factor analysis of elevated plus-maze behavior in adolescent and adult rats , 2006, Pharmacology Biochemistry and Behavior.

[18]  H. Einat.  Different behaviors and different strains: Potential new ways to model bipolar disorder , 2007, Neuroscience & Biobehavioral Reviews.

[19]  M. Meaney,et al.  The effects of chronic antidepressant treatment in an animal model of anxiety , 2004, Psychopharmacology.

[20]  Fumikazu Yokoyama,et al.  The selective serotonin reuptake inhibitor fluvoxamine suppresses post-feeding hyperactivity induced by food restriction in rats , 2007, Pharmacology Biochemistry and Behavior.

[21]  I. Kovalenko,et al.  A Model of Anxious Depression: Persistence of Behavioral Pathology , 2005, Neuroscience and Behavioral Physiology.

[22]  Kevin B Freeman,et al.  Dissociation of stress behaviors in the chick social-separation-stress procedure , 2002, Physiology & Behavior.

[23]  David P Wolfer,et al.  Assessing the effects of the 129/Sv genetic background on swimming navigation learning in transgenic mutants: a study using mice with a modified β-amyloid precursor protein gene , 1997, Brain Research.

[24]  Jacqueline N. Crawley,et al.  What's Wrong With My Mouse? , 2007 .

[25]  Maja Bucan,et al.  Behavior and mutagenesis screens: the importance of baseline analysis of inbred strains , 2000, Mammalian Genome.

[26]  F. Fumagalli,et al.  Modeling geriatric depression in animals: biochemical and behavioral effects of olfactory bulbectomy in young versus aged rats. , 1999, The Journal of pharmacology and experimental therapeutics.

[27]  L. Tecott.  The genes and brains of mice and men. , 2003, The American journal of psychiatry.

[28]  J. Crawley.  Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests 1 Published on the World Wide Web on 2 December 1998. 1 , 1999, Brain Research.

[29]  Tommy Pattij,et al.  Stress-induced hyperthermia and anxiety: pharmacological validation. , 2003, European journal of pharmacology.

[30]  D. Murphy,et al.  Hypolocomotion, anxiety and serotonin syndrome‐like behavior contribute to the complex phenotype of serotonin transporter knockout mice , 2007, Genes, brain, and behavior.

[31]  D. Murphy,et al.  Analyzing grooming microstructure in neurobehavioral experiments , 2007, Nature Protocols.

[32]  S. Dunnett,et al.  Behavioural profiles of inbred mouse strains used as transgenic backgrounds. II: cognitive tests , 2004, Genes, brain, and behavior.

[33]  J. Crawley,et al.  Impaired learning and motor behavior in heterozygous Pafah1b1 (Lis1) mutant mice. , 1999, Learning & memory.

[34]  H. Tanila,et al.  Hypothermia in mice tested in Morris water maze , 2003, Behavioural Brain Research.

[35]  J. E. Warnick,et al.  The chick separation stress paradigm: a validation study , 2004, Pharmacology Biochemistry and Behavior.

[36]  C. Wotjak,et al.  Increased water temperature renders single-housed C57BL/6J mice susceptible to antidepressant treatment in the forced swim test , 2008, Behavioural Brain Research.

[37]  D. Bartsch,et al.  Selective effects of citalopram in a mouse model of stress-induced anhedonia with a control for chronic stress , 2006, Behavioural pharmacology.

[38]  H. Einat.  Modelling facets of mania – new directions related to the notion of endophenotypes , 2006, Journal of psychopharmacology.

[39]  R. Silva,et al.  Dissociation of the effects of ethanol on memory, anxiety, and motor behavior in mice tested in the plus-maze discriminative avoidance task , 2007, Psychopharmacology.

[40]  P. Kenny.  Brain reward systems and compulsive drug use. , 2007, Trends in pharmacological sciences.

[41]  R. Hen,et al.  Recent advances in animal models of chronic antidepressant effects: The novelty-induced hypophagia test , 2005, Neuroscience & Biobehavioral Reviews.

[42]  A. Kalueff,et al.  The Suok ("ropewalking") murine test of anxiety. , 2005, Brain research. Brain research protocols.

[43]  J. Huston,et al.  “Despair” induced by extinction trials in the water maze: Relationship with measures of anxiety in aged and adult rats , 2007, Neurobiology of Learning and Memory.

[44]  Valerie J. Bolivar,et al.  Assessing autism-like behavior in mice: Variations in social interactions among inbred strains , 2007, Behavioural Brain Research.

[45]  E. Friedman,et al.  Spontaneous alternation behavior: An animal model for obsessive-compulsive disorder? , 1991, Pharmacology Biochemistry and Behavior.

[46]  M. Geyer,et al.  Serotonin1B receptor modulation of startle reactivity, habituation, and prepulse inhibition in wild-type and serotonin1B knockout mice , 1997, Psychopharmacology.

[47]  Cj Huang,et al.  Modelling the anxiety-depression continuum in chicks , 2009, Journal of psychopharmacology.

[48]  A. Kalueff,et al.  Impaired motor performance in mice lacking neurosteroid vitamin D receptors , 2004, Brain Research Bulletin.

[49]  E. Acevedo,et al.  Modeling the anxiety–depression continuum hypothesis in domestic fowl chicks , 2006, Behavioural pharmacology.

[50]  A. Walf,et al.  The use of the elevated plus maze as an assay of anxiety-related behavior in rodents , 2007, Nature Protocols.

[51]  A. Holmes,et al.  Prior exposure to the elevated plus-maze sensitizes mice to the acute behavioral effects of fluoxetine and phenelzine. , 2003, European journal of pharmacology.

[52]  A. Rabavilas,et al.  Reinforced Spatial Alternation as an Animal Model of Obsessive-Compulsive Disorder (OCD): Investigation of 5-HT2C and 5-HT1D Receptor Involvement in OCD Pathophysiology , 2005, Biological Psychiatry.

[53]  E. Nestler,et al.  Neurobehavioral assessment in the information age , 2004, Nature Neuroscience.

[54]  C. Wotjak,et al.  A mouse model of posttraumatic stress disorder that distinguishes between conditioned and sensitised fear. , 2007, Journal of psychiatric research.

[55]  D. Bartsch,et al.  Stress-induced hyperlocomotion as a confounding factor in anxiety and depression models in mice , 2005, Behavioural pharmacology.

[56]  A. Dunn,et al.  Increased open field locomotion and decreased striatal GABAA binding after activity wheel running , 1996, Physiology & Behavior.

[57]  Jacqueline N. Crawley,et al.  Reduced aggression in mice lacking the serotonin transporter , 2002, Psychopharmacology.

[58]  E. Prinssen,et al.  A combined marble burying-locomotor activity test in mice: a practical screening test with sensitivity to different classes of anxiolytics and antidepressants. , 2006, European journal of pharmacology.

[59]  Jacqueline N. Crawley,et al.  What's Wrong With My Mouse?: Behavioral Phenotyping of Transgenic and Knockout Mice , 2000 .

[60]  P. Seeburg,et al.  Complex, multimodal behavioral profile of the Homer1 knockout mouse , 2007, Genes, brain, and behavior.

[61]  N. Sousa,et al.  A hitchhiker's guide to behavioral analysis in laboratory rodents , 2006, Genes, brain, and behavior.

[62]  A. Kalueff,et al.  Behavioural characterization in rats using the elevated alley Suok test , 2005, Behavioural Brain Research.

[63]  A. Kalueff,et al.  Grooming analysis algorithm for neurobehavioural stress research. , 2004, Brain research. Brain research protocols.

[64]  P. Worley,et al.  Behavioral and neurochemical phenotyping of Homer1 mutant mice: possible relevance to schizophrenia , 2005, Genes, brain, and behavior.

[65]  Robert Lalonde.  Motor abnormalities in weaver mutant mice , 2004, Experimental Brain Research.

[66]  N. C. Weed,et al.  Construct validation of behavioral indices of isolation stress and inflammatory nociception in young domestic fowl , 1994, Physiology & Behavior.

[67]  John F. Cryan,et al.  Model organisms: The ascent of mouse: advances in modelling human depression and anxiety , 2005, Nature Reviews Drug Discovery.

[68]  D. Murphy,et al.  What's wrong with my mouse model? Advances and strategies in animal modeling of anxiety and depression , 2007, Behavioural Brain Research.

[69]  T. Gould,et al.  Animal models of bipolar disorder and mood stabilizer efficacy: A critical need for improvement , 2007, Neuroscience & Biobehavioral Reviews.

[70]  D. Murphy,et al.  Attenuation of food-restriction-induced running by chronic fluoxetine treatment. , 1993, Psychopharmacology bulletin.

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

[72]  Benjamin J. Clark,et al.  Motor activity (exploration) and formation of home bases in mice (C57BL/6) influenced by visual and tactile cues: Modification of movement distribution, distance, location, and speed , 2006, Physiology & Behavior.

[73]  J. Huston,et al.  Extinction-induced “despair” in the water maze, exploratory behavior and fear: Effects of chronic antidepressant treatment , 2007, Neurobiology of Learning and Memory.

[74]  J. W. Aldridge,et al.  Sequential super-stereotypy of an instinctive fixed action pattern in hyper-dopaminergic mutant mice: a model of obsessive compulsive disorder and Tourette's , 2005, BMC Biology.

[75]  H. Akiskal,et al.  Toward a clinical delineation of dysphoric hypomania - operational and conceptual dilemmas. , 2005, Bipolar disorders.

[76]  M. W. Feltenstein,et al.  Screening antidepressants in the chick separation-stress paradigm , 2005, Psychopharmacology.

[77]  G. Tsujimoto,et al.  Impaired social interaction and reduced anxiety-related behavior in vasopressin V1a receptor knockout mice , 2007, Behavioural Brain Research.

[78]  R. A. Hughes,et al.  Differential effects of handling on isolation-induced vocalizations, hypoalgesia, and hyperthermia in domestic fowl , 1991, Physiology & Behavior.

[79]  I. Whishaw,et al.  The point of entry contributes to the organization of exploratory behavior of rats on an open field: An example of spontaneous episodic memory , 2007, Behavioural Brain Research.

[80]  Richard G M Morris,et al.  Festina lente: Late-night thoughts on high-throughput screening of mouse behavior , 2004, Nature Neuroscience.

[81]  P. Nolan,et al.  The role of mutagenesis in defining genes in behaviour , 2006, European Journal of Human Genetics.

[82]  F. Benazzi.  A continuity between bipolar II depression and major depressive disorder? , 2006, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[83]  J. Delacour,et al.  A new one-trial test for neurobiological studies of memory in rats. II: Effects of piracetam and pramiracetam , 1989, Behavioural Brain Research.

[84]  Alessandra Valentini,et al.  Investigative burying by laboratory mice may involve non-functional, compulsive, behaviour , 1998, Behavioural Brain Research.

[85]  P. Nolan,et al.  Towards new models of disease and physiology in the neurosciences: the role of induced and naturally occurring mutations. , 2000, Human molecular genetics.

[86]  Steve D. M. Brown,et al.  Mutation of Celsr1 Disrupts Planar Polarity of Inner Ear Hair Cells and Causes Severe Neural Tube Defects in the Mouse , 2003, Current Biology.

[87]  D. Bartsch,et al.  Stress-Induced Anhedonia in Mice is Associated with Deficits in Forced Swimming and Exploration , 2004, Neuropsychopharmacology.

[88]  John G. Sled,et al.  Behavioral Phenotypes of Disc1 Missense Mutations in Mice , 2007, Neuron.

[89]  H. Würbel.  Publications should include an animal-welfare section , 2007, Nature.

[90]  D. Murphy,et al.  Locomotory patterns, spatiotemporal organization of exploration and spatial memory in serotonin transporter knockout mice , 2007, Brain Research.

[91]  V. Bolivar,et al.  Habituation in rodents: A review of behavior, neurobiology, and genetics , 2006, Neuroscience & Biobehavioral Reviews.

[92]  T. Kikusui,et al.  Wheel-running activity increases with social stress in male DBA mice , 2008, Physiology & Behavior.

[93]  Richard Paylor,et al.  The use of behavioral test batteries: Effects of training history , 2001, Physiology & Behavior.