Non-diagnostic symptoms in a mouse model of autism in relation to neuroanatomy: the BTBR strain reinvestigated

Several mouse models of autism spectrum disorder (ASD), including the BTBR T + tf/J (BTBR) inbred strain, display a diverse array of behavioral deficits with particular face validity. Here we propose that phenotyping these preclinical models of ASD should avoid excessive reliance on appearance validity of the behavioral observations. BTBR mice were examined in three non-diagnostic symptoms modalities, beside an anatomical investigation for construct validity. The BTBR strain displayed poor sensorimotor integration as reflected by shorter stride length and greater latency on the balance beam task (BBT) when compared with C57BL/6 (B6) controls. Also, locomotor indices in the open-field task (OFT) revealed that BTBR mice traveled longer distances with a remarkably faster exploration than the B6 group in favor of hyperactivity and impulsiveness. Furthermore, analysis of spatial performance including search strategies in the Morris water task (MWT) indicated spatial impairment in the BTBR strain due to failure to employ spatial strategies during navigation. Quantitative cytoarchitectonics and volumetric examinations also indicated abnormal cortical and subcortical morphology in the BTBR mice. The results are discussed in relation to the neuroanatomical correlates of motor and cognitive impairments in the BTBR strain. We conclude that non-diagnostic autistic-like symptoms in the BTBR mouse strain can be impacted by autism risk factors in a similar way than the traditional diagnostic signs.

[1]  T. Tavassoli,et al.  The Role of Sensorimotor Difficulties in Autism Spectrum Conditions , 2016, Front. Neurol..

[2]  Ruth A. Carper,et al.  Unusual brain growth patterns in early life in patients with autistic disorder , 2001, Neurology.

[3]  Eric Courchesne,et al.  Patches of disorganization in the neocortex of children with autism. , 2014, The New England journal of medicine.

[4]  S Arndt,et al.  No Difference in Hippocampus Volume Detected on Magnetic Resonance Imaging in Autistic Individuals , 1998, Journal of autism and developmental disorders.

[5]  A. Guastella,et al.  An Overview of Autism Spectrum Disorder, Heterogeneity and Treatment Options , 2017, Neuroscience Bulletin.

[6]  R. Morris,et al.  Place navigation impaired in rats with hippocampal lesions , 1982, Nature.

[7]  Stuart Maudsley,et al.  The effects of aging on the BTBR mouse model of autism spectrum disorder , 2014, Front. Aging Neurosci..

[8]  Franziska R. Richter,et al.  Reduced Hippocampal Functional Connectivity During Episodic Memory Retrieval in Autism , 2017, Cerebral cortex.

[9]  Gerry Leisman,et al.  Cognitive-motor interactions of the basal ganglia in development , 2014, Front. Syst. Neurosci..

[10]  I. Whishaw Did a change in sensory control of skilled movements stimulate the evolution of the primate frontal cortex? , 2003, Behavioural Brain Research.

[11]  Kathryn K. Chadman,et al.  Fluoxetine but not risperidone increases sociability in the BTBR mouse model of autism , 2011, Pharmacology Biochemistry and Behavior.

[12]  A. Luczak,et al.  Beyond the silence: Bilateral somatosensory stimulation enhances skilled movement quality and neural density in intact behaving rats , 2013, Behavioural Brain Research.

[13]  Lori-Ann R. Sacrey,et al.  Early Infant Development and Intervention for Autism Spectrum Disorder , 2015, Journal of child neurology.

[14]  N. Minshew,et al.  MRI volumes of amygdala and hippocampus in non–mentally retarded autistic adolescents and adults , 1999, Neurology.

[15]  Catherine Lord,et al.  The relationship of motor skills and adaptive behavior skills in young children with autism spectrum disorders. , 2013, Research in autism spectrum disorders.

[16]  B. Campbell,et al.  Motor and reflexive behavior in the aging rat. , 1980, Journal of gerontology.

[17]  R. Sutherland,et al.  Characterization of spatial performance in male and female Long-Evans rats by means of the Morris water task and the ziggurat task , 2010, Brain Research Bulletin.

[18]  P. Ashwood,et al.  Inflammatory macrophage phenotype in BTBR T+tf/J mice , 2013, Front. Neurosci..

[19]  F. N. Dempster,et al.  The rise and fall of the inhibitory mechanism: Toward a unified theory of cognitive development and aging , 1992 .

[20]  Amanda F. Mejia,et al.  Evidence for Specificity of Motor Impairments in Catching and Balance in Children with Autism , 2014, Journal of Autism and Developmental Disorders.

[21]  R. Lenroot,et al.  Heterogeneity within Autism Spectrum Disorders: What have We Learned from Neuroimaging Studies? , 2013, Front. Hum. Neurosci..

[22]  G. Kempermann,et al.  An old test for new neurons: refining the Morris water maze to study the functional relevance of adult hippocampal neurogenesis , 2013, Front. Neurosci..

[23]  L Wang,et al.  Shape mapping of the hippocampus in young children with autism spectrum disorder. , 2007, AJNR. American journal of neuroradiology.

[24]  L. Korzeniowski [On autism]. , 1967, Annales medico-psychologiques.

[25]  C. Janus Search strategies used by APP transgenic mice during navigation in the Morris water maze. , 2004, Learning & memory.

[26]  A R Damasio,et al.  A neurological model for childhood autism. , 1978, Archives of neurology.

[27]  Stewart H Mostofsky,et al.  Associations of postural knowledge and basic motor skill with dyspraxia in autism: implication for abnormalities in distributed connectivity and motor learning. , 2009, Neuropsychology.

[28]  J. Faraji,et al.  Evidence for Ancestral Programming of Resilience in a Two-Hit Stress Model , 2017, Front. Behav. Neurosci..

[29]  V. Bolivar,et al.  The BTBR T + tf/J mouse model for autism spectrum disorders–in search of biomarkers , 2013, Behavioural Brain Research.

[30]  H. van Engeland,et al.  Impaired Response Inhibition in Autism Spectrum Disorders, a Marker of Vulnerability to Schizophrenia Spectrum Disorders? , 2013, Journal of the International Neuropsychological Society.

[31]  Edvard I Moser,et al.  Spatial learning with unilateral and bilateral hippocampal networks , 2005, The European journal of neuroscience.

[32]  D. Holtzman,et al.  Morris water maze search strategy analysis in PDAPP mice before and after experimental traumatic brain injury , 2006, Experimental Neurology.

[33]  Partha P. Mitra,et al.  Comparative three-dimensional connectome map of motor cortical projections in the mouse brain , 2016, Scientific Reports.

[34]  H. McFarlane,et al.  Autism‐like behavioral phenotypes in BTBR T+tf/J mice , 2008, Genes, brain, and behavior.

[35]  E Courchesne,et al.  Development of the hippocampal formation from 2 to 42 years: MRI evidence of smaller area dentata in autism. , 2001, Brain : a journal of neurology.

[36]  Carmen Sandi,et al.  Detailed classification of swimming paths in the Morris Water Maze: multiple strategies within one trial , 2015, Scientific Reports.

[37]  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.

[38]  B. Kaang,et al.  Neuronal mechanisms and circuits underlying repetitive behaviors in mouse models of autism spectrum disorder , 2016, Behavioral and Brain Functions.

[39]  Daniel Morton,et al.  Histopathologic characterization of the BTBR mouse model of autistic-like behavior reveals selective changes in neurodevelopmental proteins and adult hippocampal neurogenesis , 2011, Molecular autism.

[40]  A R Damasio,et al.  Gait disturbances in patients with autistic behavior: a preliminary study. , 1981, Archives of neurology.

[41]  H Asanuma,et al.  Neurobiological basis of motor learning in mammals. , 1997, Neuroreport.

[42]  Bryan Kolb,et al.  Spatial mapping: definitive disruption by hippocampal or medial frontal cortical damage in the rat , 1982, Neuroscience Letters.

[43]  J. Krakauer,et al.  Are We Ready for a Natural History of Motor Learning? , 2011, Neuron.

[44]  J. N. Crawley,et al.  Unusual repertoire of vocalizations in adult BTBR T+tf/J mice during three types of social encounters , 2011, Genes, brain, and behavior.

[45]  C. Lord,et al.  Behavioural phenotyping assays for mouse models of autism , 2010, Nature Reviews Neuroscience.

[46]  E. Courchesne,et al.  Why the frontal cortex in autism might be talking only to itself: local over-connectivity but long-distance disconnection , 2005, Current Opinion in Neurobiology.

[47]  L. Nadel,et al.  Spatial memory deficits in patients with lesions to the right hippocampus and to the right parahippocampal cortex , 1998, Neuropsychologia.

[48]  Ian Q. Whishaw,et al.  A comparison of rats and mice in a swimming pool place task and matching to place task: Some surprising differences , 1995, Physiology & Behavior.

[49]  Hans-Peter Lipp,et al.  Extended analysis of path data from mutant mice using the public domain software Wintrack , 2001, Physiology & Behavior.

[50]  S. White,et al.  Emotion Dysregulation and Anxiety in Adults with ASD: Does Social Motivation Play a Role? , 2015, Journal of autism and developmental disorders.

[51]  Jacqueline N. Crawley,et al.  Mouse behavioral tasks relevant to autism: Phenotypes of 10 inbred strains , 2007, Behavioural Brain Research.

[52]  D. McVea,et al.  Mirrored Bilateral Slow-Wave Cortical Activity within Local Circuits Revealed by Fast Bihemispheric Voltage-Sensitive Dye Imaging in Anesthetized and Awake Mice , 2010, The Journal of Neuroscience.

[53]  D. Wahlsten,et al.  Localization of two new X‐linked quantitative trait loci controlling corpus callosum size in the mouse , 2007, Genes, brain, and behavior.

[54]  D. B. Bell,et al.  Low stress reactivity and neuroendocrine factors in the BTBR T+tf/J mouse model of autism , 2010, Neuroscience.

[55]  P. Patterson Modeling Autistic Features in Animals , 2011, Pediatric Research.

[56]  C. Janus,et al.  The effects of prenatal stress on learning in adult offspring is dependent on the timing of the stressor , 2009, Behavioural Brain Research.

[57]  Matthew W. Mosconi,et al.  Saccadic eye movement abnormalities in autism spectrum disorder indicate dysfunctions in cerebellum and brainstem , 2014, Molecular Autism.

[58]  M. Brimacombe,et al.  Prevalence of motor impairment in autism spectrum disorders , 2007, Brain and Development.

[59]  Brian R. Christie,et al.  Hippocampal Neurogenesis Levels Predict WATERMAZE Search Strategies in the Aging Brain , 2013, PloS one.

[60]  A. Donnellan,et al.  Rethinking autism: implications of sensory and movement differences for understanding and support , 2012, Front. Integr. Neurosci..

[61]  D. Wahlsten,et al.  Hippocampal commissure defects in crosses of four inbred mouse strains with absent corpus callosum , 2012, Genes, brain, and behavior.

[62]  H. Geurts,et al.  Prepotent Response Inhibition and Interference Control in Autism Spectrum Disorders: Two Meta‐Analyses , 2014, Autism research : official journal of the International Society for Autism Research.

[63]  D C Blanchard,et al.  Motor and cognitive stereotypies in the BTBR T+tf/J mouse model of autism , 2011, Genes, brain, and behavior.

[64]  J. Faraji,et al.  Stress inhibits psychomotor performance differently in simple and complex open field environments , 2014, Hormones and Behavior.

[65]  S. McTighe,et al.  The BTBR Mouse Model of Autism Spectrum Disorders Has Learning and Attentional Impairments and Alterations in Acetylcholine and Kynurenic Acid in Prefrontal Cortex , 2013, PloS one.

[66]  R. Mark Henkelman,et al.  Neuroanatomical analysis of the BTBR mouse model of autism using magnetic resonance imaging and diffusion tensor imaging , 2013, NeuroImage.

[67]  Caroline C Brown,et al.  Disordered connectivity in the autistic brain: challenges for the "new psychophysiology". , 2007, International journal of psychophysiology : official journal of the International Organization of Psychophysiology.

[68]  John Gormley,et al.  Gait Deviations in Children with Autism Spectrum Disorders: A Review , 2015, Autism research and treatment.

[69]  D. Amaral,et al.  Neuroanatomy of autism , 2008, Trends in Neurosciences.

[70]  Matthew W. Mosconi,et al.  Consensus Paper: Pathological Role of the Cerebellum in Autism , 2012, The Cerebellum.

[71]  Marja Cantell,et al.  Motor and gestural performance in children with autism spectrum disorders, developmental coordination disorder, and/or attention deficit hyperactivity disorder , 2007, Journal of the International Neuropsychological Society.

[72]  F. Horak,et al.  Cortical control of postural responses , 2007, Journal of Neural Transmission.

[73]  Jacqueline N. Crawley,et al.  Development of a mouse test for repetitive, restricted behaviors: Relevance to autism , 2008, Behavioural Brain Research.

[74]  P. Caroni,et al.  Goal-oriented searching mediated by ventral hippocampus early in trial-and-error learning , 2012, Nature Neuroscience.

[75]  C. Hass,et al.  Motor Coordination in Autism Spectrum Disorders: A Synthesis and Meta-Analysis , 2010, Journal of autism and developmental disorders.

[76]  Daniela Popa,et al.  Cerebellum involvement in cortical sensorimotor circuits for the control of voluntary movements , 2014, Nature Neuroscience.

[77]  D. Bowler,et al.  Spatial Navigation Impairments Among Intellectually High-Functioning Adults With Autism Spectrum Disorder: Exploring Relations With Theory of Mind, Episodic Memory, and Episodic Future Thinking , 2013, Journal of abnormal psychology.

[78]  The involvement of the motor cortex in postural control: a delicate balancing act , 2009, The Journal of physiology.

[79]  Laura R. Fenlon,et al.  Formation of functional areas in the cerebral cortex is disrupted in a mouse model of autism spectrum disorder , 2015, Neural Development.

[80]  R. Morris Developments of a water-maze procedure for studying spatial learning in the rat , 1984, Journal of Neuroscience Methods.

[81]  J. Bramham,et al.  Response Inhibition in Adults with Autism Spectrum Disorder Compared to Attention Deficit/Hyperactivity Disorder , 2011, Journal of autism and developmental disorders.

[82]  S. Mostofsky,et al.  Specificity of dyspraxia in children with autism. , 2012, Neuropsychology.

[83]  Angelo Bifone,et al.  Neuroimaging Evidence of Major Morpho-Anatomical and Functional Abnormalities in the BTBR T+TF/J Mouse Model of Autism , 2013, PloS one.

[84]  Geraldine Dawson,et al.  Basal ganglia morphometry and repetitive behavior in young children with autism spectrum disorder , 2011, Autism research : official journal of the International Society for Autism Research.

[85]  C. Mazefsky,et al.  The role of emotion regulation in autism spectrum disorder. , 2013, Journal of the American Academy of Child and Adolescent Psychiatry.

[86]  G. Kempermann,et al.  Adult-Generated Hippocampal Neurons Allow the Flexible Use of Spatially Precise Learning Strategies , 2009, PloS one.