Effects of social isolation rearing on the limbic brain: A combined behavioral and magnetic resonance imaging volumetry study in rats

Rearing rats in social isolation from weaning induces robust behavioral and neurobiological alterations resembling some of the core symptoms of schizophrenia, such as reduction in prepulse inhibition of acoustic startle (PPI) and locomotor hyperactivity in a novel arena. The aim of this study was to investigate whether social isolation rearing induces volumetric remodeling of the limbic system, and to probe for anatomical structure-behavioral interrelations. Isolation- (n=8) and group-reared (n=8) rats were examined by magnetic resonance (MR) volumetry using high-resolution T2-weighted imaging at 7 T. Volumes of medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), retrosplenial cortex (RSC) and hippocampal formation were compared between groups and with behavioral measures, i.e. PPI and locomotor activity in a novel arena. Isolation rearing induced locomotor hyperactivity and impaired PPI compared with group-housed rats. The right mPFC was significantly reduced (5.4%) in isolation-reared compared with group-reared rats, with a similar trend on the left side (5.2%). mPFC volumes changes were unrelated to behavioral abnormalities. No significant volume changes were observed in ACC, RSC or hippocampal formation. Hippocampal volumes were associated with the magnitude of PPI response in control but not in isolation-reared rats. Rearing rats in social isolation induced remodeling of the limbic brain with selective prefrontal cortex volume loss. In addition, a dissociation of the interrelation between hippocampal volume and PPI was noted in the isolation-reared rats. Taken together, limbic morphometry is sensitive to the effects of social isolation rearing but did not reveal direct brain-behavior interrelations, calling for more detailed circuitry analysis.

[1]  Tobias Bast,et al.  Hippocampal modulation of sensorimotor processes , 2003, Progress in Neurobiology.

[2]  M. Koch,et al.  Deficient Sensorimotor Gating After 6‐Hydroxydopamine Lesion of the Rat medial Prefrontal Cortex is Reversed by Haloperidol , 1994, The European journal of neuroscience.

[3]  Peng Xia,et al.  Modification of hippocampal neurogenesis and neuroplasticity by social environments , 2003, Experimental Neurology.

[4]  J. van Pelt,et al.  Sex-difference and left-right asymmetries in the prefrontal cortex during postnatal development in the rat. , 1984, Brain research.

[5]  L. DeLisi,et al.  A prospective follow-up study of brain morphology and cognition in first-episode schizophrenic patients: Preliminary findings , 1995, Biological Psychiatry.

[6]  M. Laakso,et al.  A morphometric MRI study of the hippocampus in first-episode, neuroleptic-naı̈ve schizophrenia , 2001, Schizophrenia Research.

[7]  B. Yee.  Cytotoxic lesion of the medial prefrontal cortex abolishes the partial reinforcement extinction effect, attenuates prepulse inhibition of the acoustic startle reflex and induces transient hyperlocomotion, while sparing spontaneous object recognition memory in the rat , 1999, Neuroscience.

[8]  Michael I. Miller,et al.  Abnormalities of cingulate gyrus neuroanatomy in schizophrenia , 2007, Schizophrenia Research.

[9]  B. Turetsky,et al.  Reduced dorsal and orbital prefrontal gray matter volumes in schizophrenia. , 2000, Archives of general psychiatry.

[10]  Alexander Hammers,et al.  Evidence of a smaller left hippocampus and left temporal horn in both patients with first episode schizophrenia and normal control subjects , 2000, Psychiatry Research: Neuroimaging.

[11]  G. Higgins,et al.  Reduced synaptophysin immunoreactivity in the dentate gyrus of prepulse inhibition-impaired isolation-reared rats , 1999, Brain Research.

[12]  F. Berthiaume,et al.  Isolation rearing and hyperlocomotion are associated with reduced immediate early gene expression levels in the medial prefrontal cortex , 2007, Neuroscience.

[13]  T. Sigmundsson,et al.  Hippocampal volume in familial and nonfamilial schizophrenic probands and their unaffected relatives , 2003, Biological Psychiatry.

[14]  Eve C. Johnstone,et al.  Structural Gray Matter Differences between First-Episode Schizophrenics and Normal Controls Using Voxel-Based Morphometry , 2002, NeuroImage.

[15]  M. Geyer,et al.  Deficits in prepulse inhibition and habituation in never-medicated, first-episode schizophrenia , 2003, Biological Psychiatry.

[16]  A. Valero-Cabré,et al.  EARLY SOCIAL ISOLATION DECREASES THE EXPRESSION OF CALBINDIN D-28K AND DENDRITIC BRANCHING IN THE MEDIAL PREFRONTAL CORTEX OF THE RAT , 2007, The International journal of neuroscience.

[17]  K. Fone,et al.  Behavioural and neurochemical effects of post-weaning social isolation in rodents—Relevance to developmental neuropsychiatric disorders , 2008, Neuroscience & Biobehavioral Reviews.

[18]  Robert Freedman,et al.  Increased hemodynamic response in the hippocampus, thalamus and prefrontal cortex during abnormal sensory gating in schizophrenia , 2007, Schizophrenia Research.

[19]  Tyrone D. Cannon,et al.  Progressive brain structural changes mapped as psychosis develops in ‘at risk’ individuals , 2009, Schizophrenia Research.

[20]  Dennis Velakoulis,et al.  Structural brain imaging evidence for multiple pathological processes at different stages of brain development in schizophrenia. , 2005, Schizophrenia bulletin.

[21]  M A Geyer,et al.  Using an animal model of deficient sensorimotor gating to study the pathophysiology and new treatments of schizophrenia. , 1998, Schizophrenia bulletin.

[22]  Michal Mikl,et al.  Prefrontal but not temporal grey matter changes in males with first-episode schizophrenia , 2007, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[23]  G. Teuchert-Noodt,et al.  Postnatal maturation of cortical serotonin lateral asymmetry in gerbils is vulnerable to both environmental and pharmacological epigenetic challenges , 2004, Brain Research.

[24]  N. Makris,et al.  Cortical abnormalities in schizophrenia identified by structural magnetic resonance imaging. , 1999, Archives of general psychiatry.

[25]  Paul J. Harrison.  The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications , 2004, Psychopharmacology.

[26]  M. D. de Leon,et al.  Volumetric measurement of the hippocampus, the anterior cingulate cortex, and the retrosplenial granular cortex of the rat using structural MRI. , 2002, Brain research. Brain research protocols.

[27]  Paul J. Harrison,et al.  Schizophrenia and the frontal lobes: post-mortem stereological study of tissue volume. , 2001, The British journal of psychiatry : the journal of mental science.

[28]  G. Pearlson,et al.  Structural evaluation of the prefrontal cortex in schizophrenia. , 1998, The American journal of psychiatry.

[29]  Stephan Arndt,et al.  Hippocampus and amygdala in schizophrenia: assessment of the relationship of neuroanatomy to psychopathology , 2001, Psychiatry Research: Neuroimaging.

[30]  C. Konradi,et al.  Hippocampal neurons in schizophrenia , 2002, Journal of Neural Transmission.

[31]  B. Pakkenberg,et al.  Total nerve cell number in neocortex in chronic schizophrenics and controls estimated using optical disectors , 1993, Biological Psychiatry.

[32]  M. Koch.  The septohippocampal system is involved in prepulse inhibition of the acoustic startle response in rats. , 1996, Behavioral neuroscience.

[33]  Victor A. F. Lamme,et al.  Heterotopic Cortical Afferents to the Medial Prefrontal Cortex in the Rat. A Combined Retrograde and Anterograde Tracer Study , 1992, The European journal of neuroscience.

[34]  D P Auer,et al.  Corticosteroid status influences the volume of the rat cingulate cortex - a magnetic resonance imaging study. , 2005, Journal of psychiatric research.

[35]  V. Brown,et al.  Double dissociation of social and environmental stimulation on spatial learning and reversal learning in rats , 2004, Behavioural Brain Research.

[36]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[37]  A. Vita,et al.  Brain morphology in first-episode schizophrenia: A meta-analysis of quantitative magnetic resonance imaging studies , 2006, Schizophrenia Research.

[38]  H. Whalley,et al.  Structural MRI of the brain in presumed carriers of genes for schizophrenia, their affected and unaffected siblings , 2002, Journal of neurology, neurosurgery, and psychiatry.

[39]  R Kikinis,et al.  Prefrontal gray matter volume reduction in first episode schizophrenia. , 2001, Cerebral cortex.

[40]  M. Morgan,et al.  Incentive motivation and behavioral inhibition in socially-isolated rats. , 1975 .

[41]  Trevor W. Robbins,et al.  Isolation rearing of rats produces a deficit in prepulse inhibition of acoustic startle similar to that in schizophrenia , 1993, Biological Psychiatry.

[42]  G. Teuchert-Noodt,et al.  Isolation rearing or methamphetamine traumatisation induce a “dysconnection” of prefrontal efferents in gerbils: implications for schizophrenia , 2006, Journal of Neural Transmission.

[43]  D. Amend,et al.  Reduced hippocampal N-acetylaspartate without volume loss in schizophrenia , 1999, Schizophrenia Research.

[44]  C. Marsden,et al.  Antisense Oligonucleotide‐Induced Reduction in 5‐Hydroxytryptamine7 Receptors in the Rat Hypothalamus Without Alteration in Exploratory Behaviour or Neuroendocrine Function , 1998, Journal of neurochemistry.

[45]  M. Geyer,et al.  Isolation rearing of mice induces deficits in prepulse inhibition of the startle response , 2006, Behavioural Brain Research.

[46]  C. Gentsch,et al.  Behavioural comparisons between individually- and group-housed male rats: Effects of novel environments and diurnal rhythm , 1982, Behavioural Brain Research.

[47]  K. Fuxe,et al.  Hyperactivity to novelty induced by social isolation is not correlated with changes in D2 receptor function and binding in striatum , 2003, Psychopharmacology.

[48]  M. Koch,et al.  The acoustic startle response in rats—circuits mediating evocation, inhibition and potentiation , 1997, Behavioural Brain Research.

[49]  Alan N. Francis,et al.  Prefrontal cortex and insight in schizophrenia: A volumetric MRI study , 2007, Schizophrenia Research.

[50]  Tyrone D. Cannon,et al.  Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[51]  S. Lawrie,et al.  Brain structure, genetic liability, and psychotic symptoms in subjects at high risk of developing schizophrenia , 2001, Biological Psychiatry.

[52]  F. Graham,et al.  Presidential Address, 1974. The more or less startling effects of weak prestimulation. , 1975, Psychophysiology.

[53]  Andrew Simmons,et al.  Neural correlates of tactile prepulse inhibition: a functional MRI study in normal and schizophrenic subjects , 2003, Psychiatry Research: Neuroimaging.

[54]  A. Minassian,et al.  The relationship between sensorimotor gating and clinical improvement in acutely ill schizophrenia patients , 2007, Schizophrenia Research.

[55]  John Suckling,et al.  For personal use. Only reproduce with permission from The Lancet Publishing Group. Effect of sunlight and season on serotonin turnover in the brain , 2002 .

[56]  C. Reavill,et al.  Long-term evaluation of isolation-rearing induced prepulse inhibition deficits in rats: an update , 2005, Psychopharmacology.

[57]  Yasuhiro Kawasaki,et al.  Regional changes in brain gray and white matter in patients with schizophrenia demonstrated with voxel-based analysis of MRI , 2002, Schizophrenia Research.

[58]  D. Lewis,et al.  Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. , 2000, Archives of general psychiatry.

[59]  G. Teuchert-Noodt,et al.  Contralateral prefrontal projections in gerbils mature abnormally after early methamphetamine trauma and isolated rearing , 2007, Journal of Neural Transmission.

[60]  C. Marsden,et al.  Increased 5-HT2C receptor responsiveness occurs on rearing rats in social isolation , 1996, Psychopharmacology.

[61]  N. Swerdlow,et al.  Forebrain D1 function and sensorimotor gating in rats: Effects of D1 blockade, frontal lesions and dopamine denervation , 2006, Neuroscience Letters.

[62]  J. Feldon,et al.  Behavioral, neurochemical and endocrinological characterization of the early social isolation syndrome , 2000, Neuroscience.

[63]  M. Miller,et al.  Hippocampal deformities in schizophrenia characterized by high dimensional brain mapping. , 2002, The American journal of psychiatry.

[64]  C. Gentsch,et al.  Isolation-induced locomotor hyperactivity and hypoalgesia in rats are prevented by handling and reversed by resocialization , 1988, Physiology & Behavior.

[65]  Ulrich Ettinger,et al.  Structural brain correlates of prepulse inhibition of the acoustic startle response in healthy humans , 2005, NeuroImage.

[66]  A. Cools,et al.  The role of hippocampal dopamine receptors in prepulse inhibition , 2002, The European journal of neuroscience.

[67]  Godfrey D. Pearlson,et al.  Cingulate gyrus in schizophrenic patients and normal volunteers , 1995, Psychiatry Research: Neuroimaging.

[68]  Nikos Makris,et al.  Left hippocampal volume as a vulnerability indicator for schizophrenia: a magnetic resonance imaging morphometric study of nonpsychotic first-degree relatives. , 2002, Archives of general psychiatry.

[69]  A. Cools,et al.  Prepulse inhibition and latent inhibition: the role of dopamine in the medial prefrontal cortex , 1996, Neuroscience.

[70]  M. Koch,et al.  Prepulse inhibition of the acoustic startle response of rats is reduced by 6-hydroxydopamine lesions of the medial prefrontal cortex , 2005, Psychopharmacology.

[71]  S. Totterdell,et al.  Structural and functional abnormalities of the hippocampal formation in rats with environmentally induced reductions in prepulse inhibition of acoustic startle , 2001, Neuroscience.

[72]  Patricia Desmond,et al.  Hippocampal and amygdala volumes according to psychosis stage and diagnosis: a magnetic resonance imaging study of chronic schizophrenia, first-episode psychosis, and ultra-high-risk individuals. , 2006, Archives of general psychiatry.

[73]  Nuno Sousa,et al.  Effects of altered corticosteroid milieu on rat hippocampal neurochemistry and structure--an in vivo magnetic resonance spectroscopy and imaging study. , 2008, Journal of psychiatric research.

[74]  J. Pierri,et al.  Altered Cortical Glutamate Neurotransmission in Schizophrenia , 2003 .

[75]  Hidenao Fukuyama,et al.  Anterior cingulate pathology and social cognition in schizophrenia: A study of gray matter, white matter and sulcal morphometry , 2007, NeuroImage.

[76]  J. Lieberman,et al.  Brain volume in first-episode schizophrenia , 2006, British Journal of Psychiatry.

[77]  A. Vita,et al.  Hippocampal and amygdala volume reductions in first-episode schizophrenia , 2007, British Journal of Psychiatry.

[78]  N. Swerdlow,et al.  Hippocampal modulation of acoustic startle and prepulse inhibition in the rat , 1992, Pharmacology Biochemistry and Behavior.

[79]  M. Koch,et al.  Picrotoxin in the medial prefrontal cortex impairs sensorimotor gating in rats: reversal by haloperidol , 1999, Psychopharmacology.

[80]  M. Geyer,et al.  Ontogeny of Isolation Rearing-Induced Deficits in Sensorimotor Gating in Rats , 1999, Physiology & Behavior.

[81]  R. Kalisch,et al.  Anxiety and Hippocampus Volume in the Rat , 2006, Neuropsychopharmacology.

[82]  E. Southam,et al.  Medial prefrontal cortex volume loss in rats with isolation rearing-induced deficits in prepulse inhibition of acoustic startle , 2006, Neuroscience.

[83]  J. Hagan,et al.  Isolation rearing induces recognition memory deficits accompanied by cytoskeletal alterations in rat hippocampus , 2006, The European journal of neuroscience.

[84]  J. Ehrhardt,et al.  Brain morphology in first-episode schizophrenia. , 1995, The American journal of psychiatry.

[85]  M. Martin-Iverson,et al.  Attention-dependent reduction in prepulse inhibition of the startle reflex in cannabis users and schizophrenia patients--a pilot study. , 2007, European journal of pharmacology.

[86]  M. Keshavan,et al.  Decreased left amygdala and hippocampal volumes in young offspring at risk for schizophrenia , 2002, Schizophrenia Research.

[87]  A. B. Silva-Gómez,et al.  Decreased dendritic spine density on prefrontal cortical and hippocampal pyramidal neurons in postweaning social isolation rats , 2003, Brain Research.