Early life stress-induced alterations in rat brain structures measured with high resolution MRI

Adverse experiences early in life impair cognitive function both in rodents and humans. In humans this increases the vulnerability to develop mental illnesses while in the rodent brain early life stress (ELS) abnormalities are associated with changes in synaptic plasticity, excitability and microstructure. Detailed information on the effects of ELS on rodent brain structural integrity at large and connectivity within the brain is currently lacking; this information is highly relevant for understanding the mechanism by which early life stress predisposes to mental illnesses. Here, we exposed rats to 24 hours of maternal deprivation (MD) at postnatal day 3, a paradigm known to increase corticosterone levels and thereby activate glucocorticoid receptors in the brain. Using structural magnetic resonance imaging we examined: i) volumetric changes and white/grey matter properties of the whole cerebrum and of specific brain areas; and ii) whether potential alterations could be normalized by blocking glucocorticoid receptors with mifepristone during the critical developmental window of early adolescence, i.e. between postnatal days 26 and 28. The results show that MD caused a volumetric reduction of the prefrontal cortex, particularly the ventromedial part, and the orbitofrontal cortex. Within the whole cerebrum, white (relative to grey) matter volume was decreased and region-specifically in prefrontal cortex and dorsomedial striatum following MD. A trend was found for the hippocampus. Grey matter fractions were not affected. Treatment with mifepristone did not normalize these changes. This study indicates that early life stress in rodents has long lasting consequences for the volume and structural integrity of the brain. However, changes were relatively modest and–unlike behavior- not mitigated by blockade of glucocorticoid receptors during a critical developmental period.

[1]  A. Young,et al.  Improvements in Neurocognitive Function and Mood Following Adjunctive Treatment with Mifepristone (RU-486) in Bipolar Disorder , 2004, Neuropsychopharmacology.

[2]  B. Biswal,et al.  Aberrant development of intrinsic brain activity in a rat model of caregiver maltreatment of offspring , 2017, Translational Psychiatry.

[3]  Walter Heindel,et al.  Limbic Scars: Long-Term Consequences of Childhood Maltreatment Revealed by Functional and Structural Magnetic Resonance Imaging , 2012, Biological Psychiatry.

[4]  Spenser R Radtke,et al.  Reduced hippocampal and medial prefrontal gray matter mediate the association between reported childhood maltreatment and trait anxiety in adulthood and predict sensitivity to future life stress , 2014, Biology of Mood & Anxiety Disorders.

[5]  Guillén Fernández,et al.  Stress-induced alterations in large-scale functional networks of the rodent brain , 2015, NeuroImage.

[6]  I. Goodyer,et al.  Disturbances in Morning Cortisol Secretion in Association with Maternal Postnatal Depression Predict Subsequent Depressive Symptomatology in Adolescents , 2007, Biological Psychiatry.

[7]  Jan Sijbers,et al.  Magnetic Resonance Imaging and Spectroscopy Reveal Differential Hippocampal Changes in Anhedonic and Resilient Subtypes of the Chronic Mild Stress Rat Model , 2011, Biological Psychiatry.

[8]  N. Sousa,et al.  Programming effects of antenatal dexamethasone in the developing mesolimbic pathways , 2007, Synapse.

[9]  G. Lynch,et al.  Mechanisms of Late-Onset Cognitive Decline after Early-Life Stress , 2005, The Journal of Neuroscience.

[10]  A. Solodkin,et al.  MRI uncovers disrupted hippocampal microstructure that underlies memory impairments after early‐life adversity , 2016, Hippocampus.

[11]  A. Schatzberg,et al.  Clinical and Biological Effects of Mifepristone Treatment for Psychotic Depression , 2006, Neuropsychopharmacology.

[12]  M. Joëls,et al.  Brief treatment with the glucocorticoid receptor antagonist mifepristone normalizes the reduction in neurogenesis after chronic stress , 2007, The European journal of neuroscience.

[13]  N. Koutsouleris,et al.  Interaction of childhood stress with hippocampus and prefrontal cortex volume reduction in major depression. , 2010, Journal of psychiatric research.

[14]  T. Baram,et al.  Sculpting the hippocampus from within: stress, spines, and CRH , 2012, Trends in Neurosciences.

[15]  M. Joëls,et al.  Opposite Effects of Early Maternal Deprivation on Neurogenesis in Male versus Female Rats , 2009, PloS one.

[16]  M. Joëls,et al.  Early maternal deprivation affects dentate gyrus structure and emotional learning in adult female rats , 2011 .

[17]  Jamie L. Hanson,et al.  Behavioral Problems After Early Life Stress: Contributions of the Hippocampus and Amygdala , 2015, Biological Psychiatry.

[18]  R. Fields,et al.  White matter in learning, cognition and psychiatric disorders , 2008, Trends in Neurosciences.

[19]  R. Bronen,et al.  Magnetic resonance imaging-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse—a preliminary report , 1997, Biological Psychiatry.

[20]  Diego A. Pizzagalli,et al.  Effects of early life stress on cognitive and affective function: an integrated review of human literature , 2011, Psychopharmacology.

[21]  E. Alleva,et al.  Early disruption of the mother–infant relationship: effects on brain plasticity and implications for psychopathology , 2003, Neuroscience & Biobehavioral Reviews.

[22]  J. Bischofberger,et al.  Early Life Stress Differentially Modulates Distinct Forms of Brain Plasticity in Young and Adult Mice , 2012, PloS one.

[23]  G. Fernández,et al.  Blocking glucocorticoid receptors at adolescent age prevents enhanced freezing between repeated cue-exposures after conditioned fear in adult mice raised under chronic early life stress , 2016, Neurobiology of Learning and Memory.

[24]  F. Seguin,et al.  Effects of stress throughout the lifespan on the brain, behaviour and cognition , 2009 .

[25]  S. Lazic,et al.  Chronic early life stress alters developmental and adult neurogenesis and impairs cognitive function in mice , 2015, Hippocampus.

[26]  C. Wellman,et al.  Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration. , 2001, Journal of neurobiology.

[27]  Stephen M. Smith,et al.  A global optimisation method for robust affine registration of brain images , 2001, Medical Image Anal..

[28]  M. Rutter,et al.  Amygdala, hippocampal and corpus callosum size following severe early institutional deprivation: the English and Romanian Adoptees study pilot. , 2009, Journal of child psychology and psychiatry, and allied disciplines.

[29]  M. K. Gordon,et al.  Maternal deprivation increases cell death in the infant rat brain. , 2002, Brain research. Developmental brain research.

[30]  Jennifer I. Lissemore,et al.  A longitudinal study of stress‐induced hippocampal volume changes in mice that are susceptible or resilient to chronic social defeat , 2014, Hippocampus.

[31]  L. Rowland,et al.  Reduced hippocampal volume and total white matter volume in posttraumatic stress disorder , 2002, Biological Psychiatry.

[32]  C. Nemeroff,et al.  The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies , 2001, Biological Psychiatry.

[33]  J. Morrison,et al.  Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex. , 2006, Cerebral cortex.

[34]  M. Joëls,et al.  Severe Early Life Stress Hampers Spatial Learning and Neurogenesis, but Improves Hippocampal Synaptic Plasticity and Emotional Learning under High-Stress Conditions in Adulthood , 2010, The Journal of Neuroscience.

[35]  Nicholas D. Walsh,et al.  General and specific effects of early-life psychosocial adversities on adolescent grey matter volume☆ , 2014, NeuroImage: Clinical.

[36]  Martin H. Teicher,et al.  Preliminary evidence for sensitive periods in the effect of childhood sexual abuse on regional brain development. , 2008, The Journal of neuropsychiatry and clinical neurosciences.

[37]  Matcheri S. Keshavan,et al.  Brain structures in pediatric maltreatment-related posttraumatic stress disorder: a sociodemographically matched study , 2002, Biological Psychiatry.

[38]  Rajita Sinha,et al.  Cumulative Adversity and Smaller Gray Matter Volume in Medial Prefrontal, Anterior Cingulate, and Insula Regions , 2012, Biological Psychiatry.

[39]  E. Crone,et al.  Hippocampal volume and internalizing behavior problems in adolescence , 2013, European Neuropsychopharmacology.

[40]  Eric Vermetten,et al.  Reduced volume of orbitofrontal cortex in major depression , 2002, Biological Psychiatry.

[41]  A. Aleman,et al.  Reduced Medial Prefrontal Cortex Volume in Adults Reporting Childhood Emotional Maltreatment , 2010, Biological Psychiatry.

[42]  M. Nishi,et al.  Effects of early life adverse experiences on the brain: implications from maternal separation models in rodents , 2014, Front. Neurosci..

[43]  D. C. Johnson,et al.  Medial prefrontal cortex activity can disrupt the expression of stress response habituation , 2010, Neuroscience.

[44]  S. Chattarji,et al.  Recovery after chronic stress fails to reverse amygdaloid neuronal hypertrophy and enhanced anxiety-like behavior , 2004, Neuroscience.

[45]  Stephan Eliez,et al.  Attenuation of frontal asymmetry in pediatric posttraumatic stress disorder , 2001, Biological Psychiatry.

[46]  Eric Vermetten,et al.  Childhood trauma associated with smaller hippocampal volume in women with major depression. , 2002, The American journal of psychiatry.

[47]  B. McEwen,et al.  Stress- and allostasis-induced brain plasticity. , 2011, Annual Review of Medicine.

[48]  Nagesh Adluru,et al.  Early neglect is associated with alterations in white matter integrity and cognitive functioning. , 2013, Child development.

[49]  G. Flores,et al.  Prenatal stress alters spine density and dendritic length of nucleus accumbens and hippocampus neurons in rat offspring , 2009, Synapse.

[50]  S. Chattarji,et al.  Chronic Stress Induces Contrasting Patterns of Dendritic Remodeling in Hippocampal and Amygdaloid Neurons , 2002, The Journal of Neuroscience.

[51]  Bruce S. McEwen,et al.  Stress-Induced Alterations in Prefrontal Cortical Dendritic Morphology Predict Selective Impairments in Perceptual Attentional Set-Shifting , 2006, The Journal of Neuroscience.

[52]  Michael Brady,et al.  Improved Optimization for the Robust and Accurate Linear Registration and Motion Correction of Brain Images , 2002, NeuroImage.

[53]  G. Richter-Levin,et al.  Learning under stress in the adult rat is differentially affected by 'juvenile' or 'adolescent' stress. , 2006, The international journal of neuropsychopharmacology.

[54]  C. Hammen,et al.  Hippocampal Changes Associated with Early-Life Adversity and Vulnerability to Depression , 2010, Biological Psychiatry.

[55]  Malek Bajbouj,et al.  Amygdala–Hippocampal Connectivity Changes During Acute Psychosocial Stress: Joint Effect of Early Life Stress and Oxytocin , 2015, Neuropsychopharmacology.

[56]  M. Yücel,et al.  Hippocampal volume and sensitivity to maternal aggressive behavior: A prospective study of adolescent depressive symptoms , 2011, Development and Psychopathology.

[57]  Talma Hendler,et al.  Stress‐induced reduction in hippocampal volume and connectivity with the ventromedial prefrontal cortex are related to maladaptive responses to stressful military service , 2013, Human brain mapping.

[58]  D. Hedges,et al.  Early-life stress and cognitive outcome , 2011, Psychopharmacology.

[59]  S. Rauch,et al.  Amygdala, Medial Prefrontal Cortex, and Hippocampal Function in PTSD , 2006, Annals of the New York Academy of Sciences.