Basal anxiety-like behavior predicts differences in dendritic morphology in the medial prefrontal cortex in two strains of rats

Basal differences in the brain may account for why some individuals are more vulnerable to stress than others. Although trait anxiety behavior varies greatly in human populations, most animal models of anxiety disorders tend to focus on the development of anxiety after a stressful experience. In this study, adult male Sprague-Dawley and Lewis rats were grouped according to baseline anxiety-like behavior in the open field, measured by time spent and distance traveled in the center. Individuals that fell one standard deviation above and below the mean, approximately the top and bottom 15%, were selected for the Low and High Anxiety groups. Pyramidal neurons from layer II/III of the prelimbic region of the medial prefrontal cortex were iontophoretically loaded with Lucifer yellow dye and reconstructed. In both strains, animals in the High Anxiety group had smaller apical dendrites than those in the Low Anxiety group. No difference was found in basal dendrites. Sholl analysis revealed a strain difference in the distribution of dendritic material between anxiety groups. These results illustrate significant variability in dendritic morphology in the prefrontal cortex of healthy adult male rats prior to experimental manipulation that correlates with baseline levels of anxiety-like behavior.

[1]  Y. Lee,et al.  Dorsal-ventral distinction of chronic stress-induced electrophysiological alterations in the rat medial prefrontal cortex , 2011, Neuroscience.

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

[3]  A. Ramos,et al.  Common variations in the pretest environment influence genotypic comparisons in models of anxiety , 2005, Genes, brain, and behavior.

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

[5]  Anders Björklund,et al.  Organization of catecholamine neurons projecting to the frontal cortex in the rat , 1978, Brain Research.

[6]  J. M. Koolhaas,et al.  Bidirectional shift in the cornu ammonis 3 pyramidal dendritic organization following brief stress , 2004, Neuroscience.

[7]  R. Deacon,et al.  Marked for life? Effects of early cage-cleaning frequency, delivery batch, and identification tail-marking on rat anxiety profiles. , 2008, Developmental psychobiology.

[8]  F. Champagne,et al.  Like mother, like daughter: evidence for non-genomic transmission of parental behavior and stress responsivity. , 2001, Progress in brain research.

[9]  P. Janssen,et al.  Discriminative stimulus properties of benzodiazepines, barbiturates and pharmacologically related drugs; relation to some intrinsic and anticonvulsant effects. , 1976, European journal of pharmacology.

[10]  Remco J. Renken,et al.  Neuroticism modulates amygdala—prefrontal connectivity in response to negative emotional facial expressions , 2010, NeuroImage.

[11]  P. Whalen,et al.  The Structural Integrity of an Amygdala–Prefrontal Pathway Predicts Trait Anxiety , 2009, The Journal of Neuroscience.

[12]  G. Nomikos,et al.  Individual responses to novelty are associated with differences in behavioral and neurochemical profiles , 2008, Behavioural Brain Research.

[13]  H. Anisman,et al.  Do early-life events permanently alter behavioral and hormonal responses to stressors? , 1998, International Journal of Developmental Neuroscience.

[14]  Francisco Sotres-Bayon,et al.  Prefrontal control of fear: more than just extinction , 2010, Current Opinion in Neurobiology.

[15]  K. Braun,et al.  Changes of spine density and dendritic complexity in the prefrontal cortex in offspring of mothers exposed to stress during pregnancy , 2006, The European journal of neuroscience.

[16]  M. Meaney,et al.  Influence of Naturally Occurring Variations in Maternal Care on Prepulse Inhibition of Acoustic Startle and the Medial Prefrontal Cortical Dopamine Response to Stress in Adult Rats , 2005, The Journal of Neuroscience.

[17]  G. Quirk,et al.  Activity in Prelimbic Cortex Is Necessary for the Expression of Learned, But Not Innate, Fears , 2007, The Journal of Neuroscience.

[18]  R A Bryant,et al.  Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety , 2009, Molecular Psychiatry.

[19]  Talma Hendler,et al.  Human vulnerability to stress depends on amygdala's predisposition and hippocampal plasticity , 2009, Proceedings of the National Academy of Sciences.

[20]  D. Stein,et al.  Maternal separation of rat pups increases the risk of developing depressive-like behavior after subsequent chronic stress by altering corticosterone and neurotrophin levels in the hippocampus , 2008, Neuroscience Research.

[21]  Susan C. Cook,et al.  Chronic stress alters dendritic morphology in rat medial prefrontal cortex. , 2004, Journal of neurobiology.

[22]  B. McEwen,et al.  Chronic immobilization stress alters aspects of emotionality and associative learning in the rat. , 2008, Behavioral neuroscience.

[23]  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.

[24]  T. Jay,et al.  The Prefrontal Cortex as a Key Target of the Maladaptive Response to Stress , 2007, The Journal of Neuroscience.

[25]  S. Sesack,et al.  Ultrastructural localization of the norepinephrine transporter in superficial and deep layers of the rat prelimbic prefrontal cortex and its spatial relationship to probable dopamine terminals , 2000, The Journal of comparative neurology.

[26]  D. Treit,et al.  Excitotoxic lesions of the medial prefrontal cortex attenuate fear responses in the elevated-plus maze, social interaction and shock probe burying tests , 2003, Brain Research.

[27]  J. Zohar,et al.  Blunted HPA Axis Response to Stress Influences Susceptibility to Posttraumatic Stress Response in Rats , 2006, Biological Psychiatry.

[28]  B. McEwen,et al.  Modification of Social Memory, Hypothalamic-Pituitary-Adrenal Axis, and Brain Asymmetry by Neonatal Novelty Exposure , 2003, The Journal of Neuroscience.

[29]  K. Braun,et al.  Weaning age, social isolation, and gender, interact to determine adult explorative and social behavior, and dendritic and spine morphology in prefrontal cortex of rats , 2007, Behavioural Brain Research.

[30]  A. Aleman,et al.  Regional brain volume in depression and anxiety disorders. , 2010, Archives of general psychiatry.

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

[32]  C. Sandi,et al.  Individual differences in anxiety trait are related to spatial learning abilities and hippocampal expression of mineralocorticoid receptors , 2006, Neurobiology of Learning and Memory.

[33]  B. McEwen,et al.  Chronic Psychosocial Stress Causes Apical Dendritic Atrophy of Hippocampal CA3 Pyramidal Neurons in Subordinate Tree Shrews , 1996, The Journal of Neuroscience.

[34]  Bruce Fischl,et al.  Thickness of ventromedial prefrontal cortex in humans is correlated with extinction memory. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[35]  A. Etkin,et al.  Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. , 2007, The American journal of psychiatry.

[36]  Daniel Mendelsohn,et al.  The HR/LR model: Further evidence as an animal model of sensation seeking , 2009, Neuroscience & Biobehavioral Reviews.

[37]  Jennifer S. Beer,et al.  Prefrontal involvement in the regulation of emotion: convergence of rat and human studies , 2006, Current Opinion in Neurobiology.

[38]  E. Fuchs,et al.  Morphology of Pyramidal Neurons in the Rat Prefrontal Cortex: Lateralized Dendritic Remodeling by Chronic Stress , 2007, Neural plasticity.

[39]  Gregory J. Quirk,et al.  Prefrontal Mechanisms in Extinction of Conditioned Fear , 2006, Biological Psychiatry.

[40]  M. Meaney,et al.  Environmental programming of stress responses through DNA methylation: life at the interface between a dynamic environment and a fixed genome , 2005, Dialogues in clinical neuroscience.

[41]  G. Kenis,et al.  Maternal stress-induced reduction in birth weight as a marker for adult affective state. , 2010, Frontiers in bioscience.

[42]  B. McEwen,et al.  Effects of antidepressants and benzodiazepine treatments on the dendritic structure of CA3 pyramidal neurons after chronic stress. , 1999, European journal of pharmacology.

[43]  B. McEwen,et al.  Subordination stress: Behavioral, brain, and neuroendocrine correlates , 1993, Behavioural Brain Research.

[44]  R. Sullivan,et al.  Behavioral effects of excitotoxic lesions of ventral medial prefrontal cortex in the rat are hemisphere-dependent , 2002, Brain Research.

[45]  K. Braun,et al.  Experience-induced changes of dendritic spine densities in the prefrontal and sensory cortex: correlation with developmental time windows. , 2005, Cerebral cortex.

[46]  A. Salm,et al.  Lateral amygdaloid nucleus expansion in adult rats is associated with exposure to prenatal stress. , 2004, Brain research. Developmental brain research.

[47]  B. Mcewen,et al.  Effect of brain‐derived neurotrophic factor haploinsufficiency on stress‐induced remodeling of hippocampal neurons , 2011, Hippocampus.

[48]  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.

[49]  J. Feldon,et al.  Levels of neurotrophic factors in the hippocampus and amygdala correlate with anxiety- and fear-related behaviour in C57BL6 mice , 2006, Journal of Neural Transmission.

[50]  Jordan Grafman,et al.  Neural correlates of anxiety in healthy volunteers: a voxel-based morphometry study. , 2009 .

[51]  C. Thiel,et al.  Relationship between anxiety and serotonin in the ventral striatum , 1998, Neuroreport.

[52]  P. Kalivas,et al.  Individual locomotor response to novelty predicts selective alterations in D1 and D2 receptors and mRNAs , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[53]  Nicolas Singewald,et al.  Differential Stress-Induced Neuronal Activation Patterns in Mouse Lines Selectively Bred for High, Normal or Low Anxiety , 2009, PloS one.

[54]  F. Champagne,et al.  Stress During Gestation Alters Postpartum Maternal Care and the Development of the Offspring in a Rodent Model , 2006, Biological Psychiatry.

[55]  M. Jurkowski,et al.  Blood and spleen natural killer cell cytotoxicity after exposure to open field stress in rats: the effect of spontaneous locomotor activity , 2004, Journal of Neuroimmunology.

[56]  M. Shenton,et al.  Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma , 2002, Nature Neuroscience.

[57]  Raffael Kalisch,et al.  High trait anxiety and hyporeactivity to stress of the dorsomedial prefrontal cortex: a combined phMRI and Fos study in rats , 2004, NeuroImage.

[58]  R. Schwarting,et al.  Animal models of human psychopathology based on individual differences in novelty-seeking and anxiety , 2008, Neuroscience & Biobehavioral Reviews.

[59]  W. Drevets,et al.  Imaging phenotypes of major depressive disorder: genetic correlates , 2009, Neuroscience.

[60]  B. McEwen,et al.  Early life stress followed by subsequent adult chronic stress potentiates anxiety and blunts hippocampal structural remodeling , 2012, Hippocampus.

[61]  Shannon R. Henning,et al.  Mild, short-term stress alters dendritic morphology in rat medial prefrontal cortex. , 2005, Cerebral cortex.

[62]  I. McGregor,et al.  Modulation of anxiety-related behaviours following lesions of the prelimbic or infralimbic cortex in the rat , 1997, Brain Research.

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

[64]  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.

[65]  Erik B. Bloss,et al.  Interactive Effects of Stress and Aging on Structural Plasticity in the Prefrontal Cortex , 2010, The Journal of Neuroscience.

[66]  M. Molliver,et al.  The serotonin innervation of the cerebral cortex in the rat—an immunohistochemical analysis , 1980, Neuroscience.

[67]  Axel Schäfer,et al.  Emotion regulation in spider phobia: role of the medial prefrontal cortex. , 2009, Social cognitive and affective neuroscience.

[68]  J. Feldon,et al.  Differential role of the medial and lateral prefrontal cortices in fear and anxiety. , 2000, Behavioral neuroscience.

[69]  S. Morato,et al.  Prenatal stress produces more behavioral alterations than maternal separation in the elevated plus-maze and in the elevated T-maze , 2005, Behavioural Brain Research.

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

[71]  F. Chaouloff,et al.  Differential effects of social stress on central serotonergic activity and emotional reactivity in Lewis and spontaneously hypertensive rats , 1997, Neuroscience.

[72]  F. Chaouloff,et al.  A multiple-test study of anxiety-related behaviours in six inbred rat strains , 1997, Behavioural Brain Research.

[73]  R. Holson,et al.  Mesial prefrontal cortical lesions and timidity in rats. II. Reactivity to novel stimuli , 1986, Physiology & Behavior.

[74]  F. Sharp,et al.  Relative expression of D3 dopamine receptor and alternative splice variant D3nf mRNA in high and low responders to novelty , 2006, Brain Research Bulletin.

[75]  S. Sesack,et al.  Ultrastructural localization of the norepinephrine transporter in superficial and deep layers of the rat prelimbic prefrontal cortex and its spatial relationship to probable dopamine terminals. , 2003, The Journal of comparative neurology.

[76]  Differential distribution of γ-aminobutyric acidA, receptor subunit (α 1, α 2, α 3, α 5 and β 2+3) immunoreactivity in the medial prefrontal cortex of the rat , 1996, Neuroscience Letters.

[77]  Paul E. Sawchenko,et al.  Regional Differentiation of the Medial Prefrontal Cortex in Regulating Adaptive Responses to Acute Emotional Stress , 2006, The Journal of Neuroscience.

[78]  Robert P. Vertes,et al.  Interactions among the medial prefrontal cortex, hippocampus and midline thalamus in emotional and cognitive processing in the rat , 2006, Neuroscience.

[79]  J. Morrison,et al.  Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex , 2004, Neuroscience.

[80]  B. McEwen,et al.  Prenatal stress selectively alters the reactivity of the hypothalamic-pituitary adrenal system in the female rat , 1992, Brain Research.

[81]  Joseph E LeDoux,et al.  Individual differences in fear: isolating fear reactivity and fear recovery phenotypes. , 2007, Journal of traumatic stress.

[82]  R. Schwarting,et al.  Relationship between striatal levels of interleukin-2 mRNA and plus-maze behaviour in the rat , 2003, Neuroscience Letters.

[83]  G. Quirk,et al.  Inhibition of the Amygdala: Key to Pathological States? , 2003, Annals of the New York Academy of Sciences.

[84]  E. Frank,et al.  Impaired extinction of learned fear in rats selectively bred for high anxiety – evidence of altered neuronal processing in prefrontal-amygdala pathways , 2008, The European journal of neuroscience.

[85]  A. Grace,et al.  Chronic Stress Increases the Plasmalemmal Distribution of the Norepinephrine Transporter and the Coexpression of Tyrosine Hydroxylase in Norepinephrine Axons in the Prefrontal Cortex , 2006, The Journal of Neuroscience.

[86]  H. Akil,et al.  Individual differences in novelty-seeking and emotional reactivity correlate with variation in maternal behavior , 2007, Hormones and Behavior.

[87]  S. Rauch,et al.  Fear extinction in rats: Implications for human brain imaging and anxiety disorders , 2006, Biological Psychology.

[88]  B. McEwen,et al.  Alterations in corticolimbic dendritic morphology and emotional behavior in cannabinoid CB1 receptor-deficient mice parallel the effects of chronic stress. , 2011, Cerebral cortex.

[89]  Andrew Holmes,et al.  Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease , 2008, Neuroscience & Biobehavioral Reviews.

[90]  P. Piazza,et al.  Higher and longer stress-induced increase in dopamine concentrations in the nucleus accumbens of animals predisposed to amphetamine self-administration. A microdialysis study , 1993, Brain Research.