Decreased SGK1 Expression and Function Contributes to Behavioral Deficits Induced by Traumatic Stress

Exposure to extreme stress can trigger the development of major depressive disorder (MDD) as well as post-traumatic stress disorder (PTSD). The molecular mechanisms underlying the structural and functional alterations within corticolimbic brain regions, including the prefrontal cortex (PFC) and amygdala of individuals subjected to traumatic stress, remain unknown. In this study, we show that serum and glucocorticoid regulated kinase 1 (SGK1) expression is down-regulated in the postmortem PFC of PTSD subjects. Furthermore, we demonstrate that inhibition of SGK1 in the rat medial PFC results in helplessness- and anhedonic-like behaviors in rodent models. These behavioral changes are accompanied by abnormal dendritic spine morphology and synaptic dysfunction. Together, the results are consistent with the possibility that altered SGK1 signaling contributes to the behavioral and morphological phenotypes associated with traumatic stress pathophysiology.

[1]  P. Licznerski,et al.  Remodeling of axo-spinous synapses in the pathophysiology and treatment of depression , 2013, Neuroscience.

[2]  H. Cohen,et al.  Animal Models of Post‐Traumatic Stress Disorder , 2013, Current protocols in neuroscience.

[3]  Janet B W Williams,et al.  Diagnostic and Statistical Manual of Mental Disorders , 2013 .

[4]  F. Helmstetter,et al.  NR2A- and NR2B-containing NMDA receptors in the prelimbic medial prefrontal cortex differentially mediate trace, delay, and contextual fear conditioning. , 2013, Learning & memory.

[5]  K. Tansey,et al.  Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis , 2013, Proceedings of the National Academy of Sciences.

[6]  G. Rajkowska,et al.  Decreased Expression of Synapse-Related Genes and Loss of Synapses in Major Depressive Disorder , 2012, Nature Medicine.

[7]  Nanxin Li,et al.  Neuritin produces antidepressant actions and blocks the neuronal and behavioral deficits caused by chronic stress , 2012, Proceedings of the National Academy of Sciences.

[8]  M. Cooper,et al.  Overlapping neurobiology of learned helplessness and conditioned defeat: Implications for PTSD and mood disorders , 2012, Neuropharmacology.

[9]  J. Homberg,et al.  Animal models of depression and anxiety: What do they tell us about human condition? , 2011, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[10]  I. Liberzon,et al.  The Neurocircuitry of Fear, Stress, and Anxiety Disorders , 2011, Neuropsychopharmacology.

[11]  M. Tohyama,et al.  Plasma Corticosterone Activates SGK1 and Induces Morphological Changes in Oligodendrocytes in Corpus Callosum , 2011, PloS one.

[12]  B. Bradley,et al.  Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor , 2011, Nature.

[13]  Wenhua Liu,et al.  Mechanisms for acute stress-induced enhancement of glutamatergic transmission and working memory , 2011, Molecular Psychiatry.

[14]  H. Schmidt,et al.  A negative regulator of MAP kinase causes depressive behavior. , 2010, Nature medicine.

[15]  F. Lang,et al.  Significance of SGK1 in the regulation of neuronal function , 2010, The Journal of physiology.

[16]  M. Stein,et al.  Interaction of FKBP5 with Childhood Adversity on Risk for Post-Traumatic Stress Disorder , 2010, Neuropsychopharmacology.

[17]  F. Helmstetter,et al.  Trace and contextual fear conditioning require neural activity and NMDA receptor-dependent transmission in the medial prefrontal cortex. , 2010, Learning & memory.

[18]  B. Bradley,et al.  Impaired fear inhibition is a biomarker of PTSD but not depression , 2010, Depression and anxiety.

[19]  Daniel H. Mathalon,et al.  Working Memory Overload: Fronto-Limbic Interactions and Effects on Subsequent Working Memory Function , 2010, Brain Imaging and Behavior.

[20]  Florian Holsboer,et al.  Gene Expression Patterns Associated with Posttraumatic Stress Disorder Following Exposure to the World Trade Center Attacks , 2009, Biological Psychiatry.

[21]  Ewelina Knapska,et al.  Reciprocal patterns of c-Fos expression in the medial prefrontal cortex and amygdala after extinction and renewal of conditioned fear. , 2009, Learning & memory.

[22]  W. Falls,et al.  Chronic stress increases pituitary adenylate cyclase-activating peptide (PACAP) and brain-derived neurotrophic factor (BDNF) mRNA expression in the bed nucleus of the stria terminalis (BNST): Roles for PACAP in anxiety-like behavior , 2009, Psychoneuroendocrinology.

[23]  M. Banasr,et al.  Glial Loss in the Prefrontal Cortex Is Sufficient to Induce Depressive-like Behaviors , 2008, Biological Psychiatry.

[24]  Joseph E LeDoux,et al.  Neural Circuitry Underlying the Regulation of Conditioned Fear and Its Relation to Extinction , 2008, Neuron.

[25]  P. Sah,et al.  Behavioural neuroscience: The circuit of fear , 2008, Nature.

[26]  T. Su,et al.  p11 is up-regulated in the forebrain of stressed rats by glucocorticoid acting via two specific glucocorticoid response elements in the p11 promoter , 2008, Neuroscience.

[27]  N. Breslau,et al.  The latent structure of post-traumatic stress disorder: tests of invariance by gender and trauma type , 2008, Psychological Medicine.

[28]  Richard J. Flannery,et al.  Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons , 2008, Proceedings of the National Academy of Sciences.

[29]  F. Guimarães,et al.  The Expression of Contextual Fear Conditioning Involves Activation of an NMDA Receptor–Nitric Oxide Pathway in the Medial Prefrontal Cortex , 2007, Cerebral cortex.

[30]  James C. Overholser,et al.  Gene Expression Profiling in Postmortem Prefrontal Cortex of Major Depressive Disorder , 2007, The Journal of Neuroscience.

[31]  JaneR . Taylor,et al.  Chronic Unpredictable Stress Decreases Cell Proliferation in the Cerebral Cortex of the Adult Rat , 2007, Biological Psychiatry.

[32]  Lisa M. Shin,et al.  Neurocircuitry Models of Posttraumatic Stress Disorder and Extinction: Human Neuroimaging Research—Past, Present, and Future , 2006, Biological Psychiatry.

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

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

[35]  S. Eliez,et al.  Decreased Anterior Cingulate Volume in Combat-Related PTSD , 2006, Biological Psychiatry.

[36]  S. Maier,et al.  Stressor controllability and learned helplessness: The roles of the dorsal raphe nucleus, serotonin, and corticotropin-releasing factor , 2005, Neuroscience & Biobehavioral Reviews.

[37]  R. Kalb,et al.  Serum/glucocorticoid‐inducible kinase can phosphorylate the cyclic AMP response element binding protein, CREB , 2005, FEBS letters.

[38]  Darin D Dougherty,et al.  Regional cerebral blood flow in the amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD. , 2004, Archives of general psychiatry.

[39]  H. Yamasue,et al.  Voxel-based analysis of MRI reveals anterior cingulate gray-matter volume reduction in posttraumatic stress disorder due to terrorism , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[40]  M. Kay,et al.  Helper virus-free, optically controllable, and two-plasmid-based production of adeno-associated virus vectors of serotypes 1 to 6. , 2003, Molecular therapy : the journal of the American Society of Gene Therapy.

[41]  S. Southwick,et al.  Neural correlates of declarative memory for emotionally valenced words in women with posttraumatic stress disorder related to early childhood sexual abuse , 2003, Biological Psychiatry.

[42]  S. Southwick,et al.  Neural correlates of memories of childhood sexual abuse in women with and without posttraumatic stress disorder. , 1999, The American journal of psychiatry.

[43]  Lawrence H Staib,et al.  Neural correlates of exposure to traumatic pictures and sound in Vietnam combat veterans with and without posttraumatic stress disorder: a positron emission tomography study , 1999, Biological Psychiatry.

[44]  S. Orr,et al.  Prospective study of posttraumatic stress disorder and depression following trauma. , 1998, The American journal of psychiatry.

[45]  G. Brewer,et al.  Optimized survival of hippocampal neurons in B27‐supplemented neurobasal™, a new serum‐free medium combination , 1993, Journal of neuroscience research.

[46]  G. Firestone,et al.  Immediate-early transcriptional regulation and rapid mRNA turnover of a putative serine/threonine protein kinase. , 1993, The Journal of biological chemistry.

[47]  A. C. Maiyar,et al.  Characterization of sgk, a novel member of the serine/threonine protein kinase gene family which is transcriptionally induced by glucocorticoids and serum , 1993, Molecular and cellular biology.

[48]  S. Southwick,et al.  Psychobiologic mechanisms of posttraumatic stress disorder. , 1993, Archives of general psychiatry.

[49]  J. Krystal,et al.  Inescapable shock, neurotransmitters, and addiction to trauma: Toward a psychobiology of post traumatic stress , 1985, Biological Psychiatry.

[50]  L. Swanson.  The Rat Brain in Stereotaxic Coordinates, George Paxinos, Charles Watson (Eds.). Academic Press, San Diego, CA (1982), vii + 153, $35.00, ISBN: 0 125 47620 5 , 1984 .

[51]  M. Seligman,et al.  Learned helplessness: Theory and evidence. , 1976 .

[52]  Zhen Yan,et al.  The Stress Hormone Corticosterone Increases Synaptic α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors via Serum- and Glucocorticoid-inducible Kinase (SGK) Regulation of the GDI-Rab4 Complex* , 2010, The Journal of Biological Chemistry.

[53]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[54]  HighWire Press.  The journal of neuroscience : the official journal of the Society for Neuroscience. , 1981 .