Neuroplasticity to a single-episode traumatic stress revealed by resting-state fMRI in awake rats

Substantial evidence has suggested that the brain structures of the medial prefrontal cortex (mPFC) and amygdala (AMYG) are implicated in the pathophysiology of stress-related disorders. However, little is known with respect to the system-level adaptation of their neural circuitries to the perturbations of traumatic stressors. By utilizing behavioral tests and an awake animal imaging approach, in the present study we non-invasively investigated the impact of single-episode predator odor exposure in an inescapable environment on behaviors and neural circuits in rodents. We found that predator odor exposure significantly increased the freezing behavior. In addition, animals exhibited heightened anxiety levels seven days after the exposure. Intriguingly, we also found that the intrinsic functional connectivity within the AMYG-mPFC circuit was considerably compromised seven days after the traumatic event. Our data provide neuroimaging evidence suggesting that prolonged neuroadaptation induced by a single episode of traumatic stress can be non-invasively detected in rodents. These results also support the face validity and construction validity of using the paradigm of single trauma exposure in an inescapable environment as an animal model for post-traumatic stress disorder. Taken together, the present study has opened a new avenue to investigating animal models of stress-related mental disorders by going beyond static neuroanatomy, and ultimately bridging the gap between basic biomedical and human imaging research.

[1]  Wei Chen,et al.  Procedure for minimizing stress for fMRI studies in conscious rats , 2005, Journal of Neuroscience Methods.

[2]  Israel Liberzon,et al.  Brain activation in PTSD in response to trauma-related stimuli , 1999, Biological Psychiatry.

[3]  M. Greicius Resting-state functional connectivity in neuropsychiatric disorders , 2008, Current opinion in neurology.

[4]  Nanyin Zhang,et al.  Intrinsic Organization of the Anesthetized Brain , 2012, The Journal of Neuroscience.

[5]  Tao Li,et al.  Mapping thalamocortical networks in rat brain using resting-state functional connectivity , 2013, NeuroImage.

[6]  Julia C. Lemos,et al.  Severe stress switches CRF action in the nucleus accumbens from appetitive to aversive , 2012, Nature.

[7]  B. McEwen Stress and hippocampal plasticity. , 1999, Annual review of neuroscience.

[8]  Larry W. Swanson,et al.  Brain Maps: Structure of the Rat Brain , 1992 .

[9]  Zhifeng Liang,et al.  Mapping resting-state brain networks in conscious animals , 2010, Journal of Neuroscience Methods.

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

[11]  Zhang Nanyin Uncovering intrinsic connectional architecture of functional networks in awake rat brain , 2011 .

[12]  Clas Linnman,et al.  Resting amygdala and medial prefrontal metabolism predicts functional activation of the fear extinction circuit. , 2012, The American journal of psychiatry.

[13]  J. Morrison,et al.  The Brain on Stress: Vulnerability and Plasticity of the Prefrontal Cortex over the Life Course , 2013, Neuron.

[14]  Hagit Cohen,et al.  Early Post-Stressor Intervention with High-Dose Corticosterone Attenuates Posttraumatic Stress Response in an Animal Model of Posttraumatic Stress Disorder , 2008, Biological Psychiatry.

[15]  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.

[16]  Nanyin Zhang,et al.  Fear induced neuronal alterations in a genetic model of depression: An fMRI study on awake animals , 2011, Neuroscience Letters.

[17]  Martin Wiesmann,et al.  Functional Connectivity Bias of the Orbitofrontal Cortex in Drug-Free Patients with Major Depression , 2010, Biological Psychiatry.

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

[19]  Marcelo Febo,et al.  Technical and Conceptual Considerations for Performing and Interpreting Functional MRI Studies in Awake Rats , 2011, Front. Psychiatry.

[20]  Nanyin Zhang,et al.  Multi-modal approach for investigating brain and behavior changes in an animal model of traumatic brain injury. , 2013, Journal of neurotrauma.

[21]  M. Fox,et al.  Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging , 2007, Nature Reviews Neuroscience.

[22]  Bruce S. McEwen,et al.  The neurobiology of stress: from serendipity to clinical relevance. , 2000, Brain research.

[23]  Hagit Cohen,et al.  An Animal Model of Posttraumatic Stress Disorder: The Use of Cut‐Off Behavioral Criteria , 2004, Annals of the New York Academy of Sciences.

[24]  Zhifeng Liang,et al.  Anticorrelated resting-state functional connectivity in awake rat brain , 2012, NeuroImage.

[25]  Hagit Cohen,et al.  The relevance of differential response to trauma in an animal model of posttraumatic stress disorder , 2003, Biological Psychiatry.

[26]  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.

[27]  Amir B. Geva,et al.  Unsupervised Fuzzy Clustering Analysis Supports Behavioral Cutoff Criteria in an Animal Model of Posttraumatic Stress Disorder , 2005, Biological Psychiatry.

[28]  B. Biswal,et al.  Functional connectivity in the motor cortex of resting human brain using echo‐planar mri , 1995, Magnetic resonance in medicine.

[29]  Bruce S. McEwen,et al.  Stress, memory and the amygdala , 2009, Nature Reviews Neuroscience.

[30]  S. Taylor,et al.  Corticolimbic blood flow in posttraumatic stress disorder during script-driven imagery , 2005, Biological Psychiatry.

[31]  R. Adamec,et al.  Lasting effects on rodent anxiety of a single exposure to a cat , 1993, Physiology & Behavior.