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      Longitudinal in vivo Diffusion Tensor Imaging Detects Differential Microstructural Alterations in the Hippocampus of Chronic Social Defeat Stress-Susceptible and Resilient Mice

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          Abstract

          Background: Microstructural alterations in the hippocampus may underlie stress-related disorders and stress susceptibility. However, whether these alterations are pre-existing stress vulnerability biomarkers or accumulative results of chronic stress remain unclear. Moreover, examining the whole hippocampus as one unit and ignoring the possibility of a lateralized effect of stress may mask some stress effects and contribute to the heterogeneity of previous findings.

          Methods: After C57BL/6 mice were exposed to a 10-day chronic social defeat stress (CSDS) paradigm, different stress phenotypes, i.e., susceptible ( n = 10) and resilient ( n = 7) mice, were discriminated by the behavior of the mice in a social interaction test. With in vivo diffusion tensor imaging (DTI) scans that were conducted both before and after the stress paradigm, we evaluated diffusion properties in the left and right, dorsal (dHi) and ventral hippocampus (vHi) of experimental mice.

          Results: A significantly lower fractional anisotropy (FA) was found in the right vHi of the susceptible mice prior to the CSDS paradigm than that found in the resilient mice, suggesting that pre-existing microstructural abnormalities may result in stress susceptibility. However, no significant group differences were found in the post-stress FA values of any of the hippocampal regions of interest (ROIs). In addition, mean diffusivity (MD) and radial diffusivity (RD) values were found to be significantly greater only in the right dHi of the resilient group compared to those of the susceptible mice. Furthermore, a significant longitudinal decrease was only observed in the right dHi RD value of the susceptible mice. Moreover, the social interaction (SI) ratio was positively related to post-stress left MD, right dHi MD, and right dHi RD values and the longitudinal right dHi MD percent change. Meanwhile, a negative relationship was detected between the SI ratio and bilateral mean of the post-stress left relative to right vHi FA value, highlighting the important role of right hippocampus in stress-resilience phenotype.

          Conclusion: Our findings demonstrated different longitudinal microstructural alterations in the bilateral dHi and vHi between stress-susceptible and resilient subgroups and indicated a right-sided lateralized stress effect, which may be useful in the diagnosis and prevention of stress-related disorders as well as their intervention.

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          Animal models of neuropsychiatric disorders.

          Modeling of human neuropsychiatric disorders in animals is extremely challenging given the subjective nature of many symptoms, the lack of biomarkers and objective diagnostic tests, and the early state of the relevant neurobiology and genetics. Nonetheless, progress in understanding pathophysiology and in treatment development would benefit greatly from improved animal models. Here we review the current state of animal models of mental illness, with a focus on schizophrenia, depression and bipolar disorder. We argue for areas of focus that might increase the likelihood of creating more useful models, at least for some disorders, and for explicit guidelines when animal models are reported.
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            The link between childhood trauma and depression: insights from HPA axis studies in humans.

            Childhood trauma is a potent risk factor for developing depression in adulthood, particularly in response to additional stress. We here summarize results from a series of clinical studies suggesting that childhood trauma in humans is associated with sensitization of the neuroendocrine stress response, glucocorticoid resistance, increased central corticotropin-releasing factor (CRF) activity, immune activation, and reduced hippocampal volume, closely paralleling several of the neuroendocrine features of depression. Neuroendocrine changes secondary to early-life stress likely reflect risk to develop depression in response to stress, potentially due to failure of a connected neural circuitry implicated in emotional, neuroendocrine and autonomic control to compensate in response to challenge. However, not all of depression is related to childhood trauma and our results suggest the existence of biologically distinguishable subtypes of depression as a function of childhood trauma that are also responsive to differential treatment. Other risk factors, such as female gender and genetic dispositions, interfere with components of the stress response and further increase vulnerability for depression. Similar associations apply to a spectrum of other psychiatric and medical disorders that frequently coincide with depression and are aggravated by stress. Taken together, this line of evidence demonstrates that psychoneuroendocrine research may ultimately promote optimized clinical care and help prevent the adverse outcomes of childhood trauma.
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              Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure.

              Despite widely reported clinical and preclinical studies of rapid antidepressant actions of glutamate N-methyl-D-aspartate (NMDA) receptor antagonists, there has been very little work examining the effects of these drugs in stress models of depression that require chronic administration of antidepressants or the molecular mechanisms that could account for the rapid responses. We used a rat 21-day chronic unpredictable stress (CUS) model to test the rapid actions of NMDA receptor antagonists on depressant-like behavior, neurochemistry, and spine density and synaptic function of prefrontal cortex neurons. The results demonstrate that acute treatment with the noncompetitive NMDA channel blocker ketamine or the selective NMDA receptor 2B antagonist Ro 25-6981 rapidly ameliorates CUS-induced anhedonic and anxiogenic behaviors. We also found that CUS exposure decreases the expression levels of synaptic proteins and spine number and the frequency/amplitude of synaptic currents (excitatory postsynaptic currents) in layer V pyramidal neurons in the prefrontal cortex and that these deficits are rapidly reversed by ketamine. Blockade of the mammalian target of rapamycin protein synthesis cascade abolishes both the behavioral and biochemical effects of ketamine. The results indicate that the structural and functional deficits resulting from long-term stress exposure, which could contribute to the pathophysiology of depression, are rapidly reversed by NMDA receptor antagonists in a mammalian target of rapamycin dependent manner. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Front Neurosci
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                1662-4548
                1662-453X
                29 August 2018
                2018
                : 12
                : 613
                Affiliations
                [1] 1School of Psychology, Army Medical University , Chongqing, China
                [2] 2Department of Microbiology, College of Basic Medical Sciences, Army Medical University , Chongqing, China
                Author notes

                Edited by: Pablo Blinder, Tel Aviv University, Israel

                Reviewed by: Boldizsar Czeh, University of Pécs, Hungary; James P. Kesby, University of Queensland, Australia; Rafael Delgado Y. Palacios, Federal Agency for Medicines and Health Products (FAMHP), Belgium

                *Correspondence: Zhengzhi Feng, fzz@ 123456tmmu.edu.cn

                This article was submitted to Brain Imaging Methods, a section of the journal Frontiers in Neuroscience

                Article
                10.3389/fnins.2018.00613
                6123364
                30210285
                173956de-17de-4398-af37-978c9e70134c
                Copyright © 2018 Liu, Yuan, Guang, Wang and Feng.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 07 March 2018
                : 13 August 2018
                Page count
                Figures: 2, Tables: 4, Equations: 0, References: 75, Pages: 10, Words: 0
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: NSFC 31640036
                Categories
                Neuroscience
                Original Research

                Neurosciences
                chronic social defeat stress,susceptibility,resilience,dorsoventral hippocampus,diffusion tensor imaging (dti),longitudinal

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