The role of glucocorticoid receptors in the induction and prevention of hippocampal abnormalities in an animal model of posttraumatic stress disorder

Rationale: Since the precise mechanisms of posttraumatic stress disorder (PTSD) remain unknown, effective treatment interventions have not yet been established. Numerous clinical studies have led to the hypothesis that elevated glucocorticoid levels in response to extreme stress might trigger a pathophysiological cascade which consequently leads to functional and morphological changes in the hippocampus. Objectives: To elucidate the pathophysiology of PTSD, we examined the alteration of hippocampal gene expression through the glucocorticoid receptor (GR) in the single prolonged stress (SPS) paradigm, a rat model of PTSD. Methods: We measured nuclear GRs by western blot, and the binding of GR to the promoter of Bcl-2 and Bax genes by chromatin immunoprecipitation-qPCR as well as the expression of these 2 genes by RT-PCR in the hippocampus of SPS rats. In addition, we examined the preventive effects of a GR antagonist on SPS-induced molecular, morphological, and behavioral alterations (hippocampal gene expression of Bcl-2 and Bax, hippocampal apoptosis using TUNEL staining, impaired fear memory extinction (FME) using the contextual fear conditioning paradigm). Results: Exposure to SPS increased nuclear GR expression and GR binding to Bcl-2 gene, and decreased Bcl-2 mRNA expression. Administration of GR antagonist immediately after SPS prevented activation of the glucocorticoid cascade, hippocampal apoptosis, and impairment FME in SPS rats. Conclusion: The activation of GRs in response to severe stress may trigger the pathophysiological cascade leading to impaired FME and hippocampal apoptosis. In contrast, administration of GR antagonist could be useful for preventing the development of PTSD.This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (a grant-in aid for Scientific Research, C) Grant Number JP18K07562, and Takeda Science Foundation

PTSDモデルラットにおける海馬異常の惹起と予防に関するグルココルチコイド受容体の役割の検討

内容の要旨, 審査の要旨広島大学(Hiroshima University)博士(医学)Doctor of Philosophy in Medical Sciencedoctora

What is artificial endocrine pancreas? Mechanism and history

The artificial endocrine pancreas is a feedback control instrument that regulates insulin delivery on a minute-by-minute basis according to measured blood glucose levels. Only one type of bedside-type artificial endocrine pancreas is now available in Japan: STG-22 (Nikkiso Co. Ltd., Japan). In the insulin infusion algorithm, insulin is infused on the basis of its proportional and derivative actions, to blood glucose concentrations with a constant time delay. The bedside-type artificial endocrine pancreas has been proven to be useful not only as a therapeutic tool for diabetes mellitus, but also as an elegant research tool for investigating the pathophysiology of the disease, by using the euglycemic hyperinsulinemic glucose clamp technique. The wearable type of closed-loop system has been developed recently. The breakthrough is the establishment of a needle-type glucose sensor. The development of closed-loop glycemic control systems that enable long-term physiological regulation has focused on implantable devices. Much effort has been expended to realize these devices

Long-Term Effects of Postearthquake Distress on Brain Microstructural Changes

Stressful events can have both short- and long-term effects on the brain. Our recent investigation identified short-term white matter integrity (WMI) changes in 30 subjects soon after the Japanese earthquake. Our findings suggested that lower WMI in the right anterior cingulum (Cg) was a pre-existing vulnerability factor and increased WMI in the left anterior Cg and uncinate fasciculus (Uf) after the earthquake was an acquired sign of postearthquake distress. However, the long-term effects on WMI remained unclear. Here, we examined the 1-year WMI changes in 25 subjects to clarify long-term effects on the WMI. We found differential FAs in the right anterior Cg, bilateral Uf, left superior longitudinal fasciculus (SLF), and left thalamus, suggesting that synaptic enhancement and shrinkage were long-term effects. Additionally, the correlation between psychological measures related to postearthquake distress and the degree of WMI alternation in the right anterior Cg and the left Uf led us to speculate that temporal WMI changes in some subjects with emotional distress occurred soon after the disaster. We hypothesized that dynamic WMI changes predict a better prognosis, whereas persistently lower WMI is a marker of cognitive dysfunction, implying the development of anxiety disorders

White matter microstructural changes as vulnerability factors and acquired signs of post-earthquake distress.

Many survivors of severe disasters need psychological support, even those not suffering post-traumatic stress disorder (PTSD). The critical issue in understanding the psychological response after experiencing severe disasters is to distinguish neurological microstructural underpinnings as vulnerability factors from signs of emotional distress acquired soon after the stressful life event. We collected diffusion-tensor magnetic resonance imaging (DTI) data from a group of healthy adolescents before the Great East Japan Earthquake and re-examined the DTIs and anxiety levels of 30 non-PTSD subjects from this group 3-4 months after the earthquake using voxel-based analyses in a longitudinal DTI study before and after the earthquake. We found that the state anxiety level after the earthquake was negatively associated with fractional anisotropy (FA) in the right anterior cingulum (Cg) before the earthquake (r = -0.61, voxel level p<0.0025, cluster level p<0.05 corrected), and positively associated with increased FA changes from before to after the earthquake in the left anterior Cg (r = 0.70, voxel level p<0.0025, cluster level p<0.05 corrected) and uncinate fasciculus (Uf) (r = 0.65, voxel level p<0.0025, cluster level p<0.05 corrected). The results demonstrated that lower FA in the right anterior Cg was a vulnerability factor and increased FA in the left anterior Cg and Uf was an acquired sign of state anxiety after the earthquake. We postulate that subjects with dysfunctions in processing fear and anxiety before the disaster were likely to have higher anxiety levels requiring frequent emotional regulation after the disaster. These findings provide new evidence of psychophysiological responses at the neural network level soon after a stressful life event and might contribute to the development of effective methods to prevent PTSD

ANGPTL2 activity in cardiac pathologies accelerates heart failure by perturbing cardiac function and energy metabolism

A cardioprotective response that alters ventricular contractility or promotes cardiomyocyte enlargement occurs with increased workload in conditions such as hypertension. When that response is excessive, pathological cardiac remodelling occurs, which can progress to heart failure, a leading cause of death worldwide. Mechanisms underlying this response are not fully understood. Here, we report that expression of angiopoietin-like protein 2 (ANGPTL2) increases in pathologically-remodeled hearts of mice and humans, while decreased cardiac ANGPTL2 expression occurs in physiological cardiac remodelling induced by endurance training in mice. Mice overexpressing ANGPTL2 in heart show cardiac dysfunction caused by both inactivation of AKT and sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA)2a signalling and decreased myocardial energy metabolism. Conversely, Angptl2 knockout mice exhibit increased left ventricular contractility and upregulated AKT-SERCA2a signalling and energy metabolism. Finally, ANGPTL2-knockdown in mice subjected to pressure overload ameliorates cardiac dysfunction. Overall, these studies suggest that therapeutic ANGPTL2 suppression could antagonize development of heart failure