Posttraumatic stress disorder (PTSD) is an anxiety disorder that occurs after exposure to a traumatic event. This study aimed to investigate the neurobiologic changes before and after exposure-based therapy by PET in a rat model of PTSD. Methods: Serial 18 F-FDG PET imaging studies were performed under the control (tone presentation), fear-conditioning, and extinction retrieval phases. Neuroactivity marker c-Fos protein was used for immunostaining. Results: Increased glucose metabolism was observed in the bilateral amygdala after fearconditioning (P , 0.001) and in the right posterior insular cortex under extinction retrieval (P , 0.001) compared with the control phase. Increased c-Fos expression in the posterior insular cortex under extinction retrieval was positively correlated to the glucose metabolism (P , 0.01). Conclusion: Our results indicated that the amygdala plays a key role in fear memory formation and, most importantly, the insular cortex is related to the retrieval of extinction memory. 18 F-FDG PET may provide a promising in vivo approach for evaluating exposurebased therapy of PTSD. Post traumatic stress disorder (PTSD) is the most costly psychiatric disorder, affecting up to 40% of individuals over lifetime exposure to traumatic events (1,2). Over the past decades, considerable studies have explored how fear memories are encoded in the brain. A neurocircuitry model of PTSD emphasized the importance of the amygdala, as well as its interactions with the ventral/ medial prefrontal cortex (PFC) and hippocampus (3). In accord with this model, initial neuroimaging studies of PTSD provided evidence for exaggerated amygdala responses and attenuated ventral/ medial PFC responses during exposure to reminders of the traumatic event (3). In addition, Pavlovian fear-conditioning studies highlighted the key role of the amygdala in the acquisition and storage of conditioned fear memories (4,5). Electrophysiologic recording and inactivation studies in rats suggest that fear extinction depended on increased neuroactivity in the medial PFC under extinction training (6,7). Furthermore, the amygdala has been found activated during fear acquisition (8) and positively correlated with the severity of PTSD symptoms (9). Failure to recall fear extinction memory is associated with lower activation in the hippocampus and ventral/medial PFC in PTSD patients relative to trauma-exposed healthy subjects (10).Although exposure-based therapy (conceptually based on fear extinction) has been widely used in the treatment of PTSD (1), its underlying mechanism has not been completely elucidated. Because PET has been increasingly used to characterize neural activities, we hypothesized that 18 F-FDG PET could be applied for evaluating cerebral glucose metabolism before and after exposure-based therapy and could provide a potential translational tool for future clinical applications. Thus, the present study aimed to investigate the neurobiologic changes by 18 F-FDG PET in a rat model of PTSD. MATERIALS AND METHODS AnimalsMale Sprague-Da...
This study aimed to use spatiotemporal PET imaging to investigate the dynamic metabolic changes after a combined therapeutic approach of induced pluripotent stem cells (iPSCs), neuronal stem cells (NSCs), and Chinese patent medicine in a rat model of cerebral ischemia-reperfusion injury. Methods: Cerebral ischemia was established by the middle cerebral artery occlusion approach. Thirty-six male rats were randomly assigned to 1 of the 6 groups: control phosphate-buffered saline (PBS), Chinese patent medicine (Qing-kai-ling [QKL]), induced pluripotent stem cells (iPSCs), combination of iPSCs and QKL, neuronal stem cells (NSCs), and combination of NSCs and QKL. Serial 18 F-FDG small-animal PET imaging and neurofunctional tests were performed weekly. Autoradiographic imaging and immunohistochemical and immunofluorescent analyses were performed at 4 wk after stem cell transplantation. Results: Compared with the PBS control group, significantly higher 18 F-FDG accumulations in the ipsilateral cerebral infarction were observed in 5 treatment groups from weeks 1-4. Interestingly, the most intensive 18 F-FDG accumulation was found in the NSCs 1 QKL group at week 1 but in the iPSCs 1 QKL group at week 4. The neurofunctional scores in the 5 treatment groups were significantly higher than that of the PBS group from week 3 to 4. In addition, there was a significant correlation between the PET imaging findings and neurofunctional recovery (P , 0.05) or glucose transporter-1 expression (P , 0.01). Immunohistochemical and immunofluorescence studies found that transplanted iPSCs survived and migrated to the ischemic region and expressed protein markers for cells of interest. Conclusion: Spatiotemporal PET imaging with 18 F-FDG demonstrated dynamic metabolic and functional recovery after iPSCs or NSCs combined with QKL in a rat model of cerebral ischemia-reperfusion injury. iPSCs or NSCs combined with Chinese medicine QKL seemed to be a better therapeutic approach than these stem cells used individually.Key Words: induced pluripotent stem cell (iPSC); neuronal stem cell (NSC); Qing-kai-ling (QKL); positron emission tomography (PET); middle cerebral artery occlusion (MCAO)
This study aimed to investigate in vivo dynamic metabolic changes after transplantation of induced pluripotent stem cells (iPSCs) and iPSC-derived enriched cardiomyocytes (iPSC-CMs) in a rat model of ischemic injury. Methods: Serial 18 F-FDG PET, echocardiographic, immunohistochemical, and immunofluorescence studies were performed after transplantation of iPSCs and iPSC-CMs and compared with embryonic stem cells (ESCs), ESC-CMs, and a phosphatebuffered saline control group of rats with myocardial infarction. Results: Increased glucose metabolism in periinfarct areas and improved myocardial function were observed in the stem cell transplantation groups compared with the control group, and serial immunofluorescence and immunohistochemical results exhibited the survival and migration of stem cells during the study period. Conclusion: Serial 18 F-FDG PET and echocardiographic imaging studies demonstrated the dynamic metabolic changes and recovery of myocardial function after stem cell transplantation. 18 F-FDG PET could be a potential approach to evaluating spatiotemporal dynamic metabolic changes in vivo after transplantation of iPSCs or iPSC-CMs for ischemic injury.Key Words: positron emission tomography (PET); metabolism; myocardial ischemia; induced pluripotent stem cell (iPSC); induced PSC-derived cardiomyocytes (iPSC-CMs) Med 2016; 57:2012 57: -2015 57: DOI: 10.2967 Earl y observations on the mechanisms of ischemic injury focused on relatively simple biochemical and physiologic changes known to result from interruption of circulation. Subsequent research has shown that molecular imaging has the potential ability to identify pathophysiologic changes in vivo, which is crucial for evaluating new therapeutic approaches toward ischemia injury. Recently, rapid progress in stem cell technologies has triggered increasing interest in the use of pluripotent stem cells-including embryonic stem cells (ESCs) (1,2) and a new cell type, induced pluripotent stem cells (iPSCs) (3,4)-in cardiovascular ischemic repair. iPSCs own many features similar to ESCs and can detour the risk of immune rejection and ethical issues. Although electrocardiographic studies have found that iPSC-derived cardiomyocytes (iPSC-CMs) might be an exciting cell source for renewing myocardium in vitro and improving cardiac function (5), a noninvasive, sensitive, repeatable, and quantitative imaging modality is imperative to better understand the in vivo behavior and efficacy of transplantation of iPSCs and iPSC-CMs.Since PET can be used clinically for both cell trafficking and therapeutic response monitoring, it has been referred to as one of the best-suited modalities for evaluating the therapeutic effect of stem cells (6,7). Thus, we hypothesized that 18 F-FDG PET might be useful for the in vivo evaluation of spatiotemporal dynamic metabolic changes after transplantation of iPSCs or iPSC-CMs. To verify our hypothesis, we performed 18 F-FDG small-animal PET combined with echocardiography to evaluate metabolic and functional recovery after transplanta...
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