Symposia
Perspectives in PTSD research -6 years after the Great East Japan Earthquake-／PTSD研究の現状と展望 ～東日本大震災から６年～ |
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| 3S6-1
Posttraumatic stress reactions among communities affected by the Great East Japan Earthquake and investigations into the pathogeneses of PTSD
Hiroaki Tomita
Dept Disaster Psychiat, IRIDeS, Tohoku Univ
Disasters have profound effects on mental health among affected communities. In Tohoku University, two new organizations: International Research Institute of Disaster Science, and Tohoku Medical Organization, were established following the Great East Japan Earthquake. Epidemiological studies have been conducted to grasp health condition of affected communities, and basic and clinical studies have been integrated to develop technologies effective for improving health conditions. Longitudinal health surveys conducted in people whose housings were majorly damaged in Shichigahama town indicated that over 30% of these affected residents passed the threshold for posttraumatic stress reaction (PTSR) in 2011. As of 2016, nearly one fifth of the affected residents still passed the threshold for PTSR. Factors to exacerbate and ameliorate mental health conditions have been extracted from these investigations. On the other hand, as a part of technological innovations to improve management of PTSR, we aimed to elucidate mechanisms underlying the involvement of microglia in the pathogeneses of posttraumatic stress disorder (PTSD) utilizing fear-conditioned mice as a model of PTSD. Fear-conditioned mice show freezing behavior under circumstance to evoke fear memory, while freezing behavior diminishes as the mice are acclimatized. We found production of a microglial cytokine, TNF-alpha, was elevated as mice were fear-conditioned, and the production were decreased as mice were acclimatized. Also, minocycline facilitates acclimatization, and inhibits microglial TNF-alpha production. Data suggests involvement of microglial TNF-alpha production into regulation of fear memory, and that the mechanism can be a druggable target for ameliorating PTSD symptoms. | | 3S6-2
Fear memory processes as therapeutic targets for the treatment of PTSD
Satoshi Kida1,2
1Dept. of Bioscience, Tokyo Univ. of Agriculture，2CREST, JST
Memory retrieval initiates two opposite processes; memory reconsolidation and extinction. Memory reconsolidation is thought to be a process to update, strengthen or maintain, whereas memory extinction is a process to weaken the original fear memory. These memory phases induced by memory retrieval are thought to serve as useful therapeutic targets for the treatment of emotional disorders such as post-traumatic stress disorder (PTSD) and phobias. Indeed, exposure therapy for the treatment of emotional disorders is thought to reflect some aspect of the biological basis of memory extinction. Therefore, from this clinical view, it is important to understand mechanisms underlying the regulation of fear memory after retrieval. We have investigated mechanisms by which the fate of memory is determined after retrieval; retrieved memory is either reconsolidated or extinguished. Using contextual fear conditioning and inhibitory avoidance tasks, we found that (1) memory reconsolidation and extinction are not independent processes; these memory phases interact one another at behavioral, anatomical and molecular levels, (2) memory reconsolidation and extinction are regulated by distinct neural circuits and (3) memory reconsolidation and extinction display distinct molecular signatures. These our findings indicate the dynamic nature of fear memory after retrieval. These observations also emphasize the importance of estimating whether the status of memory is in the reconsolidation or extinction phases when clinical treatments, such as exposure therapy combined with drugs, are performed. In addition, we recently proposed that memory forgetting is also a therapeutic target for PTSD (elife, 2016). I will summarize our findings of memory mechanisms that is thought to improve PTSD. | | 3S6-3
A multifaceted approach to understanding the pathogenesis of PTSD: from genes, biomarkers to phenotypes
Hiroaki Hori
Department of Adult Mental Health, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.
Posttraumatic stress disorder (PTSD) is a debilitating psychiatric condition that can develop after a traumatic event. However, not everyone who experiences such an event develops PTSD, and thus complex gene-gene and gene-environment interactions are thought to be involved in the pathogenesis. Moreover, PTSD is considered to be a heterogeneous disorder. A multifaceted approach will therefore be necessary to better understand the etiology of PTSD and to develop objective measures such as laboratory tests that will aid in its prediction and diagnosis. To address this, we have started a research project on PTSD encompassing genes, biomarkers and phenotypes. Among a variety of biological abnormalities reported in patients with PTSD, dysregulation of the hypothalamic-adrenal-pituitary (HPA) axis is one of the most well documented findings. Recent studies have shown that polymorphisms and epigenetic modifications in glucocorticoid receptor (GR) gene (NR3C1) and its co-chaperone gene (FKBP5), possibly via their effects on gene expression, play important roles in the HPA axis abnormalities of PTSD. Another well-replicated biological finding of PTSD is dysregulation of the immune system. In line with previous findings, we have obtained evidence that compared to healthy controls, patients with PTSD show elevated interleukin-6 (IL-6) levels, using peripheral blood (unpublished data). We have also found that this elevation of IL-6 can define a unique phenotypic subtype of PTSD. Finally, given that research of PTSD, or of psychiatric disorders in general, will benefit from applications of complex systems science, I would like to introduce an easily performed statistical method to investigate non-linear relationships between phenotypes and their underlying biological mechanisms. | | 3S6-4
Epigenetic studies of PTSD; development of epigenetic therapy and epigenetic biomarker
Shigeru Morinobu
Department of Occupational Therapy, School of Health Science and Social Welfare, Kibi International University
To elucidate the pathophysiology of posttraumatic stress disorder (PTSD), the establishment of an appropriate animal model is essential. In a series of our studies, we validated the single prolonged stress (SPS) as a model for PTSD. Rats subjected to SPS (immobilization for 2 h, forced swim for 20 min, and ether exposure) mimic the pathophysiological abnormalities and behavioral characteristics of PTSD, such as enhanced anxiety-like behavior and glucocorticoid negative feedback, and analgesia. In addition, SPS rats showed the enhanced freezing in response to contextual fear conditioning, and impaired extinction of fear memory, which was alleviated by administration of histone deacetylase (HDAC) inhibitor, vorinostat. In parallel, we found that the increased levels of acetylated H3 and H4 and the increase in the NR2B subunit of N-methyl-D-asparate receptor in the hippocampus, and suggested that the treatment with vorinostat during the exposure therapy might alleviate the impaired fear extinction. On the other hand, our recent study indicated that microinfusion of brain-derived neurotrophic factor (BDNF) in infralimbic medial prefrontal cortex and ventral hippocampus ameliorated the impaired fear extinction in SPS rats. Although, in our study, there was no difference in DNA methylation profiles of CpG island within the promoter of exon I between healthy subjects and patients with PTSD, Kim et al. demonstrated that the methylation status of 4 CpG sites within the promoter of exon I of the BDNF gene in combat veterans with PTSD were higher than those in veterans without PTSD. Although further studies are required, the possibility of an epigenetic biomarker of PTSD will be discussed including the genome-wide DNA methylation study in this presentation. | |
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