Elucidating Olfactory Mechanisms of PTSD Vulnerability and Trauma Resilience

阐明 PTSD 脆弱性和创伤复原力的嗅觉机制

• 批准号: 9924690
• 负责人: Evaristus A Nwulia
• 金额: $ 18.91万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924690
• 关键词: Ablation; Adult; Affective; Amygdaloid structure; Animals; Arousal; Atrophic; Binding; Biological; Brain; Candidate Disease Gene; Cells; Child Sexual Abuse; Childhood; Chronic stress; Communities; Confocal Microscopy; Control Groups; Corticotropin; Data; Development; Dimensions; Disinhibition; Endocrine; Enrollment; Event; Exposure to; Female; Follow-Up Studies; Functional disorder; Funding; Future; Galvanic Skin Response; Genes; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Goals; Growth; Heart Rate; Hippocampus (Brain); Human; Hydrocortisone; Image; In Vitro; Individual; International; Intervention; Joints; Lesion; Longitudinal Studies; Maternal Deprivation; Measures; Medial; Minority-Serving Institution; Modeling; Molecular; Morphology; N-Methylaspartate; National Institute of Mental Health; Neurites; Neurons; Neurosciences; Nose; Odors; Outcome; Participant; Pathway interactions; Patients; Pattern; Phenotype; Physiological; Post-Traumatic Stress Disorders; Prevention; Preventive measure; Process; Promoter Regions; Publishing; RNA; Receptor Signaling; Recording of previous events; Reflex action; Research; Resource Sharing; Response Elements; Reverse Transcriptase Polymerase Chain Reaction; Salivary; Sample Size; Sampling; Severities; Sexual abuse; Signal Transduction; Sleep; Solid; Stress; Structure; System; Tissues; Trauma; Universities; Untranslated RNA; Visit; Visual; assault; base; biological adaptation to stress; entorhinal cortex; epigenome; epigenomics; follow-up; genome-wide; gray matter; immune activation; immunocytochemistry; immunohistochemical markers; indexing; innovation; morphometry; neurophysiology; non-smoking; novel; olfactory bulb; perceived stress; physical abuse; post-trauma exposure; pre-clinical; prospective; psychologic; psychological trauma; psychosocial; resilience; response; sexual trauma; stress disorder; stress resilience; stressor; trauma exposure; traumatic stress; visual stimulus

ABSTRACT Faced with severe psychological trauma, some people develop post-traumatic stress disorder (PTSD), but most people don't. Current understanding of the biological mechanisms underlying resilience from, and vulnerability to PTSD remains limited. Neuroscience suggests that the olfactory bulb (OB), a key structure in odor processing, may also be involved in mechanisms of traumatic stress. In animals, chronic stress reduces OB size; while OB ablation results in stress-enhanced startle reflex, amygdala reactivity, structural reorganization of limbic structures and autonomic dysregulation. Furthermore, OB lesion causes hyperexcitability of medial amygdaloid neurons through NMDA-based mechanisms. However, OB morphometry has not been adequately studied in the development of stress disorders in humans. Our recently published study of adults who suffered sexual and/or physical abuse during childhood (N=16), revealed that OB volumes of trauma-exposed PTSD subjects (T1P1) were substantially reduced compared to OB volumes of trauma-exposed subjects who did not develop PTSD (T1P0). Additionally, while OB volumes of T1P0 and non- trauma exposed healthy control (HC) groups were statistically similar, those of T1P1 were significantly reduced compared to HC. Furthermore, preliminary findings from our ongoing longitudinal study of T1P1 and T1P0 adults with childhood sexual trauma show that reduced OB size is associated with physiological indices of amygdala disinhibition 6 months later. Given recent strong preclinical evidence of bidirectional relationships in molecular events between olfactory neurons (ON) and OB, and our discovery that immunohistochemical markers of ON survival in patient-derived olfactory tissues are predictive of their OB volumes, we compared expression patterns in ON of T1P1 and T1P0 and found differentially elevated levels of Growth arrest specific 5 (GAS5) in olfactory cells derived noninvasively from T1P0. GAS5 is a long noncoding RNA (lncRNA) that mimics corticotropin response elements in the promoter regions of genes that respond to glucocorticoids. By binding to these regions, GAS5 competitively blocks the transcriptional effects of glucocorticoids on these genes and protect the tissues from atrophy. Although a mechanistic hypothesis of GAS5 is compelling from our preliminary data, the National Institute of Mental Health is moving from funding candidate gene approaches to unbiased omic approaches. As a result, we propose a 2-year prospective R21 study on a larger sample of non- smoking subjects exposed to childhood sexual abuse (N=60, 60% females) and 20 healthy controls, to: (1) validate differences in OB and other olfactory regions in T1P0 (N=30) and T1P1 (N=30), matched on duration of assault and years since last assault; (2) quantify the relationship between OB morphometry and dimensional measures of stress and resilience, including electrodermal responses to aversive visual stimuli on all subjects at baseline (2.1) and the modulatory effects of baseline OB morphometry on future stress responses on all subjects 6 months later (2.2); and (3) explore molecular mechanisms underlying the relationship between OB structure and PTSD vulnerability through unbiased (i.e. genome-wide) RNA-based epigenomic processes and through in vitro morphologic studies (including cortisol treatments) of olfactory cells derived non-invasively from their nasal brushings. The latter is needed to generate preliminary epigenome and mechanistic data for a large-scale R01 study. Accomplishment of these aims could impact the field by introducing a novel olfactory mechanism of trauma vulnerability/resilience and by introducing a solid scientific premise for direct targeting of the olfactory structures in interventions for chronic stress disorders.

抽象的 面对严重的心理创伤，有些人会出现创伤后应激障碍（PTSD），但 大多数人不这样做。目前对恢复力背后的生物机制的理解 创伤后应激障碍 (PTSD) 的脆弱性仍然有限。神经科学表明，嗅球 (OB) 是嗅觉的关键结构。 气味处理也可能涉及创伤应激机制。在动物中，慢性压力会降低 产科尺寸；而 OB 消融会导致应激增强的惊吓反射、杏仁核反应性、结构性 边缘结构重组和自主神经失调。此外，OB病变会导致 通过基于 NMDA 的机制使内侧杏仁核神经元过度兴奋。然而，OB 形态计量学在人类应激障碍的发展方面尚未得到充分研究。我们最近 已发表的针对童年时期遭受性虐待和/或身体虐待的成年人（N=16）的研究表明， 与遭受创伤的 PTSD 受试者 (T1P1) 的 OB 体积相比，其 OB 体积大幅减少 未发生创伤后应激障碍 (PTSD) 的创伤暴露受试者 (T1P0)。此外，虽然 T1P0 和非 OB 卷 创伤暴露健康对照（HC）组在统计学上相似，T1P1显着减少 与HC相比。此外，我们正在进行的 T1P1 和 T1P0 纵向研究的初步结果 患有童年性创伤的成年人表明，OB 尺寸减小与以下生理指标相关： 6个月后杏仁核去抑制。鉴于最近强有力的临床前证据表明双向关系 嗅觉神经元 (ON) 和 OB 之间的分子事件，以及我们的发现 我们比较了患者来源的嗅觉组织中 ON 存活的标记物可以预测其 OB 体积 T1P1 和 T1P0 的 ON 中的表达模式，发现生长停滞特异性 5 的水平存在差异升高 (GAS5) 在从 T1P0 非侵入性衍生的嗅觉细胞中。 GAS5 是一种长非编码 RNA (lncRNA) 模拟对糖皮质激素有反应的基因启动子区域中的促肾上腺皮质激素反应元件。经过 通过与这些区域结合，GAS5 竞争性地阻断糖皮质激素对这些区域的转录作用。 基因并保护组织免于萎缩。尽管 GAS5 的机制假说从我们的角度来看是令人信服的 初步数据显示，国家心理健康研究所正在从资助候选基因方法转向 公正的组学方法。因此，我们建议对更大样本的非 曾遭受童年性虐待的吸烟受试者（N=60，60%为女性）和 20 名健康对照者，以：(1) 验证 T1P0 (N=30) 和 T1P1 (N=30) 中 OB 和其他嗅觉区域的差异，并与持续时间匹配 遭受袭击的次数以及距离上次袭击的年数； (2)量化OB形态测量与尺寸之间的关系 压力和恢复力的测量，包括所有受试者对厌恶性视觉刺激的皮肤电反应 基线 (2.1) 以及基线 OB 形态测定对所有个体未来应激反应的调节作用 6个月后的受试者（2.2）； (3)探索OB与OB之间关系的分子机制 通过无偏见（即全基因组）基于 RNA 的表观基因组过程来确定结构和 PTSD 脆弱性 通过对非侵入性衍生的嗅觉细胞进行体外形态学研究（包括皮质醇处理） 他们的刷鼻动作后者需要生成初步的表观基因组和机械数据 大规模R01研究。这些目标的实现可能会通过引入一种新颖的嗅觉来影响该领域 创伤脆弱性/复原力的机制，并通过引入坚实的科学前提来直接瞄准 慢性应激障碍干预中的嗅觉结构。