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，有些人患有创伤后应激障碍（PTSD），但 大多数人不。当前对来自和 对PTSD的脆弱性仍然有限。神经科学表明嗅球（OB），一个关键结构 气味加工，也可能参与创伤应力机制。在动物中，慢性压力减少 OB大小；虽然OB消融会导致压力增强的惊吓反射，但杏仁核反应性，结构性 边缘结构和自主性失调的重组。此外，ob病变会导致 通过基于NMDA的机制，内侧杏仁糖神经元过度兴奋。但是，OB 在人类的应激障碍发展中尚未充分研究形态计量学。我们最近 关于童年时期遭受性和/或身体虐待的成年人的发表研究（n = 16），表明 与OB体积相比 未发展PTSD的受伤受试者（T1P0）。另外，虽然T1P0和非 - 外伤暴露的健康对照组（HC）组在统计学上相似，T1P1的成群显着降低 与HC相比。此外，我们正在进行的T1P1和T1P0的纵向研究中的初步发现 患有儿童性创伤的成年人表明，OB大小的减小与生理指数有关 6个月后，杏仁核抑制作用。鉴于最近有强烈的临床前证据证明了双向关系 嗅觉神经元（ON）和OB之间的分子事件，以及我们发现免疫组织化学的发现 在患者衍生的嗅觉组织中生存的标记是预测其OB量的，我们比较了 ON T1P1和T1P0的表达模式，发现生长阻滞特异性的水平差异升高5 （GAS5）在源自T1P0无创源性细胞中。 GAS5是一个长的非编码RNA（lncRNA） 对糖皮质激素反应的基因启动子区域中的皮质激素反应元件。经过 与这些区域结合，GAS5竞争性地阻止了糖皮质激素对这些区域的转录作用 基因并保护组织免受萎缩。尽管GAS5的机械假设从我们的 初步数据，美国国家心理健康研究所正在从资助候选基因方法转变为 无偏的摩尼方法。结果，我们提出了一项为期2年的前瞻性R21研究 暴露于儿童性虐待（n = 60，60％女性）和20个健康对照的吸烟对象，至：（1） 验证T1P0（n = 30）和T1P1（n = 30）中OB和其他嗅觉区域的差异，持续时间匹配 自上次袭击以来的袭击和几年； （2）量化OB形态和尺寸之间的关系 压力和弹性的度量，包括对所有受试者对厌恶视觉刺激的电肌反应 基线（2.1）以及基线OB形态计量学对未来应力反应对所有人的调节作用 受试者6个月后（2.2）； （3）探索OB之间关系的基本分子机制 结构和PTSD脆弱性通过公正的（即全基因组）基于RNA的表观基因组过程和 通过体外形态学研究（包括皮质醇治疗）的嗅觉细胞非侵入性的细胞 他们的鼻刷。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。实现这些目标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/韧性的机制，并通过引入可直接定位的坚实的科学前提 慢性应激障碍干预措施中的嗅觉结构。