Elucidating Olfactory Mechanisms of PTSD Vulnerability and Trauma Resilience

摘要 面对严重的心理创伤，一些人会患上创伤后应激障碍(PTSD)，但 大多数人不知道。目前对潜在的弹性的生物机制的了解，以及 创伤后应激障碍的脆弱性仍然有限。神经科学表明，嗅球(OB)是大脑中的关键结构 气味处理，也可能参与创伤应激的机制。在动物身上，慢性压力会减少 OB大小；而OB消融导致应激增强的惊厥反射，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损伤导致 杏仁内侧神经元通过基于NMDA的机制的超兴奋性。然而，OB 形态计量学在人类应激障碍的发展中还没有得到充分的研究。我们最近 发表的对儿童期受到性虐待和/或身体虐待的成年人(N=16)的研究显示， 创伤暴露的创伤后应激障碍受试者(T1P1)的OB体积与 未发生创伤后应激障碍的创伤暴露受试者(T1P0)。此外，虽然T1P0和非OB卷 创伤暴露健康对照组(HC)在统计学上相似，T1P1显著降低 与HC相比。此外，我们正在进行的T1P1和T1P0纵向研究的初步发现 患有儿童期性创伤的成年人表明，OB大小减少与 6个月后杏仁核解除抑制。考虑到最近强有力的临床前证据表明， 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 患者来源的嗅觉组织中存活的标志物可以预测其OB体积，我们比较了 T1P1和T1P0在ON中的表达模式，并发现生长停滞特异性5水平的差异升高 (Gas5)在T1P0非侵袭性来源的嗅细胞中表达。Gas5是一种长的非编码RNA(LncRNA)，它 在对糖皮质激素有反应的基因的启动子区域模拟促肾上腺皮质激素反应元件。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效应 基因，并保护组织免受萎缩。尽管Gas5的机械假说从我们的 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 不偏不倚的学派方法。因此，我们提出了一项为期2年的前瞻性R21研究，研究对象为更大规模的非 儿童期性虐待的吸烟受试者(N=60，女性占60%)和20名健康对照：(1) 验证T1P0(N=30)和T1P1(N=30)的OB和其他嗅觉区的差异，在持续时间上匹配 攻击次数和上次攻击的年数；(2)量化OB形态测量和维度之间的关系 压力和弹性的测量，包括所有受试者对厌恶视觉刺激的皮肤电反应 基线(2.1)和基线OB形态测量对所有受试者未来应激反应的调制作用 受试者在6个月后(2.2)；以及(3)探索OB之间关系的分子机制 结构和创伤后应激障碍脆弱性通过无偏见(即全基因组)的基于RNA的表观基因组过程和 通过非侵袭性来源的嗅细胞的体外形态研究(包括皮质醇治疗) 他们的鼻毛刷。后者是生成初步表观基因组和机械学数据所必需的 大规模的R01研究。这些目标的实现可能会通过引入一种新的嗅觉来影响该领域 创伤易损性/复原力的机制，并为直接靶向 嗅觉结构在慢性应激障碍干预中的应用。

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.