Elucidating Olfactory Mechanisms of PTSD Vulnerability and Trauma Resilience

摘要 面对严重的心理创伤，有些人会患上创伤后应激障碍（PTSD）， 大多数人都不知道目前对恢复力的生物学机制的理解， 对创伤后应激障碍的脆弱性仍然有限。神经科学表明，嗅球（OB），一个关键的结构， 气味处理，也可能涉及创伤应激机制。在动物中，慢性压力 OB大小;而OB消融导致应激增强的惊吓反射、杏仁核反应性、结构性 边缘系统结构重组和自主神经失调。此外，OB病变导致 通过NMDA为基础的机制，内侧杏仁核神经元的过度兴奋。然而，OB 在人类应激障碍的发展中，形态测量学还没有得到充分的研究。我们最近 已发表的一项针对儿童时期遭受性虐待和/或身体虐待的成年人（N=16）的研究显示， 创伤暴露的PTSD受试者（T1 P1）的OB体积与创伤暴露的PTSD受试者（T1 P1）的OB体积相比显著减少。 未发生PTSD的创伤暴露受试者（T1 P0）。此外，虽然T1 P0和非T1 P0的OB体积 创伤暴露的健康对照组（HC）在统计学上相似，T1 P1显著降低 相比HC。此外，我们正在进行的T1 P1和T1 P0纵向研究的初步结果表明， 患有儿童期性创伤的成年人显示，OB大小的减少与以下生理指标有关： 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， 嗅觉神经元（ON）和OB之间的分子事件，以及我们的发现， 患者来源的嗅组织中ON存活的标志物可预测其OB体积，我们比较了 ON中T1 P1和T1 P0的表达模式，并发现生长停滞特异性5 （GAS 5）在非侵入性来源于T1 P0的嗅觉细胞中。GAS 5是一种长链非编码RNA（lncRNA）， 在响应糖皮质激素的基因的启动子区域中模拟促肾上腺皮质激素响应元件。通过 GAS 5与这些区域结合，竞争性阻断糖皮质激素对这些区域的转录作用。 基因和保护组织免受萎缩。虽然GAS 5的机械假说是令人信服的，从我们的研究， 根据初步数据，国家心理健康研究所正在从资助候选基因方法转向 无偏见的经济学方法。因此，我们提出了一项为期2年的前瞻性R21研究，样本量更大， 暴露于儿童期性虐待的吸烟受试者（N=60，60%为女性）和20名健康对照者：（1） 验证T1 P0（N=30）和T1 P1（N=30）中OB和其他嗅觉区域的差异，持续时间匹配 （2）量化OB形态计量学和尺寸之间的关系， 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电反应 在基线（2.1）和基线OB形态测量对未来应激反应的调节作用， 受试者6个月后（2.2）;（3）探索OB与 结构和创伤后应激障碍的脆弱性通过公正的（即全基因组）基于RNA的表观基因组过程， 通过对非侵入性来源于以下的嗅细胞的体外形态学研究（包括皮质醇处理）， 他们的鼻刷。需要后者来产生初步的表观基因组和机械数据， 大规模R 01研究。这些目标的实现可能会通过引入一种新的嗅觉系统来影响该领域。 创伤脆弱性/复原力的机制，并引入坚实的科学前提， 嗅觉结构在慢性应激障碍干预中的作用。

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.