Longitudinal assessment of trauma on neural circuitry development into adulthood

创伤对成年期神经回路发育的纵向评估

• 批准号: 9069514
• 负责人: JEAN A KING
• 金额: $ 35.27万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-15 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9069514
• 关键词: ARHGEF5 gene; Adolescence; Adolescent; Adult; Age; Amygdaloid structure; Animal Model; Animals; Anxiety Disorders; Behavior; Brain; Brain region; CDKN1C gene; Characteristics; Data; Development; Disease; Early Diagnosis; Early treatment; Early-life trauma; Environment; Event; Exhibits; Exposure to; Female; Functional disorder; Health; Heterogeneity; Hippocampus (Brain); Human; Image; Individual; Individual Differences; Life; Life Experience; Longevity; MAPK14 gene; Measures; Medial; Mental Depression; Mood Disorders; Neuronal Plasticity; Odors; Play; Post-Traumatic Stress Disorders; Predisposition; Prefrontal Cortex; Process; Psychopathology; Psychophysiology; Rattus; Research; Research Project Grants; Rest; Risk; Rodent; Role; Stress; Symptoms; Techniques; Trauma; Work; addiction; awake; base; behavior measurement; biomarker identification; biopsychosocial; critical developmental period; early childhood; experience; imaging modality; innovation; longitudinal design; male; mature animal; neural circuit; neuroimaging; neuromechanism; neuropsychiatric disorder; novel; novel strategies; relating to nervous system; resilience; response; stress related disorder; tool; traumatic event

DESCRIPTION (provided by applicant): Traumatic events, particularly during early life, have far-reaching consequences including increasing an individual's vulnerability to depression and anxiety disorders. However, there is a paucity of information concerning the impact of early traumatic experiences on the development of neural circuitry, and its relation to adult vulnerability to neuropsychiatric disorders. Moreover, it is known that there is considerable heterogeneity in response to traumatic stress in relation to later development of neuropsychiatric disorders. In the US, 20-30% of individuals exposed to traumatizing events subsequently exhibit symptoms of post- traumatic stress disorder (PTSD). Nonetheless, the characteristics of neural circuitries associated with either risk or resilience to these disorders re unknown. Understanding these issues is now possible with the advent of a novel approach capable of imaging resting-state functional connectivity (RSFC) in awake animals. This advancement is unique in its noninvasiveness, whole-brain coverage and high sensitivity to neuroplasticity, and thus is ideal for studying the dynamic changes of neural circuitry across brain development and under selective perturbations. By utilizing this approach, we propose to investigate the impact of early trauma on the development of the neural circuits implicated in stress-induced disorders in an animal model. Specifically, with a longitudinal design in which traumatic stress is administered during juvenile, adolescence or adulthood, we will characterize the impact of early trauma on the developmental trajectories of the neural circuits of medial prefrontal cortex (mPFC), amygdala (AMYG) and hippocampus (HP). In addition, we will examine the difference in these circuits in animals exhibiting high vulnerability to developing PTSD-like behaviors. This vulnerability will be evaluated based on cut-off criteria of an established PTSD animal model. Our preliminary data showed that the neural circuits of mPFC, AMYG and HP are still immature during adolescence. We also demonstrated that trauma exposure can induce long-lasting effects on the same neural circuits in adult rats. Importantly, vulnerable rats showed much weaker RSFC strength within the mPFC-AMYG circuit compared to resilient rats, implying that RSFC may predict vulnerability to PTSD. Based on these pilot data, we plan to accomplish the research objectives by pursuing three specific aims. In Aim 1, we will characterize the normal developmental trajectories of the neural circuits of mPFC, AMYG and HP. In Aim 2, we will evaluate the impact of early trauma exposure on the developmental trajectories of these neural circuits. In Aim 3 we will assess the neural substrate underlying the vulnerability to PTSD in an animal model. The proposed work is innovative, because it combines novel neuroimaging tools and behavioral measurement to investigate the development of critical neural circuits and their vulnerability to traumatic stress. The impact of this research is highly significant because understanding the role of early trauma in neuroplastic changes in the circuitries subserving mood and anxiety disorders is critical to earlier diagnosis and treatment of these disorders.

描述（由申请人提供）：创伤事件，特别是在生命早期，会产生深远的影响，包括增加个人患抑郁症和焦虑症的可能性。然而，关于早期创伤经历对神经回路发育的影响及其与成人易患神经精神疾病的关系的信息很少。此外，众所周知，与神经精神疾病的后期发展相关的创伤应激反应存在相当大的异质性。在美国，20-30% 经历过创伤事件的人随后会表现出创伤后应激障碍 (PTSD) 的症状。尽管如此，与这些疾病的风险或恢复力相关的神经回路的特征尚不清楚。随着一种能够对清醒动物的静息态功能连接（RSFC）进行成像的新方法的出现，了解这些问题成为可能。这一进展的独特之处在于其非侵入性、全脑覆盖和对神经可塑性的高度敏感性，因此非常适合研究大脑发育过程中和选择性扰动下神经回路的动态变化。通过利用这种方法，我们建议在动物模型中研究早期创伤对与应激诱发疾病有关的神经回路发育的影响。具体来说，通过在青少年、青春期或成年期施加创伤应激的纵向设计，我们将描述早期创伤对内侧前额叶皮层（mPFC）、杏仁核（AMYG）和海马体（HP）神经回路发育轨迹的影响。此外，我们还将研究极易发生类似 PTSD 行为的动物中这些回路的差异。这种脆弱性将根据已建立的 PTSD 动物模型的截止标准进行评估。我们的初步数据表明，青春期时mPFC、AMYG和HP的神经回路仍不成熟。我们还证明，创伤暴露会对成年大鼠的相同神经回路产生长期影响。重要的是，与恢复力强的大鼠相比，脆弱的大鼠在 mPFC-AMYG 回路中表现出更弱的 RSFC 强度，这意味着 RSFC 可以预测对 PTSD 的脆弱性。根据这些试点数据，我们计划通过追求三个具体目标来实现研究目标。在目标 1 中，我们将描述 mPFC、AMYG 和 HP 神经回路的正常发育轨迹。在目标 2 中，我们将评估早期创伤暴露对这些神经回路发育轨迹的影响。在目标 3 中，我们将评估动物模型中易患 PTSD 的神经基质。拟议的工作具有创新性，因为它结合了新颖的神经影像工具和行为测量来研究关键神经回路的发展及其对创伤应激的脆弱性。这项研究的影响非常重要，因为了解早期创伤在促进情绪和焦虑症的神经回路神经塑性变化中的作用对于早期诊断和治疗这些疾病至关重要。