Longitudinal assessment of trauma on neural circuitry development into adulthood

描述(由申请人提供)：创伤事件，特别是在生命早期，具有深远的后果，包括增加个人对抑郁和焦虑症的易感性。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神经精神障碍易感性的关系的信息很少。此外，众所周知，创伤应激的反应与神经精神障碍的后期发展有相当大的异质性。在美国，20%-30%的人暴露在创伤事件中，随后会出现创伤后应激障碍(PTSD)的症状。然而，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。随着一种能够成像清醒动物静息状态功能连接(RSFC)的新方法的出现，理解这些问题现在是可能的。这一进展具有无创、全脑覆盖和对神经可塑性高度敏感的独特之处，因此是研究大脑发育和选择性扰动下神经回路动态变化的理想方法。通过使用这种方法，我们建议在一个动物模型中研究早期创伤对与应激诱导障碍有关的神经回路发育的影响。具体地说，通过在青少年、青春期或成年期施加创伤应激的纵向设计，我们将表征早期创伤对内侧前额叶皮质(MPFC)、杏仁核(AMYG)和海马区(HP)神经回路发育轨迹的影响。此外，我们将研究这些回路在表现出高度易患创伤后应激障碍类行为的动物中的差异。这一脆弱性将根据已建立的创伤后应激障碍动物模型的截断标准进行评估。我们的初步数据显示，在青春期，mPFC、AMYG和HP的神经回路仍然不成熟。我们还证明，创伤暴露可以对成年大鼠的相同神经回路产生长期影响。重要的是，易受伤害的大鼠在mPFC-AMYG回路中表现出比弹性大鼠更弱的RSFC强度，这意味着RSFC可能预测PTSD的易感性。在这些试点数据的基础上，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，我们将在动物模型中评估创伤后应激障碍易感性的神经底物。这项拟议的工作具有创新性，因为它结合了新的神经成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。这项研究的影响是非常重要的，因为了解早期创伤在为情绪和焦虑障碍服务的回路中神经可塑性变化中的作用对于这些疾病的早期诊断和治疗至关重要。

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.