Immediate and Long-Term Impact of Early-Life Trauma

描述（由申请人提供）：童年早期的创伤是成年后焦虑症（如创伤后应激障碍（PTSD））发展的主要风险因素。确定这种关系的根本原因仍然是非常具有挑战性的。特别是，确定创伤时大脑的功能状态如何导致创伤后应激障碍及其神经基础仍然是一个难以捉摸的目标。先前的努力，使用动物模型主要集中在母亲分离程序作为早期生活的压力。我们建议使用痛苦的足部电击作为创伤程序，因为它是虐待儿童的主要组成部分。这一程序在不同的出生后年龄提出了重要的见解个体发育的恐惧学习。我们的实验室在成人恐惧条件反射方面拥有丰富的经验，在成熟动物中进行上述程序，导致对创伤的终身记忆，这取决于杏仁核（AMY），海马（HIPP）和前额叶皮层（PFC）。重要的是，如果这种恐惧体验足够强烈，它会导致持续的脆弱性，即使是对原始创伤的轻微提醒也会过度夸大恐惧反应。这种敏感的恐惧反应是PTSD的一个主要特征。我们的方法基于早期生活创伤的时间确定了3个关键假设（图A）：1）第1阶段期间的出生后早期创伤：在AMY功能成熟之前，恐惧学习系统无法充分激活。2)中期产后创伤阶段2：在AMY功能成熟后，但在海马上下文处理通路成熟之前，不能建立关联性恐惧反应，但非关联性恐惧敏感化和神经内分泌反应持续存在。3)第三阶段的晚期产后创伤：随着两个系统的成熟，可以获得适当的条件反应，以及持续的成年增强杏仁核为基础的恐惧学习。为了验证这些假设，我们建议确定早期生活创伤的恐惧神经回路的功能状态，以及这如何有助于成人PTSD相关神经病学的发展。这将通过使用神经解剖学的方法来实现，在该方法中，我们能够表征杏仁核及其相关的传入和传出脑区域内的早期基因的表达，以响应在早期（P8），中期（P19）和晚期（P35）出生后发育期间的反复足电击创伤。接下来，我们将讨论创伤在这些发育时间点对成人恐惧和神经内分泌功能的长期影响。通过了解成熟的大脑如何容易受到早期生活创伤的影响，这可以提供对诸如创伤后应激障碍等使人衰弱的焦虑症的潜在机制的深入了解。

DESCRIPTION (provided by applicant): Trauma during early childhood is a major risk factor for the adult development of anxiety disorders such as post-traumatic stress disorder (PTSD). Determining the underlying causes of this relationship has remained extraordinarily challenging. In particular, determining how the functional state of the brain at the time of trauma contributes to PTSD and its neural underpinnings remains an elusive goal. Prior efforts, using animal models have mainly focused on maternal-separation procedures as early life stressors. We propose the use of painful foot shocks as a trauma procedure given that it is a major component of child abuse. This procedure when presented at different post-natal ages has yielded important insights into the ontogeny of fear learning. Our laboratory has substantial experience in adult fear conditioning, with the above procedure in the mature animal resulting in a life-long memory of the trauma that depends on the amygdala (AMY), hippocampus (HIPP) and prefrontal cortex (PFC). Importantly, if this fear experience is strong enough it results in a sustained vulnerability to over-exaggerate fear responses even to mild reminders of the original trauma. This sensitized fear response is a central characteristic of PTSD. Our approach identifies 3 key hypotheses based on the timing of early life trauma (figure A): 1) Early Post-natal trauma during Stage 1: Prior to the functional maturation of AMY, fear learning systems cannot be sufficiently activated. 2) Middle Post-natal trauma during Stage 2: After the functional maturation of the AMY, but prior to the maturation of hippocampal context processing pathways, associative fear responses cannot be established, yet non-associative sensitization of fear and neuroendocrine responses persist. 3) Late Post-natal trauma during Stage 3: With the maturation of both systems both appropriate conditional responses can be acquired as well as a sustained adult enhancement of amygdala-based fear learning. To test these hypothesize we propose to identify the functional status of the fear neural circuits to early life trauma and how this contributes to development of adult PTSD related symptomology. This will be accomplished by using a neuroanatomical approach in which we are capable of characterizing the expression of immediately early genes within the amygdala and its associated afferent and efferent brain regions in response to repeated footshock trauma during early (P8), middle (P19) and late (P35) post-natal development. Next we address the long-lasting impact of trauma at these developmental time points on adult fear and neuroendocrine function. By understanding the how the maturing brain is susceptible to early-life trauma, this could provide great insight into mechanisms underlying a debilitating anxiety disorders such as PTSD.