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: 8836593
• 负责人: JEAN A KING
• 金额: $ 35.3万
• 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 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8836593
• 关键词: ARHGEF5 gene; Adolescence; Adolescent; Adult; Age; Amygdaloid structure; Animal Model; Animals; Anxiety Disorders; Behavior; Biological Markers; 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; biopsychosocial; critical developmental period; early childhood; experience; imaging modality; innovation; longitudinal design; male; mature animal; neural circuit; neuroimaging; neuromechanism; neuropsychiatry; 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，尤其是在早期生命中，带来了深远的后果，包括增加个人对抑郁症和焦虑症的脆弱性。但是，关于早期创伤经历对神经回路发展的影响及其与成人与神经精神疾病的关系的信息很少。此外，众所周知，与后来的神经精神疾病有关的创伤压力有很大的异质性。在美国，暴露于创伤事件的人中有20-30％随后表现出创伤后应激障碍（PTSD）的症状。但是，与这些疾病的风险或韧性相关的神经电路的特征是未知。现在，通过一种能够在清醒动物中对静止状态功能连接（RSFC）进行成像的新方法的出现，现在可以理解这些问题。这种进步在其无创性，全脑覆盖范围和对神经塑性的敏感性高度方面是独特的，因此是研究跨大脑发育和选择性扰动的神经回路动态变化的理想选择。通过利用这种方法，我们建议研究早期创伤对动物模型中涉及压力引起的疾病的神经回路发展的影响。具体而言，采用纵向设计，其中在青少年，青春期或成年期间施加了创伤性压力，我们将表征早期创伤对内侧前额叶皮质（MPFC），杏仁核（Amygdala（Amyg）和Hippocampus（HPFC）内侧前额叶皮层（MPFC）神经回路发育轨迹的影响。此外，我们将研究这些电路中这些电路的差异，这些动物表现出很大的脆弱性，这些动物易受发展PTSD样行为的脆弱性。将根据已建立的PTSD动物模型的截止标准评估这种漏洞。我们的初步数据表明，在青春期，MPFC，AMYG和HP的神经回路仍然不成熟。我们还证明，创伤暴露会对成年大鼠的相同神经回路产生持久影响。重要的是，与弹性大鼠相比，脆弱的大鼠在MPFC-AMYG电路内表现出较弱的RSFC强度，这意味着RSFC可能预测了PTSD的脆弱性。基于这些试点数据，我们计划通过追求三个特定目标来实现研究目标。在AIM 1中，我们将表征MPFC，AMYG和HP神经回路的正常发育轨迹。在AIM 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AIM 3中，我们将评估动物模型中PTSD脆弱性的基础神经底物。拟议的工作具有创新性，因为它结合了新型的神经影像学工具和行为测量，以研究关键神经回路的发展及其易受创伤性压力的脆弱性。这项研究的影响非常重大，因为了解早期创伤在循环症中的神经塑性变化中的作用，这对于早期诊断和治疗这些疾病至关重要。