Dissecting neural circuits underlying early life stress-induced PFC dysfunction

项目摘要 自闭症谱系障碍（ASD）包括一组严重的神经发育障碍， 沟通障碍和社交障碍鉴于症状的发作发生在3岁， 大多数人同意神经元功能障碍发生在大脑发育的早期。一个发育中的大脑 根据经验进行塑料变化的显着能力;因此，它的发展最容易受到影响 会破坏正常大脑功能的环境因素早期生活压力的表现形式是 在大脑发育的关键时期，虐待/忽视已经证明了行为和心理 在动物模型和人类研究中，这些缺陷与自闭症症状非常相似。因此， 确定早期生活压力引起的社会功能障碍的神经机制， ASD儿童复杂行为缺陷的治疗策略最近的研究表明， 啮齿类动物的生活压力诱导长期的大脑改变，类似于ASD患者中所见的缺陷， 包括前额叶皮层（PFC）功能障碍和源自大脑皮层的压力/奖励相关回路。 腹侧被盖区（VTA）。前额叶皮层兴奋性突触的形成是大脑皮层神经元活动的基础。 功能性神经回路的建立。相反，突触发育中断会损害PFC功能 并且被认为是多种神经发育障碍的病理基础。PFC是密集的 由多巴胺能轴突终末支配，并与可能是 在自闭症等疾病中受到破坏。在这个R21提案中，我们利用了一种新的方法组合，包括 早期社会剥夺应激范式和双光子成像和uncaging来验证我们的假设， 生活压力引起的PFC投射多巴胺神经元的失调构成了一种神经机制， 生命早期的不良事件会改变PFC功能，并可能导致成年后的行为功能障碍。指导 强有力的初步数据，我们将在两个特定的目标来检验这一假设：1）定义功能的变化， PFC投射腹侧被盖区多巴胺神经元后的早期生活压力。2)确定多巴胺的机制- 在早期生活应激后诱导PFC中的突触发育。这些研究的结果将进一步促进我们的 了解多巴胺调节大脑发育的独特而详细的机制， 与神经发育障碍的细胞基础密切相关。约每100名儿童中有1名 是虐待和忽视的受害者。我们希望，我们的研究结果将突出新的途径， 早期扰动引起的神经发育障碍的病理生理学研究 多巴胺信号

Project Summary Autism Spectrum Disorders (ASDs) comprise a group of severe neurodevelopmental disorders that are typified by communication deficits and social impairment. Given that the onset of symptoms occurs by the age of 3, it is largely agreed that neuronal dysfunction arises during early brain development. A developing brain shows a remarkable capacity for plastic changes in response to experiences; thus, its development is most vulnerable to the environmental factors that can derail normal brain function. Exposure to early life stress in the form of abuse/neglect during a critical period of brain development has demonstrated behavioral and psychological deficits that closely resemble autistic symptoms in both animal models and human studies. Thus, it is essential to identify the neural mechanisms underlying early life stress-induced social dysfunction for the development of treatment strategies for complex behavioral deficits in children with ASD. Recent studies have shown that early life stress in rodents induces long-lasting brain alterations similar to the deficits seen in patients with ASDs, including dysfunctions in the prefrontal cortex (PFC) and the stress/reward-related circuitry originating in the ventral tegmental area (VTA). Formation of excitatory synapses in the PFC is known to be essential for the initial establishment of functional neural circuits. Conversely, disrupted synapse development impairs PFC function and is thought to underlie the pathology of multiple neurodevelopmental disorders. The PFC is densely innervated by dopaminergic axon terminals and associated with higher cognitive processes that may be disrupted in illnesses such as ASDs. In this R21 proposal, we utilize a novel combination of methods including early social deprivation stress paradigm and two-photon imaging and uncaging to test our hypothesis that early life stress-induced dysregulation of PFC-projecting dopamine neurons constitutes a neural mechanism by which adverse events early in life alter PFC function and may cause behavioral dysfunction in adulthood. Guided by strong preliminary data, we will examine this hypothesis in two specific aims: 1) Define functional changes in PFC-projecting VTA dopamine neurons following early life stress. 2) Determine mechanisms of dopamine- induced synapse development in the PFC following early life stress. Results from these studies will further our understanding of the unique and detailed mechanisms by which dopamine regulates brain development, with critical relevance to cellular underpinnings of neurodevelopmental disorders. Approximately 1 per 100 children in the U.S. is a victim of abuse and neglect. We expect that our results will highlight new avenues into the investigation of the pathophysiology underlying neurodevelopmental disorders resulting from early perturbation of dopamine signaling.