Emotion regulation in the prefrontal - basal forebrain-amygdala circuit

摘要 创伤后应激障碍(PTSD)是一种由压力和创伤引起的疾病，影响数百万人 在美国，女性患创伤后应激障碍的比例几乎是男性的两倍。创伤后应激障碍的特征是 持续性焦虑，自主神经系统失调，回避行为，并经常与 严重的抑郁障碍和药物滥用。内侧前额叶皮质参与减少 伴随着杏仁基底外侧核(BLA)的过度活跃是情绪调节失调的重要原因 与创伤后应激障碍相关的反应。在消亡学习期间，内侧前额叶皮质被认为抑制了 BLA活动，从而减少对非威胁性线索的防御性反应，这一过程在 创伤后应激障碍。有许多证据支持前额叶直接输入影响大脑中脑区可塑性的观点，并且 使杏仁核的兴奋性-抑制性平衡转向抑制性。然而，这一现象的机制 电路级的相互作用还没有被很好地理解。值得注意的是，内侧前额叶皮质不是一个整体结构， 在啮齿类动物中，其相邻的亚区被指定为前缘(PL)和下缘(IL)，它们是相关的 防御反应分别增加和减少。虽然已经提出了一些想法， 到目前为止，还没有发现PL和IL与BLA的直接相互作用的差异，这可以解释他们的 功能性二分法。这种知识上的差距阻碍了更有针对性的治疗方法的发展。 治疗创伤后应激障碍。一种可能性是PL和IL可能通过间接的方式对杏仁核功能产生不同的影响 小路。前人的工作表明，PL和IL与基底前脑有不同的联系，这是一种关键的 杏仁核中调节恐惧和灭绝学习的区域。基底前脑提供了强大的 胆碱能、谷氨酸和GABA能传入杏仁核、皮质外套膜和海马体， 使其成为下游灭绝学习前额叶调制的有趣集中地点 结构。这些实验的目的是为了揭示PL和IL-base的结构和功能 灭绝期间的前脑-杏仁核通讯。为此，我将在特定的目标中使用病毒跟踪和 免疫组织化学揭示PL和IL与杏仁核投射细胞连接的详细回路 在腹侧苍白球/无名质，以及基底前脑斜角带的水平支内。 然后，在特定的目标2和3中，我将使用光遗传学来操纵IL和PL输入到基底前脑，以及 多点活体记录跨IL/PL-基底前脑-BLA环路的神经生理学 恐惧条件作用、消亡训练和回忆。对神经活动的其他免疫组织化学分析将 指出在消亡期间，PL和IL在基底前脑中驱动的细胞类型。所有的实验都将是 在男女中进行，以评估这一回路是否有助于提高创伤后应激障碍的诊断率 女人。这种方法是专门为提高我们对物种灭绝背后的电路的理解而设计的 学习，并致力于寻找新的治疗方法，以改善创伤后应激障碍的治疗结果。

Abstract Post-traumatic stress disorder (PTSD) is a stress- and trauma- induced condition that affects millions of Americans, with women facing PTSD diagnoses at almost twice the rate of men. PTSD is characterized by persistent anxiety, a dysregulated autonomic nervous system, avoidance behaviors, and is often co-morbid with major depressive disorder and substance abuse. Diminished engagement of the medial prefrontal cortex concomitant with a hyperactive basolateral amygdala (BLA) strongly contribute to the dysregulated emotional responses associated with PTSD. During extinction learning, the medial prefrontal cortex is thought to suppress BLA activity, thereby decreasing defensive responding to non-threatening cues, a process that is disrupted in PTSD. There is much evidence to support the idea that direct prefrontal input affects plasticity in the BLA, and shifts the excitatory-inhibitory balance in the amygdala towards inhibition. However, the mechanisms of this circuit-level interaction are not well understood. Notably, the medial prefrontal cortex is not a monolithic structure, and its contiguous subregions, in rodents designated as the prelimbic (PL) and infralimbic (IL), are associated with increased and decreased defensive responding, respectively. Although some ideas have been proposed, thus far no differences have been found in direct PL vs. IL interactions with the BLA that can account for their functional dichotomy. This gap in knowledge prevents the development of more targeted therapeutic treatments for PTSD. One possibility is that the PL and IL may have differential effects upon amygdala function via indirect pathways. Previous work shows that the PL and IL are differentially connected with the basal forebrain, a critical region for modulating fear and extinction learning in the amygdala. The basal forebrain provides strong cholinergic, glutamatergic, and GABAergic inputs to the amygdala, the cortical mantle, and the hippocampus, making it an intriguing centralized location for prefrontal modulation of extinction learning in downstream structures. The goal of the proposed experiments is to uncover the structure and function of PL and IL -basal forebrain -amygdala communication during extinction. To this end, in Specific Aim I will use viral tracing and immunohistochemistry to uncover the detailed circuitry of PL and IL connectivity with amygdala-projecting cells in the ventral pallidum/substantia innominata, and horizontal limb of the diagonal band of the basal forebrain. Then, in Specific Aims 2 and 3, I will use optogenetics to manipulate IL and PL inputs to the basal forebrain, and multi-site in-vivo recordings to record the neurophysiology across the IL/PL-basal forebrain-BLA circuit during fear conditioning, extinction training and recall. Additional immunohistochemical analyses of neural activity will indicate which cell types the PL and IL drive in the basal forebrain during extinction. All experiments will be performed in both sexes to assess whether this circuit contributes to increased rates of PTSD diagnosis in women. This approach is specifically designed to improve our understanding of the circuitry underlying extinction learning, and is geared toward finding novel therapeutic approaches for improving treatment outcomes in PTSD.