Modulation of fear and safety in the basal forebrain-amygdala-prefrontal network

 描述（由申请人提供）：焦虑症是一组使人衰弱的病症，其影响超过18%的美国成年人口（Kessler等人，2005年）。当焦虑程度高时，无论是先天催化的（例如广泛性焦虑症（GAD）），还是创伤事件（例如创伤后应激障碍（PTSD）），患者都会受到严重的压力和痛苦，经常变得孤立，无法参与日常生活。焦虑症也给我们的社会带来了巨大的经济负担，据估计，仅2013年美国的支出就花费了近340亿美元（Shirneshan et al，2013）。全面了解普遍恐惧背后的神经回路以及区分威胁和安全的能力对于有效治疗焦虑至关重要。这项研究的目的是确定前额叶-基底前脑-杏仁核回路内的相互作用如何有助于处理威胁和安全。基底前脑有密集的抑制性和胆碱能投射到杏仁核，这两种神经递质在情绪学习过程中塑造杏仁核活动中起着重要作用。然而，我们还没有很好地了解来自基底前脑的不同神经化学输入如何影响杏仁核的生理学和影响行为。为了解决这个问题，该提案的目标1是建立从基底前脑到杏仁核的抑制信号在威胁和安全处理过程中的作用。与基底前脑-杏仁核相比，前额叶皮层和杏仁核之间的连接因其介导恐惧辨别的作用而受到更多关注。然而，已知前额叶皮质驱动基底前脑中的抑制性细胞（Guyengési等人，2008），并且抑制性细胞从基底前脑中产生。 基底前脑具有已知的到杏仁核的投射（McDonald等人，2011年）。因此，基底前脑可能在焦虑处理过程中充当前额叶皮层和杏仁核之间的重要界面。为了验证这一观点，该提案的目标2是分离出间接前额叶-基底前脑-杏仁核投射对区分威胁性和安全性刺激的贡献。这些研究将采用临床相关行为范例，大规模神经生理学记录，新型解剖追踪方法和行为期间电路功能的光遗传学控制的组合。前额叶-基底前脑-杏仁核网络有可能对调节与威胁相关的杏仁核活动和情感处理至关重要。所提出的研究是必要的，以更好地了解这个欠研究的电路如何有助于自适应厌恶学习。这项工作对于建立广泛恐惧的转化模型至关重要，这可以为患有学习性焦虑障碍（如PTSD）的患者提供有针对性的治疗。

 DESCRIPTION (provided by applicant): Anxiety disorders are a cluster of debilitating conditions that affect more than 18% of the adult US population (Kessler et al., 2005). When anxiety is high, whether catalyzed innately (e.g.Generalized Anxiety Disorder (GAD)), or by a traumatic event (e.g. Post-Traumatic Stress Disorder (PTSD)), a patient is severely stressed and in anguish, often becoming isolated and unable to participate in daily life. Anxiety disorders also pose a substantial economic burden on our society, estimated to cost almost $34 billion in US spending in 2013 alone (Shirneshan et al, 2013). A thorough understanding of the neural circuits underlying generalized fear and the ability to differentiate threat from safety is critica to effectively treating anxiety. The goal of the proposed research is to identify how interactions within the prefrontal-basal forebrain-amygdala circuit contribute to processing threat and safety. The basal forebrain has dense inhibitory and cholinergic projections to the amygdala, and both of these neurotransmitters are known to play an important role in shaping amygdala activity during emotional learning. However, we do not yet have a good understanding how different neurochemical inputs from the basal forebrain impact amygdala physiology and affect behavior. To address this, aim 1 of the proposal is to establish the role of inhibitory signaling from the basal forebrain to the amygdala during threat and safety processing. In contrast to the basal forebrain-amygdala, connectivity between the prefrontal cortex and the amygdala has received more attention for its role mediating fear discrimination. However, the prefrontal cortex is known to drive inhibitory cells in the basal forebrain (Guyengési et al, 2008) and inhibitory cells from the basal forebrain have known projections to the amygdala (McDonald et al., 2011). Thus, the basal forebrain may serve as an important interface between the prefrontal cortex and the amygdala during anxiety processing. To test this idea, Aim 2 of the proposal is to isolate the contribution of the indirect prefrontal-basal forebrain-amygdala projection to differentiating threatening and safe stimuli. These studies will employ a combination of clinically relevant behavioral paradigms, large-scale neurophysiological recordings, novel anatomical tracing methods and optogenetic control of circuit function during behavior. The prefrontal-basal forebrain-amygdala network has the potential to be critical for regulating threat-related amygdala activity and affective processing. The proposed research is necessary for a better understanding of how this understudied circuit contributes to adaptive aversive learning. This work will be essential for building a translational model for generalized fear, which can lead to targeted therapies for patients suffering from disorders of learned anxiety, such as PTSD.