Vulnerability and resilience to pathological fear memory - a role for neuropetidergic modulation in the dentate gyrus

对压力和恐惧事件的记忆对于行为适应潜在危险的环境至关重要。然而，夸张的恐惧记忆可能会随着创伤应激源的经历而发展，并导致创伤后应激障碍等疾病。因此，实验恐惧条件反射范式有助于解决神经系统中信息存储的基本机制，并有助于研究应激诱导的精神病理学的发展。齿状回作为通往海马体结构的门户，在情境恐惧记忆的形成和提取中起着关键作用。齿状回的活动和可塑性受到应激的调节，并受应激反应神经回路的控制。GABA能局部环路神经元似乎在这一调节中起着关键作用，以一种应激依赖的方式控制齿状回的信息流和兴奋性。在拟议的项目中，我们的目标是确定两组GABA能中间神经元及其相关神经肽-神经肽Y和胆囊收缩素-如何控制适应性和非适应性恐惧记忆的形成。在该项目的特定预实验中，我们发现应激暴露会导致这两种神经肽的表达发生持久的变化，这两种神经肽不仅是不同的中间神经元群体的标志，而且本身也是焦虑状态的有力修饰者。因此，我们将利用一个已建立的青少年应激诱导的病理性恐惧的动物模型，结合一种新的行为特征分析方法来确定个体恐惧水平如何与神经肽Y和CCK在齿状回的表达和功能有关。申请者进一步结合他们在分析恐惧的分子和生理机制方面的专业知识，以描绘和功能描述利用这些肽的神经元间回路及其通过不同应激经历的招募。我们将确定心理参数，特别是作为不适应恐惧记忆的易感因素的可控性，如何作用于局部回路组件，并可能导致病理或持久适应。作用于这些中间神经元群体的激活机制将通过高分辨率的受体表达谱和杏仁核启动实验来检验，我们之前已经证明了这些实验可以模拟与压力相关的齿状回活动和可塑性的修改。最后，我们将招募特定和选择性的分子干预工具来检查这些神经肽在局部回路中的功能及其对恐惧行为和恐惧记忆的控制。我们期望这项跨学科的研究将对恐惧适应的神经机制、个体对压力的脆弱性以及与压力相关的精神病理学产生重要的理解。

Memories for stressful and fear-inducing events are of vital importance for behavioral adaptation to a potentially dangerous environment. However, exaggerated fear memories can develop following the experience of a traumatic stressor and lead to diseases such as post-traumatic stress disorder. Thus, experimental fear conditioning paradigms have been instrumental in resolving fundamental mechanisms of information storage in the nervous system and in studying the development of stress-induced psychopathology. The dentate gyrus as a gateway to the hippocampal formation plays a critical role in the formation and retrieval of contextual fear memory. Activity and plasticity in the dentate gyrus are modulated by stress and are under control of stress-responsive neural circuits. GABAergic local circuit neurons appear to play a pivotal role in this regulation, controlling information flow and excitability in the dentate gyrus in a stress-dependent manner. In the proposed project we aim to determine how two populations of GABAergic interneurons and their associated neuropeptides, neuropeptide Y and cholecystokinin, control adaptive and maladaptive fear memory formation. In specific pre-experiments to this project we found that stress exposure induces lasting expression alterations in these two neuropeptides, which are not only markers for distinct populations of interneurons but themselves act as potent modifiers of anxiety state. We will therefore utilize an established animal model of juvenile stress-induced pathological fear in combination with a novel behavioral profiling approach to determine how individual fear levels relate to the expression and function of neuropeptide Y and cholecystokinin in the dentate gyrus. The applicants further combine their expertise in the analysis of molecular and physiological mechanisms of fear in order to delineate and functionally characterize the interneuron circuits that utilize these peptides and their recruitment by different stress experiences. We will determine how psychological parameters, in particular of controllability as a predisposing factor for maladaptive fear memory, act on local circuit components and may lead to pathology or lasting adaptation. Activation mechanisms acting on these interneuron populations will be examined with high resolution profiling of receptor expression and through amygdala priming experiments that we have previously shown to simulate stress-related modification of dentate gyrus activity and plasticity. Finally, we will recruit specific and selective molecular intervention tools to examine the function of those neuropeptides in the local circuitry and their control of fear behavior and fear memory. We expect that this interdisciplinary study will yield critical understanding of the neural mechanisms of fear adaptation, the individual vulnerability to stress and stress-related psychopathology.