Role of the p75NTR, LTD and the cholinergic system in mediating coping mechanism

压力相关焦虑症的细胞和分子机制仍然是未知的。 很明显，暴露于压力有助于焦虑症的发展，包括创伤后应激障碍（PTSD）。 研究这些疾病的发病机制的一种方法是在动物模型中检查大脑如何控制和响应压力。 研究表明，压力反应对动物的短期生存至关重要，但如果不加控制，它们可能会变得有害，导致适应不良的应对机制和改变大脑生理学，化学和解剖学。 这些研究旨在更好地了解p75神经营养因子受体（p75NTR）和长期抑郁症（一种突触可塑性形式）在介导焦虑发展和介导应激反应中的作用。这些研究集中在1）海马生理学中p75 NTR缺失的生理效应以及与胆碱能信号的关系，以及2）这些过程的中断如何影响焦虑样行为的发展和对急性应激的反应。 在成人脑中，p75 NTR主要在基底前脑胆碱能神经元中表达，其是海马胆碱能神经支配的主要来源。暴露于急性行为应激使成年海马体中的一种称为长期抑郁（LTD）的突触可塑性形式成为可能。 海马LTD的生物学功能，特别是在成年人中，仍然不清楚。 最近的研究结果表明，LTD可能通过确保对环境变化的适应性反应来调节行为灵活性。我们发现缺乏p75NTR的转基因小鼠不会表现出应激诱导的长期抑郁。 我们还发现，p75NTR突变体表现出焦虑样行为水平的增加。 用毒蕈碱拮抗剂东莨菪碱抑制胆碱能传递也阻断了海马中的应激性LTD，导致焦虑样行为增加。 然后，我们通过使用特定的肽抑制剂直接阻断LTD并检查焦虑样行为，证实这些行为效应与压力激活的LTD缺陷有关。 正如预期的那样，肽抑制剂的施用减少了应激诱导的LTD并加剧了焦虑样行为。 我们的研究为进一步探索压力激活的LTD如何调节急性压力下的情绪提供了良好的基础。

The cellular and molecular mechanisms underlying development of stress-related anxiety disorders remain largely unknown. It is clear that exposure to stress contributes to the development of anxiety disorders, including post-traumatic stress disorder (PTSD). One approach to studying the pathogenesis of these disorders is to examine how the brain controls and responds to stress in animal models. Studies show that stress responses are critical for the animal's short-term survival, but they can become harmful if uncontrolled, leading to maladaptive coping mechanisms and altered brain physiology, chemistry, and anatomy. These studies were designed to better understand the roles of the p75 neurotrophin receptor (p75NTR) and long-term depression, a form of synaptic plasticity, in mediating development of anxiety and mediating the stress response. These studies focused on 1) the physiological effects of loss of p75NTR in hippocampal physiology and the relationship to cholinergic signaling and 2) how disruption of these processes affects development of anxiety-like behavior and the response to acute stress. In the adult brain, p75NTR is primarily expressed in basal forebrain cholinergic neurons, which are the major source of cholinergic innervation to the hippocampus. Exposure to acute behavioral stress enables a form of synaptic plasticity called long-term depression (LTD) in the adult hippocampus. The biological functions of hippocampal LTD, especially in the adult, remain obscure. Recent findings have suggested that LTD may mediate behavioral flexibility by ensuring adaptive responses to environmental changes. We found that transgenic mice lacking the p75NTR do not exhibit stress-induced long-term depression. We also found that the p75NTR mutants show increased levels of anxiety-like behavior. Inhibiting cholinergic transmission with the muscarinic antagonist scopolamine also blocked stress-enabled LTD in the hippocampus, leading to increased anxiety-like behavior. We then confirmed that these behavioral effects were related to a deficiency in stress-enabled LTD by blocking LTD directly using a specific peptide inhibitor and examining anxiety-like behavior. As expected, administration of the peptide inhibitor reduced stress-induced LTD and exacerbated anxiety-like behavior. Our studies provide an excellent foundation for further exploration of how stress-enabled LTD regulates mood in response to acute stress.