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

p75NTR、LTD 和胆碱能系统在调解应对机制中的作用

• 批准号: 8158151
• 负责人: MILES A. HERKENHAM
• 金额: $ 59.34万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8158151
• 关键词: Mediating; NGFR Protein; Role; System; cholinergic; coping mechanism

The cellular and molecular mechanisms underlying development of depressive and anxiety disorders remain largely unknown. Psychological stress has been shown to contribute to the development of anxiety disorders such as post-traumatic stress disorder (PTSD) and generalized anxiety disorder (GAD). One approach to studying the pathogenesis of these disorders is to examine how the brain controls and responds to acute and chronic stress in animal models. Studies show proper control of the acute stress response is critical for the animal's short-term survival. However, chronic exposure to stress can become harmful if uncontrolled, leading to maladaptive coping mechanisms and altered brain physiology, chemistry, and anatomy. We and others have shown in mice that stress enables a form of synaptic plasticity called long-term depression (LTD) in the adult hippocampus. In contrast to the well-studied role of long-term potentiation (LTP) in learning and memory, the biological functions of hippocampal LTD, especially in the adult, remain obscure. Recent findings have suggested that LTD may be a cellular mechanism to ensure adequate or proper behavioral responses to environmental changes. In the present study, we hypothesized that acute stress-enabled hippocampal LTD might be a necessary coping mechanism aiding the recovery from acutely stressful and/or traumatic situations. The p75 neurotrophin receptor (p75NTR) is a candidate for participating in LTD and mediating responses to acute stress. The p75NTR is a pan-neurotrophin receptor that is activated by all members of the neurotrophin family. Neurotrophins play important roles in neuronal development, synaptic plasticity, learning and memory, and mediating long-term stress responses in the brain. We found that transgenic mice lacking the p75NTR do not exhibit stress-induced LTD. We also found that the p75NTR mutants show increased levels of anxiety-like behavior. In the adult brain, p75NTR is primarily expressed in basal forebrain cholinergic neurons, which are the major source of cholinergic innervation to the hippocampus. Inhibiting cholinergic transmission with the muscarinic antagonist scopolamine also blocked stress-enabled LTD in the hippocampus, and led 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. We have further studied the cellular targets of induction of stress-induced LTD by using neuronal activation mapping in stress-related areas of the brain. We found that exposure to acute stress leads to increased neuronal activity, as assessed by immediate early gene expression in all three sub-regions of the hippocampus (CA1, CA3 and the dentate gyrus). However, this activation is attenuated in both the p75NTR knockout animal as well as in animals that are administered the LTD blocking peptide. We have also found that both deletion of the p75NTR gene and administration of the LTD blocking peptide reduces stress resiliency in a chronic social defeat model. Our findings suggest novel molecular targets and neurotransmitter pathways responsible for the acute stress response. In particular, our studies have pointed to a potential utility for acetylcholinesterase inhibitors and muscarinic agonists in helping to mediate a normal acute stress response by aiding the induction of hippocampal LTD. Studies to elucidate novel molecular and cellular targets are crucial for the development of new therapies for anxiety disorders, particularly PTSD. Creating powerful fear memories following trauma exposure is a major part of PTSD and GAD. Since induction of synaptic plasticity mechanisms such as LTD are highly implicated in the ability to form and store new memories, our research provides an exciting area for better understanding how fear memories may be induced after exposure to acute trauma and the development of therapies to help patients who develop improper recall of traumatic events.

抑郁症和焦虑症发生的细胞和分子机制在很大程度上仍然未知。心理压力已被证明会导致焦虑症的发生，例如创伤后应激障碍（PTSD）和广泛性焦虑症（GAD）。研究这些疾病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应对急性和慢性应激。研究表明，适当控制急性应激反应对于动物的短期生存至关重要。 然而，如果不加控制，长期承受压力可能会变得有害，导致适应不良的应对机制并改变大脑的生理、化学和解剖学。 我们和其他人在小鼠身上证明，压力会导致成年海马体出现一种称为长期抑郁（LTD）的突触可塑性。与长时程增强 (LTP) 在学习和记忆中的作用得到充分研究相反，海马长期增强 (LTP) 的生物学功能，尤其是在成人中，仍然不清楚。最近的研究结果表明，LTD 可能是一种细胞机制，可确保对环境变化做出充分或正确的行为反应。在本研究中，我们假设急性压力导致的海马LTD可能是一种必要的应对机制，有助于从急性压力和/或创伤情况中恢复。 p75 神经营养素受体 (p75NTR) 是参与 LTD 并介导急性应激反应的候选者。 p75NTR 是一种泛神经营养蛋白受体，由神经营养蛋白家族的所有成员激活。神经营养素在神经元发育、突触可塑性、学习和记忆以及调节大脑长期应激反应中发挥着重要作用。我们发现缺乏 p75NTR 的转基因小鼠不会表现出应激诱导的 LTD。我们还发现 p75NTR 突变体表现出焦虑样行为水平增加。在成人大脑中，p75NTR 主要在基底前脑胆碱能神经元中表达，这是海马胆碱能神经支配的主要来源。用毒蕈碱拮抗剂东莨菪碱抑制胆碱能传递也能阻断海马体中应激引起的LTD，并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，证实这些行为影响与压力引发的 LTD 缺陷有关。正如预期的那样，肽抑制剂的施用减少了压力诱导的LTD并加剧了焦虑样行为。我们通过使用大脑压力相关区域的神经元激活图谱，进一步研究了诱导压力诱导的LTD的细胞靶标。 我们发现，根据海马体所有三个亚区（CA1、CA3 和齿状回）立即早期基因表达的评估，暴露于急性应激会导致神经元活动增加。 然而，这种激活在 p75NTR 敲除动物以及施用 LTD 阻断肽的动物中均减弱。 我们还发现，p75NTR 基因的删除和 LTD 阻断肽的施用都会降低慢性社交失败模型中的压力恢复能力。 我们的研究结果表明新的分子靶点和神经递质途径负责急性应激反应。 特别是，我们的研究指出乙酰胆碱酯酶抑制剂和毒蕈碱激动剂在通过帮助诱导海马LTD来帮助介导正常的急性应激反应方面具有潜在的用途。 阐明新分子和细胞靶点的研究对于开发治疗焦虑症（尤其是创伤后应激障碍）的新疗法至关重要。 经历创伤后产生强烈的恐惧记忆是创伤后应激障碍（PTSD）和广泛性焦虑症（GAD）的一个重要组成部分。 由于LTD等突触可塑性机制的诱导与形成和存储新记忆的能力密切相关，因此我们的研究提供了一个令人兴奋的领域，可以更好地了解暴露于急性创伤后如何诱导恐惧记忆，并开发治疗方法来帮助对创伤事件产生不当回忆的患者。