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

抑郁症和焦虑症发生的细胞和分子机制在很大程度上仍不清楚。心理应激已被证明与创伤后应激障碍(PTSD)和广泛性焦虑症(GAD)等焦虑症的发生有关。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应对急性和慢性压力。研究表明，对急性应激反应的适当控制对动物的短期生存至关重要。然而，如果不加以控制，长期暴露在压力下可能会变得有害，导致适应不良的应对机制，并改变大脑的生理、化学和解剖结构。 我们和其他人已经在老鼠身上表明，压力可以使成年海马体中一种称为长期抑制(LTD)的突触可塑性。与长时程增强(LTP)在学习和记忆中的作用形成鲜明对比的是，海马区LTD的生物学功能，尤其是在成人中的生物学功能，仍然不清楚。最近的研究结果表明，LTD可能是一种细胞机制，以确保对环境变化做出足够或适当的行为反应。在目前的研究中，我们假设急性应激使能的海马体LTD可能是一种必要的应对机制，有助于从急性应激和/或创伤情况下恢复。P75神经营养素受体(P75NTR)是参与LTD和介导急性应激反应的候选分子。P75NTR是一种泛神经营养因子受体，可被神经营养因子家族的所有成员激活。神经营养因子在神经元发育、突触可塑性、学习和记忆以及大脑中的长期应激反应中发挥重要作用。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突变体表现出更高水平的焦虑样行为。在成人脑中，p75NTR主要在基底前脑胆碱能神经元表达，这些神经元是胆碱能神经支配海马区的主要来源。用毒扁豆碱拮抗剂东莨菪碱抑制胆碱能传递也阻断了应激激活的海马区LTD，并导致焦虑样行为增加。然后，我们通过使用特定的多肽抑制剂直接阻断LTD，并检查焦虑样行为，证实了这些行为效应与应激启用LTD的缺陷有关。正如预期的那样，多肽抑制剂的使用减少了应激诱导的LTD，并加剧了焦虑样行为。我们利用应激相关脑区的神经元激活图谱，进一步研究了应激诱导LTD的细胞靶点。我们发现，暴露在急性应激下会导致神经元活性增加，这是通过海马区所有三个亚区(CA1、CA3和齿状回)的即刻早期基因表达来评估的。然而，在p75NTR基因敲除动物和给予LTD封闭肽的动物中，这种激活都被减弱。我们还发现，在慢性社会失败模型中，p75NTR基因的缺失和LTD封闭肽的管理都降低了应激弹性。我们的发现提示了新的分子靶点和神经递质通路与急性应激反应有关。特别是，我们的研究指出了乙酰胆碱酯酶抑制剂和毒扁豆碱激动剂通过辅助诱导海马区LTD来帮助介导正常的急性应激反应的潜在用途。阐明新的分子和细胞靶点的研究对于开发治疗焦虑症，特别是创伤后应激障碍的新疗法至关重要。在创伤暴露后创造强大的恐惧记忆是创伤后应激障碍和广泛性抑郁的主要部分。由于突触可塑性机制的诱导，如LTD，与形成和存储新记忆的能力密切相关，我们的研究为更好地理解急性创伤后恐惧记忆是如何诱导的，以及帮助患者发展对创伤事件的不当回忆的治疗方法的发展提供了一个令人兴奋的领域。

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.