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仍不清楚。心理压力已被证明有助于焦虑症的发展，如创伤后应激障碍（PTSD）和广泛性焦虑症（GAD）。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急性和慢性应激。研究表明，适当控制急性应激反应对动物的短期生存至关重要。 然而，长期暴露于压力下如果不加控制，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。 我们和其他人已经在小鼠身上证明，压力使成年海马体中一种称为长期抑郁（LTD）的突触可塑性形式成为可能。相对于长时程增强（LTP）在学习记忆中的作用，海马LTD的生物学功能，特别是在成年人中的生物学功能仍不清楚。最近的研究结果表明，LTD可能是一种细胞机制，以确保足够或适当的行为反应，以环境变化。在本研究中，我们假设急性应激激活的海马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神经营养因子受体（p75 NTR）是参与LTD和介导急性应激反应的候选者。p75 NTR是一种泛神经营养因子受体，由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、学习和记忆以及介导脑中的长期应激反应中发挥重要作用。我们发现缺乏p75 NTR的转基因小鼠不表现出应激诱导的LTD。我们还发现p75 NTR突变体表现出焦虑样行为水平的增加。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。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，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。我们进一步研究了诱导应激诱导LTD的细胞靶点，通过使用脑内应激相关区域的神经元激活映射。 我们发现，暴露于急性应激导致神经元活动增加，评估海马体的所有三个子区域（CA 1，CA 3和齿状回）的立即早期基因表达。 然而，这种激活在p75 NTR敲除动物以及施用LTD阻断肽的动物中均减弱。 我们还发现p75 NTR基因的缺失和LTD阻断肽的施用都降低了慢性社交失败模型中的应激弹性。 我们的研究结果表明，新的分子靶点和神经递质通路负责急性应激反应。 特别是，我们的研究已经指出了一个潜在的效用，乙酰胆碱酯酶抑制剂和毒蕈碱激动剂在帮助介导正常的急性应激反应，帮助诱导海马LTD. Studies阐明新的分子和细胞靶点是至关重要的焦虑症，特别是创伤后应激障碍的新疗法的发展。 创伤暴露后产生强大的恐惧记忆是PTSD和GAD的主要部分。 由于诱导突触可塑性机制（如LTD）与形成和储存新记忆的能力密切相关，我们的研究为更好地了解暴露于急性创伤后如何诱导恐惧记忆以及开发治疗方法以帮助患者发展创伤事件的不当回忆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.