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

抑郁症和焦虑症发展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，如果不加控制，长期暴露在压力下会变得有害，导致适应不良的应对机制和改变大脑的生理、化学和解剖结构。

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.