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Effects of NPY on Hippocampal Circuit Function

NPY 对海马回路功能的影响

基本信息

批准号：
10214528
负责人：
LYNN E DOBRUNZ
金额：
$ 65.92万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10214528
关键词：
Affect Animals Anti-Anxiety Agents Anxiety Anxiety Disorders Attenuated Axon Bathing Behavior Behavioral Behavioral Symptoms Brain Brain Diseases Cells Clinical Research Complex Data Dense Core Vesicle Electrophysiology (science)Exposure to Fright Functional disorder Funding Genetic Goals Grant Hippocampus (Brain)Human Impairment Injections Knowledge Lead Learning Location Measures Mediating Memory Methods Mus Neuropeptide Y Receptor Pathway interactions Patients Peptides Pharmacology Physiological Post-Traumatic Stress Disorders Property Rodent Rodent Model Sensory Signal Transduction Slice Stress Stress Tests Study models Synapses Testing Training anxiety symptoms avoidance behavior behavior test depressive symptoms designer receptors exclusively activated by designer drugs experimental study genetic approach improved inhibitory neuron memory consolidation mood regulation neural circuit neuropeptide Y neuroregulation new therapeutic target novel strategies novel therapeutic intervention optogenetics preclinical study preservation prevent receptor recruit response spatiotemporal stress resilience synaptic function traumatic stress treatment of anxiety disorders

项目摘要

Neuropeptide Y (NPY) has robust anxiolytic (anti-anxiety) properties and is thought to be a stress resilience factor. Clinical and pre-clinical studies have shown that NPY signaling regulates stress-dependent behavior in both humans and rodents. Our knowledge of the mechanisms by which NPY affects synaptic and circuit function to alter behavior is incomplete. NPY has been implicated in a wide variety of anxiety disorders, including post- traumatic stress disorder (PTSD). Low levels of NPY have been measured in patients with PTSD and in animals exposed to traumatic stress. Modulation of NPY has been proposed as a potential therapy for PTSD and other anxiety disorders. The hippocampus has been implicated in anxiety disorders including PTSD, which can be considered maladaptive forms of learning. NPY and its receptors are found at high levels in hippocampus, and direct injections of NPY into hippocampus attenuate avoidance behavior in rodents. Importantly, the levels of NPY in hippocampus are reduced in rodents exposed to traumatic stress. The mechanism underlying this decrease is not known. However, the reduction in NPY expression by traumatic stress is important, because injection of NPY into hippocampus alleviates behavioral symptoms. In the previous funding period, we showed that traumatic stress causes the loss of NPY release in the temporammonic pathway in the CA1 region of hippocampus, a pathway that is important for memory consolidation and fear learning. In this funding period, we will determine the effects of NPY release in the TA pathway on hippocampal circuit function and behavior, investigate the mechanisms of decreased NPY release caused by traumatic stress, and test whether enhancing release of NPY in the TA pathway can rescue the behavioral effects of traumatic stress. These studies could lead to new therapeutic strategies to alleviate anxiety symptoms in PTSD patients.

神经肽 Y (NPY) 具有强大的抗焦虑（抗焦虑）特性，被认为具有抗压能力因素。临床和临床前研究表明，NPY 信号调节应激依赖性行为人类和啮齿动物。我们对 NPY 影响突触和回路功能机制的了解改变行为是不完整的。 NPY 与多种焦虑症有关，包括术后焦虑症。创伤性应激障碍（PTSD）。在 PTSD 患者和动物中测量到低水平的 NPY 暴露于创伤性应激。 NPY 的调节已被提议作为治疗 PTSD 和其他疾病的潜在疗法焦虑症。海马体与包括创伤后应激障碍 (PTSD) 在内的焦虑症有关，这可能是被认为是适应不良的学习形式。 NPY 及其受体在海马体中含量很高，并且直接将 NPY 注射到海马体中会减弱啮齿类动物的回避行为。重要的是，水平遭受创伤应激的啮齿类动物海马体 NPY 降低。这背后的机制减少情况未知。然而，创伤应激导致的 NPY 表达减少很重要，因为将 NPY 注射到海马体可以减轻行为症状。在之前的融资期间，我们展示了创伤应激导致 CA1 区颞氨途径中 NPY 释放的丧失海马体，一条对于记忆巩固和恐惧学习很重要的通路。在本次资助期间，我们将确定 TA 通路中 NPY 释放对海马回路功能和行为的影响，研究创伤应激引起的 NPY 释放减少的机制，并测试是否增强 TA 通路中 NPY 的释放可以挽救创伤应激的行为影响。这些研究可以导致缓解 PTSD 患者焦虑症状的新治疗策略。