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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：
10616491
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/10616491
关键词：
Affect Amygdaloid structure 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 Human Impairment Injections Knowledge Learning Location Measures Mediating Memory Mental Depression Methods Modeling Mus Neuropeptide Y Receptor Pathway interactions Patients Peptides Pharmacology Physiological Post-Traumatic Stress Disorders Property Rodent Rodent Model Sensory Signal Transduction Slice Stress Study models Synapses Testing Training anxiety symptoms avoidance behavior behavior test depressive symptoms designer receptors exclusively activated by designer drugs entorhinal cortex experimental study genetic approach improved inhibitory neuron memory consolidation mood regulation neuropeptide Y neuroregulation new therapeutic target novel strategies novel therapeutic intervention optogenetics pharmacologic postsynaptic preclinical study preservation prevent receptor recruit resilience factor response spatiotemporal stress reduction 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，被认为是一种压力弹性因素。临床和临床前研究表明，NPY信号调节应激依赖行为。无论是人类还是啮齿动物。我们对NPY影响突触和回路功能的机制的了解改变行为是不完整的。NPY与多种焦虑症有关，包括后焦虑症。创伤应激障碍(PTSD)。在创伤后应激障碍患者和动物身上都检测到了低水平的NPY 暴露在创伤性压力之下。NPY的调节已被认为是治疗创伤后应激障碍和其他疾病的一种潜在疗法焦虑症。海马体与焦虑障碍有关，包括创伤后应激障碍，这可能是被认为是不适应的学习形式。神经肽Y及其受体在海马区高水平存在，海马区直接注射NPY可减弱啮齿动物的回避行为。重要的是，暴露于创伤应激的啮齿动物海马神经肽Y减少。这背后的机制是下降的情况尚不清楚。然而，创伤应激减少NPY的表达是很重要的，因为海马区注射NPY可减轻行为症状。在上一个资助期，我们展示了创伤应激导致大鼠脑CA1区暂时性氨通道NPY释放的丧失海马体，一条对巩固记忆和学习恐惧很重要的途径。在此资助期内，我们将确定TA通路中NPY的释放对海马回路功能和行为的影响，探讨创伤应激导致NPY释放减少的机制，并检测在TA通路中释放NPY可以挽救创伤应激的行为效应。这些研究可能引导新的治疗策略来缓解创伤后应激障碍患者的焦虑症状。