Stress, Depression, Serotonin, and Plasticity of Excitatory Transmission

压力、抑郁、血清素和兴奋性传递的可塑性

基本信息

批准号：
7888851
负责人：
Xiang Cai
金额：
$ 37.78万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-15 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7888851
关键词：
AMPA Receptors Alcohol or Other Drugs use Anhedonia Animal Model Animals Antidepressive Agents Apical Behavioral Behavioral Symptoms Biological Biological Assay Biotinylation Brain Brain region Calcium/calmodulin-dependent protein kinase Cell surface Cells Chemosensitization Chronic Chronic stress Cognitive Communication Control Animal Data Dendrites Distal Dominant-Negative Mutation Down-Regulation Emotional Emotions Excitatory Postsynaptic Potentials Experimental Designs Functional disorder Glutamate Receptor Glutamates Hippocampus (Brain)Human Immunoblotting Lead Learning Long-Term Potentiation Mediating Memory Mental Depression Mental disorders Modeling Outcome Pathway interactions Pharmaceutical Preparations Phospho-Specific Antibodies Phosphorylation Physiological Play Process Prosencephalon Rattus Receptor Activation Research Design Role Second Messenger Systems Sensory Serotonin Serotonin Receptor 5-HT1B Signal Pathway Signal Transduction Site Slice Source Stress Synapses Synaptic Transmission Synaptic plasticity System Techniques Testing Therapeutic Effect Transfection Transgenic Mice Up-Regulation Western Blotting base behavior measurement calmodulin-dependent protein kinase II density design entorhinal cortex hippocampal pyramidal neuron improved information processing innovation multidisciplinary novel photolysis postsynaptic public health relevance receptor research study response second messenger social social stress synaptic function transmission process treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Serotonin signaling is a primary target of antidepressant medication, and may be dysregulated in psychiatric diseases. Serotonergic afferents and serotonin 5-HT1B receptors to the hippocampus are concentrated in stratum lacunosum-moleculare (SLM), where glutamatergic synaptic input from the entorhinal cortex, the temporo-ammonic (TA) pathway, also terminates. The TA pathway provides the only direct input to CA1 pyramidal neurons from the cortex and is thus a main source of sensory information. OBJECTIVE: to determine how 5-HT1B receptors regulate TA-CA1 synaptic transmission and determine how these processes are dysregulated in depression and restored by chronic antidepressant treatment. PRELIMINARY RESULTS: activation of 5-HT1B receptors potentiates excitatory postsynaptic potentials (field EPSPs and EPSPs) elicited by TA stimulation in CA1 SLM, but not by Schaffer collateral stimulation. The potentiation is mediated by increased postsynaptic AMPA receptor mediated transmission and accompanied by phosphorylation of the AMPA receptor GluR1 at the PKC/CaMKII Ser831 site. The effects of 5-HT1B receptor activation on TA-CA1 synaptic transmission are enhanced in rats subjected to chronic unpredictable stress (CUS), an accepted animal model of depression, and blocked by chronic antidepressant treatment. SPECIFIC AIMS: 1. Test whether 5-HT1B receptor-induced potentiation and activity-dependent synaptic plasticity share common signaling mechanisms that lead to AMPA receptor insertion at TA-CA1 synapses. 2. Determine how potentiation of TA-CA1 synaptic transmission by 5-HT1B receptors is enhanced after chronic unpredictable stress. 3. Determine why potentiation of TA-CA1 synaptic transmission by 5-HT1B receptors is absent after chronic antidepressant treatment. 4. Test whether chronic antidepressant treatment can reverse a behavioral sign of depression, anhedonia, when 5-HT1B receptors are blocked pharmacologically or when serotonin-induced potentiation is absent in GluR1 S831A transgenic mice. RESEARCH DESIGN: we will combine electrophysiological techniques, including glutamate photolysis, with cell biological techniques such as transfection with constitutively active and dominant negative constructs, western blotting, and biotinylation assays, to investigate the actions of 5-HT1B receptors in hippocampal slices taken from control animals and animals subjected to CUS and chronic antidepressant treatment. OUTCOMES: The proposed project will expand our understanding of the physiological actions of serotonin and determine whether depression results, in part, from a dysregulation of the strength of excitatory synaptic transmission in multiple brain regions involved in cognitive and emotional function. A better understanding of serotonin actions and their alteration by stress will lead to improved antidepressant treatment strategies. PUBLIC HEALTH RELEVANCE: Depression and other forms of mental illness are treated with drugs that act on a specific communication system in the brain that uses the substance serotonin. The normal function of this system is not well understood. Our experiments are designed to better understand the role played by this system in information processing in the healthy brain and how it may malfunction in mental illness.

描述（由申请人提供）：血清素信号传导是抗抑郁药物的主要目标，并且可能在精神疾病中失调。海马的血清素能传入神经和血清素 5-HT1B 受体集中在腔隙分子层 (SLM)，来自内嗅皮层的谷氨酸突触输入、颞氨 (TA) 途径也在此终止。 TA 通路提供从皮质到 CA1 锥体神经元的唯一直接输入，因此是感觉信息的主要来源。目的：确定 5-HT1B 受体如何调节 TA-CA1 突触传递，并确定这些过程如何在抑郁症中失调并通过长期抗抑郁治疗恢复。初步结果：5-HT1B 受体的激活增强了 CA1 SLM 中 TA 刺激引起的兴奋性突触后电位（场 EPSP 和 EPSP），但不增强 Schaffer 侧支刺激。这种增强作用是通过增加突触后 AMPA 受体介导的传递来介导的，并伴随着 PKC/CaMKII Ser831 位点的 AMPA 受体 GluR1 的磷酸化。 5-HT1B 受体激活对 TA-CA1 突触传递的影响在遭受慢性不可预测应激 (CUS)（一种公认的抑郁症动物模型）的大鼠中增强，并被长期抗抑郁治疗阻断。具体目标： 1. 测试 5-HT1B 受体诱导的增强和活性依赖性突触可塑性是否具有共同的信号机制，导致 AMPA 受体插入 TA-CA1 突触。 2. 确定在长期不可预测的应激后，5-HT1B 受体对 TA-CA1 突触传递的增强作用是如何增强的。 3. 确定为什么长期抗抑郁治疗后不存在 5-HT1B 受体对 TA-CA1 突触传递的增强作用。 4.测试当5-HT1B受体被药物阻断或当GluR1 S831A转基因小鼠中不存在5-羟色胺诱导的增强作用时，长期抗抑郁治疗是否可以逆转抑郁、快感缺乏的行为体征。研究设计：我们将把包括谷氨酸光解在内的电生理学技术与细胞生物学技术（例如用组成型活性和显性失活结构转染、蛋白质印迹和生物素化测定）相结合，以研究取自对照的海马切片中 5-HT1B 受体的作用动物和接受 CUS 和长期抗抑郁治疗的动物。结果：拟议的项目将扩大我们对血清素生理作用的理解，并确定抑郁症是否部分由涉及认知和情绪功能的多个大脑区域的兴奋性突触传递强度失调引起。更好地了解血清素的作用及其因压力而发生的变化将有助于改进抗抑郁治疗策略。公共健康相关性：抑郁症和其他形式的精神疾病可以通过作用于大脑中使用血清素物质的特定通信系统的药物来治疗。该系统的正常功能尚不清楚。我们的实验旨在更好地了解该系统在健康大脑信息处理中所发挥的作用，以及它在精神疾病中如何发生故障。