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：
8609067
负责人：
Xiang Cai
金额：
$ 37.2万
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 2015-07-06
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8609067
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 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 Pathway interactions Pharmaceutical Preparations Phospho-Specific Antibodies Phosphorylation Physiological Play Process Prosencephalon Rattus Receptor Activation 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.

描述（由申请人提供）：5-羟色胺信号传导是抗抑郁药的主要靶标，在精神疾病中可能失调。海马对海马的血清素能传入和5-羟色胺5-HT1B受体集中在lacunosum-Moleculare（SLM）中，其中来自内嗅皮层的谷氨酸能突触输入，颞虫 - ammammonic（TA）途径，也终止。 TA途径提供了来自皮质的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突触传播，并确定这些过程在抑郁症中如何失调，并通过慢性抗抑郁治疗恢复。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（现场EPSP和EPSP），但不能通过Schaffer侧支刺激。该增强是由突触后AMPA受体介导的传播增加的介导的，并伴随着PKC/CAMKII SER831位点的AMPA受体GlUR1的磷酸化。在接受慢性不可预测的胁迫（CUS）（一种公认的抑郁症动物模型，并被慢性抗抑郁药治疗阻塞的大鼠）中，5-HT1B受体激活对TA-CA1突触传播的影响增强了。具体目的：1。测试5-HT1B受体诱导的增强和活动依赖性突触可塑性是否具有常见的信号传导机制，从而导致TA-CA1突触处AMPA受体插入。 2。确定在慢性不可预测的压力后，如何增强5-HT1B受体的TA-CA1突触传播的增强。 3。确定为什么在慢性抗抑郁药治疗后不存在5-HT1B受体的TA-CA1突触传播的原因。 4。测试当5-HT1B受体在药理学上阻塞，还是在Glur1 S831a转基因小鼠中不存在5- ht1b受体时，是否可以扭转慢性抗抑郁治疗的行为症状，即抗抑郁症。研究设计：我们将结合电生理技术，包括谷氨酸光解，以及细胞生物学技术，例如与组成型活性和主导的负面负面结构，蛋白质印迹和生物素化测定，以研究从对照动物和动物中受到对照动物和镀铬的疗法的治疗方法，以研究5-HT1B受体的作用。结果：拟议的项目将扩展我们对5-羟色胺生理作用的理解，并确定抑郁症是否部分是由于涉及认知和情感功能的多个大脑区域的兴奋性突触传播强度的失调而导致的。更好地了解5-羟色胺作用及其对压力的改变将导致改善抗抑郁药的治疗策略。