Neural Mechanisms Underlying Stress-Induced Changes In Behavior

压力引起的行为变化的神经机制

基本信息

批准号：
8038334
负责人：
Matthew A Cooper
金额：
$ 14.14万
依托单位：
UNIVERSITY OF TENNESSEE KNOXVILLE
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：
2010-03-05 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8038334
关键词：
Affect Aggressive behavior Agonist Amygdaloid structure Animal Model Anxiety Autoreceptors Behavior Behavior Control Brain region Brain-Derived Neurotrophic Factor Cyclic AMP-Responsive DNA-Binding Protein Data Development Exposure to Generalized Anxiety Disorder Hamsters Human Individual Injection of therapeutic agent Lead Link Major Depressive Disorder Mediating Memory Mental Depression Mental disorders Mesocricetus auratus Messenger RNA Modeling Molecular Mood Disorders N-Methyl-D-Aspartate Receptors Nature Neuronal Plasticity Neurons Panic Attack Pathway interactions Pharmacological Treatment Phosphorylation Play Post-Traumatic Stress Disorders Psychopathology Psychosocial Stress Receptor Activation Reporting Risk Role Selective Serotonin Reuptake Inhibitor Serotonin Serotonin Receptor 5-HT1A Serotonin Receptor 5-HT2C Signal Transduction Stimulus Stress Testing Treatment Efficacy Viral Work conditioned fear dorsal raphe nucleus experience immunoreactivity improved interest mRNA Expression neural circuit neurochemistry neuromechanism neurotransmission neurotrophic factor psychosocial public health relevance relating to nervous system research study social social model

项目摘要

DESCRIPTION (provided by applicant): Exposure to stressful, psychosocial stimuli can lead to a variety of affective disorders, including depression, generalized anxiety disorder, and post-traumatic stress disorder. Serotonin is a key neurochemical signal that plays a pivotal role in the expression and treatment of stress-sensitive psychopathologies. In animal models, serotonin acts in several brain regions, including the basolateral amygdala (BLA), to regulate stress-induced changes in behavior indicative of anxiety and depression. In the current proposal, we will use a social defeat model in Syrian hamsters, called conditioned defeat, to investigate stress-induced changes in behavior within a psychosocial context. In our conditioned defeat model, social defeat results in a complete loss of species-typical territorial aggression and a substantial increase in submissive and defensive behavior when individuals are later tested with a smaller, non-aggressive opponent. In our working model, we propose that social defeat activates 5-HT neurons and that serotonin in turn modulates the formation of conditioned defeat by affecting key factors that regulate neural plasticity in the BLA such as cAMP response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF). More specifically, we propose that serotonin modulates the formation of conditioned defeat by acting at 5-HT1A receptors in the BLA to impair the CREB-BDNF pathway and acting at 5-HT2C receptors in the BLA to facilitate the CREB-BDNF pathway. In the current proposal we will test four predictions. First, we will test the prediction that injection of a 5-HT1A receptor antagonist into the BLA will enhance the acquisition and expression of conditioned defeat. Second, we will test the prediction that systemic administration of a 5-HT2C receptor agonist will enhance the acquisition and expression of conditioned defeat, and that the effects of the 5-HT2C receptor agonist will be blocked by injection of a 5-HT2C receptor antagonist into the BLA. Third, we will test the prediction that pharmacological activation of 5-HT1A autoreceptors in the dorsal raphe nucleus will block defeat-induced increases in phosphorylated CREB immunoreactivity within the BLA. Fourth, we will test the prediction that pharmacological activation of 5-HT1A autoreceptors in the dorsal raphe nucleus will block defeat-induced increases in BDNF mRNA expression within the BLA. PUBLIC HEALTH RELEVANCE: Exposure to stressful, psychosocial stimuli can lead to a variety of mood disorders, including major depression, generalized anxiety disorder, and post-traumatic stress disorder. In this proposal, we are investigating how neurochemical signals in select brain regions control the behavioral changes that occur following social defeat experience. Studying the neural mechanisms underlying defeat-induced changes in behavior should lead to a better understanding of stress-related psychopathologies, and ultimately to the development of better treatment options for these mental disorders.

描述（由申请人提供）：暴露于压力性社会心理刺激可能导致各种情感障碍，包括抑郁症、广泛性焦虑症和创伤后应激障碍。血清素是一种关键的神经化学信号，在压力敏感的精神病理学的表达和治疗中发挥着关键作用。在动物模型中，血清素作用于多个大脑区域，包括基底外侧杏仁核（BLA），调节压力引起的焦虑和抑郁行为变化。在当前的提案中，我们将使用叙利亚仓鼠的社会失败模型（称为条件性失败）来研究心理社会背景下压力引起的行为变化。在我们的条件性失败模型中，社会失败会导致物种典型的领土攻击性完全丧失，并且当个体随后与较小的、非攻击性的对手进行测试时，顺从和防御行为大幅增加。在我们的工作模型中，我们提出，社交失败会激活 5-HT 神经元，而血清素反过来又会通过影响调节 BLA 中神经可塑性的关键因素（例如 cAMP 反应元件结合蛋白 (CREB) 和脑神经元）来调节条件性失败的形成。衍生神经营养因子（BDNF）。更具体地说，我们提出血清素通过作用于 BLA 中的 5-HT1A 受体以损害 CREB-BDNF 通路并作用于 BLA 中的 5-HT2C 受体以促进 CREB-BDNF 通路来调节条件性失败的形成。在当前的提案中，我们将测试四个预测。首先，我们将测试以下预测：将 5-HT1A 受体拮抗剂注射到 BLA 中将增强条件性失败的获得和表达。其次，我们将测试以下预测：全身施用 5-HT2C 受体激动剂将增强条件性失败的获得和表达，并且注射 5-HT2C 受体拮抗剂将阻断 5-HT2C 受体激动剂的作用进入 BLA。第三，我们将测试这一预测，即中缝背核中 5-HT1A 自身受体的药理学激活将阻止 BLA 内磷酸化 CREB 免疫反应性的失败诱导增加。第四，我们将测试这样的预测：中缝背核中 5-HT1A 自身受体的药理学激活将阻止 BLA 内失败诱导的 BDNF mRNA 表达增加。公共健康相关性：暴露于压力、社会心理刺激可能导致各种情绪障碍，包括重度抑郁症、广泛性焦虑症和创伤后应激障碍。在这项提案中，我们正在研究特定大脑区域的神经化学信号如何控制社交失败经历后发生的行为变化。研究失败引起的行为变化背后的神经机制应该有助于更好地理解与压力相关的精神病理学，并最终为这些精神障碍开发更好的治疗方案。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Social status alters defeat-induced neural activation in Syrian hamsters.

DOI：
10.1016/j.neuroscience.2012.03.002
发表时间：
2012-05-17
期刊：
NEUROSCIENCE
影响因子：
3.3
作者：
Morrison, K. E.;Curry, D. W.;Cooper, M. A.
通讯作者：
Cooper, M. A.

Overlapping neurobiology of learned helplessness and conditioned defeat: implications for PTSD and mood disorders.

DOI：
10.1016/j.neuropharm.2011.02.024
发表时间：
2012-02
期刊：
NEUROPHARMACOLOGY
影响因子：
4.7
作者：
Hammack, Sayamwong E.;Cooper, Matthew A.;Lezak, Kimberly R.
通讯作者：
Lezak, Kimberly R.

A role for 5-HT1A receptors in the basolateral amygdala in the development of conditioned defeat in Syrian hamsters.

DOI：
10.1016/j.pbb.2011.09.005
发表时间：
2012-01
期刊：
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
影响因子：
3.6
作者：
Morrison, Kathleen E.;Cooper, Matthew A.
通讯作者：
Cooper, Matthew A.

Effects of dominance status on conditioned defeat and expression of 5-HT1A and 5-HT2A receptors.

DOI：
10.1016/j.physbeh.2011.02.033
发表时间：
2011-08-03
期刊：
Physiology & behavior
影响因子：
2.9
作者：
Morrison KE;Swallows CL;Cooper MA
通讯作者：
Cooper MA

5-HT1A receptor activation reduces fear-related behavior following social defeat in Syrian hamsters.

DOI：
10.1016/j.pbb.2014.03.024
发表时间：
2014-07
期刊：
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
影响因子：
3.6
作者：
Bader, Lauren R.;Carboni, Joseph D.;Burleson, Cody A.;Cooper, Matthew A.
通讯作者：
Cooper, Matthew A.

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Matthew A Cooper其他文献

Design, synthesis, conformational analysis and nucleic acid hybridisation properties of thymidyl pyrrolidine-amide oligonucleotide mimics (POM).

胸苷基吡咯烷酰胺寡核苷酸模拟物 (POM) 的设计、合成、构象分析和核酸杂交特性。

DOI：
10.1039/b306156f
发表时间：
2003
期刊：
Organic & biomolecular chemistry
影响因子：
3.2
作者：
David T Hickman;T. Tan;J. Morral;Paul M King;Matthew A Cooper;Jason Micklefield
通讯作者：
Jason Micklefield