Mechanisms of Emotional Stress Effects on Hypothalamus

情绪压力对下丘脑影响的机制

• 批准号: 7077629
• 负责人: Paul E. Sawchenko
• 金额: $ 42.05万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7077629
• 关键词: behavioral /social science research tag; behavioral habituation /sensitization; cAMP response element binding protein; catecholamines; conditioning; emotional crisis; gamma aminobutyrate; genetic transcription; glucocorticoids; hormone regulation /control mechanism; hypothalamic pituitary adrenal axis; hypothalamus; immunocytochemistry; in situ hybridization; laboratory rat; microarray technology; neurons; neurotransmitter receptor; paraventricular nucleus; psychological adaptation; psychological stressor; regulatory gene; reinforcer; transfection; transfection /expression vector

DESCRIPTION (provided by applicant): The paraventricular nucleus of the hypothalamus (PVH) is a pivotal structure in organizing adaptive responses to emotional stress, largely by virtue of its indispensable role in activating pituitary-adrenal (glucocorticoid) responses. Four sets of experiments are proposed to clarify the circuits and cellular mechanisms that mediate PVH responses to acute emotional stress, and how these come to be modified by repeated stress exposure. First, an immediate-early gene-guided ablation strategy will test the hypothesis that PVH responses to an acute emotional stress, footshock, are mediated via spinal nociceptive pathways that access the forebrain via the thalamus. A classical conditioning paradigm will be used to determine whether and how the afferent mediation of PVH recruitment by acute footshock may be transferred to pathways subserving a different sensory modality. Second, we will test the hypothesis that catecholamine inputs modulate PVH responses to acute emotional stress by reinforcing a primary drive initiated by other systems. The functional organization of local inhibitory inputs to PVH will be characterized by assessing stress and steroidal influences on identified sources of GABAergic afferents. We will attempt to establish a method for selective GABAergic denervation of PVH, to allow the role of this innervation to be assessed directly. Immunotoxin ablations will be used to [pursue] preliminary indications of an involvement of the orexin peptide system in emotional stress effects on PVH. Third, transcriptional profiling of microdissected PVH subregions will be carried out to test the hypothesis that intrinsic mechanisms are involved in habituation of PVH response to repeated emotional stress. Animals with controlled glucocorticoid levels will be used to determine how and where the hormone interacts with afferent circuitry to effect habituation. Finally, to begin to relate circuitry to cellular mechanisms, pharmacologic methods will be used to assess the role of adrenergic neurotransmission in acute stress effects on the transcription of genes encoding peptides that interact to govern pituitary-adrenal output. Lentiviral vector-mediated gene transfer will be used to evaluate the role in this context of a key transcription factor, the cyclic AMP response element-binding protein. Glucocorticoid products of the pituitary-adrenal system facilitate coping with acute emergencies, but sustained elevations in hormone levels, as seen in chronic emotional stress, is a contributing or exacerbating factor in diverse systemic, psychiatric and even neurodegenerative disorders. A fuller basic understanding of circuits and mechanisms underlying these adaptations will promote more effective management of stress related disease.

描述(申请人提供)：下丘脑室旁核(PVH)是组织对情绪应激的适应性反应的关键结构，在很大程度上是由于它在激活垂体-肾上腺(糖皮质激素)反应中不可或缺的作用。提出了四组实验，以阐明介导PVH对急性情绪应激反应的电路和细胞机制，以及这些机制如何被反复的应激暴露所改变。首先，一种即刻-早期基因引导的消融策略将检验PVH对急性情绪应激(足部电击)的反应是通过通过丘脑进入前脑的脊髓伤害性通路来调节的假设。一个经典的条件作用范式将被用来确定是否以及如何将由急性足部电击引起的PVH募集的传入中介转移到服务于不同感觉通道的通路。其次，我们将检验儿茶酚胺输入通过加强由其他系统启动的主要驱动力来调节PVH对急性情绪应激的反应的假设。PVH局部抑制输入的功能组织将通过评估应激和类固醇对已识别的GABA能传入来源的影响来表征。我们将尝试建立一种选择性GABA能去神经支配PVH的方法，以便直接评估这种神经支配的作用。免疫毒素消融将被用来[追踪]食欲素肽系统参与PVH情绪应激效应的初步迹象。第三，将对显微切割的PVH亚区进行转录图谱分析，以检验PVH对重复情绪应激反应的习惯化涉及内在机制的假设。控制糖皮质激素水平的动物将被用来确定激素如何以及在哪里与传入回路相互作用，以实现习惯化。最后，为了开始将电路与细胞机制联系起来，将使用药理学方法评估肾上腺素能神经传递在急性应激对编码多肽的基因转录的影响中所起的作用，这些基因相互作用，控制垂体-肾上腺的输出。慢病毒载体介导的基因转移将被用来评估关键转录因子，环状AMP反应元件结合蛋白在这一背景下的作用。垂体-肾上腺系统的糖皮质激素产物有助于应对紧急情况，但激素水平的持续升高，如慢性情绪应激所见，是各种全身、精神甚至神经退行性疾病的促成或加剧因素。对这些适应背后的回路和机制有更全面的基本了解，将促进对应激相关疾病的更有效管理。