Mechanisms of Emotional Stress Effects on Hypothalamus

情绪压力对下丘脑影响的机制

• 批准号: 6895261
• 负责人: Paul E. Sawchenko
• 金额: $ 43.06万
• 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/6895261
• 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（由申请人提供）：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，主要是由于其在激活垂体-肾上腺（糖皮质激素）反应中不可或缺的作用。提出了四组实验来阐明介导PVH对急性情绪压力的反应的电路和细胞机制，以及这些如何通过反复的压力暴露来修改。首先，立即早期基因引导的消融策略将测试以下假设：PVH对急性情绪应激（足电击）的反应是通过经由丘脑进入前脑的脊髓伤害性通路介导的。将使用经典条件反射范式来确定急性足电击引起的PVH募集的传入介导是否以及如何转移到促进不同感觉方式的途径。第二，我们将测试的假设，即儿茶酚胺输入调节PVH的反应，急性情绪压力，通过加强其他系统发起的主要驱动。PVH的局部抑制性输入的功能组织将通过评估应激和类固醇对已确定的GABA能传入来源的影响来表征。我们将尝试建立一种方法，选择性GABA能去神经PVH，让这种神经支配的作用，以直接评估。免疫毒素消融将被用来[追求]食欲肽系统参与PVH的情绪应激效应的初步迹象。第三，转录分析的microdisserted PVH亚区将进行测试的假设，即内在机制参与PVH反应的习惯化反复的情绪压力。具有受控糖皮质激素水平的动物将用于确定激素如何以及在何处与传入回路相互作用以影响习惯化。最后，为了开始将电路与细胞机制联系起来，将使用药理学方法来评估肾上腺素能神经传递在急性应激效应中对编码相互作用以控制垂体-肾上腺输出的肽的基因转录的作用。慢病毒载体介导的基因转移将被用来评估在这种情况下的一个关键的转录因子，环磷酸腺苷反应元件结合蛋白的作用。垂体-肾上腺系统的糖皮质激素产物有助于应对急性紧急情况，但激素水平的持续升高，如慢性情绪应激中所见，是各种系统性、精神性甚至神经退行性疾病的促成或加剧因素。对这些适应性变化背后的电路和机制有更全面的基本了解，将有助于更有效地管理与压力相关的疾病。