Mechanisms of Emotional Stress Effects on Hypothalamus

情绪压力对下丘脑影响的机制

• 批准号: 7261241
• 负责人: Paul E. Sawchenko
• 金额: $ 40.83万
• 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 2008-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7261241
• 关键词: Ablation; Acute; Adrenal Glands; Adrenergic Agents; Adrenergic Antagonists; Animals; Argipressin; Auditory; Biological Assay; Brain region; CREB1 gene; Catecholamines; Categories; Cells; Chronic; Condition; Corticotropin; Corticotropin-Releasing Hormone; Cyclic AMP-Responsive DNA-Binding Protein; Denervation; Disease; Dominant-Negative Mutation; Elevation; Emergency Situation; Emotional; Emotional Stress; Exposure to; Feedback; Gene Transfer; Genes; Genetic Transcription; Glucocorticoids; Goals; HPSE gene; Health; Hormonal; Hormones; Human; Hypothalamic structure; Immediate-Early Genes; Immunotoxins; In Situ; Interneurons; Lateral Hypothalamic Area; Lentivirus Vector; Localized; Mediating; Mediation; Methods; Modality; Modeling; Molecular; Neuraxis; Neurodegenerative Disorders; Neurons; Neurosecretory Systems; Neurotransmitters; Nociception; Output; Pathway interactions; Peptides; Physiological; Pituitary Gland; Pituitary-Adrenal System; Play; Prosencephalon; RNA; Resistance; Resources; Risk; Role; Sensory; Source; Spinal; Stimulus; Stress; Structure; System; Testing; Thalamic structure; Time; Transcriptional Activation; Transcriptional Regulation; Work; acute stress; adrenergic; biological adaptation to stress; classical conditioning; coping; day; design; gamma-Aminobutyric Acid; hypocretin; hypothalamic-pituitary-adrenal axis; nerve supply; neurotransmission; paraventricular nucleus; relating to nervous system; research study; response; restraint; restraint stress; stress management; stressor; transcription factor

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）是组织对情绪压力的适应性反应的关键结构，很大程度上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回路和细胞机制，以及这些回路和细胞机制如何通过反复的压力暴露而改变。首先，立即早期基因引导消融策略将检验以下假设：PVH 对急性情绪压力、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介导的。将使用经典条件范式来确定是否以及如何将急性足部电击引起的PVH募集的传入介导转移到有利于不同感觉模式的途径。其次，我们将检验这样的假设：儿茶酚胺输入通过增强其他系统发起的主要驱动力来调节 PVH 对急性情绪压力的反应。 PVH 局部抑制输入的功能组织将通过评估压力和类固醇对已确定的 GABA 传入源的影响来表征。我们将尝试建立一种选择性 GABA 能去神经 PVH 的方法，以便直接评估这种神经支配的作用。免疫毒素消除将用于[追踪]食欲素肽系统参与情绪应激对PVH影响的初步迹象。第三，将进行显微解剖的 PVH 亚区域的转录分析，以检验以下假设：内在机制涉及 PVH 对重复情绪压力的反应的习惯化。糖皮质激素水平受控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。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对编码肽的基因转录的影响中的作用，这些肽相互作用以控制垂体-肾上腺输出。慢病毒载体介导的基因转移将用于评估关键转录因子（环 AMP 反应元件结合蛋白）在这种情况下的作用。垂体-肾上腺系统的糖皮质激素产品有助于应对急性紧急情况，但激素水平的持续升高（如慢性情绪压力中所见）是多种系统性疾病、精神疾病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的更全面的基本了解将促进对压力相关疾病的更有效的管理。