Dopamine and stress: connections of the BNST and central nucleus

多巴胺和压力：BNST 和中央核的连接

• 批准号: 8213552
• 负责人: JULIE L. FUDGE
• 金额: $ 44.84万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8213552
• 关键词: Alcohols; Amygdaloid structure; Anatomy; Animals; Antidepressive Agents; Aversive Stimulus; Brain Stem; Brain region; Cell Nucleus; Cells; Chronic stress; Cognition; Corpus striatum structure; Data; Dissociation; Dopamine; Drug Addiction; Efferent Pathways; Event; Exposure to; Fiber; Goals; Hippocampus (Brain); Human; Hypothalamic structure; Injection of therapeutic agent; Label; Laboratories; Lateral; Life; Macaca fascicularis; Medial; Mediating; Memory; Mental disorders; Midbrain structure; Modeling; Molecular; Monkeys; Mood Disorders; Neurotransmitters; Oranges; Output; Pathway interactions; Physiological; Play; Population; Positioning Attribute; Prefrontal Cortex; Primates; Process; Property; Prosencephalon; Psychotic Disorders; Rattus; Relative (related person); Reporting; Risk Factors; Rodent; Role; Schizophrenia; Signal Transduction; Site; Stimulus; Stress; Structure; Structure of terminal stria nuclei of preoptic region; Substantia nigra structure; Symptoms; System; Testing; Tracer; Ventral Striatum; Work; addiction; base; biological adaptation to stress; density; dopamine system; dopaminergic neuron; drug of abuse; emotional stimulus; hippocampal subregions; motivated behavior; nonhuman primate; novel; public health relevance; response; severe mental illness

DESCRIPTION (provided by applicant): Symptoms of many psychiatric disorders are exacerbated by stressful life events. The amygdala, which signals the presence of emotionally aversive stimuli and is dysregulated in many psychiatric disorders, has massive outputs to two key nodes of the 'stress circuit': the bed nucleus of the stria terminalis (BNST) and the central amygdaloid nucleus (CeN). Our previous work shows that the BNST and CeN have direct access to the midbrain dopamine system, which is also dysregulated by repeated stress. In this proposal we will use a monkey model to 1) examine the scope and organization of afferent inputs to specific subdivisions of the BNST and CeN, and 2) determine how information channeled through these two key nodes of the stress circuit are positioned to afferently regulate specific DA neurons and their output paths. Heightened stress reactivity is proposed to be a major risk factor for a broad range of mental illnesses, yet little is known of the organization of stress circuitry in primate models. The BNST and CeN form the rostral and caudal poles, respectively, of the central 'extended amygdala', which has been conceptualized as a unified macrostructure involved in responses to stressful stimuli. In rats, specific subdivisions of the BNST and CeN have differential responses to chronic stress, antidepressants, alcohol, and to drugs of abuse, suggesting subdivision-specific input/output paths. Despite the apparent 'symmetrical' organization of the BNST and CeN, dissociations in BNST and CeN responses to various types of stimuli suggest fundamental connectional differences. Our preliminary data in nonhuman primate indicate that while some brain regions send inputs to both BNST and CeN, other afferent systems selectively target only the BNST. This organization suggests that the BNST and CeN play related but separate roles in stress responses, and that there are fundamental differences from the rat model. The DA system is activated by novel and stressful stimuli. Since even mild stress has a significant impact on DA efflux in mesolimbic and mesocortical targets, connections between the BNST and CeN is one direct way aversive stimuli can afferently regulate this system. Our previous studies show that the DA neurons receive input from the BNST and CeN. Here, we propose to 1) more directly examine whether there is a differential afferent influence of the amygdala, hippocampus, and cortex on the BNST and CeN (Aims 1 and 2), and 2) examine how open loop systems from specific amygdaloid nuclei are channeled through BNST and/or CeN subregions to target specific DA neuron/output paths in the same animal (Aim 3). PUBLIC HEALTH RELEVANCE: Stressful life events are channeled through brain regions that regulate motivated behaviors through transmitters such as dopamine. We will examine how brain regions involved in cognition influence stress circuits, as well as specific ways that stress-related information can influence motivated behavior through the dopamine system.

描述（由申请人提供）：许多精神疾病的症状会因紧张的生活事件而加重。杏仁核是情绪厌恶刺激的信号，在许多精神疾病中是失调的，它向“压力回路”的两个关键节点大量输出：终纹床核（BNST）和中央杏仁核（CeN）。我们之前的工作表明，BNST和CeN直接进入中脑多巴胺系统，该系统也因反复应激而失调。在这个提议中，我们将使用一个猴子模型来1)检查传入输入到BNST和CeN的特定细分的范围和组织，以及2)确定通过应力回路的这两个关键节点的信息通道如何定位来传入调节特定的DA神经元及其输出路径。高应激反应被认为是一系列精神疾病的主要危险因素，但对灵长类动物模型中应激回路的组织知之甚少。bst和CeN分别形成中央“扩展杏仁核”的吻极和尾极，这被概念化为一个统一的宏观结构，涉及对压力刺激的反应。在大鼠中，BNST和CeN的特定细分对慢性应激、抗抑郁药、酒精和滥用药物有不同的反应，这表明细分特定的输入/输出路径。尽管BNST和CeN具有明显的“对称”组织，但BNST和CeN对各种刺激反应的解离表明了根本的连接差异。我们在非人类灵长类动物中的初步数据表明，虽然某些大脑区域同时向中脑皮层和中枢神经网络发送输入，但其他传入系统选择性地只针对中脑皮层。这一组织表明，BNST和CeN在应激反应中起着相关但不同的作用，并且与大鼠模型存在根本差异。新刺激和压力刺激会激活DA系统。由于即使是轻微的应激也会对中脑边缘和中脑皮层的DA外排产生显著影响，因此，BNST和CeN之间的联系是厌恶刺激传入调节该系统的一种直接方式。我们之前的研究表明，DA神经元接收来自BNST和CeN的输入。在这里，我们建议1)更直接地研究杏仁核、海马体和皮层对BNST和CeN是否存在不同的传入影响（目的1和2），以及2)研究来自特定杏仁核的开环系统如何通过BNST和/或CeN亚区在同一动物中靶向特定的DA神经元/输出路径（目的3）。