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）：压力性的生活事件使许多精神疾病的症状加剧。杏仁核标志着情绪厌恶刺激的存在，并且在许多精神病障碍中失调，其大量输出对“应力电路”的两个关键节点：Stria terminalis（BNST）的床核（BNST）和中枢amygdaloid核（CEN）。我们以前的工作表明，BNST和CEN可以直接访问中脑多巴胺系统，这也因重复应力而失调。在此提案中，我们将使用猴子模型来进行1）检查与BNST和CEN特定细分的传入输入的范围和组织，以及2）确定如何通过应力电路的这两个关键节点传达的信息定位，以将传入调节特定的DA神经元及其输出路径。提出的压力反应性提高被认为是多种精神疾病的主要危险因素，但对于灵长类动物模型中的压力回路的组织知之甚少。 BNST和CEN分别形成了中央“扩展杏仁核”的尾杆和尾杆，该电线已被概念化为参与对压力刺激的响应的统一宏观结构。在大鼠中，BNST和CEN的特定细分对慢性应激，抗抑郁药，酒精和对滥用药物的反应有所不同，这表明细分特定的输入/输出路径。尽管BNST和CEN明显地“对称”组织，但BNST和CEN对各种类型刺激的反应中的解离表明了基本的联系差异。我们在非人类灵长类动物中的初步数据表明，尽管某些大脑区域向BNST和CEN发送输入，但其他传入系统选择性地仅针对BNST。该组织建议BNST和CEN发挥作用，但在压力反应中的作用是单独的，并且与大鼠模型存在根本差异。 DA系统被新颖和压力的刺激激活。由于即使轻度应激对中脑膜和中皮层靶标的DA外排也有重大影响，因此BNST和CEN之间的连接是一种直接的厌恶刺激可以呈现这种系统的直接方式。我们先前的研究表明，DA神经元从BNST和CEN接收意见。在这里，我们建议1）更直接地检查杏仁核，海马和皮层对BNST和CEN是否存在差异的传入影响（目标1和2），以及2）研究如何通过BNST和/或CEN neuron/CATE DAURON/CATES OUTION/OTATION/OTATION/OTATION/OTATION/CATE TATE TATE TATE TACHS ATION/OTATE TATE TATE（3）研究3个特定杏仁核的开放式循环系统。 公共卫生相关性：压力大的生活事件是通过大脑区域引发的，这些事件通过多巴胺等发射器来调节动机行为。我们将研究参与认知的大脑区域如何影响压力电路，以及与压力相关信息可以通过多巴胺系统影响动机行为的特定方式。