Serotonin-limbic system interactions that mediate anxiety

介导焦虑的血清素-边缘系统相互作用

• 批准号: 8429579
• 负责人: SHERYL G BECK
• 金额: $ 25.13万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-21 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8429579
• 关键词: 18 year old; Adult; Age; Anxiety; Anxiety Disorders; Area; Autoreceptors; Behavior; Behavioral; Cell physiology; Cells; Cellular Morphology; Characteristics; Data; Development; Dorsal; Electrophysiology (science); Engineering; Environment; Enzymes; Etiology; Exhibits; Fiber; Genetically Engineered Mouse; Glutamates; Goals; Immunohistochemistry; Incidence; Intervention; Knock-out; Knockout Mice; Knowledge; Lead; Life; Light; Limbic System; Medial; Mediating; Mental disorders; Midbrain structure; Modeling; Modification; Mood Disorders; Mus; National Institute of Mental Health; Neurons; Neurotransmitters; Phenotype; Physiological; Physiology; Predisposition; Prefrontal Cortex; Process; Prosencephalon; Public Health; Pyramidal Cells; Recording of previous events; Research; Rhodopsin; Rodent; SP1 gene; Serotonin; Serotonin Receptor 5-HT1A; Severities; Stress; Symptoms; Synapses; System; Techniques; Testing; Time; Transgenic Mice; Transgenic Organisms; base; behavior test; critical period; density; dorsal raphe nucleus; fiber cell; hippocampal pyramidal neuron; inhibitor/antagonist; innovation; mouse model; nerve supply; neural circuit; neurodevelopment; neuron development; neuronal cell body; neurotransmitter release; new technology; optogenetics; postnatal; prenatal; promoter; pup; raphe nuclei; receptor; relating to nervous system; research study; response; reuptake; serotonin receptor; therapy development; tool; trait; transcription factor

DESCRIPTION (provided by applicant): Anxiety is normal and adaptive. In its pathological form anxiety impairs the ability to optimally respond to the environment and can be debilitating. Anxiety states begin early in life; normal trait anxiety symptoms emerge around age 6, and anxiety disorders may present as early as age 11. Approximately 8% of 13-18 year olds exhibit pathological anxiety (NIMH). The incidence and etiology of anxiety suggest that early life is a critical time for the development of anxiety disorders. Serotonin (5-HT, 5-hydroxytryptamine) is one of the key neurotransmitters involved in anxiety disorders. Direct dysregulation of the midbrain 5-HT system early in development, but not in adulthood, results in a more anxious phenotype in rodents. The 5-HT system is connected to many forebrain areas also implicated in mediating anxiety, leading to the hypothesis that alterations are also occurring in these areas. Our recent studies in mice show that the cellular characteristics, synaptic activity, and 5-HT receptor-mediated responses of 5-HT neurons are immature and develop during the first several weeks of postnatal life. In contrast characteristics recorded from 5-HT1A receptor and Pet-1 knockout mice, that exhibit anxiety phenotype, were similar to each other, immature with enhanced excitability. Unfortunately, the development of raphe-limbic system circuitry is not well understood. Our long- term goal is to elucidate the changes at the cellular level within the 5-HT-limbic system that underlie the development of normal and pathological anxiety. In this proposal our current goal is to focus on the 5-HT- mPFC connection. Our hypothesis is that there is a critical period during the first few weeks of life in which 5- HT innervation of mPFC coordinates the morphological and physiological development of its local circuits. The following Specific Aims (SA) will test this hypothesis. SP1: To determine the developmental profile of layer 5 pyramidal neurons in the mPFC in concert with responses elicited by activation of 5-HT fibers Transgenic Pet-1 ChR2 mice for optogenetic stimulation will be used to test the hypothesis that projection fibers to the mPFC mature between P12-P21 leading to the release of both glutamate and 5-HT and that mPFC neurons mature physiologically between P4 and P21. SP2: To determine the developmental profile of layer 5 pyramidal cells in the mPFC in 5-HT1A and Pet-1 knockout mice. The hypothesis is that the neural development of the layer 5 pyramidal neurons will be disrupted leading to neurons with immature phenotypes. Aim 3: To determine the consequences of losing 5-HT neural activity on behavior and 5-HT-mPFC neural development. We hypothesize that a lack of 5-HT neuron activity in the dorsal raphe between P12-P21 will lead to increased anxiety-related behavior in pups and a higher anxiety in adults. The raphe and mPFC neurons will have immature phenotypes. Mice engineered with a synthetic pharmacologically activated inhibitory receptor located only in dorsal and median raphe neurons will be used. The new technology provides an innovative approach that will provide information at a functional level of 5-HT action on developing circuits. PUBLIC HEALTH RELEVANCE: The cellular mechanisms underlying stress induced behaviors and the development and treatment of stress related psychiatric disorders most likely involve both the 5- hydroxytryptamine (5-HT) cell body containing nuclei of the raphe as well as their projection areas in the limbic forebrain. This project is investigating the postnatal development of the raphe and one its projection areas, the medial prefrontal cortex. This research is relevant to public health because stress at an early age is known to result in mood disorders as adults; knowledge about the neural circuitry of the raphe-limbic system and its development will provide information about where modifications may occur to produce mood disorders.

描述（由申请人提供）：焦虑是正常且具有适应性的。在其病理形式中，焦虑会损害对环境做出最佳反应的能力，并可能使人衰弱。焦虑状态在生命早期就开始出现。正常特质焦虑症状在 6 岁左右出现，焦虑症最早可能在 11 岁时出现。13-18 岁的人中大约 8% 表现出病理性焦虑 (NIMH)。焦虑症的发病率和病因表明，生命早期是焦虑症发生的关键时期。血清素（5-HT、5-羟色胺）是与焦虑症相关的关键神经递质之一。中脑 5-HT 系统在发育早期（而非成年期）的直接失调会导致啮齿类动物更加焦虑的表型。 5-HT 系统与许多也参与调节焦虑的前脑区域相连，因此我们推测这些区域也发生了改变。我们最近对小鼠的研究表明，5-HT 神经元的细胞特征、突触活性和 5-HT 受体介导的反应尚未成熟，并在出生后的最初几周内发育。相比之下，5-HT1A 受体和 Pet-1 敲除小鼠记录的表现出焦虑表型的特征彼此相似，不成熟且兴奋性增强。不幸的是，中缝边缘系统电路的发展还没有被很好地理解。我们的长期目标是阐明 5-HT 边缘系统内细胞水平的变化，这些变化是正常和病理性焦虑发展的基础。在本提案中，我们当前的目标是关注 5-HT-mPFC 连接。我们的假设是，在生命的最初几周有一个关键时期，mPFC 的 5-HT 神经支配协调其局部回路的形态和生理发育。以下具体目标 (SA) 将检验这一假设。 SP1：为了确定 mPFC 中第 5 层锥体神经元的发育概况，与激活 5-HT 纤维引起的反应相一致，用于光遗传学刺激的转基因 Pet-1 ChR2 小鼠将用于测试投射纤维到 mPFC 成熟的假设P12-P21 之间的这一过程导致谷氨酸和 5-HT 的释放，并且 mPFC 神经元在 P4 和 P21 之间生理成熟。 SP2：确定 5-HT1A 和 Pet-1 敲除小鼠中 mPFC 中第 5 层锥体细胞的发育概况。假设第 5 层锥体神经元的神经发育将受到干扰，导致神经元具有不成熟的表型。目标 3：确定失去 5-HT 神经活动对行为和 5-HT-mPFC 神经发育的影响。我们假设 P12-P21 之间中缝背侧 5-HT 神经元活性的缺乏将导致幼犬焦虑相关行为的增加以及成年犬焦虑程度的增加。中缝和 mPFC 神经元将具有不成熟的表型。将使用仅位于背侧和中缝神经元中的合成药理激活抑制性受体的工程小鼠。这项新技术提供了一种创新方法，将在功能水平上提供 5-HT 对开发电路的作用信息。 公共卫生相关性：压力诱发行为的细胞机制以及压力相关精神疾病的发展和治疗很可能涉及包含中缝核的 5-羟色胺 (5-HT) 细胞体及其在边缘系统中的投影区域前脑。该项目正在研究中缝及其投影区域（内侧前额叶皮层）的出生后发育。这项研究与公共健康相关，因为众所周知，幼年时的压力会导致成年后的情绪障碍。关于中缝边缘系统的神经回路及其发育的知识将提供有关可能发生情绪障碍的修改的信息。