Kisspeptin: A novel calendar cell mechanism mediating sesaonal reproduction?

Kisspeptin：一种介导季节繁殖的新型日历细胞机制？

• 批准号: 7622557
• 负责人: Deborah I. Lutterschmidt
• 金额: $ 5.01万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7622557
• 关键词: Alzheimer' s Disease; Behavior Control; Behavioral; Biology; Bipolar Disorder; Brain; Calendar; Cells; Circadian Rhythms; Complex; Cues; Development; Disease; Foundations; Genes; Gonadotropin Hormone Releasing Hormone; Hormonal; Hormones; Hypothalamic structure; Immunohistochemistry; In Situ Hybridization; Interdisciplinary Study; Knowledge; Label; Mediating; Melatonin; Melatonin Receptors; Mental Health; Mental disorders; Modeling; Molecular; Nature; Nervous system structure; Neuronal Plasticity; Neurons; Neuropeptides; Neurosciences; Pattern; Physiological; Process; Psyche structure; Public Health; Reproduction; Research; Role; Seasonal Affective Disorder; Seasonal Variations; Series; Signal Transduction; System; Testing; age related; brain behavior; burden of illness; depression; disability; fitness; insight; kisspeptin; novel; receptor; relating to nervous system; reproductive function; research study; response; social

DESCRIPTION (provided by applicant): A fundamental, long-term objective of this project is to develop an integrative, multidisciplinary research model that evaluates the mechanisms underlying environmental control of seasonal variation in brain and behavior relationships. Traditionally, the hypothalamic gonadotropin-releasing hormone (GnRH) system has been considered to be the pinnacle of hierarchical control of reproductive function. However, the upstream mechanisms governing how the GnRH neuronal system receives, integrates, and responds to environmental cues remain largely unknown. The specific research objectives are to test the hypothesis that long-term timekeeping mechanisms in calendar cells both generate endogenous circannual rhythms in GnRH secretion and integrate these rhythms with environmental and social cues. The experiments described herein aim to test this hypothesis by investigating the neuroanatomical and neuroendocrinological relationships between GnRH neurons, the neuropeptide kisspeptin, and the pineal hormone melatonin. The anatomical relationships between these neural and hormonal signals will be evaluated using a combination of double-label immunohistochemistry and in situ hybridization to identify co-expression patterns of clock genes, melatonin receptors, GnRH, kisspeptin, and kisspeptin receptors. Functional tests of this neuroanatomical circuit in the control of reproduction will then be performed using a series of pharmacological manipulations and behavioral experiments. Collectively, these experiments will provide valuable insight into how extrinsic environmental and social cues are integrated with intrinsic neural, physiological, and behavioral responses, a process that is crucial to the survival and fitness of all species. Studies of the molecular mechanisms underlying this integration are imperative for understanding the factors that regulate and control plasticity in the nervous system. Such fundamental knowledge about the nature of neuroplasticity will provide a more thorough understanding of mental health disorders and may aid in the development of potential avenues for reducing the burdens of illness and disability. The relevance of this research to public health is evident in the profound role of brain plasticity in the neuroscience of mental health. For example, disruptions in circadian biology and melatonin signaling have been implicated in age-related changes in brain function as well as mental disease states such as seasonal affective disorder, depression, bipolar disorder, and Alzheimer's disease. The results obtained from this research will provide a foundation for developing an integrative model for the complex mechanisms that mediate seasonal and persistent changes in brain and behavior relationships.

描述（由申请人提供）：该项目的一个基本、长期目标是开发一个综合的、多学科的研究模型，评估大脑和行为关系季节性变化的环境控制机制。传统上，下丘脑促性腺激素释放激素（GnRH）系统被认为是生殖功能分级控制的顶峰。然而，控制 GnRH 神经元系统如何接收、整合和响应环境线索的上游机制仍然很大程度上未知。具体研究目标是检验日历细胞中的长期计时机制在 GnRH 分泌中产生内源性昼夜节律并将这些节律与环境和社会线索整合起来的假设。本文描述的实验旨在通过研究 GnRH 神经元、神经肽 Kisspeptin 和松果体激素褪黑激素之间的神经解剖学和神经内分泌学关系来检验这一假设。将使用双标记免疫组织化学和原位杂交相结合来评估这些神经和激素信号之间的解剖关系，以识别时钟基因、褪黑激素受体、GnRH、Kisspeptin 和 Kisspeptin 受体的共表达模式。然后将使用一系列药理学操作和行为实验对该神经解剖回路在控制生殖中的功能进行测试。总的来说，这些实验将为了解外在环境和社会线索如何与内在神经、生理和行为反应相结合提供有价值的见解，这一过程对于所有物种的生存和适应至关重要。研究这种整合背后的分子机制对于理解调节和控制神经系统可塑性的因素至关重要。这种关于神经可塑性本质的基础知识将提供对精神健康障碍的更透彻的理解，并可能有助于开发减轻疾病和残疾负担的潜在途径。这项研究与公共健康的相关性从大脑可塑性在心理健康神经科学中的深远作用中可见一斑。例如，昼夜节律生物学和褪黑激素信号传导的破坏与年龄相关的大脑功能变化以及季节性情感障碍、抑郁症、双相情感障碍和阿尔茨海默病等精神疾病状态有关。这项研究获得的结果将为开发介导大脑和行为关系季节性和持续变化的复杂机制的综合模型奠定基础。