Calcium Signaling in Suprachiasmatic Nucleus Neurons

视交叉上核神经元中的钙信号传导

• 批准号: 7195730
• 负责人: Charles N Allen
• 金额: $ 25.77万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7195730
• 关键词: AMPA Receptors; Action Potentials; Behavioral; Calcium Signaling; Cell Nucleus; Cells; Chemosensitization; Circadian Rhythms; Cues; Cultured Cells; Dependence; Disease; Event; Feedback; Fire - disasters; Frequencies; Gene Expression; Genetic Transcription; Glutamates; Goals; Imaging Techniques; Individual; Ion Channel; Light; Mediating; Microelectrodes; Modeling; Molecular; Monitor; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurons; Nitric Oxide; Nuclear; Numbers; Organism; Output; Performance; Phase; Physiological; Play; Process; Property; Psyche structure; Receptor Activation; Regulation; Research; Rest; Role; Ryanodine; Signal Pathway; Signal Transduction; Signaling Molecule; Slice; Source; Techniques; Testing; Time; Work; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; base; cellular imaging; circadian pacemaker; day; innovation; pituitary adenylate cyclase activating polypeptide; receptor coupling; research study; response; suprachiasmatic nucleus; voltage

DESCRIPTION (provided by applicant): Disturbances in circadian rhythms contribute to a variety of diseases and impair mental and physical performance. Circadian rhythms in physiological and behavioral processes are generated by a molecular clock located in the suprachiasmatic nucleus. This clock receives environmental information from cues such as light and subsequently creates timing information that is sent to the rest of the organism. While the signaling pathways involved in this chain of information are poorly understood, evidence suggests a possible role for Ca2+ as a signaling molecule for both input to and output from the circadian clock. But the source of this Ca2+ is unknown. One model proposes that glutamate released from terminals of the retinohypothalamic tract activates NMDA receptors, which generate nitric oxide and release Ca2+ from ryanodine-sensitive stores. However, the release of Ca2+ from ryanodine-sensitive stores by glutamate or nitric oxide has not been directly demonstrated. NMDA receptor activation increases the nuclear Ca2+ concentration of SCN neurons. Nuclear Ca2+ regulates gene expression, including possibly clock gene expression. The long-term goal of this work is to characterize the functional properties of SCN neurons and how the circadian clock regulates these properties. This proposal will determine the roles that cytoplasmic and nuclear Ca2+ play as circadian input and output signals. Our central hypothesis is that changes in cytoplasmic and nuclear Ca2+ concentration are a critical step in light's regulation of the circadian clock. This proposal uses an innovative combination of fluorescent imaging techniques, cell culture, and electrophysiological recording techniques to study the regulation of Ca2+ in SCN neurons during different portions of the circadian day. This research will identify the early steps in the light-signaling pathway. The Specific Aims of the proposal are: 1) Identify the mechanisms and circadian regulation of the increase of the cytoplasmic Ca2+ concentration produced by activating NMDA and AMPA receptors. 2) Determine the mechanisms and circadian phase dependence of the increase in the nuclear Ca2+ concentration produced by NMDA receptor activation. 3) Determine the role that PACAP plays in regulating changes in the cytoplasmic and nuclear Ca2+ concentration induced by NMDA and AMPA receptor activation. 4) Investigate whether the peak of the cytoplasmic Ca2+ rhythm precedes the peak of action potential firing frequency rhythm in SCN neurons. Together, these experiments will identify the early steps in the light-signaling pathway, thus contributing to a better understanding of the cellular basis of circadian rhythms.

描述（由申请人提供）：昼夜节律的障碍会导致各种疾病并损害心理和身体表现。生理和行为过程中的昼夜节律是由位于上核核中的分子时钟产生的。该时钟从光线（例如光线）中接收到环境信息，然后创建发送给其他生物体的定时信息。尽管对此信息链中涉及的信号通路的理解很少，但有证据表明Ca2+是昼夜节律时钟输入和输出的信号分子的可能作用。但是此CA2+的来源未知。一个模型提出，谷氨酸是从视网膜丘脑末端释放的，它激活了NMDA受体，该受体会产生一氧化氮并从ryanodine敏感的商店中释放Ca2+。然而，尚未直接证明从谷氨酸或一氧化氮对Ryanodine敏感的商店中释放Ca2+。 NMDA受体激活增加了SCN神经元的核Ca2+浓度。核Ca2+调节基因表达，包括可能的时钟基因表达。这项工作的长期目标是表征SCN神经元的功能特性以及昼夜节律时钟如何调节这些特性。该建议将确定细胞质和核Ca2+作为昼夜节律输入和输出信号的作用。我们的中心假设是，细胞质和核Ca2+浓度的变化是Light调节昼夜节律时钟的关键步骤。该建议使用荧光成像技术，细胞培养和电生理记录技术的创新组合来研究昼夜节律不同部分中SCN神经元中Ca2+的调节。这项研究将确定光信号途径的早期步骤。该提案的具体目的是：1）确定通过激活NMDA和AMPA受体产生的细胞质Ca2+浓度增加的机制和昼夜节律调节。 2）确定NMDA受体激活产生的核Ca2+浓度增加的机理和昼夜节相依赖性。 3）确定PACAP在调节NMDA和AMPA受体激活诱导的细胞质和核Ca2+浓度变化中发挥的作用。 4）研究细胞质Ca2+节奏的峰是否先于SCN神经元中动作电位触发频率节奏的峰值。这些实验将共同确定光信号途径的早期步骤，从而更好地理解昼夜节律的细胞基础。