Mechanisms of interval timing

间隔计时机制

• 批准号: 10023189
• 负责人: Michael A Crickmore
• 金额: $ 47.26万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-23 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10023189
• 关键词: Animals; Automobile Driving; Behavior; Behavior Disorders; Behavioral; Biochemical; Brain; Calcium; Calcium Channel; Circadian Rhythms; Consensus; Cyclic AMP; Data; Disease; Down-Regulation; Drosophila genus; Event; Feedback; Female; Genes; Genetic Transcription; Goals; Hour; Human; Image; Intervention; Life; Measures; Membrane; Memory; Mental disorders; Molecular; Monitor; Mood Disorders; Motivation; Nervous system structure; Neurons; Neuropeptides; Neurosciences; Output; Partner in relationship; Process; Reporting; Role; Signal Transduction; System; Testing; Time; Translating; Work; addiction; base; calmodulin-dependent protein kinase II; circadian pacemaker; cognitive process; design; falls; insight; male; mating behavior; millisecond; neural network; novel; phosphoric diester hydrolase; prevent; screening; sperm cell; time interval; tool; voltage

Project Summary Understanding how neuronal networks construct long lasting and slowly evolving states is an outstanding problem in behavioral neuroscience, both basic and disease-related. My lab focuses on motivation, as its dysregulation is central to addiction and mood disorders. Motivations evolve over minutes to hours, much longer than the timescale of standard neuronal processes, with membrane capacitive time constants of 10-100 milliseconds. The circadian clock keeps intracellular time through transcriptional and translational oscillators, but this mechanism is likely too slow to accurately measure the shorter time periods relevant for most behaviors. We have recently developed mating duration in Drosophila as a powerful system for exploring a change in motivation over time as behavioral goals are achieved. At six minutes into the mating, sperm is transferred from the male to the female and a dramatic shift takes place within the male's nervous system: he will no longer sacrifice his life to sustain the mating. These simultaneous events are caused by the output of four male-specific neurons that produce the neuropeptide Corazonin (Crz). If the Crz neurons are inhibited sperm is not transferred and the male does not downregulate his motivation, leading to matings that last for hours instead of the usual ~23 minutes. We exploit the robustness, experimental tractability, and neuronal localization of these phenomena to gain insights into the molecular and circuit bases of interval timing. Our preliminary data point to CaMKII as a molecular interval timer that functions to delay the activity of the Crz neurons for the first six minutes of mating. The timer works through the gradual decay of sustained autophosphorylation following an initial rise in calcium. This proposal centers on understanding i) how the decay rate of CaMKII is tuned to measure out various time intervals in different neurons, and ii) how the CaMKII timer is read out and translated into a timed signal. We have identified multiple candidate factors that may work to sculpt the rise and fall of CaMKII activity, and thereby set the time interval to be measured. For the timing mechanism itself, I propose to test the hypothesis that CaMKII activation prevents the accumulation of cyclic AMP that would otherwise arise from mutual excitation within the Crz network during mating. The decay of CaMKII activity allows super-threshold cyclic AMP accumulation, leading to a large calcium influx that synchronizes the four Crz neurons and generates a single event that drives sperm transfer and the shifts the motivational state at six minutes after the initiation of mating. This would be the first mechanistic description of a neuronal interval timing system. The high conservation and ubiquitous expression of the molecules involved suggest similar functions in long-lasting brain functions across the animal kingdom, including humans.

项目摘要 了解神经元网络如何构建持久和缓慢发展的状态是一个杰出的 基本和疾病有关的行为神经科学问题。我的实验室专注于动力 失调对于成瘾和情绪障碍至关重要。动机会在数分钟到几个小时内发展，更长的时间 比标准神经元过程的时间尺度，膜电容时间常数为10-100 毫秒。昼夜节律通过转录和翻译振荡器保持细胞内时间，但 这种机制可能太慢，无法准确测量与大多数行为相关的较短时间段。 我们最近在果蝇中开发了交配持续时间，作为探索变化的强大系统 随着行为目标的实现，随着时间的推移动机。交配后六分钟，精子从 雄性到雌性的戏剧性转变发生在男性的神经系统中：他将不再 牺牲自己的生命以维持交配。这些同时事件是由四个男性特异性的输出引起的 产生神经肽Corazonin（CRZ）的神经元。如果抑制精子的CRZ神经元未转移 男性并没有下调他的动力，导致持续数小时而不是通常 〜23分钟。我们利用这些现象的鲁棒性，实验性障碍和神经元定位 为了洞悉间隔时间的分子和电路基础。 我们的初步数据指向CAMKII是一个分子间隔计时器，该计时器可延迟CRZ的活性 神经元在交配的前六分钟。计时器可以通过持续的逐渐衰减来工作 钙初始升高后自磷酸化。该提议以理解为中心i） CAMKII的速率调整为测量不同神经元的各种时间间隔，ii）CAMKII计时器如何 读出并翻译成一个定时信号。我们已经确定了可能有效的多个候选因素 雕刻CaMKII活动的兴衰，从而设定要测量的时间间隔。对于时间 机制本身，我建议测试CAMKII激活的假设可防止循环积累 否则将在交配过程中CRZ网络中的相互激发产生的AMP。衰减 CAMKII活动允许超阈值环状AMP积累，导致大量的钙涌入， 同步四个CRZ神经元，并产生一个驱动精子转移的单个事件，而移动则是 交配启动六分钟后的动机状态。这将是一个的第一个机械描述 神经元间隔系统。涉及的分子的高保护和无处不在的表达 建议在包括人类在内的整个动物界的长期脑功能中的功能相似。