Mechanisms of interval timing

间隔计时机制

基本信息

  • 批准号:
    10442565
  • 负责人:
  • 金额:
    $ 47.26万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-09-23 至 2024-06-30
  • 项目状态:
    已结题

项目摘要

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.
项目总结

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Biochemical evidence accumulates across neurons to drive a network-level eruption.
  • DOI:
    10.1016/j.molcel.2020.12.029
  • 发表时间:
    2021-02-18
  • 期刊:
  • 影响因子:
    16
  • 作者:
    Thornquist SC;Pitsch MJ;Auth CS;Crickmore MA
  • 通讯作者:
    Crickmore MA
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Michael A Crickmore其他文献

Michael A Crickmore的其他文献

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{{ truncateString('Michael A Crickmore', 18)}}的其他基金

Mechanisms of interval timing
间隔计时机制
  • 批准号:
    10207685
  • 财政年份:
    2019
  • 资助金额:
    $ 47.26万
  • 项目类别:
Mechanisms of interval timing
间隔计时机制
  • 批准号:
    10023189
  • 财政年份:
    2019
  • 资助金额:
    $ 47.26万
  • 项目类别:
Circuit principles of demotivation in the decision to switch behaviors
决定改变行为时动机丧失的电路原理
  • 批准号:
    10612399
  • 财政年份:
    2019
  • 资助金额:
    $ 47.26万
  • 项目类别:
Circuit principles of demotivation in the decision to switch behaviors
决定改变行为时动机丧失的电路原理
  • 批准号:
    10396538
  • 财政年份:
    2019
  • 资助金额:
    $ 47.26万
  • 项目类别:
Mating behavior in Drosophila as a model for understanding and controlling aberrant dopaminergic responses
果蝇的交配行为作为理解和控制异常多巴胺能反应的模型
  • 批准号:
    10221658
  • 财政年份:
    2017
  • 资助金额:
    $ 47.26万
  • 项目类别:
Mating behavior in Drosophila as a model for understanding and controlling aberrant dopaminergic responses
果蝇的交配行为作为理解和控制异常多巴胺能反应的模型
  • 批准号:
    9982280
  • 财政年份:
    2017
  • 资助金额:
    $ 47.26万
  • 项目类别:
Mating behavior in Drosophila as a model for understanding and controlling aberrant dopaminergic responses
果蝇的交配行为作为理解和控制异常多巴胺能反应的模型
  • 批准号:
    9376434
  • 财政年份:
    2017
  • 资助金额:
    $ 47.26万
  • 项目类别:

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