Identification of a dopamine circuit mediating day eating and diet-induced obesity in mice

介导小鼠日间饮食和饮食诱导肥胖的多巴胺回路的鉴定

基本信息

  • 批准号:
    10730567
  • 负责人:
  • 金额:
    $ 44.1万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-01 至 2026-08-31
  • 项目状态:
    未结题

项目摘要

Project Summary Excess body fat significantly increases the risk for a range of maladies including diabetes, cancer, and cardiovascular diseases. An estimated 45 million adult Americans go on diets and spend over $30 billion on weight loss products each year. Most of these interventions fail, leaving individuals overweight and susceptible to metabolic disorders like type 2 diabetes. This trend is likely due to the easy availability of palatable, energy-rich foods which incentivizes food consumption for pleasure regardless of the energy need (hedonic feeding). Dopaminergic neurons of the ventral tegmental area (VTA) compute the potential value of food reward and release dopamine (DA) to tune the activity of downstream targets. One of the results of this reward computation is the encoding of the necessary drive for retrieval and consumption of food. Uncoupling food consumption from energy need guided by the reward circuitry leads to continuous snacking rather than a meal-based pattern of feeding. Mounting evidence suggests that in addition to increased caloric intake, this type of irregular meal timing promotes desynchrony of precisely timed metabolic processes, which further contributes to the maladaptive effects of overeating. Indeed, disorganization of mealtimes by manipulation of circadian rhythms is correlated with weight gain and metabolic syndrome in humans and animal models. How do rewarding foods influence meal timing? The suprachiasmatic nucleus (SCN) is the primary regulator of circadian rhythms and integrates sensory and physiologic information to synchronize homeostatic functions to the day/night cycles. The basis for how reward, feeding and circadian circuitry interact to promote normal and pathological feeding represents a significant gap in our knowledge. Here, we propose to test the hypothesis that dopaminergic input from a select group of VTA-DA neurons to the SCN is an integral part of the hedonic feeding neurocircuitry. We will genetically and anatomically define the subpopulation of VTA neurons that releases DA in the SCN in response to palatable foods. We will ablate DA production in these select neurons to validate their direct functional SCN input. This proposal employs innovative approaches while leveraging our expertise in mouse genetics, stereotaxic viral delivery, and functional neural circuitry mapping strategies. Using these tools, we will identify the group of DA neurons that govern feeding behavior by modulating the activity of central circadian clock neurons. This work will have broad implications for understanding how reward circuitry overcomes homeostatic control while providing unique avenues for therapeutic approaches against the obesity epidemic.
项目总结

项目成果

期刊论文数量(0)
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Andrew David Steele其他文献

Andrew David Steele的其他文献

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{{ truncateString('Andrew David Steele', 18)}}的其他基金

Deciphering dopaminergic circuits required for food anticipatory activity in mice
破译小鼠食物预期活动所需的多巴胺能回路
  • 批准号:
    10629786
  • 财政年份:
    2023
  • 资助金额:
    $ 44.1万
  • 项目类别:
Investigating dopaminergic neuronal circuits mediating circadian entrainment to scheduled feeding
研究介导昼夜节律与计划喂养的多巴胺能神经元回路
  • 批准号:
    10093069
  • 财政年份:
    2018
  • 资助金额:
    $ 44.1万
  • 项目类别:

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