The contribution of tanycyte signalling to the function of hypothalamic networks

单胞信号传导对下丘脑网络功能的贡献

• 批准号: MR/J003786/1
• 负责人: Nicholas Dale
• 金额: $ 77.52万
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ003786%2F1
• 关键词: contribution; tanycyte; signalling; function; hypothalamic

An area of the brain called the hypothalamus contains key neural circuits involved in the control of appetite, feeding and energy expenditure (collectively "energy balance"). Stimulated by the inexorable rise of obesity and consequent health problems, there has been intense study of these neural circuits. However, the possible role of non-neuronal cells in the brain has not been extensively considered. We have previously demonstrated that hypothalamic tanycytes, cells that contact cerebrospinal fluid in the ventricles of the brain and send processes into the hypothalamus, respond to both neuron-derived and circulating agents that signal energy status and arousal. Our data therefore suggest that tanycytes have the potential to actively participate in the control of energy balance. There is also abundant data from other researchers showing, for example, that processes of tanycytes come into close contact with neurons (very suggestive of communication passing between them) that supports the idea that tanycytes may be active players in the hypothalamic network.We propose to test directly the idea that tanycyte-neuron communication exists and to characterize where and how it occurs (which neurons receive signals from tanycytes and what are the chemical signals released by tanycytes to effect this communication). Our approach will employ and develop selective optical methods to allow us to activate only the tanycytes. We shall combine this with functional imaging methods to screen for consequent responses in individual neurons, giving an efficient and comprehensive way of mapping these interactions. While some selective approaches for selective tanycyte activation already exist (and we shall use them), an important aspect of our project is to develop new potentially more powerful genetic methods to accomplish this aim. We shall develop ways to target light sensitive ion channels so that they express only in tanycytes thereby allowing illumination of the correct wavelength of light to selectively activate them. We shall verify that our methods do indeed work and use this new approach, along with existing methods, to map the tanycyte-neuron interactions. A further important aspect of our approach will be to identify the types of neurons that tanycytes influence. The nature of these interactions, and the types of neurons that tanycytes communicate with is central to our being able to hypothesize the potential functional roles of tanycytes. Finally there is evidence that the way the hypothalamic network functions depends upon metabolic state (e.g. fasting, diet induced obesity). We shall therefore also examine whether tanycyte-neuron interactions also depends upon metabolic state.Our work will be influential in the design of future experiments both by proposing specific hypotheses for tanycyte function and by developing the tools necessary to rigorously link tanycyte signalling to behaviour. This has the potential to radically alter our understanding of how the brain controls energy balance and may suggest new ways to regulate appetite, and hence help to reduce the burden to society of obesity related illnesses.

大脑中有一个叫做下丘脑的区域，它包含了控制食欲、进食和能量消耗（统称为“能量平衡”）的关键神经回路。由于肥胖和随之而来的健康问题的不可阻挡的增长，人们对这些神经回路进行了大量的研究。然而，非神经元细胞在大脑中的可能作用尚未得到广泛考虑。我们之前已经证明，下丘脑伸长细胞（与脑室中的脑脊液接触并将过程传递到下丘脑的细胞）对神经元来源的和循环的药物都有反应，这些药物发出能量状态和觉醒的信号。因此，我们的数据表明，伸长细胞具有积极参与能量平衡控制的潜力。其他研究人员也有大量数据表明，例如，伸长细胞的过程与神经元密切接触（非常暗示它们之间的通信传递），这支持了伸长细胞可能是下丘脑网络中活跃参与者的观点。我们建议直接测试伸长细胞-神经元通讯存在的想法，并描述它发生的位置和方式（哪些神经元从伸长细胞接收信号，伸长细胞释放什么化学信号来影响这种通讯）。我们的方法将采用和发展选择性光学方法，使我们能够只激活伸长细胞。我们将结合功能成像方法来筛选单个神经元的后续反应，提供一种有效而全面的方法来绘制这些相互作用。虽然一些选择性鞣剂细胞激活的选择性方法已经存在（我们将使用它们），但我们项目的一个重要方面是开发新的可能更强大的遗传方法来实现这一目标。我们将开发针对光敏离子通道的方法，使它们仅在伸长细胞中表达，从而允许正确波长的光照选择性地激活它们。我们将验证我们的方法确实有效，并使用这种新方法，以及现有的方法，来绘制伸长细胞-神经元的相互作用。我们方法的另一个重要方面将是确定伸长细胞影响的神经元类型。这些相互作用的性质，以及与伸长细胞交流的神经元类型，是我们能够假设伸长细胞潜在功能角色的核心。最后，有证据表明，下丘脑网络的功能方式取决于代谢状态（如禁食，饮食引起的肥胖）。因此，我们还将研究伸长细胞-神经元的相互作用是否也取决于代谢状态。我们的工作将对未来实验的设计产生影响，既可以提出关于伸长细胞功能的具体假设，也可以开发将伸长细胞信号传导与行为严格联系起来所需的工具。这有可能从根本上改变我们对大脑如何控制能量平衡的理解，并可能提出调节食欲的新方法，从而有助于减轻肥胖相关疾病给社会带来的负担。

项目成果

A classic review on extracellular ATP and its signalling functions that helped to define the field's agenda for many years

对细胞外 ATP 及其信号传导功能的经典回顾，多年来帮助定义了该领域的议程

• DOI: 10.1042/bj20121145
• 发表时间: 2012
• 期刊: Biochemical Journal
• 影响因子: 4.1
• 作者: Dale N

Hypothalamic tanycytes: potential roles in the control of feeding and energy balance.

• DOI: 10.1016/j.tins.2012.12.008
• 发表时间: 2013-02
• 期刊: Trends in neurosciences
• 影响因子: 15.9
• 作者: Bolborea M;Dale N
• 通讯作者: Dale N

A sweet taste receptor-dependent mechanism of glucosensing in hypothalamic tanycytes.

• DOI: 10.1002/glia.23125
• 发表时间: 2017-05
• 期刊: Glia
• 影响因子: 6.2
• 作者: Benford H;Bolborea M;Pollatzek E;Lossow K;Hermans-Borgmeyer I;Liu B;Meyerhof W;Kasparov S;Dale N
• 通讯作者: Dale N