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.

一个称为下丘脑的大脑区域包含涉及食欲，喂养和能量消耗的关键神经回路（统称“能量平衡”）。由于肥胖的不可阻碍和随之而来的健康问题的刺激，对这些神经回路进行了深入的研究。但是，非神经元细胞在大脑中的可能作用尚未被广泛考虑。我们先前已经证明了下丘脑tanycytes，这些细胞是在大脑心室接触脑脊液并将过程发送到下丘脑的细胞，对神经元衍生的和循环剂响应，并循环表明表明能量能量状态和唤醒。因此，我们的数据表明，tanycytes有可能积极参与能量平衡的控制。 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通过tanycytes实现这种交流）。我们的方法将采用并开发选择性的光学方法，使我们只能激活tanycytes。我们应将其与功能成像方法相结合，以筛选在单个神经元中的响应，从而提供有效而全面的映射这些相互作用的方法。尽管已经存在一些选择性tanycyte激活的选择性方法（我们将使用它们），但我们项目的一个重要方面是开发新的潜在强大的遗传方法来实现这一目标。我们将开发靶向光敏离子通道的方法，以便它们仅在tanycytes中表达，从而允许照明正确的光的光长度以选择性地激活它们。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方法来映射tanycyte-neuron的相互作用。我们方法的另一个重要方面是确定坦率影响的神经元的类型。这些相互作用的性质以及与坦率交流的神经元的类型对于我们能够假设tanycytes的潜在功能作用至关重要。最后，有证据表明，下丘脑网络功能取决于代谢状态（例如禁食，饮食诱导的肥胖）。因此，我们还将检查tanycyte-neuron的相互作用是否还取决于代谢状态。我们的工作将通过提出特定的tanycyte功能的特定假设以及开发严格的工具来将tanycytes信号与行为联系起来，在未来实验的设计中具有影响力。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，从而有助于减轻与肥胖相关疾病的负担。

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