Thermoregulation in mice: The road to understanding torpor hypothermia and the shortcomings of a circuit for generating fever.
Thermoregulation in mice: The road to understanding torpor hypothermia and the shortcomings of a circuit for generating fever.
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小鼠的温度调节：了解托普体温过低的道路和发烧的电路缺点。
DOI：
10.1080/23328940.2021.2021059
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发表时间：
2022
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在他们的综述“调节小鼠体温的视前神经元的遗传鉴定”中，马查多和Saper [1]总结和解释了最近几项研究的结果，其中采用最新的遗传和分子方法对小鼠视前区（POA）的热反应神经元群体进行遗传学鉴定，并观察核心体温（Tc）的变化。通过刺激或抑制它们的细胞体或轴突末梢诱发。这篇评论是一个有用的总结，许多相关的POA温度调节神经元，将需要纳入功能模型的神经回路介导的小鼠温度调节反应，不仅包括冷和温暖的防御，但也发烧和低温的冷诱发的麻痹。与大鼠和人类形成鲜明对比的是，小鼠在很大程度上依赖于躯体活动产热和麻木的冷防御机制，这表明它们的体温调节回路的功能组织必须有几个方面，包括POA，这是小鼠所独有的。因此，这将是特别感兴趣的，以确定更广泛的适用性，以其他哺乳动物物种的新发现的中央温度调节电路正在通过遗传操作的方法在小鼠。然而，尽管对小鼠体温调节神经元进行了几项详细的研究，包括本综述中描述的那些，但神经回路的许多基本方面甚至可以解释小鼠体温调节的最基本方面，例如冷或热防御，节能麻痹低温和病原体对抗发热，仍有待阐明。作者描述了一些已知的相当大的异质性方面的遗传学，投影模式，以及小鼠POA中表达VGLUT 2的神经元群体内的受体和神经递质表达。此类POA神经元可能包括投射神经元和中间神经元，以及那些可能参与交感神经兴奋或交感神经抑制途径的神经元[2，3]。在这种背景下，令人惊讶的是，作者基于在激活或抑制这些群体中的任何一个中的所有POA神经元后观察到的对Tc的影响，对VGLUT 2和VGAT表达神经元的温度调节作用做出了全面的结论。一个简单的例子说明了从这种非生理学的方法（即，这些群体中的任何一个中的所有神经元都不可能同时被兴奋或抑制）得出结论的问题。激活POA中的所有VGLUT 2表达神经元将同时驱动两种途径：（a）作者图表中的VGLUT 2表达神经元，其靶向RPa中的GABA能中间神经元并抑制BAT交感神经前运动神经元以减少BAT产热并降低Tc，以及（B）VGLUT 2表达的交感神经元，其激发DMH中的产热促进神经元以在寒冷防御和发热期间驱动BAT [3]。然而，由于RPa神经元被途径（a）抑制，因此通常由潜在（在小鼠中）途径（B）引起的BAT活化将不会发生，从而导致POA中的大多数VGLUT 2表达神经元是“体温过低”的错误结论。购买到这样一个错误的结论掩盖了机会，揭示了潜在的mnPO兴奋性输入DMH，可以提供所需的Tc发热增加的生热促进神经元的兴奋。马查多和萨珀的评论强调了他们最近的发现.
In their review,“Genetic identification of preoptic neurons that regulate body temperature in mice”, Machado and Saper [1] summarize and interpret the results of several recent studies in which the latest genetic and molecular approaches were employed to genetically specify populations of thermally responsive neurons in the preoptic area (POA) of mice and to observe the changes on core body temperature (Tc) evoked by stimulating or inhibiting their cell bodies or axon terminals. This review is a useful summary of many of the key findings related to POA thermoregulatory neurons that would need to be incorporated in functional models of the neural circuitry mediating mouse thermoregulatory responses, including not only cold-and warm-defense, but also fever and the hypothermia of cold-evoked torpor. In stark contrast to rats and humans, mice depend heavily on the cold-defense mechanisms of somatic activity thermogenesis and torpor, suggesting that there must be several aspects of the functional organization of their thermoregulatory circuitry, including that in the POA, that are unique to mice. Thus, it will be of particular interest to determine the wider applicability to other mammalian species of the new discoveries regarding central thermoregulatory circuits being made through genetic manipulation approaches in mice. However, despite several detailed studies on thermoregulatory neurons in mice, including those described in this review, many of the fundamental aspects of the neural circuits that function to explain even the most basic aspects of mouse thermoregulation, such as cold-or warm-defense, energy-conserving torpor hypothermia, and pathogen-combating fever, remain to be elucidated.The authors describe some of what is known of the considerable heterogeneity with regard to genetics, projection patterns, and receptor and neurotransmitter expression within the population of VGLUT2-expressing neurons in the mouse POA. Such POA neurons would presumably include projection neurons and interneurons, as well as those potentially involved in either sympathoexcitatory or sympathoinhibitory pathways [2, 3]. Against this background, it is surprising that the authors make sweeping conclusions about the thermoregulatory roles of VGLUT2-and VGAT-expressing neurons based on the effects on Tc observed after activating or inhibiting all of the POA neurons in either of these populations. A simple example illustrates the problem with deriving conclusions from this unphysiological (ie, it is unlikely that all neurons in either of these populations are excited or inhibited simultaneously) approach to circuit analysis. Activating all VGLUT2-expressing neurons in the POA would simultaneously drive two pathways:(a) the VGLUT2-expressing neurons in the authors’ graphic targeting GABAergic interneurons in RPa and inhibiting BAT sympathetic premotor neurons to reduce BAT thermogenesis and decrease Tc, and (b) the VGLUT2-expressing, glutamatergic neurons that excite thermogenesis-promoting neurons in the DMH to drive BAT during cold defense and fever [3]. However, because RPa neurons are being inhibited by pathway (a), the BAT activation that would normally be caused by potential (in mice) pathway (b) would not occur, leading to the incorrect conclusion that most VGLUT2-expressing neurons in the POA are “hypothermic”. Buying into such an erroneous conclusion masks the opportunity to reveal a potential glutamatergic excitatory input to DMH from MnPO that could provide the excitation of thermogenesis-promoting neurons required for the febrile increase in Tc. The review by Machado and Saper highlights their recent discovery …