Brainstem cold-defense circuitry

摘要 作为温血(吸热)动物，我们的生存需要神经元能够感知寒冷的温度和 启动适应性反应。这些至关重要的“防寒”适应能力使我们能够适应不同的气候。太冷了- 防御反应是一组有动机的行为和自主变化，帮助我们在寒冷的时候 产生并保持热量的。然而，通常情况下，这些反应会因衰老、疾病、药物或 神经损伤。许多患者患有慢性耐寒，意外体温过低仍然是一种 重大的公共卫生问题，但我们调查潜在机制的能力受到 不能有选择地以中枢寒冷防御神经元为目标。缩小这一知识鸿沟是我们的首要目标 这个项目的。拟议工作的成功完成将为以下项目提供机会 关于耐寒的翻译研究进展，以及肥胖症的生热治疗和 改进了治疗低温的方案。我们首先观察到冷激活的神经元 脑干中称为臂旁核(PB)的特定区域可能是一个脆弱的瓶颈 在这条赛道上。这个区域的神经元收集来自整个身体表面的信息，通过神经元在每个 脊髓水平，他们使用这些信息来激活前脑中的目标位置。冷激活PB 神经元是一个可接近的入口点，但它们与其他不同的PB神经元群体混合在一起，并且 它们的分子身份仍不确定。我们假设在寒冷的环境温度下生存 在这个位置需要特定的神经元子集，它促进寒冷防御行为并激活 自主反应。在我们的初步实验中，消除谷氨酸能PB神经元不会改变身体 在室温下的温度或唤醒。然而，寒冷的暴露导致核心体温 在这些PB消融的小鼠中，在不会导致PB完整的失代偿的环境温度下，铅中毒 控制小鼠。这些初步发现表明，PB神经元不仅参与，而且是必要的 冷防御反应。在拟议的研究中，我们将使用严格和系统的方法来确定 寒冷防御所需的PB神经元的身份。我们还将确定行为和自主神经 通过激活这些神经元而产生的变化。最后，我们将确定哪些PB激活的行为和 在长时间的寒冷暴露中，需要自主反应来维持核心体温。 拟议的探险的成功完成将决定神经元和神经回路机制 使哺乳动物能够在寒冷中生存。除了从根本上提高我们对这种生活的理解- 关键神经回路，这项工作将提高我们对遗传定义的联系和 混合神经元亚群在前庭神经元中的功能。我们的结果将通过开放产生更广泛的影响 为重症监护设计诱导和维持治疗性低温的新方法的机会， 野战医学，器官移植，也许有一天，太空飞行。

ABSTRACT As warm-blooded (endothermic) animals, our survival requires neurons that detect cold temperatures and initiate adaptive responses. These vital “cold-defense” adaptations allow us to inhabit diverse climates. Cold- defense responses are a set of motivated behaviors and autonomic changes that help us avoid the cold while generating and retaining heat. Often, however, these responses are impaired by aging, disease, drugs, or neurologic injury. Many patients suffer from chronic cold intolerance, and accidental hypothermia remains a significant public health concern, but our ability to investigate the underlying mechanisms is constrained by an inability to selectively target central cold-defense neurons. Closing this knowledge gap is the primary objective of this project. Successful completion of the proposed work will provide information that opens opportunities for progress in translational research on cold intolerance, as well as thermogenic treatments for obesity and improved protocols for therapeutic hypothermia. We begin by observing that cold-activated neurons in a specific region of the brainstem known as the parabrachial nucleus (PB) may represent a vulnerable bottleneck in this circuit. Neurons in this region collect input from the entire body surface, relayed via neurons at every level of the spinal cord, and they use this information to activate target sites in the forebrain. Cold-activated PB neurons are an accessible entry point, but they intermingle with other, diverse populations of PB neurons, and their molecular identity remains uncertain. We hypothesized that surviving at a cold ambient temperature requires a specific subset of neurons in this location, which promote cold-defense behaviors and activate autonomic responses. In our preliminary experiments, eliminating glutamatergic PB neurons did not alter body temperature or arousal at room temperature. However, cold exposure caused core body temperature to plummet in these PB-ablated mice, at ambient temperatures that do not cause decompensation in PB-intact control mice. These preliminary findings suggest that PB neurons are not only involved in, but necessary for cold-defense responses. In the proposed studies, we will use a rigorous and systematic approach to determine the identity of PB neurons required for cold defense. We will also determine the behavioral and autonomic changes produced by activating these neurons. Finally, we will determine which PB-activated behavioral and autonomic responses are required to sustain core body temperature during prolonged cold exposure. Successful completion of the proposed expeirments will determine the neurons and neural circuit mechanisms that allow mammals to survive in the cold. In addition to fundamentally advancing our understanding of this life- critical neural circuit, this work will improve our understanding of the genetically defined connections and functions of intermingled neuronal subpopulations in the PB. Our results will have broader impact by opening opportunities to engineer new methods of inducing and sustaining therapeutic hypothermia for critical care, field medicine, organ transplant, and someday, perhaps, spaceflight.