Brainstem cold-defense circuitry

脑干冷防御电路

• 批准号: 10735327
• 负责人: Joel Charles Geerling
• 金额: $ 58.56万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735327
• 关键词: Ablation; Accidents; Aging; Animals; Arousal; Axon; Behavior; Behavioral; Behavioral Assay; Behavioral Mechanisms; Bilateral; Body Surface; Body Temperature; Brain; Brain Injuries; Brain Stem; Cause of Death; Chronic; Classification; Climate; Critical Care; Critical Illness; Disease; Elderly; Electroencephalography; Engineering; Exposure to; FOXP2 gene; Food; Genetic; Glutamates; Goals; Heart Arrest; Hypothalamic structure; Impairment; Investigation; Knowledge; Lateral; Life; Location; Mammals; Measures; Medicine; Methods; Molecular; Motivation; Motor Activity; Mus; Nervous System Trauma; Neurologic; Neurons; Ontology; Organ Transplantation; Outcome; Patients; Peripheral; Pharmaceutical Preparations; Phase; Population Heterogeneity; Prosencephalon; Protocols documentation; Public Health; Rewards; Sensory; Site; Skin; Sleep; Sleep Deprivation; Space Flight; Spinal; Spinal Cord; Stimulant; Temperature; Testing; Therapeutic; Thermogenesis; Translating; Translational Research; Vertebral column; Wakefulness; Work; behavioral response; circadian; cold temperature; comorbidity; defense response; experimental study; falls; improved; metabolic rate; motivated behavior; natural hypothermia; neural circuit; neuronal circuitry; neuroprotection; obesity treatment; parabrachial nucleus; practical application; pre-clinical; preference; prevent; response; sensory input; translational study

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.

摘要 作为温血（吸热）动物，我们的生存需要神经元检测寒冷的温度， 启动适应性反应。这些至关重要的“寒冷防御”适应使我们能够居住在不同的气候中。冷- 防御反应是一系列有动机的行为和自主变化，帮助我们避免寒冷， 产生并保持热量。然而，这些反应通常会受到衰老、疾病、药物或其他因素的影响。 神经损伤许多患者患有慢性冷耐受不良，意外的体温过低仍然是一个常见的问题。 重大的公共卫生问题，但我们调查潜在机制的能力受到限制， 无法选择性地攻击中枢冷防御神经元。缩小这一知识差距是首要目标 这个项目的。成功完成拟议的工作将提供信息， 冷不耐受转化研究的进展，以及肥胖症的产热治疗， 低温治疗的改进方案。我们开始观察到，冷激活的神经元在一个 脑干的一个特定区域，即臂旁核（PB），可能是一个脆弱的瓶颈 在这个电路中。这个区域的神经元收集来自整个身体表面的输入，通过神经元在每一个 他们利用这些信息来激活前脑中的目标部位。冷活化PB 神经元是一个可访问的入口点，但它们与其他不同的PB神经元群体混合， 它们的分子身份仍然不确定。我们假设在寒冷的环境温度下生存 需要在这个位置的神经元的特定子集，促进冷防御行为和激活 自主反应在我们的初步实验中，消除多巴胺能PB神经元并没有改变身体 温度或唤醒在室温下。然而，寒冷暴露导致核心体温下降， 在这些PB消融小鼠中，在不引起PB完整小鼠失代偿的环境温度下， 对照小鼠。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 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 在长时间的冷暴露期间，需要自主反应来维持核心体温。 实验的成功完成将决定神经元和神经回路的机制 使哺乳动物能够在寒冷中生存除了从根本上推进我们对这个生命的理解- 关键的神经回路，这项工作将提高我们对遗传定义的连接的理解， PB中混合神经元亚群的功能。我们的研究结果将通过开放 为重症监护设计诱导和维持治疗性低温的新方法的机会， 战地医疗，器官移植，也许有一天，太空飞行。