Brainstem cold-defense circuitry

脑干冷防御电路

基本信息

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
项目类别：
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

项目摘要

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.

抽象的作为温血（吸热）动物，我们的生存需要能够检测低温和这些重要的“寒冷防御”适应使我们能够适应不同的气候。防御反应是一系列有动机的行为和自主变化，可以帮助我们在寒冷时避免寒冷然而，这些反应通常会因衰老、疾病、药物或药物而受到损害。许多患者患有慢性寒冷不耐受症，意外体温过低仍然是一个常见问题。重大的公共卫生问题，但我们调查潜在机制的能力受到无法选择性地瞄准中枢冷防御神经元是主要目标。该项目的成功完成将提供为以下方面提供机会的信息。寒冷不耐受以及肥胖和产热治疗的转化研究进展我们首先观察冷激活神经元的低温治疗方案。脑干的特定区域，称为臂旁核（PB），可能是一个脆弱的瓶颈在这个回路中，该区域的神经元收集来自整个身体表面的输入，并通过每个神经元进行中继。他们利用这些信息来激活前脑的冷激活 PB 中的目标位点。神经元是一个可访问的入口点，但它们与其他不同的 PB 神经元群体混合在一起，并且它们的分子身份仍然不确定。我们努力在寒冷的环境温度下生存。需要该位置的特定神经元子集，这会促进冷防御行为并激活在我们的初步实验中，消除谷氨酸能 PB 神经元并没有改变身体。然而，寒冷暴露会导致核心体温降低。在不会导致 PB 完整的失代偿的环境温度下，这些 PB 消融的小鼠中的这些初步发现表明 PB 神经元不仅参与，而且是必要的。在拟议的研究中，我们将使用严格且系统的方法来确定。我们还将确定冷防御所需的 PB 神经元的行为和自主神经元的身份。最后，我们将确定哪些 PB 激活了行为和变化。在长时间的寒冷暴露下，需要自主反应来维持核心体温。成功完成拟议的实验将确定神经元和神经回路机制除了从根本上增进我们对这种生命的理解之外，还使哺乳动物能够在寒冷中生存。关键的神经回路，这项工作将提高我们对基因定义的连接和通过开放PB中混合神经元亚群的功能，我们的结果将产生更广泛的影响。有机会设计新方法来诱导和维持重症监护的低温治疗，野战医学、器官移植，也许有一天还会进行太空飞行。