Contribution of Gigantocellular neurons of the medullar reticular formation to awakening from a low brain activity state

髓质网状结构的巨细胞神经元对从低脑活动状态唤醒的贡献

• 批准号: 9008978
• 负责人: Diany Paola Calderon
• 金额: $ 37.72万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9008978
• 关键词: Adrenergic Agents; Anesthesia procedures; Animals; Anterior; Anterior Hypothalamus; Area; Arousal; Basic Science; Behavior; Bilateral; Brain; Brain Injuries; Brain Stem; Cell Nucleus; Cells; Cervical; Coma; Complement; Conscious; Data; Deep Brain Stimulation; Disinhibition; Dorsal; Elements; FOS gene; Fire - disasters; Functional Magnetic Resonance Imaging; Glutamates; Goals; Hypothalamic structure; Imaging technology; Intralaminar Nuclear Group; Label; Light; Location; Methodology; Midbrain structure; Motor; Neurons; Parvalbumins; Pathway interactions; Patients; Pontine structure; Population; Posterior Hypothalamus; Recovery; Recruitment Activity; Reticular Formation; Role; Sensory; Site; Sleep; Stimulus; Structure; System; Testing; Thalamic structure; Unconscious State; Ventral Tegmental Area; Wakefulness; Weather; awake; basal forebrain; cholinergic neuron; diencephalon; dorsal raphe nucleus; extracellular; gamma-Aminobutyric Acid; improved; in vivo; innovative technologies; locus ceruleus structure; midbrain central gray substance; neuronal circuitry; neuroregulation; new technology; noradrenergic; novel; novel strategies; optogenetics; parabrachial nucleus; prevent; public health relevance; relating to nervous system; response

 DESCRIPTION (provided by applicant): Neuromodulation is a promising novel methodology deployed to improve the conditions of thousands of patients whose consciousness is impaired after brain injury. Attempts at neuromodulation using deep brain stimulation (DBS) have targeted a number of loci in the brain arousal pathways such as the thalamus, mesencephalon and cervical cord. However, recovery following single location stimulation remains modest, especially in comatose patients. Although some of these pathways can trigger awakening from sleep or light planes of anesthesia upon activation are insufficient to promote arousal from a deeper arousal state like coma. Furthermore, selective damage to one of these regions, even bilateral, rarely results in permanent unconsciousness. Interpretation of these results suggests that arousal pathways are redundant however, they are not functionally interchangeable. While this implies that the full complement of arousal from a deep arousal state requires coordination of multiple pathways, the mechanism through which this coordination is achieved by the brain is poorly understood. We aim to overcome this challenge uncovering novel neuronal circuits that promote wakefulness through basic research. Considering that medullary reticular neurons project to arousal- modulating areas throughout the brain, integrate a broad range of sensory and autonomic inputs, and fire in response to salient stimuli in close association with the initiation of behaviors, we modulated their activity during a pharmacologic induced coma (PIC). Our results showed that activation of an area located at the anterior border of the nucleus gigantocellularis (aNGC)- elicited robust cortical, autonomic and motor arousal during a state of PIC. To understand how this small subpopulation of neurons exerts such widespread activational effects on arousal, we analyzed immunolabeling of c-Fos-a well-established marker of neuronal activation-following pharmacologic activation of aNGC neurons. C-Fos labeling was sparse and largely limited to structures known to participate in arousal including rhombenchephalon (locus coeruleus and parabrachial nucleus); mesencephalon (periaqueductal gray and ventral tegmental area); diencephalon (intralaminar thalamic nuclei as well as posterior and anterior hypothalamus); and basal forebrain. These findings suggest that aNGC is able to recruit these pathways to trigger arousal from a dense PIC. This proposal characterizes aNGC as a new site to promote arousal from a coma-like state and proposes recruitment of multiple arousal pathways through aNGC as new mechanism to produce widespread activational state resulting in wakefulness. Using extracellular in vivo recordings and innovative technology like optogenetic functional magnetic resonance imaging (ofMRI) we will dissect the circuitry involved in aNGC- stimulated arousal and we will visualize the dynamics of multi-area activation. Results of this study will uncover novel mechanisms leading to new approaches for emerging treatments for patients under coma state.

 描述(由申请人提供)：神经调节是一种很有前途的新方法，用于改善数千名脑损伤后意识受损的患者的状况。使用脑深部刺激(DBS)进行神经调节的尝试针对大脑觉醒通路中的一些位点，如丘脑、中脑和颈髓。然而，单一部位刺激后的恢复仍然有限，特别是在昏迷的患者。虽然这些通路中的一些可以触发从睡眠中唤醒或激活时的麻醉光平面，但不足以促进从更深层次的唤醒状态如昏迷中唤醒。此外，选择性损伤其中一个区域，甚至双侧，很少会导致永久性昏迷。对这些结果的解释表明，唤醒途径是多余的，但它们在功能上是不可互换的。虽然这意味着从深度唤醒状态的完整唤醒需要多条途径的协调，但大脑实现这种协调的机制却鲜为人知。我们的目标是克服这一挑战，通过基础研究发现促进觉醒的新神经元电路。考虑到延髓网状神经元投射到整个大脑的唤醒调节区，整合了广泛的感觉和自主神经输入，并对与行为启动密切相关的显著刺激做出反应，我们在药物诱导昏迷(PIC)期间调节了它们的活动。我们的结果表明，在PIC状态下，激活位于巨细胞核(ANGC)前缘的一个区域--诱发强烈的皮质、自主神经和运动觉醒。为了了解这一小部分神经元如何对觉醒产生如此广泛的激活效应，我们分析了药物激活aNGC神经元后c-Fos的免疫标记-一个公认的神经元激活标记。C-Fos标记很少，而且主要局限于已知的参与觉醒的结构，包括菱形突起(蓝斑和臂旁核)，中脑(导水管周围灰质和腹侧被盖区)，间脑(丘脑板内核以及下丘脑的后部和前部)，以及基底前脑。这些发现表明，aNGC能够招募这些通路来触发从密集的PIC中唤醒。这一建议将aNGC描述为促进从昏迷状态唤醒的新场所，并建议通过aNGC招募多条唤醒途径作为产生广泛激活状态导致觉醒的新机制。利用细胞外的活体记录和光遗传功能磁共振成像(OfMRI)等创新技术，我们将剖析NGC刺激的唤醒过程中涉及的电路，并可视化多区域激活的动力学。这项研究的结果将揭示新的机制，为昏迷状态下的患者提供新的治疗方法。