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）：神经调节是一种有前途的新颖方法，可用于改善数千名脑损伤后意识受损的患者的状况。使用深部脑刺激（DBS）进行神经调节的尝试已针对大脑唤醒中的多个位点。然而，单点刺激后的恢复仍然有限，特别是在昏迷的患者中，尽管其中一些通路可以触发从睡眠或光平面中醒来。激活后的麻醉不足以促进从昏迷等更深的唤醒状态中唤醒。此外，对这些区域之一（甚至是双侧）的选择性损伤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，但事实并非如此。虽然这意味着深度唤醒状态的完整唤醒需要多个途径的协调，但我们对大脑实现这种协调的机制知之甚少，我们的目标是克服这一挑战，揭示新的神经元。考虑到髓质网状神经元投射到整个大脑的唤醒整合调节区域、广泛的感觉和自主输入，并响应与行为启动密切相关的显着刺激，我们发现了促进觉醒的电路。我们的研究结果表明，位于巨细胞核（aNGC）前缘的区域的激活会引发强大的皮质、自主神经和运动功能。为了了解这一小群神经元如何对唤醒产生如此广泛的激活作用，我们分析了 c-Fos（一种公认的神经元激活标记物）在 aNGC 神经元药理学激活后的免疫标记。标记很少，并且主要局限于已知参与唤醒的结构，包括菱脑核（蓝斑和臂旁核）； （导水管周围灰质和腹侧被盖区）；丘脑内侧核以及下丘脑前部和后部；这些发现表明 aNGC 能够募集这些通路来触发密集 PIC 的唤醒。作为促进从昏迷状态中唤醒的新位点，并提出通过 aNGC 招募多种唤醒途径作为产生广泛激活的新机制使用细胞外体内记录和光遗传学功能磁共振成像 (ofMRI) 等创新技术，我们将剖析参与 aNGC 刺激的唤醒的电路，并将多区域激活的动态可视化。揭示新的机制，从而为昏迷状态患者提供新的治疗方法。