Brainwide Computations Underlying Future Action Plans

未来行动计划的全脑计算

• 批准号: 10161874
• 负责人: Timothy Aloysius Machado
• 金额: $ 12.32万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10161874
• 关键词: Acute; Advisory Committees; Aging; Amyotrophic Lateral Sclerosis; Anger; Animals; Area; Arousal; Automobile Driving; Behavior; Behavioral; Behavioral Assay; Brain; Brain Injuries; Brain Stem; Brain region; Cell Nucleus; Chronic; Chronic Brain Injury; Communities; Degenerative Disorder; Disease; Dorsal; Electrophysiology (science); Ensure; Face; Faculty; Fright; Future; Generations; Goals; Image; Impairment; Individual; Infarction; Injury; Learning; Lesion; Link; Logic; Measures; Memory; Mentors; Mentorship; Methods; Monitor; Motor; Motor Cortex; Motor Neurons; Motor Pathways; Motor output; Movement; Mus; Nervous system structure; Neurologic; Neurons; Pathway interactions; Phase; Play; Positioning Attribute; Postdoctoral Fellow; Pyramidal Tracts; Red nucleus structure; Reflex action; Research; Rewards; Role; Sensory; Signal Transduction; Stroke; Structure; System; Technology; Thirst; Training; Universities; Use of New Techniques; Water; Work; comparative; experience; experimental study; motor behavior; motor neuron degeneration; mouse model; neural circuit; optogenetics; orofacial; post-doctoral training; programs; recruit; relating to nervous system; superior colliculus Corpora quadrigemina; tenure track

How do the neural circuits controlling movement combine sensory information, memories of past experiences, and internal state information (e.g. thirst, arousal, anger, fear) to produce even simple actions? And how does descending command activity change when a specific action (e.g. a lick in a specific direction) is made for different reasons (e.g. a reflexive vs. memory-guided lick)? Individual motor neurons receive thousands of inputs from across the brain and then integrate that information nonlinearly over dendritic arbors that span hundreds of microns. This complexity makes it difficult to assign a specific causative role to any single upstream circuit. Indeed, past studies have shown that many parallel circuits, from those involving cortex, the superior colliculus, the red nucleus, and simple reflexes in the brainstem, are each involved in driving similar orofacial movements. However, comparatively little is known about how these different pathways normally coordinate their activity with each other during normal behavior. One consequence of this gap in understanding pertains to disease. While many neurological impairments cause localized damage to movement-related brain regions (e.g. motor neuron degeneration in ALS, or the areas surrounding an infarction following a stroke), it is still unclear why some lesions cause permanent deficits while others can be compensated for by changes in the neural activity of other circuits in unaffected parts of the brain. The goal of this project is to discover the logic governing the coordination between different descending motor pathways, to determine how their recruitment depends on brain state (e.g. thirst or arousal), and to measure how such coordination changes following an acute or chronic brain injury. To do this, we will use recently developed large-scale neural recording technologies to interrogate many brain areas— including the motor nuclei themselves. First, using a new method for simultaneously monitoring many areas across dorsal cortex using Ca2+ imaging, I will explore the structure of neural activity contained in corticobulbar (i.e. cortex to medulla) projection neurons preceding both sensory and memory-guided directional lick bouts. Second, I will obtain electrophysiological recordings (using Neuropixels probes) from pyramidal tract neurons in motor cortex, the superior colliculus, and/or the medullar motor circuits themselves. Finally, I will study the acute and chronic effects of shutting down parts of the brain during licking behavior (using both optogenetic- silencing, and a mouse model of ALS to gradually kill motor neurons). These aims will be pursued at Stanford University, working under the co-mentorship of Karl Deisseroth and Surya Ganguli. This exceptional research community has an outstanding track record of both training postdoctoral fellows and successfully placing them in tenure-track faculty positions. My advisory committee will further ensure that I implement my training plan successfully and am able to establish my own lab to study how global brain computations drive specific actions.

控制运动的神经元如何结合感官信息，对过去经历的记忆以及内部状态信息（例如3，唤醒，愤怒，恐惧），甚至产生简单的动作？当特定的动作（例如，在特定方向上舔）出于不同的原因（例如，反身和记忆引导引导的舔），下降命令活动如何改变？单个运动神经元从整个大脑中接收数千个输入，然后在跨越数百微米的树突状乔木上非线性地整合该信息。这种复杂性使得很难为任何单个上游电路分配特定的严重角色。实际上，过去的研究表明，许多平行电路，来自涉及的皮层，上丘，红色核和脑干中的简单反射，每个平行电路都参与驱动相似的口面运动。但是，对于这些不同的途径在正常行为期间通常彼此协调它们的活性如何相对较少。理解与疾病有关的差距的结果。尽管许多神经系统损伤会对运动相关的大脑区域（例如，ALS的运动神经元变性或中风后梗塞周围的区域）造成局部损害），但仍不清楚某些病变为什么会导致永久性缺陷，而其他病变则可以通过其他环球活动的变化来弥补大脑的神经元活动的变化。该项目的目的是发现管理不同降落电路路径之间协调的逻辑，以确定其招募如何依赖大脑状态（例如3或唤醒），并测量这种配位变化如何遵循急性或慢性脑损伤。为此，我们将使用最近开发的大规模中性记录技术来询问许多大脑区域，包括运动核本身。首先，使用一种新方法使用CA2+成像来简单地监测背侧皮质的许多区域，我将探讨在感官和记忆引导的定向舔钻头之前的Corticobulbar（即皮层的髓质）投影神经元中包含的神经元活性的结构。其次，我将从运动皮层，上丘丘和/或髓质运动电路本身中获得来自锥体管神经元的电生理记录（使用神经固定问题）。最后，我将研究在舔行为过程中关闭大脑部分的急性和慢性作用（使用光遗传沉默和ALS小鼠模型以逐渐杀死运动神经元）。这些目标将在斯坦福大学（Stanford University）追求，在Karl Deisseroth和Surya Ganguli的合法下工作。这个杰出的研究社区拥有培训博士后研究员的出色记录，并成功地将他们置于终身任职教师职位。我的咨询委员会将进一步确保我成功实施培训计划，并能够建立自己的实验室来研究全球大脑计算如何推动特定的行动。