Predictive Functions and Neural Mechanisms of Spontaneous Cortical Activity

自发皮质活动的预测功能和神经机制

• 批准号: 10572486
• 负责人: Anish Mitra
• 金额: $ 19.41万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572486
• 关键词: Address; Advisory Committees; Animal Behavior; Area; Arousal; Automobile Driving; Behavior; Behavioral; Belief; Bilateral; Brain; Calcium; Cells; Complex; Data; Decision Making; Detection; Development; Dorsal; Environment; Expert Systems; Fellowship; Female; Functional Magnetic Resonance Imaging; Future; Generations; Goals; Halorhodopsins; Head; Human; Image; Injections; Interneurons; Investigation; Knowledge; Link; Mathematics; Mental Depression; Mental disorders; Mentors; Mentorship; Methods; Modeling; Mus; National Institute of Mental Health; Nervous System; Neurocognitive; Neurons; Noise; Pattern; Perception; Physicians; Positioning Attribute; Post-Traumatic Stress Disorders; Process; Psychiatric Diagnosis; Psychiatry; Psychophysics; Publications; Recording of previous events; Reporting; Reproducibility; Research; Research Personnel; Rest; Rewards; Rodent; Role; Schizophrenia; Scientist; Shapes; Signal Transduction; Somatostatin; Specificity; Stimulus; Structure; System; Technology; Testing; Training; Variant; Visual; Visual Cortex; Visual System; Water; Work; behavior prediction; behavioral response; career; cognitive control; cognitive neuroscience; cognitive process; hippocampal pyramidal neuron; insight; male; mouse model; multidisciplinary; neural; neurocognitive disorder; neuroimaging; neuromechanism; neuroregulation; novel; optical imaging; optogenetics; predicting response; response; sensory stimulus; theories; visual processing

The mammalian cortex is spontaneously active even in the absence of external stimuli. Initially dismissed as neural noise, pioneering work established that the internal brain states produced by spontaneous activity are highly structured and responsible for the dramatic variability in both neural and perceptual responses to the same sensory stimulus. The discovery that varying spontaneous cortical states (SCS) drive different responses to identical stimuli suggested that altered perceptions of the environment across psychiatry could derive from aberrant SCS. On this basis, ongoing resting state fMRI studies continue to search for reproducible links between SCS and psychiatric diagnoses, including schizophrenia, depression, and PTSD, among others. Yet our fundamental understanding of the cognitive processes and circuit mechanisms underlying SCS remains limited. One leading theory, drawn from human fMRI recordings during visual detection tasks, suggests that SCS represent predictions about the environment. In this model, predictive spontaneous cortical states influence perceptual decision making on the basis of prior beliefs. However, several critical gaps remain in this theory. At present, there is no causal evidence, either through closed-loop behavior or direct neural modulation, linking SCS to perceptual decisions. Moreover, the circuit mechanisms of SCS, including the role of interneurons in producing SCS and specific cortical areas in driving spontaneous cortex-wide states, are completely unknown. My proposal aims to address these knowledge gaps by investigating SCS in a mouse model. Having trained mice in a two-alternative forced choice visual detection task, I have applied optical imaging of the dorsal cortex to find that specific spontaneous states predict behavioral response. Leveraging my preliminary data, I will investigate how specific interneuron types contribute to SCS (Aim 1), test the causal influence of predictive SCS over perceptual decisions through a closed-loop behavior (Aim 2), and apply optogenetic modulation of neural activity to test the role of a specific cortical area, the retrosplenial cortex, in driving predictive SCS (Aim 3). The proposed studies will offer novel insights into the neurocognitive mechanisms underlying spontaneous activity, including in human resting state fMRI. In the process, I will supplement my background in human resting state neuroimaging with critical training in rodent behavior, psychophysics methods, and optogenetics. My proposal will be guided by a world-class advisory committee consisting of my primary mentor Dr. Karl Deisseroth, an expert in optogenetics and animal behavior, Dr. Michael Stryker, a mouse visual system expert, Dr. Brian Wandell, an expert in perceptual decision making, Dr. Robert Malenka, a rodent nervous system expert, and Dr. Nolan Williams, an expert in human neuromodulation. I will further take full advantage of the vibrant training environment at Stanford by engaging in targeted coursework and high-quality professional development. By the end of the fellowship, I will be positioned to launch a career as an independent investigator studying how the neurocognitive processes embedded in spontaneous activity contribute to psychiatric illness.

即使没有外部刺激，哺乳动物皮质也会自发活跃。最初被驳回为 神经噪声，开创性工作确定自发活动产生的内部大脑状态是 高度结构化和负责神经和感知反应的显着变异性 感觉刺激。发现自发皮质状态（SC）的发现推动了不同的反应 相同的刺激表明，跨精神病学的环境的改变可能来自 异常SC。在此基础上，正在进行的休息状态fMRI研究继续寻找可再现的联系 SCS和精神诊断，包括精神分裂症，抑郁症和PTSD等。但是我们的 对SCS基础的认知过程和电路机制的基本理解仍然有限。 一个主要理论是从人类fMRI在视觉检测任务中录制的，这表明SCS 表示有关环境的预测。在此模型中，预测性自发皮质状态影响 基于先前信念的知觉决策。但是，这一理论仍然存在一些关键差距。在 目前，没有因果证据，无论是通过闭环行为还是直接的神经调制， SCS到感知决定。此外，SC的电路机制，包括中间神经元在 在驱动自发性皮质状态的驱动自发的SC和特定皮质区域是完全未知的。 我的建议旨在通过研究鼠标模型中的SC来解决这些知识差距。经过训练 在两种强制选择的视觉检测任务中，我已经应用了背皮层的光学成像 找到特定的自发状态预测行为反应。利用我的初步数据，我将 研究特定的中间神经元类型如何对SCS贡献（AIM 1），测试预测性SC的因果影响 通过闭环行为（AIM 2）进行过度的知觉决定，并应用神经的光遗传学调制 活性测试特定皮质区域，泛胞性皮质的作用，在驱动预测性SC中（AIM 3）。 拟议的研究将为自发性的神经认知机制提供新的见解 活动，包括在人类休息状态fMRI。在此过程中，我将补充我的背景 在啮齿动物行为，心理物理学方法和光遗传学中进行关键训练的状态神经影像学。我的 提案将由我的主要导师Karl Deisseroth博士组成的世界一流咨询委员会指导， 鼠标视觉系统专家Michael Stryker博士Brian博士Michael Stryker博士 Wandell是感知决策的专家，啮齿动物神经系统专家Robert Malenka博士和博士 诺兰·威廉姆斯（Nolan Williams），人类神经调节专家。我将进一步充分利用充满活力的训练 斯坦福大学的环境通过参与有针对性的课程和高质量的专业发展。由 奖学金的结束，我将成为一个独立调查员的职业，研究如何 嵌入自发活动的神经认知过程会导致精神病。