Brain-wide representations of behavior during aversive internal states in C. elegans

线虫厌恶的内部状态下的全脑行为表征

• 批准号: 10638999
• 负责人: Steven Willem Flavell
• 金额: $ 38.1万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10638999
• 关键词: Animal Model; Animals; Arousal; Atlases; Behavior; Behavioral; Behavioral Paradigm; Brain; Brain region; Caenorhabditis elegans; Calcium; Cells; Complex; Computer Models; Cues; Data; Data Set; Eating; Environment; Generations; Genetic; Goals; Hour; Image; Infection; Modality; Modeling; Moods; Motivation; Motor; Motor output; Nematoda; Nervous System; Neuromodulator; Neurons; Output; Pathway interactions; Population; Process; Role; Sensory; Signal Transduction; Stereotyping; Stimulus; Structure; System; Time; Work; behavior influence; flexibility; imaging approach; insight; neural; neural circuit; neural correlate; neural model; neuromechanism; neuroregulation; pathogen; pathogenic bacteria; programs; tool; virtual

As animals navigate their environments, their nervous systems transition between a wide range of internal states that influence how sensory information is processed and how behaviors are generated. These states of arousal, motivation, and mood typically persist for long durations of time, from minutes to hours, and exert widespread effects across multiple sensory modalities and motor systems. Although most animals organize their behavioral outputs in this state-like fashion, the neural mechanisms that underlie the generation of these states are poorly understood. One prevailing hypothesis to explain how internal states are generated suggests that fast timescale neural dynamics, which underlie moment-by-moment behavioral changes, might be controlled over slower timescales by ascending pathways, most notably the neuromodulatory systems. Indeed, small, defined subsets of neuromodulator-producing neurons can elicit internal state transitions in many animals. Moreover, recent population-level recordings of neural activity have revealed that internal states are accompanied by widespread, distributed changes in activity across many brain regions. Remarkably, recent work has also shown that granular, moment-by-moment motor actions are reflected in neural activity across many brain regions. This gives rise to a view that sensory signals, granular behavioral signals, and internal state signals all co-occur in most brain circuits. However, how population-level activity encodes a diverse set of behavioral parameters and how this encoding is influenced by internal states to give rise to state-dependent behavioral changes is unknown. Here, we propose to tackle this problem in the nematode C. elegans, whose crystalline nervous system, well-defined set of motor programs, and genetic tractability should make it possible to build complete models of how neural activity encodes behavior across distinct states. This proposal builds off new preliminary data. First, we developed a new recording platform that enables brain-wide calcium imaging of freely-moving C. elegans with simultaneous quantification of the diverse motor programs of the animal. We also built computational models that relate neural activity to behavior with a high degree of precision. Surprisingly, this reveals that many C. elegans neurons encode multiple ongoing motor programs and these encodings flexibly change over time. Moreover, we have developed two behavioral paradigms in which we can elicit robust, stereotyped aversive internal states that unfold over either minutes-long (Aim 1) or hours-long (Aim 2) timescales. We now propose to decipher how each neuron across the C. elegans brain encodes precise behavioral features, creating an atlas of how behaviors are encoded across the nervous system. We will then determine how minutes- or hours-long internal states modulate neural activity across the brain. The comprehensive datasets that we will generate, along with the computational models that we will build, will give rise to a clear understanding of internal state structure in this animal and reveal basic principles that should guide future research in many animal models.

当动物在环境中导航时，它们的神经系统在广泛的 影响感觉信息处理方式和行为产生方式的内部状态。这些 觉醒、动力和情绪的状态通常会持续很长时间，从几分钟到几个小时不等，而且 对多种感觉模式和运动系统产生广泛影响。尽管大多数动物都会组织 它们的行为输出以这种状态类似的方式，神经机制基础上的这些 各国对此知之甚少。解释内部状态如何产生的一个流行假说 这表明，作为行为改变基础的快速时间尺度神经动力学，可能 被提升路径控制在较慢的时间尺度上，最显著的是神经调节系统。 事实上，神经调节剂产生神经元的小的、已定义的子集可以在 很多动物。此外，最近人口水平的神经活动记录显示，内部 状态伴随着大脑许多区域活动的广泛、分布的变化。 值得注意的是，最近的研究还表明，颗粒状的、瞬间的运动动作反映在 大脑多个区域的神经活动。这引发了一种观点，即感觉信号、颗粒行为 信号和内部状态信号在大多数大脑回路中都是共存的。然而，人口层面的活动如何 对一组不同的行为参数进行编码，以及内部状态对此编码的影响 引起状态依赖的行为变化是未知的。在这里，我们建议在 线虫，其水晶神经系统，一套明确的运动程序，和基因 易操纵性应该使建立神经活动如何对行为进行编码的完整模型成为可能 不同的州。这项提案建立在新的初步数据基础上。首先，我们开发了一个新的录音平台 这使得自由活动的线虫的全脑钙成像能够同时定量 动物的不同运动程序。我们还建立了计算模型，将神经活动与 行为具有高度精确度。令人惊讶的是，这揭示了许多线虫神经元编码 多个正在进行的运动程序，这些编码随着时间的推移灵活地改变。此外，我们有 开发了两个行为范例，在其中我们可以引出健壮的、刻板印象的厌恶的内部状态 在几分钟(目标1)或数小时(目标2)的时间范围内展开。我们现在建议破译如何 线虫大脑中的每个神经元都对精确的行为特征进行编码，从而创建了一个图谱 整个神经系统都对行为进行了编码。然后我们将确定几分钟或几个小时的长度 内部状态调节整个大脑的神经活动。我们将生成的全面数据集， 与我们将要构建的计算模型一起，将引起对内部状态的清晰理解 并揭示了指导未来在许多动物模型中研究的基本原则。