Fronto-sensory circuit mechanisms of perceptual novelty processing

感知新奇处理的额感觉回路机制

• 批准号: 9430604
• 负责人: Jordan P Hamm
• 金额: $ 12.6万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9430604
• 关键词: 3-Dimensional; Area; Attention; Auditory; Auditory area; Axon; Basic Science; Behavior; Behavioral; Biological; Biological Markers; Biological Models; Brain; Brain region; Calcium; Cells; Cerebral cortex; Clinical Research; Cognition; Cognitive; Cognitive deficits; Correlation Studies; Data; Deltastab; Detection; Dimensions; Disease; Doctor of Philosophy; Electroencephalography; Elements; Environment; Event; Exhibits; Experimental Designs; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Head; Heritability; Human; Ii-Key; Image; Impairment; Individual; Interneurons; Investigation; Label; Laser Scanning Microscopy; Lasers; Learning; Light; Link; Mediating; Mental disorders; Microscopy; Mus; Nature; Neurobiology; Neurons; Neurosciences; Onset of illness; Optics; Parvalbumins; Patients; Pattern; Phase; Population; Positioning Attribute; Postdoctoral Fellow; Prefrontal Cortex; Process; Protocols documentation; Psychotic Disorders; Repetitive Sequence; Research; Rest; Role; Running; Schizophrenia; Sensory; Somatostatin; Stimulus; Support System; Taxonomy; Techniques; Testing; Time; Training; Translating; V1 neuron; Visual; Visual Cortex; Work; Yang; awake; career; cell type; daily functioning; design; deviant; experimental study; flexibility; insight; mouse model; neocortical; novel; novel strategies; novelty processing; optogenetics; preference; programs; relating to nervous system; response; sensory cortex; sensory stimulus; spatiotemporal; therapy development; tool; two-photon

PROJECT SUMMARY Sensory stimuli are naturally perceived within a spatiotemporal and behavioral context, wherein novel events are processed and repetitive elements ignored. Novelty detection is thus cognitive as well as perceptual and is critical for daily function and survival. Studies using “oddball” stimuli demonstrate that psychiatric disorders, including schizophrenia (SZ), involve abnormal sensorineuronal processing of novelty which predicts deficits in cognition and everyday functioning. In his PhD, the candidate characterized the multivariate complexity and heritability of oddball EEG responses to show how they could help build a biological taxonomy of psychosis. Yet a mechanistic understanding of how brain circuits process context, and the pathophysiology underlying patient deficits, is unattainable with human studies alone. As a postdoc, the candidate mastered two-photon calcium imaging (2P-Ca++) and chemicogenetics to develop a mouse model of novelty detection in visual cortical circuits (V1), showing a key role for somatostatin interneurons, a pathophysiologically relevant cell type in SZ. While context processing involves ongoing adaptations within sensory cortex, it also requires information about the past and behavioral goals, which may implicate larger brain networks involving prefrontal cortex (PFC). AIM1 expands the candidates work in V1 to study the mechanisms and nature of PFC’s top-down influence. Experiments will test how direct axonal inputs from PFC actively modify the multicellular circuit dynamics in V1 during in oddball paradigms. To this end, the candidate must learn a state of the art holographic technique using spatial light modulators (SLM) developed in the host lab (NIkolenko et al, 2008; Yang et al 2016) to enable the i) simultaneous observation of layer I (PFC axons) and underlying layer 2-5 (V1 neurons) with fast 3D 2P-Ca++, and ii) holographic optogenetic manipulation of specific circuit elements (e.g. PFC inputs to interneurons) to uncover the causal interactions among three critical neurobiological scales: cells, ensembles, and networks. Patient oddball studies highlight deficits in both passive (automatic) and active (attentional) aspects of novelty processing, which may involve non-overlapping neural pathophysiology. In AIM2, the candidate will uncover the behavioral relevance of this PFC-V1 circuit. Working closely with consultants Drs. Churchland and Gogos, the candidate will learn to design behavioral training protocols in head-fixed mice, eliciting responses to novelty in a dynamic oddball paradigm. Building on findings from in AIM1, the candidate will differentiate attentive from pre-attentive circuit functions and establish when and how context is encoded and used to guide behavior. These studies will yield i) biomechanistic information for interpreting novelty processing deficits in humans and ii) key insights into how emergent activity of the cerebral cortex arises from cellular diversity and interregional connectivity. This work will position the candidate to pursue his career goal of a research program which translates empirical biomarkers of sensory and cognitive deficits to model systems, wherein basic research with cutting edge neuroscience tools can provide promising insights and strategies for novel treatments.

项目摘要 感官刺激是在时空和行为背景下自然感知的，其中新颖的感官刺激可以被感知。 处理事件并忽略重复元素。因此，新奇检测既是认知的，也是感知的 并且对于日常功能和生存至关重要。使用“古怪”刺激的研究表明，精神病学 包括精神分裂症（SZ）在内的精神疾病涉及对新奇事物的异常感觉神经元加工， 认知和日常功能的缺陷。在他的博士学位，候选人的特点是多元复杂性 以及古怪脑电反应的遗传性，以展示它们如何帮助建立精神病的生物分类学。 然而，对大脑回路如何处理环境的机械理解，以及其背后的病理生理学， 病人的缺陷，是无法实现的人类研究单独。作为博士后，候选人掌握了双光子 钙成像（2 P-Ca ++）和化学遗传学，以建立视觉皮层新奇检测的小鼠模型 回路（V1），显示生长抑素中间神经元的关键作用，SZ中的病理生理相关细胞类型。 虽然上下文处理涉及感觉皮层内的持续适应，但它也需要信息 关于过去和行为目标，这可能涉及到涉及前额叶皮层（PFC）的更大的大脑网络。 AIM 1扩展了V1中候选人的工作，以研究PFC自上而下影响的机制和性质。 实验将测试来自PFC的直接轴突输入如何主动修改V1中的多细胞回路动力学 在古怪的范例中。为此，候选人必须学习最先进的全息技术， 在主机实验室开发的空间光调制器（SLM）（Nikolenko等人，2008; Yang等人，2016）， i）用快速3D 2 P-Ca ++同时观察I层（PFC轴突）和下面的2-5层（V1神经元）， 和ii）特定电路元件（例如，对中间神经元的PFC输入）的全息光遗传学操纵， 揭示三个关键神经生物学尺度之间的因果关系：细胞，集合和网络。 病人古怪的研究强调缺陷，在被动（自动）和主动（注意力）方面， 新奇处理，这可能涉及非重叠的神经病理生理学。在AIM 2中，候选人将 揭示PFC-V1电路的行为相关性。与顾问丘奇兰博士密切合作， Gogos，候选人将学习设计头部固定小鼠的行为训练方案， 一个动态古怪范例中的新奇事物。根据AIM 1中的调查结果，候选人将区分注意力 从预先注意的电路功能，并建立何时以及如何编码和使用上下文来指导行为。 这些研究将产生i）生物力学信息，用于解释人类的新奇处理缺陷 以及ii）大脑皮层的紧急活动如何从细胞多样性和区域间差异中产生的关键见解 连通性。这项工作将定位候选人追求他的研究计划的职业目标， 将感觉和认知缺陷的经验生物标志物转化为模型系统，其中基础研究 尖端的神经科学工具可以为新的治疗方法提供有希望的见解和策略。