Fronto-sensory circuit mechanisms of perceptual novelty processing

项目总结 感觉刺激是在时空和行为环境中自然感知的，其中新颖的 事件被处理，重复元素被忽略。因此，新颖性检测既是认知的，也是感知的 对日常功能和生存至关重要。使用“古怪”刺激的研究表明，精神病患者 精神障碍，包括精神分裂症(SZ)，涉及对新奇事物的异常感觉神经元处理，这预示着 认知和日常功能的缺陷。在他的博士学位中，候选人描述了多变量的复杂性 以及奇怪的脑电反应的遗传性，以表明它们如何帮助建立精神病的生物学分类。 然而，对大脑回路如何处理上下文以及其背后的病理生理机制的机械理解 患者缺陷，仅靠人体研究是无法达到的。作为博士后，这位候选人掌握了双光子 钙成像(2P-Ca~(++))和化学遗传学建立小鼠视觉皮质新颖性检测模型 回路(V1)，显示了生长抑素中间神经元的关键作用，生长抑素中间神经元是深圳一种与病理生理相关的细胞类型。 虽然语境处理涉及到感觉皮质内的持续适应，但它也需要信息 关于过去和行为目标，这可能意味着更大的大脑网络涉及前额叶皮质(PFC)。 AIM1扩展了V1中的候选工作，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改变V1中的多细胞电路动力学 在古怪的范例中。为此，候选人必须学习最先进的全息技术，使用 在主办实验室开发的空间光调制器(SLM)(Nikolenko等人，2008年；Yang等人2016年)，以使 I)同时观察到第I层(PFC轴突)和下层2-5(V1神经元)的快速3D2P-Ca++， 和ii)对特定电路元件(例如中间神经元的PFC输入)进行全息光遗传操作，以 揭示三个关键神经生物学尺度之间的因果相互作用：细胞、群体和网络。 患者古怪的研究突出了在被动(自动)和主动(注意)方面的缺陷 新奇加工，这可能涉及非重叠的神经病理生理学。在AIM2中，候选人将 发现这个PFC-V1电路的行为相关性。与顾问Churchland博士和 Gogos，候选人将学习在头部固定的小鼠中设计行为训练方案，引发对 一个动态古怪的范例中的新鲜感。根据AIM1中的发现，候选人将区分注意力 根据预先注意的电路功能，确定何时以及如何对上下文进行编码并使用它来指导行为。 这些研究将产生：1)用于解释人类新奇加工缺陷的生物力学信息 以及二)关于大脑皮层的紧急活动如何由细胞多样性和区域间引起的关键见解 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记物转化为模型系统，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。

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.