Identifying the neurostructural determinants of minimal cognition using embodied 3D bioengineered brain models

认知功能是人类最复杂的机械功能之一。为了探索认知的神经机制，早期的研究者将神经损伤与功能丧失联系起来，并刺激人类和非人类动物的大脑来绘制结构-功能关系。这些早期的方法最终让位于当代使用动物模型来研究与动物认知相关的精细神经回路。不幸的是，动物模型是低通量的，并且缺乏人类生理学的关键要素。为了解决这些问题，认知科学家已经开始探索在单细胞和组织中测量认知的可能性，并取得了显着的成功。简单的反应模式中的最小的生命积木可能代表的表达“最低认知”的前身，复杂的，高阶的认知功能。同样，越来越流行的观点认为，认知从根本上是“体现”或与脑-体界面密不可分，这表明感觉-运动反馈回路可能是智力、学习和决策的基础。因此，全面理解认知可能需要评估其最基本的形式，即具体组织内的信息处理。为此，生物材料和三维（3D）神经组织培养技术的进步使得在体外用可定制的细胞结构对3D脑组织进行生物工程化成为可能。这些生物工程脑模型（BBM）可以用人类和非人类组织制成，从而克服了传统单层细胞培养的许多局限性以及遗传决定的动物和类器官脑结构的不灵活性。我开发了一种高度易处理和可定制的3D-BBM，它来自于嵌入在蚕丝支架中的人类诱导多能干细胞（iPSC），可以稳定培养多年，显示出习惯性学习反应和突触可塑性。在最近的一次高影响力的评论中，我预测，如果3D-BBM被具体化，使得它可以输出到运动效应器（例如，肌肉、移动的机器人）与反馈，最小认知的显示将是可实现的。拟议的为期5年的NSERC DG研究计划将建立在生物工程和神经机器人领域的这些重大进展的基础上，通过将3D-BBM与计算机接口集成，以记录深层组织电生理动力学，实现实施，程序响应模式，并显示最小的认知功能。主要成果包括用于神经认知研究的变革性体外工具和识别最小认知功能的因果机制。拟议研究的结果还将推动33名HQP的培训，并指导和指导具有商业和工业应用的新型人工智能和混合智能的设计。

Cognitive functions are among the most mechanistically complex yet defining features of the human species. In pursuit of neural mechanisms underlying cognition, early investigators correlated neural damage with loss-of-function and stimulated the brains of both humans and non-human animals to map structure-function relationships. These early methods eventually gave way to the contemporary use of animal models to study fine-scale neural circuits associated with animal cognition. Unfortunately, animal models are low-throughput and lack key elements of human physiology. To address these pitfalls, cognitive scientists have started to explore the possibility of measuring cognition in single cells and tissues with notable success. Simple response patterns among the smallest building blocks of life may represent expressions of "minimal cognition" - precursors to complex, high-order cognitive functions. Similarly, the increasingly prevalent view that cognition is fundamentally "embodied" or inextricably linked to brain-body interfaces suggests that sensory-motor feedback loops may be fundamental to intelligence, learning, and decision-making. Therefore, a comprehensive understanding of cognition may require an assessment of its most rudimentary forms as information-processing within embodied tissues. To that end, advances in biomaterials and three-dimensional (3D) neural tissue culture techniques have made it possible to biologically engineer 3D brain tissues in vitro with customizable cytoarchitectures. These bioengineered brain models (BBMs) can be made with both human and non-human tissues, thus overcoming many of the limitations of traditional monolayer cell culture and the inflexibility of genetically-determined animal and organoid brain structure. I have developed a highly tractable and customizable 3D-BBM derived from human induced pluripotent stem cells (iPSC) embedded in silk scaffolds that can be stably cultured for years, displays habituation-like learning responses, and synaptic plasticity. In a recent high-impact review, I predicted that if the 3D-BBM were embodied such that it could output to a motor effector (e.g., muscles, mobile robots) with feedback, displays of minimal cognition would be achievable. The proposed 5-year NSERC DG research program will build on these significant advances in the fields of bioengineering and neurorobotics by integrating 3D-BBMs with computer interfaces to record deep tissue electrophysiological dynamics, achieve embodiment, program response patterns, and display minimal cognitive functions. The main outcomes include transformative in vitro tools for neurocognitive research and the identification of causal mechanisms of minimal cognitive function. The results of the proposed research will also fuel the training of 33 HQP as well as instruct and inform the design of new artificial and hybrid intelligences with commercial and industrial applications.