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

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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.