Engineered Cortical Microcircuits for Investigations of Neuroplasticity

Abstract

Recent advances in neural engineering have unlocked unprecedented opportunities for manipulating and studying the impact of topology on neural network function and malfunction. Leveraging microfluidic technologies, it is possible to establish modular circuit motifs with a fine-tuned balance between segregated and integrated information processing, resembling those observed in vivo. However, the impact of such topologies on network dynamics and disease adaptation remains largely unresolved. In this work, we demonstrate the utilization of microfluidic platforms with 12 interconnected nodes to structure modular, cortical engineered neural networks. By implementing geometrical constraints inspired by a Tesla valve within the connecting microtunnels, we additionally exert control over the direction of axonal outgrowth between the nodes. Interfacing these platforms with nanoporous microelectrode arrays reveals that the resulting laminar cortical networks exhibit pronounced segregated and integrated functional dynamics across layers, reminiscent of the feedforward, hierarchical information processing observed in the neocortex. The multi-nodal configuration also facilitates the induction of localized perturbations to individual nodes within the networks. To illustrate this, we induce hypoxia, a key factor in the pathogenesis of various neurological disorders, in well-connected nodes within the networks. Our findings demonstrate that such perturbations induce ablation of information flow across the hypoxic node, while enabling the study of plasticity and information processing adaptations in neighboring nodes and neural communication pathways. In summary, our presented model system recapitulates fundamental attributes of the microcircuit organization of neocortical neural networks, rendering it highly pertinent for preclinical neuroscience research. This model system holds promise for yielding new insights into the development, topological organization, and neuroplasticity mechanisms of the neocortex across the micro- and mesoscale, in both healthy and pathological conditions.