Exploring neuronal circuitry in neurodegenerative diseases: from traditional models to cutting-edge techniques

Current treatments of neurodegenerative diseases primarily address symptoms rather than halting pathology progression. This gap is due to the lack of effective methods for monitoring neural circuitry and dynamics over time. In this context, the development of in vitro models that more accurately replicate the human brain microenvironment has become essential. Traditional two-dimensional (2D) cell cultures, while providing valuable insights, fail to capture the intricate complexity of the human brain. Recent advancements in neuroscience spotlight the emergence of more sophisticated three-dimensional (3D) models, which can more faithfully recapitulate the intricacies of the brain. This review discusses the evolution of in vitro brain models, emphasizing the transition from traditional 2D cultures to sophisticated 3D systems, including neurospheroids, brain organoids, assembloids and micro-tissue engineered neuronal networks (micro-TENNs). We further highlight the emergence of brain-on-chip platforms, combining microfluidics with cell culture technologies to create precisely controlled environments mimicking the physiological conditions of the human brain. Furthermore, we discuss the application of 3D bioprinting technology enabling the generation of neural constructs with precise control over cell placement. Lastly, we delve into the potential of integrating brain organoids with 3D bioprinting technology, aiming to recapitulate the true three-dimensional complexity of the brain, thereby improving the physiological accuracy of brain models for advancing our understanding of neurodegenerative diseases.