Brain-on-a chip demonstrates the importance of extracellular matrix in distinguishing brain regions

Written by Jonathan Wilkinson

Researchers from Harvard University (MA, USA) have developed a multiregional brain-on-a-chip that models the connectivity between three separate regions of the brain: the amygdala, hippocampus and prefrontal cortex. These are the regions of the brain found to be significantly affected by schizophrenia. The in vitro model not only recreates these connections, but can also characterize the differences between the neurons found in these three areas. The findings have been published in the Journal of Neurophysiology.
Ben Maoz (Harvard University), co-first author of the study, explained why the group developed this brain-on-a-chip: “The brain is so much more than individual neurons. It’s about the different types of cells and the connectivity between different regions of the brain. When modeling the brain, you need to be able to recapitulate that connectivity because there are many different diseases that attack those connections.”

Kit Parker (Harvard University), senior author of the study, commented further:  “Roughly 26% of the US healthcare budget is spent on neurological and psychiatric disorders. Tools to support the development of therapeutics to alleviate the suffering of these patients is not only the human thing to do, it is the best means of reducing this cost.”

In the first part of the study, the researchers characterized the cell composition, protein expression, metabolism and electrical activity of the neurons from each of the three regions. Stephanie Dauth (Harvard University), co-first author, discussed the group’s findings: “It’s no surprise that neurons in distinct regions of the brain are different but it is surprising just how different they are. We found that the cell-type ratio, the metabolism, the protein expression and the electrical activity all differ between regions in vitro. This shows that it does make a difference which brain region’s neurons you’re working with.”

In the next part of their study, the authors investigated how the neurons might change when they are communicating with each other. The cells were all cultured independently and then allowed to establish connections using guided pathways that had been embedded in the chip. When cell composition and electrical activity were measured again, it was found that the cells dramatically changed when they were in contact with neurons from different regions.

Maoz explained: “When the cells are communicating with other regions, the cellular composition of the culture changes, the electrophysiology changes – all these inherent properties of the neurons change. This shows how important it is to implement different brain regions into in vitro models, especially when studying how neurological diseases impact connected regions of the brain.”

Finally, to demonstrate how effective the brain-on-a-chip could be in modeling disease, the researchers doped the brain regions with phencyclidine hydrochloride, which simulates schizophrenia. The chip allowed the observation of both the drug’s impact on the individual regions as well as its downstream effect on the interconnected regions in vitro.

Parker summarized the potential significance of the group’s study: “To date, the Connectome project has not recognized all of the networks in the brain. In our studies, we are showing that the extracellular matrix network is an important part of distinguishing different brain regions and that, subsequently, physiological and pathophysiological processes in these brain regions are unique. This advance will not only enable the development of therapeutics, but fundamental insights as to how we think, feel and survive.”

Sources: Dauth S, Maoz BM,  Sheehy SP et al. Neurons derived from different brain regions are inherently different in vitro: a novel multiregional brain-on-a-chip. J. Neurophysiol. Doi:10.1152/jn.00575.2016 (2016) (Epub ahead of print); www.seas.harvard.edu/news/2017/01/multiregional-brain-on-chip