Learning and synaptic plasticity in 3D bioengineered neural tissues.

Though neuroscientists have historically relied upon measurement of established nervous systems, contemporary advances in bioengineering have made it possible to design and build artificial neural tissues with which to investigate normative and diseased states [1-5] however, their potential to display features of learning and memory remains unexplored. Here, we demonstrate response patterns characteristic of habituation, a form of non-associative learning, in 3D bioengineered neural tissues exposed to repetitive injections of current to elicit evoked-potentials (EPs). A return of the evoked response following rest indicated learning was transient and partially reversible. Applying patterned current as massed or distributed pulse trains induced differential expression of immediate early genes (IEG) that are known to facilitate synaptic plasticity and participate in memory formation [6,7]. Our findings represent the first demonstration of a learning response in a bioengineered neural tissue in vitro.

A 3D Tissue Model of Traumatic Brain Injury with Excitotoxicity That Is Inhibited by Chronic Exposure to Gabapentinoids.

Injury progression associated with cerebral laceration is insidious. Following the initial trauma, brain tissues become hyperexcitable, begetting further damage that compounds the initial impact over time. Clinicians have adopted several strategies to mitigate the effects of secondary brain injury; however, higher throughput screening tools with modular flexibility are needed to expedite mechanistic studies and drug discovery that will contribute to the enhanced protection, repair, and even the regeneration of neural tissues. Here we present a novel bioengineered cortical brain model of traumatic brain injury (TBI) that displays characteristics of primary and secondary injury, including an outwardly radiating cell death phenotype and increased glutamate release with excitotoxic features. DNA content and tissue function were normalized by high-concentration, chronic administrations of gabapentinoids. Additional experiments suggested that the treatment effects were likely neuroprotective rather than regenerative, as evidenced by the drug-mediated decreases in cell excitability and an absence of drug-induced proliferation. We conclude that the present model of traumatic brain injury demonstrates validity and can serve as a customizable experimental platform to assess the individual contribution of cell types on TBI progression, as well as to screen anti-excitotoxic and pro-regenerative compounds.

Matrix Deformation with Ectopic Cells Induced by Rotational Motion in Bioengineered Neural Tissues.

The brain's extracellular matrix (ECM) is a dynamic protein-based scaffold within which neural networks can form, self-maintain, and re-model. When the brain incurs injuries, microscopic tissue tears and active ECM re-modelling give way to abnormal brain structure and function including the presence of ectopic cells. Post-mortem and neuroimaging data suggest that the brains of jet pilots and astronauts, who are exposed to rotational forces, accelerations, and microgravity, display brain anomalies which could be indicative of a mechanodisruptive pathology. Here we present a model of non-impact-based brain injury induced by matrix deformation following mechanical shaking. Using a bioengineered 3D neural tissue platform, we designed a repetitive shaking paradigm to simulate subtle rotational acceleration. Our results indicate shaking induced ectopic cell clustering that could be inhibited by physically restraining tissue movement. Imaging revealed that the collagen substrate surrounding cells was deformed following shaking. Applied to neonatal rat brains, shaking induced deformation of extracellular spaces within the cerebral cortices and reduced the number of cell bodies at higher accelerations. We hypothesize that ECM deformation may represent a more significant role in brain injury progression than previously assumed and that the present model system contributes to its understanding as a phenomenon.

A Long-Living Bioengineered Neural Tissue Platform to Study Neurodegeneration.

The prevalence of dementia and other neurodegenerative diseases continues to rise as age demographics in the population shift, inspiring the development of long-term tissue culture systems with which to study chronic brain disease. Here, it is investigated whether a 3D bioengineered neural tissue model derived from human induced pluripotent stem cells (hiPSCs) can remain stable and functional for multiple years in culture. Silk-based scaffolds are seeded with neurons and glial cells derived from hiPSCs supplied by human donors who are either healthy or have been diagnosed with Alzheimer's disease. Cell retention and markers of stress remain stable for over 2 years. Diseased samples display decreased spontaneous electrical activity and a subset displays sporadic-like indicators of increased pathological ß-amyloid and tau markers characteristic of Alzheimer's disease with concomitant increases in oxidative stress. It can be concluded that the long-term stability of the platform is suited to study chronic brain disease including neurodegeneration.