Connecting the Brain to Itself through an Emulation.

Pilot clinical trials of human patients implanted with devices that can chronically record and stimulate ensembles of hundreds to thousands of individual neurons offer the possibility of expanding the substrate of cognition. Parallel trains of firing rate activity can be delivered in real-time to an array of intermediate external modules that in turn can trigger parallel trains of stimulation back into the brain. These modules may be built in software, VLSI firmware, or biological tissue as in vitro culture preparations or in vivo ectopic construct organoids. Arrays of modules can be constructed as early stage whole brain emulators, following canonical intra- and inter-regional circuits. By using machine learning algorithms and classic tasks known to activate quasi-orthogonal functional connectivity patterns, bedside testing can rapidly identify ensemble tuning properties and in turn cycle through a sequence of external module architectures to explore which can causatively alter perception and behavior. Whole brain emulation both (1) serves to augment human neural function, compensating for disease and injury as an auxiliary parallel system, and (2) has its independent operation bootstrapped by a human-in-the-loop to identify optimal micro- and macro-architectures, update synaptic weights, and entrain behaviors. In this manner, closed-loop brain-computer interface pilot clinical trials can advance strong artificial intelligence development and forge new therapies to restore independence in children and adults with neurological conditions

Plasticity and Adaptation in Neuromorphic Biohybrid Systems

Neuromorphic systems take inspiration from the principles of biological information processing to form hardware platforms that enable the large-scale implementation of neural networks. The recent years have seen both advances in the theoretical aspects of spiking neural networks for their use in classification and control tasks and a progress in electrophysiological methods that is pushing the frontiers of intelligent neural interfacing and signal processing technologies. At the forefront of these new technologies, artificial and biological neural networks are tightly coupled, offering a novel \u201cbiohybrid\u201d experimental framework for engineers and neurophysiologists. Indeed, biohybrid systems can constitute a new class of neuroprostheses opening important perspectives in the treatment of neurological disorders. Moreover, the use of biologically plausible learning rules allows forming an overall fault-tolerant system of co-developing subsystems. To identify opportunities and challenges in neuromorphic biohybrid systems, we discuss the field from the perspectives of neurobiology, computational neuroscience, and neuromorphic engineering. \ua9 2020 The Author(s

In vitro cell models merging circadian rhythms and brain waves for personalized neuromedicine

New evidence is emerging about the dynamics of interaction between circadian rhythms and brain waves, whose coordination occurs through the entrainment process. The so-called “oscillopathies” or dysfunctions in synchronization of neuronal oscillation in key brain networks lead to the onset of neurodegenerative diseases. A typical example of alteration is insomnia, a risk factor for the oscillopathies, increasingly widespread worldwide. Recently, synchronization of circadian rhythms in cell cultures has allowed an improvement in the physiological relevance of responses to stimuli. Furthermore, brain organoids and neurons cultured in microfluidic systems are the latest frontiers for in vitro reproduction of rhythmic electrical signals. In this review, the combination of these in vitro experimental approaches is proposed as suitable for a more direct investigation on the common mechanisms and neurophysiological substrates underlying brain waves and circadian oscillations, and useful to evaluate the effects of “oscillotherapeutic” drugs for personalized neuromedicine

Microenvironments Matter:Advances in Brain-on-Chip

To highlight the particular needs with respect to modeling the unique and complex organization of the human brain structure, we reviewed the state-of-the-art in devising brain models with engineered instructive microenvironments. To acquire a better perspective on the brain’s working mechanisms, we first summarize the importance of regional stiffness gradients in brain tissue, varying per layer and the cellular diversities of the layers. Through this, one can acquire an understanding of the essential parameters in emulating the brain in vitro. In addition to the brain’s organizational architecture, we addressed also how the mechanical properties have an impact on neuronal cell responses. In this respect, advanced in vitro platforms emerged and profoundly changed the methods of brain modeling efforts from the past, mainly focusing on animal or cell line research. The main challenges in imitating features of the brain in a dish are with regard to composition and functionality. In neurobiological research, there are now methods that aim to cope with such challenges by the self-assembly of human-derived pluripotent stem cells (hPSCs), i.e., brainoids. Alternatively, these brainoids can be used stand-alone or in conjunction with Brain-on-Chip (BoC) platform technology, 3D-printed gels, and other types of engineered guidance features. Currently, advanced in vitro methods have made a giant leap forward regarding cost-effectiveness, ease-of-use, and availability. We bring these recent developments together into one review. We believe our conclusions will give a novel perspective towards advancing instructive microenvironments for BoCs and the understanding of the brain’s cellular functions either in modeling healthy or diseased states of the brain.</p

Comprehensive Techniques to Study Activity-dependent and Neurogenic Mechanisms in Stem Cell-derived Neuron Models

Accurately modeling human-related neuronal phenomena remains at the forefront of neuroscience. This thesis utilizes already-established in vitro models of mouse embryonic stem cells, designing an efficient method to optogenetically stimulate neurons derived from mouse stem cells and expounds upon their scope with novel protocols to generate hippocampal neurons from human induced pluripotent stem cells. First, a novel platform for optogenetic stimulation was built and tested on mouse embryonic stem cells to demonstrate functionality of optogenetic channels in mouse embryonic stem cell-derived neurons. The device was built from 3D printed materials and validated with oscilloscopy and spectrophotometry while neurons were cultured for over 30 days in vitro and assayed first for electrical activity by electrophysiology, calcium signaling, and small molecule activation of glutamatergic receptors. When verified that both device and neurons were functional, cells were transduced with a ChannelRhodopsin variant, ChR2-eYFP-NpHR, and were stimulated over several light cycle parameters and assayed for CFOS expression. Having shown that neurons responded in an activity-dependent manner to the device, I established preliminary studies into human hippocampal embryonic neurogenesis. I derived a novel protocol to differentiate hiPSCs to hippocampal neural progenitors using small molecules and specific laminar substrates unique to the subgranular zone. Hippocampal progenitors were assayed for literature-established genetic markers including WNT7b, WNT8a, PROX1, FOXG1, and ZBTB20, and then allowed to spontaneously differentiate into neurons expressing canonical neural, synaptic, glutamatergic, and constitutive hippocampal markers. These cells were expanded over 200 days in vitro. When allowed to spontaneously differentiate or forced to differentiate under NOTCH inhibition, neuronal cultures sustained ZBTB20 and FOXG1 coexpression over the terminal differentiation path though cultures at ~200 days old did not differentiate at the same rate as cultures from ~30 days. When transplanted in vivo, human hippocampal progenitors differentiated fully after 4 months, projected toward the CA3 from the dentate gyrus, and established synaptic connections with host neurons identified by staining synaptic markers. In conclusion, several novel findings are demonstrated throughout this thesis, though the most pertinent include: 1.) mESC-derived neurons may be optogenetically stimulated by ergonomic device fabrication. 2.) Sustained or adult neurogenesis is dependent on the laminin isoform expressed in the subgranular zone. 3.) Hippocampal progenitors from human induced pluripotent stem cells behave like neurons and can be optogenetically targeted and are transplantable in vivo hippocampus in which they integrate into pre-existing hippocampal networks. Future investigations include merging activity-dependent Tau phosphorylation in mESC- and hiPSC-derived human hippocampal neurons and transplantation of human hippocampa

Optogenetic Brain Interfaces

The brain is a large network of interconnected neurons where each cell functions as a nonlinear processing element. Unraveling the mysteries of information processing in the complex networks of the brain requires versatile neurostimulation and imaging techniques. Optogenetics is a new stimulation method which allows the activity of neurons to be modulated by light. For this purpose, the cell-types of interest are genetically targeted to produce light-sensitive proteins. Once these proteins are expressed, neural activity can be controlled by exposing the cells to light of appropriate wavelengths. Optogenetics provides a unique combination of features, including multimodal control over neural function and genetic targeting of specific cell-types. Together, these versatile features combine to a powerful experimental approach, suitable for the study of the circuitry of psychiatric and neurological disorders. The advent of optogenetics was followed by extensive research aimed to produce new lines of light-sensitive proteins and to develop new technologies: for example, to control the distribution of light inside the brain tissue or to combine optogenetics with other modalities including electrophysiology, electrocorticography, nonlinear microscopy, and functional magnetic resonance imaging. In this paper, the authors review some of the recent advances in the field of optogenetics and related technologies and provide their vision for the future of the field.United States. Defense Advanced Research Projects Agency (Space and Naval Warfare Systems Center, Pacific Grant/Contract No. N66001-12-C-4025)University of Wisconsin--Madison (Research growth initiative; grant 101X254)University of Wisconsin--Madison (Research growth initiative; grant 101X172)University of Wisconsin--Madison (Research growth initiative; grant 101X213)National Science Foundation (U.S.) (MRSEC DMR-0819762)National Science Foundation (U.S.) (NSF CAREER CBET-1253890)National Institutes of Health (U.S.) (NIH/NIBIB R00 Award (4R00EB008738)National Institutes of Health (U.S.) (NIH Director’s New Innovator award (1-DP2-OD002989))Okawa Foundation (Research Grant Award)National Institutes of Health (U.S.) (NIH Director’s New Innovator Award (1DP2OD007265))National Science Foundation (U.S.) (NSF CAREER Award (1056008)Alfred P. Sloan Foundation (Fellowship)Human Frontier Science Program (Strasbourg, France) (Grant No. 1351/12)Israeli Centers of Research Excellence (I-CORE grant, program 51/11)MINERVA Foundation (Germany