BRAIN Initiative Models of the Developing Human Nervous System

Presenter:

David Panchision, Ph.D.
Division of Neuroscience and Basic Behavioral Science

Goal:

The goal of this BRAIN Initiative is to stimulate basic research to develop next-generation human cell-derived assays, including those involving human induced pluripotent stem cells (hiPSCs), with improved fidelity to complex human brain, spinal cord, and/or sensory end organ circuit physiology, particularly with respect to developmental trajectories.

Rationale:

While the BRAIN Initiative is making significant investments in generating both non-invasive and invasive approaches to monitoring and modulating human brain function, there remain significant practical and ethical limitations to the involvement of human subjects in basic research. Among these are challenges in performing experimental manipulations (e.g., gene editing), linking measures across levels of analysis (e.g., genomic to cellular to circuit), and establishing mechanism (e.g., necessity and sufficiency), especially in the context of key developmental processes.

Basic research is needed to develop next-generation human cell-derived assays with improved fidelity. These models would have a multi-lineage, complex architecture representing the normal characteristics and functions of the relevant nervous system structure (e.g., sensory input systems, brain or spinal integrative systems, motor output systems) and would substantially exceed the state of the art in cellular maturation and integration, allowing reproducible measurement of human-relevant circuit-level activity under physiological conditions over a long period.  Optimizing these models could potentially address critical basic science analytic challenges in studying the human brain and facilitate analysis of brain diseases by a mechanistic linkage of complex genetic contributions to higher order function.

Example approaches could include, but are not limited to:

• Utilization of novel materials, substrates or synthesis technologies (e.g., 3D printing, bioreactors, microfluidic platforms) to promote anatomically and physiologically relevant tissue organization and/or maturation.
• Integration of defined cell types consistent with relevant nervous system anatomy (e.g., excitatory, inhibitory and modulatory neurons, astrocytes, oligodendrocytes, microglia, pericytes, endothelial cells) into functional units (assembloids) that may include multipartite synapses, vascularization-perfusion, blood-brain barrier, glymphatic system and/or cerebrospinal fluid flow.
• Novel strategies to reproduce relevant regional cellular organization (e.g., dorsoventral, rostrocaudal, laminar, columnar or nuclei structure), with both short- and long-range anatomical connectivity (e.g., local inhibitory-excitatory and/or modulatory connections, projections to distant lamina or nuclei).
• Development of human cell-based assays with complex functional features potentially relevant to complex nervous system disorders and diseases (e.g., intrinsic and/or dynamical network properties of cell assemblies such as neural oscillatory activity, activity-dependent plasticity).
• Inclusion of conditional or intersectional strategies that allow temporally and/or spatially cell-selective monitoring or manipulation of gene expression/function or of live cell activity and function.
• Evaluation of how data obtained from the proposed assay compares with human anatomical, histological or systems-level data, or data from other physiologically relevant paradigms, to facilitate assay validation. Investigators would be encouraged to explore data and tools being developed under the NIH BRAIN Initiative, BrainSpan, PsychENCODE Human Brain Development Atlas, Human Connectome Project, AMP-AD, or related efforts which if utilized could further the authentication of human brain cell-derived assays.