Research Projects

Experimental models of the human developing brain are needed to investigate human-specific aspects of brain development, evolution, and neurological disease. Progress in the field has been hampered by the lack of models, considering that the endogenous developing human brain cannot be directly investigated; animal models often fail to recapitulate human disorders and cannot feasibly be used to study complex polygenic states spanning many genes.

The human induced pluripotent stem cell (hiPSC) technology promises major advances in disease modeling and personalized medicine. Using hiPSCs, organoid systems have been generated in recent years that resemble the identity of several brain regions, including cortex, basal ganglia, cerebellum and spinal cord. Major shortfalls of these models are the lack of a reproducible topography of the cell types and tissue architecture that are generated, and the failure to recapitulate the full range of cellular and molecular diversity that characterizes in vivo systems.

SUMMARY The modular organization of the cerebral cortex is defined by anatomically and functionally segregated cortical columns, as well as layer-specific anatomical and functional connections that span multiple columns. Dysregulation of the developmental processes governing cortical formation can result in dysmorphic features that have been implicated in numerous neurological and psychiatric disorders.

Abstract Transcranial alternating current stimulation (TACS) non-invasively alters neuroelectric activity in the human brain by applying weak, time-varying electric currents to the scalp. It is increasingly being explored as a therapeutic intervention for various brain disorders by affecting pathological oscillatory neural activity. Despite its increasing popularity and rapidly growing literature, the basic physiological mechanisms of TACS are still not well understood.

Project Summary/Abstract We will develop a novel technology for noninvasive transcranial magnetic stimulation (TMS) of the human brain. TMS is a standard tool in experimental brain science and is FDA cleared for treatment of depression, obsessive- compulsive disorder, and migraine as well as pre-surgical brain mapping. However, the underlying high-power electromagnetic pulse technology has substantial limitations. First, the temporal waveform of conventional TMS pulses is exclusively sinusoidal with fixed shape and duration.

Project Summary/Abstract Over the past decade, serial-section electron microscopy has come into its own as a method to study the connectivity of neural circuits, from local circuits in mammals to entire invertebrate brains. Recently, the emphasis in the field has been to create increasingly large data sets, while comparatively little effort has been spent on making the tools of EM connectomics available to a large number of circuit neuroscientists. Obstacles exist at multiple levels.

SUMMARY Electrical synapses, also known as gap junctions, occur frequently in all nervous systems, including the human brain. They are composed of connexins, arranged to form intercellular channels between adjacent, coupled cells. Connexin36 (Cx36) is the predominant connexin in the CNS. In many brain and retinal circuits, gap junctions provide direct and specific connections between cells. In addition, electrical synapses mediate network properties such as signal averaging, noise reduction and synchronization.

Abstract The ability to noninvasively modulate and image the brain with spatial and temporal precision is highly desirable for understanding brain circuits in health and disease. Transcranial magnetic stimulation (TMS) is a method for stimulating the superficial cortex with high spatial and temporal precision, and its effects can be aimed at deeper targets by leveraging the trans-synaptic connectivity of brain circuits. Functional magnetic resonance imaging (fMRI) has high spatial resolution but limited temporal precision, and the opposite holds for electroencephalography (EEG).

Project Summary / Abstract A fundamental goal in neuroscience is understanding how neural network function arises from circuit structure. However, the immense complexity of most brain networks has been a significant barrier to progress. We do not have a comprehensive wiring diagram for any mammalian local circuit, much less a whole brain. We do not yet have a comprehensive list of cell types and how they are defined for even the simplest mammalian neuronal circuit.

Project Summary The human retina is one of the most complex microcircuits of the central nervous system (CNS) and is a model of CNS neurodegenerative disease with unique advantages for microconnectomics technology advancement. The central retina or fovea mediates high acuity vision, drives activity in half of the brain, and is a critical locus for prevalent blinding disease. The fovea is small (