Research Projects

ABSTRACT The mammalian brain is an enormously complex organ with myriad cell types cohesively working together to carry out a host of intricate tasks, from motor functions, to the storing and execution of consciousness. These cell types broadly fall into neuronal and non-neuronal classifications, the latter of which substantially outnumber the former and provide the support system and maintenance for the electrically active neuronal component.

ABSTRACT Astrocytes are the most abundant glial cells in the human brain. Interactions of astrocytes with synapses via thin perisynaptic astrocytic processes are critical for proper synaptic connectivity and function. Each mouse astrocyte sends out an extensive array of processes that are estimated to contact over 100,000 synapses. The number of astrocytes and the extent of their interactions with synapses have increased throughout evolution, indicating a close link between astrocytes and cognition.

SUMMARY In order to understand how the CNS encodes, modifies, stores and retrieves information it is necessary to explore the diverse cell populations that comprise the CNS. There is an emerging consensus that the CNS cannot be satisfactorily understood solely as a collection of circuits1. One significant missing aspect in our collective strategy to comprehensively understand the CNS is the largely unmet need to understand additional cell types such as astrocytes1. Astrocytes represent around 40% of all CNS cells and are found throughout the brain.

PROJECT SUMMARY The choroid plexus (ChP) is a vital tissue located in each ventricle in the brain. The ChP is composed of two parallel sheets of epithelial cells with an intervening network of primarily non-neural cell types and vasculature. The ChP (1) produces cerebrospinal fluid (CSF) containing growth-promoting factors for the brain, (2) forms a blood-CSF barrier that gates communication between the central nervous system (CNS) and the systemic milieu, (3) provides for immune cell entry into the brain, and (4) offers an enticing framework for enhanced drug delivery.

Project Summary/Abstract: Proper function of precisely wired neural circuits depends on a close physical and functional relationship with an equally complex and overlapping vascular network. Vascular and perivascular cells are heterogeneous both within and across brain regions, and this heterogeneity is thought to underlie the functional specialization that caters to local neuronal circuitry demands.

Project Summary: While traditionally conceived as passive support elements for neuronal networks, non-neuronal brain cells are now appreciated as dynamic integral components of central nervous system (CNS) circuitry. Astrocytes, for example, serve as powerful regulators of neuronal spiking, synaptic plasticity, and brain blood flow. Similarly, microglia not only respond to a wide range of CNS perturbations, but also participate in circuit development and plasticity through the active elimination of synaptic connections.

This application, "Neuro-glio-vascular interactions in vivo probed with optical imaging", will address the broad challenge of the BRAIN Initiative (Innovative Neurotechnologies) and the targeted challenge (tools to target, identify and characterize non-neuronal cells in the brain).

Summary While glial research has advanced in rodent models, significantly less progress has been made in understanding human-specific diversity of glia at a molecular and a functional level, both during development and in adulthood. To this end, our lab has led an active effort for the past several years to develop novel methodologies that isolate glial populations from normal and pathological human brain tissue, capturing more accurately the cells' native niche and molecular imprint and preserving their viability for subsequent functional analyses [1-4].

Summary The mammalian central nervous system supports a multitude of cognitive and behavioral functions through coordinated action of different neural circuits that are composed of diverse sets of differentiated cell types, including both neurons and non-neuronal cells. Glial cells are essential constituents of the brain and play vital roles in the development and function of the neural circuits. Compared to neurons, however, glial cells have been understudied in the past. One significant hurdle is the limited tools and technologies to precisely target and manipulate these cells in vivo.

Project Summary To accomplish their diverse maintenance and protective roles, microglia must be extremely plastic, dynamically sensing and responding to specific local challenges throughout the brain. Recent results have called into question whether state-of-the-art models of microglial biology accurately capture the rich interactive environment encountered by human microglia in the living brain. To understand microglial biology, we need new robust and experimentally feasible technologies to systematically reveal the dynamic nature of these cells.