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.
PROJECT SUMMARY While numerous transgenic tools and approaches exist to enable manipulation of gene expression in many cell types in the healthy brain, tools designed to target and study cells present only in the dis- eased or damaged brain are lacking. Common to virtually all neurodegenerative diseases, brain injuries and infections is a neuroinflammatory and immune response characterized by changes in astrocytes, which become “reactive”. Astrocytes ordinarily provide critical support for neurons and only turn into reactive astrocytes (RAs) in brain disease and inflammation.
ABSTRACT The mammalian brain is composed of 50% neurons and 50% non-neuronal glial cells, including astrocytes (20%) which regulate synaptic transmission and provide metabolic support for neurons, oligodendrocytes (25%) that speed up neuronal action potential conduction, and microglia (5-15%) which are tissue-resident macrophages with important roles in homeostasis and protection from infection. The ability to genetically target subsets of glial cells within a circuit, e.g. astrocytes in a given layer of the cortex, or astrocytes in the cortex and not in the thalamus, is lacking.
Astrocytes are a major class of non-neuronal cells in the brain whose crosstalk with neurons at the synaptic and circuit levels remains poorly understood. While in vivo two-photon microscopy has revealed spatiotemporally diverse astrocytic signatures of intracellular Ca2+ transients, the scarcity of tools that manipulate the genetic makeup and physiological activity of astrocytes with spatial and temporal precision in vivo has restricted investigation of their physiological impact on neurons to predominantly correlational studies.
PROJECT SUMMARY/ABSTRACT Neuropsychiatric disorders represent a leading cause of disability, affecting nearly 19% of the US population. Only 9% of neuropsychiatric drugs entering clinical trials reach the market, which is one of the lowest success rates across all therapeutic areas. Fundamental differences between the neurobiology of rodents and humans have been proposed to account for translational failures in development of effective therapeutic strategies to mitigate neurological or neurodegenerative diseases or disorders.
PROJECT SUMMARY While mice are essential models for many areas of neuroscience, there are also many aspects of higher brain function and dysfunction that cannot be adequately modeled in rodents. Thus, there is a need for new genetic models that have brain structure and function closer to humans. For these reasons, non-human primates (NHP) provide an attractive model to study higher brain function and brain disorders. A promising emerging NHP model is the common marmoset, a small New World primate that has many advantages as a genetic model.
ABSTRACT The common marmoset provides a very relevant primate model for understanding the organization of the human nervous system and the diseases that affect it. Like humans, marmosets also demonstrate cooperative social behavior and have advanced cognitive processes, making them of great interest in the field for modeling developmental and psychiatric diseases and their therapies. They are also ideal for multigenerational genetic experiments as they give birth twice a year and mature faster than most primates.
