Research Projects

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.

Abstract In response to the

PROJECT SUMMARY/ABSTRACT: Hypoxic-Ischemic brain Injury (HII) is a severe injury caused by oxygen deprivation to the brain at or near time of birth in preterm and/or low birth weight newborns. It is very important to recognize HII as soon as possible because early intervention improves outcomes. HII is one of the most common causes of mortality and morbidity in preterm neonates with an occurrence of ~60%. Preterm neonates experiencing HII are at risk for developing hypoxic-ischemic encephalopathy, cerebral palsy, periventricular leukomalacia, and hydrocephalus.

PROJECT SUMMARY Methods that improve upon the temporal resolution of current fMRI techniques are urgently needed to better understand the temporal characteristics of healthy brain function and to better identify the drivers of brain dysfunction. Our current functional Magnetic Resonance Elastography (fMRE) data shows that functionally activated regions of the brain undergo a change in their mechanical stiffness. These mechanical changes are observed at frequencies as high as 10Hz, which is two orders of magnitude faster than traditional fMRI.

SUMMARY The goal of this proposal is to develop technology that is both novel and disruptive in order to achieve anatomical quality, dynamic B0 corrected, whole brain, microscale (≤ 500 µm isotropic) fMRI. Our Brain Initiative work thus far has demonstrated that, with the significant SNR gains of MR Corticography and SLIDER technologies, ultra-high 500 µm resolution fMRI is feasible at 7T. However, significant barriers remain that make microscale imaging of the whole brain extremely challenging, if not impossible.

 DESCRIPTION (provided by applicant): Functional magnetic resonance imaging (fMRI) has become one of the leading research tools to study brain function and is playing a pivotal role in several large-scale brain mapping projects worldwide. Despite ongoing technical advancements in MRI which have greatly increased its availability and helped improve the resolution for functional brain mapping, we still have very limited understanding of what fMRI signals really represent.

 DESCRIPTION (provided by applicant): Functional magnetic resonance imaging (fMRI) has become one of the leading research tools to study brain function and is playing a pivotal role in several large-scale brain mapping projects worldwide. Despite ongoing technical advancements in MRI which have greatly increased its availability and helped improve the resolution for functional brain mapping, we still have very limited understanding of what fMRI signals really represent.

This revised proposal is in response to PAR-15-090 "BRAIN Initiative: Development, Optimization, and Validation of Novel Tools and Technologies for Neuroscience Research".