Research Projects

Project Summary This RFA is aimed at bringing together interdisciplinary teams to focus on novel, transformative and integrative efforts that will revolutionize our understanding of the biological and bioinformatics content of the data collected from non-invasive human functional brain imaging techniques. Our proposal does exactly this. We are a multidisciplinary team of scientists with combined expertise in optogenetics, two photon Ca2+ imaging, biomedical engineering, molecular biology, animal and human fMRI, network theory, data analysis and modeling.

Neuronal Substrates of Hemodynamic Signals in the Prefrontal Cortex    PIs: Dr. John P. O'Doherty and Dr. Doris Tsao  Institution: California Institute of Technology PROJECT SUMMARY fMRI is the dominant technique for probing human prefrontal cortex functions in cognition, learning and decision-making. This work is predicated on the assumption that fMRI activation relates in a principled manner to the underlying neuronal activity in a given area of prefrontal cortex.

PROJECT SUMMARY Blood-oxygenation-level-dependent functional magnetic resonance imaging (BOLD fMRI) is widely used in to study human brain function; however the cellular and molecular mechanisms underlying the BOLD signal remain poorly understood. The BOLD signal is highly complex as it represents disproportionate interactions of cerebral blood flow (CBF), cerebral blood volume (CBV), and cerebral metabolic rate of oxygen (CMRO2) during neuronal activation.

Principal Investigators(Last, first, middle):KLEINFELD, DAVID and ROSEN, BRUCE R. Functional magnetic resonant imaging (fMRI) is the only means to infer neuronal activity within the entire volume of the human brain. A powerful aspect of fMRI concerns coordinated fluctuations in the amplitude of blood oxygen level dependent (BOLD) signals across distant regions of the brain, which are interpreted as "resting-state functional connections". Here we address the underlying biophysical mechanism that underlies resting-state functional connectivity.

Intrinsic ‘functional connectivity’ (iFC), a measure of correlation between spontaneous fluctuations in the blood oxygen level dependent (BOLD) signal, reliably distinguish networks of cortical and subcortical areas during both rest and active task performance. iFC methods can map the functional architecture of the human brain in both healthy and pathological conditions, in high detail using as little as 5 minutes of data.

PROJECT SUMMARY Functional MRI (fMRI) is performed at a macroscopic scale of 1 to 3 millimeters spatial resolution. The term `mesoscale' has come to denote the resolution of a finer granularity of neuronal organization, to show functional organization across the depth and along the surface of the cortex. Mesoscale fMRI representation of neural activity, however, is not firmly established. A primary objective of this research is to evaluate fMRI's ability to accurately differentiate neuronal activity in cortical layers and columns.

Project Summary/Abstract Synaptic plasticity is thought to be a basis of learning and memory of the brain. Signaling mechanisms underlying synaptic and behavioral plasticity have been extensively studied with the aid of pharmacological and genetic manipulation of signaling. However, it has been difficult to assess the spatiotemporal aspects of signaling activity particularly.

Project Summary Neuropeptides are essential neuromodulators in the brain. They are released into the extrasynaptic space, where they diffuse over long distances and signal through G protein coupled neuropeptide receptors. Neuropeptides control cognition, sensorimotor processing, and energetics through changes in vascular tone and blood flow in the nervous system. Pharmacological and molecular genetic studies have implicated alterations in neuropeptide signaling as a contributor to brain dysfunctions, including migraines, addiction, motivation and stress.

Project Summary/Abstract The mammalian brain is a highly diverse structure in which large numbers of cell types, grouped into broad functional areas, serve defined functions according to their developmental origin, shape and connectivity, transcriptional program and intrinsic biophysical properties. A mechanistic understanding of how the brain works, and how dysfunctions lead to neurological disorders, will require a systematic characterization of neural cell types.

PROJECT SUMMARY We will use high throughput techniques to produce a set of viral vectors that will allow selective expression of transgenes in specific populations of neurons in the brain. Along with many other applications, this will allow optogenetic control, recording, and genomic modification of targeted neuronal populations without the need for production of transgenic or knock-out lines.