Research Projects

Project Summary/Abstract The long-term goal of these investigations is to develop methods based on high- throughput DNA sequencing for determining neuronal circuitry. Neurons transmit information to distant brain regions via long-range axonal projections. In some cases, functionally distinct populations of neurons are intermingled within a small region. Disruptions of connectivity may underlie many neuropsychiatric disorders including autism and schizophrenia. At present, neuroanatomical techniques—particularly those with single neuron resolution—are expensive and labor intensive.

7. PROJECT SUMMARY Background. Electro- and magneto-encephalographic (EEG/MEG) responses to a stimulus are systematically attenuated– by up to 80%– if the same stimulus was presented less than 8-12 seconds ago. This dynamic modulation of response amplitude to identical stimuli is one of the most striking and fundamental properties of the EEG/MEG signal.

Project Summary The primary goal of this application is to elucidate the neural basis of resting-state functional magnetic resonance imaging (rsfMRI) signal using multi-modal approaches including multi-echo (ME)- rsfMRI, MR-compatible calcium signal recording, optogenetics and multi-laminar electrophysiology in awake rats. Despite the prominent role of rsfMRI in studying brain network function in health and disease, the neural basis of rsfMRI signal remains poorly understood.

Project Summary / Abstract: The blood oxygenation level dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) signal source has been long debated since the invention of fMRI in the early 90s. While fMRI is one of the most successful technologies utilized in numerous studies, the debate over the source of fMRI signal source continue to generate controversies over the utility of fMRI and the interpretation of fMRI studies.

Abstract Resting state functional magnetic resonance imaging (rs-fMRI) is an important modality for imaging the human brain. Capturing fluctuations in the blood oxygen level dependent (BOLD) signal while the brain is `at rest', rs- fMRI can detect distant, and often bilaterally-symmetric regions where activity is synchronized. Such regions are inferred to have `functional connectivity', and patterns of these networks have been found to be altered in a wide range of otherwise indistinguishable disease states.

The six layers of cortex form distinct computational units that together govern the information flow and processing required for complex behavior. Hence, unravelling the brain's computational strategies requires understanding the layer-specific organization of the neocortex. Until recently, layer-resolved recordings have been confined to animal models, ignoring specific properties of the human brain and limiting our ability to study uniquely human functions such as language.

Although considerable information about neuronal circuits has been generated from experiments where retrograde transsynaptic tracing has been performed using Rabies Virus, there is no comparable technique for transsynaptic tracing in the anterograde direction. The purpose of this grant is to optimize and validate a method for mediating anterograde transsynaptic tracing from genetically or physiologically determined cells. This method is monosynaptic, only marks cells that are postsynaptic to the starter cells and has negligible toxicity.

Abstract While functional magnetic resonance (fMRI) has proved invaluable for identifying where in the brain activation is occurring during a particular task, it has had less to say about how the dynamics of that activation actually contribute to task performance. Indeed, because of the belief that fMRI signals are sluggish and temporally imprecise, fMRI experimental paradigms traditionally have used sustained block designs which deliberately preclude measuring the rapid changes in sensory and motor signals that underlie everyday actions.

PROJECT SUMMARY Measures of functional magnetic resonance imaging (fMRI) functional connectivity – correlated blood oxygen level dependent (BOLD) responses – are fundamental to understanding the circuit-level mechanisms of brain function and dysfunction. The use of fMRI functional connectivity for understanding long-range dynamic interaction between areas is limited, however, because the physiological basis of this measure is unknown. This is because our knowledge is limited to correlative relationships between neural activity and BOLD functional connectivity.

Project Summary Brain-wide correlation of single-cell firing properties to patterns of gene expression Every neuron expresses thousands of proteins which, through their interactions with each other and with other small molecules, imbue the neuron with its functional properties. The primary function of each neuron is to receive synaptic inputs, to produce electrical spikes, and to release neurotransmitters to its downstream neighbors. Neurons show widely varying patterns of gene expression, and also show widely varying patterns of electrical spiking.