The cerebral cortex houses our mental functions like perception, cognition and action. Despite major advances in discovering the properties of single cells and molecular-level processes, we still do not know how the cortex works at the circuit level. The essence of the problem lies in understanding how the billions of neurons communicating through trillions of connections orchestrate their activities to give rise to our mental faculties. We are far from being able to simultaneously measure the activity of all the myriads of cortical cells and assemble their physical wiring diagram (connectome). However, if there are underlying principles and rules that govern this complexity, discovering these principles provides an obvious strategy for understanding how the cortex functions. Indeed, it has been hypothesized that the cortex is composed of elementary information processing modules. For almost a century anatomists have observed remarkable regularity in the cortical microarchitecture: strings of cells derived from a common progenitor cell and having a propensity of being synaptically connected are arranged to form small columns orthogonal to the cortical surface. These microcolumns are hypothesized to be the elementary functional units of cortical circuitry. If one were able to understand their organizing principles, the task of understanding how the cortex works would be simplified immensely. Discovering the function of these elementary modules would be analogous to the discovery of the gene, which ultimately led to the molecular revolution of the 20th century. So far, these structures could not be studied in detail due to technical limitations. To understand the function of a microcolumn, it is imperative to simultaneously monitor the activity of all its constituting neurons in vivo. It is our goal to overcome these technical challenges and develop in-vivo methods to study an entire microlumn. We propose to develop in vivo microscopy based on 3D random-access multi-photon (3D-RAMP) excitation. This tour de force microscope will employ a series of acousto-optical deflectors operating at long wavelengths that will generate any desired 3D scanning path at frame rates two orders of magnitude faster than current state-of-the-art two-photon imaging systems. This will allow simultaneous in-vivo recordings of the activity of an entire column of sister cells across all six cortical layers. The microscope will employ two 3D-RAMP scanners that will enable simultaneous recording and photostimulation of neural activity to assemble the functional connectivity diagram of the microcolumn. Viral and genetic methods will be used to identify and label ontogenetic microcolumns in vivo. Through collaboration their connectome will be assembled. We plan to create a database of the Microcolumn Architecture of the Cortex that will include functional, anatomical and ontogenetic information about the organization of microcolumns across cortical areas, species and animal models of diseases. Our proposal promises to unravel the elementary principles of how cortical circuits are organized to give rise to mental function. If we succeed our results will constitute a quantum leap in our quest to understand the brain.
Numerous neurological and psychiatric illnesses such as autism spectrum disorders, stroke and schizophrenia are associated with cerebral cortical malfunction, underscoring the importance of understanding how the cortex works. We aspire to jumpstart a novel mesoscopic approach to research in systems neuroscience that will make it possible to bridge the chasm between macroscopic phenomena like cognition and the microscopic properties of billions of individual cortical neurons. Insights into the circuit level function and malfunction of the cortex promises to be a more principled and scientifically informed strategy to develop drugs and genetic interventions.
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