Rafael Yuste, MD, PhD

Cortical Circuits and Dendritic Spines

The goal of our laboratory is to understand the function of the cortical microcircuit. The cortex constitutes the larger part of the brain in mammals. In humans it is the primary site of mental functions like perception, memory, control of voluntary movements, imagination, language and music. No accepted unitary theory of cortical function exists yet; nevertheless, the basic cortical microcircuitry develops in stereotyped fashion, is similar in different cortical areas and in different species, and has apparently not changed much in evolution since its appearance. At the same time, the cortex participates in apparently widely different computational tasks, resembling a "Turing machine". Because of this, it is conceivable that a "canonical" cortical microcircuit may exist and implement a relatively simple, and flexible, computation.

We attempt to reverse-engineer the cortical microcircuit using brain slices from mouse neocortex as our experimental preparation. The techniques applied are electrophysiology, anatomy, and a variety of optical methods, including infrared-DIC, voltage- and ion-sensitive dye imaging with confocal, two-photon and second harmonic microscopy. We also use laser uncaging, biolistics, electroporation, electron microscopy and numerical simulations, and make extensive use of genetically modified mouse strains.

We focus on two major questions:

1. What is the function of dendritic spines?Spines are an essential element in cortical circuits and are still poorly understood. Two-photon microscopy has enabled functional studies of dendritic spines and has shown that they compartmentalize calcium because of their morphological features and local calcium influx and efflux mechanisms. Recent data indicates that spines can serve as electrical compartments and that can linearize input summation, indicating that cortical circuits could be essentially linear networks. Also, spines exhibit rapid morphological plasticity, raising the possibility that the function of the spine, or the synapse, is equally dynamic.
2. What are the multicellular patterns of activity under spontaneous or evoked activation of the circuit? It is still unknown if adult cortical neurons respond individually, or if there are multicellular units of activation that may represent a functional state of the circuit, such as an attractor. Optical imaging of populations of cells make it possible to visualize circuit dynamics, deduce its potential circuit architecture and explore if canonical microcircuits exist. We are also interested in understanding how epileptic seizures can recruit apparently normal cortical circuits.