| Despite progress in space traveling and quantum physics, we still do not understand how the brain works. We do not know whether the number of impulses in a brain cell, or rather a temporal relation between them, is used to represent and process incoming stimuli and motor commands. Evidence is accumulating in favor of both mechanisms. Synchronous and oscillatory electrical activity seems to be widely used by the brain in feature binding, visual attention, spatial navigation, and memory. These mechanisms are disturbed in psychiatric disorders such a schizophrenia. In order to advance research, we need a tool such as computational neuroscience to integrate neurophysiological data and to investigate the mechanisms behind the generation of oscillations, as well as their functional role in the brain, and to generate verifiable predictions. In this dissertation I am presenting multiple components of such an approach. I have developed new algorithms for more optimal compartmentalization of neural models. I discovered a possible new mechanism of burst generation in a hippocampal CA3 pyramidal cell model. In a model of a thin dendritic branch, I showed the feasibility of multiple stability states in the membrane potential due to the interaction between N-Methyl-D-aspartic Acid (NMDA) and Gamma-Aminobutyric Acid (GABA) currents. I constructed a small network of neurons capable of time sequence compression from seconds to milliseconds. I developed and applied methods for analyzing electrophysiological in vivo recordings. This led to the discovery that ketamine, an NMDA receptors open channel blocker, changes spontaneous and event related oscillations in the theta (3-12 Hz) and gamma (30-80 Hz) frequency ranges. I built a large, biophysical model of a cortical local circuit, and investigated a possible mechanism underlying the ketamine effects on oscillations. I found that a specific blockage of NMDA receptors by ketamine on a subpopulation of interneurons produced changes in ongoing oscillations similar to those visible in vivo. I was able to reverse these changes by selectively stimulating this subpopulation of neurons. This intervention suggests the possibility of a new therapeutic approach to schizophrenia. |
