PRIMARY UNIFYING HYPOTHESES: The Computational Core is guided by three main unifying hypotheses. These hypotheses are as follows: 1.) a decrease in feedback inhibition due to loss of NMDA receptor activation on interneurons should contribute to greater spread of excitatory associative activity in models of region CA3, 3.) a decrease in perforant path input to hippocampus should prevent the matching mechanism in region CA1 (and subiculum) which normally regulates the nature of representations spreading along feedback connections to the neocortex. These two physiological level hypotheses underlie the third hypothesis: 3.) increased associative spread and decreased including delusions, hallucinations and loosening of associations, as well as certain negative symptoms, such as impaired memory performance. This would result from activity spread causing strengthening of erroneous associations, and lack of effective matching allowing erroneous representations to become consolidated in neocortex due to consolidation mechanisms summarized in a recent review. The process of matching has been analyzed extensively in the Hasselmo laboratory. Detailed modeling in the Computational Core will address hypotheses concerning the specific projects in this grant, linking the cellular, systems and behavioral levels. These include testing how NAAG effects could decrease Sternberg task performance, and D-cycloserine could increase performance (negative symptoms testing in Project VI), testing how NAAG effects could decrease verbal recall (negative symptoms studied in Project V), testing how NAAG and DA effects a perforant path input could underlie positive symptoms of schizophrenia (relating to physiological parameters studied in Projects II and II), testing how loss of GABAergic modulation could increases in place field size and decrease in sensitivity to cue rotation (relating the GABAergic parameters to place cell recording in Project I), and testing how differential sensitivity of interneuron NMDA receptors to NAAG could underlie both positive and negative symptoms (relating to physiological parameters tested in Project III).
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