Grant: Discovery Grants Program - Individual

In the past grant period, our laboratory has contributed to original studies that elucidated a role of the medial septum and hippocampus in schizophrenia-like behaviors and in loss of righting reflex induced by general anesthesia. Schizophrenia and general anesthesia are accompanied, respectively, by high and low amplitudes of a hippocampal electrical activity called the gamma (30-100 Hz) waves. A class of drugs called N-methyl-D-aspartate receptor (NMDAR) antagonist induced schizophrenia-like behaviours and high hippocampal gamma activity, while general anaesthesia suppressed hippocampal gamma activity. We hypothesize that manipulations that selectively increase (or decrease) hippocampal gamma activity will increase (or decrease) schizophrenia-like symptoms induced by an NMDAR antagonist. Similarly, increase (or decrease) hippocampal gamma activity will decrease (or increase) behavioral sensitivity to general anesthesia. Hippocampal gamma activity will be decreased or increased by local application of inhibitory gamma-aminobutyric acid B receptor (GABABR) agonist or antagonist, respectively. Depletion of acetylcholine in the hippocampus is also hypothesized to decrease hippocampal gamma waves and enhance the anesthesia effect of isoflurane, a volatile general anesthetic. The brain networks that correlate with general anesthesia will be studied by estimating the connectivity between brain regions using magnetic signals measured during functional magnetic resonance imaging. The limbic network that mediates general anesthesia, which is expected to include the hippocampus and related structures, will be revealed by comparing functional connectivity, electrical activity and behavioral responses at different concentrations of isoflurane. The proposal will be a comprehensive study of different behaviors mediated by the hippocampus and its gamma activity, and it will elucidate the brain network through which the hippocampus and limbic system mediate general anesthesia.