Effects of Cannabinoids and Novelty on Hippocampal Electrophysiology

Exposure to novel environments alters hippocampal cell and theta local field potential activity to support the formation of new or updated spatial representations. It induces remapping of place cell fields, a reduction in CA1 theta frequency and an increase in the spatial scale of entorhinal grid cell fields. A recent model proposes that a reduction in the slope of the theta frequency-running speed relationship (TFRSR) can account for these effects (Burgess, 2008, Hippocampus). In contrast, the model proposes that the Y-axis intercept of the TFRSR is unaffected by novelty but instead correlates with anxiety/arousal. Thus, the theta frequency reduction elicited by a wide range of anxiolytic drugs (Gray & McNaughton, 2000) is suggested to result from a decrease in the intercept. Cannabinoids are anxiolytic at low doses, reduce theta frequency and disrupt the theta-timescale dynamics of place cell firing. In contrast, environmental novelty elicits a coordinated shift in CA1 place cell firing to a later theta-phase. This thesis examines the electrophysiological effects of environmental familiarity or novelty in combination with a low, intraperitoneal dose of the cannabinoid agonist O-2545, or its vehicle, saline. It was found that exposure to novel environments reduced the slope of the TFRSR whereas the cannabinoid reduced the intercept, in agreement with the model. These effects were not due to decreased body temperature or changes in behaviour. Combining novelty and drug reduced both slope and intercept. Furthermore, the extent of novelty-induced place cell remapping correlated with the reduction in slope. The mean theta-phase of place cell firing shifted later in novelty, but this was disrupted by the cannabinoid. In contrast, the mean theta-phase of the interneuron population was stable across conditions, but novelty increased the dispersion of interneuron theta-phase preferences. These results help to elucidate the mechanisms underlying novelty processing and cannabinoid action in the hippocampus.