The effect of ketamine on delta-range coupling between prefrontal cortex and hippocampus supported by respiratory rhythmic input from the olfactory bulb.

Respiratory rhythm plays an important role in cognitive functions in rodents, as well as in humans. Respiratory related oscillation (RRO), generated in the olfactory bulb (OB), is an extrinsic rhythm imposed on brain networks. In rats, RRO can couple with intrinsic brain oscillations at theta frequency during sniffing and in the delta range outside of such episodes. Disruption of gamma synchronization in cortical networks by ketamine is well established whereas its effects on slow rhythms are poorly understood. We found in this study, that RRO in prefrontal cortex (PFC) and hippocampus (HC) remains present after ketamine injection, even on the background of highly unstable respiratory rate, co-incident with "psychotic-like" behavior and abnormal cortical gamma activity. Guided by the timing of ketamine-induced gamma reaction, pairwise coherences between structures exhibiting RRO and their correlation structure was statistically tested in 5-min segments post-injection (0-25 min) and during recovery (1, 5, 10 h). As in control, RRO in the OB was firmly followed by cortical-bound OB exits directed toward PFC but not to HC. RRO between these structures, however, significantly correlated with OB-HC but not with OB-PFC. The only exception to this general observation was observed during a short transitional period, immediately after injection. Ketamine has a remarkable history in psychiatric research. Modeling chronic NMDA-hypofunction using acute NMDA-receptor blockade shifted the primary focus of schizophrenia research to dysfunctional cortical microcircuitry and the recent discovery of ketamine's antidepressant actions extended investigations to neurophysiology of anxiety and depression. Cortical oscillations are relevant for understanding their pathomechanism.