Over the past decade, high frequency oscillations (HFO, 130‑180 Hz) recorded in field potentials have been shown to be robustly potentiated by ketamine adminis‑ tration. This rhythm has been recorded in functionally and neuroanatomically diverse cortical and subcortical regions, most notably in the ventral striatum. Howev‑ er, the precise locus of generation remains largely un‑ known. There is compelling evidence that olfactory regions can drive oscillations in distant areas. Here, we tested the hypothesis that the olfactory bulb (OB) exerts a top‑down role in the generation of ketamine‑HFO. We examined the effect of ketamine on electrophysiologi‑ cal activity of the OB and ventral striatum in vivo. Field potential recordings, local inhibition, naris blockade, current source density and unit recordings were used. Ketamine‑HFO in the OB was larger and preceded HFO recorded in the ventral striatum. Granger causality anal‑ ysis was consistent with directional flow from the OB. Unilateral local inhibition of the OB, and naris blockade, attenuated HFO recorded locally and in the ventral stri‑ atum. Within the OB, current source density analysis revealed HFO current dipoles close to the mitral layer and unit firing of mitral/tufted cells was phase locked to HFO. Our results demonstrate a hierarchical top‑down relationship between ketamine‑HFO in the OB and the ventral striatum. The OB plays a primary role in the gen‑ eration of ketamine‑HFO and orchestrates this activity in a distant region. These findings provide a new con‑ ceptual understanding on how ketamine influences fun‑ damental brain activity which may have implications for schizophrenia.
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