It was recently proposed that fast gamma oscillations (60-150 Hz) convey spatial information from the medial entorhinal cortex (EC) to the CA1 region of the hippocampus. However, here we describe 2 functionally distinct oscillations within this frequency range, both coupled to the theta rhythm during active exploration and rapid eye movement sleep: an oscillation with peak activity at ∼80 Hz and a faster oscillation centered at ∼140 Hz. The 2 oscillations are differentially modulated by the phase of theta depending on the CA1 layer; theta-80 Hz coupling is strongest at stratum lacunosum-moleculare, while theta-140 Hz coupling is strongest at stratum oriens-alveus. This laminar profile suggests that the ∼80 Hz oscillation originates from EC inputs to deeper CA1 layers, while the ∼140 Hz oscillation reflects CA1 activity in superficial layers. We further show that the ∼140 Hz oscillation differs from sharp wave-associated ripple oscillations in several key characteristics. Our results demonstrate the existence of novel theta-associated high-frequency oscillations and suggest a redefinition of fast gamma oscillations.
Phase-amplitude coupling between theta and multiple gamma sub-bands is a hallmark of hippocampal activity and believed to take part in information routing. More recently, theta and gamma oscillations were also reported to exhibit phase-phase coupling, or n:m phase-locking, suggesting an important mechanism of neuronal coding that has long received theoretical support. However, by analyzing simulated and actual LFPs, here we question the existence of theta-gamma phase-phase coupling in the rat hippocampus. We show that the quasi-linear phase shifts introduced by filtering lead to spurious coupling levels in both white noise and hippocampal LFPs, which highly depend on epoch length, and that significant coupling may be falsely detected when employing improper surrogate methods. We also show that waveform asymmetry and frequency harmonics may generate artifactual n:m phase-locking. Studies investigating phase-phase coupling should rely on appropriate statistical controls and be aware of confounding factors; otherwise, they could easily fall into analysis pitfalls.DOI: http://dx.doi.org/10.7554/eLife.20515.001
Recent studies show that higher order oscillatory interactions such as cross-frequency coupling are important for brain functions that are impaired in schizophrenia, including perception, attention and memory. Here we investigated the dynamics of oscillatory coupling in the hippocampus of awake rats upon NMDA receptor blockade by ketamine, a pharmacological model of schizophrenia. Ketamine (25, 50 and 75 mg/kg i.p.) increased gamma and high-frequency oscillations (HFO) in all depths of the CA1-dentate axis, while theta power changes depended on anatomical location and were independent of a transient increase of delta oscillations. Phase coherence of gamma and HFO increased across hippocampal layers. Phase-amplitude coupling between theta and fast oscillations was markedly altered in a dose-dependent manner: ketamine increased hippocampal theta-HFO coupling at all doses, while theta-gamma coupling increased at the lowest dose and was disrupted at the highest dose. Our results demonstrate that ketamine alters network interactions that underlie cognitively relevant theta-gamma coupling.
Recent reports converge to the idea that high-frequency oscillations in local field potentials (LFPs) represent multiunit activity. In particular, the amplitude of LFP activity above 100 Hz-commonly referred to as "high-gamma" or "epsilon" band-was found to correlate with firing rate. However, other studies suggest the existence of true LFP oscillations at this frequency range that are different from the well established ripple oscillations. Using multisite recordings of the hippocampus of freely moving rats, we show here that high-frequency LFP oscillations can represent either the spectral leakage of spiking activity or a genuine rhythm, depending on recording location. Both spike-leaked, spurious activity and true fast oscillations couple to theta phase; however, the two phenomena can be clearly distinguished by other key features, such as preferred coupling phase and spectral signatures. Our results argue against the idea that all high-frequency LFP activity stems from spike contamination and suggest avoiding defining brain rhythms solely based on frequency range. IntroductionOver the last 5 years, a growing consensus has emerged that highfrequency activity (Ͼ100 Hz) in local field potentials (LFPs) essentially reflects spiking activity (Ray et al., 2008b;Ray et al., 2008c;Jia and Kohn, 2011; Ray and Maunsell, 2011;Belluscio et al., 2012; Buzsáki and Wang, 2012; see also Manning et al., 2009). This upper part of the LFP spectrum has been called "high-gamma" (Canolty et al., 2006;Ray et al., 2008a;Ray and Maunsell, 2011) or "epsilon" band (Freeman, 2007;Belluscio et al., 2012). Some researchers have stressed the broadband nature of the power changes associated with spiking activity (Manning et al., 2009) and advocated avoiding the term "oscillations" when referring to these phenomena (Jacobs et al., 2010). The evidence that high-frequency LFP activity stems from extracellular spikes is several fold: (1) the power of broadband high-gamma activity correlates well with firing rate (Ray et al., 2008c; Ray and Maunsell, 2011); (2) local increases of high-frequency LFP activity are restricted to cortical regions expected to present increased spiking activity (Miller et al., 2009;Miller, 2010); (3) The notion that the upper LFP spectrum may reflect multiunit activity implies that examining broadband changes in LFP power could be a proxy for tracking neuronal activity (Manning et al., 2009; Buzsáki and Wang, 2012;; this is particularly good news to those interested in brain-machine interfaces (Crone et al., 2006;Miller et al., 2009). The purpose of the present work, however, is to challenge the emerging view of highfrequency LFP activity as essentially denoting spiking activity. Recent work of ours has provided evidence for genuine LFP oscillations above 100 Hz in the hippocampus and neocortex of rodents (Tort et al., 2008; Scheffzük et al., 2011; Scheffer-Teixeira et al., 2012), which we refer to as high-frequency oscillations (HFO). We have previously shown that HFOs differ from sharp wave-associated ripple osc...
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