Adriano B. L. Tort

Dynamic cross-frequency couplings of local field potential oscillations in rat striatum and hippocampus during performance of a T-maze task

Oscillatory rhythms in different frequency ranges mark different behavioral states and are thought to provide distinct temporal windows that coherently bind cooperating neuronal assemblies. However, the rhythms in different bands can also interact with each other, suggesting the possibility of higher-order representations of brain states by such rhythmic activity. To explore this possibility, we analyzed local field potential oscillations recorded simultaneously from the striatum and the hippocampus. As rats performed a task requiring active navigation and decision making, the amplitudes of multiple high-frequency oscillations were dynamically modulated in task-dependent patterns by the phase of cooccurring theta-band oscillations both within and across these structures, particularly during decision-making behavioral epochs. Moreover, the modulation patterns uncovered distinctions among both high- and low-frequency subbands. Cross-frequency coupling of multiple neuronal rhythms could be a general mechanism used by the brain to perform network-level dynamical computations underlying voluntary behavior.

Measuring Phase-Amplitude Coupling Between Neuronal Oscillations of Different Frequencies

Neuronal oscillations of different frequencies can interact in several ways. There has been particular interest in the modulation of the amplitude of high-frequency oscillations by the phase of low-frequency oscillations, since recent evidence suggests a functional role for this type of cross-frequency coupling (CFC). Phase-amplitude coupling has been reported in continuous electrophysiological signals obtained from the brain at both local and macroscopic levels. In the present work, we present a new measure for assessing phase-amplitude CFC. This measure is defined as an adaptation of the Kullback-Leibler distance-a function that is used to infer the distance between two distributions-and calculates how much an empirical amplitude distribution-like function over phase bins deviates from the uniform distribution. We show that a CFC measure defined this way is well suited for assessing the intensity of phase-amplitude coupling. We also review seven other CFC measures; we show that, by some performance benchmarks, our measure is especially attractive for this task. We also discuss some technical aspects related to the measure, such as the length of the epochs used for these analyses and the utility of surrogate control analyses. Finally, we apply the measure and a related CFC tool to actual hippocampal recordings obtained from freely moving rats and show, for the first time, that the CA3 and CA1 regions present different CFC characteristics.

Hippocampal theta rhythm and its coupling with gamma oscillations require fast inhibition onto parvalbumin-positive interneurons

Hippocampal theta (5–10 Hz) and gamma (35–85 Hz) oscillations depend on an inhibitory network of GABAergic interneurons. However, the lack of methods for direct and cell-type-specific interference with inhibition has prevented better insights that help link synaptic and cellular properties with network function. Here, we generated genetically modified mice (PV-Δγ2) in which synaptic inhibition was ablated in parvalbumin-positive (PV+) interneurons. Hippocampal local field potential and unit recordings in the CA1 area of freely behaving mice revealed that theta rhythm was strongly reduced in these mice. The characteristic coupling of theta and gamma oscillations was strongly altered in PV-Δγ2 mice more than could be accounted for by the reduction in theta rhythm only. Surprisingly, gamma oscillations were not altered. These data indicate that synaptic inhibition onto PV+ interneurons is indispensable for theta- and its coupling to gamma oscillations but not for rhythmic gamma-activity in the hippocampus. Similar alterations in rhythmic activity were obtained in a computational hippocampal network model mimicking the genetic modification, suggesting that intrahippocampal networks might contribute to these effects.

OLM interneurons differentially modulate CA3 and entorhinal inputs to hippocampal CA1 neurons

The vast diversity of GABAergic interneurons is believed to endow hippocampal microcircuits with the required flexibility for memory encoding and retrieval. However, dissection of the functional roles of defined interneuron types has been hampered by the lack of cell-specific tools. We identified a precise molecular marker for a population of hippocampal GABAergic interneurons known as oriens lacunosum-moleculare (OLM) cells. By combining transgenic mice and optogenetic tools, we found that OLM cells are important for gating the information flow in CA1, facilitating the transmission of intrahippocampal information (from CA3) while reducing the influence of extrahippocampal inputs (from the entorhinal cortex). Furthermore, we found that OLM cells were interconnected by gap junctions, received direct cholinergic inputs from subcortical afferents and accounted for the effect of nicotine on synaptic plasticity of the Schaffer collateral pathway. Our results suggest that acetylcholine acting through OLM cells can control the mnemonic processes executed by the hippocampus.

Sharp edge artifacts and spurious coupling in EEG frequency comodulation measures

Recent electroencephalogram (EEG), electrocorticogram (ECoG), and local field potential (LFP) observations suggest that distinct frequency bands interact. Numerous measures have been proposed to analyze such interactions, including the amplitude envelope modulation of high frequency activity by the phase or signal of low frequency activity. In this short communication, we describe how abrupt increases or decreases in voltage data may produce spurious coupling in these measures and suggest techniques to detect these effects.

On the formation of gamma-coherent cell assemblies by oriens lacunosum-moleculare interneurons in the hippocampus

Gamma frequency (30–80 Hz) network oscillations have been observed in the hippocampus during several behavioral paradigms in which they are often modulated by a theta frequency (4–12 Hz) oscillation. Interneurons of the hippocampus have been shown to be crucially involved in rhythms generation, and several subtypes with distinct anatomy and physiology have been described. In particular, the oriens lacunosum-moleculare (O-LM) interneurons were shown to synapse on distal apical dendrites of pyramidal cells and to spike preferentially at theta frequency, even in the presence of gamma-field oscillations. O-LM cells have also recently been shown to present higher axonal ramification in the longitudinal axis of the hippocampus. By using a hippocampal network model composed of pyramidal cells and two types of interneurons (O-LM and basket cells), we show here that the O-LM interneurons lead to gamma coherence between anatomically distinct cell modules. We thus propose that this could be a mechanism for coupling longitudinally distant cells excited by entorhinal cortex inputs into gamma-coherent assemblies.

Impaired hippocampal rhythmogenesis in a mouse model of mesial temporal lobe epilepsy.

Mesial temporal lobe epilepsy (mTLE) is one of the most common forms of epilepsy, characterized by hippocampal sclerosis and memory deficits. Injection of kainic acid (KA) into the dorsal hippocampus of mice reproduces major electrophysiological and histopathological characteristics of mTLE. In extracellular recordings from the morphologically intact ventral hippocampus of KA-injected epileptic mice, we found that theta-frequency oscillations were abolished, whereas gamma oscillations persisted both in vivo and in vitro. Whole-cell recordings further showed that oriens-lacunosum-moleculare (O-LM) interneurons, key players in the generation of theta rhythm, displayed marked changes in their intrinsic and synaptic properties. Hyperpolarization-activated mixed cation currents (Ih) were significantly reduced, resulting in an increase in the input resistance and a hyperpolarizing shift in the resting membrane potential. Additionally, the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) was increased, indicating a stronger excitatory input to these neurons. As a consequence, O-LM interneurons increased their firing rate from theta to gamma frequencies during induced network activity in acute slices from KA-injected mice. Thus, our physiological data together with network simulations suggest that changes in excitatory input and synaptic integration in O-LM interneurons lead to impaired rhythmogenesis in the hippocampus that in turn may underlie memory deficit.

Theta Phase Modulates Multiple Layer-Specific Oscillations in the CA1 Region

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.

On high-frequency field oscillations (>100 Hz) and the spectral leakage of spiking activity.

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.

Ketamine alters oscillatory coupling in the hippocampus

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.