Faculty Bibliography

Inhibitory neurons in cortical circuits play critical roles in composing spike timing and oscillatory patterns in neuronal activity. These roles in turn require coherent activation of interneurons at different timescales. To investigate how the local circuitry provides for these activities, we applied resampled cross-correlation analyses to large-scale recordings of neuronal populations in the cornu ammonis 1 (CA1) and CA3 regions of the hippocampus of freely moving rats. Significant counts in the cross-correlation of cell pairs, relative to jittered surrogate spike-trains, allowed us to identify the effective couplings between neurons in CA1 and CA3 hippocampal regions on the timescale of milliseconds. In addition to putative excitatory and inhibitory monosynaptic connections, we uncovered prominent millisecond timescale synchrony between cell pairs, observed as peaks in the central 0 ms bin of cross-correlograms. This millisecond timescale synchrony appeared to be independent of network state, excitatory input, and gamma oscillations. Moreover, it was frequently observed between cells of differing putative interneuronal type, arguing against gap junctions as the sole underlying source. Our observations corroborate recent in vitro findings suggesting that inhibition alone is sufficient to synchronize interneurons at such fast timescales. Moreover, we show that this synchronous spiking may cause stronger inhibition and rebound spiking in target neurons, pointing toward a potential function for millisecond synchrony of interneurons in shaping and affecting timing in pyramidal populations within and downstream from the circuit.

Precisely how rhythms support neuronal communication remains obscure. We investigated interregional coordination of gamma oscillations using high-density electrophysiological recordings in the rat hippocampus and entorhinal cortex. We found that 30-80 Hz gamma dominated CA1 local field potentials (LFPs) on the descending phase of CA1 theta waves during navigation, with 60-120 Hz gamma at the theta peak. These signals corresponded to CA3 and entorhinal input, respectively. Above 50 Hz, interregional phase-synchronization of principal cell spikes occurred mostly for LFPs in the axonal target domain. CA1 pyramidal cells were phase-locked mainly to fast gamma (>100 Hz) LFP patterns restricted to CA1, which were strongest at the theta trough. While theta phase coordination of spiking across entorhinal-hippocampal regions depended on memory demands, LFP gamma patterns below 100 Hz in the hippocampus were consistently layer specific and largely reflected afferent activity. Gamma synchronization as a mechanism for interregional communication thus rapidly loses efficacy at higher frequencies.

Theta oscillations in the limbic system depend on the integrity of the medial septum. The different populations of medial septal neurons (cholinergic and GABAergic) are assumed to affect different aspects of theta oscillations. Using optogenetic stimulation of cholinergic neurons in ChAT-Cre mice, we investigated their effects on hippocampal local field potentials in both anesthetized and behaving mice. Cholinergic stimulation completely blocked sharp wave ripples and strongly suppressed the power of both slow oscillations (0.5-2 Hz in anesthetized, 0.5-4 Hz in behaving animals) and supratheta (6-10 Hz in anesthetized, 10-25 Hz in behaving animals) bands. The same stimulation robustly increased both the power and coherence of theta oscillations (2-6 Hz) in urethane-anesthetized mice. In behaving mice, cholinergic stimulation was less effective in the theta (4-10 Hz) band yet it also increased the ratio of theta/slow oscillation and theta coherence. The effects on gamma oscillations largely mirrored those of theta. These findings show that medial septal cholinergic activation can both enhance theta rhythm and suppress peri-theta frequency bands, allowing theta oscillations to dominate.

Using silicon-based recording electrodes, we recorded neuronal activity of the dorsal hippocampus and dorsomedial entorhinal cortex from behaving rats. The entorhinal neurons were classified as principal neurons and interneurons based on monosynaptic interactions and wave-shapes. The hippocampal neurons were classified as principal neurons and interneurons based on monosynaptic interactions, wave-shapes and burstiness. The data set contains recordings from 7,736 neurons (6,100 classified as principal neurons, 1,132 as interneurons, and 504 cells that did not clearly fit into either category) obtained during 442 recording sessions from 11 rats (a total of 204.5 hours) while they were engaged in one of eight different behaviours/tasks. Both original and processed data (time stamp of spikes, spike waveforms, result of spike sorting and local field potential) are included, along with metadata of behavioural markers. Community-driven data sharing may offer cross-validation of findings, refinement of interpretations and facilitate discoveries.

High-frequency ripple oscillations, observed most prominently in the hippocampal CA1 pyramidal layer, are associated with memory consolidation. The cellular and network mechanisms underlying the generation, frequency control, and spatial coherence of the rhythm are poorly understood. Using multisite optogenetic manipulations in freely behaving rodents, we found that depolarization of a small group of nearby pyramidal cells was sufficient to induce high-frequency oscillations, whereas closed-loop silencing of pyramidal cells or activation of parvalbumin- (PV) or somatostatin-immunoreactive interneurons aborted spontaneously occurring ripples. Focal pharmacological blockade of GABAA receptors abolished ripples. Localized PV interneuron activation paced ensemble spiking, and simultaneous induction of high-frequency oscillations at multiple locations resulted in a temporally coherent pattern mediated by phase-locked interneuron spiking. These results constrain competing models of ripple generation and indicate that temporally precise local interactions between excitatory and inhibitory neurons support ripple generation in the intact hippocampus.

Although neuronal spikes can be readily detected from extracellular recordings, synaptic and subthreshold activity remains undifferentiated within the local field potential (LFP). In the hippocampus, neurons discharge selectively when the rat is at certain locations, while LFPs at single anatomical sites exhibit no such place-tuning. Nonetheless, because the representation of position is sparse and distributed, we hypothesized that spatial information can be recovered from multiple-site LFP recordings. Using high-density sampling of LFP and computational methods, we show that the spatiotemporal structure of the theta rhythm can encode position as robustly as neuronal spiking populations. Because our approach exploits the rhythmicity and sparse structure of neural activity, features found in many brain regions, it is useful as a general tool for discovering distributed LFP codes.

We often assume that the variables of functional and structural brain parameters - such as synaptic weights, the firing rates of individual neurons, the synchronous discharge of neural populations, the number of synaptic contacts between neurons and the size of dendritic boutons - have a bell-shaped distribution. However, at many physiological and anatomical levels in the brain, the distribution of numerous parameters is in fact strongly skewed with a heavy tail, suggesting that skewed (typically lognormal) distributions are fundamental to structural and functional brain organization. This insight not only has implications for how we should collect and analyse data, it may also help us to understand how the different levels of skewed distributions - from synapses to cognition - are related to each other.

Identification and manipulation of different GABAergic interneuron classes in the behaving animal are important to understand their role in circuit dynamics and behavior. The combination of optogenetics and large-scale neuronal recordings allows specific interneuron populations to be identified and perturbed for circuit analysis in intact animals. A crucial aspect of this approach is coupling electrophysiological recording with spatially and temporally precise light delivery. Focal multisite illumination of neuronal activators and silencers in predetermined temporal configurations or a closed loop manner opens the door to addressing many novel questions. Recent progress demonstrates the utility and power of this novel technique for interneuron research.

Oscillations and synchrony are often used synonymously. However, oscillatory mechanisms involving both excitation and inhibition can generate non-synchronous yet coordinated firing patterns. Using simultaneous recordings from multiple layers of the entorhinal-hippocampal loop, we found that coactivation of principal cell pairs (synchrony) was lowest during exploration and rapid-eye-movement (REM) sleep, associated with theta oscillations, and highest in slow wave sleep. Individual principal neurons had a wide range of theta phase preference. Thus, while theta oscillations reduce population synchrony, they nevertheless coordinate the phase (temporal) distribution of neurons. As a result, multiple cell assemblies can nest within the period of the theta cycle.

Several network patterns allow for information exchange between the neocortex and the entorhinal-hippocampal complex, including theta oscillations and sleep spindles. How neurons are organized in these respective patterns is not well understood. We examined the cellular-synaptic generation of sleep spindles and theta oscillations in the waking rat and during rapid eye movement (REM) sleep by simultaneously recording local field and spikes in the regions and layers of the hippocampus and entorhinal cortex (EC). We show the following: (1) current source density analysis reveals that similar anatomical substrates underlie spindles and theta in the hippocampus, although the hippocampal subregions are more synchronized during spindles than theta; (2) the spiking of putative principal cells and interneurons in the CA1, CA3, and dentate gyrus subregions of the hippocampus, as well as layers 2, 3, and 5 of medial EC, are significantly phase locked to spindles detected in CA1; (3) the relationship between local field potential (LFP) phase and unit spiking differs between spindles and theta; (4) individual hippocampal principal cells generally do not fire in a rhythmic manner during spindles; (5) power in gamma (30-90 Hz) and epsilon (>90 Hz) bands of hippocampal LFP is modulated by the phase of spindle oscillations; and (6) unit firing rates during spindles were not significantly affected by whether spindles occurred during non-REM or transitions between non-REM and REM sleep. Thus, despite the similar current generator inputs and macroscopic appearance of the LFP, the organization of neuronal firing patterns during spindles bears little resemblance to that of theta oscillations.