Featured publications

Long-duration Hippocampal Sharp Wave Ripples Improve Memory

Fernández-Ruiz A*, Oliva A*, Fermino de Oliveira E, Rocha-Almeida F, Tinlgey D, Buzsáki G. (2019). Science 364 (6445), 1082-1086. (* equal contribution)
Hippocampal sharp wave ripples (SPW-Rs) have been hypothesized as a mechanism for memory consolidation and action planning. The duration of ripples shows a skewed distribution with a minority of long-duration events. We discovered that long-duration ripples are increased in situations demanding memory in rats. Prolongation of spontaneously occurring ripples by optogenetic stimulation, but not randomly induced ripples, increased memory during maze learning. The neuronal content of randomly induced ripples was similar to short-duration spontaneous ripples and contained little spatial information. The spike content of the optogenetically prolonged ripples was biased by the ongoing, naturally initiated neuronal sequences. Prolonged ripples recruited new neurons that represented either arm of the maze. Long-duration hippocampal SPW-Rs replaying large parts of planned routes are critical for memory.

Layer-specific physiological features and interlaminar interactions in the primary visual cortex of the mouse.

Senzai Y*, Fernández-Ruiz A*, Buzsáki G. (2019) Neuron 101,1-14. (* equal contribution)
The relationship between mesoscopic local field potentials (LFPs) and single-neuron firing in the multi-layered neocortex is poorly understood. Simultaneous recordings from all layers in the primary visual cortex (V1) of the behaving mouse revealed functionally defined layers in V1. The depth of maximum spike power and sink-source distributions of LFPs provided consistent laminar landmarks across animals. Coherence of gamma oscillations (30–100 Hz) and spike-LFP coupling identified six physiological layers and further sublayers. Firing rates, burstiness, and other electrophysiological features of neurons displayed unique layer and brain state dependence. Spike transmission strength from layer 2/3 cells to layer 5 pyramidal cellsand interneurons was stronger during waking compared with non-REM sleep but stronger during non-REM sleep among deep-layer excitatory neurons. A subset of deep-layer neurons was active exclusively in the DOWN state of non-REM sleep. These results bridge mesoscopic LFPs and single-neuron interactions with laminar structure in V1.

Entorhinal-CA3 dual-input control of spike timing in the hippocampus by theta-gamma coupling.

Fernández-Ruiz A, Oliva A, Nagy GA, Maurer AP, Berényi A, Buzsáki G. (2017). Neuron, 93:1213-1226.
Theta-gamma phase coupling and spike timing within theta oscillations are prominent features of the hippocampus and are often related to navigation and memory. However, the mechanisms that give rise to these relationships are not well understood. Using high spatial resolution electrophysiology, we investigated the influence of CA3 and entorhinal inputs on the timing of CA1 neurons. The theta-phase preference and excitatory strength of the afferent CA3 and entorhinal inputs effectively timed the principal neuron activity, as well as regulated distinct CA1 interneuron populations in multiple tasks and behavioral states. Feedback potentiation of distal dendritic inhibition by CA1 place cells attenuated the excitatory entorhinal input at place field entry, coupled with feedback depression of proximal dendritic and perisomatic inhibition, allowing the CA3 input to gain control toward the exit. Thus, upstream inputs interact with local mechanisms to determine theta-phase timing of hippocampal neurons to support memory and spatial navigation.

Role of hippocampal CA2 region in triggering sharp-wave ripples.

Oliva A, Fernández-Ruiz A, Buzsáki G, Berényi A. (2016). Neuron 91:1342-1355.
Sharp-wave ripples (SPW-Rs) in the hippocampus are implied in memory consolidation, as shown by observational and interventional experiments. However, the mechanism of their generation remains unclear. Using two-dimensional silicon probe arrays, we investigated the propagation of SPW-Rs across the hippocampal CA1, CA2, and CA3 subregions. Synchronous activation of CA2 ensembles preceded SPW-R-related population activity in CA3 and CA1 regions. Deep CA2 neurons gradually increased their activity prior to ripples and were suppressed during the population bursts of CA3-CA1 neurons (ramping cells). Activity of superficial CA2 cells preceded the activity surge in CA3-CA1 (phasic cells). The trigger role of the CA2 region in SPW-R was more pronounced during waking than sleeping. These results point to the CA2 region as an initiation zone for SPW-Rs.

Theta phase segregation of input-specific gamma patterns in entorhinal-hippocampal networks.

Schomburg EW*, Fernández-Ruiz A*, Berényi A, Mizuseki K, Anastassiou CA, Koch C, Buzsáki G. (2014). Neuron. 84:470-485.
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.

Schaffer-specific local field potentials reflect discrete excitatory events at gamma-frequency that may fire postsynaptic hippocampal CA1 units.

Fernandez-Ruiz A, Makarov VA, Benito N, Herreras O. (2012). J Neurosci. 32:5165-5176.
Information processing and exchange between brain nuclei are made through spike series sent by individual neurons in highly irregular temporal patterns. Synchronization in cell assemblies, proposed as a network language for internal neural representations, still has little experimental support. We use a novel technique to extract pathway-specific local field potentials (LFPs) in the hippocampus to explore the ongoing temporal structure of a single presynaptic input, the CA3 Schaffer pathway, and its contribution to the spontaneous output of CA1 units in anesthetized rat. We found that Schaffer-specific LFPs are composed of a regular succession of pulse-like excitatory packages initiated by spontaneous clustered firing of CA3 pyramidal cells to which individual units contribute variably. A fraction of these packages readily induce firing of CA1 pyramidal cells and interneurons, the so-called Schaffer-driven spikes, revealing the presynaptic origin in the output code of single CA1 units. The output of 70% of CA1 pyramidal neurons contains up to 10% of such spikes. Our results suggest a hierarchical internal operation of the CA3 region based on sequential oscillatory activation of pyramidal cell assemblies whose activity partly gets in the output code at the next station. We conclude that CA1 output may directly reflect the activity of specific ensembles of CA3 neurons. Thus, the fine temporal structure of pathway-specific LFPs, as an accurate readout of the activity of a presynaptic population, is useful in searching for hidden presynaptic code in irregular spikes series of individual neurons and assemblies.

Other publications

Oliva A*, Fernández-Ruiz A*, Fermino de Oliveira E, Buzsáki G. (2018) Origin of gamma frequency power during hippocampal sharp-wave ripples. Cell Reports, 25 (7), 1693-1700. (* equal contribution).

Barth A.M., Domonkos A., Fernandez-Ruiz A., Freund T.F., Varga V (2018) Hippocampal network dynamics during rearing episodes. Cell Reports, 23 (6), 1706.

Vöröslakos M, Takeuchi Y, Brinyiczki K, Zombori T, Oliva A, Fernández-Ruiz A, Kozák G, Kincses Z, Iványi B, Buzsáki G, Berényi A. (2018). Direct effects of transcranial electric stimulation on brain circuits in rats and humans. Nat Comm, 9 (1): 483.

Buzsáki G, Fernández-Ruiz A. (2017) Hippocampus: network physiology. In: Handbook of Brain Microcircuits, Ed: Sheperd GM and Grillner S. Oxford University Press.

Oliva A, Fernández-Ruiz A, Buzsáki G, Berényi A. (2016) Spatial coding and physiological properties of hippocampal neurons in the Cornu Ammonis subregions. Hippocampus, 26: 1593–1607.

Fernández-Ruiz A, Oliva A. (2016) Distributed representation of "what" and "where" information in the parahippocampal region. J Neurosci, 36:8286-8288.

Oliva A, Fernández-Ruiz A. (2016) Incorporating single cell contribution into network models of ripple generation. J Physiol, 595(1):9-10.

Fernández-Ruiz A (2016) Extracellular potentials in the hippocampus. Springer. (book)

Benito N*, Fernandez-Ruiz A*, Makarov VA, Makarova J, Korovaichuk A, Herreras O. (2014) Spatial blocks of coherent pathway-specific LFPs in the hippocampus reflect different modes of presynaptic synchronization. Cereb Cortex. 24:1738-52 (* equal contribution).

Enriquez-Barreto L, Cuesto G, Dominguez-Iturza N, Gavilán E, Ruano D, Sandi C, Fernández-Ruiz A, Martín-Vázquez G, Herreras O, Morales M. (2014) Learning improvement after PI3K activation correlates with de novo formation of functional small spines. Front Mol Neurosci 2;6:54.

Fernández-Ruiz A*, Schomburg EW*. (2013) The rules of entrainment: are CA1 gamma oscillations externally imposed or locally governed? J Neurosci 33:19045-19047. (* equal contribution).

Fernandez-Ruiz A, Muñoz S, Sancho M, Makarov VA, Herreras O. (2013) Cytoarchitectonic and dynamic origins of giant positive LFPs in the Dentate Gyrus. J Neurosci 33:15518-15532.

Fernández-Ruiz A, Herreras O. (2013) Identifying the synaptic origin of ongoing neuronal oscillations through spatial discrimination of electric fields. Front Comput Neurosci 7:5.

Fernandez-Ruiz A, Makarov VA, Herreras O. (2012) Sustained increase of spontaneous input and spike transfer in the CA3-CA1 following long-term potentiation in vivo. Front Neural Circuits. 6:71.