Antonio Fernández-Ruiz

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

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.

Entorhinal-CA3 Dual-Input Control of Spike Timing in the Hippocampus by Theta-Gamma Coupling

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

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.

Spatial coding and physiological properties of hippocampal neurons in the Cornu Ammonis subregions

It is well‐established that the feed‐forward connected main hippocampal areas, CA3, CA2, and CA1 work cooperatively during spatial navigation and memory. These areas are similar in terms of the prevalent types of neurons; however, they display different spatial coding and oscillatory dynamics. Understanding the temporal dynamics of these operations requires simultaneous recordings from these regions. However, simultaneous recordings from multiple regions and subregions in behaving animals have become possible only recently. We performed large‐scale silicon probe recordings simultaneously spanning across all layers of CA1, CA2, and CA3 regions in rats during spatial navigation and sleep and compared their behavior‐dependent spiking, oscillatory dynamics and functional connectivity. The accuracy of place cell spatial coding increased progressively from distal to proximal CA1, suddenly dropped in CA2, and increased again from CA3a toward CA3c. These variations can be attributed in part to the different entorhinal inputs to each subregions, and the differences in theta modulation of CA1, CA2, and CA3 neurons. We also found that neurons in the subregions showed differences in theta modulation, phase precession, state‐dependent changes in firing rates and functional connectivity among neurons of these regions. Our results indicate that a combination of intrinsic properties together with distinct intra‐ and extra‐hippocampal inputs may account for the subregion‐specific modulation of spiking dynamics and spatial tuning of neurons during behavior.

Hippocampal Network Dynamics during Rearing Episodes

Summary Animals build a model of their surroundings on the basis of information gathered during exploration. Rearing on the hindlimbs changes the vantage point of the animal, increasing the sampled area of the environment. This environmental knowledge is suggested to be integrated into a cognitive map stored by the hippocampus. Previous studies have found that damage to the hippocampus impairs rearing. Here, we characterize the operational state of the hippocampus during rearing episodes. We observe an increase of theta frequency paralleled by a sink in the dentate gyrus and a prominent theta-modulated fast gamma transient in the middle molecular layer. On the descending phase of rearing, a decrease of theta power is detected. Place cells stop firing during rearing, while a different subset of putative pyramidal cells is activated. Our results suggest that the hippocampus switches to a different operational state during rearing, possibly to update spatial representation with information from distant sources.

Distributed Representation of "What" and "Where" Information in the Parahippocampal Region.

A large body of evidence supports a key role for medial temporal lobe (MTL) structures in declarative memory. Initial theories assigned specific cognitive processes to particular subregions and suggested a hierarchical serial processing stream that converges in the hippocampus ([Eichenbaum et al.,

The Rules of Entrainment: Are CA1 Gamma Oscillations Externally Imposed or Locally Governed?

Gamma oscillations (∼30–90 Hz) in the local field potential (LFP) are a widespread signature of information processing in neural circuits and have been linked to cognitive functions ranging from sensory perception and attention to memory encoding and the organization of neuronal assemblies (Engel et al., 2001; Buzsaki and Wang, 2012). Special emphasis has been placed on the gamma-band phase-synchronization among different brain areas, which has been proposed as a mechanism to bind together information processed in distant regions into a unified representation (Engel et al., 2001) or to coordinate different networks engaged in a common memory task (Montgomery and Buzsaki, 2007).

Incorporating single cell contribution into network models of ripple generation

Numerous lines of experimental evidence support the fundamental role of hippocampal sharp-wave-ripples (SPW-Rs) in memory consolidation. These complexes are composed of a fast frequency oscillation ( 150 Hz) in the pyramidal layer (termed a ‘ripple’) and a large negative wave in the stratum radiatum (termed a ‘sharp-wave’). It is accepted that the sharp-wave is generated by excitatory inputs from the CA3 area but there is considerable debate about the mechanisms of ripple generation, demonstrated by the number of different models put forth to explain it. In general terms, all of these models are based on circuit properties, and account for the high spiking synchrony characteristic of ripples with connectivity or functional network features. On the other hand, there has been significant experimental demonstration of precise transmembrane conductance and spiking dynamics of single cells during SPW-Rs. However, the difficulty of isolating individual synaptic contributions during in vivo experiments (such as small inhibitory potentials) and the inherent limitations of in vitro studies (drug effects, differences in the slice preparation and absence of long range connectivity) have prevented measurement of the contribution of single cells to SPW-Rs. A precise quantification of this contribution has recently been provided by Bazelot et al. (2016), offering a framework for the integration of the subcellular, single cell, and network mechanisms into a comprehensive model of ripple generation. One popular network model of ripple generation states that ripples are mediated by axo-axonic electrical synapses between pyramidal neurons (Draguhn et al. 1998). Detailed computational models in combination with in vitro data support this theory, which describes how ectopic action potentials (APs) can be generated in axons of pyramidal cells and then propagate both orthodromically and antidromically to pace the ripple oscillation. A local network of pyramidal cells in the CA3 area could then synchronize by electrotonic coupling through gap junctions, generating oscillations at ripple frequency. However, recent experimental evidence obtained in vivo argues against the mechanism proposed by this model. First, a combination of intracellular and extracellular recording of APs in CA1 showed exclusive orthodromic propagation during ripples (English et al. 2014) and, second, optogenetic silencing of either CA1 pyramidal cells or interneurons abolishes ripple events, suggesting the necessity of both interneuron and pyramidal cell activation, and the interplay between them, for ripple generation and maintenance (Stark et al. 2014). Thus, although distinct mechanisms could be interacting in the generation of CA1 and CA3 ripples, it is difficult for the electrical coupling model to stand alone as the unique mechanism of ripple generation. A second class of model proposes that the recurrent properties of a local network act as a pacemaker of ripple oscillations. Reciprocal inhibition between perisomatic targeting interneurons could synchronize rhythmically the firing of pyramidal cell assemblies through inhibitory rebound spiking. Another possible mechanism of recurrent activity that would generate ripple frequency oscillations comes from the feedback inhibition of pyramidal cells by perisomatic interneurons. Also, as suggested by recent data from local optogenetic manipulation of CA1 activity (Stark et al. 2014), a combination of both mechanisms described by the second type of model could also explain ripple generation. However, in all these different models the contribution of single cell activity is not specified. Bazelot et al. (2016) have shed light on this issue, describing how a single CA3 pyramidal neuron can influence the generation of ripples. The authors performed intracellular recordings of individual CA3 pyramidal cells and elicited single APs using precise intracellular current injection. They found that ripples followed induced action potentials after an interval of 2–6 ms. This time window between when an AP is delivered and the ripple initiation could be explained by the synaptic delays of local recurrent activity. Latencies for pyramidal cell–interneuron interactions within the CA3 region in in vitro preparations have been measured to be 3 ms, which would be enough to recruit other neurons via recurrent collaterals. In addition, the authors also found that the same pyramidal cell can trigger ripple events and also activate interneurons, which elicit inhibitory postsynaptic potentials (IPSPs) with similar probability. Furthermore, interneuron spiking is correlated in time and magnitude with IPSPs occurring in the stratum pyramidale during ripples. The coincidence of successive ripple cycles with depolarizing events onto fast-spiking interneurons supports the fundamental role of excitation–inhibition loops as described during in vivo ripples (English et al. 2014; Stark et al. 2014). Interestingly, the authors could differentiate distinct IPSP patterns. The distance within which different IPSP patterns could be recorded matched with the spatial extent of the arborization of perisomatic targeting interneurons (Gulyas et al. 2010), pointing to their causal relation. Further data with paired recordings including different subtypes of interneurons would help to distinguish the role attributed to distinct types of inhibitory cells during ripple generation and maintenance (English et al. 2014; Stark et al. 2014). Together, the main findings of Bazelot et al. (2016) suggest a continuum, rather than two separated modes, between IPSPs and ripple generation. It has been shown that during ripples both inhibitory and excitatory activity compete to control spiking (English et al. 2014). Considering the results of Bazelot et al. within this framework, the excitation–inhibition balance would lead to either only IPSP generation or ripple generation, depending upon which of them predominate. Hence, only when the excitatory tone is high enough can a ripple could be generated. Characteristics that facilitate the dominance of local excitation over inhibition are a high excitability of principal cells, intrinsic bursting properties and strong recurrent collateral excitatory connections. These features have been

Theta-Gamma Cross-Frequency Coupling in the Hippocampus-Entorhinal Circuit

The hippocampal-entorhinal system is characterized by the ubiquitous occurrence of distinct oscillatory patterns, including the prominent theta and gamma rhythms.

Current Sources of Hippocampal LFPs

One of the ultimate goals of the investigations on neural circuit dynamics is to understand the input-output transformation of neuronal signals, i.e., how neuronal activity in an upstream region affects the firing rate and spike timing in neurons of a downstream region.