Utility of the Idling Brain: Abstraction of New Knowledge.

Using clever experimental design and exploiting the high temporal resolution power of magnetoencephalography, Liu et al. show in humans how "offline" reactivation of brain patterns allows the abstraction of new knowledge from previous experience. The key mechanism may involve hippocampal sharp-wave ripples.

Hippocampal CA2 sharp-wave ripples reactivate and promote social memory.

The consolidation of spatial memory depends on the reactivation ('replay') of hippocampal place cells that were active during recent behaviour. Such reactivation is observed during sharp-wave ripples (SWRs)-synchronous oscillatory electrical events that occur during non-rapid-eye-movement (non-REM) sleep1-8 and whose disruption impairs spatial memory3,5,6,8. Although the hippocampus also encodes a wide range of non-spatial forms of declarative memory, it is not yet known whether SWRs are necessary for such memories. Moreover, although SWRs can arise from either the CA3 or the CA2 region of the hippocampus7,9, the relative importance of SWRs from these regions for memory consolidation is unknown. Here we examine the role of SWRs during the consolidation of social memory-the ability of an animal to recognize and remember a member of the same species-focusing on CA2 because of its essential role in social memory10-12. We find that ensembles of CA2 pyramidal neurons that are active during social exploration of previously unknown conspecifics are reactivated during SWRs. Notably, disruption or enhancement of CA2 SWRs suppresses or prolongs social memory, respectively. Thus, SWR-mediated reactivation of hippocampal firing related to recent experience appears to be a general mechanism for binding spatial, temporal and sensory information into high-order memory representations, including social memory.

Interictal epileptiform discharges affect memory in an Alzheimer's disease mouse model.

Interictal epileptiform discharges (IEDs) are transient abnormal electrophysiological events commonly observed in epilepsy patients but are also present in other neurological diseases, such as Alzheimer's disease (AD). Understanding the role IEDs have on the hippocampal circuit is important for our understanding of the cognitive deficits seen in epilepsy and AD. We characterize and compare the IEDs of human epilepsy patients from microwire hippocampal recording with those of AD transgenic mice with implanted multilayer hippocampal silicon probes. Both the local field potential features and firing patterns of pyramidal cells and interneurons were similar in the mouse and human. We found that as IEDs emerged from the CA3-1 circuits, they recruited pyramidal cells and silenced interneurons, followed by post-IED suppression. IEDs suppressed the incidence and altered the properties of physiological sharp-wave ripples, altered their physiological properties, and interfered with the replay of place field sequences in a maze. In addition, IEDs in AD mice inversely correlated with daily memory performance. Together, our work implies that IEDs may present a common and epilepsy-independent phenomenon in neurodegenerative diseases that perturbs hippocampal-cortical communication and interferes with memory.

CA2 orchestrates hippocampal network dynamics.

The hippocampus is composed of various subregions: CA1, CA2, CA3, and the dentate gyrus (DG). Despite the abundant hippocampal research literature, until recently, CA2 received little attention. The development of new genetic and physiological tools allowed recent studies characterizing the unique properties and functional roles of this hippocampal subregion. Despite its small size, the cellular content of CA2 is heterogeneous at the molecular and physiological levels. CA2 has been heavily implicated in social behaviors, including social memory. More generally, the mechanisms by which the hippocampus is involved in memory include the reactivation of neuronal ensembles following experience. This process is coordinated by synchronous network events known as sharp-wave ripples (SWRs). Recent evidence suggests that CA2 plays an important role in the generation of SWRs. The unique connectivity and physiological properties of CA2 pyramidal cells make this region a computational hub at the core of hippocampal information processing. Here, we review recent findings that support the role of CA2 in coordinating hippocampal network dynamics from a systems neuroscience perspective.

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. © 2016 Wiley Periodicals, Inc.

Cytoarchitectonic and dynamic origins of giant positive local field potentials in the dentate gyrus.

To determine why some pathways but not others produce sizable local field potentials (LFPs) and how far from the source can these be recorded, complementary experimental analyses and realistic modeling of specific brain structures are required. In the present study, we combined multiple in vivo linear recordings in rats and a tridimensional finite element model of the dentate gyrus, a curved structure displaying abnormally large positive LFPs. We demonstrate that the polarized dendritic arbour of granule cells (GCs), combined with the curved layered configuration of the population promote the spatial clustering of GC currents in the interposed hilus and project them through the open side at a distance from cell domains. LFPs grow up to 20 times larger than observed in synaptic sites. The dominant positive polarity of hilar LFPs was only produced by the synchronous activation of GCs in both blades by either somatic inhibition or dendritic excitation. Moreover, the corresponding anatomical pathways must project to both blades of the dentate gyrus as even a mild decrease in the spatial synchronization resulted in a dramatic reduction in LFP power in distant sites, yet not in the GC domains. It is concluded that the activation of layered structures may establish sharply delimited spatial domains where synaptic currents from one or another input appear to be segregated according to the topology of afferent pathways and the cytoarchitectonic features of the target population. These also determine preferred directions for volume conduction in the brain, of relevance for interpretation of surface EEG recordings.

A hippocampal circuit mechanism to balance memory reactivation during sleep.

Memory consolidation involves the synchronous reactivation of hippocampal cells active during recent experience in sleep sharp-wave ripples (SWRs). How this increase in firing rates and synchrony after learning is counterbalanced to preserve network stability is not understood. We discovered a network event generated by an intrahippocampal circuit formed by a subset of CA2 pyramidal cells to cholecystokinin-expressing (CCK+) basket cells, which fire a barrage of action potentials ("BARR") during non-rapid eye movement sleep. CA1 neurons and assemblies that increased their activity during learning were reactivated during SWRs but inhibited during BARRs. The initial increase in reactivation during SWRs returned to baseline through sleep. This trend was abolished by silencing CCK+ basket cells during BARRs, resulting in higher synchrony of CA1 assemblies and impaired memory consolidation.

Ventral hippocampal parvalbumin interneurons gate the acute anxiolytic action of the serotonergic psychedelic DOI.

There has been a recent renewal of interest in the therapeutic potential of serotonergic psychedelics. Here, we uncover the essential role of ventral hippocampus (vHpc) GABAergic interneurons in the anxiolytic effect evoked by the serotonergic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI). Integrating anatomical, pharmacological, and genetic approaches, we show that 5-HT2A receptors in the CA1/subiculum (CA1/sub) region of the vHpc are required for the anxiolytic action of DOI. In vivo electrophysiology and opto-tagging experiments indicate that DOI enhances the firing rate of hippocampal fast-spiking parvalbumin (PV)-positive interneurons, most of which express the 5-HT2A receptors. Restoration of 5-HT2A receptors in PV-positive interneurons in a loss-of-function background reinstated the anxiolytic responses evoked by DOI in the vHpc CA1/sub region. Collectively, our results localize the acute anxiolytic action of a serotonergic psychedelic to 5-HT2A receptors in the ventral hippocampus and specifically identify PV-positive fast-spiking cells as a cellular trigger for the psychedelic-induced relief of anxiety-like behavior.

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

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.

Associative and predictive hippocampal codes support memory-guided behaviors.

Episodic memory involves learning and recalling associations between items and their spatiotemporal context. Those memories can be further used to generate internal models of the world that enable predictions to be made. The mechanisms that support these associative and predictive aspects of memory are not yet understood. In this study, we used an optogenetic manipulation to perturb the sequential structure, but not global network dynamics, of place cells as rats traversed specific spatial trajectories. This perturbation abolished replay of those trajectories and the development of predictive representations, leading to impaired learning of new optimal trajectories during memory-guided navigation. However, place cell assembly reactivation and reward-context associative learning were unaffected. Our results show a mechanistic dissociation between two complementary hippocampal codes: an associative code (through coactivity) and a predictive code (through sequences).

Over and above frequency: Gamma oscillations as units of neural circuit operations.

Gamma oscillations (∼30-150 Hz) are widespread correlates of neural circuit functions. These network activity patterns have been described across multiple animal species, brain structures, and behaviors, and are usually identified based on their spectral peak frequency. Yet, despite intensive investigation, whether gamma oscillations implement causal mechanisms of specific brain functions or represent a general dynamic mode of neural circuit operation remains unclear. In this perspective, we review recent advances in the study of gamma oscillations toward a deeper understanding of their cellular mechanisms, neural pathways, and functional roles. We discuss that a given gamma rhythm does not per se implement any specific cognitive function but rather constitutes an activity motif reporting the cellular substrates, communication channels, and computational operations underlying information processing in its generating brain circuit. Accordingly, we propose shifting the attention from a frequency-based to a circuit-level definition of gamma oscillations.

Hippocampo-cortical circuits for selective memory encoding, routing, and replay.

Traditionally considered a homogeneous cell type, hippocampal pyramidal cells have been recently shown to be highly diverse. However, how this cellular diversity relates to the different hippocampal network computations that support memory-guided behavior is not yet known. We show that the anatomical identity of pyramidal cells is a major organizing principle of CA1 assembly dynamics, the emergence of memory replay, and cortical projection patterns in rats. Segregated pyramidal cell subpopulations encoded trajectory and choice-specific information or tracked changes in reward configuration respectively, and their activity was selectively read out by different cortical targets. Furthermore, distinct hippocampo-cortical assemblies coordinated the reactivation of complementary memory representations. These findings reveal the existence of specialized hippocampo-cortical subcircuits and provide a cellular mechanism that supports the computational flexibility and memory capacities of these structures.

Interictal epileptiform discharges affect memory in an Alzheimer's Disease mouse model.

Interictal epileptiform discharges (IEDs) are transient abnormal electrophysiological events commonly observed in epilepsy patients but are also present in other neurological disease, such as Alzheimer's Disease (AD). Understanding the role IEDs have on the hippocampal circuit is important for our understanding of the cognitive deficits seen in epilepsy and AD. We characterize and compare the IEDs of human epilepsy patients from microwire hippocampal recording with those of AD transgenic mice with implanted multi-layer hippocampal silicon probes. Both the local field potential features and firing patterns of pyramidal cells and interneurons were similar in mouse and human. We found that as IEDs emerged from the CA3-1 circuits, they recruited pyramidal cells and silenced interneurons, followed by post-IED suppression. IEDs suppressed the incidence and altered the properties of physiological sharp-wave ripples (SPW-Rs), altered their physiological properties, and interfered with the replay of place field sequences in a maze. In addition, IEDs in AD mice inversely correlated with daily memory performance. Together, our work implicates that IEDs may present a common and epilepsy-independent phenomenon in neurodegenerative diseases that perturbs hippocampal-cortical communication and interferes with memory. Significant Statement: Prevalence of neurodegenerative diseases and the number of people with dementia is increasing steadily. Therefore, novel treatment strategies for learning and memory disorders are urgently necessary. IEDs, apart from being a surrogate for epileptic brain regions, have also been linked to cognitive decline. Here we report that IEDs in human epilepsy patients and AD mouse models have similar local field potential characteristics and associated firing patterns of pyramidal cells and interneurons. Mice with more IEDs displayed fewer hippocampal SPW-Rs, poorer replay of spatial trajectories, and decreased memory performance. IED suppression is an unexplored target to treat cognitive dysfunction in neurodegenerative diseases.

Extrinsic control and intrinsic computation in the hippocampal CA1 circuit.

In understanding circuit operations, a key problem is the extent to which neuronal spiking reflects local computation or responses to upstream inputs. We addressed this issue in the hippocampus by performing combined optogenetic and pharmacogenetic local and upstream inactivation. Silencing the medial entorhinal cortex (mEC) largely abolished extracellular theta and gamma currents in CA1 while only moderately affecting firing rates. In contrast, CA3 and local CA1 silencing strongly decreased firing of CA1 neurons without affecting theta currents. Each perturbation reconfigured the CA1 spatial map. However, the ability of the CA1 circuit to support place field activity persisted, maintaining the same fraction of spatially tuned place fields and reliable assembly expression as in the intact mouse. Thus, the CA1 network can induce and maintain coordinated cell assemblies with minimal reliance on its inputs, but these inputs can effectively reconfigure and assist in maintaining stability of the CA1 map.

High-resolution optogenetics in space and time.

To understand the neural mechanisms of behavior, it is necessary to both monitor and perturb the activity of ensembles of neurons with high specificity. While neural ensemble recordings have been available for decades, progress in high-resolution manipulation techniques has lagged behind. Optogenetics has enabled the manipulation of genetically defined cell types in behaving animals, and recent developments, including multipoint nanofabricated light sources, provide spatiotemporal resolution on a par with that of physiological recordings. Here we review current advances in optogenetic methods for cellular-resolution stimulation and intervention, as well as their integration with real-time neural recordings for closed-loop experimentation. We discuss how these approaches open the door to new kinds of experiments aimed at dissecting the role of specific neural patterns and discrete cellular populations in orchestrating the activity of brain circuits that support behavior and cognition.

HectoSTAR µLED Optoelectrodes for Large-Scale, High-Precision In Vivo Opto-Electrophysiology.

Dynamic interactions within and across brain areas underlie behavioral and cognitive functions. To understand the basis of these processes, the activities of distributed local circuits inside the brain of a behaving animal must be synchronously recorded while the inputs to these circuits are precisely manipulated. Even though recent technological advances have enabled such large-scale recording capabilities, the development of the high-spatiotemporal-resolution and large-scale modulation techniques to accompany those recordings has lagged. A novel neural probe is presented in this work that enables simultaneous electrical monitoring and optogenetic manipulation of deep neuronal circuits at large scales with a high spatiotemporal resolution. The "hectoSTAR" micro-light-emitting-diode (µLED) optoelectrode features 256 recording electrodes and 128 stimulation µLEDs monolithically integrated on the surface of its four 30-µm thick silicon micro-needle shanks, covering a large volume with 1.3-mm × 0.9-mm cross-sectional area located as deep as 6 mm inside the brain. The use of this device in behaving mice for dissecting long-distance network interactions across cortical layers and hippocampal regions is demonstrated. The recording-and-stimulation capabilities hectoSTAR µLED optoelectrodes enables will open up new possibilities for the cellular and circuit-based investigation of brain functions in behaving animals.

Subcircuits of Deep and Superficial CA1 Place Cells Support Efficient Spatial Coding across Heterogeneous Environments.

The hippocampus is thought to guide navigation by forming a cognitive map of space. Different environments differ in geometry and the availability of cues that can be used for navigation. Although several spatial coding mechanisms are known to coexist in the hippocampus, how they are influenced by various environmental features is not well understood. To address this issue, we examined the spatial coding characteristics of hippocampal neurons in mice and rats navigating in different environments. We found that CA1 place cells located in the superficial sublayer were more active in cue-poor environments and preferentially used a firing rate code driven by intra-hippocampal inputs. In contrast, place cells located in the deep sublayer were more active in cue-rich environments and used a phase code driven by entorhinal inputs. Switching between these two spatial coding modes was supported by the interaction between excitatory gamma inputs and local inhibition.

Gamma rhythm communication between entorhinal cortex and dentate gyrus neuronal assemblies.

Gamma oscillations are thought to coordinate the spike timing of functionally specialized neuronal ensembles across brain regions. To test this hypothesis, we optogenetically perturbed gamma spike timing in the rat medial (MEC) and lateral (LEC) entorhinal cortices and found impairments in spatial and object learning tasks, respectively. MEC and LEC were synchronized with the hippocampal dentate gyrus through high- and low-gamma-frequency rhythms, respectively, and engaged either granule cells or mossy cells and CA3 pyramidal cells in a task-dependent manner. Gamma perturbation disrupted the learning-induced assembly organization of target neurons. Our findings imply that pathway-specific gamma oscillations route task-relevant information between distinct neuronal subpopulations in the entorhinal-hippocampal circuit. We hypothesize that interregional gamma-time-scale spike coordination is a mechanism of neuronal communication.