Ensemble Place Codes in Hippocampus: CA1, CA3, and Dentate Gyrus Place Cells Have Multiple Place Fields in Large Environments

Previously we reported that the hippocampus place code must be an ensemble code because place cells in the CA1 region of hippocampus have multiple place fields in a more natural, larger-than-standard enclosure with stairs that permitted movements in 3-D. Here, we further investigated the nature of hippocampal place codes by characterizing the spatial firing properties of place cells in the CA1, CA3, and dentate gyrus (DG) hippocampal subdivisions as rats foraged in a standard 76-cm cylinder as well as a larger-than-standard box (1.8 m×1.4 m) that did not have stairs or any internal structure to permit movements in 3-D. The rats were trained to forage continuously for 1 hour using computer-controlled food delivery. We confirmed that most place cells have single place fields in the standard cylinder and that the positional firing pattern remapped between the cylinder and the large enclosure. Importantly, place cells in the CA1, CA3 and DG areas all characteristically had multiple place fields that were irregularly spaced, as we had reported previously for CA1. We conclude that multiple place fields are a fundamental characteristic of hippocampal place cells that simplifies to a single field in sufficiently small spaces. An ensemble place code is compatible with these observations, which contradict any dedicated coding scheme

A theoretical account of cue averaging in the rodent head direction system

Head direction (HD) cell responses are thought to be derived from a combination of internal (or idiothetic) and external (or allothetic) sources of information. Recent work from the Jeffery laboratory shows that the relative influence of visual versus vestibular inputs upon the HD cell response depends on the disparity between these sources. In this paper, we present simulation results from a model designed to explain these observations. The model accurately replicates the Knight et al. data. We suggest that cue conflict resolution is critically dependent on plastic remapping of visual information onto the HD cell layer. This remap results in a shift in preferred directions of a subset of HD cells, which is then inherited by the rest of the cells during path integration. Thus, we demonstrate how, over a period of several minutes, a visual landmark may gain cue control. Furthermore, simulation results show that weaker visual landmarks fail to gain cue control as readily. We therefore suggest a second longer term plasticity in visual projections onto HD cell areas, through which landmarks with an inconsistent relationship to idiothetic information are made less salient, significantly hindering their ability to gain cue control. Our results provide a mechanism for reliability-weighted cue averaging that may pertain to other neural systems in addition to the HD system

Theta-paced flickering between place-cell maps in the hippocampus

The ability to recall discrete memories is thought to depend on the formation of attractor states in recurrent neural networks. In such networks, representations can be reactivated reliably from subsets of the cues that were present when the memory was encoded, at the same time as interference from competing representations is minimized. Theoretical studies have pointed to the recurrent CA3 system of the hippocampus as a possible attractor network. Consistent with predictions from these studies, experiments have shown that place representations in CA3 and downstream CA1 tolerate small changes in the configuration of the environment but switch to uncorrelated representations when dissimilarities become larger. The kinetics supporting such network transitions, at the subsecond time scale, is poorly understood, however. Here we show that instantaneous transformation of the spatial context (\u2018teleportation\u2019) does not change the hippocampal representation all at once but is followed by temporary bistability in the discharge activity of CA3 ensembles. Rather than sliding through a continuum of intermediate activity states, the CA3 network undergoes a short period of competitive flickering between pre-formed representations for past and present environment, before settling on the latter. Network flickers are extremely fast, often with complete replacement of the active ensemble from one theta cycle to the next. Within individual cycles, segregation is stronger towards the end, when firing starts to decline, pointing to the theta cycle as a temporal unit for expression of attractor states in the hippocampus. Repetition of pattern-completion processes across successive theta cycles may facilitate error correction and enhance discriminative power in the presence of weak and ambiguous input cues

Patterns of Coupled Theta Activity in Amygdala-Hippocampal-Prefrontal Cortical Circuits during Fear Extinction

Signals related to fear memory and extinction are processed within brain pathways involving the lateral amygdala (LA) for formation of aversive stimulus associations, the CA1 area of the hippocampus for context-dependent modulation of these associations, and the infralimbic region of the medial prefrontal cortex (mPFC) for extinction processes. While many studies have addressed the contribution of each of these modules individually, little is known about their interactions and how they function as an integrated system. Here we show, by combining multiple site local field potential (LFP) and unit recordings in freely behaving mice in a fear conditioning paradigm, that theta oscillations may provide a means for temporally and functionally connecting these modules. Theta oscillations occurred with high specificity in the CA1-LA-mPFC network. Theta coupling increased between all areas during retrieval of conditioned fear, and declined during extinction learning. During extinction recall, theta coupling partly rebounded in LA-mPFC and CA1-mPFC, and remained at a low level in CA1-LA. Interfering with theta coupling through local electrical microstimulation in CA1-LA affected conditioned fear and extinction recall depending on theta phase. These results support the hypothesis that theta coupling provides a means for inter-areal coordination in conditioned behavioral responsiveness. More specifically, theta oscillations seem to contribute to a population code indicating conditioned stimuli during recall of fear memory before and after extinction

Accurate path integration in continuous attractor network models of grid cells

Grid cells in the rat entorhinal cortex display strikingly regular firing responses to the animal's position in 2-D space and have been hypothesized to form the neural substrate for dead-reckoning. However, errors accumulate rapidly when velocity inputs are integrated in existing models of grid cell activity. To produce grid-cell-like responses, these models would require frequent resets triggered by external sensory cues. Such inadequacies, shared by various models, cast doubt on the dead-reckoning potential of the grid cell system. Here we focus on the question of accurate path integration, specifically in continuous attractor models of grid cell activity. We show, in contrast to previous models, that continuous attractor models can generate regular triangular grid responses, based on inputs that encode only the rat's velocity and heading direction. We consider the role of the network boundary in the integration performance of the network and show that both periodic and aperiodic networks are capable of accurate path integration, despite important differences in their attractor manifolds. We quantify the rate at which errors in the velocity integration accumulate as a function of network size and intrinsic noise within the network. With a plausible range of parameters and the inclusion of spike variability, our model networks can accurately integrate velocity inputs over a maximum of ~10–100 meters and ~1–10 minutes. These findings form a proof-of-concept that continuous attractor dynamics may underlie velocity integration in the dorsolateral medial entorhinal cortex. The simulations also generate pertinent upper bounds on the accuracy of integration that may be achieved by continuous attractor dynamics in the grid cell network. We suggest experiments to test the continuous attractor model and differentiate it from models in which single cells establish their responses independently of each other

Functional Differences in the Backward Shifts of CA1 and CA3 Place Fields in Novel and Familiar Environments

Insight into the processing dynamics and other neurophysiological properties of different hippocampal subfields is critically important for understanding hippocampal function. In this study, we compared shifts in the center of mass (COM) of CA3 and CA1 place fields in a familiar and completely novel environment. Place fields in CA1 and CA3 were simultaneously recorded as rats ran along a closed loop track in a familiar room followed by a session in a completely novel room. This process was repeated each day over a 4-day period. CA3 place fields shifted backward (opposite to the direction of motion of the rat) only in novel environments. This backward shift gradually diminished across days, as the novel environment became more familiar with repeated exposures. Conversely, CA1 place fields shifted backward across all days in both familiar and novel environments. Prior studies demonstrated that CA1 place fields on average do not exhibit a backward shift during the first exposure to an environment in which the familiar cues are rearranged into a novel configuration, although CA3 place fields showed a strong backward shift. Under the completely novel conditions of the present study, no dissociation was observed between CA3 and CA1 during the first novel session (although a strong dissociation was observed in the familiar sessions and the later novel sessions). In summary, this is the first study to use simultaneous recordings in CA1 and CA3 to compare place field COM shift and other associated properties in truly novel and familiar environments. This study further demonstrates functional differentiation between CA1 and CA3 as the plasticity of CA1 place fields is affected differently by exposure to a completely novel environment in comparison to an altered, familiar environment, whereas the plasticity of CA3 place fields is affected similarly during both types of environmental novelty

Speed Controls the Amplitude and Timing of the Hippocampal Gamma Rhythm

Cortical and hippocampal gamma oscillations have been implicated in many behavioral tasks. The hippocampus is required for spatial navigation where animals run at varying speeds. Hence we tested the hypothesis that the gamma rhythm could encode the running speed of mice. We found that the amplitude of slow (20–45 Hz) and fast (45–120 Hz) gamma rhythms in the hippocampal local field potential (LFP) increased with running speed. The speed-dependence of gamma amplitude was restricted to a narrow range of theta phases where gamma amplitude was maximal, called the preferred theta phase of gamma. The preferred phase of slow gamma precessed to lower values with increasing running speed. While maximal fast and slow gamma occurred at coincident phases of theta at low speeds, they became progressively more theta-phase separated with increasing speed. These results demonstrate a novel influence of speed on the amplitude and timing of the hippocampal gamma rhythm which could contribute to learning of temporal sequences and navigation

Using Strategic Movement to Calibrate a Neural Compass: A Spiking Network for Tracking Head Direction in Rats and Robots

The head direction (HD) system in mammals contains neurons that fire to represent the direction the animal is facing in its environment. The ability of these cells to reliably track head direction even after the removal of external sensory cues implies that the HD system is calibrated to function effectively using just internal (proprioceptive and vestibular) inputs. Rat pups and other infant mammals display stereotypical warm-up movements prior to locomotion in novel environments, and similar warm-up movements are seen in adult mammals with certain brain lesion-induced motor impairments. In this study we propose that synaptic learning mechanisms, in conjunction with appropriate movement strategies based on warm-up movements, can calibrate the HD system so that it functions effectively even in darkness. To examine the link between physical embodiment and neural control, and to determine that the system is robust to real-world phenomena, we implemented the synaptic mechanisms in a spiking neural network and tested it on a mobile robot platform. Results show that the combination of the synaptic learning mechanisms and warm-up movements are able to reliably calibrate the HD system so that it accurately tracks real-world head direction, and that calibration breaks down in systematic ways if certain movements are omitted. This work confirms that targeted, embodied behaviour can be used to calibrate neural systems, demonstrates that ‘grounding’ of modelled biological processes in the real world can reveal underlying functional principles (supporting the importance of robotics to biology), and proposes a functional role for stereotypical behaviours seen in infant mammals and those animals with certain motor deficits. We conjecture that these calibration principles may extend to the calibration of other neural systems involved in motion tracking and the representation of space, such as grid cells in entorhinal cortex

Impact of cognitive stimulation on ripples within human epileptic and non-epileptic hippocampus

Background: Until now there has been no way of distinguishing between physiological and epileptic hippocampal ripples in intracranial recordings. In the present study we addressed this by investigating the effect of cognitive stimulation on interictal high frequency oscillations in the ripple range (80-250 Hz) within epileptic (EH) and non-epileptic hippocampus (NH). Methods: We analyzed depth EEG recordings in 10 patients with intractable epilepsy, in whom hippocampal activity was recorded initially during quiet wakefulness and subsequently during a simple cognitive task. Using automated detection of ripples based on amplitude of the power envelope, we analyzed ripple rate (RR) in the cognitive and resting period, within EH and NH. Results: Compared to quiet wakefulness we observed a significant reduction of RR during cognitive stimulation in EH, while it remained statistically marginal in NH. Further, we investigated the direct impact of cognitive stimuli on ripples (i.e. immediately post-stimulus), which showed a transient statistically significant suppression of ripples in the first second after stimuli onset in NH only. Conclusion: Our results point to a differential reactivity of ripples within EH and NH to cognitive stimulation