Hippocampal Place Cell Firing Research Articles

Hippocampal place cells exhibit impairments in spatial information coding in an APP‐knock in model of Alzheimer’s Disease

AbstractBackgroundThe hippocampus is one of the first cortical regions to exhibit Alzheimer’s Disease (AD) pathology. The spatially‐related firing of hippocampal place cells provides the cellular basis for spatial memory and this is impaired relatively early in AD, yet few studies examine place cell activity in AD mouse models. We undertook an in‐depth characterisation of hippocampal pyramidal cell activity in an APP knock‐in model of AD.MethodMicrodrives carrying 8 tetrodes were implanted into the left CA1 hippocampal subfield of 14‐month female mice (four APPNL‐G‐F, four wild‐type littermates). Mice undertook daily foraging sessions in an open field and ran on a linear track as CA1 activity was recorded. On completion of experiments, 40µm coronal sections of fixed brain tissue were stained using Cresyl Violet to verify tetrode placement and Thioflavin‐S to quantify amyloid β plaque burden.Result270 cells were recorded (119 wild‐type, 151 APPNL‐G‐F). CA1 pyramidal cells were classified as “place cells” or “non‐place cells” based on their spatial information content (bits/spike). Pyramidal cells recorded in wild‐type mice had significantly greater spatial information content than APPNL‐G‐F pyramidal cells (Figure 1), and a higher proportion were classified as place cells. Wild‐type place cells had significantly greater spatial information content than APPNL‐G‐F place cells. Corresponding differences were identified in place field size (Figures 2, 3). A positive correlation was identified between Aβ plaque burden and pyramidal cell spatial information content in the four APPNL‐G‐F mice (Figure 4).Coordination of place cell firing by the hippocampal theta rhythm was disrupted in APPNL‐G‐F mice; phase‐locking of pyramidal cells and place cells was significantly reduced (Figure 5), there was less coherence in the preferred theta phase across the pyramidal cell population, and a reduction in theta phase precession was observed.ConclusionAPPNL‐G‐F CA1 place cells exhibited deficits in both rate coding and temporal coding of spatial information indicating that amyloid β pathology, in the absence tau tangles, was associated with a disruption of hippocampal place cell function. These results provide preliminary support for the hypothesis that disruption of hippocampal function by AD pathology manifests as altered place cell activity and spatial behaviour.

Role of Pharmacological Modulation of Tonic Inhibition in Hippocampal Sharp Wave Ripples Amplitude and Place Cell Firing Dynamics

Hippocampal hyperactivity is a hallmark of memory dysfunction associated with age related mild cognitive impairment (aMCI) and Alzheimer’s disease, leading to the hypothesis that hippocampal trisynaptic circuit hyperactivity impairs memory function. As a test of this hypothesis, we sought to pharmacologically recapitulate hyperactivity in young adults by attenuating tonic inhibition in the hippocampal trisynaptic circuit. We used chronically implanted arrays of 96 electrodes arranged as tetrodes and 32 channel silicon probes to record place cell activity within and across the CA1 subregion of young adult rats either foraging in familiar and novel environments or resting in a familiar environment (without foraging) while awake but immobile for ripple band recordings. We demonstrate that oral administration of the nootropic drug α5IA, a selective negative modulator of tonically active predominantly extrasynaptic α5 GABA receptors, enhances CA1 place cell firing rates but does not augment spatial information content or pattern separation expected a priori to reflect nootropic drug action. This conundrum is resolved by the finding that α5IA substantially increases the sharp wave ripple (SPW‐R) amplitude, which is known to correlate with improved remembering. We replicated to result in three strains of rats (Long Evans, Fisher 344, and Sprague Dawley) and found that the outcomes were not strain specific. These observations indicate that the nootropic actions of α5IA may result from enhancement of aspects of memory function influenced by CA1 SPW‐R amplitude such as consolidation of encoded information. We posit that modulation of ripple dynamics may be controlled via alterations in extrasynaptic tonic inhibition mediated in part by α5 GABA‐A receptors.

Cognitive mapping: Anchoring our brain’s sense of space in a dynamic world

In complex environments, we rely on knowing our current location and pathways to others in order to flexibly navigate. But viable routes often change. New research suggests how the brain tracks where we are regardless of paths available to us.

Altered Hippocampal Place Cell Representation and Theta Rhythmicity following Moderate Prenatal Alcohol Exposure

Prenatal alcohol exposure (PAE) leads to profound deficits in spatial memory and synaptic and cellular alterations to the hippocampus that last into adulthood. Neurons in the hippocampus called place cells discharge as an animal enters specific places in an environment, establish distinct ensemble codes for familiar and novel places, and are modulated by local theta rhythms. Spatial memory is thought to critically depend on the integrity of hippocampal place cell firing. Therefore, we tested the hypothesis that hippocampal place cell firing is impaired after PAE by performing invivo recordings from the hippocampi (CA1 and CA3) of moderate PAE and control adult rats. Our results show that hippocampal CA3 neurons from PAE rats have reduced spatial tuning. Second, CA1 and CA3 neurons from PAE rats are less likely to orthogonalize their firing between directions of travel on a linear track and between changes in contextual stimuli in an open arena compared to control neurons. Lastly, reductions in the number of hippocampal place cells exhibiting significant theta rhythmicity and phase precession were observed, which may suggest changes to hippocampal microcircuit function. Together, the reduced spatial tuning and sensitivity to contextual changes provide a neural systems-level mechanism to explain spatial memory impairment after moderate PAE.

Lesions of the head direction cell system impair direction discrimination.

Previous results suggest that directional information from the head direction cell circuit may inform hippocampal place cell firing when an animal is confronted with visually identical environments. To investigate whether such information might also be essential for spatial behavior, we tested adult, male Lister Hooded rats that had received either bilateral lateral mammillary nuclei (LMN) lesions or sham lesions on a four-way, conditional odor-location discrimination in compartments arranged at 60° to one another. We found that significantly fewer rats in the LMN lesion group were able to learn the task compared to the Sham group. We also found that the extent of the behavioral impairment was highly correlated with the degree of tissue loss in the LMN resulting from the lesion. Animals with LMN lesions were also impaired in a nonmatching-to-sample task in a T maze, and the extent of impairment likewise depended on the extent of the lesion. Performance in the odor-location and T-maze tasks was not affected by tissue loss in the medial mammillary nuclei. Together, these results indicate that the LMN, a key node in the head direction circuit, is critical for solving a spatial task that requires a directional discrimination. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The Integration of Goal-Directed Signals onto Spatial Maps of Hippocampal Place Cells

Spatial firing of hippocampal place cells varies dependingon the animal's behavior relative to its goals. Here, rats were trained to approach visually guided reward ports in a two-dimensional open field. Hippocampal place cells encoded two independent pieces of information, spatial representation and goal-directed representation, by amplifying firing rates within their place fields specifically while the animalwas moving toward a specific goal location. Irrespectiveof running speed and direction, substantial place-selective firing was observed that sustained a basal spatial map independent of goal-directed signals.When animals were allowed to freely forage in the field, in-field firing rates similarly increased when the animals transiently ran toward remembered goal locations. Disruption of medial septal activity significantly decreased goal-directed firing while maintaining spatial representation patterns. The findings indicate that the integrated encoding of spatial and goal-directed signals by hippocampal circuits is crucial for flexible spatial navigation to a goal location.

Comparing Mouse and Rat Hippocampal Place Cell Activities and Firing Sequences in the Same Environments

Hippocampal place cells are key to spatial representation and spatial memory processing. They fire at specific locations in a space (place fields) and fire in precise patterns during theta sequences and during ripple-associated replay events. These phenomena have been extensively studied in rats, but to a less extent in mice. The availability of versatile genetic manipulations gives mice an advantage for place cell studies. However, it is unknown how place fields and place cell sequences in the same environment differ between mice and rats. Here, we provide a quantitative comparison in place field properties, as well as theta sequences and replays, between rats and mice as they ran on the same novel track and as they rested afterwards. We found that place cells in mice display less spatial specificity with more but smaller place fields. Theta oscillations, theta phase precession and aspects of theta sequences in mice are similar as those in rats. The ripple-associated replay, however, is relatively rare during stopping on the novel track in mice. The replay is present during resting after the track running, but is weaker in mice than the replay in rats. Our results suggest that place cells in mice and rats are qualitatively similar, but with substantial quantitative differences.

Navigation Patterns and Scent Marking: Underappreciated Contributors to Hippocampal and Entorhinal Spatial Representations?

According to the currently prevailing theory, hippocampal formation constructs and maintains cognitive spatial maps. Most of the experimental evidence for this theory comes from the studies on navigation in laboratory rats and mice, typically male animals. While these animals exhibit a rich repertoire of behaviors associated with navigation, including locomotion, head movements, whisking, sniffing, raring and scent marking, the contribution of these behavioral patterns to the hippocampal spatially-selective activity has not been sufficiently studied. Instead, many publications have considered animal position in space as the major variable that affects the firing of hippocampal place cells and entorhinal grid cells. Here we argue that future work should focus on a more detailed examination of different behaviors exhibited during navigation to better understand the mechanism of spatial tuning in hippocampal neurons. As an inquiry in this direction, we have analyzed data from two datasets, shared online, containing recordings from rats navigating in square and round arenas. Our analyses revealed patchy navigation patterns, evident from the spatial maps of animal position, velocity and acceleration. Moreover, grid cells available in the datasets exhibited similar periodicity as the navigation parameters. These findings indicate that activity of grid cells could affect navigation parameters and/or vice versa. Additionally, we speculate that scent marks left by navigating animals could contribute to neuronal responses while rats and mice sniff their environment; the act of sniffing could modulate neuronal discharges even in virtual visual environments. Accordingly, we propose that future experiments should contain additional controls for navigation patterns, whisking, sniffing and maps composed of scent marks.

Ventral Midline Thalamus Is Necessary for Hippocampal Place Field Stability and Cell Firing Modulation.

The reuniens (Re) and rhomboid (Rh) nuclei of the ventral midline thalamus are reciprocally connected with the hippocampus (Hip) and the medial prefrontal cortex (mPFC). Growing evidence suggests that these nuclei might play a crucial role in cognitive processes requiring Hip-mPFC interactions, including spatial navigation. Here, we tested the effect of ReRh lesions on the firing properties and spatial activity of dorsal hippocampal CA1 place cells as male rats explored a familiar or a novel environment. We found no change in the spatial characteristics of CA1 place cells in the familiar environment following ReRh lesions. Contrariwise, spatial coherence was decreased during the first session in a novel environment. We then investigated field stability of place cells recorded across 5 d both in the familiar and in a novel environment presented in a predefined sequence. While the remapping capacity of the place cells was not affected by the lesion, our results clearly demonstrated a disruption of the CA1 cellular representation of both environments in ReRh rats. More specifically, we found ReRh lesions to produce (1) a pronounced and long-lasting decrease of place field stability and (2) a strong alteration of overdispersion (i.e., firing variability). Thus, in ReRh rats, exploration of a novel environment appears to interfere with the representation of the familiar one, leading to decreased field stability in both environments. The present study shows the involvement of ReRh nuclei in the long-term spatial stability of CA1 place fields.SIGNIFICANCE STATEMENT Growing evidence suggest that the ventral midline thalamic nuclei (reuniens and rhomboid) might play a substantial role in various cognitive tasks including spatial memory. In the present article, we show that the lesions of these nuclei impair the spatial representations encoded by CA1 place cells of both familiar and novel environments. First, reduced variability of place cell firing appears to indicate an impairment of attentional processes. Second, impaired stability of place cell representations could explain the long-term memory deficits observed in previous behavioral studies.

The functional role of human right hippocampal/parahippocampal theta rhythm in environmental encoding during virtual spatial navigation.

Low frequency theta band oscillations (4-8 Hz) are thought to provide a timing mechanism for hippocampal place cell firing and to mediate the formation of spatial memory. In rodents, hippocampal theta has been shown to play an important role in encoding a new environment during spatial navigation, but a similar functional role of hippocampal theta in humans has not been firmly established. To investigate this question, we recorded healthy participants' brain responses with a 160-channel whole-head MEG system as they performed two training sets of a virtual Morris water maze task. Environment layouts (except for platform locations) of the two sets were kept constant to measure theta activity during spatial learning in new and familiar environments. In line with previous findings, left hippocampal/parahippocampal theta showed more activation navigating to a hidden platform relative to random swimming. Consistent with our hypothesis, right hippocampal/parahippocampal theta was stronger during the first training set compared to the second one. Notably, theta in this region during the first training set correlated with spatial navigation performance across individuals in both training sets. These results strongly argue for the functional importance of right hippocampal theta in initial encoding of configural properties of an environment during spatial navigation. Our findings provide important evidence that right hippocampal/parahippocampal theta activity is associated with environmental encoding in the human brain. Hum Brain Mapp 38:1347-1361, 2017. © 2016 Wiley Periodicals, Inc.

Optogenetically Blocking Sharp Wave Ripple Events in Sleep Does Not Interfere with the Formation of Stable Spatial Representation in the CA1 Area of the Hippocampus.

During hippocampal sharp wave/ripple (SWR) events, previously occurring, sensory input-driven neuronal firing patterns are replayed. Such replay is thought to be important for plasticity-related processes and consolidation of memory traces. It has previously been shown that the electrical stimulation-induced disruption of SWR events interferes with learning in rodents in different experimental paradigms. On the other hand, the cognitive map theory posits that the plastic changes of the firing of hippocampal place cells constitute the electrophysiological counterpart of the spatial learning, observable at the behavioral level. Therefore, we tested whether intact SWR events occurring during the sleep/rest session after the first exploration of a novel environment are needed for the stabilization of the CA1 code, which process requires plasticity. We found that the newly-formed representation in the CA1 has the same level of stability with optogenetic SWR blockade as with a control manipulation that delivered the same amount of light into the brain. Therefore our results suggest that at least in the case of passive exploratory behavior, SWR-related plasticity is dispensable for the stability of CA1 ensembles.

Vicarious trial and error

When rats come to a decision point, they sometimes pause and look back and forth as if deliberating over the choice; at other times, they proceed as if they have already made their decision. In the 1930s, this pause-and-look behaviour was termed 'vicarious trial and error' (VTE), with the implication that the rat was 'thinking about the future'. The discovery in 2007 that the firing of hippocampal place cells gives rise to alternating representations of each of the potential path options in a serial manner during VTE suggested a possible neural mechanism that could underlie the representations of future outcomes. More-recent experiments examining VTE in rats suggest that there are direct parallels to human processes of deliberative decision making, working memory and mental time travel.

Modeling place field activity with hierarchical slow feature analysis.

What are the computational laws of hippocampal activity? In this paper we argue for the slowness principle as a fundamental processing paradigm behind hippocampal place cell firing. We present six different studies from the experimental literature, performed with real-life rats, that we replicated in computer simulations. Each of the chosen studies allows rodents to develop stable place fields and then examines a distinct property of the established spatial encoding: adaptation to cue relocation and removal; directional dependent firing in the linear track and open field; and morphing and scaling the environment itself. Simulations are based on a hierarchical Slow Feature Analysis (SFA) network topped by a principal component analysis (ICA) output layer. The slowness principle is shown to account for the main findings of the presented experimental studies. The SFA network generates its responses using raw visual input only, which adds to its biological plausibility but requires experiments performed in light conditions. Future iterations of the model will thus have to incorporate additional information, such as path integration and grid cell activity, in order to be able to also replicate studies that take place during darkness.

Prenatal immune activation alters hippocampal place cell firing characteristics in adult animals.

Prenatal maternal immune activation (MIA) is a risk factor for several developmental neuropsychiatric disorders, including autism, bipolar disorder and schizophrenia. Adults with these disorders display alterations in memory function that may result from changes in the structure and function of the hippocampus. In the present study we use an animal model to investigate the effect that a transient prenatal maternal immune activation episode has on the spatially-modulated firing activity of hippocampal neurons in adult animals. MIA was induced in pregnant rat dams with a single injection of the synthetic cytokine inducer polyinosinic:polycytidylic acid (poly I:C) on gestational day 15. Control dams were given a saline equivalent. Firing activity and local field potentials (LFPs) were recorded from the CA1 region of the adult male offspring of these dams as they moved freely in an open arena. Most neurons displayed characteristic spatially-modulated 'place cell' firing activity and while there was no between-group difference in mean firing rate between groups, place cells had smaller place fields in MIA-exposed animals when compared to control-group cells. Cells recorded in MIA-group animals also displayed an altered firing-phase synchrony relationship to simultaneously recorded LFPs. When the floor of the arena was rotated, the place fields of MIA-group cells were more likely to shift in the same direction as the floor rotation, suggesting that local cues may have been more salient for these animals. In contrast, place fields in control group cells were more likely to shift firing position to novel spatial locations suggesting an altered response to contextual cues. These findings show that a single MIA intervention is sufficient to change several important characteristics of hippocampal place cell activity in adult offspring. These changes could contribute to the memory dysfunction that is associated with MIA, by altering the encoding of spatial context and by disrupting plasticity mechanisms that are dependent on spike timing synchrony.

DNA methylation regulates neurophysiological spatial representation in memory formation

Epigenetic mechanisms including altered DNA methylation are critical for altered gene transcription subserving synaptic plasticity and the retention of learned behavior. Here, we tested the idea that one role for activity-dependent altered DNA methylation is stabilization of cognition-associated hippocampal place cell firing in response to novel place learning. We observed that a behavioral protocol (spatial exploration of a novel environment) known to induce hippocampal place cell remapping resulted in alterations of hippocampal Bdnf DNA methylation. Further studies using neurophysiological in vivo single-unit recordings revealed that pharmacological manipulations of DNA methylation decreased long-term but not short-term place field stability. Together, our data highlight a role for DNA methylation in regulating neurophysiological spatial representation and memory formation.

How reduction of theta rhythm by medial septum inactivation may covary with disruption of entorhinal grid cell responses due to reduced cholinergic transmission

Oscillations in the coordinated firing of brain neurons have been proposed to play important roles in perception, cognition, attention, learning, navigation, and sensory-motor control. The network theta rhythm has been associated with properties of spatial navigation, as has the firing of entorhinal grid cells and hippocampal place cells. Two recent studies reduced the theta rhythm by inactivating the medial septum (MS) and demonstrated a correlated reduction in the characteristic hexagonal spatial firing patterns of grid cells. These results, along with properties of intrinsic membrane potential oscillations (MPOs) in slice preparations of medial entorhinal cortex (MEC), have been interpreted to support oscillatory interference models of grid cell firing. The current article shows that an alternative self-organizing map (SOM) model of grid cells can explain these data about intrinsic and network oscillations without invoking oscillatory interference. In particular, the adverse effects of MS inactivation on grid cells can be understood in terms of how the concomitant reduction in cholinergic inputs may increase the conductances of leak potassium (K+) and slow and medium after-hyperpolarization (sAHP and mAHP) channels. This alternative model can also explain data that are problematic for oscillatory interference models, including how knockout of the HCN1 gene in mice, which flattens the dorsoventral gradient in MPO frequency and resonance frequency, does not affect the development of the grid cell dorsoventral gradient of spatial scales, and how hexagonal grid firing fields in bats can occur even in the absence of theta band modulation. These results demonstrate how models of grid cell self-organization can provide new insights into the relationship between brain learning and oscillatory dynamics.

Evolution of hippocampal spatial representation over time in mice

To investigate the intriguing and paradoxical contrast between the time-limited role of the hippocampus in memory consolidation and its permanent contribution to spatial memory as revealed by place cell activity, we carefully monitored the temporal evolution of the same set of place cells in normal naïve mice throughout their familiarization to a spatial context and their consolidation of memory about space. Over six daily recording sessions, despite their widely reported stability, we observed gradual changes in hippocampal place fields and cell firing patterns. These changes were interpreted in terms of both improvement and impoverishment of spatial codes: improvement due to intrinsic place cell plasticity, and impoverishment as a consequence of attentional filtering of allocentric spatial information reaching the hippocampus due to the procedural behavioral requirements of the task, or to hippocampal disengagement as learning progresses.

Cholinergic modulation of the CAN current may adjust neural dynamics for active memory maintenance, spatial navigation and time-compressed replay

Suppression of cholinergic receptors and inactivation of the septum impair short-term memory, and disrupt place cell and grid cell activity in the medial temporal lobe (MTL). Location-dependent hippocampal place cell firing during active waking, when the acetylcholine level is high, switches to time-compressed replay activity during quiet waking and slow-wave-sleep (SWS), when the acetylcholine level is low. However, it remains largely unknown how acetylcholine supports short-term memory, spatial navigation, and the functional switch to replay mode in the MTL. In this paper, we focus on the role of the calcium-activated non-specific cationic (CAN) current which is activated by acetylcholine. The CAN current is known to underlie persistent firing, which could serve as a memory trace in many neurons in the MTL. Here, we review the CAN current and discuss possible roles of the CAN current in short-term memory and spatial navigation. We further propose a novel theoretical model where the CAN current switches the hippocampal place cell activity between real-time and time-compressed sequential activity during encoding and consolidation, respectively.

The neural substrates of deliberative decision making: contrasting effects of hippocampus lesions on performance and vicarious trial-and-error behavior in a spatial memory task and a visual discrimination task

Vicarious trial-and-errors (VTEs) are back-and-forth movements of the head exhibited by rodents and other animals when faced with a decision. These behaviors have recently been associated with prospective sweeps of hippocampal place cell firing, and thus may reflect a rodent model of deliberative decision-making. The aim of the current study was to test whether the hippocampus is essential for VTEs in a spatial memory task and in a simple visual discrimination (VD) task. We found that lesions of the hippocampus with ibotenic acid produced a significant impairment in the accuracy of choices in a serial spatial reversal (SR) task. In terms of VTEs, whereas sham-lesioned animals engaged in more VTE behavior prior to identifying the location of the reward as opposed to repeated trials after it had been located, the lesioned animals failed to show this difference. In contrast, damage to the hippocampus had no effect on acquisition of a VD or on the VTEs seen in this task. For both lesion and sham-lesion animals, adding an additional choice to the VD increased the number of VTEs and decreased the accuracy of choices. Together, these results suggest that the hippocampus may be specifically involved in VTE behavior during spatial decision making.

Increased Size and Stability of CA1 and CA3 Place Fields in HCN1 Knockout Mice

Hippocampal CA1 and CA3 pyramidal neuron place cells encode the spatial location of an animal through localized firing patterns called "place fields." To explore the mechanisms that control place cell firing and their relationship to spatial memory, we studied mice with enhanced spatial memory resulting from forebrain-specific knockout of the HCN1 hyperpolarization-activated cation channel. HCN1 is strongly expressed in CA1 neurons and in entorhinal cortex grid cells, which provide spatial information to the hippocampus. Both CA1 and CA3 place fields were larger but more stable in the knockout mice, with the effect greater in CA1 than CA3. As HCN1 is only weakly expressed in CA3 place cells, their altered activity likely reflects loss of HCN1 in grid cells. The more pronounced changes in CA1 likely reflect the intrinsic contribution of HCN1. The enhanced place field stability may underlie the effect of HCN1 deletion to facilitate spatial learning and memory.