Stable Place Fields Research Articles

Metabotropic glutamate receptor, mGlu5, mediates enhancements of hippocampal long-term potentiation after environmental enrichment in young and old mice

The metabotropic glutamate (mGlu) receptor, mGlu5, is of particular relevance for hippocampal function. It is critically required for the expression of long-term potentiation (LTP) and long-term depression (LTD), regulates neuronal oscillations, maintains the stability of place fields and is required for hippocampus-dependent memory. MGlu5-dysfunctions are associated with profound cognitive deficits in humans, and mGlu5 has been targeted as a putative cognitive enhancer. Cognitive enhancement, by means of environmental enrichment (EE) in rodents, results in improved hippocampal synaptic plasticity and memory. Here, we explored whether mGlu5 contributes to these enhancements. MGlu5-antagonism dose-dependently impaired the early phase of LTP (>4 h) in the CA1 region of young(3–4 month old) mice. Late-LTP (>24 h) was also impaired. LTP (>24 h) elicited in old (10–14 month old) mice displayed reduced sensitivity to mGlu5 antagonism. Short-term potentiation (STP, < 2 h) that was elicited by weaker afferent stimulation was unaffected by mGlu5-antagonism in both age-groups.EE significantly amplified STP (<2 h) in old and young animals, but did not increase the duration of synaptic potentiation, or promote induction of LTP. The improvement in STP was prevented by mGlu5-antagonism, in both young and old animals. These results indicate that modifications of the synapse that underlie improvements of LTP by EE require the contribution of mGlu5. Strikingly, although LTP in old mice does not critically depend on mGlu5, improvements in synaptic potentiation resulting from EE are mGlu5-dependent in old mice. Regarded in light of the known role for mGlu5 in hippocampal function and pathophysiology, these data suggest that mGlu5 regulation of synaptic information storage is pivotal to optimal hippocampal function.This article is part of the Special Issue entitled ‘Metabotropic Glutamate Receptors, 5 years on’.

A Developmental Switch in Place Cell Accuracy Coincides with Grid Cell Maturation

SummaryPlace cell firing relies on information about self-motion and the external environment, which may be conveyed by grid and border cells, respectively. Here, we investigate the possible contributions of these cell types to place cell firing, taking advantage of a developmental time window during which stable border cell, but not grid cell, inputs are available. We find that before weaning, the place cell representation of space is denser, more stable, and more accurate close to environmental boundaries. Boundary-responsive neurons such as border cells may, therefore, contribute to stable and accurate place fields in pre-weanling rats. By contrast, place cells become equally stable and accurate throughout the environment after weaning and in adulthood. This developmental switch in place cell accuracy coincides with the emergence of the grid cell network in the entorhinal cortex, raising the possibility that grid cells contribute to stable place fields when an organism is far from environmental boundaries.

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.

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.

Place field stability requires the metabotropic glutamate receptor, mGlu5.

The metabotropic glutamate (mGlu) receptors are critically involved in enabling the persistency of forms of synaptic plasticity that are believed to underlie hippocampus-dependent memory. These receptors and in particular, mGlu5, are also required for hippocampus-dependent learning and memory. In the hippocampus, synaptic plasticity is one of the mechanisms by which spatial information may be represented. Another mechanism involves increased firing of place cells. Place cells increase their firing activity when an animal is in a specific spatial location. Inhibition of factors that are essential for synaptic plasticity, such as N-methyl-d-aspartate receptors or protein synthesis, also impair place cell activity. This raises the question as to whether mGlu receptors, that are so important for synaptic plasticity and spatial memory, are also important for place cell encoding. We examined location-dependent place cell firing i.e. place fields. We observed that antagonism of mGlu5, using 2-methyl-6-(phenylethynyl) pyridine (MPEP) had no effect on place field profiles in a familiar environment. However, in a novel environment mGlu5-antagonism affected long-term place field stability, reduced place cell firing and spatial information. These data strongly suggest a role for mGlu5 in the mechanisms underlying informational content and long-term stability of place fields, and add to evidence supporting the importance of these receptors for hippocampal function.

Spatial representations of place cells in darkness are supported by path integration and border information.

Effective spatial navigation is enabled by reliable reference cues that derive from sensory information from the external environment, as well as from internal sources such as the vestibular system. The integration of information from these sources enables dead reckoning in the form of path integration. Navigation in the dark is associated with the accumulation of errors in terms of perception of allocentric position and this may relate to error accumulation in path integration. We assessed this by recording from place cells in the dark under circumstances where spatial sensory cues were suppressed. Spatial information content, spatial coherence, place field size, and peak and infield firing rates decreased whereas sparsity increased following exploration in the dark compared to the light. Nonetheless it was observed that place field stability in darkness was sustained by border information in a subset of place cells. To examine the impact of encountering the environment’s border on navigation, we analyzed the trajectory and spiking data gathered during navigation in the dark. Our data suggest that although error accumulation in path integration drives place field drift in darkness, under circumstances where border contact is possible, this information is integrated to enable retention of spatial representations.

Impairments in experience-dependent scaling and stability of hippocampal place fields limit spatial learning in a mouse model of Alzheimer's disease.

Impaired spatial memory characterizes many mouse models for Alzheimer's disease, but we understand little about how this trait arises. Here, we use a transgenic model of amyloidosis to examine the relationship between behavioral performance in tests of spatial navigation and the function of hippocampal place cells. We find that amyloid precursor protein (APP) mice require considerably more training than controls to reach the same level of performance in a water maze task, and recall the trained location less well 24 h later. At a single cell level, place fields from control mice become more stable and spatially restricted with repeated exposure to a new environment, while those in APP mice improve less over time, ultimately producing a spatial code of lower resolution, accuracy, and reliability than controls. The limited refinement of place fields in APP mice likely contributes to their delayed water maze acquisition, and provides evidence for circuit dysfunction underlying cognitive impairment.

Attentive scanning behavior drives one-trial potentiation of hippocampal place fields

The hippocampus is thought to play a critical role in episodic memory by incorporating the sensory input of an experience onto a spatial framework embodied by place cells. Although the formation and stability of place fields requires exploration, the interaction between discrete exploratory behaviors and the specific, immediate, and persistent modifications of neural representations required by episodic memory has not been established. We recorded place cells in rats and found that increased neural activity during exploratory head-scanning behaviors predicted the formation and potentiation of place fields on the next pass through that location, regardless of environmental familiarity and across multiple testing days. These results strongly suggest that, during the attentive behaviors that punctuate exploration, place cell activity mediates the one-trial encoding of ongoing experiences necessary for episodic memory.

Active Dendrites under Parental Supervision

Pyramidal cell dendrites are able to produce a variety of active calcium signals in brain slices. In this issue of Neuron, Grienberger etal. (2014) investigate dendritic function in the hippocampus of live mice.

Spatial Olfactory Learning Contributes to Place Field Formation in the Hippocampus

Spatial encoding in the hippocampus is multifactorial, and it is well established that metric information about space is conferred by place cells that fire when an animal finds itself in a specific environmental location. Visuospatial contexts comprise a key element in the formation of place fields. Nevertheless, hippocampus does not only use visual cues to generate spatial representations. In the absence of visual input, both humans and other vertebrates studied in this context, are capable of generating very effective spatial representations. However, little is known about the relationship between nonvisual sensory modalities and the establishment of place fields. Substantial evidence exists that olfactory information can be used to learn spatial contexts. Here, we report that learning about a distinct odor constellation in an environment, where visual and auditory cues are suppressed, results in stable place fields that rotate when the odor constellations are rotated and remap when the odor constellations are shuffled. These data support that the hippocampus can use nonvisuospatial resources, and specifically can use spatial olfactory information, to generate spatial representations. Despite the less precise nature of olfactory stimuli compared with visual stimuli, these can substitute for visual inputs to enable the acquisition of metric information about space.

Fear conditioning alters neuron-specific hippocampal place field stability via the basolateral amygdala

It is well established that physical changes to an environment result in plasticity of hippocampal place cell activity, while in the absence of changes, place fields are remarkably stable. Manipulations of a rat's perception of the environment without physically changing the environment also result in plasticity of place cell firing. Here, we tested the hypothesis that a rat's perception of an environment could be changed by introducing an auditory fear-conditioned stimulus (CS) to a previously neutral environment, inducing plasticity of hippocampal place fields. First, stable place fields were isolated for rats exploring a radial-arm maze in one environment, and then the rats were fear-conditioned to an auditory CS in a completely separate environment. Later, the CS was specifically paired once with a location in the previously neutral radial-arm maze, either within the given neuron's place field (in-field) or an area outside of the place field (out-of-field). A single, paired presentation of the CS with a location in-field for a specific place cell disrupted the stability of that neuron's place field, whereas pairing the CS with a location out-of-field did not affect place field stability. We further showed that this place field disruption for a CS presented in-field was mediated by inputs from the basolateral amygdala (BLA). Temporarily inactivating the BLA immediately post-CS re-exposure attenuated the CS-induced place field destabilization. Our results show neuron-specific conditional plasticity for actively firing hippocampal place cells, and that the BLA mediates this plasticity when an emotionally arousing or fear-related CS is used.

Spatial scale and place field stability in a grid‐to‐place cell model of the dorsoventral axis of the hippocampus

The rodent hippocampus and entorhinal cortex contain spatially modulated cells that serve as the basis for spatial coding. Both medial entorhinal grid cells and hippocampal place cells have been shown to encode spatial information across multiple spatial scales that increase along the dorsoventral axis of these structures. Place cells near the dorsal pole possess small, stable, and spatially selective firing fields, while ventral cells have larger, less stable, and less spatially selective firing fields. One possible explanation for these dorsoventral changes in place field properties is that they arise as a result of similar dorsoventral differences in the properties of the grid cell inputs to place cells. Here, we test the alternative hypothesis that dorsoventral place field differences are due to higher amounts of nonspatial inputs to ventral hippocampal cells. We use a computational model of the entorhinal-hippocampal network to assess the relative contributions of grid scale and nonspatial inputs in determining place field size and stability. In addition, we assess the consequences of grid node firing rate heterogeneity on place field stability. Our results suggest that dorsoventral differences in place cell properties can be better explained by changes in the amount of nonspatial inputs, rather than by changes in the scale of grid cell inputs, and that grid node heterogeneity may have important functional consequences. The observed gradient in field size may reflect a shift from processing primarily spatial information in the dorsal hippocampus to processing more nonspatial, contextual, and emotional information near the ventral hippocampus.

Hippocampal Place Cells Can Encode Multiple Trial-Dependent Features through Rate Remapping

The activity of hippocampal pyramidal cells reflects both the current position of the animal and information related to its current behavior. Here we investigated whether single hippocampal neurons can encode several independent features defining trials during a memory task. We also tested whether task-related information is represented by partial remapping of the place cell population or, instead, via firing rate modulation of spatially stable place cells. To address these two questions, the activity of hippocampal neurons was recorded in rats performing a conditional discrimination task on a modified T-maze in which the identity of a food reward guided behavior. When the rat was on the central arm of the maze, the firing rate of pyramidal cells changed depending on two independent factors: (1) the identity of the food reward given to the animal and (2) the previous location of the animal on the maze. Importantly, some pyramidal cells encoded information relative to both factors. This trial-type specific and retrospective coding did not interfere with the spatial representation of the maze: hippocampal cells had stable place fields and their theta-phase precession profiles were unaltered during the task, indicating that trial-related information was encoded via rate remapping. During error trials, encoding of both trial-related information and spatial location was impaired. Finally, we found that pyramidal cells also encode trial-related information via rate remapping during the continuous version of the rewarded alternation task without delays. These results suggest that hippocampal neurons can encode several task-related cognitive aspects via rate remapping.

Maintaining a Cognitive Map in Darkness: The Need to Fuse Boundary Knowledge with Path Integration

Spatial navigation requires the processing of complex, disparate and often ambiguous sensory data. The neurocomputations underpinning this vital ability remain poorly understood. Controversy remains as to whether multimodal sensory information must be combined into a unified representation, consistent with Tolman's “cognitive map”, or whether differential activation of independent navigation modules suffice to explain observed navigation behaviour. Here we demonstrate that key neural correlates of spatial navigation in darkness cannot be explained if the path integration system acted independently of boundary (landmark) information. In vivo recordings demonstrate that the rodent head direction (HD) system becomes unstable within three minutes without vision. In contrast, rodents maintain stable place fields and grid fields for over half an hour without vision. Using a simple HD error model, we show analytically that idiothetic path integration (iPI) alone cannot be used to maintain any stable place representation beyond two to three minutes. We then use a measure of place stability based on information theoretic principles to prove that featureless boundaries alone cannot be used to improve localization above chance level. Having shown that neither iPI nor boundaries alone are sufficient, we then address the question of whether their combination is sufficient and – we conjecture – necessary to maintain place stability for prolonged periods without vision. We addressed this question in simulations and robot experiments using a navigation model comprising of a particle filter and boundary map. The model replicates published experimental results on place field and grid field stability without vision, and makes testable predictions including place field splitting and grid field rescaling if the true arena geometry differs from the acquired boundary map. We discuss our findings in light of current theories of animal navigation and neuronal computation, and elaborate on their implications and significance for the design, analysis and interpretation of experiments.

Coding, stability, and non-spatial inputs in a modular grid-to-place cell model

Grid cells in the medial entorhinal cortex (mEC) and place cells in the hippocampus are paradigms for population coding of spatial information [1]. Both the spatiallyperiodic firing fields of grid cells and the spatially localized firing fields of place cells show systematic increases in spatial scale along the dorso-ventral axes of the mEC and hippocampus, respectively [2,3], which has led to speculation that place field size is determined simply by the spatial scale of a place cell’s grid cell inputs. However, in addition to receiving spatially-modulated entorhinal inputs, place cells receive contextual, non-spatial inputs from sources such as the amygdala and hypothalamus [4], which may be important in determining place cell firing properties. These non-spatial inputs are particularly prominent toward the ventral pole of the hippocampus [4], and thus could also play a role in producing dorso-ventral place cell differences. In order to understand the relative contributions of grid cells and non-spatial inputs in determining place field size and stability, we propose a computational model of the hippocampal-entorhinal network that includes a modular organization of grid cell inputs arranged in order of increasing spatial scale, as is seen experimentally in the mEC. Our underlying place cell model is a firing-rate based model inspired by previous work [5], in which place fields are formed via competition between place cells. We also introduce a dorsoventral gradient in the amount of non-spatial input to place cells, with ventral cells receiving more input from non-spatial sources. Finally, we introduce heterogeneity into the firing rates of grid vertices within individual grid fields. This heterogeneity is observed in experimental recordings [6] but has received relatively little attention in experimental or theoretical work, despite its potential impact on place field stability. Our main findings suggest that: 1.) For a wide range of parameters, the relative amounts of spatial and non-spatial inputs to place cells plays a more important role in determining place field size and stability than the spatial scale of grid cell inputs. This implies that the dorso-ventral gradient in place field size may reflect a dorso-ventral gradient in non-spatial inputs, rather than grid scale, and is agreement with prior suggestions of a functional distinction between the dorsal and ventral regions of the hippocampus [7]. 2.) In our model, place fields are sensitive to changes in the firing rates of the grid vertices of individual grid cells, emphasizing the potential implications of this grid field heterogeneity for place field formation and stability.

Remembering to Learn: Independent Place and Journey Coding Mechanisms Contribute to Memory Transfer

The neural mechanisms that integrate new episodes with established memories are unknown. When rats explore an environment, CA1 cells fire in place fields that indicate locations. In goal-directed spatial memory tasks, some place fields differentiate behavioral histories ("journey-dependent" place fields) while others do not ("journey-independent" place fields). To investigate how these signals inform learning and memory for new and familiar episodes, we recorded CA1 and CA3 activity in rats trained to perform a "standard" spatial memory task in a plus maze and in two new task variants. A "switch" task exchanged the start and goal locations in the same environment; an "altered environment" task contained unfamiliar local and distal cues. In the switch task, performance was mildly impaired, new firing maps were stable, but the proportion and stability of journey-dependent place fields declined. In the altered environment, overall performance was strongly impaired, new firing maps were unstable, and stable proportions of journey-dependent place fields were maintained. In both tasks, memory errors were accompanied by a decline in journey codes. The different dynamics of place and journey coding suggest that they reflect separate mechanisms and contribute to distinct memory computations. Stable place fields may represent familiar relationships among environmental features that are required for consistent memory performance. Journey-dependent activity may correspond with goal-directed behavioral sequences that reflect expectancies that generalize across environments. The complementary signals could help link current events with established memories, so that familiarity with either a behavioral strategy or an environment can inform goal-directed learning.

Contribution of Ih to LTP, Place Cells, and Grid Cells

The brain's grid and place cells, which contribute to spatial representations of the external environment, are thought to be modulated by the hyperpolarization-activated cation current (I(h)). Giocomo et al. and Hussaini et al. now provide new insights into these cells' unique activity patterns by studying transgenic mice lacking I(h).

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.

A stable hippocampal representation of a space requires its direct experience

In humans and other mammals, the hippocampus is critical for episodic memory, the autobiographical record of events, including where and when they happen. When one records from hippocampal pyramidal neurons in awake, behaving rodents, their most obvious firing correlate is the animal's position within a particular environment, earning them the name "place cells." When an animal explores a novel environment, its pyramidal neurons form their spatial receptive fields over a matter of minutes and are generally stable thereafter. This experience-dependent stabilization of place fields is therefore an attractive candidate neural correlate of the formation of hippocampal memory. However, precisely how the animal's experience of a context translates into stable place fields remains largely unclear. For instance, we still do not know whether observation of a space is sufficient to generate a stable hippocampal representation of that space because the animal must physically visit a spot to demonstrate which cells fire there. We circumvented this problem by comparing the relative stability of place fields of directly experienced space from merely observed space following blockade of NMDA receptors, which preferentially destabilizes newly generated place fields. This allowed us to determine whether place cells stably represent parts of the environment the animal sees, but does not actually occupy. We found that the formation of stable place fields clearly requires direct experience with a space. This suggests that place cells are part of an autobiographical record of events and their spatial context, consistent with providing the "where" information in episodic memory.

Ventral tegmental area disruption selectively affects CA1/CA2 but not CA3 place fields during a differential reward working memory task.

Hippocampus (HPC) receives dopaminergic (DA) projections from the ventral tegmental area (VTA) and substantia nigra. These inputs appear to provide a modulatory signal that influences HPC dependent behaviors and place fields. We examined how efferent projections from VTA to HPC influence spatial working memory and place fields when the reward context changes. CA1 and CA3 process environmental context changes differently and VTA preferentially innervates CA1. Given these anatomical data and electrophysiological evidence that implicate DA in reward processing, we predicted that CA1 place fields would respond more strongly to both VTA disruption and changes in the reward context than CA3 place fields. Rats (N = 9) were implanted with infusion cannula targeting VTA and recording tetrodes aimed at HPC. Then they were tested on a differential reward, win-shift working memory task. One recording session consisted of 5 baseline and 5 manipulation trials during which place cells in CA1/CA2 (N = 167) and CA3 (N = 94) were recorded. Prior to manipulation trials rats were infused with either baclofen or saline and then subjected to control or reward conditions during which the learned locations of large and small reward quantities were reversed. VTA disruption resulted in an increase in errors, and in CA1/CA2 place field reorganization. There were no changes in any measures of CA3 place field stability during VTA disruption. Reward manipulations did not affect performance or place field stability in CA1/CA2 or CA3; however, changes in the reward locations "rescued" performance and place field stability in CA1/CA2 when VTA activity was compromised, perhaps by trigging compensatory mechanisms. These data support the hypothesis that VTA contributes to spatial working memory performance perhaps by maintaining place field stability selectively in CA1/CA2.