Place Cell Activity Research Articles

The Ventral Midline Thalamus Mediates Hippocampal Spatial Information Processes upon Spatial Cue Changes.

The ventral midline thalamus, consisting of the reuniens and rhomboid nuclei (RE/Rh), is a thalamic structure interconnected with the limbic systems including the hippocampus. Recently, many studies have revealed that this structure plays distinctive roles in spatial learning and memory in collaboration with hippocampal functions. However, what aspects of spatial information process are influenced by the RE/Rh is not clearly known. To elucidate the roles of RE/Rh in spatial information processing and its effects on hippocampal activity, specifically with the manipulation of spatial contents, we measured hippocampal-dependent spatial memory performance and hippocampal place cell activities after RE/Rh lesion using male C57BL/6J × 129/SvJae hybrid mice. We found that the lesion altered the behavioral aptitude in recognizing locational changes of an object. Furthermore, CA1 place cells in the lesion group showed different spatial representation patterns in recognizing the environment with cue locational changes compared with the control group. Interestingly, the patterns of CA1 place cells in recognizing the same environment previously visited were not disrupted in the lesion group compared with the control group. These findings demonstrate that the ventral midline thalamus (RE/Rh) is important in recognizing the spatial relationships, especially when spatial rearrangement of cue position was introduced.SIGNIFICANCE STATEMENT The ventral midline thalamic nuclei (reuniens and rhomboid) interact with the hippocampus to influence various cognitive functions requiring spatial memories, yet what aspects of spatial information process are influenced by these nuclei is not clearly known. Here, we reveal that these nuclei play a crucial role in modulating hippocampal properties only with locational rearrangement of cues, not with the familiar arrangement. These nuclei are distinctively involved in cue-dependent spatial information processes of CA1 place cells. In particular, we suggest that these nuclei modulate spatial information processing on discrete components, especially when the spatial cue relationship is modified.

Replays of spatial memories suppress topological fluctuations in cognitive map.

The spiking activity of the hippocampal place cells plays a key role in producing and sustaining an internalized representation of the ambient space—a cognitive map. These cells do not only exhibit location-specific spiking during navigation, but also may rapidly replay the navigated routs through endogenous dynamics of the hippocampal network. Physiologically, such reactivations are viewed as manifestations of “memory replays” that help to learn new information and to consolidate previously acquired memories by reinforcing synapses in the parahippocampal networks. Below we propose a computational model of these processes that allows assessing the effect of replays on acquiring a robust topological map of the environment and demonstrate that replays may play a key role in stabilizing the hippocampal representation of space.

Abnormal Locus Coeruleus Sleep Activity Alters Sleep Signatures of Memory Consolidation and Impairs Place Cell Stability and Spatial Memory

Sleep is critical for proper memory consolidation. The locus coeruleus (LC) releases norepinephrine throughout the brain except when the LC falls silent throughout rapid eye movement (REM) sleep and prior to each non-REM (NREM) sleep spindle. We hypothesize that these transient LC silences allow the synaptic plasticity that is necessary to incorporate new information into pre-existing memory circuits. We found that spontaneous LC activity within sleep spindles triggers a decrease in spindle power. By optogenetically stimulating norepinephrine-containing LC neurons at 2Hz during sleep, we reduced sleep spindle occurrence, as well as NREM delta power and REM theta power, without causing arousals or changing sleep amounts. Stimulating the LC during sleep following a hippocampus-dependent food location learning task interfered with consolidation of newly learned locations and reconsolidation of previous locations, disrupting next-day place cell activity. The LC stimulation-induced reduction in NREM sleep spindles, delta, and REM theta and reduced ripple-spindle coupling all correlated with decreased hippocampus-dependent performance on the task. Thus, periods of LC silence during sleep following learning are essential for normal spindle generation, delta and theta power, and consolidation of spatial memories.

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.

A neural-level model of spatial memory and imagery.

We present a model of how neural representations of egocentric spatial experiences in parietal cortex interface with viewpoint-independent representations in medial temporal areas, via retrosplenial cortex, to enable many key aspects of spatial cognition. This account shows how previously reported neural responses (place, head-direction and grid cells, allocentric boundary- and object-vector cells, gain-field neurons) can map onto higher cognitive function in a modular way, and predicts new cell types (egocentric and head-direction-modulated boundary- and object-vector cells). The model predicts how these neural populations should interact across multiple brain regions to support spatial memory, scene construction, novelty-detection, 'trace cells', and mental navigation. Simulated behavior and firing rate maps are compared to experimental data, for example showing how object-vector cells allow items to be remembered within a contextual representation based on environmental boundaries, and how grid cells could update the viewpoint in imagery during planning and short-cutting by driving sequential place cell activity.

The importance of forgetting: Limiting memory improves recovery of topological characteristics from neural data.

We develop of a line of work initiated by Curto and Itskov towards understanding the amount of information contained in the spike trains of hippocampal place cells via topology considerations. Previously, it was established that simply knowing which groups of place cells fire together in an animal’s hippocampus is sufficient to extract the global topology of the animal’s physical environment. We model a system where collections of place cells group and ungroup according to short-term plasticity rules. In particular, we obtain the surprising result that in experiments with spurious firing, the accuracy of the extracted topological information decreases with the persistence (beyond a certain regime) of the cell groups. This suggests that synaptic transience, or forgetting, is a mechanism by which the brain counteracts the effects of spurious place cell activity.

Utilizing Miniature Fluorescence Microscopy to Image Hippocampal Place Cell Ensemble Function in Thy1.GCaMP6f Transgenic Mice.

Imaging neuronal activity in awake behaving mice with miniature fluorescence microscopes requires the implementation of a variety of procedures. Surgeries are performed to gain access to the cell population of interest and to implant microscope components. After a recovery period, mice are trained to exhibit a desired behavior. Finally, neuronal activity is imaged and synchronized with that behavior. To take full advantage of the technology, selection of the calcium indicator and experimental design must be carefully considered. In this article, we explain the procedures and considerations that are critical for obtaining high-quality calcium imaging data. As an example, we describe how to utilize miniature fluorescence microscopy to image hippocampal place cell activity during linear track running in Thy1.GCaMP6f transgenic mice. © 2018 by John Wiley & Sons, Inc.

Open source modules for tracking animal behavior and closed-loop stimulation based on Open Ephys and Bonsai

Objective. A major goal in systems neuroscience is to determine the causal relationship between neural activity and behavior. To this end, methods that combine monitoring neural activity, behavioral tracking, and targeted manipulation of neurons in closed-loop are powerful tools. However, commercial systems that allow these types of experiments are usually expensive and rely on non-standardized data formats and proprietary software which may hinder user-modifications for specific needs. In order to promote reproducibility and data-sharing in science, transparent software and standardized data formats are an advantage. Here, we present an open source, low-cost, adaptable, and easy to set-up system for combined behavioral tracking, electrophysiology, and closed-loop stimulation. Approach. Based on the Open Ephys system (www.open-ephys.org) we developed multiple modules to include real-time tracking and behavior-based closed-loop stimulation. We describe the equipment and provide a step-by-step guide to set up the system. Combining the open source software Bonsai (bonsai-rx.org) for analyzing camera images in real time with the newly developed modules in Open Ephys, we acquire position information, visualize tracking, and perform tracking-based closed-loop stimulation experiments. To analyze the acquired data we provide an open source file reading package in Python. Main results. The system robustly visualizes real-time tracking and reliably recovers tracking information recorded from a range of sampling frequencies (30–1000 Hz). We combined electrophysiology with the newly-developed tracking modules in Open Ephys to record place cell and grid cell activity in the hippocampus and in the medial entorhinal cortex, respectively. Moreover, we present a case in which we used the system for closed-loop optogenetic stimulation of entorhinal grid cells. Significance. Expanding the Open Ephys system to include animal tracking and behavior-based closed-loop stimulation extends the availability of high-quality, low-cost experimental setup within standardized data formats serving the neuroscience community.

Hippocampal place cell dysfunction and the effects of muscarinic M1 receptor agonism in a rat model of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease that disproportionately impacts memory and the hippocampus. However, it is unclear how AD pathology influences the activity of surviving neurons in the hippocampus to contribute to the memory symptoms in AD. One well-understood connection between spatial memory and neuronal activity in healthy brains is the activity of place cells, neurons in the hippocampus that fire preferentially in a specific location of a given environment (the place field of the place cell). In the present study, place cells were recorded from the hippocampus in a recently-developed rat model of AD (Tg-F344 AD) at an age (12-20 months) at which the AD rats showed marked spatial memory deficits. Place cells in the CA2 and CA3 pyramidal regions of the hippocampus in AD rats showed sharply reduced spatial fidelity relative to wild-type (WT) rats. In contrast, spiking activity of place cells recorded in region CA1 in AD rats showed good spatial fidelity that was similar to CA1 place cells in WT rats. Oral administration of the M1 muscarinic acetylcholine receptor agonist VU0364572 impacted place cell firing rates in CA1 and CA2/3 hippocampal regions, but did not improve the spatial fidelity of CA2/3 hippocampal place cells in AD rats. The results indicated that, to the extent the spatial memory impairment in AD rats was attributable to hippocampal dysfunction, the memory impairment was more attributable to dysfunction in hippocampal regions CA2 and CA3 rather than CA1.

Recurrent network model for learning goal-directed sequences through reverse replay.

Reverse replay of hippocampal place cells occurs frequently at rewarded locations, suggesting its contribution to goal-directed path learning. Symmetric spike-timing dependent plasticity (STDP) in CA3 likely potentiates recurrent synapses for both forward (start to goal) and reverse (goal to start) replays during sequential activation of place cells. However, how reverse replay selectively strengthens forward synaptic pathway is unclear. Here, we show computationally that firing sequences bias synaptic transmissions to the opposite direction of propagation under symmetric STDP in the co-presence of short-term synaptic depression or afterdepolarization. We demonstrate that significant biases are created in biologically realistic simulation settings, and this bias enables reverse replay to enhance goal-directed spatial memory on a W-maze. Further, we show that essentially the same mechanism works in a two-dimensional open field. Our model for the first time provides the mechanistic account for the way reverse replay contributes to hippocampal sequence learning for reward-seeking spatial navigation.

Differential Representation of Landmark and Self-Motion Information along the CA1 Radial Axis: Self-Motion Generated Place Fields Shift toward Landmarks during Septal Inactivation.

Spatial location in the environment can be defined in relation to specific landmarks or in relation to the global context, and is estimated from both the sensing of landmarks and the inner sense of cumulated locomotion referred to as path-integration. The respective contribution of landmark and path-integration to place-cell activity in the hippocampus is still unclear and complicated by the fact that the two mechanisms usually overlap. To bias spatial mechanisms toward landmark or path-integration, we use a treadmill equipped with a long belt on which male mice run sequentially through a zone enriched and a zone impoverished in visual-tactile cues. We show that inactivation of the medial septum (MS), which is known to disrupt the periodic activity of grid cells, impairs mice ability to anticipate the delivery of a reward in the cue-impoverished zone and transiently alter the spatial configuration of place fields in the cue-impoverished zone selectively: following MS inactivation, place fields in the cue-impoverished zone progressively shift backward and stabilize near the cues, resulting in the contraction of the spatial representation around cues; following MS recovery, the initial spatial representation is progressively restored. Furthermore, we found that place fields in the cue-rich and cue-impoverished zones are preferentially generated by cells from the deep and superficial sublayers of CA1, respectively. These findings demonstrate with mechanistic insights the contribution of MS to the spread of spatial representations in cue-impoverished zones, and indicate a segregation of landmark-based and path-integration-assisted spatial mechanisms into deep and superficial CA1, respectively.SIGNIFICANCE STATEMENT Cells encoding a cue-impoverished zone and the vicinity of landmarks responded differentially to septal inactivation and resided in distinct sublayers of CA1. These findings provide new insights on place field mechanisms: septal activity is critical for maintaining the spread of place fields in cue-impoverished areas, but not for the generation of place fields; Following MS inactivation, trial-by-trial network modifications by activity-dependent mechanisms are responsible for the gradual collapse of spatial representations. Furthermore, the findings suggest parallel coding streams for landmark and self-motion information. Superficial CA1 cells are better suited for encoding global position via the assist of path-integration, whereas deep CA1 cells can support spatial memory processes on an object-specific basis.

Persistent Sodium Current Mediates the Steep Voltage Dependence of Spatial Coding in Hippocampal Pyramidal Neurons

The mammalian hippocampus forms a cognitive map using neurons that fire according to an animal's position ("place cells") and many other behavioral and cognitive variables. The responses of these neurons are shaped by their presynaptic inputs and the nature of their postsynaptic integration. In CA1 pyramidal neurons, spatial responses invivo exhibit a strikingly supralinear dependence on baseline membrane potential. The biophysical mechanisms underlying this nonlinear cellular computation are unknown. Here, through a combination of invitro, invivo, and in silico approaches, we show that persistent sodium current mediates the strong membrane potential dependence of place cell activity. This current operates at membrane potentials below the action potential threshold and over seconds-long timescales, mediating a powerful and rapidly reversible amplification of synaptic responses, which drives place cell firing. Thus, we identify a biophysical mechanism that shapes the coding properties of neurons composing the hippocampal cognitive map.

Uncovering temporal structure in hippocampal output patterns.

Place cell activity of hippocampal pyramidal cells has been described as the cognitive substrate of spatial memory. Replay is observed during hippocampal sharp-wave-ripple-associated population burst events (PBEs) and is critical for consolidation and recall-guided behaviors. PBE activity has historically been analyzed as a phenomenon subordinate to the place code. Here, we use hidden Markov models to study PBEs observed in rats during exploration of both linear mazes and open fields. We demonstrate that estimated models are consistent with a spatial map of the environment, and can even decode animals' positions during behavior. Moreover, we demonstrate the model can be used to identify hippocampal replay without recourse to the place code, using only PBE model congruence. These results suggest that downstream regions may rely on PBEs to provide a substrate for memory. Additionally, by forming models independent of animal behavior, we lay the groundwork for studies of non-spatial memory.

Manipulating Hippocampal Place Cell Activity by Single-Cell Stimulation in Freely Moving Mice

Learning critically depends on the ability to rapidly form and store non-overlapping representations of the external world. In line with their postulated role in episodic memory, hippocampal place cells can undergo a rapid reorganization of their firing fields upon contextual manipulations. To explore the mechanisms underlying such global remapping, we juxtacellularly stimulated 42 hippocampal neurons in freely moving mice during spatial exploration. We found that evoking spike trains in silent neurons was sufficient for creating place fields, while in place cells, juxtacellular stimulation induced a rapid remapping of their place fields to the stimulus location. The occurrence of complex spikes was most predictive of place field plasticity. Our data thus indicate that plasticity-inducing stimuli are able to rapidly bias place cell activity, simultaneously suppressing existing place fields. We propose that such competitive place field dynamics could support the orthogonalization of the hippocampal map during global remapping.

New Hippocampal Circuit Organization Revealed by Viral‐genetic Tracing and Functional Circuit Mapping

The hippocampal formation plays essential roles in learning and memory, and spatial navigation. Although the general anatomy and circuit organization of hippocampal CA1 has been well‐studied, most of our understanding of hippocampal circuits comes from the conventional anatomical tracing studies which lack cell‐type specificity and quantitative measurements of connectional strengths. New advances in virology and molecular genetics complement traditional approaches and are powerful tools for mapping cell‐type‐specific circuit connectivity and function. Using monosynaptic rabies tracing, we recently discovered a non‐canonical but significant set of back‐projections comprised of both excitatory and inhibitory elements from the subiculum to CA1 in the mouse. This discovery suggests previously unconsidered functional roles for direct subicular modulation of hippocampal CA1 circuit activity. In this talk, I will first report our quantitative analysis of canonical‐ and non‐canonical inputs to excitatory neurons in dorsal hippocampal CA1. We find that comparable strength of subiculum complex and entorhinal cortex (EC) inputs to CA1, significant inputs from presubiculum and parasubiculum to CA1, and a threefold stronger input to proximal versus distal CA1 from CA3. Non‐canonical subicular complex inputs exhibit opposing topographic connectivity gradients whereby the subiculum‐CA1 input strength systematically increases but the presubiculum‐CA1 input strength decreases along the proximal‐distal axis. These results reveal a novel anatomical framework by which to determine the circuit bases for CA1 physiological representations. Further, to test the hypothesis that CA1‐projecting subiculum neurons integrate strong CA1 and local subicular inputs to exert direct feedback regulation of CA1 circuit activity, we map and compare global circuit input and output connections of CA1‐projecting and other excitatory subicular neurons using retrograde monosynaptic rabies tracing and anterograde directed herpes simplex virus (H129 strain) in intact brains, respectively. In conjunction with behavior analysis and genetically targeted neuronal activation and inactivation, in vivo GCaMP6‐based calcium imaging of CA1 neurons in freely moving animals is used to resolve how CA1‐projecting subicular neurons modulate CA1 place cell activity and how they contribute to location dependent learning and memory. Together, these studies provide new insights into this subicular‐CA1 pathway, and advance our understanding of how the subiculum interacts with CA1 to regulate hippocampal circuit activity and learning and memory behaviors.Support or Funding InformationThis research is supported by the National Institutes of Health grant (R01NS078434).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A boundary vector cell model of place field repetition

ABSTRACTHippocampal place cells are thought to form the neural substrate of a global cognitive map. However, in multicompartment mazes, these cells exhibit locally repeating representations, undermining the global cognitive map view of place cells. This phenomenon appears to be related to the repetitive layout of these mazes, but still no hypothesis adequately explains it. Here, we use a boundary vector cell (BVC) model of place cell firing to model the activity of place cells in numerous multicompartment environments. The activity of modeled place cells bears a striking resemblance to experimental data, replicating virtually every major experimental result. Our results support the BVC model and indicate that locally repeating place cell firing could result purely from local geometry.

Spatial representations of self and other in the hippocampus.

An animal's awareness of its location in space depends on the activity of place cells in the hippocampus. How the brain encodes the spatial position of others has not yet been identified. We investigated neuronal representations of other animals' locations in the dorsal CA1 region of the hippocampus with an observational T-maze task in which one rat was required to observe another rat's trajectory to successfully retrieve a reward. Information reflecting the spatial location of both the self and the other was jointly and discretely encoded by CA1 pyramidal cells in the observer rat. A subset of CA1 pyramidal cells exhibited spatial receptive fields that were identical for the self and the other. These findings demonstrate that hippocampal spatial representations include dimensions for both self and nonself.

The Hippocampal Ensemble Code for Spatial Navigation and Episodic Memory.

In our minds we can vividly re-experience a series of past events or episodes that occurred along space and time. In 1957, a highly influential clinical investigation published by Scoville and Milner suggested that episodic memory retrieval is severely impaired after physical damage occurs to the hippocampus. In fact, loss of the hippocampus can lead to a profound disturbance to spatial navigation. Within the hippocampus reside place cells: excitatory pyramidal cells that maximally fire at a particular location. The presence of hippocampal place cells across several mammalian species, including mice, rats, bats, and primates, has led to a theory that the hippocampus is a locus of the 'where' element of episodic memory. However, growing evidence suggests that place cell's firings do not merely encode spatial information, but also represent a series of experienced events that occur along the spatiotemporal continuum. This suggestion inspires the following questions: is the ensemble activity of place cells a neuronal substrate for forming or recalling episodic memory? And, why does the hippocampus enable flexible spatial navigation?To address these questions, in this chapter I review several compelling investigations on the firing pattern of place cells, and the temporal flow and reactivation of their ensemble activity. I argue that the sequential activity pattern of hippocampal place cells is capable of encoding not only future trajectory but also future events that occur along space and time. Furthermore, their activity can be reactivated in a temporally compressed fashion while the animal briefly pauses. These pivotal reports strongly support a view that the hippocampal neuronal ensemble enables flexible spatial navigation and contributes to the capacities of episodic memory: mental time travel and foreseeing future situations.

Neuronal Bases of Systemic Organization of Behavior.

Despite the years of studies in the field of systems neuroscience, functions of neural circuits and behavior-related systems are still not entirely clear. The systems description of brain activity has recently been associated with cognitive concepts, e.g. a cognitive map, reconstructed via place-cell activity analysis and the like, and a cognitive schema, modeled in consolidation research. The issue we find of importance is that a cognitive unit reconstructed in neuroscience research is mainly formulated in terms of environment. In other words, the individual experience is considered as a model or reflection of the outside world and usually lacks a biological meaning, such as describing a given part of the world for the individual. In this chapter, we present the idea of a cognitive component that serves as a model of behavioral interaction with environment, rather than a model of the environment itself. This intangible difference entails the need in substantial revision of several well-known phenomena, including the long-term potentiation.The principal questions developed here are how the cognitive units appear and change upon learning and performance, and how the links between them create the whole structure of individual experience. We argue that a clear distinction between processes that provide the emergence of new components and those underlying the retrieval and/or changes in the existing ones is necessary in learning and memory research. We then describe a view on learning and corresponding neuronal activity analysis that may help set this distinction.

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.