Place Cells Research Articles

Chronic implantable flexible serpentine probe reveals impaired spatial coding of place cells in epilepsy

Abstract Developing minimally invasive and reliable electrode probes for neural signal recording is crucial for advancing neuroscience and treating major brain disorders. Flexible neural probes offer superior long-term recording capabilities over traditional rigid probes. This study introduces a parylene-based serpentine electrode probe for stable, long-term neural monitoring. Inspired by the flexibility and morphology of snakes, the probe's serpentine design ensures stable anchorage within the brain tissue during subject movement. The probe features a hydrophilic surface and is combined with a biodegradable silk fibroin-PEG coating, significantly enhancing biocompatibility and mitigating inflammatory responses. In vivo experiments demonstrate that these probes maintain stable, high-quality neural recordings for over eight months. The probes are also used to investigate the neural bases of epilepsy-induced cognitive deficits. By analyzing place cell dynamics in mice pre- and post-epileptic events, we identified the correlation between impaired spatial encoding and the observed cognitive deficits in epileptic mice. This study highlights the potential of our flexible probes in neurological research and medical applications.

Shortcutting from self-motion signals reveals a cognitive map in mice.

Animals navigate by learning the spatial layout of their environment. We investigated spatial learning of mice in an open maze where food was hidden in one of a hundred holes. Mice leaving from a stable entrance learned to efficiently navigate to the food without the need for landmarks. We developed a quantitative framework to reveal how the mice estimate the food location based on analyses of trajectories and active hole checks. After learning, the computed 'target estimation vector' (TEV) closely approximated the mice's route and its hole check distribution. The TEV required learning both the direction and distance of the start to food vector, and our data suggests that different learning dynamics underlie these estimates. We propose that the TEV can be precisely connected to the properties of hippocampal place cells. Finally, we provide the first demonstration that, after learning the location of two food sites, the mice took a shortcut between the sites, demonstrating that they had generated a cognitive map.

Shortcutting from self-motion signals reveals a cognitive map in mice

Animals navigate by learning the spatial layout of their environment. We investigated spatial learning of mice in an open maze where food was hidden in one of a hundred holes. Mice leaving from a stable entrance learned to efficiently navigate to the food without the need for landmarks. We developed a quantitative framework to reveal how the mice estimate the food location based on analyses of trajectories and active hole checks. After learning, the computed ‘target estimation vector’ (TEV) closely approximated the mice’s route and its hole check distribution. The TEV required learning both the direction and distance of the start to food vector, and our data suggests that different learning dynamics underlie these estimates. We propose that the TEV can be precisely connected to the properties of hippocampal place cells. Finally, we provide the first demonstration that, after learning the location of two food sites, the mice took a shortcut between the sites, demonstrating that they had generated a cognitive map.

A cellular basis for mapping behavioural structure.

To flexibly adapt to new situations, our brains must understand the regularities in the world, as well as those in our own patterns of behaviour. A wealth of findings is beginning to reveal the algorithms that we use to map the outside world1-6. However, the biological algorithms that map the complex structured behaviours that we compose to reach our goals remain unknown. Here we reveal a neuronal implementation of an algorithm for mapping abstract behavioural structure and transferring it to new scenarios. We trained mice on many tasks that shared a common structure (organizing a sequence of goals) but differed in the specific goal locations. The mice discovered the underlying task structure, enabling zero-shot inferences on the first trial of new tasks. The activity of most neurons in the medial frontal cortex tiled progress to goal, akin to how place cells map physical space. These 'goal-progress cells' generalized, stretching and compressing their tiling to accommodate different goal distances. By contrast, progress along the overall sequence of goals was not encoded explicitly. Instead, a subset of goal-progress cells was further tuned such that individual neurons fired with a fixed task lag from a particular behavioural step. Together, these cells acted as task-structured memory buffers, implementing an algorithm that instantaneously encoded the entire sequence of future behavioural steps, and whose dynamics automatically computed the appropriate action at each step. These dynamics mirrored the abstract task structure both on-task and during offline sleep. Our findings suggest that schemata of complex behavioural structures can be generated by sculpting progress-to-goal tuning into task-structured buffers of individual behavioural steps.

Spatial representation: How fish know their place

Mammalian place cells are active at one or a few specific locations in the environment. First described in the rodent hippocampus, and subsequently across the mammalian evolutionary tree, place cells have now been discovered in the larval zebrafish telencephalon.

A universal hippocampal memory code across animals and environments.

How learning is affected by context is a fundamental question of neuroscience, as the ability to generalize learning to different contexts is necessary for navigating the world. An example of swift contextual generalization is observed in conditioning tasks, where performance is quickly generalized from one context to another. A key question in identifying the neural substrate underlying this ability is how the hippocampus (HPC) represents task-related stimuli across different environments, given that HPC cells exhibit place-specific activity that changes across contexts (remapping). In this study, we used calcium imaging to monitor hippocampal neuron activity as animals performed a conditioning task across multiple spatial contexts. We investigated whether hippocampal cells, which encode both spatial locations (place cells) and task-related information, could maintain their task representation even when their spatial encoding remapped in a new spatial context. To assess the consistency of task representations, we used advanced dimensionality reduction techniques combined with machine learning to develop manifold representations of population level HPC activity. The results showed that task-related neural representations remained stable even as place cell representations of spatial context changed, thus demonstrating similar embedding geometries of neural representations of the task across different spatial contexts. Notably, these patterns were not only consistent within the same animal across different contexts but also significantly similar across different animals, suggesting a standardized neural encoding or 'neural syntax' in the hippocampus. These findings bridge a critical gap between memory and navigation research, revealing how the hippocampus maintains cognitive consistency across different spatial environments. These findings also suggest that hippocampal function is governed by a neural framework shared between animals, an observation that may have broad implications for understanding memory, learning, and related cognitive processes. Looking ahead, this work opens new avenues for exploring the fundamental principles underlying hippocampal encoding strategies.

Integration of rate and phase codes by hippocampal cell-assemblies supports flexible encoding of spatiotemporal context.

Spatial information is encoded by location-dependent hippocampal place cell firing rates and sub-second, rhythmic entrainment of spike times. These rate and temporal codes have primarily been characterized in low-dimensional environments under limited cognitive demands; but how is coding configured in complex environments when individual place cells signal several locations, individual locations contribute to multiple routes and functional demands vary? Quantifying CA1 population dynamics of male rats during a decision-making task, here we show that the phase of individual place cells' spikes relative to the local theta rhythm shifts to differentiate activity in different place fields. Theta phase coding also disambiguates repeated visits to the same location during different routes, particularly preceding spatial decisions. Using unsupervised detection of cell assemblies alongside theoretical simulation, we show that integrating rate and phase coding mechanisms dynamically recruits units to different assemblies, generating spiking sequences that disambiguate episodes of experience and multiplexing spatial information with cognitive context.

Intrinsic dynamics of randomly clustered networks generate place fields and preplay of novel environments.

During both sleep and awake immobility, hippocampal place cells reactivate time-compressed versions of sequences representing recently experienced trajectories in a phenomenon known as replay. Intriguingly, spontaneous sequences can also correspond to forthcoming trajectories in novel environments experienced later, in a phenomenon known as preplay. Here, we present a model showing that sequences of spikes correlated with the place fields underlying spatial trajectories in both previously experienced and future novel environments can arise spontaneously in neural circuits with random, clustered connectivity rather than pre-configured spatial maps. Moreover, the realistic place fields themselves arise in the circuit from minimal, landmark-based inputs. We find that preplay quality depends on the network's balance of cluster isolation and overlap, with optimal preplay occurring in small-world regimes of high clustering yet short path lengths. We validate the results of our model by applying the same place field and preplay analyses to previously published rat hippocampal place cell data. Our results show that clustered recurrent connectivity can generate spontaneous preplay and immediate replay of novel environments. These findings support a framework whereby novel sensory experiences become associated with preexisting "pluripotent" internal neural activity patterns.

Intrinsic dynamics of randomly clustered networks generate place fields and preplay of novel environments

During both sleep and awake immobility, hippocampal place cells reactivate time-compressed versions of sequences representing recently experienced trajectories in a phenomenon known as replay. Intriguingly, spontaneous sequences can also correspond to forthcoming trajectories in novel environments experienced later, in a phenomenon known as preplay. Here, we present a model showing that sequences of spikes correlated with the place fields underlying spatial trajectories in both previously experienced and future novel environments can arise spontaneously in neural circuits with random, clustered connectivity rather than pre-configured spatial maps. Moreover, the realistic place fields themselves arise in the circuit from minimal, landmark-based inputs. We find that preplay quality depends on the network’s balance of cluster isolation and overlap, with optimal preplay occurring in small-world regimes of high clustering yet short path lengths. We validate the results of our model by applying the same place field and preplay analyses to previously published rat hippocampal place cell data. Our results show that clustered recurrent connectivity can generate spontaneous preplay and immediate replay of novel environments. These findings support a framework whereby novel sensory experiences become associated with preexisting “pluripotent” internal neural activity patterns.

Mechanisms of memory-supporting neuronal dynamics in hippocampal area CA3.

Hippocampal CA3 is central to memory formation and retrieval. Although various network mechanisms have been proposed, direct evidence is lacking. Using intracellular Vm recordings and optogenetic manipulations in behaving mice, we found that CA3 place-field activity is produced by a symmetric form of behavioral timescale synaptic plasticity (BTSP) at recurrent synapses among CA3 pyramidal neurons but not at synapses from the dentate gyrus (DG). Additional manipulations revealed that excitatory input from the entorhinal cortex (EC) but not the DG was required to update place cell activity based on the animal's movement. These data were captured by a computational model that used BTSP and an external updating input to produce attractor dynamics under online learning conditions. Theoretical analyses further highlight the superior memory storage capacity of such networks, especially when dealing with correlated input patterns. This evidence elucidates the cellular and circuit mechanisms of learning and memory formation in the hippocampus.

Neuronal activity in the ventral tegmental area during goal-directed navigation recorded by low-curvature microelectrode arrays

Navigating toward destinations with rewards is a common behavior among animals. The ventral tegmental area (VTA) has been shown to be responsible for reward coding and reward cue learning, and its response to other variables, such as kinematics, has also been increasingly studied. These findings suggest a potential relationship between animal navigation behavior and VTA activity. However, the deep location and small volume of the VTA pose significant challenges to the precision of electrode implantation, increasing the uncertainty of measurement results during animal navigation and thus limiting research on the role of the VTA in goal-directed navigation. To address this gap, we innovatively designed and fabricated low-curvature microelectrode arrays (MEAs) via a novel backside dry etching technique to release residual stress. Histological verification confirmed that low-curvature MEAs indeed improved electrode implantation precision. These low-curvature MEAs were subsequently implanted into the VTA of the rats to observe their electrophysiological activity in a freely chosen modified T-maze. The results of the behavioral experiments revealed that the rats could quickly learn the reward probability corresponding to the left and right paths and that VTA neurons were deeply involved in goal-directed navigation. Compared with those in no-reward trials, VTA neurons in reward trials presented a significantly greater firing rate and larger local field potential (LFP) amplitude during the reward-consuming period. Notably, we discovered place fields mapped by VTA neurons, which disappeared or were reconstructed with changes in the path–outcome relationship. These results provide new insights into the VTA and its role in goal-directed navigation. Our designed and fabricated low-curvature microelectrode arrays can serve as a new device for precise deep brain implantation in the future.

Dendritic, delayed, stochastic CaMKII activation in behavioural time scale plasticity

Behavioural time scale plasticity (BTSP) is non-Hebbian plasticity induced by integrating presynaptic and postsynaptic components separated by a behaviourally relevant time scale (seconds)1. BTSP in hippocampal CA1 neurons underlies place cell formation. However, the molecular mechanisms that enable synapse-specific plasticity on a behavioural time scale are unknown. Here we show that BTSP can be induced in a single dendritic spine using two-photon glutamate uncaging paired with postsynaptic current injection temporally separated by a behavioural time scale. Using an improved Ca2+/calmodulin-dependent kinase II (CaMKII) sensor, we did not detect CaMKII activation during this BTSP induction. Instead, we observed dendritic, delayed and stochastic CaMKII activation (DDSC) associated with Ca2+ influx and plateau potentials 10–100 s after BTSP induction. DDSC required both presynaptic and postsynaptic activity, which suggests that CaMKII can integrate these two signals. Also, optogenetically blocking CaMKII 15–30 s after the BTSP protocol inhibited synaptic potentiation, which indicated that DDSC is an essential mechanism of BTSP. IP3-dependent intracellular Ca2+ release facilitated both DDSC and BTSP. Thus, our study suggests that non-synapse-specific CaMKII activation provides an instructive signal with an extensive time window over tens of seconds during BTSP.

Category boundaries modulate memory in a place-cell-like manner

Concepts describe how instances of the same kind are related, enabling the categorization and interpretation of new information.1,2 How concepts are represented is a longstanding question. Category boundaries have been considered defining features of concept representations, which can guide categorical inference,3 with fMRI evidence showing category-boundary signals in the hippocampus.4,5 The underlying neural mechanism remains unclear. The hippocampal-entorhinal system, known for its spatially tuned neurons that form cognitive maps of space,6,7 may support conceptual knowledge formation, with place cells encoding locations in conceptual space.4,8,9,10,11 Physical boundaries anchor spatial representations and boundary shifts affect place and grid fields,12,13,14,15,16 as well as human spatial memory,17,18,19 along manipulated dimensions. These place cell responses are likely driven by boundary vector cells, which respond to boundaries at specific allocentric distances and directions,20,21,22,23 the neural correlates of which have been identified in the subiculum and entorhinal cortex20,24,25. We hypothesize similar patterns of memory adaptations in response to shifting category boundaries. Our findings show that after category boundary shifts, participants' memory for category exemplars distorts along the changed dimension, mirroring place field deformations. We demonstrate that the boundary vector cell model of place cell firing best accounts for these distortions compared with alternative geometric explanations. Our study highlights a role of category boundaries in human cognition and establishes a new complementary link between hippocampal coding properties with respect to boundaries and human concept representation, bridging spatial and conceptual domains.

Experience of Euclidean geometry sculpts the development and dynamics of rodent hippocampal sequential cell assemblies

Euclidean space is the fabric of the world we live in. Whether and how geometric experience shapes our spatial-temporal representations of the world remained unknown. We deprived male rats of experience with crucial features of Euclidean geometry by rearing them inside spheres, and compared activity of large hippocampal neuronal ensembles during navigation and sleep with that of cuboid cage-reared controls. Sphere-rearing from birth permitted emergence of accurate neuronal ensemble spatial codes and preconfigured and plastic time-compressed neuronal sequences. However, sphere-rearing led to diminished individual place cell tuning, more similar neuronal mapping of different track ends/corners, and impaired pattern separation and plasticity of multiple linear tracks, coupled with reduced preconfigured sleep network repertoires. Subsequent experience with multiple linear environments over four days largely reversed these effects. Thus, early-life experience with Euclidean geometry enriches the hippocampal repertoire of preconfigured neuronal patterns selected toward unique representation and discrimination of multiple linear environments.

Distinct Disruptions in CA1 and CA3 Place Cell Function in Alzheimer's Disease Mice.

The hippocampus, a critical brain structure for spatial learning and memory, is susceptible to neurodegenerative disorders such as Alzheimer's disease (AD). The APPswe/PSEN1dE9 (APP/PS1) transgenic mouse model is widely used to study the pathology of AD. Although previous research has established AD-associated impairments in hippocampal-dependent learning and memory, the neurophysiological mechanisms underlying these cognitive dysfunctions remain less understood. To address this gap, we investigated the activities of place cells in both CA1 and CA3 hippocampal subregions, which have distinct yet complementary computational roles. Behaviorally, APP/PS1 mice demonstrated impaired spatial recognition memory compared to wild-type (WT) mice in the object location test. Physiologically, place cells in APP/PS1 mice showed deterioration in spatial representation compared to WT. Specifically, CA1 place cells exhibited significant reductions in coherence and spatial information, while CA3 place cells displayed a significant reduction in place field size. Both CA1 and CA3 place cells in APP/PS1 mice also showed significant disruptions in their ability to stably encode the same environment. Furthermore, the burst firing properties of these cells were altered to forms correlated with reduced cognition. Additionally, the theta rhythm was significantly attenuated in CA1 place cells of APP/PS1 mice compared to WT. Our results suggest that distinct alteration in the physiological properties of CA1 and CA3 place cells, coupled with disrupted hippocampal theta rhythm in CA1, may collectively contribute to impaired hippocampal-dependent spatial learning and memory in AD.

Social odors drive hippocampal CA2 place cell responses to social stimuli.

Hippocampal region CA2 is essential for social memory processing. Interaction with social stimuli induces changes in CA2 place cell firing during active exploration and sharp wave-ripples during rest following a social interaction. However, it is unknown whether these changes in firing patterns are caused by integration of multimodal social stimuli or by a specific sensory modality associated with a social interaction. Rodents rely heavily on chemosensory cues in the form of olfactory signals for social recognition processes. To determine the extent to which social olfactory signals contribute to CA2 place cell responses to social stimuli, we recorded CA2 place cells in rats freely exploring environments containing stimuli that included or lacked olfactory content. We found that CA2 place cell firing patterns significantly changed only when social odors were prominent. Also, place cells that increased their firing in the presence of social odors alone preferentially increased their firing during subsequent sharp wave-ripples. Our results suggest that social olfactory cues are essential for changing CA2 place cell firing patterns during and after social interactions. These results support prior work suggesting CA2 performs social functions and shed light on processes underlying CA2 responses to social stimuli.

Investigating Egocentric Tuning in Hippocampal CA1 Neurons.

Navigation requires integrating sensory information with a stable schema to create a dynamic map of an animal's position using egocentric and allocentric coordinate systems. In the hippocampus, place cells encode allocentric space, but their firing rates may also exhibit directional tuning within egocentric or allocentric reference frames. We compared experimental and simulated data to assess the prevalence of tuning to egocentric bearing (EB) among hippocampal cells in rats foraging in an open field. Using established procedures, we confirmed egocentric modulation of place cell activity in recorded data; however, simulated data revealed a high false-positive rate (FPR). When we accounted for false positives by comparing with shuffled data that retain correlations between the animal's direction and position, only a very low number of hippocampal neurons appeared modulated by EB. Our study highlights biases affecting FPRs and provides insights into the challenges of identifying egocentric modulation in hippocampal neurons.

Alzheimer's pathology disrupts flexible place cell coding and hippocampal-prefrontal neural dynamics during risky foraging decisions in mice.

This study investigates the neural activity patterns associated with impaired decision-making in Alzheimer's disease (AD) by examining the effects of amyloid pathology on prefrontal-hippocampal circuit dynamics in 5XFAD mice, a model system known for its pronounced early amyloid pathology. Using ecologically relevant "approach food-avoid predator" paradigms, we revealed that 5XFAD mice display impaired decision strategies in risky foraging tasks, characterized by rigid hippocampal place fields and diminished sharp-wave ripple (SWR) frequencies, accompanied by disrupted prefrontal-hippocampal connectivity. These neural deficits align with behavioral inflexibility in dynamic threat scenarios. Our findings indicate that disrupted SWR dynamics and corticolimbic connectivity contribute to decision-making deficits in AD, emphasizing the potential of targeting these specific neural mechanisms to ameliorate cognitive impairments. This research contributes significantly to our understanding of AD's impact on cognition, providing insights that could lead to more targeted therapeutic strategies.

Building a Versatile and Efficient Service Design Team

At its core, service design is about addressing ambiguity to drivetransformational changes. As service designers, working with ambiguity is one of the first things we learn to dealwith, and it’s what we excel at. It might even be what drew us to the service design field in the first place.

Brain–computer interface for simultaneous dual‐region spatial coding in hippocampal and somatosensory cortex of freely behaving rats

AbstractDecoding of spatial information from place cells is currently limited to individual brain regions, severely constraining the understanding of the brain's spatial navigation mechanisms. In this study, synchronized detection of dual‐brain region spatial encoding was conducted using brain–computer interface (BCI). Therefore, an implantable microelectrode array (MEA) was developed tailored for the simultaneous detection of neuronal activities in the CA1 of the hippocampus and the Barrel Cortex (BC) of the somatosensory cortex in rats as BCI. The MEA was improved by modifying the nanocomposite PtNP/PEDOT:PSS to improve their electrical properties (reducing impedance from 1.82 ± 0.17 MΩ to 3.4 ± 0.3 kΩ), facilitating neural recordings in freely behaving rats. The neural activities were obtained from the CA1 and the BC simultaneously and validated the existence of place cells in both brain regions. This study highlighted the potential of PtNP/PEDOT:PSS‐modified MEA as BCI in concurrently detecting neural activity associated with spatial encoding in two brain regions, offering novel perspectives on the processing of tactile stimuli and the formation of cognitive maps for navigation.