entorhinal cortex

Unpacking the role of the medial septum in spatial coding in the medial entorhinal cortex

Single-neuron correlates of perception and memory in the human medial temporal lobe

The human medial temporal lobe contains neurons that respond selectively to the semantic contents of a presented stimulus. These "concept cells" may respond to very different pictures of a given person and even to their written or spoken name. Their response latency is far longer than necessary for object recognition, they follow subjective, conscious perception, and they are found in brain regions that are crucial for declarative memory formation. It has thus been hypothesized that they may represent the semantic "building blocks" of episodic memories. In this talk I will present data from single unit recordings in the hippocampus, entorhinal cortex, parahippocampal cortex, and amygdala during paradigms involving object recognition and conscious perception as well as encoding of episodic memories in order to characterize the role of concept cells in these cognitive functions.

Cognitive maps as expectations learned across episodes – a model of the two dentate gyrus blades

How can the hippocampal system transition from episodic one-shot learning to a multi-shot learning regime and what is the utility of the resultant neural representations? This talk will explore the role of the dentate gyrus (DG) anatomy in this context. The canonical DG model suggests it performs pattern separation. More recent experimental results challenge this standard model, suggesting DG function is more complex and also supports the precise binding of objects and events to space and the integration of information across episodes. Very recent studies attribute pattern separation and pattern integration to anatomically distinct parts of the DG (the suprapyramidal blade vs the infrapyramidal blade). We propose a computational model that investigates this distinction. In the model the two processing streams (potentially localized in separate blades) contribute to the storage of distinct episodic memories, and the integration of information across episodes, respectively. The latter forms generalized expectations across episodes, eventually forming a cognitive map. We train the model with two data sets, MNIST and plausible entorhinal cortex inputs. The comparison between the two streams allows for the calculation of a prediction error, which can drive the storage of poorly predicted memories and the forgetting of well-predicted memories. We suggest that differential processing across the DG aids in the iterative construction of spatial cognitive maps to serve the generation of location-dependent expectations, while at the same time preserving episodic memory traces of idiosyncratic events.

Relations and Predictions in Brains and Machines

Humans and animals learn and plan with flexibility and efficiency well beyond that of modern Machine Learning methods. This is hypothesized to owe in part to the ability of animals to build structured representations of their environments, and modulate these representations to rapidly adapt to new settings. In the first part of this talk, I will discuss theoretical work describing how learned representations in hippocampus enable rapid adaptation to new goals by learning predictive representations, while entorhinal cortex compresses these predictive representations with spectral methods that support smooth generalization among related states. I will also cover recent work extending this account, in which we show how the predictive model can be adapted to the probabilistic setting to describe a broader array of generalization results in humans and animals, and how entorhinal representations can be modulated to support sample generation optimized for different behavioral states. In the second part of the talk, I will overview some of the ways in which we have combined many of the same mathematical concepts with state-of-the-art deep learning methods to improve efficiency and performance in machine learning applications like physical simulation, relational reasoning, and design.

A specialized role for entorhinal attractor dynamics in combining path integration and landmarks during navigation

During navigation, animals estimate their position using path integration and landmarks. In a series of two studies, we used virtual reality and electrophysiology to dissect how these inputs combine to generate the brain’s spatial representations. In the first study (Campbell et al., 2018), we focused on the medial entorhinal cortex (MEC) and its set of navigationally-relevant cell types, including grid cells, border cells, and speed cells. We discovered that attractor dynamics could explain an array of initially puzzling MEC responses to virtual reality manipulations. This theoretical framework successfully predicted both MEC grid cell responses to additional virtual reality manipulations, as well as mouse behavior in a virtual path integration task. In the second study (Campbell*, Attinger* et al., 2021), we asked whether these principles generalize to other navigationally-relevant brain regions. We used Neuropixels probes to record thousands of neurons from MEC, primary visual cortex (V1), and retrosplenial cortex (RSC). In contrast to the prevailing view that “everything is everywhere all at once,” we identified a unique population of MEC neurons, overlapping with grid cells, that became active with striking spatial periodicity while head-fixed mice ran on a treadmill in darkness. These neurons exhibited unique cue-integration properties compared to other MEC, V1, or RSC neurons: they remapped more readily in response to conflicts between path integration and landmarks; they coded position prospectively as opposed to retrospectively; they upweighted path integration relative to landmarks in conditions of low visual contrast; and as a population, they exhibited a lower-dimensional activity structure. Based on these results, our current view is that MEC attractor dynamics play a privileged role in resolving conflicts between path integration and landmarks during navigation. Future work should include carefully designed causal manipulations to rigorously test this idea, and expand the theoretical framework to incorporate notions of uncertainty and optimality.

Minute-scale periodic sequences in medial entorhinal cortex

The medial entorhinal cortex (MEC) hosts many of the brain’s circuit elements for spatial navigation and episodic memory, operations that require neural activity to be organized across long durations of experience. While location is known to be encoded by a plethora of spatially tuned cell types in this brain region, little is known about how the activity of entorhinal cells is tied together over time. Among the brain’s most powerful mechanisms for neural coordination are network oscillations, which dynamically synchronize neural activity across circuit elements. In MEC, theta and gamma oscillations provide temporal structure to the neural population activity at subsecond time scales. It remains an open question, however, whether similarly coordination occurs in MEC at behavioural time scales, in the second-to-minute regime. In this talk I will show that MEC activity can be organized into a minute-scale oscillation that entrains nearly the entire cell population, with periods ranging from 10 to 100 seconds. Throughout this ultraslow oscillation, neural activity progresses in periodic and stereotyped sequences. The oscillation sometimes advances uninterruptedly for tens of minutes, transcending epochs of locomotion and immobility. Similar oscillatory sequences were not observed in neighboring parasubiculum or in visual cortex. The ultraslow periodic sequences in MEC may have the potential to couple its neurons and circuits across extended time scales and to serve as a scaffold for processes that unfold at behavioural time scales.

Lateral entorhinal cortex directly influences medial entorhinal cortex through synaptic connections in layer 1

Standard models of episodic memory suggest that lateral (LEC) and medial entorhinal cortex (MEC) send independent inputs to the hippocampus, each carrying different types of information. Here, we describe a pathway by which information is integrated between LEC and MEC prior to reaching hippocampus. We demonstrate that LEC sends strong projections to MEC arising from neurons that receive neocortical inputs. Activation of LEC inputs drives excitation of hippocampal-projecting neurons in MEC layer 2, typically followed by inhibition that is accounted for by parallel activation of local inhibitory neurons. We therefore propose that local circuits in MEC may support integration of ‘what’ and ‘where’ information.

Extrinsic control and intrinsic computation in the hippocampal CA1 network

A key issue in understanding circuit operations is the extent to which neuronal spiking reflects local computation or responses to upstream inputs. Several studies have lesioned or silenced inputs to area CA1 of the hippocampus - either area CA3 or the entorhinal cortex and examined the effect on CA1 pyramidal cells. However, the types of the reported physiological impairments vary widely, primarily because simultaneous manipulations of these redundant inputs have never been performed. In this study, I combined optogenetic silencing of unilateral and bilateral mEC, of the local CA1 region, and performed bilateral pharmacogenetic silencing of CA3. I combined this with high spatial resolution extracellular recordings along the CA1-dentate axis. Silencing the medial entorhinal largely abolished extracellular theta and gamma currents in CA1, without affecting firing rates. In contrast, CA3 and local CA1 silencing strongly decreased firing of CA1 neurons without affecting theta currents. Each perturbation reconfigured the CA1 spatial map. Yet, the ability of the CA1 circuit to support place field activity persisted, maintaining the same fraction of spatially tuned place fields. In contrast to these results, unilateral mEC manipulations that were ineffective in impacting place cells during awake behavior were found to alter sharp-wave ripple sequences activated during sleep. Thus, intrinsic excitatory-inhibitory circuits within CA1 can generate neuronal assemblies in the absence of external inputs, although external synaptic inputs are critical to reconfigure (remap) neuronal assemblies in a brain-state dependent manner.

Extrinsic control and autonomous computation in the hippocampal CA1 circuit

In understanding circuit operations, a key issue is the extent to which neuronal spiking reflects local computation or responses to upstream inputs. Because pyramidal cells in CA1 do not have local recurrent projections, it is currently assumed that firing in CA1 is inherited from its inputs – thus, entorhinal inputs provide communication with the rest of the neocortex and the outside world, whereas CA3 inputs provide internal and past memory representations. Several studies have attempted to prove this hypothesis, by lesioning or silencing either area CA3 or the entorhinal cortex and examining the effect of firing on CA1 pyramidal cells. Despite the intense and careful work in this research area, the magnitudes and types of the reported physiological impairments vary widely across experiments. At least part of the existing variability and conflicts is due to the different behavioral paradigms, designs and evaluation methods used by different investigators. Simultaneous manipulations in the same animal or even separate manipulations of the different inputs to the hippocampal circuits in the same experiment are rare. To address these issues, I used optogenetic silencing of unilateral and bilateral mEC, of the local CA1 region, and performed bilateral pharmacogenetic silencing of the entire CA3 region. I combined this with high spatial resolution recording of local field potentials (LFP) in the CA1-dentate axis and simultaneously collected firing pattern data from thousands of single neurons. Each experimental animal had up to two of these manipulations being performed simultaneously. Silencing the medial entorhinal (mEC) largely abolished extracellular theta and gamma currents in CA1, without affecting firing rates. In contrast, CA3 and local CA1 silencing strongly decreased firing of CA1 neurons without affecting theta currents. Each perturbation reconfigured the CA1 spatial map. Yet, the ability of the CA1 circuit to support place field activity persisted, maintaining the same fraction of spatially tuned place fields, and reliable assembly expression as in the intact mouse. Thus, the CA1 network can maintain autonomous computation to support coordinated place cell assemblies without reliance on its inputs, yet these inputs can effectively reconfigure and assist in maintaining stability of the CA1 map.

Efficient reuse of computations in planning

Solving complex planning problems efficiently and flexibly requires reusing expensive previous computations. The brain can do this, but how? I present a new theory that addresses this question and connects planning to hitherto distinct areas within cognitive neuroscience, such as entorhinal representation of cognitive maps and cognitive control.

Mapping Individual Trajectories of Structural and Cognitive Decline in Mild Cognitive Impairment

The US has an aging population. For the first time in US history, the number of older adults is projected to outnumber that of children by 2034. This combined with the fact that the prevalence of Alzheimer's Disease increases exponentially with age makes for a worrying combination. Mild cognitive impairment (MCI) is an intermediate stage of cognitive decline between being cognitively normal and having full-blown Dementia, with every third person with MCI progressing to dementia of the Alzheimer's Type (DAT). While there is no known way to reverse symptoms once they begin, early prediction of disease can help stall its progression and help with early financial planning. While grey matter volume loss in the Hippocampus and Entorhinal Cortex (EC) are characteristic biomarkers of DAT, little is known about the rates of decrease of these volumes within individuals in MCI state across time. We used longitudinal growth curve models to map individual trajectories of volume loss in subjects with MCI. We then looked at whether these rates of volume decrease could predict progression to DAT right in the MCI stage. Finally, we evaluated whether these rates of Hippocampal and EC volume loss were correlated with individual rates of decline of episodic memory, visuospatial ability, and executive function.

Distance-tuned neurons drive specialized path integration calculations in medial entorhinal cortex

During navigation, animals estimate their position using path integration and landmarks, engaging many brain areas. Whether these areas follow specialized or universal cue integration principles remains incompletely understood. We combine electrophysiology with virtual reality to quantify cue integration across thousands of neurons in three navigation-relevant areas: primary visual cortex (V1), retrosplenial cortex (RSC), and medial entorhinal cortex (MEC). Compared with V1 and RSC, path integration influences position estimates more in MEC, and conflicts between path integration and landmarks trigger remapping more readily. Whereas MEC codes position prospectively, V1 codes position retrospectively, and RSC is intermediate between the two. Lowered visual contrast increases the influence of path integration on position estimates only in MEC. These properties are most pronounced in a population of MEC neurons, overlapping with grid cells, tuned to distance run in darkness. These results demonstrate the specialized role that path integration plays in MEC compared with other navigation-relevant cortical areas.

Phase precession in the human hippocampus and entorhinal cortex

Knowing where we are, where we have been, and where we are going is critical to many behaviors, including navigation and memory. One potential neuronal mechanism underlying this ability is phase precession, in which spatially tuned neurons represent sequences of positions by activating at progressively earlier phases of local network theta oscillations. Based on studies in rodents, researchers have hypothesized that phase precession may be a general neural pattern for representing sequential events for learning and memory. By recording human single-neuron activity during spatial navigation, we show that spatially tuned neurons in the human hippocampus and entorhinal cortex exhibit phase precession. Furthermore, beyond the neural representation of locations, we show evidence for phase precession related to specific goal states. Our find- ings thus extend theta phase precession to humans and suggest that this phenomenon has a broad func- tional role for the neural representation of both spatial and non-spatial information.

Self-organized formation of discrete grid cell modules from smooth gradients

Modular structures in myriad forms — genetic, structural, functional — are ubiquitous in the brain. While modularization may be shaped by genetic instruction or extensive learning, the mechanisms of module emergence are poorly understood. Here, we explore complementary mechanisms in the form of bottom-up dynamics that push systems spontaneously toward modularization. As a paradigmatic example of modularity in the brain, we focus on the grid cell system. Grid cells of the mammalian medial entorhinal cortex (mEC) exhibit periodic lattice-like tuning curves in their encoding of space as animals navigate the world. Nearby grid cells have identical lattice periods, but at larger separations along the long axis of mEC the period jumps in discrete steps so that the full set of periods cluster into 5-7 discrete modules. These modules endow the grid code with many striking properties such as an exponential capacity to represent space and unprecedented robustness to noise. However, the formation of discrete modules is puzzling given that biophysical properties of mEC stellate cells (including inhibitory inputs from PV interneurons, time constants of EPSPs, intrinsic resonance frequency and differences in gene expression) vary smoothly in continuous topographic gradients along the mEC. How does discreteness in grid modules arise from continuous gradients? We propose a novel mechanism involving two simple types of lateral interaction that leads a continuous network to robustly decompose into discrete functional modules. We show analytically that this mechanism is a generic multi-scale linear instability that converts smooth gradients into discrete modules via a topological “peak selection” process. Further, this model generates detailed predictions about the sequence of adjacent period ratios, and explains existing grid cell data better than existing models. Thus, we contribute a robust new principle for bottom-up module formation in biology, and show that it might be leveraged by grid cells in the brain.

Dynamic maps of a dynamic world

Extensive research has revealed that the hippocampus and entorhinal cortex maintain a rich representation of space through the coordinated activity of place cells, grid cells, and other spatial cell types. Frequently described as a ‘cognitive map’ or a ‘hippocampal map’, these maps are thought to support episodic memory through their instantiation and retrieval. Though often a useful and intuitive metaphor, a map typically evokes a static representation of the external world. However, the world itself, and our experience of it, are intrinsically dynamic. In order to make the most of their maps, a navigator must be able to adapt to, incorporate, and overcome these dynamics. Here I describe three projects where we address how hippocampal and entorhinal representations do just that. In the first project, I describe how boundaries dynamically anchor entorhinal grid cells and human spatial memory alike when the shape of a familiar environment is changed. In the second project, I describe how the hippocampus maintains a representation of the recent past even in the absence of disambiguating sensory and explicit task demands, a representation which causally depends on intrinsic hippocampal circuitry. In the third project, I describe how the hippocampus preserves a stable representation of context despite ongoing representational changes across a timescale of weeks. Together, these projects highlight the dynamic and adaptive nature of our hippocampal and entorhinal representations, and set the stage for future work building on these techniques and paradigms.

Information Dynamics in the Hippocampus and Cortex and their alterations in epilepsy

Neurological disorders share common high-level alterations, such as cognitive deficits, anxiety, and depression. This raises the possibility of fundamental alterations in the way information conveyed by neural firing is maintained and dispatched in the diseased brain. Using experimental epilepsy as a model of neurological disorder we tested the hypothesis of altered information processing, analyzing how neurons in the hippocampus and the entorhinal cortex store and exchange information during slow and theta oscillations. We equate the storage and sharing of information to low level, or primitive, information processing at the algorithmic level, the theoretical intermediate level between structure and function. We find that these low-level processes are organized into substates during brain states marked by theta and slow oscillations. Their internal composition and organization through time are disrupted in epilepsy, losing brain state-specificity, and shifting towards a regime of disorder in a brain region dependent manner. We propose that the alteration of information processing at an algorithmic level may be a mechanism behind the emergent and widespread co-morbidities associated with epilepsy, and perhaps other disorders.

Using extra-hippocampal cognitive maps for goal-directed spatial navigation

Goal-directed navigation requires precise estimates of spatial relationships between current position and future goal, as well as planning of an associated route or action. While neurons in the hippocampal formation can represent the animal’s position and nearby trajectories, their role in determining the animal’s destination or action has been questioned. We thus hypothesize that brain regions outside the hippocampal formation may play complementary roles in navigation, particularly for guiding goal-directed behaviours based on the brain’s internal cognitive map. In this seminar, I will first describe a subpopulation of neurons in the retrosplenial cortex (RSC) that increase their firing when the animal approaches environmental boundaries, such as walls or edges. This boundary coding is independent of direct visual or tactile sensation but instead depends on inputs from the medial entorhinal cortex (MEC) that contains spatial tuning cells, such as grid cells or border cells. However, unlike MEC border cells, we found that RSC border cells encode environmental boundaries in a self-centred egocentric coordinate frame, which may allow an animal for efficient avoidance from approaching walls or edges during navigation. I will then discuss whether the brain can possess a precise estimate of remote target location during active environmental exploration. Such a spatial code has not been described in the hippocampal formation. However, we found that neurons in the rat orbitofrontal cortex (OFC) form spatial representations that persistently point to the animal’s subsequent goal destination throughout navigation. This destination coding emerges before navigation onset without direct sensory access to a distal goal, and are maintained via destination-specific neural ensemble dynamics. These findings together suggest key roles for extra-hippocampal regions in spatial navigation, enabling animals to choose appropriate actions toward a desired destination by avoiding possible dangers.

Memory, learning to learn, and control of cognitive representations

Biological neural networks can represent information in the collective action potential discharge of neurons, and store that information amongst the synaptic connections between the neurons that both comprise the network and govern its function. The strength and organization of synaptic connections adjust during learning, but many cognitive neural systems are multifunctional, making it unclear how continuous activity alternates between the transient and discrete cognitive functions like encoding current information and recollecting past information, without changing the connections amongst the neurons. This lecture will first summarize our investigations of the molecular and biochemical mechanisms that change synaptic function to persistently store spatial memory in the rodent hippocampus. I will then report on how entorhinal cortex-hippocampus circuit function changes during cognitive training that creates memory, as well as learning to learn in mice. I will then describe how the hippocampus system operates like a competitive winner-take-all network, that, based on the dominance of its current inputs, self organizes into either the encoding or recollection information processing modes. We find no evidence that distinct cells are dedicated to those two distinct functions, rather activation of the hippocampus information processing mode is controlled by a subset of dentate spike events within the network of learning-modified, entorhinal-hippocampus excitatory and inhibitory synapses.

Memory, learning to learn, and control of cognitive representations

Biological neural networks can represent information in the collective action potential discharge of neurons, and store that information amongst the synaptic connections between the neurons that both comprise the network and govern its function. The strength and organization of synaptic connections adjust during learning, but many cognitive neural systems are multifunctional, making it unclear how continuous activity alternates between the transient and discrete cognitive functions like encoding current information and recollecting past information, without changing the connections amongst the neurons. This lecture will first summarize our investigations of the molecular and biochemical mechanisms that change synaptic function to persistently store spatial memory in the rodent hippocampus. I will then report on how entorhinal cortex-hippocampus circuit function changes during cognitive training that creates memory, as well as learning to learn in mice. I will then describe how the hippocampus system operates like a competitive winner-take-all network, that, based on the dominance of its current inputs, self organizes into either the encoding or recollection information processing modes. We find no evidence that distinct cells are dedicated to those two distinct functions, rather activation of the hippocampus information processing mode is controlled by a subset of dentate spike events within the network of learning-modified, entorhinal-hippocampus excitatory and inhibitory synapses.

Locally-ordered representation of 3D space in the entorhinal cortex

When animals navigate on a two-dimensional (2D) surface, many neurons in the medial entorhinal cortex (MEC) are activated as the animal passes through multiple locations (‘firing fields’) arranged in a hexagonal lattice that tiles the locomotion-surface; these neurons are known as grid cells. However, although our world is three-dimensional (3D), the 3D volumetric representation in MEC remains unknown. Here we recorded MEC cells in freely-flying bats and found several classes of spatial neurons, including 3D border cells, 3D head-direction cells, and neurons with multiple 3D firing-fields. Many of these multifield neurons were 3D grid cells, whose neighboring fields were separated by a characteristic distance – forming a local order – but these cells lacked any global lattice arrangement of their fields. Thus, while 2D grid cells form a global lattice – characterized by both local and global order – 3D grid cells exhibited only local order, thus creating a locally ordered metric for space. We modeled grid cells as emerging from pairwise interactions between fields, which yielded a hexagonal lattice in 2D and local order in 3D – thus describing both 2D and 3D grid cells using one unifying model. Together, these data and model illuminate the fundamental differences and similarities between neural codes for 3D and 2D space in the mammalian brain.

A distinct subcircuit in medial entorhinal cortex mediates learning of interval timing behavior during immobility

Over 60 years of research has established that medial temporal lobe structures, including the hippocampus and entorhinal cortex, are necessary for the formation of episodic memories (i.e. memories of specific personal events that occur in spatial and temporal context). While prior work to establish the neural mechanisms underlying episodic memory has largely focused on questions related spatial context, recently we have begun to investigate how these brain structures could be involved in encoding aspects of temporal context. In particular, we have focused on how medial entorhinal cortex, a structure well known for its role in spatial memory, may also be involved in encoding interval time. To answer this question we have developed an instrumental paradigm for head-fixed mice that requires both immobile interval timing and locomotion-dependent navigation behavior. By combining this behavioral paradigm with large-scale cellular resolution functional imaging and optogenetic-mediated inactivation, our results suggest that MEC is required for learning of interval timing behavior and that interval timing could be mediated through regular, sequential neural activity of a distinct subpopulation of neurons in MEC that encode elapsed time during periods of immobility (Heys and Dombeck, 2018; Heys et al, 2020; Issa et al., 2020). In this talk, I will discuss these findings and discuss our on-going work to investigate the principles underlying the role of medial temporal lobe structures in timing behavior and episodic memory.

The Cognitive Map Theory – 40 Years On

John O’Keefe is a Professor of Cognitive Neuroscience at UCL and he received the Nobel Prize in Physiology or Medicine in 2014 for his “discoveries of cells that constitute a positioning system in the brain". His revolutionary research on hippocampal place cells provided deeper insight into the neural processes underlying the sense of space. His lab in Sainsbury Wellcome Centre applies a wide range of methods to facilitate our understanding of the role of the entorhinal cortex and hippocampus in spatial memory and the neural mechanisms underlying short-term memories in the amygdala.

Slow global population dynamics propagating through the medial entorhinal cortex

The medial entorhinal cortex (MEC) supports the brain’s representation of space with distinct cell types whose firing is tuned to features of the environment (grid, border, and object-vector cells) or navigation (head-direction and speed cells). While the firing properties of these functionally-distinct cell types are well characterized, how they interact with one another remains unknown. To determine how activity self-organizes in the MEC network, we tested mice in a spontaneous locomotion task under sensory-deprived conditions. Using 2-photon calcium imaging, we monitored the activity of large populations of MEC neurons in head-fixed mice running on a wheel in darkness, in the absence of external sensory feedback tuned to navigation. We unveiled the presence of motifs that involve the sequential activation of cells in layer II of MEC (MEC-L2). We call these motifs waves. Waves lasted tens of seconds to minutes, were robust, swept through the entire network of active cells and did not exhibit any anatomical organization. Furthermore, waves did not map the position of the mouse on the wheel and were not restricted to running epochs. The majority of MEC-L2 neurons participate in this global sequential dynamics, that ties all functional cell types together. We found the waves in the most lateral region of MEC, but not in adjacent areas such as PaS or in a sensory cortex such as V1.

Linking neural representations of space by multiple attractor networks in the entorhinal cortex and the hippocampus

In the past decade evidence has accumulated in favor of the hypothesis that multiple sub-networks in the medial entorhinal cortex (MEC) are characterized by low-dimensional, continuous attractor dynamics. Much has been learned about the joint activity of grid cells within a module (a module consists of grid cells that share a common grid spacing), but little is known about the interactions between them. Under typical conditions of spatial exploration in which sensory cues are abundant, all grid-cells in the MEC represent the animal’s position in space and their joint activity lies on a two-dimensional manifold. However, if the grid cells in a single module mechanistically constitute independent attractor networks, then under conditions in which salient sensory cues are absent, errors could accumulate in the different modules in an uncoordinated manner. Such uncoordinated errors would give rise to catastrophic readout errors when attempting to decode position from the joint grid-cell activity. I will discuss recent theoretical works from our group, in which we explored different mechanisms that could impose coordination in the different modules. One of these mechanisms involves coordination with the hippocampus and must be set up such that it operates across multiple spatial maps that represent different environments. The other mechanism is internal to the entorhinal cortex and independent of the hippocampus.

The Role of Hippocampal Replay in Memory Consolidation

The hippocampus lies at the centre of a network of brain regions thought to support spatial and episodic memory. Place cells - the principal cell of the hippocampus, represent information about an animal’s spatial location. Yet, during rest and awake quiescence place cells spontaneously recapitulate past trajectories (‘replay’). Replay has been hypothesised to support systems consolidation – the stabilisation of new memories via maturation of complementary cortical memory traces. Indeed, in recent work we found place and grid cells, from the deep medial entorhinal cortex (dMEC, the principal cortical output region of the hippocampus), replayed coherently during rest periods. Importantly, dMEC grid cells lagged place cells by ~11ms; suggesting the coordination may reflect consolidation. Moreover, preliminary data shows that the dMEC-hippocampal coordination strengthens as an animal becomes familiar with a task and that it may be led by directionally modulated cells. Finally, on-going work, in my recently established lab, shows replay may represent the mechanism underlying the maturation of episodic/spatial memory in pre-weanling pups. Together, these results indicate replay may play a central role in ensuring the permanency of memories.

Multiple maps for navigation

Over the last several decades, the tractable response properties of parahippocampal neurons have provided a new access key to understanding the cognitive process of self-localization: the ability to know where you are currently located in space. Defined by functionally discrete response properties, neurons in the medial entorhinal cortex and hippocampus are proposed to provide the basis for an internal neural map of space, which enables animals to perform path-integration based spatial navigation and supports the formation of spatial memories. My lab focuses on understanding the mechanisms that generate this neural map of space and how this map is used to support behavior. In this talk, I’ll discuss how learning and experience shapes our internal neural maps of space to guide behavior.

Emergent scientists discuss Alzheimer's disease

This seminar is part of our “Emergent Scientists” series, an initiative that provides a platform for scientists at the critical PhD/postdoc transition period to share their work with a broad audience and network. Summary: These talks cover Alzheimer’s disease (AD) research in both mice and humans. Christiana will discuss in particular the translational aspects of applying mouse work to humans and the importance of timing in disease pathology and intervention (e.g. timing between AD biomarkers vs. symptom onset, timing of therapy, etc.). Siddharth will discuss a rare variant of Alzheimer’s disease called “Logopenic Progressive Aphasia”, which presents with temporo-parietal atrophy yet relative sparing of hippocampal circuitry. Siddharth will discuss how, despite the unusual anatomical basis underlying this AD variant, degeneration of the angular gyrus in the left inferior parietal lobule contributes to memory deficits similar to those of typical amnesic Alzheimer’s disease. Christiana’s abstract: Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder that causes severe deterioration of memory, cognition, behavior, and the ability to perform daily activities. The disease is characterized by the accumulation of two proteins in fibrillar form; Amyloid-β forms fibrils that accumulate as extracellular plaques while tau fibrils form intracellular tangles. Here we aim to translate findings from a commonly used AD mouse model to AD patients. Here we initiate and chronically inhibit neuropathology in lateral entorhinal cortex (LEC) layer two neurons in an AD mouse model. This is achieved by over-expressing P301L tau virally and chronically activating hM4Di DREADDs intracranially using the ligand dechloroclozapine. Biomarkers in cerebrospinal fluid (CSF) is measured longitudinally in the model using microdialysis, and we use this same system to intracranially administer drugs aimed at halting AD-related neuropathology. The models are additionally tested in a novel contextual memory task. Preliminary findings indicate that viral injections of P301L tau into LEC layer two reveal direct projections between this region and the outer molecular layer of dentate gyrus and the rest of hippocampus. Additionally, phosphorylated tau co-localize with ‘starter cells’ and appear to spread from the injection site. Preliminary microdialysis results suggest that the concentrations of CSF amyloid-β and tau proteins mirror changes observed along the disease cascade in patients. The disease-modifying drugs appear to halt neuropathological development in this preclincial model. These findings will lead to a novel platform for translational AD research, linking the extensive research done in rodents to clinical applications. Siddharth’s abstract: A distributed brain network supports our ability to remember past events. The parietal cortex is a critical member of this network, yet, its exact contributions to episodic remembering remain unclear. Neurodegenerative syndromes affecting the posterior neocortex offer a unique opportunity to understand the importance and role of parietal regions to episodic memory. In this talk, I introduce and explore the rare neurodegenerative syndrome of Logopenic Progressive Aphasia (LPA), an aphasic variant of Alzheimer’s disease presenting with early, left-lateralized temporo-parietal atrophy, amidst relatively spared hippocampal integrity. I then discuss two key studies from my recent Ph.D. work showcasing pervasive episodic and autobiographical memory dysfunction in LPA, to a level comparable to typical, amnesic Alzheimer’s disease. Using multimodal neuroimaging, I demonstrate how degeneration of the angular gyrus in the left inferior parietal lobule, and its structural connections to the hippocampus, contribute to amnesic profiles in this syndrome. I finally evaluate these findings in the context of memory profiles in other posterior cortical neurodegenerative syndromes as well as recent theoretical models underscoring the importance of the parietal cortex in the integration and representation of episodic contextual information.

The Synaptic Organization of the Human Entorhinal Cortex: A 3D Electron Microscopy Study on the Gateway to Hippocampus

Long-term potentiation (LTP) requires astrocytes and D-serine at entorhinal cortex LIII – CA1 synapses

FENS Forum 2024

Entorhinal cortex as a hub in the gut microbiome–brain axis

FENS Forum 2024

A hierarchical representation of sequences in human entorhinal cortex

COSYNE 2022

A hierarchical representation of sequences in human entorhinal cortex

COSYNE 2022

Object × position coding in the entorhinal cortex of flying bats

COSYNE 2022

Object × position coding in the entorhinal cortex of flying bats

COSYNE 2022

Mechanisms underlying flexible, context-dependent timing in medial entorhinal cortex

COSYNE 2023

NeuralPlayground: A Standardised Environment for Evaluating Models of Hippocampus and Entorhinal Cortex

COSYNE 2023

The role of the entorhinal cortex in reward-guided spatial navigation

COSYNE 2023

Vector production via mental navigation in the entorhinal cortex

COSYNE 2023

Behaviour of Medial Entorhinal Cortex Cells During A Radial Eight Arm Maze Task

Communication between the nucleus incertus and the medial septum and the entorhinal cortex

Entorhinal cortex lesion induces homeostatic synaptic plasticity of CA3 pyramidal neurons

Exploring the role of the Lateral Entorhinal Cortex in the modulation of the Piriform Cortex neuronal activity

Grid-like codes in the human entorhinal cortex map visual space during memory formation

Hippocampal output processing in layer VI of the medial entorhinal cortex

Integration of Medial and Lateral Entorhinal Cortex in Hippocampal Area CA3

The internal direction signal in medial entorhinal cortex/parasubiculum is qualitatively different from the head direction signal in upstream brain regions

The Lateral Entorhinal Cortex modulates dendritic excitability in the CA1 by recruiting a local disinhibitory microcircuit

Local integration of long-range inputs from the lateral entorhinal cortex in hippocampal area CA3 drives dendritic non-linearities and somatic output

Neuronal activity in the medial entorhinal cortex is coordinated with thalamic head-direction cells during sleep

Neuronal underpinnings of episodic-like memory in the mouse lateral entorhinal cortex

Organisation of inputs from the baso-amygdala to the medial and lateral entorhinal cortex

Persistent Homology of the UMAP Complex Reveals Tori in the Entorhinal Cortex of Head-Fixed Mice

Rapid odor processing by layer 2 subcircuits in lateral entorhinal cortex

Resting-state activity in the basal forebrain predicts functional degeneration in the entorhinal cortex and decreases with Alzheimer’s Disease progression

The role of inputs from hippocampus and entorhinal cortex to the prefrontal cortex in spatial memory impairments in a mouse model of Alzheimer's disease

Role of TRPC-4 and -5 channels in persistent firing in Medial Entorhinal Cortex Layer II

Social and spatial codes in hippocampus CA2 and entorhinal cortex

Cell type emergence in the developing medial entorhinal cortex is regulated by Bcl11b

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Cellular and molecular changes in the medial entorhinal cortex during aging

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Dentate granule cell neurogenesis in adult mice following denervation in the entorhinal cortex lesion model

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Grid representation for future spatial information in the medial entorhinal cortex

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So excited to see you! Visual object-in-place learning increases neuronal excitability in lateral entorhinal cortex engram cells

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Exploring social and spatial coding in the lateral and medial entorhinal cortex

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Two forms of presynaptic spike timing-dependent depression at entorhinal cortex-hippocampal synapses are mediated by astrocyte activity

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Functional organization of medial entorhinal cortex layer VI

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Impaired spatial coding and weak hyperactivity in the medial entorhinal cortex of aged APP knock-in mice

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Laminar synaptic characteristics of the human entorhinal cortex

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