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Barry, C.

Publications and source records attributed to Barry, C..

At least 19 recordsLinked to original sources

Firing rate adaptation in grid cells produces macroscopic hexadirectional modulation

Hexadirectional modulation (HexMod) of macroscopic neural activity by movement direction is widely used to measure grid cell activity in human neuroimaging, but its neuronal origin is unclear. Two mechanisms have been proposed: conjunctive gridxdirection cells whose preferred directions align with the grid axes, and firing rate adaptation, which reduces firing when grid fields are visited in quick succession during movement along grid axes. Analysing almost 4,000 grid cells from foraging rats, we found that conjunctive cells' directional tuning was broad and unaligned with grid axes, whereas firing was reduced shortly after grid field visits, consistent with firing rate adaptation. Simulations of realistic grid cell populations demonstrate HexMod with the typical trajectories of human experiments, and show how it depends on grid scale, adaptation time constant, movement speed, and controlling for variation with location. We show firing rate adaptation provides a plausible mechanism for HexMod and a framework for relating human neuroimaging to neuronal activity.

neuroscience↗

Systematic drug profiling across BAF complex perturbations reveals distinct dependencies

Chromatin remodeling by BAF complexes regulates access to DNA with implications in transcription, replication and the sensing and repair of DNA lesions, processes that are closely coupled to cell growth control. BAF complexes exist in three major subtypes each composed of a unique subset of about a dozen subunits. While for individual BAF subunits direct functions in DNA repair and cell growth have been described, we lack a more systematic interrogation of BAF perturbation and its implications in these processes. To fill this need, we subjected an isogenic BAF knockout collection to treatment with diverse genotoxic and cytotoxic compounds quantifying proliferation, cell cycle phase distributions, cell fate decisions, DNA double-strand break signaling, and transcriptional responses. The screen uncovered vulnerabilities of selected BAF-deficient cells to MEK and EGFR pathway inhibition, as well as unexpected resistance toward checkpoint inhibitors and certain DNA-damaging agents. Notably, loss of distinct ARID paralogs produced markedly divergent phenotypes, indicating limited functional redundancy and subtype-specific contributions to genome stability and cell cycle regulation. Collectively, these results provide a comparative resource linking BAF complex composition to genotoxic and cytotoxic stress responses, highlighting candidate synthetic-lethal interactions and generating hypotheses for mechanistic studies of BAF complexes in genome maintenance and cell growth control.

molecular biology↗

Decoding medial entorhinal cortical dynamics produces planning-like alternations in hippocampal theta sequences

The hippocampus is central to memory and spatial planning. A prominent candidate mechanism supporting navigational decision making is hippocampal theta sequences--brief ([~]120ms) place-cell sequences representing future trajectories--which have been interpreted as planning signals based on their alternation between maze arms in T-maze tasks. However, recent work suggests that intrinsic left-right alternation in medial entorhinal cortex (MEC) theta sequences may underlie this phenomenon. Here, we test this hypothesis using a model of MEC theta dynamics in a T-maze and show that standard Bayesian decoding yields hippocampal theta sequences that alternate between arms. Analysis of simultaneous MEC-hippocampal recordings reveals tight coupling of MEC and hippocampus and coordinated left-right alternation. Notably, this alternation occurs not only at choice points but also during inbound and forced-turn trials. These findings suggest that left-right alternation in hippocampal theta sequences is a ubiquitous phenomenon driven by MEC dynamics, challenging the interpretation that these specifically reflect intentional decision-making or planning processes.

neuroscience↗

From movement to cognitive maps: recurrent neural networks reveal how locomotor development shapes hippocampal spatial coding

AO_SCPLOWBSTRACTC_SCPLOWThe hippocampus contains neurons whose firing correlates with an animals location and orientation in space. Collectively, these neurons are held to support a cognitive map of the environment, enabling the recall of and navigation to specific locations. Although recent studies have characterised the timelines of spatial neuron development, no unifying mechanistic model has yet been proposed. Moreover, the processes driving the emergence of spatial representations in the hippocampus remain unclear (Tan et al., 2017). Here, we combine computational analysis of postnatal locomotor development with a recurrent neural network (RNN) model of hippocampal function to demonstrate how changes in movement statistics - and the resulting sensory experiences - shape the formation of spatial tuning. First, we identify distinct developmental stages in rat locomotion during open-field exploration using published experimental data. Then, we train shallow RNNs to predict upcoming visual stimuli from concurrent visual and vestibular inputs, exposing them to trajectories that reflect progressively maturing locomotor patterns. Our findings reveal that these changing movement statistics drive the sequential emergence of spatially tuned units, mirroring the developmental timeline observed in rats. The models generate testable predictions about how spatial tuning properties mature - predictions we confirm through analysis of hippocampal recordings. Critically, we demonstrate that replicating the specific statistics of developmental locomotion - rather than merely accelerating sensory change - is essential for the emergence of an allocentric spatial representation. These results establish a mechanistic link between embodied sensorimotor experience and the ontogeny of hippocampal spatial neurons, with significant implications for neurodevelopmental research and predictive models of navigational brain circuits.*

neuroscience↗

Disordered Hippocampal Reactivations Predict Spatial Memory Deficits in a Mouse Model of Alzheimer's Disease

Alzheimers disease (AD) is characterised by progressive memory decline associated with hippocampal degeneration. However, the specific physiological mechanisms underlying hippocampal dysfunction in AD remain poorly understood and improved knowledge may aid both diagnosis and help identify new avenues for therapeutic intervention. We investigated how disruptions in hippocampal reactivations relate to place cell stability and spatial memory deficits in an AD mouse model. Using the APP knock-in mouse model NL-G-F, we conducted simultaneous behavioural and electrophysiological recordings in a radial arm maze. NL-G-F mice exhibited significant impairments in memory performance, demonstrated by an increased propensity to revisit arms, compared to wild-type controls. These memory deficits were associated with a reduction in the stability of hippocampal place cells, which occurred over short timescales and was accentuated across rest. While the rate of hippocampal reactivation events during rest was unchanged, the structure of these events was significantly degraded in NL-G-F mice. The decreased structure of reactivations was predictive of decreased stability in place cell firing. These findings suggest that disrupted reactivation sequences may act as a mechanism of memory disorder in AD.

neuroscience↗

SIMPL: Scalable and hassle-free optimization of neural representations from behaviour

Neural activity in the brain is known to encode low-dimensional, time-evolving, behaviour-related variables. A long-standing goal of neural data analysis has been to identify these variables and their mapping to neural activity. A productive and canonical approach has been to simply visualise neural "tuning curves" as a function of behaviour. In reality, significant discrepancies between behaviour and the true latent variables--such as an agent thinking of position Y whilst located at position X--distort and blur the tuning curves, decreasing their interpretability. To address this, latent variable models propose to learn the latent variable from data; these are typically expensive, hard to tune, or scale poorly, complicating their adoption. Here we propose SIMPL (Scalable Iterative Maximization of Population-coded Latents), an EM-style algorithm which iteratively optimises latent variables and tuning curves. SIMPL is fast, scalable and exploits behaviour as an initial condition to further improve convergence and identifiability. It can accurately recover latent variables in spatial and non-spatial tasks. When applied to a large hippocampal dataset SIMPL converges on smaller, more numerous, and more uniformly sized place fields than those based on behaviour, suggesting the brain may encode space with greater resolution than previously thought.

neuroscience↗

Unifying Subicular Function: A Predictive Map Approach

The successor representation has emerged as a powerful model for understanding mammalian navigation and memory; explaining the spatial coding properties of hippocampal place cells and entorhinal grid cells. However, the diverse spatial responses of subicular neurons, the primary output of the hippocampus, have eluded a unified account. Here, we demonstrate that incorporating rodent behavioural biases into the successor representation successfully reproduces the heterogeneous activity patterns of subicular neurons. This framework accounts for the emergence of boundary and corner cells - neuronal types absent in upstream hippocampal regions. We provide evidence that subicular firing patterns are more accurately described by the successor representation than a purely spatial or boundary vector cell model of subiculum. Our work reveals a temporal hierarchy in hippocampal-subicular processing, with subiculum encoding predictive representations over longer time horizons than CA1, capturing extended behavioural patterns and environmental affordances.

neuroscience↗

Environmental sphagnum-associated fungi target thiol homeostasis to compete with Mycobacterium tuberculosis.

Mycobacterial species in nature are found in abundance in sphagnum peat bogs where they compete for nutrients with a variety of microorganisms including fungi. We screened a collection of fungi isolated from sphagnum bogs by co-culture with Mycobacterium tuberculosis (Mtb) to look for inducible expression of antitubercular agents and identified five fungi that produced cidal antitubercular agents upon exposure to live Mtb. Whole genome sequencing of these fungi followed by fungal RNAseq after Mtb exposure allowed us to identify biosynthetic gene clusters induced by co-culture. Three of these fungi induced expression of patulin, one induced citrinin expression and one induced the production of nidulalin A. The biosynthetic gene clusters for patulin and citrinin have been previously described but the genes involved in nidulalin A production have not been described before. All three of these potent electrophiles react with thiols and treatment of Mtb cells with these agents followed by Mtb RNAseq showed that these natural products all induce profound thiol stress suggesting a rapid depletion of mycothiol. The induction of thiol-reactive mycotoxins through three different systems in response to exposure to Mtb suggests that fungi have identified this as a highly vulnerable target in a similar microenvironment to that of the caseous human lesion.

microbiology↗

Symmetry and Generalization in Local Learning of Predictive Representations

In spatial cognition, the Successor Representation (SR) from reinforcement learning provides a compelling candidate of how predictive representations are used to encode space. In particular, hippocampal place cells are hypothesized to encode the SR. Here, we investigate how varying the temporal symmetry in learning rules influences those representations. To this end, we use a simple local learning rule which can be made insensitive to the temporal order. We analytically find that a symmetric learning rule results in a successor representation under a symmetrized version of the experienced transition structure. We then apply this rule to a two-layer neural network model loosely resembling hippocampal subfields CA3 - with a symmetric learning rule and recurrent weights - and CA1 - with an asymmetric learning rule and no recurrent weights. Here, when exposed repeatedly to a linear track, neurons in our model in CA3 show less shift of the centre of mass than those in CA1, in line with existing empirical findings. Investigating the functional benefits of such symmetry, we employ a simple reinforcement learning agent which may learn symmetric or classical successor representations. Here, we find that using a symmetric learning rule yields representations which afford better generalization, when the agent is probed to navigate to a new target without relearning the SR. This effect is reversed when the state space is not symmetric anymore. Thus, our results hint at a potential benefit of the inductive bias afforded by symmetric learning rules in areas employed in spatial navigation, where there naturally is a symmetry in the state space. Author summaryThe hippocampus is a brain region which plays a crucial role in spatial navigation for both animals and humans. Contemporarily, its thought to store predictive representations of the environment, functioning like maps that indicate the likelihood of visiting certain locations in the future. In our study, we used an artificial neural network model to learn these predictive representations by adjusting synaptic connections between neurons according to local learning rules. Unlike previous research, our model includes learning rules that are invariant to the temporal order of events, meaning they are symmetric with respect to the reversal of input timings. This approach produces predictive representations particularly useful for understanding spatial relationships, as navigating from one point to another is often equivalent to the reverse. Our model offers additional insights: it replicates observed properties of hippocampal cells and helps an artificial agent solve navigation tasks. The agent trained with our model not only learns to navigate but also generalizes better to new targets compared to traditional models. Our findings suggest that symmetric learning rules enhance the brains ability to create useful predictive maps for problems which are inherently symmetric, as is navigation.

neuroscience↗

Repix: reliable, reusable, versatile chronic Neuropixels implants using minimal components

Neuropixels probes represent the state-of-the-art for high-yield electrophysiology in neuroscience: the simultaneous recording of hundreds of neurons is now routinely carried out in head-restrained animals. In contrast, neural recording in unrestrained animals, as well as recording and tracking neurons over days, remains challenging, though it is possible using chronic implants. A major challenge is the availability of simple methods that can be implemented with limited or no prior experience with Neuropixels probes, while achieving reliable, reusable, versatile high-density electrophysiology. Here we developed, deployed, and evaluated the real-world performance of Repix, a chronic implantation system that permits the repeated re-use of Neuropixels probes. The lightweight system allows implanted animals to express a full range of natural behaviors, including social behaviors. We show that Repix allows the recording of hundreds of neurons across many months, up to a year, with implants across cortical and subcortical brain regions. Probes can be reused repeatedly with stable yield. Repix has been used by 16 researchers in 10 laboratories to date, and we evaluated the real-world performance of Repix in a variety of chronic recording paradigms in both mice and rats with a combined 209 implantations. We found that the key advantage of Repix is robustness and simplicity. Adopters of Repix became proficient at five procedures on average, regardless of prior experience with in vivo electrophysiology. With the companion protocol alongside this article, the performance and user-friendliness of Repix should facilitate a wide uptake of chronic Neuropixels recordings.

neuroscience↗

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

Neural processes in the hippocampus and entorhinal cortex are thought to be crucial for spatial cognition. A growing variety of theoretical models have been proposed to capture the rich neural and behavioral phenomena associated with these circuits. However, systematic comparison of these theories, both against each other and against empirical data, remains challenging. To address this gap, we present NeuralPlayground, an open-source standardised software framework for comparisons between theory and experiment in the domain of spatial cognition. This Python software package offers a reproducible way to compare models against a centralised library of published experimental results, including neural recordings and animal behavior. The framework implements three Agents embodying different computational models; three Experiments comprising publicly available neural and behavioral datasets; a customisable 2-dimensional Arena (continuous and discrete) able to generate common and novel spatial layouts; and a Comparison tool that facilitates systematic comparisons between models and data. Each module can also be used separately, allowing standardised and flexible access to influential models and data sets. We hope NeuralPlayground, available on GitHub3, provides a starting point for a shared, standardized, open, and reproducible computational understanding of the role of the hippocampus and entorhinal cortex in spatial cognition.

neuroscience↗

A generative model of the hippocampal formation trained with theta driven local learning rules

Advances in generative models have recently revolutionised machine learning. Meanwhile, in neuroscience, generative models have long been thought fundamental to animal intelligence. Understanding the biological mechanisms that support these processes promises to shed light on the relationship between biological and artificial intelligence. In animals, the hippocampal formation is thought to learn and use a generative model to support its role in spatial and non-spatial memory. Here we introduce a biologically plausible model of the hippocampal formation tantamount to a Helmholtz machine that we apply to a temporal stream of inputs. A novel component of our model is that fast theta-band oscillations (5-10 Hz) gate the direction of information flow throughout the network, training it akin to a high-frequency wake-sleep algorithm. Our model accurately infers the latent state of high-dimensional sensory environments and generates realistic sensory predictions. Furthermore, it can learn to path integrate by developing a ring attractor connectivity structure matching previous theoretical proposals and flexibly transfer this structure between environments. Whereas many models trade-off biological plausibility with generality, our model captures a variety of hippocampal cognitive functions under one biologically plausible local learning rule.

neuroscience↗

Theta phase precession at encoding predicts subsequent memory of sensory-driven vector fields, & occurs in memory-dependent fields at retrieval

Theta phase precession is thought to confer key computational advantages (e.g. temporal compression suiting spike-timing related plasticity, cognitive relations as phase distances, and population-level coding for directions and sequences). However, direct evidence speaking to: 1) its widely-theorised role in enhancing memorability; 2) its dependence upon sensory input, is lacking. We leveraged the Vector trace cell (VTC) phenomenon to examine these issues. VTCs in subiculum show a simple, unambiguous memory correlate: VTCs remember the distance and direction to a cue after the cue is removed, with a new trace field which was not present before the cue was inserted. Regarding memorability, here we show that subsequently-remembered cue fields (those which become trace fields) exhibit higher levels of phase precession than subsequently-forgotten cue fields (those which produce no trace). Thus, phase precession does appear to enhance memorability, consistent with long-established theory. The second issue concerns the extent of phase precession in sensory-elicited vs memory-dependent firing. Phase precession in CA1 is strongly disrupted following deprivation of its Entorhinal, but not CA3, inputs; this could indicate that theta phase precession is largely sensory-driven and absent in memory-dependent fields. Here, however, we show that phase precession is robust in subicular VTC trace fields, i.e. when the cue that originally elicited the new vector field is no longer present. Thus, the much-theorised benefits of phase precession likely apply to memory-dependent fields. These findings have wide implications for oscillatory-based models of memory.

neuroscience↗

The influence of environment geometry on subiculum boundary vector cells in adulthood and early development

Boundaries to movement form a specific class of landmark information used for navigation: Boundary Vector Cells (BVCs) are neurons which encode an animals location as a vector displacement from boundaries. Here we report the first objective characterisation of the prevalence and spatial tuning of subiculum BVCs. Manipulations of boundary geometry reveal two novel features of BVC firing. Firstly, BVC directional tunings align with environment walls in squares, but are uniformly distributed in circles, demonstrating that environmental geometry alters BVC receptive fields. Secondly, inserted barriers uncover both excitatory and inhibitory components to BVC receptive fields, demonstrating that inhibitory inputs contribute to BVC field formation. During post-natal development, subiculum BVCs mature slowly, contrasting with the earlier maturation of boundary-responsive cells in upstream Entorhinal Cortex. However, Subiculum and Entorhinal BVC receptive fields are altered by boundary geometry as early as tested, suggesting this is an inherent feature of the hippocampal representation of space.

neuroscience↗

RatInABox: A toolkit for modelling locomotion and neuronal activity in continuous environments

Generating synthetic locomotory and neural data is a useful yet cumbersome step commonly required to study theoretical models of the brains role in spatial navigation. This process can be time consuming and, without a common framework, makes it difficult to reproduce or compare studies which each generate test data in different ways. In response we present RatInABox, an open-source Python toolkit designed to model realistic rodent locomotion and generate synthetic neural data from spatially modulated cell types. This software provides users with (i) the ability to construct one-or two-dimensional environments with configurable barriers and visual cues, (ii) a physically realistic random motion model fitted to experimental data, (iii) rapid online calculation of neural data for many of the known self-location or velocity selective cell types in the hippocampal formation (including place cells, grid cells, boundary vector cells, head direction cells) and (iv) a framework for constructing custom cell types, multi-layer network models and data-or policy-controlled motion trajectories. The motion and neural models spatially and temporally continuous as well as topographically sensitive to boundary conditions and walls. We demonstrate that out-of-the-box parameter settings replicate many aspects of rodent foraging behaviour such as velocity statistics and the tendency of rodents to over-explore walls. Numerous tutorial scripts are provided, including examples where RatInABox is used for decoding position from neural data or to solve a navigational reinforcement learning task. We hope this tool significantly streamline computational research into the brains role in navigation.

neuroscience↗

Rapid learning of predictive maps with STDP and theta phase precession

The predictive map hypothesis is a promising candidate principle for hippocampal function. A favoured formalisation of this hypothesis, called the successor representation, proposes that each place cell encodes the expected state occupancy of its target location in the near future. This predictive framework is supported by behavioural as well as electrophysiological evidence and has desirable consequences for both the generalisability and efficiency of reinforcement learning algorithms. However, it is unclear how the successor representation might be learnt in the brain. Error-driven temporal difference learning, commonly used to learn successor representations in artificial agents, is not known to be implemented in hippocampal networks. Instead, we demonstrate that spike-timing dependent plasticity (STDP), a form of Hebbian learning, acting on temporally compressed trajectories known as "theta sweeps", is sufficient to rapidly learn a close approximation to the successor representation. The model is biologically plausible - it uses spiking neurons modulated by theta-band oscillations, diffuse and overlapping place cell-like state representations, and experimentally matched parameters. We show how this model maps onto known aspects of hippocampal circuitry and explains substantial variance in the temporal difference successor matrix, consequently giving rise to place cells that demonstrate experimentally observed successor representation-related phenomena including backwards expansion on a 1D track and elongation near walls in 2D. Finally, our model provides insight into the observed topographical ordering of place field sizes along the dorsal-ventral axis by showing this is necessary to prevent the detrimental mixing of larger place fields, which encode longer timescale successor representations, with more fine-grained predictions of spatial location.

neuroscience↗

Faster growth enhances low carbon fuel and chemical production through gas fermentation

Gas fermentation offers both fossil carbon-free sustainable production of fuels and chemicals and recycling of gaseous and solid waste using gas-fermenting microbes. Bioprocess development, systems-level analysis of biocatalyst metabolism, and engineering of cell factories are advancing the widespread deployment of the commercialised technology. Acetogens are particularly attractive biocatalysts but effects of the key physiological parameter - specific growth rate () - on acetogen metabolism and the gas fermentation bioprocess have not been established yet. Here, we investigate the -dependent bioprocess performance of the model-acetogen Clostridium autoethanogenum in CO and syngas (CO+CO2+H2) grown chemostat cultures and assess systems-level metabolic responses using gas analysis, metabolomics, transcriptomics, and metabolic modelling. We were able to obtain steady-states up to ~2.8 day-1 (~0.12 h-1) and show that faster growth supports both higher yields and productivities for reduced by-products ethanol and 2,3-butanediol. Transcriptomics data revealed differential expression of 1,337 genes with increasing and suggest that C. autoethanogenum uses transcriptional regulation to a large extent for facilitating faster growth. Metabolic modelling showed significantly increased fluxes for faster growing cells that were, however, not accompanied by gene expression changes in key catabolic pathways for CO and H2 metabolism. Cells thus seem to maintain sufficient "baseline" gene expression to rapidly respond to CO and H2 availability without delays to kick-start metabolism. Our work advances understanding of transcriptional regulation in acetogens and shows that faster growth of the biocatalyst improves the gas fermentation bioprocess.

systems biology↗