Marianne Hafting Fyhn

• Nymoen, Ingeborg; Rogge, Frederik Sebastian; Aasen, Anna Hjertvik; Grødem, Sverre; Malthe-Sørenssen, Anders & Lepperød, Mikkel Elle [Vis alle 9 forfattere av denne artikkelen] (2026). Task and Behavior-Related Variables Are Encoded by the Postrhinal and Medial Entorhinal Cortex During Non-Spatial Associative Learning. eLIFE. 14. doi: 10.7554/elife.106095.1. Fulltekst i vitenarkiv Vis sammendrag

  The medial entorhinal cortex (MEC) is pivotal in spatial computations and episodic memory. In particular, an animal’s position can be decoded from the activity of entorhinal grid cells. However, it remains elusive whether MEC could play a more general role in different types of associative learning and how the representations develop during the learning process. It has been shown that the postrhinal cortex (POR), which is directly connected to MEC, integrates visual stimuli with salient outcomes. Here, we use a non-spatial visual association task to investigate whether MEC neurons represent low-level visual cues during learning. Using a Go/NoGo visual association task, we recorded neural activity in MEC and POR throughout the learning phase as mice associated drifting gratings with rewarded, aversive, or neutral outcomes. Our findings reveal that the neural tuning curves in both the POR and MEC change with the learning of the task. From the start of training, the POR neurons exhibited response tuning to the visual cues, and the tuning was stable to cue orientations during learning. In contrast, MEC neurons did not initially respond very strongly to visual cues but developed a robust tuning toward the rewarded trials. While the MEC’s representation of visual information was limited, it encoded other task elements. A large fraction of the neurons formed distinct functional clusters that were either activated or suppressed by reward-related behavior. Remarkably, these clusters segregated anatomically in MEC and maintained strong within-cluster correlations before and after training. Notably, although the same functional clusters were apparent in the POR, they did not show any anatomical structure as in the MEC. Task reversal induced significant changes in network responses across both regions, with a decrease in overall task-responsive neurons but a slight increase in stimulus representation. Strikingly, information about the choice to lick emerged with learning in both brain areas, and most significantly within the functional cell clusters representing reward consumption and plus-cue stimulus. Our results demonstrate that although neurons in MEC and POR develop behavior-modulated tuning during learning of a non-spatial visual association task, the MEC exhibits stronger within-cluster correlations and anatomical organization. Conversely, the POR population exhibits less structural organization and more specific stimulus-tuning, which is reflective of being a higher visual association area. Our findings reveal that the MEC can encode task– and behavior-related variables beyond spatial information.

• Stöber, Tristan Manfred; Lehr, Andrew B.; Nikzad, Arash; Ganjtabesh, Mohammad; Fyhn, Marianne & Kumar, Arvind (2025). Competition and cooperation of assembly sequences in recurrent neural networks. PLoS Computational Biology. ISSN 1553-734X. 21(9). doi: 10.1371/journal.pcbi.1013403. Fulltekst i vitenarkiv Vis sammendrag

  Neural activity sequences are ubiquitous in the brain and play pivotal roles in functions such as long-term memory formation and motor control. While conditions for storing and reactivating individual sequences have been thoroughly characterized, it remains unclear how multiple sequences may interact when activated simultaneously in recurrent neural networks. This question is especially relevant for weak sequences, comprised of fewer neurons, competing against strong sequences. Using a non-linear rate -based and a spiking model with discrete, pre-configured assemblies, we demonstrate that weak sequences can compensate for their competitive disadvantage either by increasing excitatory connections between subsequent assemblies or by cooperating with other co-active sequences. Further, our models suggest that such cooperation can negatively affect sequence speed unless subsequently active assemblies are paired. Our analysis characterizes the conditions for successful sequence progression in isolated, competing, and cooperating assembly sequences, and identifies the distinct contributions of recurrent and feed-forward projections. This proof-of-principle study shows how even disadvantaged sequences can be prioritized for reactivation, a process which has recently been implicated in hippocampal memory processing.

• Grødem, Sverre; Thompson, Elise Holter; Røe, Malin Benum; Vatne, Guro Helén; Nymoen, Ingeborg & Buccino, Alessio Paolo [Vis alle 10 forfattere av denne artikkelen] (2025). Differential impacts of germline and adult aggrecan knockout in PV+ neurons on perineuronal nets and PV+ neuronal function. Molecular Psychiatry. ISSN 1359-4184. 30, s. 2907–2921. doi: 10.1038/s41380-025-02894-5. Fulltekst i vitenarkiv Vis sammendrag

  Perineuronal nets (PNNs) are a condensed form of extracellular matrix primarily found around parvalbumin-expressing (PV+) interneurons. The postnatal maturation of PV+ neurons is accompanied with the formation of PNNs and reduced plasticity. Alterations in PNN and PV+ neuron function have been described for mental disorders such as schizophrenia and autism. The formation of PNNs is highly dependent on aggrecan, a proteoglycan encoded by the ACAN gene, but it remains unknown if it is produced by the PV+ neurons themselves. Thus, we established a knockout (KO) mouse model (ACANflx/PVcre) and an adeno-associated virus to specifically eliminate aggrecan production from PV+ neurons, in the germline or adult animals, respectively. The germline KO (ACANflx/PVcre) eliminated the expression of PNNs labeled by Wisteria floribunda agglutinin (WFA), the most commonly used PNN marker. Surprisingly, electrophysiological properties of PV+ interneurons and ocular dominance plasticity of adult ACANflx/PVcre mice were similar to controls. In contrast, AAV-mediated ACAN knockout in adult mice increased ocular dominance plasticity. Moreover, in vivo Chondroitinase ABC treatment of KO mice resulted in reduced firing rate of PV+ cells and increased frequency of spontaneous excitatory postsynaptic currents (sEPSC), a phenotype associated with chABC treatment of WT animals. These findings suggest that compensatory mechanisms may be activated during development in response to the germline loss of aggrecan. Indeed, qPCR of bulk tissue indicates that other PNN components, including neurocan and tenascin-R, are expressed at higher levels in the KO animals. Finally, behavioral testing revealed that ACANflx/PVcre mice had similar long-term memory as controls in the Morris water maze. However, they employed bolder search strategies during spatial learning and showed lower level of anxiety-related behavior in an open field and zero maze.

• Schøyen, Vemund Sigmundson; Beshkov, Kosio; Pettersen, Markus Borud; Hermansen, Erik; Holzhausen, Konstantin & Malthe-Sørenssen, Anders [Vis alle 8 forfattere av denne artikkelen] (2025). Hexagons all the way down: grid cells as a conformal isometric map of space. PLoS Computational Biology. ISSN 1553-734X. 21(2). doi: 10.1371/journal.pcbi.1012804. Fulltekst i vitenarkiv Vis sammendrag

  Grid cells in the entorhinal cortex are known for their hexagonal spatial activity patterns and are thought to provide a neural metric for space, and support path integration. In this study, we further investigate grid cells as a metric of space by optimising them for a conformal isometric (CI) map of space using a model based on a superposition of plane waves. By optimising the phases within a single grid cell module, we find that the module can form a CI of two-dimensional flat space with phases arranging into a regular hexagonal pattern, supporting an accurate spatial metric. Additionally, we find that experimentally recorded grid cells exhibit CI properties, with one example module showing a phase arrangement similar to the hexagonal pattern observed in our model. These findings provide computational and preliminary experimental support for grid cells as a CI-based spatial representation. We also examine other properties that emerge in CI-optimised modules, including consistent energy expenditure across space and the minimal cell count required to support unique representation of space and maximally topologically persistent toroidal population activity. Altogether, our results suggest that grid cells are well-suited to form a CI map, with several beneficial properties arising from this organisation.

• Lensjø, Kristian; Nymoen, Ingeborg; Rogge, Frederik Sebastian; Tøndel, Kristin; Sugden, Arthur & Shurnayte, Inga [Vis alle 11 forfattere av denne artikkelen] (2025). Local inhibitory circuits mediate cortical reactivations and memory consolidation. Science Advances. 11(22), s. 1–14. doi: 10.1126/sciadv.adu9800. Fulltekst i vitenarkiv Vis sammendrag

  Highly salient events activate neurons across various brain regions. During subsequent rest or sleep, the activity patterns of these neurons often correlate with those observed during the preceding experience. Growing evidence suggests that these reactivations play a crucial role in memory consolidation, the process by which experiences are solidified in cortical networks for long-term storage. Here, we use longitudinal two-photon Ca2+ imaging alongside paired LFP recordings in the hippocampus and cortex, to show that targeted manipulation of PV+ inhibitory neurons in the lateral visual cortex after daily training selectively attenuates cue-specific reactivations and learning, with only minute effects on spontaneous activity and no apparent effect on normal function such as visual cue–elicited responses during training. In control mice, reactivations were biased toward salient cues, persisted for hours after training had ended, and the prevalence of reactivations was aligned with the learning process. Overall, our results underscore a crucial role for cortical reactivations in memory consolidation.

• Beshkov, Kosio; Fyhn, Marianne; Hafting, Torkel & Einevoll, Gaute (2024). Topological structure of population activity in mouse visual cortex encodes densely sampled stimulus rotations. iScience. 27(4). doi: 10.1016/j.isci.2024.109370. Fulltekst i vitenarkiv Vis sammendrag

  The primary visual cortex is one of the most well understood regions supporting the processing involved in sensory computation. Following the popularization of high-density neural recordings, it has been observed that the activity of large neural populations is often constrained to low dimensional manifolds. In this work, we quantify the structure of such neural manifolds in the visual cortex. We do this by analyzing publicly available two-photon optical recordings of mouse primary visual cortex in response to visual stimuli with a densely sampled rotation angle. Using a geodesic metric along with persistent homology, we discover that population activity in response to such stimuli generates a circular manifold, encoding the angle of rotation. Furthermore, we observe that this circular manifold is expressed differently in subpopulations of neurons with differing orientation and direction selectivity. Finally, we discuss some of the obstacles to reliably retrieving the truthful topology generated by a neural population.

• Schøyen, Vemund; Pettersen, Markus; Holzhausen, Konstantin; Fyhn, Marianne; Malthe-Sørenssen, Anders & Lepperød, Mikkel (2023). Coherently remapping toroidal cells but not Grid cells are responsible for path integration in virtual agents. iScience. Fulltekst i vitenarkiv
• Lepperød, Mikkel Elle; Stöber, Tristan Manfred; Hafting, Torkel; Fyhn, Marianne & Kording, Konrad Paul (2023). Inferring causal connectivity from pairwise recordings and optogenetics. PLoS Computational Biology. ISSN 1553-734X. 19(11). doi: 10.1371/journal.pcbi.1011574. Fulltekst i vitenarkiv Vis sammendrag

  To understand the neural mechanisms underlying brain function, neuroscientists aim to quantify causal interactions between neurons, for instance by perturbing the activity of neuron A and measuring the effect on neuron B. Recently, manipulating neuron activity using light-sensitive opsins, optogenetics, has increased the specificity of neural perturbation. However, using widefield optogenetic interventions, multiple neurons are usually perturbed, producing a confound—any of the stimulated neurons can have affected the postsynaptic neuron making it challenging to discern which neurons produced the causal effect. Here, we show how such confounds produce large biases in interpretations. We explain how confounding can be reduced by combining instrumental variables (IV) and difference in differences (DiD) techniques from econometrics. Combined, these methods can estimate (causal) effective connectivity by exploiting the weak, approximately random signal resulting from the interaction between stimulation and the absolute refractory period of the neuron. In simulated neural networks, we find that estimates using ideas from IV and DiD outperform naïve techniques suggesting that methods from causal inference can be useful to disentangle neural interactions in the brain.

• Beshkov, Kosio; Fyhn, Marianne; Hafting, Torkel & Einevoll, Gaute Tomas (2023). Topological Structure of Population Activity in Mouse Visual Cortex Encodes Densely Sampled Visual Scene Rotations. Social Science Research Network (SSRN). doi: 10.2139/ssrn.4495668. Fulltekst i vitenarkiv
• Schøyen, Vemund Sigmundson; Pettersen, Markus Borud; Holzhausen, Konstantin; Fyhn, Marianne; Malthe-Sørenssen, Anders & Lepperød, Mikkel Elle (2023). Coherently remapping toroidal cells but not Grid cells are responsible for path integration in virtual agents. iScience. 26(11), s. 1–17. doi: 10.1016/j.isci.2023.108102. Fulltekst i vitenarkiv Vis sammendrag

  It is widely believed that grid cells provide cues for path integration, with place cells encoding an animal’s location and environmental identity. When entering a new environment, these cells remap concurrently, sparking debates about their causal relationship. Using a continuous attractor recurrent neural network, we study spatial cell dynamics in multiple environments. We investigate grid cell remapping as a function of global remapping in place-like units through random resampling of place cell centers. Dimensionality reduction techniques reveal that a subset of cells manifest a persistent torus across environments. Unexpectedly, these toroidal cells resemble band-like cells rather than high grid score units. Subsequent pruning studies reveal that toroidal cells are crucial for path integration while grid cells are not. As we extend the model to operate across many environments, we delineate its generalization boundaries, revealing challenges with modeling many environments in current models.

• Hanssen, Kine Ødegård; Grødem, Sverre; Fyhn, Marianne; Hafting, Torkel; Einevoll, Gaute & Ness, Torbjørn V [Vis alle 7 forfattere av denne artikkelen] (2023). Responses in fast-spiking interneuron firing rates to parameter variations associated with degradation of perineuronal nets. Journal of Computational Neuroscience. ISSN 0929-5313. 51, s. 283–298. doi: 10.1007/s10827-023-00849-9. Fulltekst i vitenarkiv Vis sammendrag

  The perineuronal nets (PNNs) are sugar coated protein structures that encapsulate certain neurons in the brain, such as parvalbumin positive (PV) inhibitory neurons. As PNNs are theorized to act as a barrier to ion transport, they may effectively increase the membrane charge-separation distance, thereby affecting the membrane capacitance. Tewari et al. (2018) found that degradation of PNNs induced a 25%-50% increase in membrane capacitance cm and a reduction in the firing rates of PV-cells. In the current work, we explore how changes in cm affects the firing rate in a selection of computational neuron models, ranging in complexity from a single compartment Hodgkin-Huxley model to morphologically detailed PV-neuron models. In all models, an increased cm lead to reduced firing, but the experimentally reported increase in cm was not alone sufficient to explain the experimentally reported reduction in firing rate. We therefore hypothesized that PNN degradation in the experiments affected not only cm, but also ionic reversal potentials and ion channel conductances. In simulations, we explored how various model parameters affected the firing rate of the model neurons, and identified which parameter variations in addition to cm that are most likely candidates for explaining the experimentally reported reduction in firing rate.

• Grødem, Sverre; Nymoen, Ingeborg; Vatne, Guro Helén; Rogge, Frederik Sebastian; Björnsdottir, Valgerdur & Lensjø, Kristian [Vis alle 7 forfattere av denne artikkelen] (2023). An updated suite of viral vectors for in vivo calcium imaging using intracerebral and retro-orbital injections in male mice. Nature Communications. 14(1), s. 608–1. doi: 10.1038/s41467-023-36324-3. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Genetically encoded Ca 2+ indicators (GECIs) are widely used to measure neural activity. Here, we explore the use of systemically administered PHP.eB AAVs for brain-wide expression of GECIs and compare the expression properties to intracerebrally injected AAVs in male mice. We show that systemic administration is a promising strategy for imaging neural activity. Next, we establish the use of EE-RR- (soma) and RPL10a (Ribo) soma-targeting peptides with the latest jGCaMP and show that EE-RR-tagged jGCaMP8 gives rise to strong expression but limited soma-targeting. In contrast, Ribo-tagged jGCaMP8 lacks neuropil signal, but the expression rate is reduced. To combat this, we modified the linker region of the Ribo-tag (RiboL1-). RiboL1-jGCaMP8 expresses faster than Ribo-jGCaMP8 but remains too dim for reliable use with systemic virus administration. However, intracerebral injections of the RiboL1-tagged jGCaMP8 constructs provide strong Ca 2+ signals devoid of neuropil contamination, with remarkable labeling density.

• Fawcett, James W.; Fyhn, Marianne; Jendelova, Pavla; Kwok, Jessica C. F.; Ruzicka, Jiri & Sorg, Barbara A. (2022). The extracellular matrix and perineuronal nets in memory. Molecular Psychiatry. ISSN 1359-4184. 27, s. 3192–3203. doi: 10.1038/s41380-022-01634-3. Fulltekst i vitenarkiv Vis sammendrag

  Abstract All components of the CNS are surrounded by a diffuse extracellular matrix (ECM) containing chondroitin sulphate proteoglycans (CSPGs), heparan sulphate proteoglycans (HSPGs), hyaluronan, various glycoproteins including tenascins and thrombospondin, and many other molecules that are secreted into the ECM and bind to ECM components. In addition, some neurons, particularly inhibitory GABAergic parvalbumin-positive (PV) interneurons, are surrounded by a more condensed cartilage-like ECM called perineuronal nets (PNNs). PNNs surround the soma and proximal dendrites as net-like structures that surround the synapses. Attention has focused on the role of PNNs in the control of plasticity, but it is now clear that PNNs also play an important part in the modulation of memory. In this review we summarize the role of the ECM, particularly the PNNs, in the control of various types of memory and their participation in memory pathology. PNNs are now being considered as a target for the treatment of impaired memory. There are many potential treatment targets in PNNs, mainly through modulation of the sulphation, binding, and production of the various CSPGs that they contain or through digestion of their sulphated glycosaminoglycans.

• Hanssen, Kine Ødegård; Grødem, Sverre; Fyhn, Marianne; Hafting, Torkel; Einevoll, Gaute & Ness, Torbjørn Vefferstad [Vis alle 7 forfattere av denne artikkelen] (2022). Effects of perineuronal nets on neural ring properties. Research Square. ISSN 2693-5015. doi: 10.21203/rs.3.rs-2198467/v1. Fulltekst i vitenarkiv
• Lehr, Andrew; Kumar, Arvind; Tezlaff, Christian; Hafting, Torkel; Fyhn, Marianne & Stöber, Tristan Manfred (2021). CA2 beyond social memory: Evidence for a fundamental role in hippocampal information processing. Neuroscience and Biobehavioral Reviews. ISSN 0149-7634. 126, s. 398–412. doi: 10.1016/j.neubiorev.2021.03.020. Fulltekst i vitenarkiv Vis sammendrag

  Hippocampal region CA2 has received increased attention due to its importance in social recognition memory. While its specific function remains to be identified, there are indications that CA2 plays a major role in a variety of situations, widely extending beyond social memory. In this targeted review, we highlight lines of research which have begun to converge on a more fundamental role for CA2 in hippocampus-dependent memory processing. We discuss recent proposals that speak to the computations CA2 may perform within the hippocampal circuit.

• Lepperød, Mikkel Elle; Christensen, Ane Charlotte; Lensjø, Kristian Kinden; Buccino, Alessio Paolo; Yu, Jai & Fyhn, Marianne [Vis alle 7 forfattere av denne artikkelen] (2021). Optogenetic pacing of medial septum parvalbumin-positive cells disrupts temporal but not spatial firing in grid cells. Science Advances. 7(19). doi: 10.1126/sciadv.abd5684. Fulltekst i vitenarkiv Vis sammendrag

  Grid cells in the medial entorhinal cortex (MEC) exhibit remarkable spatial activity patterns with spikes coordinated by theta oscillations driven by the medial septal area (MSA). Spikes from grid cells progress relative to the theta phase in a phenomenon called phase precession, which is suggested as essential to create the spatial periodicity of grid cells. Here, we show that optogenetic activation of parvalbumin-positive (PV+) cells in the MSA enabled selective pacing of local field potential (LFP) oscillations in MEC. During optogenetic stimulation, the grid cells were locked to the imposed pacing frequency but kept their spatial patterns. Phase precession was abolished, and speed information was no longer reflected in the LFP oscillations but was still carried by rate coding of individual MEC neurons. Together, these results support that theta oscillations are not critical to the spatial pattern of grid cells and do not carry a crucial velocity signal.

• Christensen, Ane Charlotte; Lensjø, Kristian Kinden; Lepperød, Mikkel Elle; Dragly, Svenn-Arne; Sutterud, Hallvard & Blackstad, Jan Sigurd [Vis alle 8 forfattere av denne artikkelen] (2021). Perineuronal nets stabilize the grid cell network. Nature Communications. 12. doi: 10.1038/s41467-020-20241-w. Fulltekst i vitenarkiv Vis sammendrag

  Grid cells are part of a widespread network which supports navigation and spatial memory. Stable grid patterns appear late in development, in concert with extracellular matrix aggregates termed perineuronal nets (PNNs) that condense around inhibitory neurons. It has been suggested that PNNs stabilize synaptic connections and long-term memories, but their role in the grid cell network remains elusive. We show that removal of PNNs leads to lower inhibitory spiking activity, and reduces grid cells’ ability to create stable representations of a novel environment. Furthermore, in animals with disrupted PNNs, exposure to a novel arena corrupted the spatiotemporal relationships within grid cell modules, and the stored representations of a familiar arena. Finally, we show that PNN removal in entorhinal cortex distorted spatial representations in downstream hippocampal neurons. Together this work suggests that PNNs provide a key stabilizing element for the grid cell network.

• Stöber, Tristan Manfred; Lehr, Andrew B; Hafting, Torkel; Kumar, Arvind & Fyhn, Marianne (2020). Selective neuromodulation and mutual inhibition within the CA3-CA2 system can prioritize sequences for replay. Hippocampus. ISSN 1050-9631. doi: 10.1002/hipo.23256. Fulltekst i vitenarkiv Vis sammendrag

  To make optimal use of previous experiences, important neural activity sequences must be prioritized during hippocampal replay. Integrating insights about the interplay between CA3 and CA2, we propose a conceptual framework that allows the two regions to control which sequences are reactivated. We suggest that neuromodulatory‐gated plasticity and mutual inhibition enable discrete assembly sequences in both regions to support each other while suppressing competing sequences. This perspective provides a coherent interpretation for a variety of seemingly disconnected functional properties of CA2 and paves the way for a more general understanding of CA2.

• Lepperød, Mikkel Elle; Dragly, Svenn-Arne; Buccino, Alessio Paolo; Mobarhan, Milad; Malthe-Sørenssen, Anders & Hafting, Torkel [Vis alle 7 forfattere av denne artikkelen] (2020). Experimental Pipeline (Expipe): A Lightweight Data Management Platform to Simplify the Steps From Experiment to Data Analysis. Frontiers in Neuroinformatics. 14. doi: 10.3389/fninf.2020.00030. Fulltekst i vitenarkiv Vis sammendrag

  As experimental neuroscience is moving toward more integrative approaches, with a variety of acquisition techniques covering multiple spatiotemporal scales, data management is becoming increasingly challenging for neuroscience laboratories. Often, datasets are too large to practically be stored on a laptop or a workstation. The ability to query metadata collections without retrieving complete datasets is therefore critical to efficiently perform new analyses and explore the data. At the same time, new experimental paradigms lead to constantly changing specifications for the metadata to be stored. Despite this, there is currently a serious lack of agile software tools for data management in neuroscience laboratories. To meet this need, we have developed Expipe, a lightweight data management framework that simplifies the steps from experiment to data analysis. Expipe provides the functionality to store and organize experimental data and metadata for easy retrieval in exploration and analysis throughout the experimental pipeline. It is flexible in terms of defining the metadata to store and aims to solve the storage and retrieval challenges of data/metadata due to ever changing experimental pipelines. Due to its simplicity and lightweight design, we envision Expipe as an easy-to-use data management solution for experimental laboratories, that can improve provenance, reproducibility, and sharing of scientific projects.

• Mäki-Marttunen, Tuomo; Kaufmann, Tobias; Elvsåshagen, Torbjørn; Devor, Anna; Djurovic, Srdjan & Westlye, Lars Tjelta [Vis alle 23 forfattere av denne artikkelen] (2019). Biophysical Psychiatry—How Computational Neuroscience Can Help to Understand the Complex Mechanisms of Mental Disorders. Frontiers in Psychiatry. 10. doi: 10.3389/fpsyt.2019.00534. Fulltekst i vitenarkiv Vis sammendrag

  The brain is the most complex of human organs, and the pathophysiology underlying abnormal brain function in psychiatric disorders is largely unknown. Despite the rapid development of diagnostic tools and treatments in most areas of medicine, our understanding of mental disorders and their treatment has made limited progress during the last decades. While recent advances in genetics and neuroscience have a large potential, the complexity and multidimensionality of the brain processes hinder the discovery of disease mechanisms that would link genetic findings to clinical symptoms and behavior. This applies also to schizophrenia, for which genome-wide association studies have identified a large number of genetic risk loci, spanning hundreds of genes with diverse functionalities. Importantly, the multitude of the associated variants and their prevalence in the healthy population limit the potential of a reductionist functional genetics approach as a stand-alone solution to discover the disease pathology. In this review, we outline the key concepts of a “biophysical psychiatry,” an approach that employs large-scale mechanistic, biophysics-founded computational modelling to increase transdisciplinary understanding of the pathophysiology and strive toward robust predictions. We discuss recent scientific advances that allow a synthesis of previously disparate fields of psychiatry, neurophysiology, functional genomics, and computational modelling to tackle open questions regarding the pathophysiology of heritable mental disorders. We argue that the complexity of the increasing amount of genetic data exceeds the capabilities of classical experimental assays and requires computational approaches. Biophysical psychiatry, based on modelling diseased brain networks using existing and future knowledge of basic genetic, biochemical, and functional properties on a single neuron to a microcircuit level, may allow a leap forward in deriving interpretable biomarkers and move the field toward novel treatment options.

• Raheel, Tayyaba Qureshi; Sørensen, Christina; Berghuis, Paul; Jensen, Vidar; Dobszay, Marton B. & Farkas, Tamás [Vis alle 15 forfattere av denne artikkelen] (2019). The glutamine transporter Slc38a1 regulates GABAergic neurotransmission and synaptic plasticity. Cerebral Cortex. ISSN 1047-3211. 29(12), s. 5166–5179. doi: 10.1093/cercor/bhz055. Fulltekst i vitenarkiv Vis sammendrag

  GABA signaling sustains fundamental brain functions, from nervous system development to the synchronization of population activity and synaptic plasticity. Despite these pivotal features, molecular determinants underscoring the rapid and cell-autonomous replenishment of the vesicular neurotransmitter GABA and its impact on synaptic plasticity remain elusive. Here, we show that genetic disruption of the glutamine transporter Slc38a1 in mice hampers GABA synthesis, modifies synaptic vesicle morphology in GABAergic presynapses and impairs critical period plasticity. We demonstrate that Slc38a1-mediated glutamine transport regulates vesicular GABA content, induces high-frequency membrane oscillations and shapes cortical processing and plasticity. Taken together, this work shows that Slc38a1 is not merely a transporter accumulating glutamine for metabolic purposes, but a key component regulating several neuronal functions.

• Christensen, Ane Charlotte; Lepperød, Mikkel; Lensjø, Kristian Kinden; Dragly, Svenn-Arne; Blackstad, Jan Sigurd Beddari & Fyhn, Marianne [Vis alle 7 forfattere av denne artikkelen] (2019). Perineuronal nets stabilize the grid cell network. BioRxiv. ISSN 0362-4331. doi: 10.1101/796342. Fulltekst i vitenarkiv
• Mäki-Marttunen, Tuomo; Krull, Florian; Bettella, Francesco; Hagen, Espen; Næss, Solveig & Ness, Torbjørn V [Vis alle 16 forfattere av denne artikkelen] (2019). Alterations in schizophrenia-associated genes can lead to increased power in delta oscillations. Cerebral Cortex. ISSN 1047-3211. 29(2), s. 875–891. doi: 10.1093/cercor/bhy291. Fulltekst i vitenarkiv Vis sammendrag

  Genome-wide association studies have implicated many ion channels in schizophrenia pathophysiology. Although the functions of these channels are relatively well characterized by single-cell studies, the contributions of common variation in these channels to neurophysiological biomarkers and symptoms of schizophrenia remain elusive. Here, using computational modeling, we show that a common biomarker of schizophrenia, namely, an increase in delta-oscillation power, may be a direct consequence of altered expression or kinetics of voltage-gated ion channels or calcium transporters. Our model of a circuit of layer V pyramidal cells highlights multiple types of schizophrenia-related variants that contribute to altered dynamics in the delta-frequency band. Moreover, our model predicts that the same membrane mechanisms that increase the layer V pyramidal cell network gain and response to delta-frequency oscillations may also cause a deficit in a single-cell correlate of the prepulse inhibition, which is a behavioral biomarker highly associated with schizophrenia.

• Buccino, Alessio Paolo; Lepperød, Mikkel Elle; Dragly, Svenn-Arne; Häfliger, Philipp; Fyhn, Marianne & Hafting, Torkel (2018). Open source modules for tracking animal behavior and closed-loop stimulation based on Open Ephys and Bonsai. Journal of Neural Engineering. ISSN 1741-2560. 15, s. 1–12. doi: 10.1088/1741-2552/aacf45. Fulltekst i vitenarkiv Vis sammendrag

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

• Dragly, Svenn-Arne; Mobarhan, Milad; Lepperød, Mikkel Elle; Tennøe, Simen; Fyhn, Marianne & Hafting, Torkel [Vis alle 7 forfattere av denne artikkelen] (2018). Experimental directory structure (Exdir): An alternative to HDF5 without introducing a new file format. Frontiers in Neuroinformatics. 12. doi: 10.3389/fninf.2018.00016. Fulltekst i vitenarkiv
• Thompson, Elise Holter; Lensjø, Kristian Kinden; Wigestrand, Mattis B; Malthe-sørenssen, Anders; Hafting, Torkel & Fyhn, Marianne (2018). Removal of perineuronal nets disrupts recall of a remote fear memory. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 115(3), s. 607–612. doi: 10.1073/pnas.1713530115. Fulltekst i vitenarkiv Vis sammendrag

  Throughout life animals learn to recognize cues that signal danger and instantaneously initiate an adequate threat response. Memories of such associations may last a lifetime and far outlast the intracellular molecules currently found to be important for memory processing. The memory engram may be supported by other more stable molecular components, such as the extracellular matrix structure of perineuronal nets (PNNs). Here, we show that recall of remote, but not recent, visual fear memories in rats depend on intact PNNs in the secondary visual cortex (V2L). Supporting our behavioral findings, increased synchronized theta oscillations between V2L and basolateral amygdala, a physiological correlate of successful recall, was absent in rats with degraded PNNs in V2L. Together, our findings suggest a role for PNNs in remote memory processing by stabilizing the neural network of the engram.

• Buccino, Alessio Paolo; Kordovan, Michael; Ness, Torbjørn V; Merkt, Benjamin; Häfliger, Philipp & Fyhn, Marianne [Vis alle 9 forfattere av denne artikkelen] (2018). Combining biophysical modeling and deep learning for multielectrode array neuron localization and classification. Journal of Neurophysiology. ISSN 0022-3077. 120(3), s. 1212–1232. doi: 10.1152/jn.00210.2018. Fulltekst i vitenarkiv Vis sammendrag

  Neural circuits typically consist of many different types of neurons, and one faces a challenge in disentangling their individual contributions in measured neural activity. Classification of cells into inhibitory and excitatory neurons and localization of neurons on the basis of extracellular recordings are frequently employed procedures. Current approaches, however, need a lot of human intervention, which makes them slow, biased, and unreliable. In light of recent advances in deep learning techniques and exploiting the availability of neuron models with quasi-realistic three-dimensional morphology and physiological properties, we present a framework for automatized and objective classification and localization of cells based on the spatiotemporal profiles of the extracellular action potentials recorded by multielectrode arrays. We train convolutional neural networks on simulated signals from a large set of cell models and show that our framework can predict the position of neurons with high accuracy, more precisely than current state-of-the-art methods. Our method is also able to classify whether a neuron is excitatory or inhibitory with very high accuracy, substantially improving on commonly used clustering techniques. Furthermore, our new method seems to have the potential to separate certain subtypes of excitatory and inhibitory neurons. The possibility of automatically localizing and classifying all neurons recorded with large high-density extracellular electrodes contributes to a more accurate and more reliable mapping of neural circuits.

• Rowlands, Daire; Lensjø, Kristian Kinden; Dinh, Tovy; Yang, Sujeon; Andrews, Melissa & Hafting, Torkel [Vis alle 9 forfattere av denne artikkelen] (2018). Aggrecan directs extracellular matrix mediated neuronal plasticity. Journal of Neuroscience. ISSN 0270-6474. 38(47), s. 10102–10113. doi: 10.1523/JNEUROSCI.1122-18.2018. Fulltekst i vitenarkiv Vis sammendrag

  In the adult brain, the extracellular matrix (ECM) influences recovery after injury, susceptibility to mental disorders, and is in general a strong regulator of neuronal plasticity. The proteoglycan aggrecan is a core component of the condensed ECM structures termed perineuronal nets (PNNs), and the specific role of PNNs on neural plasticity remains elusive. Here, we genetically targeted the Acan gene encoding for aggrecan utilizing a novel animal model. This allowed for conditional and targeted loss of aggrecan in vivo, which ablated the PNN structure and caused a shift in the population of parvalbumin expressing inhibitory interneurons towards a high plasticity state. Selective deletion of the Acan gene in the visual cortex of male adult mice reinstated juvenile ocular dominance plasticity, which was mechanistically identical to critical period plasticity. Brain-wide targeting improved object recognition memory.

• Martínez-Cañada, Pablo; Mobarhan, Milad; Halnes, Geir; Fyhn, Marianne; Morillas, Christian & Pelayo, Francisco [Vis alle 7 forfattere av denne artikkelen] (2018). Biophysical network modeling of the dLGN circuit: Effects of cortical feedback on spatial response properties of relay cells. PLoS Computational Biology. ISSN 1553-734X. 14(1), s. 1–45. doi: 10.1371/journal.pcbi.1005930. Fulltekst i vitenarkiv Vis sammendrag

  Despite half-a-century of research since the seminal work of Hubel and Wiesel, the role of the dorsal lateral geniculate nucleus (dLGN) in shaping the visual signals is not properly understood. Placed on route from retina to primary visual cortex in the early visual pathway, a striking feature of the dLGN circuit is that both the relay cells (RCs) and interneurons (INs) not only receive feedforward input from retinal ganglion cells, but also a prominent feedback from cells in layer 6 of visual cortex. This feedback has been proposed to affect synchronicity and other temporal properties of the RC firing. It has also been seen to affect spatial properties such as the center-surround antagonism of thalamic receptive fields, i.e., the suppression of the response to very large stimuli compared to smaller, more optimal stimuli. Here we explore the spatial effects of cortical feedback on the RC response by means of a a comprehensive network model with biophysically detailed, single-compartment and multicompartment neuron models of RCs, INs and a population of orientation-selective layer 6 simple cells, consisting of pyramidal cells (PY). We have considered two different arrangements of synaptic feedback from the ON and OFF zones in the visual cortex to the dLGN: phase-reversed (‘push-pull’) and phase-matched (‘push-push’), as well as different spatial extents of the corticothalamic projection pattern. Our simulation results support that a phase-reversed arrangement provides a more effective way for cortical feedback to provide the increased center-surround antagonism seen in experiments both for flashing spots and, even more prominently, for patch gratings. This implies that ON-center RCs receive direct excitation from OFF-dominated cortical cells and indirect inhibitory feedback from ON-dominated cortical cells. The increased center-surround antagonism in the model is accompanied by spatial focusing, i.e., the maximum RC response occurs for smaller stimuli when feedback is present.

• Mobarhan, Milad; Halnes, Geir; Martínez-Cañada, Pablo; Hafting, Torkel; Fyhn, Marianne & Einevoll, Gaute (2018). Firing-rate based network modeling of the dLGN circuit: Effects of cortical feedback on spatiotemporal response properties of relay cells. PLoS Computational Biology. ISSN 1553-734X. 14(5). doi: 10.1371/journal.pcbi.1006156. Fulltekst i vitenarkiv Vis sammendrag

  Visually evoked signals in the retina pass through the dorsal geniculate nucleus (dLGN) on the way to the visual cortex. This is however not a simple feedforward flow of information: there is a significant feedback from cortical cells back to both relay cells and interneurons in the dLGN. Despite four decades of experimental and theoretical studies, the functional role of this feedback is still debated. Here we use a firing-rate model, the extended difference-of-Gaussians (eDOG) model, to explore cortical feedback effects on visual responses of dLGN relay cells. For this model the responses are found by direct evaluation of two- or three-dimensional integrals allowing for fast and comprehensive studies of putative effects of different candidate organizations of the cortical feedback. Our analysis identifies a special mixed configuration of excitatory and inhibitory cortical feedback which seems to best account for available experimental data. This configuration consists of (i) a slow (long-delay) and spatially widespread inhibitory feedback, combined with (ii) a fast (short-delayed) and spatially narrow excitatory feedback, where (iii) the excitatory/inhibitory ON-ON connections are accompanied respectively by inhibitory/excitatory OFF-ON connections, i.e. following a phase-reversed arrangement. The recent development of optogenetic and pharmacogenetic methods has provided new tools for more precise manipulation and investigation of the thalamocortical circuit, in particular for mice. Such data will expectedly allow the eDOG model to be better constrained by data from specific animal model systems than has been possible until now for cat. We have therefore made the Python tool pyLGN which allows for easy adaptation of the eDOG model to new situations.

• Wigestrand, Mattis B; Schiff, Hillary C.; Fyhn, Marianne; LeDoux, Joseph E & Sears, Robert M. (2017). Primary auditory cortex regulates threat memory specificity. Learning & memory (Cold Spring Harbor, N.Y.). ISSN 1072-0502. 24(1), s. 55–58. doi: 10.1101/lm.044362.116. Fulltekst i vitenarkiv
• Aasebø, Ida E. J.; Lepperød, Mikkel Elle; Stavrinou, Maria; Nøkkevangen, Sandra; Einevoll, Gaute & Hafting, Torkel [Vis alle 7 forfattere av denne artikkelen] (2017). Temporal processing in the visual cortex of the awake and anesthetized rat. eNeuro. 4:e0059-17.2017(4), s. 1–26. doi: 10.1523/ENEURO.0059-17.2017. Fulltekst i vitenarkiv Vis sammendrag

  The activity pattern and temporal dynamics within and between neuron ensembles are essential features of information processing and believed to be profoundly affected by anesthesia. Much of our general understanding of sensory information processing, including computational models aimed at mathematically simulating sensory information processing, rely on parameters derived from recordings conducted on animals under anesthesia. Due to the high variety of neuronal subtypes in the brain, population-based estimates of the impact of anesthesia may conceal unit- or ensemble-specific effects of the transition between states. Using chronically implanted tetrodes into primary visual cortex (V1) of rats, we conducted extracellular recordings of single units and followed the same cell ensembles in the awake and anesthetized states. We found that the transition from wakefulness to anesthesia involves unpredictable changes in temporal response characteristics. The latency of single-unit responses to visual stimulation was delayed in anesthesia, with large individual variations between units. Pair-wise correlations between units increased under anesthesia, indicating more synchronized activity. Further, the units within an ensemble show reproducible temporal activity patterns in response to visual stimuli that is changed between states, suggesting state-dependent sequences of activity. The current dataset, with recordings from the same neural ensembles across states, is well suited for validating and testing computational network models. This can lead to testable predictions, bring a deeper understanding of the experimental findings and improve models of neural information processing. Here, we exemplify such a workflow using a Brunel network model.

• Lensjø, Kristian Kinden; Lepperød, Mikkel Elle; Dick, Gunnar; Hafting, Torkel & Fyhn, Marianne (2017). Removal of perineuronal nets unlocks juvenile plasticity through network mechanisms of decreased inhibition and increased gamma Activity. Journal of Neuroscience. ISSN 0270-6474. 37(5), s. 1269–1283. doi: 10.1523/JNEUROSCI.2504-16.2016. Fulltekst i vitenarkiv
• Lensjø, Kristian Kinden; Christensen, Ane Charlotte; Tennøe, Simen; Fyhn, Marianne & Hafting, Torkel (2017). Differential Expression and Cell-Type Specificity of Perineuronal Nets in Hippocampus, Medial Entorhinal Cortex and Visual Cortex Examined in the Rat and Mouse. eNeuro. 4(3), s. 1–18. doi: 10.1523/ENEURO.0379-16.2017. Fulltekst i vitenarkiv Vis sammendrag

  Perineuronal nets (PNNs) are specialized extracellular matrix (ECM) structures that condense around the soma and proximal dendrites of subpopulations of neurons. Emerging evidence suggests that they are involved in regulating brain plasticity. However, the expression of PNNs varies between and within brain areas. A lack of quantitative studies describing the distribution and cell-specificity of PNNs makes it difficult to reveal the functional roles of PNNs. In the current study, we examine the distribution of PNNs and the identity of PNN-enwrapped neurons in three brain areas with different cognitive functions: the dorsal hippocampus, medial entorhinal cortex (mEC) and primary visual cortex (V1). We compared rats and mice as knowledge from these species are often intermingled. The most abundant expression of PNNs was found in the mEC and V1, while dorsal hippocampus showed strikingly low levels of PNNs, apart from dense expression in the CA2 region. In hippocampus we also found apparent species differences in expression of PNNs. While we confirm that the PNNs enwrap parvalbumin-expressing (PV+) neurons in V1, we found that they mainly colocalize with excitatory CamKII-expressing neurons in CA2. In mEC, we demonstrate that in addition to PV+ cells, the PNNs colocalize with reelin-expressing stellate cells. We also show that the maturation of PNNs in mEC coincides with the formation of grid cell pattern, while PV+ cells, unlike in other cortical areas, are present from early postnatal development. Finally, we demonstrate considerable effects on the number of PSD-95-gephyrin puncta after enzymatic removal of PNNs.

• Dragly, Svenn-Arne; Mobarhan, Milad; Solbrå, Andreas Våvang; Tennøe, Simen; Hafreager, Anders & Malthe-Sørenssen, Anders [Vis alle 9 forfattere av denne artikkelen] (2017). Neuronify: An educational simulator for neural circuits. eNeuro. 4(2:e0022-17.2017), s. 1–13. doi: 10.1523/ENEURO.0022-17.2017. Fulltekst i vitenarkiv Vis sammendrag

  Educational software (apps) can improve science education by providing an interactive way of learning about complicated topics that are hard to explain with text and static illustrations. However, few educational apps are available for simulation of neural networks. Here, we describe an educational app, Neuronify, allowing the user to easily create and explore neural networks in a plug-and-play simulation environment. The user can pick network elements with adjustable parameters from a menu, i.e., synaptically connected neurons modelled as integrate-and-fire neurons and various stimulators (current sources, spike generators, visual, and touch) and recording devices (voltmeter, spike detector, and loudspeaker). We aim to provide a low entry point to simulation-based neuroscience by allowing students with no programming experience to create and simulate neural networks. To facilitate the use of Neuronify in teaching, a set of premade common network motifs is provided, performing functions such as input summation, gain control by inhibition, and detection of direction of stimulus movement. Neuronify is developed in C++ and QML using the cross-platform application framework Qt and runs on smart phones (Android, iOS) and tablet computers as well personal computers (Windows, Mac, Linux).

Se alle arbeider i NVA

• Olsen, Elise; Fjeldstad, Maria; Thon, Sarah; Haug, Nicolai; Lepperød, Mikkel & Sugar, Jørgen [Vis alle 8 forfattere av denne artikkelen] (2025). Oscillatory Rhythms in the Hippocampus and Entorhinal Cortex During Social Recognition. Fulltekst i vitenarkiv
• Kleven, Tina; Grødem, Sverre; Ciosk, Rafal & Fyhn, Marianne (2025). Temperature-dependent neuronal plasticity in a mouse model of induced hypothermia. Fulltekst i vitenarkiv
• Rogge, Frederik Sebastian; Lensjø, Kristian; Nymoen, Ingeborg; Grødem, Sverre & Fyhn, Marianne (2025). Visual cue representations in the postrhinal and medial entorhinal cortex during spatial navigation. Fulltekst i vitenarkiv
• Danieli, Krubeal; Fyhn, Marianne & Lepperød, Mikkel (2024). Neuromodulated online cognitive maps for reinforcement learning. Fulltekst i vitenarkiv
• Thon, Sarah Kriebel; Olsen, Elise Reppe; Fjeldstad, Maria Perona; Schøyen, Vemund Sigmundson; Lepperød, Mikkel Elle & Christensen, Ane Charlotte [Vis alle 8 forfattere av denne artikkelen] (2024). Social and spatial codes in the hippocampus. Fulltekst i vitenarkiv
• Nymoen, Ingeborg; Rogge, Frederik Sebastian; Grødem, Sverre; Lepperød, Mikkel Elle; Hafting, Torkel & Lensjø, Kristian [Vis alle 7 forfattere av denne artikkelen] (2024). Visual associative learning in the medial entorhinal cortex. Fulltekst i vitenarkiv
• Olsen, Elise Reppe; Fjeldstad, Maria Perona; Thon, Sarah Kriebel; Schøyen, Vemund Sigmundson; Lepperød, Mikkel Elle & Sugar, Jørgen Afseth [Vis alle 8 forfattere av denne artikkelen] (2024). Exploring social and spatial coding in the lateral and medial entorhinal cortex. Fulltekst i vitenarkiv
• Fjeldstad, Maria Perona; Lepperød, Mikkel Elle; Schøyen, Vemund Sigmundson; Christensen, Ane Charlotte; Grødem, Sverre & Fyhn, Marianne [Vis alle 7 forfattere av denne artikkelen] (2024). Theta modulation of grid cells in the medial entorhinal cortex in a novel environment task. Fulltekst i vitenarkiv
• Danieli, Krubeal; Fyhn, Marianne & Lepperød, Mikkel (2023). Online and memory-driven navigation through neuromodulation-based synaptic plasticity. Fulltekst i vitenarkiv
• Banono, Nancy Saana; Gawel, Kinga Aurelia; Mäki-Marttunen, Tuomo; Ent, Wietske van der; Kukula-Koch, Wirginia & Fyhn, Marianne [Vis alle 10 forfattere av denne artikkelen] (2023). Novel zebrafish model for studying neurodevelopment in Timothy syndrome. Fulltekst i vitenarkiv
• Beshkov, Kosio; Fyhn, Marianne; Hafting, Torkel & Einevoll, Gaute Tomas (2023). Topological Structure of Population Activity in Mouse Visual Cortex Encodes Densely Sampled Visual Scene Rotations. Fulltekst i vitenarkiv
• Beshkov, Kosio; Fyhn, Marianne; Hafting, Torkel & Einevoll, Gaute Tomas (2023). Topological Structure of Population Activity in Mouse Visual Cortex Encodes Densely Sampled Visual Scene Rotations. Fulltekst i vitenarkiv
• Rogge, Frederik; Malthe-Sørenssen, Anders; Fyhn, Marianne & Lepperød, Mikkel (2022). On the Structural Sensitivity of the Successor Representation. Fulltekst i vitenarkiv
• Rogge, Frederik Sebastian; Nymoen, Ingeborg; Lepperød, Mikkel Elle; Hafting, Torkel; Fyhn, Marianne & Lensjø, Kristian (2022). Learning flexibility in parahippocampal networks. doi: https:/fensforum.org/wp-content/uploads/2023/01/FENS2022.pdf. Fulltekst i vitenarkiv Vis sammendrag

  Mammals show remarkable flexibility of behaviors, and have the ability to abstract specific rules and learning sets into generalized low dimensional structures that can be applied in new conditions. Recent work suggests that this generalization could take place in parahippocampal regions, in particular in the entorhinal cortex (EC). Here, the medial part (MEC) seems to extract the structure of state space irrespective of modality (e.g. spatial or sound). The lateral part (LEC) receives input about complex features of objects and multimodal sensory information from association cortices, including the postrhinal cortex (POR). This puts the EC in a unique position to function as an integration center for higher order representations. To investigate the role of the entorhinal cortex in abstracting and generalizing task content, we have established a set of simple association tasks for mice that enable both rule switching and change of sensory modality. We train mice in these tasks over multiple sessions and record large neuronal populations in the EC during and after training using two-photon imaging. To this end, we utilize custom right-angle prism assemblies that cover either the MEC, or POR and LEC. We hypothesize that both MEC and LEC will display learning-induced changes in the low dimensional neural representations over time, with consistent structures that are used and transferred across different tasks. Our preliminary data from mice trained in a visual association task indicate that neurons in both regions develop representations of task structure with training.

• Lepperød, Mikkel Elle; Stöber, Tristan; Hafting, Torkel; Fyhn, Marianne & Kording, Konrad (2022). Inferring causal connectivity from pairwise recordings and optogenetics. BioRxiv. ISSN 0362-4331. doi: 10.1101/463760. Fulltekst i vitenarkiv
• Schøyen, Vemund Sigmundson; Pettersen, Markus Borud; Holzhousen, Konstantin; Fyhn, Marianne; Malthe-Sørenssen, Anders & Lepperød, Mikkel Elle (2022). Coherently Remapping Toroidal Cells But Not Grid Cells are Responsible for Path Integration in Virtual Agents. BioRxiv. ISSN 0362-4331. doi: 10.1101/2022.08.18.504379. Fulltekst i vitenarkiv
• Thon, Sarah Kriebel; Christensen, Ane Charlotte; Fjeldstad, Maria P; Schøyen, Vemund Sigmundson; Olsen, Elise Reppe & Lepperød, Mikkel Elle [Vis alle 8 forfattere av denne artikkelen] (2022). Social and spatial codes in hippocampus CA2 and entorhinal cortex. Fulltekst i vitenarkiv
• Schlegel, Ulrike; Hjallar, Viktor A.; Lensjø, Kristian; Uggerud, Ida Margrethe; Bjaalie, Jan G. & Hvoslef-Eide, Martha [Vis alle 8 forfattere av denne artikkelen] (2022). Mapping of parahippocampal and visual neural networks in mice: Preliminary evidence for feedback projections from perirhinal cortex to visual areas. Fulltekst i vitenarkiv Vis sammendrag

  Feedback projections from higher-order processing areas to lower-order areas within the visual system havebeen observed in several species. While much is known about the function of feedforward connections in thevisual processing pathway, feedback connections are not as well studied. They are thought to cause behaviorssuch as (selective) attention or expectations, but the exact mechanism and underlying neural connectivity isstill unknown. The perirhinal cortex (PRH) forms the intersection between perceptual and mnemonic areas ofthe visual processing pathway. Evidence from rats, monkeys and humans suggests that it is involved in bothobject memory and perceptual tasks, which is reflected in its connectivity. PRH forms numerous feedforwardand feedback projections with other areas of the visual processing pathway. However, little is known about thefunction and organization of feedback projections from PRH, and other parahippocampal regions, to visualareas in mice. Given the widespread availability of genetic and molecular tools, novel opportunities toinvestigate the function of these feedback projections would be enabled by mapping them in mice. Here wepresent preliminary data from anterograde and retrograde tract tracing experiments showing feedbackprojections from PRH, and other parahippocampal regions, to visual areas. We have found first evidence forfeedback projections from PRH to lower-order visual areas that were assumed to be exclusive to higher-developed animals such as monkeys or humans. Further, we have identified feedback projections from otherparahippocampal regions with specific subregional distribution.

• Engebretsen, Solveig; Goodwin, Morten; Fyhn, Marianne & Jemterud, Torkild (2022). Abels tårn. [Radio]. NRK P2. Fulltekst i vitenarkiv
• Banono, Nancy Saana; Ent, Wietske van der; Gawel, Kinga Aurelia; Marttunen, Tuomo; Kukula, Wirginia Koch & Fyhn, Marianne [Vis alle 9 forfattere av denne artikkelen] (2022). Zebrafish larvae with cacna1c mutations display both shared and distinct phenotypes. Fulltekst i vitenarkiv
• Sørensen, Christina; Qureshi, Tayyaba; Fyhn, Marianne; Hafting, Torkel & Chaudhry, Farrukh Abbas (2021). GABA er essensielt for normal hjerneutvikling og synaptisk plastisitet. NBS-nytt. ISSN 0801-3535. Fulltekst i vitenarkiv
• Banono, Nancy Saana; Ent, Wietske van der; Gawel, Kinga Aurelia; Mäki-Marttunen, Tuomo; Kukula-Koch, Wirginia & Einevoll, Gaute [Vis alle 9 forfattere av denne artikkelen] (2021). Functional characterisation of cacna1c mutations in zebrafish larvae. Fulltekst i vitenarkiv
• Iannella, Nicolangelo Libero; Prydz, Kristian; Malthe-Sørensen, Anders; Einevoll, Gaute & Fyhn, Marianne (2020). A framework for modelling neuronal-ECM signalling. Fulltekst i vitenarkiv
• Fyhn, Marianne; Malthe-Sørenssen, Anders; Mørken, Knut Martin; Nederbragt, Alexander Johan; Odden, Tor Ole & Sundnes, Joakim (2019). Beregningsorientering og utdanningsutvikling. Fulltekst i vitenarkiv
• Iannella, Nicolangelo Libero; Prydz, Kristian; Malthe-Sørensen, Anders; Einevoll, Gaute & Fyhn, Marianne (2019). A new framework for modelling neural-ECM signalling and interaction. Fulltekst i vitenarkiv
• Iannella, Nicolangelo Libero; Prydz, Kristian; Malthe-Sørensen, Anders; Einevoll, Gaute & Fyhn, Marianne (2019). A new framework for modelling neural-ECM signaling. Fulltekst i vitenarkiv
• Håberg, Asta & Fyhn, Marianne (2019). Hvor god stendsans har du? [Radio]. NRK P1. Fulltekst i vitenarkiv
• Hagen, Espen; Stasik, Alexander Johannes; Billeh, Yazan N.; Siegle, Joshua H.; Dai, Kael & Rimehaug, Atle Eskeland [Vis alle 14 forfattere av denne artikkelen] (2019). Comparing spikes and the local field potential (LFP) in V1 between experimental data and a comprehensive biophysical model. Fulltekst i vitenarkiv
• Røe, Malin Benum; Aasebø, Ida Elisabeth Jørgensen; Mobarhan, Milad; Lensjø, Kristian Kinden; Einevoll, Gaute & Hafting, Torkel [Vis alle 7 forfattere av denne artikkelen] (2019). Stable orientation tuning in the freely moving rat: Movement-robust orientation-selective neurons in the deep layers of the primary visual cortex. Fulltekst i vitenarkiv
• Hagen, Espen; Stasik, Alexander Johannes; Billeh, Yazan; Siegle, Joshua H.; Dai, Kael & Rimehaug, Atle Eskeland [Vis alle 14 forfattere av denne artikkelen] (2019). Comparing spikes and the local field potential (LFP) in V1 between experimental data and a comprehensive biophysical model. Fulltekst i vitenarkiv
• Røe, Malin Benum; Aasebø, Ida Elisabeth Jørgensen; Mobarhan, Milad; Lensjø, Kristian Kinden; Einevoll, Gaute & Hafting, Torkel [Vis alle 7 forfattere av denne artikkelen] (2019). Stable orientation tuning in the freely moving rat: Movement-robust orientation-selective neurons in the deep layers of the primary visual cortex. Fulltekst i vitenarkiv
• Fyhn, Marianne & Einevoll, Gaute (2019). Hjernen digitaliseres - hvordan moderne datateknologi brukes til å forstå biologiske mekanismer i hjernen. Fulltekst i vitenarkiv
• Røe, Malin Benum; Aasebø, Ida Elisabeth Jørgensen; Mobarhan, Milad; Lensjø, Kristian Kinden; Einevoll, Gaute & Hafting, Torkel [Vis alle 7 forfattere av denne artikkelen] (2018). Movement-resistant orientation selectivity of cells in the deep layers of the rat visual cortex. Fulltekst i vitenarkiv
• Røe, Malin Benum; Aasebø, Ida Elisabeth Jørgensen; Mobarhan, Milad; Lensjø, Kristian Kinden; Einevoll, Gaute & Hafting, Torkel [Vis alle 7 forfattere av denne artikkelen] (2018). Stable orientation tuning in the freely moving rat: Movement-robust orientation selective neurons in the deep layers of the primary visual cortex. Fulltekst i vitenarkiv
• Aasebø, Ida Elisabeth Jørgensen; Røe, Malin Benum; Mobarhan, Milad; Lensjø, Kristian Kinden; Stöber, Tristan Manfred & Einevoll, Gaute [Vis alle 8 forfattere av denne artikkelen] (2018). Orientation selectivity in the freely moving rat: Movement-robust orientation-selectivity (MROS) of units in the deep layers of the rat visual cortex. Fulltekst i vitenarkiv
• Grødem, Sverre; Sandvik, Guro Katrine; Hazen, Jennifer; Lensjø, Kristian Kinden; Hafting, Torkel & Fyhn, Marianne (2018). A CRISPR-Cas9 platform for genetic perturbations of brain extracellular matrix regulators in vivo. Fulltekst i vitenarkiv
• Røe, Malin Benum; Aasebø, Ida Elisabeth Jørgensen; Mobarhan, Milad; Lensjø, Kristian Kinden; Stöber, Tristan Manfred & Einevoll, Gaute [Vis alle 8 forfattere av denne artikkelen] (2018). Stable orientation tuning in the freely moving rat: Movement-robust orientation-selective neurons in the deep layers of the primary visual cortex. Fulltekst i vitenarkiv
• Lensjø, Kristian Kinden; Rowlands, Daire; Dinh, Tovy; Thompson, Elise Holter; Andrews, Melissa & Hafting, Torkel [Vis alle 9 forfattere av denne artikkelen] (2018). Conditional knock-out of the Acan gene removes perineuronal nets in adult mice and induces life-long brian plasticity. Fulltekst i vitenarkiv
• Hazen, Jennifer; Wigestrand, Mattis B; Aasebø, Ida Elisabeth Jørgensen; Tully, Annabelle; Dinh, Tovy & Lepperød, Mikkel [Vis alle 8 forfattere av denne artikkelen] (2018). Lateral hypothalamic area projection neurons contribute to an innate freezing response. Fulltekst i vitenarkiv
• Dragly, Svenn-Arne; Mobarhan, Milad; Lepperød, Mikkel Elle; Tennøe, Simen; Stasik, Alexander Johannes & Fyhn, Marianne [Vis alle 8 forfattere av denne artikkelen] (2018). Exdir An alternative to HDF5 that uses Numpy files for data, YAML for metadata and simple directories to define the hierarchy. Fulltekst i vitenarkiv
• Fyhn, Marianne; Kristensen, Solveig; Mørken, Knut Martin; Sølna, Hanne; Tellefsen, Cathrine Wahlstrøm & Villanger, Ilan Dehli (2017). Helhetlig fokus på utdanningsutvikling. Fulltekst i vitenarkiv
• Buccino, Alessio Paolo; Ness, Torbjørn Vefferstad; Einevoll, Gaute; Cauwenberghs, Gert; Fyhn, Marianne & Hafting, Torkel [Vis alle 7 forfattere av denne artikkelen] (2017). Classification of Neural Cell-types from Extracellular Signatures on Multi-Electrode Arrays using Deep Learning. Fulltekst i vitenarkiv
• Dinh, Tovy; Lensjø, Kristian Kinden; Lanton, Rune Alexander; Dick, Gunnar; Fyhn, Marianne & Hafting, Torkel (2017). Increased ocular dominance plasticity in adult visual cortex after genetic knock out of aggrecan, an essential component of perineuronal nets. Fulltekst i vitenarkiv
• Aasebø, Ida E. J.; Mobarhan, Milad; Røe, Malin Benum; Lensjø, Kristian Kinden; Einevoll, Gaute & Hafting, Torkel [Vis alle 7 forfattere av denne artikkelen] (2017). Movement-resistant orientation-selective units in the deep layers of the visual cortex. Fulltekst i vitenarkiv
• Mobarhan, Milad; Halnes, Geir; Martínez-Cañada, Pablo; Hafting, Torkel; Fyhn, Marianne & Einevoll, Gaute (2017). Firing-rate Based Network Modeling of the dLGN Circuit: Effects of Cortical Feedback on Spatiotemporal Response Properties of Relay Cells. Fulltekst i vitenarkiv
• Christensen, Ane Charlotte; Lensjø, Kristian Kinden; Lepperød, Mikkel Elle; Fyhn, Marianne & Hafting, Torkel (2017). The role of extracellular matrix molecules for spatial representations in medial entorhinal cortex. Fulltekst i vitenarkiv
• Lepperød, Mikkel Elle; Lai, Yi Ming; Fyhn, Marianne; Einevoll, Gaute; Solstad, Trygve & Hafting, Torkel [Vis alle 7 forfattere av denne artikkelen] (2017). Population density model of the entorhinal stellate-cell network with adaptation. Fulltekst i vitenarkiv
• Dragly, Svenn-Arne; Mobarhan, Milad; Solbrå, Andreas Våvang; Tennøe, Simen; Hafreager, Anders & Malthe-Sørenssen, Anders [Vis alle 9 forfattere av denne artikkelen] (2017). Neuronify: An Educational Simulator for Neural Circuits. Fulltekst i vitenarkiv Vis sammendrag

  Neurons are cells in the brain that are able to rapidly change the electric field across their cell membrane. These changes allow neurons to communicate with each other and is the basis for the complex computations in the brain. Understanding how neurons communicate and the properties of neuronal networks is essential for neuroscience students. Traditionally, students draw networks with pen and paper and qualitatively deduce features of the network by analyzing the static drawings. Here, we present Neuronify, an app that allows students to draw the same networks on a computer or mobile device and run dynamic simulations without programming. The students can test their analysis by running the network and check their predictions against the outcome. Educational software (apps) can improve science education by providing an interactive way of learning about complicated topics that are hard to explain with text and static illustrations. Such software is readily available in many areas of natural science such as physics and electrical engineering. However, few educational apps are available for simulation of neural networks. Neuronify allows the user to easily create and explore neural networks in a plug-and-play simulation environment. The user can drag and drop network elements such as neurons, electrical stimulation tools and recording devices. The components can then easily be connected to one another. Building intuition for how neurons and neural networks behave has been a top priority in designing Neuronify. We aim to provide a low entry point to simulation-based neuroscience. Most undergraduate students do not have the computational experience to create their own neural simulator. Neuronify offers them an opportunity to build and experiment with neural networks in a graphical and easy-to-understand interface. By playing around with the networks, the students can develop a good understanding of their properties. To facilitate the use of Neuronify in teaching, a set of premade common network motifs is provided, performing functions such as input summation and detection of direction of stimulus movement. Neuronify is developed in C++ and QML using the cross-platform application framework Qt. It has been downloaded more than 30,000 times since its launch and is available on smart phones (Android, iOS), tablet computers as well personal computers (Windows, Mac, Linux).

• Thompson, Elise Holter; Lensjø, Kristian Kinden; Wigestrand, Mattis B; Hafting, Torkel; Malthe-Sørenssen, Anders & Fyhn, Marianne (2017). The perineuronal nets in the lateral secondary visual cortex are essential for remote visual fear memory. Fulltekst i vitenarkiv
• Christensen, Ane Charlotte; Fyhn, Marianne & Hafting, Torkel (2017). The role of perineuronal nets in spatial representations. Fulltekst i vitenarkiv
• Wigestrand, Mattis B; Aasebø, Ida E. J.; Tully, Annabelle; Lepperød, Mikkel Elle; Hafting, Torkel & Fyhn, Marianne (2016). Lateral hypothalamic outputs control innate defensive responses. Fulltekst i vitenarkiv Vis sammendrag

  When facing a threat, animals display defensive behaviors that are critical for survival. The hypothalamus is believed to mediate such defensive responses, but the prevailing view includes a medial/lateral separation, where medial hypothalamus is thought to influence defensive responses, while the lateral hypothalamic area (LHA) regulates feeding and arousal. Here we identify two distinct neural populations in the LHA with surprising survival functions in rats. The two neural populations, defined by their output projections to either the periaqueductal gray (PAG) or the lateral habenula (LHb) have distinct anatomical placements along the anterior-posterior axis of the LHA and express distinct biochemical markers. Optogenetic stimulation of the two LHA populations robustly induced opposite active- or passive defensive responses. Further, chemogenetic silencing of LHA and optogenetic silencing of the LHA-PAG projection disrupted innate defensive responses to a predator-like looming shadow. Using single-unit recordings in the downstream LHb and PAG, we show that the LHA-LHb projection is largely excitatory, while the LHA-PAG projection is mainly inhibitory. We are currently using a miniaturized microscope to image the calcium activity of the two LHA populations during threat processing in behaving rats. Overall, our findings identify a novel LHA circuit that is critical for appropriate defensive responses to innate visual threats. The location of the LHA defense circuits, intermingled within circuitry that governs feeding, suggests that this circuit may provide rapid cross-talk between circuits that govern foraging- and anti-predator behaviors.

• Blackstad, Jan Sigurd; Christensen, Ane Charlotte; Lensjø, Kristian Kinden; Hafting, Torkel & Fyhn, Marianne (2016). Involvement of perineuronal nets in spatial information transfer between the entorhinal cortex and hippocampus. Fulltekst i vitenarkiv
• Lepperød, Mikkel Elle; Wigestrand, Mattis B; Frey, M.M.; Lensjø, Kristian Kinden; Einevoll, Gaute & Solstad, Trygve [Vis alle 8 forfattere av denne artikkelen] (2016). Role of input-specific perturbations of medial septal projections to the grid cell network. Fulltekst i vitenarkiv
• Lepperød, Mikkel Elle; Wigestrand, Mattis B; Lensjø, Kristian Kinden; Frey, M.M.; Dragly, Svenn-Arne & Einevoll, Gaute [Vis alle 9 forfattere av denne artikkelen] (2016). Grid cell network resilient to input-specific medial septum perturbations. Fulltekst i vitenarkiv
• Wigestrand, Mattis B; Aasebø, Ida E. J.; Tully, Annabelle; Dinh, Vy To; Lepperød, Mikkel Elle & Hafting, Torkel [Vis alle 7 forfattere av denne artikkelen] (2016). Lateral hypothalamic outputs control innate defensive responses. Fulltekst i vitenarkiv
• Lepperød, Mikkel Elle; Wigestrand, Mattis B; Frey, Mina Martine; Lensjø, Kristian Kinden; Einevoll, Gaute & Solstad, Trygve [Vis alle 8 forfattere av denne artikkelen] (2016). On the role of input-specific perturbations of medial septal projections to the grid cell network. Fulltekst i vitenarkiv
• Blackstad, Jan Sigurd; Christensen, Ane Charlotte; Lensjø, Kristian Kinden; Hafting, Torkel & Fyhn, Marianne (2016). Involvement of perineuronal nets in spatial information transfer between the entorhinal cortex and hippocampus. Fulltekst i vitenarkiv
• Thompson, Elise Holter; Lensjø, Kristian Kinden; Wigestrand, Mattis B; Hafting, Torkel; Fyhn, Marianne & Malthe-Sørenssen, Anders (2016). The perineuronal nets in the lateral secondary visual cortex are essential for remote visual memory. Fulltekst i vitenarkiv
• Bjerke, Line; Wigestrand, Mattis B; Aasebø, Ida E. J.; Fyhn, Marianne & Hafting, Torkel (2016). Inhibitory outputs from lateral hypothalamus to paraqueductal grey control innate defensive behavior. Fulltekst i vitenarkiv
• Røe, Malin Benum; Aasebø, Ida E. J.; Lensjø, Kristian Kinden; Hafting, Torkel & Fyhn, Marianne (2016). Orientation selective cells in layer six of the primary visual cortex are resistant to the animal's movement. Fulltekst i vitenarkiv
• Thompson, Elise Holter; Lensjø, Kristian Kinden; Wigestrand, Mattis B; Hafting, Torkel & Fyhn, Marianne (2016). The perineuronal nets in the lateral secondary visual cortex and their impact on remote visual fear memory. Fulltekst i vitenarkiv
• Rogge, Frederik Sebastian; Fyhn, Marianne; Malthe-Sørenssen, Anders; Lepperød, Mikkel Elle & Lensjø, Kristian (2026). Normative and Experimental Analyses of Learning-Dependent Representations in the Hippocampal-Parahippocampal System. Universitetet i Oslo. Fulltekst i vitenarkiv Vis sammendrag

  The brain is thought to build a cognitive map of both physical and abstract spaces, helping us navigate the world, organize knowledge, and form new memories. In this thesis, I investigated key brain subregions to uncover the principles underlying the emergence of neural representations. I focused on the general properties of the neural code, how visual inputs are integrated, and how these representations reorganize through learning. To address these questions, I combined large-scale chronic two-photon calcium imaging in mice with normative modeling in artificial neural networks. We show that neurons in the medial entorhinal cortex (MEC) develop task-relevant tuning during learning of a purely visual association task, pointing to a broader role beyond its classical link to spatial coding. In parallel, selective disruption of specific neuron types in the postrhinal cortex (POR) impaired learning of the same task, demonstrating their causal contribution. Furthermore, using artificial neural networks, we uncovered computational principles governing how spatial representations emerge and transform. Finally, we revealed dissociable contributions of POR and MEC to visually guided navigation, highlighting their distinct roles. Together, these results shed new light on the emergence of neural representations in different brain regions and their transformation through learning.

• Banono, Nancy Saana; Esguerra, Camila; Fyhn, Marianne & Andreassen, Ole (2021). Functional analysis of psychiatric risk genes in zebrafish (Danio rerio): a focus on the L-type voltage-gated calcium channel subtypes CaV1.2 and CaV1.3. Universitetet i Oslo. Fulltekst i vitenarkiv Vis sammendrag

  CACNA1C and CACNA1D are voltage-gated calcium channel genes that have been repeatedly associated with psychiatric disorders by various genomic studies. These genes are involved in gene expression regulation, neurotransmitter release and integration of dendritic information in the brain, but the mechanisms through which they cause disease are poorly understood. The goal of this thesis was to characterise the effects of mutations in CACNA1C and CACNA1D on early brain function using three zebrafish mutant lines (one cacna1d and two cacna1c mutants) that were characterised through an arsenal of molecular, behavioural, neurophysiological and pharmacological methods. Larval zebrafish with global cacna1da haploinsufficiency showed a hyperlocomotor phenotype that could be improved or reversed using the antipsychotics haloperidol and risperidone and the mood stabiliser, valproate. Furthermore, larvae with global loss-of-function (LOF) of cacna1c was associated with observable dysmorphologies, changes in downstream molecular targets, compensatory overexpression of cacna1d, and deficits in sensorimotor gating. In addition, spectral analysis of local field potential recordings and neurotransmitter analysis revealed gross neural excitability in the cacna1c LOF mutants. Together, we have shown that mutations that alter the function of cacna1da and cacna1c lead to a wide-range of phenotypes reminiscent of relevant functional domains observed in psychiatric disorders.

• Aasebø, Ida Elisabeth Jørgensen; Fyhn, Marianne; Hafting, Torkel & Einevoll, Gaute (2018). Behavioural state and neuronal activity: how the freely moving paradigm can uncover novel response characteristics. Universitetet i Oslo. Fulltekst i vitenarkiv
• Johansen, Finn-Eirik; Brautaset, Trygve; Aune, Marie Hjelmseth; Patriksson, Alexandra; Falkenberg, Liv Eggset & Kleppe, Rune [Vis alle 19 forfattere av denne artikkelen] (2018). Centre for Digital Life Norway - Annual report 2017. Senter for Digialt Liv Norge. Fulltekst i vitenarkiv Vis sammendrag

  Centre for Digital Life Norway (DLN) is a virtual centre, institutionally anchored at NTNU, UiO and UiB. It is funded by the Research Council of Norway under the Digital Life (DL) initiative and receives in kind support from the host universities. The centre is built around the 12 research projects are currently funded through the research council’s Digital Life initiative. DLNs mission is to build capacities for disciplinary convergence in digital biotechnology through education and training, to strengthen shared digital infrastructures, to leverage innovation and industrial partnerships, and to foster social responsibility. The following illustrates some of the centre’s many networking activities during 2017, most of which adressed a need in one or more of the centre’s research projects.

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