TY - THES AU - Chiossi, Heloisa ID - 14821 SN - 2663 - 337X TI - Adaptive hierarchical representations in the hippocampus ER - TY - JOUR AB - Despite the considerable progress of in vivo neural recording techniques, inferring the biophysical mechanisms underlying large scale coordination of brain activity from neural data remains challenging. One obstacle is the difficulty to link high dimensional functional connectivity measures to mechanistic models of network activity. We address this issue by investigating spike-field coupling (SFC) measurements, which quantify the synchronization between, on the one hand, the action potentials produced by neurons, and on the other hand mesoscopic “field” signals, reflecting subthreshold activities at possibly multiple recording sites. As the number of recording sites gets large, the amount of pairwise SFC measurements becomes overwhelmingly challenging to interpret. We develop Generalized Phase Locking Analysis (GPLA) as an interpretable dimensionality reduction of this multivariate SFC. GPLA describes the dominant coupling between field activity and neural ensembles across space and frequencies. We show that GPLA features are biophysically interpretable when used in conjunction with appropriate network models, such that we can identify the influence of underlying circuit properties on these features. We demonstrate the statistical benefits and interpretability of this approach in various computational models and Utah array recordings. The results suggest that GPLA, used jointly with biophysical modeling, can help uncover the contribution of recurrent microcircuits to the spatio-temporal dynamics observed in multi-channel experimental recordings. AU - Safavi, Shervin AU - Panagiotaropoulos, Theofanis I. AU - Kapoor, Vishal AU - Ramirez Villegas, Juan F AU - Logothetis, Nikos K. AU - Besserve, Michel ID - 12862 IS - 4 JF - PLoS Computational Biology TI - Uncovering the organization of neural circuits with Generalized Phase Locking Analysis VL - 19 ER - TY - JOUR AB - The execution of cognitive functions requires coordinated circuit activity across different brain areas that involves the associated firing of neuronal assemblies. Here, we tested the circuit mechanism behind assembly interactions between the hippocampus and the medial prefrontal cortex (mPFC) of adult rats by recording neuronal populations during a rule-switching task. We identified functionally coupled CA1-mPFC cells that synchronized their activity beyond that expected from common spatial coding or oscillatory firing. When such cell pairs fired together, the mPFC cell strongly phase locked to CA1 theta oscillations and maintained consistent theta firing phases, independent of the theta timing of their CA1 counterpart. These functionally connected CA1-mPFC cells formed interconnected assemblies. While firing together with their CA1 assembly partners, mPFC cells fired along specific theta sequences. Our results suggest that upregulated theta oscillatory firing of mPFC cells can signal transient interactions with specific CA1 assemblies, thus enabling distributed computations. AU - Nardin, Michele AU - Käfer, Karola AU - Stella, Federico AU - Csicsvari, Jozsef L ID - 14314 IS - 9 JF - Cell Reports TI - Theta oscillations as a substrate for medial prefrontal-hippocampal assembly interactions VL - 42 ER - TY - JOUR AB - Although much is known about how single neurons in the hippocampus represent an animal's position, how circuit interactions contribute to spatial coding is less well understood. Using a novel statistical estimator and theoretical modeling, both developed in the framework of maximum entropy models, we reveal highly structured CA1 cell-cell interactions in male rats during open field exploration. The statistics of these interactions depend on whether the animal is in a familiar or novel environment. In both conditions the circuit interactions optimize the encoding of spatial information, but for regimes that differ in the informativeness of their spatial inputs. This structure facilitates linear decodability, making the information easy to read out by downstream circuits. Overall, our findings suggest that the efficient coding hypothesis is not only applicable to individual neuron properties in the sensory periphery, but also to neural interactions in the central brain. AU - Nardin, Michele AU - Csicsvari, Jozsef L AU - Tkačik, Gašper AU - Savin, Cristina ID - 14656 IS - 48 JF - The Journal of Neuroscience TI - The structure of hippocampal CA1 interactions optimizes spatial coding across experience VL - 43 ER - TY - JOUR AB - The mammalian hippocampal formation (HF) plays a key role in several higher brain functions, such as spatial coding, learning and memory. Its simple circuit architecture is often viewed as a trisynaptic loop, processing input originating from the superficial layers of the entorhinal cortex (EC) and sending it back to its deeper layers. Here, we show that excitatory neurons in layer 6b of the mouse EC project to all sub-regions comprising the HF and receive input from the CA1, thalamus and claustrum. Furthermore, their output is characterized by unique slow-decaying excitatory postsynaptic currents capable of driving plateau-like potentials in their postsynaptic targets. Optogenetic inhibition of the EC-6b pathway affects spatial coding in CA1 pyramidal neurons, while cell ablation impairs not only acquisition of new spatial memories, but also degradation of previously acquired ones. Our results provide evidence of a functional role for cortical layer 6b neurons in the adult brain. AU - Ben Simon, Yoav AU - Käfer, Karola AU - Velicky, Philipp AU - Csicsvari, Jozsef L AU - Danzl, Johann G AU - Jonas, Peter M ID - 11951 JF - Nature Communications KW - General Physics and Astronomy KW - General Biochemistry KW - Genetics and Molecular Biology KW - General Chemistry KW - Multidisciplinary SN - 2041-1723 TI - A direct excitatory projection from entorhinal layer 6b neurons to the hippocampus contributes to spatial coding and memory VL - 13 ER - TY - JOUR AB - Editorial on the Research Topic AU - Gambino, Giuditta AU - Bhik-Ghanie, Rebecca AU - Giglia, Giuseppe AU - Puig, M. Victoria AU - Ramirez Villegas, Juan F AU - Zaldivar, Daniel ID - 12149 JF - Frontiers in Neural Circuits KW - Cellular and Molecular Neuroscience KW - Cognitive Neuroscience KW - Sensory Systems KW - Neuroscience (miscellaneous) SN - 1662-5110 TI - Editorial: Neuromodulatory ascending systems: Their influence at the microscopic and macroscopic levels VL - 16 ER - TY - THES AB - The ability to form and retrieve memories is central to survival. In mammals, the hippocampus is a brain region essential to the acquisition and consolidation of new memories. It is also involved in keeping track of one’s position in space and aids navigation. Although this space-memory has been a source of contradiction, evidence supports the view that the role of the hippocampus in navigation is memory, thanks to the formation of cognitive maps. First introduced by Tolman in 1948, cognitive maps are generally used to organize experiences in memory; however, the detailed mechanisms by which these maps are formed and stored are not yet agreed upon. Some influential theories describe this process as involving three fundamental steps: initial encoding by the hippocampus, interactions between the hippocampus and other cortical areas, and long-term extra-hippocampal consolidation. In this thesis, I will show how the investigation of cognitive maps of space helped to shed light on each of these three memory processes. The first study included in this thesis deals with the initial encoding of spatial memories in the hippocampus. Much is known about encoding at the level of single cells, but less about their co-activity or joint contribution to the encoding of novel spatial information. I will describe the structure of an interaction network that allows for efficient encoding of noisy spatial information during the first exploration of a novel environment. The second study describes the interactions between the hippocampus and the prefrontal cortex (PFC), two areas directly and indirectly connected. It is known that the PFC, in concert with the hippocampus, is involved in various processes, including memory storage and spatial navigation. Nonetheless, the detailed mechanisms by which PFC receives information from the hippocampus are not clear. I will show how a transient improvement in theta phase locking of PFC cells enables interactions of cell pairs across the two regions. The third study describes the learning of behaviorally-relevant spatial locations in the hippocampus and the medial entorhinal cortex. I will show how the accumulation of firing around goal locations, a correlate of learning, can shed light on the transition from short- to long-term spatial memories and the speed of consolidation in different brain areas. The studies included in this thesis represent the main scientific contributions of my Ph.D. They involve statistical analyses and models of neural responses of cells in different brain areas of rats executing spatial tasks. I will conclude the thesis by discussing the impact of the findings on principles of memory formation and retention, including the mechanisms, the speed, and the duration of these processes. AU - Nardin, Michele ID - 11932 SN - 2663-337X TI - On the encoding, transfer, and consolidation of spatial memories ER - TY - JOUR AB - The infiltration of immune cells into tissues underlies the establishment of tissue-resident macrophages and responses to infections and tumors. Yet the mechanisms immune cells utilize to negotiate tissue barriers in living organisms are not well understood, and a role for cortical actin has not been examined. Here, we find that the tissue invasion of Drosophila macrophages, also known as plasmatocytes or hemocytes, utilizes enhanced cortical F-actin levels stimulated by the Drosophila member of the fos proto oncogene transcription factor family (Dfos, Kayak). RNA sequencing analysis and live imaging show that Dfos enhances F-actin levels around the entire macrophage surface by increasing mRNA levels of the membrane spanning molecular scaffold tetraspanin TM4SF, and the actin cross-linking filamin Cheerio, which are themselves required for invasion. Both the filamin and the tetraspanin enhance the cortical activity of Rho1 and the formin Diaphanous and thus the assembly of cortical actin, which is a critical function since expressing a dominant active form of Diaphanous can rescue the Dfos macrophage invasion defect. In vivo imaging shows that Dfos enhances the efficiency of the initial phases of macrophage tissue entry. Genetic evidence argues that this Dfos-induced program in macrophages counteracts the constraint produced by the tension of surrounding tissues and buffers the properties of the macrophage nucleus from affecting tissue entry. We thus identify strengthening the cortical actin cytoskeleton through Dfos as a key process allowing efficient forward movement of an immune cell into surrounding tissues. AU - Belyaeva, Vera AU - Wachner, Stephanie AU - György, Attila AU - Emtenani, Shamsi AU - Gridchyn, Igor AU - Akhmanova, Maria AU - Linder, M AU - Roblek, Marko AU - Sibilia, M AU - Siekhaus, Daria E ID - 10614 IS - 1 JF - PLoS Biology SN - 1544-9173 TI - Fos regulates macrophage infiltration against surrounding tissue resistance by a cortical actin-based mechanism in Drosophila VL - 20 ER - TY - GEN AB - Hippocampal and neocortical neural activity is modulated by the position of the individual in space. While hippocampal neurons provide the basis for a spatial map, prefrontal cortical neurons generalize over environmental features. Whether these generalized representations result from a bidirectional interaction with, or are mainly derived from hippocampal spatial representations is not known. By examining simultaneously recorded hippocampal and medial prefrontal neurons, we observed that prefrontal spatial representations show a delayed coherence with hippocampal ones. We also identified subpopulations of cells in the hippocampus and medial prefrontal cortex that formed functional cross-area couplings; these resembled the optimal connections predicted by a probabilistic model of spatial information transfer and generalization. Moreover, cross-area couplings were strongest and had the shortest delay preceding spatial decision-making. Our results suggest that generalized spatial coding in the medial prefrontal cortex is inherited from spatial representations in the hippocampus, and that the routing of information can change dynamically with behavioral demands. AU - Nardin, Michele AU - Käfer, Karola AU - Csicsvari, Jozsef L ID - 10080 T2 - bioRxiv TI - The generalized spatial representation in the prefrontal cortex is inherited from the hippocampus ER - TY - JOUR AB - The brain efficiently performs nonlinear computations through its intricate networks of spiking neurons, but how this is done remains elusive. While nonlinear computations can be implemented successfully in spiking neural networks, this requires supervised training and the resulting connectivity can be hard to interpret. In contrast, the required connectivity for any computation in the form of a linear dynamical system can be directly derived and understood with the spike coding network (SCN) framework. These networks also have biologically realistic activity patterns and are highly robust to cell death. Here we extend the SCN framework to directly implement any polynomial dynamical system, without the need for training. This results in networks requiring a mix of synapse types (fast, slow, and multiplicative), which we term multiplicative spike coding networks (mSCNs). Using mSCNs, we demonstrate how to directly derive the required connectivity for several nonlinear dynamical systems. We also show how to carry out higher-order polynomials with coupled networks that use only pair-wise multiplicative synapses, and provide expected numbers of connections for each synapse type. Overall, our work demonstrates a novel method for implementing nonlinear computations in spiking neural networks, while keeping the attractive features of standard SCNs (robustness, realistic activity patterns, and interpretable connectivity). Finally, we discuss the biological plausibility of our approach, and how the high accuracy and robustness of the approach may be of interest for neuromorphic computing. AU - Nardin, Michele AU - Phillips, James W. AU - Podlaski, William F. AU - Keemink, Sander W. ID - 10635 JF - Peer Community Journal TI - Nonlinear computations in spiking neural networks through multiplicative synapses VL - 1 ER - TY - JOUR AB - The hippocampus has a major role in encoding and consolidating long-term memories, and undergoes plastic changes during sleep1. These changes require precise homeostatic control by subcortical neuromodulatory structures2. The underlying mechanisms of this phenomenon, however, remain unknown. Here, using multi-structure recordings in macaque monkeys, we show that the brainstem transiently modulates hippocampal network events through phasic pontine waves known as pontogeniculooccipital waves (PGO waves). Two physiologically distinct types of PGO wave appear to occur sequentially, selectively influencing high-frequency ripples and low-frequency theta events, respectively. The two types of PGO wave are associated with opposite hippocampal spike-field coupling, prompting periods of high neural synchrony of neural populations during periods of ripple and theta instances. The coupling between PGO waves and ripples, classically associated with distinct sleep stages, supports the notion that a global coordination mechanism of hippocampal sleep dynamics by cholinergic pontine transients may promote systems and synaptic memory consolidation as well as synaptic homeostasis. AU - Ramirez Villegas, Juan F AU - Besserve, Michel AU - Murayama, Yusuke AU - Evrard, Henry C. AU - Oeltermann, Axel AU - Logothetis, Nikos K. ID - 8818 IS - 7840 JF - Nature SN - 00280836 TI - Coupling of hippocampal theta and ripples with pontogeniculooccipital waves VL - 589 ER - TY - GEN AB - Although much is known about how single neurons in the hippocampus represent an animal’s position, how cell-cell interactions contribute to spatial coding remains poorly understood. Using a novel statistical estimator and theoretical modeling, both developed in the framework of maximum entropy models, we reveal highly structured cell-to-cell interactions whose statistics depend on familiar vs. novel environment. In both conditions the circuit interactions optimize the encoding of spatial information, but for regimes that differ in the signal-to-noise ratio of their spatial inputs. Moreover, the topology of the interactions facilitates linear decodability, making the information easy to read out by downstream circuits. These findings suggest that the efficient coding hypothesis is not applicable only to individual neuron properties in the sensory periphery, but also to neural interactions in the central brain. AU - Nardin, Michele AU - Csicsvari, Jozsef L AU - Tkačik, Gašper AU - Savin, Cristina ID - 10077 T2 - bioRxiv TI - The structure of hippocampal CA1 interactions optimizes spatial coding across experience ER - TY - JOUR AB - Nearby grid cells have been observed to express a remarkable degree of long-rangeorder, which is often idealized as extending potentially to infinity. Yet their strict peri-odic firing and ensemble coherence are theoretically possible only in flat environments, much unlike the burrows which rodents usually live in. Are the symmetrical, coherent grid maps inferred in the lab relevant to chart their way in their natural habitat? We consider spheres as simple models of curved environments and waiting for the appropriate experiments to be performed, we use our adaptation model to predict what grid maps would emerge in a network with the same type of recurrent connections, which on the plane produce coherence among the units. We find that on the sphere such connections distort the maps that single grid units would express on their own, and aggregate them into clusters. When remapping to a different spherical environment, units in each cluster maintain only partial coherence, similar to what is observed in disordered materials, such as spin glasses. AU - Stella, Federico AU - Urdapilleta, Eugenio AU - Luo, Yifan AU - Treves, Alessandro ID - 6796 IS - 4 JF - Hippocampus SN - 10509631 TI - Partial coherence and frustration in self-organizing spherical grids VL - 30 ER - TY - JOUR AB - Temporally organized reactivation of experiences during awake immobility periods is thought to underlie cognitive processes like planning and evaluation. While replay of trajectories is well established for the hippocampus, it is unclear whether the medial prefrontal cortex (mPFC) can reactivate sequential behavioral experiences in the awake state to support task execution. We simultaneously recorded from hippocampal and mPFC principal neurons in rats performing a mPFC-dependent rule-switching task on a plus maze. We found that mPFC neuronal activity encoded relative positions between the start and goal. During awake immobility periods, the mPFC replayed temporally organized sequences of these generalized positions, resembling entire spatial trajectories. The occurrence of mPFC trajectory replay positively correlated with rule-switching performance. However, hippocampal and mPFC trajectory replay occurred independently, indicating different functions. These results demonstrate that the mPFC can replay ordered activity patterns representing generalized locations and suggest that mPFC replay might have a role in flexible behavior. AU - Käfer, Karola AU - Nardin, Michele AU - Blahna, Karel AU - Csicsvari, Jozsef L ID - 7472 IS - 1 JF - Neuron SN - 0896-6273 TI - Replay of behavioral sequences in the medial prefrontal cortex during rule switching VL - 106 ER - TY - JOUR AU - Gridchyn, Igor AU - Schönenberger, Philipp AU - O'Neill, Joseph AU - Csicsvari, Jozsef L ID - 7684 IS - 2 JF - Neuron SN - 08966273 TI - Assembly-specific disruption of hippocampal replay leads to selective memory deficit VL - 106 ER - TY - JOUR AB - In vitro work revealed that excitatory synaptic inputs to hippocampal inhibitory interneurons could undergo Hebbian, associative, or non-associative plasticity. Both behavioral and learning-dependent reorganization of these connections has also been demonstrated by measuring spike transmission probabilities in pyramidal cell-interneuron spike cross-correlations that indicate monosynaptic connections. Here we investigated the activity-dependent modification of these connections during exploratory behavior in rats by optogenetically inhibiting pyramidal cell and interneuron subpopulations. Light application and associated firing alteration of pyramidal and interneuron populations led to lasting changes in pyramidal-interneuron connection weights as indicated by spike transmission changes. Spike transmission alterations were predicted by the light-mediated changes in the number of pre- and postsynaptic spike pairing events and by firing rate changes of interneurons but not pyramidal cells. This work demonstrates the presence of activity-dependent associative and non-associative reorganization of pyramidal-interneuron connections triggered by the optogenetic modification of the firing rate and spike synchrony of cells. AU - Gridchyn, Igor AU - Schönenberger, Philipp AU - O'Neill, Joseph AU - Csicsvari, Jozsef L ID - 8740 JF - eLife TI - Optogenetic inhibition-mediated activity-dependent modification of CA1 pyramidal-interneuron connections during behavior VL - 9 ER - TY - DATA AB - Supplementary data provided for the provided for the publication: Igor Gridchyn , Philipp Schoenenberger , Joseph O'Neill , Jozsef Csicsvari (2020) Optogenetic inhibition-mediated activity-dependent modification of CA1 pyramidal-interneuron connections during behavior. Elife. AU - Csicsvari, Jozsef L AU - Gridchyn, Igor AU - Schönenberger, Philipp ID - 8563 TI - Optogenetic alteration of hippocampal network activity ER - TY - GEN AB - The infiltration of immune cells into tissues underlies the establishment of tissue resident macrophages, and responses to infections and tumors. Yet the mechanisms immune cells utilize to negotiate tissue barriers in living organisms are not well understood, and a role for cortical actin has not been examined. Here we find that the tissue invasion of Drosophila macrophages, also known as plasmatocytes or hemocytes, utilizes enhanced cortical F-actin levels stimulated by the Drosophila member of the fos proto oncogene transcription factor family (Dfos, Kayak). RNA sequencing analysis and live imaging show that Dfos enhances F-actin levels around the entire macrophage surface by increasing mRNA levels of the membrane spanning molecular scaffold tetraspanin TM4SF, and the actin cross-linking filamin Cheerio which are themselves required for invasion. Cortical F-actin levels are critical as expressing a dominant active form of Diaphanous, a actin polymerizing Formin, can rescue the Dfos Dominant Negative macrophage invasion defect. In vivo imaging shows that Dfos is required to enhance the efficiency of the initial phases of macrophage tissue entry. Genetic evidence argues that this Dfos-induced program in macrophages counteracts the constraint produced by the tension of surrounding tissues and buffers the mechanical properties of the macrophage nucleus from affecting tissue entry. We thus identify tuning the cortical actin cytoskeleton through Dfos as a key process allowing efficient forward movement of an immune cell into surrounding tissues. AU - Belyaeva, Vera AU - Wachner, Stephanie AU - Gridchyn, Igor AU - Linder, Markus AU - Emtenani, Shamsi AU - György, Attila AU - Sibilia, Maria AU - Siekhaus, Daria E ID - 8557 T2 - bioRxiv TI - Cortical actin properties controlled by Drosophila Fos aid macrophage infiltration against surrounding tissue resistance ER - TY - JOUR AB - Hippocampal activity patterns representing movement trajectories are reactivated in immobility and sleep periods, a process associated with memory recall, consolidation, and decision making. It is thought that only fixed, behaviorally relevant patterns can be reactivated, which are stored across hippocampal synaptic connections. To test whether some generalized rules govern reactivation, we examined trajectory reactivation following non-stereotypical exploration of familiar open-field environments. We found that random trajectories of varying lengths and timescales were reactivated, resembling that of Brownian motion of particles. The animals’ behavioral trajectory did not follow Brownian diffusion demonstrating that the exact behavioral experience is not reactivated. Therefore, hippocampal circuits are able to generate random trajectories of any recently active map by following diffusion dynamics. This ability of hippocampal circuits to generate representations of all behavioral outcome combinations, experienced or not, may underlie a wide variety of hippocampal-dependent cognitive functions such as learning, generalization, and planning. AU - Stella, Federico AU - Baracskay, Peter AU - O'Neill, Joseph AU - Csicsvari, Jozsef L ID - 6338 JF - Neuron TI - Hippocampal reactivation of random trajectories resembling Brownian diffusion VL - 102 ER - TY - JOUR AB - Hippocampus is needed for both spatial working and reference memories. Here, using a radial eight-arm maze, we examined how the combined demand on these memories influenced CA1 place cell assemblies while reference memories were partially updated. This was contrasted with control tasks requiring only working memory or the update of reference memory. Reference memory update led to the reward-directed place field shifts at newly rewarded arms and to the gradual strengthening of firing in passes between newly rewarded arms but not between those passes that included a familiar-rewarded arm. At the maze center, transient network synchronization periods preferentially replayed trajectories of the next chosen arm in reference memory tasks but the previously visited arm in the working memory task. Hence, reference memory demand was uniquely associated with a gradual, goal novelty-related reorganization of place cell assemblies and with trajectory replay that reflected the animal's decision of which arm to visit next. AU - Xu, Haibing AU - Baracskay, Peter AU - O'Neill, Joseph AU - Csicsvari, Jozsef L ID - 5828 IS - 1 JF - Neuron SN - 10974199 TI - Assembly responses of hippocampal CA1 place cells predict learned behavior in goal-directed spatial tasks on the radial eight-arm maze VL - 101 ER -