The relationship between structure, dynamics, and function of neural networks in nervous systems is still an open question in the neuroscience community. Nevertheless, for certain areas of the mammalian nervous system we do have sufficient data to impose constraints on the organisation of the network structure. One of these areas is the medial entorhinal cortex which contains cells with hexagonally repeating spatial receptive fields, called grid cells. Another intriguing property of entorhinal cortex and other cortical regions is a population oscillatory activity, with frequency in the theta (4-10 Hz) and gamma (30-100 Hz) range. This leads to a question, whether these oscillations are a common circuit mechanism that is functionally relevant and how the oscillatory activity interacts with the computation performed by grid cells. This thesis deals with applying the continuous attractor network theory to modelling of the microcircuit of layer II in the medial entorhinal cortex. Based on recent experimental evidence on connectivity between stellate cells, and fast spiking interneurons, I first develop a two-population spiking attractor network model that is capable of reproducing the activity of a population of grid cells in layer II. The network was implemented with exponential integrate and fire neurons that allowed me to address both the attractor states and the oscillatory activity in this region. Subsequently, I show that the network can produce theta-nested gamma oscillations with properties that are similar to the cross-frequency coupling observed in vivo and in vitro in entorhinal cortex, and that these theta-nested gamma oscillations can co-exist with grid-like receptive fields generated by the network. I also show that the connectivity inspired by anatomical evidence produces a number of directly testable predictions about the firing fields of interneurons in layer II of the medial entorhinal cortex. The excitatory-inhibitory attractor network, together with the theta-nested gamma oscillations, allowed me to explore potential relationships between nested gamma oscillations and grid field computations. I show, by varying the overall level of excitatory and inhibitory synaptic strengths, and levels of noise, in the network, that this relationship is complex, and not easily predictable. Specifically, I show that noise promotes generation of grid firing fields and theta-nested gamma oscillations by the model. I subsequently demonstrate that theta-nested gamma oscillations are dissociable from the grid field computations performed by the network. By changing the relative strengths of interactions between excitatory and inhibitory neurons in the network, the power and frequency of the gamma oscillations changes without disrupting the rate-coded grid field computations. Since grid cells have been suggested to be a part of the spatial cognitive circuit in the brain, these results have potential implications for several cognitive disorders, including autism and schizophrenia, as well as theories that propose a cognitive role for gamma oscillations.

Studies of spatial memory provide valuable insight into more general mnemonic functions, for by observing the activity of cells such as place cells, one can follow a subject’s dynamic representation of a changing environment. I investigate how place cells resolve conflicting neuronal input signals by developing computational models that integrate synaptic inputs on two scales. First, I construct reduced models of morphologically accurate neurons that preserve neuronal structure and the spatial specificity of inputs. Second, I use a parallel implementation to examine the dynamics among a network of interconnected place cells. Both models elucidate possible roles for the inputs and mechanisms involved in spatial memory.

The work presented in this dissertation focuses on the use of computational and mathematical models to investigate how mammalian brains construct and maintain stable representations of space and location. Recordings of the activities of cells in the hippocampus and entorhinal cortex have provided strong, direct evidence that these cells and brain areas are involved in generating internal representations of the location of an animal in space. The emphasis of the first two portions of the dissertation are on understanding the factors that influence the scale and stability of these representations, both of which are important for accurate spatial navigation. In addition, it is argued in both cases that many of the computations observed in these systems emerge at least in part as a consequence of a particular type of network structure, where excitatory neurons are driven by external sources, and then mutually inhibit each other via interactions mediated by inhibitory cells. The first contribution of this thesis, which is described in chapter 2, is an investigation into the origin of the change in the scale of spatial representations across the dorsoventral axis of the hippocampus. Here it will be argued that this change in scale is due to increased processing of nonspatial information, rather than a dorsoventral change in the scale of the spatially-modulated inputs to this structure. Chapter 3 explores the factors influencing the dynamical stability of class of pattern-forming networks known as continuous attractor networks, which have been used to model various components of the spatial navigation systems, including head direction cells, place cells, and grid cells. Here it will be shown that network architecture, the amount of input drive, and the timescales at which cells interact all influence the stability of the patterns formed by these networks. Finally, in chapter 4, a new technique for analyzing neural data is introduced. This technique is a spike train similarity measure designed to compare spike trains on the basis of shared inhibition and bursts.

The ability to self-localize and navigate in both stable and changing environments is crucial for the survival of many species. Research conducted on the non-human mammalian hippocampus and surrounding brain structures has uncovered several classes of spatial related cells. These cells provide the rest of the brain with knowledge of the animal’s location and direction—knowledge that is subsequently used in spatial navigation. This thesis provides an overview of three types of cells underlying this ability in rodents. First, place cells located in the hippocampus encode the animal’s specific location in the environment. Second, head direction cells found throughout the Papez circuit convey the angular direction of the animal’s head. Last, grid cells in the medial entorhinal cortex generate a regular triangular grid spanning the entire explored setting. The focus of this review lies on the most salient features of these types of cells. It is also considered how the cells respond to manipulations of external and internal information, as well as how different lesions affect their activity.

Schicht 2 des mediale entorhinale Kortex (MEK) beinhaltet die größte Anzahl von Gitterzellen, welche durch ein hexagonales Aktivitätsmuster während räumlicher Exploration gekennzeichnet sind. In dieser Arbeit wurde gezeigt, dass spezielle Pyramidenzellen, die das Protein Calbindin exprimieren, in einem hexagonalen Gitter im Gehirn der Ratte angeordnet sind und cholinerg innerviert werden. Es ist bekannt, dass die cholinerge Innervation wichtig für die Aktivität von Gitterzellen ist. Weiterhin ergaben neuronale Ableitungen und Methoden zur Identifikaktion einzelner Neurone in frei verhaltenden Ratten, dass Calbindin-positive Pyramidenzellen (Calbindin+) eine große Anzahl von Gitterzellen beinhalten. Reelin-positive Sternzellen (Reelin+) im MEK, zeigten keine anatomische Periodizität und ihre Aktivität orientierte sich an den Begrenzungen der Umgebung. Eine weitere Studie untersucht die Architektur des MEK in verschiedenen Säugetieren, die von der Etrusker Spitzmaus, bis hin zum Menschen ~100 Millionen Jahre evolutionäre Vielfalt und ~20,000 fache Variation der Gehirngröße umfassen. Alle Arten zeigten jeweils eine periodische Anhäufung der Calbindin+ Zellen, was deren evolutive Bedeutung unterstreicht. Eine Studie zur Ontogenese der Calbindin Anhäufungen ergab, dass die periodische Struktur der Calbindin+ Zellen, sowie die verstreute Anordnung der Reelin+ Sternzellen schon zum Zeitpunkt der Geburt erkennbar war. Weitere Ergebnisse zeigen, dass Calbindin+ Zellen strukturell später ausreifen als Reelin+ Sternzellen - passend zu der Erkenntnis, dass Gitterzellen funktionell später reifen als Grenzzellen. Eine Untersuchung des Parasubiculums ergab, dass Verbindungen zum MEK präferiert in die Calbindin Anhäufungen in Schicht 2 projizieren. Zusammenfassend beschreibt diese Doktorarbeit eine Dichotomie von Struktur und Funktion in Schicht 2 des MEK, welche fundamental für das Verständnis von Gedächtnisbildung und deren zugrundeliegenden Mikroschaltkreisen ist. / The medial entorhinal cortex (MEC) is an important hub in the memory circuit in the brain. This thesis comprises of a group of studies which explores the architecture and microcircuits of the MEC. Layer 2 of MEC is home to grid cells, neurons which exhibit a hexagonal firing pattern during exploration of an open environment. The first study found that a group of pyramidal cells in layer 2 of the MEC, expressing the protein calbindin, were clustered in the rat brain. These patches were physically arranged in a hexagonal grid in the MEC and received preferential cholinergic-inputs which are known to be important for grid-cell activity. A combination of identified single-cell and extracellular recordings in freely behaving rats revealed that grid cells were mostly calbindin-positive pyramidal cells. Reelin-positive stellate cells in MEC were scattered throughout layer 2 and contributed mainly to the border cell population– neurons which fire at the borders of an environment. The next study explored the architecture of the MEC across evolution. Five mammalian species, spanning ~100 million years of evolutionary diversity and ~20,000 fold variation in brain size exhibited a conserved periodic layout of calbindin-patches in the MEC, underscoring their importance. An investigation of the ontogeny of the MEC in rats revealed that the periodic structure of the calbindin-patches and scattered layout of reelin-positive stellate cells was present around birth. Further, calbindin-positive pyramidal cells matured later in comparison to reelin-positive stellate cells mirroring the difference in functional maturation profiles of grid and border cells respectively. Inputs from the parasubiculum, selectively targeted calbindin-patches in the MEC indicating its role in shaping grid-cell function. In summary, the thesis uncovered a structure-function dichotomy of neurons in layer 2 of the MEC which is a fundamental aspect of understanding the microcircuits involved in memory formation.

Es ist noch weitgehend ungeklärt, mittels welcher Mechanismen die elektrische Aktivität von Nervenzellpopulationen des Gehirns Verhalten ermöglicht. Die Orientierung im Raum ist eine Fähigkeit des Gehirns, für die im Säugetier der mediale entorhinale Teil der Großhirnrinde als entscheidende Struktur identifiziert wurde. Hier wurden Nervenzellen gefunden, die die Umgebung des Individuums in einer gitterartigen Anordnung repräsentieren. Die neuronalen Schaltkreise, welche diese geordnete Nervenzellaktivität im medialen entorhinalen Kortex (MEK) ermöglichen, sind noch wenig verstanden. Die vorliegende Dissertation hat eine Klärung der zellulären Architektur und der neuronalen Schaltkreise in der zweiten Schicht des MEK der Ratte zum Ziel. Zunächst werden die Beiträge zur Entdeckung der hexagonal angeordneten zellulären Anhäufungen in Schicht 2 des MEK sowie zur Beschreibung der Dichotomie der Haupt-Nervenzelltypen dargestellt. Im zweiten Teil wird erstmalig eine konnektomische Analyse des MEK beschrieben. Die detaillierte Untersuchung der Architektur einzelner exzitatorischer Axone ergab das überraschende Ergebnis der präzisen Sortierung von Synapsen entlang axonaler Pfade. Die neuronalen Schaltkreise, in denen diese Neurone eingebettet sind, zeigten eine starke zeitliche Bevorzugung der hemmenden Neurone. Die hier erhobenen Daten tragen zu einem detaillierteren Verständnis der neuronalen Schaltkreise im MEK bei. Sie enthalten die erste Beschreibung überraschend präziser axonaler synaptischer Ordnung im zerebralen Kortex der Säugetiere. Diese Schaltkreisarchitektur lässt einen Effekt auf die Weiterleitung synchroner elektrischer Populationsaktivität im MEK vermuten. In zukünftigen Studien muss insbesondere geklärt werden, ob es sich bei den hier berichteten Ergebnissen um eine Besonderheit des MEK oder ein generelles Verschaltungsprinzip der Hirnrinde des Säugetiers handelt. / The mechanisms by which the electrical activity of ensembles of neurons in the brain give rise to an individual’s behavior are still largely unknown. Navigation in space is one important capacity of the brain, for which the medial entorhinal cortex (MEC) is a pivotal structure in mammals. At the cellular level, neurons that represent the surrounding space in a grid-like fashion have been identified in MEC. These so-called grid cells are located predominantly in layer 2 (L2) of MEC. The detailed neuronal circuits underlying this unique activity pattern are still poorly understood. This thesis comprises studies contributing to a mechanistic description of the synaptic architecture in rat MEC L2. First, this thesis describes the discovery of hexagonally arranged cell clusters and anatomical data on the dichotomy of the two principle cell types in L2 of the MEC. Then, the first connectomic study of the MEC is reported. An analysis of the axonal architecture of excitatory neurons revealed synaptic positional sorting along axons, integrated into precise microcircuits. These microcircuits were found to involve interneurons with a surprising degree of axonal specialization for effective and fast inhibition. Together, these results contribute to a detailed understanding of the circuitry in MEC. They provide the first description of highly precise synaptic arrangements along axons in the cerebral cortex of mammals. The functional implications of these anatomical features were explored using numerical simulations, suggesting effects on the propagation of synchronous activity in L2 of the MEC. These findings motivate future investigations to clarify the contribution of precise synaptic architecture to computations underlying spatial navigation. Further studies are required to understand whether the reported synaptic specializations are specific for the MEC or represent a general wiring principle in the mammalian cortex.

Komplexe kognitive Funktionen wie Gedächtnisbildung, Navigation und Entscheidungsprozesse hängen von der Kommunikation zwischen Hippocampus und Neokortex ab. An der Schnittstelle dieser beiden Gehirnregionen liegt der entorhinale Kortex - ein Areal, das Neurone mit bemerkenswerten räumlichen Repräsentationen enthält: Gitterzellen. Gitterzellen sind Neurone, die abhängig von der Position eines Tieres in seiner Umgebung feuern und deren Feuerfelder ein dreieckiges Muster bilden. Man vermutet, dass Gitterzellen Navigation und räumliches Gedächtnis unterstützen, aber die Mechanismen, die diese Muster erzeugen, sind noch immer unbekannt. In dieser Dissertation untersuche ich mathematische Modelle neuronaler Schaltkreise, um die Entstehung, Weitervererbung und Verstärkung von Gitterzellaktivität zu erklären. Zuerst konzentriere ich mich auf die Entstehung von Gittermustern. Ich folge der Idee, dass periodische Repräsentationen des Raumes durch Konkurrenz zwischen dauerhaft aktiven, räumlichen Inputs und der Tendenz eines Neurons, durchgängiges Feuern zu vermeiden, entstehen könnten. Aufbauend auf vorangegangenen theoretischen Arbeiten stelle ich ein Einzelzell-Modell vor, das gitterartige Aktivität allein durch räumlich-irreguläre Inputs, Feuerratenadaptation und Hebbsche synaptische Plastizität erzeugt. Im zweiten Teil der Dissertation untersuche ich den Einfluss von Netzwerkdynamik auf das Gitter-Tuning. Ich zeige, dass Gittermuster zwischen neuronalen Populationen weitervererbt werden können und dass sowohl vorwärts gerichtete als auch rekurrente Verbindungen die Regelmäßigkeit von räumlichen Feuermustern verbessern können. Schließlich zeige ich, dass eine entsprechende Konnektivität, die diese Funktionen unterstützt, auf unüberwachte Weise entstehen könnte. Insgesamt trägt diese Arbeit zu einem besseren Verständnis der Prinzipien der neuronalen Repräsentation des Raumes im medialen entorhinalen Kortex bei. / High-level cognitive abilities such as memory, navigation, and decision making rely on the communication between the hippocampal formation and the neocortex. At the interface between these two brain regions is the entorhinal cortex, a multimodal association area where neurons with remarkable representations of self-location have been discovered: the grid cells. Grid cells are neurons that fire according to the position of an animal in its environment and whose firing fields form a periodic triangular pattern. Grid cells are thought to support animal's navigation and spatial memory, but the cellular mechanisms that generate their tuning are still unknown. In this thesis, I study computational models of neural circuits to explain the emergence, inheritance, and amplification of grid-cell activity. In the first part of the thesis, I focus on the initial formation of grid-cell tuning. I embrace the idea that periodic representations of space could emerge via a competition between persistently-active spatial inputs and the reluctance of a neuron to fire for long stretches of time. Building upon previous theoretical work, I propose a single-cell model that generates grid-like activity solely form spatially-irregular inputs, spike-rate adaptation, and Hebbian synaptic plasticity. In the second part of the thesis, I study the inheritance and amplification of grid-cell activity. Motivated by the architecture of entorhinal microcircuits, I investigate how feed-forward and recurrent connections affect grid-cell tuning. I show that grids can be inherited across neuronal populations, and that both feed-forward and recurrent connections can improve the regularity of spatial firing. Finally, I show that a connectivity supporting these functions could self-organize in an unsupervised manner. Altogether, this thesis contributes to a better understanding of the principles governing the neuronal representation of space in the medial entorhinal cortex.

No description available.

Le travail de recherche réalisé au cours de cette thèse s'intéresse à la nature des représentations spatiales formées par le cortex entorhinal médian (CEM). Tout d'abord, nous montrons que le CEM code spécifiquement une information de distance, l'une des composantes nécessaires pour que l'animal puisse réaliser un type de navigation reposant sur les informations idiothétiques, appelé intégration des trajets. Puis, nous observons que le système vestibulaire, une source importante d'informations idiothétiques, influence l'activité thêta du CEM et permet la modulation de ce rythme thêta par la vitesse de déplacement des animaux. Ensuite, nous montrons que l'activité du CEM est nécessaire à la stabilité de l'activité des cellules de lieu. Parallèlement, nous observons que l'activité des cellules grilles du CEM est modifiée par les informations contenues dans l'environnement (allothétiques).Dans leur ensemble, nos résultats montrent que le CEM traite et intègre des informations idiothétiques mais aussi des informations allothétiques. Ces données suggèrent que la carte spatiale du CEM ne fournit pas une métrique universelle reposant sur les informations idiothétiques, mais possède un certain degré de flexibilité en réponse aux changements environnementaux. De plus, cette carte spatiale entorhinale n'est pas requise pour la formation de l'activité spatiale des cellules de lieu, contrairement à ce que suggère l'hypothèse dominante. / The work conducted during my PhD thesis was aimed at understanding the nature of the spatial representation formed by the the medial entorhinal cortex (MEC). First, we show that the MEC codes specifically distance information which is necessary for a type of navigation based on idiothetic cues, called path integration. Then, we observe that the vestibular system, an important source of idiothetic information in the brain, influences the MEC theta rhythm and its modulation by the animal velocity. In addition, we show that MEC activity is necessary for the stability of place cells activity. Finally, we observe that entorhinal grid cells activity is modified by the information available in the environment (allothetic information).Together, our results show that the MEC processes and integrates idiothetic information as well as allothetic information. These data suggest that the entorhinal map is not a universal metric based on idiothetic information, but is flexible and dependant on the information present in the environment. In addition, the entorhinal map is not required for the generation of place cells activity, contrary to the dominant hypothesis.