Large-scale circuit reconstruction in medial entorhinal cortex

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

Cholinergic modulation of cognitive processing: insights drawn from computational models

Acetylcholine plays an important role in cognitive function, as shown by pharmacological manipulations that impact working memory, attention, episodic memory, and spatial memory function. Acetylcholine also shows striking modulatory influences on the cellular physiology of hippocampal and cortical neurons. Modeling of neural circuits provides a framework for understanding how the cognitive functions may arise from the influence of acetylcholine on neural and network dynamics. We review the influences of cholinergic manipulations on behavioral performance in working memory, attention, episodic memory, and spatial memory tasks, the physiological effects of acetylcholine on neural and circuit dynamics, and the computational models that provide insight into the functional relationships between the physiology and behavior. Specifically, we discuss the important role of acetylcholine in governing mechanisms of active maintenance in working memory tasks and in regulating network dynamics important for effective processing of stimuli in attention and episodic memory tasks. We also propose that theta rhythm plays a crucial role as an intermediary between the physiological influences of acetylcholine and behavior in episodic and spatial memory tasks. We conclude with a synthesis of the existing modeling work and highlight future directions that are likely to be rewarding given the existing state of the literature for both empiricists and modelers

Spatial Representations in the Entorhino-Hippocampal Circuit

After a general introduction and a brief review of the available experimental data on spatial representations (chapter 2), this thesis is divided into two main parts. The first part, comprising the chapters from 3 to 6, is dedicated to grid cells. In chapter 3 we present and discuss the various models proposed for explaining grid cells formation. In chapter 4 and 5 we study our model of grid cells generation based on adaptation in the case of non-planar environments, namely in the case of a spherical environment and of three-dimensional space. In chapter 6 we propose a variant of the model where the alignment of the grid axes is induced through reciprocal inhibition, and we suggest that that the inhibitory connections obtained during this learning process can be used to implement a continuous attractor in mEC. The second part, comprising chapters from 7 to 10 is instead focused on place cell representations. In chapter 7 we analyze the differences between place cells and grid cells in terms on information content, in chapter 8 we describe the properties of attractor dynamics in our model of the Ca3 net- work, and in the following chapter we study the effects of theta oscillations on network dynamics. Finally, in Chapter 10 we analyze to what extent the learning of a new representation, can preserve the topology and the exact metric of physical space

Biophysical foundation and function of depolarizing afterpotentials in principal cells of the medial entorhinal cortex

Neurons in layer II of the rodent medial entorhinal cortex (MEC) encode spatial information. One particular type, grid cells, tends to fire at specific spatial locations that form hexagonal lattices covering the explored environment. Within these firing fields grid cells frequently show short high-frequency spike sequences. Such bursts have received little attention but may contribute substantially to encoding spatial information. On the other hand, in vitro recordings of MEC principal cells have revealed that action potentials are followed by prominent depolarizing afterpotentials (DAP). Their biophysical foundation and function, however, are poorly understood. The objective of this study is to understand the mechanism behind the DAP by creating a biophysical realistic model of a stellate cell and to draw a connection between DAPs and burst firing in vivo. The developed single-compartment model reproduced the main electrophysi- ological characteristics of stellate cells in the MEC layer II, that are a DAP, sag, tonic firing in response to positive step currents and resonance. Using virtual blocking experiments, it was found that for the generation of the DAP only a NaP , KDR and leak current were necessary whereby the NaP current also exhibited a resurgent component. This suggests that for the generation of the DAP a balance between several currents is needed. In addition, the persistent and resurgent sodium current might play an important role. We analyzed the relevance of DAPs in vivo using whole-cell recordings of grid cells from Domnisoru et al. (2013). We found that around 20% of the cells exhibited a DAP. However, the percentage of cells was much lower than estimates from in vitro recordings. We showed that this is partly due to the quality of the recording as selecting APs from presumably good parts of the recording improved the visibility of DAPs. To investigate the relationship between DAPs and burst firing all cells were classified into bursty and non-bursty based on the spike-time autocorrelation. All cells with a DAP were bursty except the cell with the smallest DAP. Moreover, taking the mean of the spike-triggered average of the membrane potential for all bursty and non-bursty cells respectively showed a clear DAP for bursty but not for non-bursty cells. In summary, we found that the DAP can be realized in a single-compartment model by a NaP , KDR and leak current and provided evidence for the relevance of DAPs for burst firing in vivo

A model of head direction and landmark coding in complex environments

Environmental information is required to stabilize estimates of head direction (HD) based on angular path integration. However, it is unclear how this happens in real-world (visually complex) environments. We present a computational model of how visual feedback can stabilize HD information in environments that contain multiple cues of varying stability and directional specificity. We show how combinations of feature-specific visual inputs can generate a stable unimodal landmark bearing signal, even in the presence of multiple cues and ambiguous directional specificity. This signal is associated with the retrosplenial HD signal (inherited from thalamic HD cells) and conveys feedback to the subcortical HD circuitry. The model predicts neurons with a unimodal encoding of the egocentric orientation of the array of landmarks, rather than any one particular landmark. The relationship between these abstract landmark bearing neurons and head direction cells is reminiscent of the relationship between place cells and grid cells. Their unimodal encoding is formed from visual inputs via a modified version of Oja's Subspace Algorithm. The rule allows the landmark bearing signal to disconnect from directionally unstable or ephemeral cues, incorporate newly added stable cues, support orientation across many different environments (high memory capacity), and is consistent with recent empirical findings on bidirectional HD firing reported in the retrosplenial cortex. Our account of visual feedback for HD stabilization provides a novel perspective on neural mechanisms of spatial navigation within richer sensory environments, and makes experimentally testable predictions