Functional architecture of the rat parasubiculum

The parasubiculum is a major input structure of layer 2 of medial entorhinal cortex, where most grid cells are found. Here we investigated parasubicular circuits of the rat by anatomical analysis combined with juxtacellular recording/labeling and tetrode recordings during spatial exploration. In tangential sections, the parasubiculum appears as a linear structure flanking the medial entorhinal cortex mediodorsally. With a length of ∼5.2 mm and a width of only ∼0.3 mm (approximately one dendritic tree diameter), the parasubiculum is both one of the longest and narrowest cortical structures. Parasubicular neurons span the height of cortical layers 2 and 3, and we observed no obvious association of deep layers to this structure. The "superficial parasubiculum" (layers 2 and 1) divides into ∼15 patches, whereas deeper parasubicular sections (layer 3) form a continuous band of neurons. Anterograde tracing experiments show that parasubicular neurons extend long "circumcurrent" axons establishing a "global" internal connectivity. The parasubiculum is a prime target of GABAergic and cholinergic medial septal inputs. Other input structures include the subiculum, presubiculum, and anterior thalamus. Functional analysis of identified and unidentified parasubicular neurons shows strong theta rhythmicity of spiking, a large fraction of head-direction selectivity (50%, 34 of 68), and spatial responses (grid, border and irregular spatial cells, 57%, 39 of 68). Parasubicular output preferentially targets patches of calbindin-positive pyramidal neurons in layer 2 of medial entorhinal cortex, which might be relevant for grid cell function. These findings suggest the parasubiculum might shape entorhinal theta rhythmicity and the (dorsoventral) integration of information across grid scales

Doctor of Philosophy

dissertationThe brain's medial entorhinal cortex (MEC) plays a key role in spatial navigation, serving as the node between the hippocampus and the rest of the mammalian cortex. In the last 10 years, spatially-modulated "grid" cells in the superficial MEC have been shown to preferentially fire as the animal moves into the apices of a hexagonal grid. Our incomplete understanding of the inhibitory dynamics within the MEC, however, limits our knowledge of how this brain structure executes such spatial navigation functions. Here, we explore various roles that inhibition plays in the superficial MEC and characterize the neuronal population that elicits this inhibition. We find that excitatory stellate cells in the layer 2 MEC exhibit membrane-dependent, nonlinear synaptic integration of inhibitory inputs, amplifying inputs that arrive near their firing threshold and dampening those that arrive closer to rest. Our next study is the first systematic anatomical/electrophysiological characterization of the superficial MEC's inhibitory interneuron population. We find that they are best classified into four clusters with distinct anatomical/electrophysiological profiles. In our last study, we investigated the viability of a novel, inhibition-mediated gamma rhythm model, finding that superficial MEC interneurons can exhibit resonant behaviors that could be key to generating neuronal network oscillations. The work presented here provides valuable groundwork for understanding MEC cortical computation

Intrinsic electrophysiological properties of entorhinal cortex stellate cells and their contribution to grid cell firing fields

The medial entorhinal cortex (MEC) is an increasingly important focus for investigation of mechanisms for spatial representation. Grid cells found in layer II of the MEC are likely to be stellate cells, which form a major projection to the dentate gyrus. Entorhinal stellate cells are distinguished by distinct intrinsic electrophysiological properties, but how these properties contribute to representation of space is not yet clear. Here, we review the ionic conductances, synaptic, and excitable properties of stellate cells, and examine their implications for models of grid firing fields. We discuss why existing data are inconsistent with models of grid fields that require stellate cells to generate periodic oscillations. An alternative possibility is that the intrinsic electrophysiological properties of stellate cells are tuned specifically to control integration of synaptic input. We highlight recent evidence that the dorsal-ventral organization of synaptic integration by stellate cells, through differences in currents mediated by HCN and leak potassium channels, influences the corresponding organization of grid fields. Because accurate cellular data will be important for distinguishing mechanisms for generation of grid fields, we introduce new data comparing properties measured with whole-cell and perforated patch-clamp recordings. We find that clustered patterns of action potential firing and the action potential after-hyperpolarization (AHP) are particularly sensitive to recording condition. Nevertheless, with both methods, these properties, resting membrane properties and resonance follow a dorsal-ventral organization. Further investigation of the molecular basis for synaptic integration by stellate cells will be important for understanding mechanisms for generation of grid fields

Stochastically Gating Ion Channels Enable Patterned Spike Firing through Activity-Dependent Modulation of Spike Probability

The transformation of synaptic input into patterns of spike output is a fundamental operation that is determined by the particular complement of ion channels that a neuron expresses. Although it is well established that individual ion channel proteins make stochastic transitions between conducting and non-conducting states, most models of synaptic integration are deterministic, and relatively little is known about the functional consequences of interactions between stochastically gating ion channels. Here, we show that a model of stellate neurons from layer II of the medial entorhinal cortex implemented with either stochastic or deterministically gating ion channels can reproduce the resting membrane properties of stellate neurons, but only the stochastic version of the model can fully account for perithreshold membrane potential fluctuations and clustered patterns of spike output that are recorded from stellate neurons during depolarized states. We demonstrate that the stochastic model implements an example of a general mechanism for patterning of neuronal output through activity-dependent changes in the probability of spike firing. Unlike deterministic mechanisms that generate spike patterns through slow changes in the state of model parameters, this general stochastic mechanism does not require retention of information beyond the duration of a single spike and its associated afterhyperpolarization. Instead, clustered patterns of spikes emerge in the stochastic model of stellate neurons as a result of a transient increase in firing probability driven by activation of HCN channels during recovery from the spike afterhyperpolarization. Using this model, we infer conditions in which stochastic ion channel gating may influence firing patterns in vivo and predict consequences of modifications of HCN channel function for in vivo firing patterns

The role of Cav3.2 Ca2+ channels in influencing the activity of the layer II stellate cells of the Medial Entorhinal Cortex

Layer II (L II) Medial Entorhinal Cortex (MEC) stellate cell (SC) intrinsic membrane properties vary along the MEC dorsal-ventral axis. This has been attributed partly to altered HCN and K+ conductances (Garden et al. 2008; Giocomo and Hasselmo 2008). The subthreshold active T-type CaV3.2 Ca2+ channels, though, are also expressed in the MEC (Huang et al. 2011). CaV3.2 channels are known to influence neuronal excitability but their effects on dorsal and ventral LII MEC SC properties remain unknown. To investigate this, I obtained acute brain slices from CaV3.2 wild type (CaV3.2+/+) and null (CaV3.2-/-) 5-8 week old mice and made electrophysiological recordings from dorsal and ventral L II MEC SC. CaV3.2-/- ventral neurons displayed significantly reduced input resistance but little difference in resting membrane potential (RMP) compared with CaV3.2+/+ ventral neurons. Consequently, depolarizing steps resulted in fewer action potentials in CaV3.2-/- ventral SC than in wild type neurons. In contrast, dorsal CaV3.2-/- and CaV3.2+/+ SC properties were similar. Furthermore, CaV3.2+/+ ventral cells had a significantly higher α excitatory post synaptic potentials (αEPSP) summation ratio (at 50 Hz) in comparison to CaV3.2-/- ventral neurons. The Cav3 inhibitors, NiCl2 and TTA-P2, also significantly reduced input resistance and action potential firing in CaV3.2+/+ ventral neurons, whilst having little effect on CaV3.2+/+ dorsal or CaV3.2-/- neurons. Furthermore, voltage-clamp experiments revealed a significantly greater T-type Cav3.2 Ca2+ current in ventral than dorsal neurons. Our results suggest that Cav3.2 channels selectively affect L II MEC ventral SC properties, thereby contributing to the intrinsic membrane gradient across the MEC dorsal-ventral axis

Models of spatial representation in the medial entorhinal 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

Inter- and intra-animal variation of integrative properties of stellate cells in the medial entorhinal cortex

Funding Information: We thank Vanessa Stempel for comments on the manuscript, Tor Stensola and Edvard Moser for sharing published data, and Lukas Solanka and Lukas Fischer for help with building the large cage. This work was supported by grants to MN from the Wellcome Trust (200855/Z/16/Z) and the BBSRC (BB/L010496/1, BB/1022147/1 and BB/H020284/1). Publisher Copyright: © 2020, eLife Sciences Publications Ltd. All rights reserved.Peer reviewedPublisher PD

Up and down states and memory consolidation across somatosensory, entorhinal, and hippocampal cortices

In the course of a day, brain states fluctuate, from conscious awake information-acquiring states to sleep states, during which previously acquired information is further processed and stored as memories. One hypothesis is that memories are consolidated and stored during "offline" states such as sleep, a process thought to involve transfer of information from the hippocampus to other cortical areas. Up and Down states (UDS), patterns of activity that occur under anesthesia and sleep states, are likely to play a role in this process, although the nature of this role remains unclear. Here we review what is currently known about these mechanisms in three anatomically distinct but interconnected cortical areas: somatosensory cortex, entorhinal cortex, and the hippocampus. In doing so, we consider the role of this activity in the coordination of "replay" during sleep states, particularly during hippocampal sharp-wave ripples. We conclude that understanding the generation and propagation of UDS may provide key insights into the cortico-hippocampal dialogue linking archi- and neocortical areas during memory formation