Influence of slow oscillation on hippocampal activity and ripples through cortico-hippocampal synaptic interactions, analyzed by a cortical-CA3-CA1 network model

Hippocampal sharp wave-ripple complexes (SWRs) involve the synchronous discharge of thousands of cells throughout the CA3-CA1-subiculum-entorhinal cortex axis. Their strong transient output affects cortical targets, rendering SWRs a possible means for memory transfer from the hippocampus to the neocortex for long-term storage. Neurophysiological observations of hippocampal activity modulation by the cortical slow oscillation (SO) during deep sleep and anesthesia, and correlations between ripples and UP states, support the role of SWRs in memory consolidation through a cortico-hippocampal feedback loop. We couple a cortical network exhibiting SO with a hippocampal CA3-CA1 computational network model exhibiting SWRs, in order to model such cortico-hippocampal correlations and uncover important parameters and coupling mechanisms controlling them. The cortical oscillatory output entrains the CA3 network via connections representing the mossy fiber input, and the CA1 network via the temporoammonic pathway (TA). The spiking activity in CA3 and CA1 is shown to depend on the excitation-to-inhibition ratio, induced by combining the two hippocampal inputs, with mossy fiber input controlling the UP-state correlation of CA3 population bursts and corresponding SWRs, whereas the temporoammonic input affects the overall CA1 spiking activity. Ripple characteristics and pyramidal spiking participation to SWRs are shaped by the strength of the Schaffer collateral drive. A set of in vivo recordings from the rat hippocampus confirms a model-predicted segregation of pyramidal cells into subgroups according to the SO state where they preferentially fire and their response to SWRs. These groups can potentially play distinct functional roles in the replay of spike sequences

Constraining the function of CA1 in associative memory models of the hippocampus

Institute for Adaptive and Neural ComputationCA1 is the main source of afferents from the hippocampus, but the function of CA1 and its perforant path (PP) input remains unclear. In this thesis, Marr’s model of the hippocampus is used to investigate previously hypothesized functions, and also to investigate some of Marr’s unexplored theoretical ideas. The last part of the thesis explains the excitatory responses to PP activity in vivo, despite inhibitory responses in vitro. Quantitative support for the idea of CA1 as a relay of information from CA3 to the neocortex and subiculum is provided by constraining Marr’s model to experimental data. Using the same approach, the much smaller capacity of the PP input by comparison implies it is not a one-shot learning network. In turn, it is argued that the entorhinal-CA1 connections cannot operate as a short-term memory network through reverberating activity. The PP input to CA1 has been hypothesized to control the activity of CA1 pyramidal cells. Marr suggested an algorithm for self-organising the output activity during pattern storage. Analytic calculations show a greater capacity for self-organised patterns than random patterns for low connectivities and high loads, confirmed in simulations over a broader parameter range. This superior performance is maintained in the absence of complex thresholding mechanisms, normally required to maintain performance levels in the sparsely connected networks. These results provide computational motivation for CA3 to establish patterns of CA1 activity without involvement from the PP input. The recent report of CA1 place cell activity with CA3 lesioned (Brun et al., 2002. Science, 296(5576):2243-6) is investigated using an integrate-and-fire neuron model of the entorhinal-CA1 network. CA1 place field activity is learnt, despite a completely inhibitory response to the stimulation of entorhinal afferents. In the model, this is achieved using N-methyl-D-asparate receptors to mediate a significant proportion of the excitatory response. Place field learning occurs over a broad parameter space. It is proposed that differences between similar contexts are slowly learnt in the PP and as a result are amplified in CA1. This would provide improved spatial memory in similar but different contexts

Influence of slow oscillation on hippocampal activity and ripples through cortico-hippocampal synaptic interactions, analyzed by a cortical-CA3-CA1 network model

Hippocampal sharp wave-ripple complexes (SWRs) involve the synchronous discharge of thousands of cells throughout the CA3-CA1-subiculum-entorhinal cortex axis. Their strong transient output affects cortical targets, rendering SWRs a possible means for memory transfer from the hippocampus to the neocortex for long-term storage. Neurophysiological observations of hippocampal activity modulation by the cortical slow oscillation (SO) during deep sleep and anesthesia, and correlations between ripples and UP states, support the role of SWRs in memory consolidation through a cortico-hippocampal feedback loop. We couple a cortical network exhibiting SO with a hippocampal CA3-CA1 computational network model exhibiting SWRs, in order to model such cortico-hippocampal correlations and uncover important parameters and coupling mechanisms controlling them. The cortical oscillatory output entrains the CA3 network via connections representing the mossy fiber input, and the CA1 network via the temporoammonic pathway (TA). The spiking activity in CA3 and CA1 is shown to depend on the excitation-to-inhibition ratio, induced by combining the two hippocampal inputs, with mossy fiber input controlling the UP-state correlation of CA3 population bursts and corresponding SWRs, whereas the temporoammonic input affects the overall CA1 spiking activity. Ripple characteristics and pyramidal spiking participation to SWRs are shaped by the strength of the Schaffer collateral drive. A set of in vivo recordings from the rat hippocampus confirms a model-predicted segregation of pyramidal cells into subgroups according to the SO state where they preferentially fire and their response to SWRs. These groups can potentially play distinct functional roles in the replay of spike sequences

Control of neuronal input-output coupling by recurrent inhibition in the hippocampus

During different states of hippocampal network activity neurons receive excitatory synaptic input on dendritic compartments and transform it into axonal action potential output. The ensemble output of pyramidal neurons activates local inhibitory microcircuits, which provide recurrent compartment-specific inhibition. In the present study it was observed that neuronal activity patterns that are likely to be present during sharp-waves recruit recurrent inhibition differently than repetitive activity at theta frequency. The observed results suggest that this could adapt the efficacy of input-output conversion to the network-state. In the present study dendritic spikes and their activity-dependent plasticity were identified as specialized signals, which endow correlated excitatory branch input with the ability to withstand recurrent inhibition and to generate precisely timed action potential output independent of the previous activity. These findings suggest that dendritic spikes may provide a cellular correlate for reliable and temporally precise reactivation of behaviorally relevant neuronal assemblies during both exploration and sleep

A General Hippocampal Computational Model Combining Episodic and Spatial Memory in a Spiking Model

Institute for Adaptive and Neural ComputationThe hippocampus, in humans and rats, plays crucial roles in spatial tasks and nonspatial tasks involving episodic-type memory. This thesis presents a novel computational model of the hippocampus (CA1, CA3 and dentate gyrus) which creates a framework where spatial memory and episodic memory are explained together. This general model follows the approach where the memory function of the rodent hippocampus is seen as a “memory space” instead of a “spatial memory”. The innovations of this novel model are centred around the fact that it follows detailed hippocampal architecture constraints and uses spiking networks to represent all hippocampal subfields. This hippocampal model does not require stable attractor states to produce a robust memory system capable of pattern separation and pattern completion. In this hippocampal theory, information is represented and processed in the form of activity patterns. That is, instead of assuming firing-rate coding, this model assumes that information is coded in the activation of specific constellations of neurons. This coding mechanism, associated with the use of spiking neurons, raises many problems on how information is transferred, processed and stored in the different hippocampal subfields. This thesis explores which mechanisms are available in the hippocampus to achieve such control, and produces a detailed model which is biologically realistic and capable of explaining how several computational components can work together to produce the emergent functional properties of the hippocampus. In this hippocampal theory, precise explanations are given to why mossy fibres are important for storage but not recall, what is the functional role of the mossy cells (excitatory interneurons) in the dentate gyrus, why firing fields can be asymmetric with the firing peak closer to the end of the field, which features are used to produce “place fields”, among others. An important property of this hippocampal model is that the memory system provided by the CA3 is a palimpsest memory: after saturation, the number of patterns that can be recalled is independent of the number of patterns engraved in the recurrent network. In parallel with the development of the hippocampal computational model, a simulation environment was created. This simulation environment was tailored for the needs and assumptions of the hippocampal model and represents an important component of this thesis

Functional role of parallel circuits in the hippocampus

The hippocampal formation is one of the primary structures involved in episodic and spatial memory. Although the gross anatomy of hippocampus and its role in learning has been studied extensively, little is known about the microcircuits that underlie the computations involved and most of the studies also treat hippocampus as a single unit. However, the discovery of segregated parallel pathways of principal neurons in the hippocampus (Deguchi Y et al, 2011) across the three main sub regions (Dentate gyrus to CA3, CA3 to CA3, CA3 to CA1) implies that there could be differential processing of incoming information with little or complete absence of interference. In this thesis, the main question I address is what could be the role of these parallel circuits in the hippocampus and how does selective connectivity contribute to their role. In the first part I investigated the roles of principal neuron subpopulations in various hippocampal learning paradigms using activity and plasticity markers. The data from this part suggests that different principal neuron subpopulations are recruited by different types of learning. In the second part of the thesis, I explored how the selective connectivity contributes to the hippocampal memory formation by pharmacologically altering the selective connectivity during early stages of circuit development. The structural and behavioral evidence from the mice with altered connectivity clearly show that they have impaired hippocampal learning. In summary, the results in my thesis provide insight about the role of parallel circuits in hippocampus during different forms of learning and provides strong evidence that hippocampal circuits use biased connectivity to extract and process specific types of information

Intrahippocampal pathways involved in learning/memory mechanisms are affected by intracerebral infusions of amyloid-beta25-35 peptide and hydrated fullerene C60 in rats

Primary memory impairments associated with increased level of amyloid-beta (Аβ) in the brain have been shown to be linked, partially, with early pathological changes in the entorhinal cortex (EC) which spread on the whole limbic system. While the hippocampus is known to play a key role in learning and memory mechanisms, it is as yet unclear how its structures are involved in the EC pathology. In this study, changes in memory and neuronal morphology in male Wistar rats intrahippocampally injected with Аβ25–35 were correlated on days 14 and 45 after the injection to reveal specific cognitive - structural associations. The main focus was on the dentate gyrus (DG) and hippocampal areas of CA1 and CA3 because of their involvement in afferent flows from EC to the hippocampus through tri-synaptic (EC DG CA3 CA1) and/or mono-synaptic (EC CA1) pathways. Evident memory impairments were observed at both time points after Аβ25–35 injection. However, on day 14, populations of morphological intact neurons were decreased in CA3 and, drastically, in CA1, and the DG supramedial bundle was significantly damaged. On day 45, this bundle largely and СА1 neurons partially recovered, whereas CA3 neurons remained damaged. We suggest that Аβ25–35 primarily affects the tri-synaptic pathway, destroying the granular cells in the DG supramedial area and neurons in CA3 and, through the Schaffer collaterals, in CA1. Intrahippocampal pretreatment with hydrated fullerene С60 allows the neurons and their connections to survive the amyloidosis, thus supporting the memory mechanisms

해마 하위 영역 CA1과 CA3의 장면 자극에 기반한 장소 표상 형성 연구

학위논문 (박사) -- 서울대학교 대학원 : 자연과학대학 뇌인지과학과, 2021. 2. 이인아.When we recall the past experiences, we usually think of a scene which is a combination of what we saw, the sounds we hear, and the feeling we felt at that moment. Since the scene is an essential component of episodic memory, studying how scene stimuli are represented and stored in the brain is important in understanding the processes of formation, storage, and retrieval of our memories. One of the brain regions important for episodic memory is the hippocampus. It has been reported that patients or animals with damage to the hippocampus have trouble with retrieving past experiences or forming new memories. The hippocampus is involved not only in episodic memory but also in the formation of a cognitive map. In particular, the place cells observed in the rodent hippocampus play a key role in these functions. However, research on place cells has mainly focused on the firing patterns of cells during foraging in a space, and it has not been clear how hippocampal cells represent and make use of visual scenes for behavior. To find how scene stimuli are represented in place cells, I measured spiking activities of single neurons in the CA1, one of the subregions of hippocampus, and the subiculum, a major output of the hippocampus. Neuronal spiking activity was monitored when the rat performed a task of selecting right or left associated to the scene stimulus presented on monitors. As a result, I found that the place cells in the CA1 and subiculum showed rate modulation according to the scene stimulus. In addition, I also conducted an experiment using a virtual reality system to investigate the neural mechanisms of the formation of a place field based on visual scenes. In this experiment, the rat ran on a virtual linear track as visual cues were added one by one to make a scene-like environment. Neuronal activities of place cells were recorded in the CA1 and CA3 simultaneously to study the neural mechanisms of the development of a place field on the basis of external visual stimuli. Place fields appeared in the CA1 even with a single visual cue, whereas in the CA3, place fields only emerged when a sufficient number of visual cues were collectively arranged in a scene-like fashion. The results suggest that that scene is one of the key stimulus that effectively recruits the hippocampus.우리는 과거의 경험을 떠올릴 때 그 때를 묘사하는 문장을 떠올리는 것이 아니라 경험 한 순간에 보았던 것, 들렸던 소리, 느꼈던 감정 등이 복합적으로 어우러진 장면을 떠올리게 된다. 이렇게 장면은 일화 기억을 구성하는 중요한 요소라 할 수 있기에 장면 자극이 뇌에서 어떻게 표상되며 저장되는지를 연구하는 것은 우리 기억의 형성과 저장, 재인 과정을 이해하는데 있어 매우 중요하다고 볼 수 있다. 뇌에서 일화 기억을 담당한다고 알려진 영역은 해마로써, 해마에 손상을 입은 환자들 또는 동물들이 과거의 기억을 인출하거나 새로운 기억을 형성하는데 있어 어려움을 겪는다는 것이 여러 실험을 통해 보고 된 바 있다. 해마는 일화 기억뿐만 아니라 공간에 대한 지도를 형성하는 데에도 관여하는데, 특히, 설치류 해마에서 관찰 되는 장소 세포가 이러한 해마의 기능들을 수행하는데 핵심적인 역할을 하는 것으로 알려져 있다. 하지만 장소 세포는 주로 쥐가 공간을 탐색하는 과정에서의 발화 패턴을 관측한 연구가 주를 이루었으며 장면 자극이 개별 장소 세포의 발화 패턴을 통해 어떻게 표상이 되는지에 대한 연구는 미미한 수준이다. 이 논문에서 나는 장면 자극이 해마의 장소 세포에서 어떻게 표상되는지를 알아보고자 쥐가 모니터에 제시 된 장면 자극을 보고 오른쪽이나 왼쪽을 선택해야 하는 과제를 수행 할 때 해마의 하위 영역인 CA1과 해마의 정보를 전달 받아 뇌의 다른 영역으로 정보를 전달하는 해마이행부의 단일 세포 활동을 측정하였다. 그 결과 CA1과 해마이행부에서 관찰 된 장소 세포들이 장면 자극에 따른 발화율 변화를 보인다는 것을 확인 할 수 있었다. 이에 더하여 나는 해마의 장소 세포들이 장소장을 형성하기 위해서 필요한 시각 자극이 무엇이며, 이에 장면 자극이 어떤 역할을 하는지 확인하기 위해 가상 환경을 이용한 실험을 수행하였다. 이 실험에서는 쥐가 선형 트랙을 달릴 때, 빈 공간에서 시작하여 장면 자극을 형성 할 때까지 시각 자극을 하나씩 추가하면서 해마의 하위 영역인 CA1과 CA3의 장소 세포 활동을 측정 하는 과정을 통해 어떤 시각 자극이 장소 세포의 장소장 형성에 가장 큰 영향을 미치는 것인지 알아보았다. 그 결과 CA1의 장소 세포는 간단한 시각 자극의 추가에도 장소장을 잘 형성하는 모습을 보인 반면 CA3의 장소 세포들은 충분한 시각 자극이 모여서 장면 자극을 형성 한 경우에 장소장을 형성하는 것이 관찰되었다. 이러한 일련의 실험을 통하여 나는 장면 자극이 해마의 장소 세포 발화를 통해 표상되며, 해마의 하위 영역이 모두 장면 자극 처리에 관여하지만 그 중에서도 특히 CA3가 장면 자극을 처리 할 때에 한하여 큰 활성을 보인다는 것을 밝혔다.Abstract i Table of Contents iii List of Figures iv Background 1 Scene processing in the hippocampus 2 Anatomical connections of CA1 and CA3 4 Properties of place cell activity 7 Chapter 1. Visual scene representation of CA1 and subiculum in the visual scene memory task 10 Introduction 11 Materials and methods 14 Results 31 Discussion 60 Chapter 2. Role of the visual scene stimulus for place field formation in CA1 and CA3 65 Introduction 66 Materials and methods 68 Results 80 Discussion 107 General Discussion 118 Bibliography 124 국문초록 140Docto

Microcircuit remodeling processes underlying learning in the adult

One of the most intriguing discoveries in neuroscience of the past decades has been showing that experience is able to induce structural modifications in cortical microcircuit that might underlie the formation of memories upon learning (for a review, see Caroni, Donato and Muller 2012). Hence, learning induces phases of synapse formation and elimination that are strictly regulated by a variety of mechanisms, which impact on cortical microcircuits affecting both excitatory and inhibitory neurons. Nevertheless, the extent to which specific configurations might be implemented to support specific phases of learning, as well as the impact of experience-induced structural modifications on further learning, is still largely unknown. Here, I explore how the remodeling of identified microcircuits in the mouse hippocampus and neocortex supports learning in the adult. In the first part, I identifiy a microcircuit module engaging VIP and Parvalbumin (PV) positive interneurons to regulate the state of the PV+ network upon experience. This defines states of enhanced or reduced structural plasticity and learning based on the distribution of PV intensity in the network. In the second part, I demonstrate how specific hippocampal subdivisions are exploited to learn subtasks of trial-and-errors forms of learning via the deployment of increasingly precise searching strategies, and sequential recruitment of ventral, intermediate, and dorsal hippocampus. In the third part, I highlight the existence of genetically matched subpopulations of principal cells in the hippocampus, which achieve selective connectivity across hippocampal subdivisions via matched windows of neurogenesis and synaptogenesis during development. In the fourth part, I investigate the maturation of microcircuits mediating feedforward inhibition in the hippocampus, and highlight windows during development for the establishment of the proper baseline configuration in the adult. Moreover, I identify a critical window for cognitive enhancement during hippocampal development. In the fifth part, I study how ageing affects the PV network in hippocampal CA3, providing evidence for which age related neuronal loss correlates to reduced incidental learning performances in old mice. Therefore, by manipulating the PV network early during life, I provide strategies to modulate cognitive decline