What is the functional role of adult neurogenesis in the hippocampus?

The dentate gyrus is part of the hippocampal memory system and special in that it generates new neurons throughout life. Here we discuss the question of what the functional role of these new neurons might be. Our hypothesis is that they help the dentate gyrus to avoid the problem of catastrophic interference when adapting to new environments. We assume that old neurons are rather stable and preserve an optimal encoding learned for known environments while new neurons are plastic to adapt to those features that are qualitatively new in a new environment. A simple network simulation demonstrates that adding new plastic neurons is indeed a successful strategy for adaptation without catastrophic interference

Il-15/il-15rα signalling and synaptic transmission: a crosstalk between the immune and the nervous system?

Immune and nervous system have been traditionally considered separately, but from ‘90s many studies had unraveled the deep interconnection and interdependence between these two systems, enough to coin the term “neuroimmune system” to define this relationship. While it was well known that central nervous system (CNS) actively communicates with the immune system to control immune responses both centrally and peripherally, the opposite action was just recently discovered. Related to the role of immune system in defending and react, the interactions between immune system and CNS have been classically studied in contexts of neuroinflammation such as trauma, injury and disease [1] [2]. Recent evidences about the neuroinflammatory process in non-pathological conditions and the discovery of the important involvement of adaptive immune system in healthy brain development and activity [3], have opened many questions about physiological neuroimmune cross-talk. In this view, the cytokine network, well known to operate in a bidirectional way affecting both immune and nervous system, has a pivotal role in neuroimmune cross-talk [4]. Traditionally seen as immunomodulators, in the last years has been evident that cytokines are also potent neuromodulators [5]. In the complex cytokine system, interleukin 15 (IL-15) is considered a bridge between adaptive and innate immune system and it is one of the first upregulated cytokines in neuroinflammation [6]. It has many bioregulatory roles which range from those of modulator of selected adaptive immune responses [7] [8] and central player in the development and homeostasis of several immunocyte populations [9] to those of a potent, general inhibitor of apoptosis in multiple systems [9]. Interestingly, has been shown that IL-15 and IL-15Rα deletions affect memory and neurotransmitters concentration suggesting a major role of this signalling in cerebral functions which cannot be compensated during the development [10] [11] [12]. IL-15Rα KO mice, in particular, show decreased retention of spatial memory and contextual fear, both related to hippocampus-dependent memory, and alteration in GABA concentration. Their hippocampal ultrastructure is, however, well preserved, suggesting that the modulatory changes may involve neural plasticity even if the exact role of IL15 in modulating neurotransmission has not been investigated so far. The understandings about the mechanism by which IL-15/IL-15Rα system affect the synaptic transmission may be useful to get insight into the mechanisms of cross talk between the immune and the nervous system and eventually to develop strategies to treat pathologies whose symptoms are memory impairments and neuroinflammation

해마 하위 영역 CA1과 CA3의 시각 자극 변화에 따른 장소 표상 패턴 연구

학위논문(박사) -- 서울대학교대학원 : 자연과학대학 뇌인지과학과, 2023. 2. 이인아.우리가 일상에서 경험하는 사건들은 하나의 스토리로 구성되어 일화 기억으로 형성된다. 해마는 과거에 경험한 일 들 뿐만 아니라 현재 경험하고 있는 사건들에 대한 일화 기억을 처리할 때 필수적인 뇌 영역이라고 알려져 있다. 설치류의 해마에서 관찰되는 장소 세포는 해마가 동물이 인지하고 있는 공간에 대한 지도를 형성하는 핵심적인 역할을 하는 것으로 알려져 있다. 특히 특정한 공간에서만 선별적으로 발화하는 장소 세포는 환경에 변화가 주어졌을 때 remapping이라는 현상으로 환경의 변화를 반영한다고 알려져 있다. 환경에 변화가 있을 때, 장소 세포가 동일한 위치에서 활동하며 발화 빈도를 조정하거나 전혀 다른 장소에서 활동하는 패턴으로 관찰된다. 이러한 장소 세포의 변화는 i) 기존의 기억을 조금 변형하거나, ii) 새로운 기억을 형성하는 일화 기억의 형태를 가지고 있다. 하지만 장소 세포가 불규칙적인 패턴으로 공간의 변화를 표상함에 따라 이들의 활동이 갖는 의미는 불분명하게 남아있다. 또한 장소 세포가 복합적인 감각 정보들을 반영한다는 특징은, 이들이 어떤 인지적 의미를 가지며 활동을 하는 것인지에 대한 난제를 남겼다. 본인은 해마의 장소 세포가 일화 기억에 어떤 기여를 할 것인지, 특히 변화된 환경에서 무엇을 새로 기억하고 기존에 알고 있는 정보는 어떻게 처리할 것인지 연산하는 과정을 해마의 하위 영역인 CA1과 CA3에서 각각 어떻게 표상하는지 알아보고자 하였다. 이에 대한 답을 찾기 위해 본인은 동물이 상호작용하며 경험할 수 있는 가상 현실 (VR) 시스템을 제작하여 가상 환경의 시각 자극을 정량적으로 조작하였다. 이 과정에서 본인은 동물이 경험하는 시각 자극의 변화와 (i.e., input) 해마 장소세포의 전기적 활동 (i.e., output) 간의 관계를 조사하였다. 첫 번째 질문으로는 본인이 구축한 가상 현실 시스템에서 장소 세포가 발현되는지를 확인하였다. 그 결과로 기존 문헌에서 보고되었던 결과와 비슷한 수준의 장소 세포들을 검증할 수 있었다. 본인이 구축한 가상 현실 시스템에서 장소 세포가 관찰된다는 것을 확인한 이후에는, 기존 환경에 정량적인 시각적 변화를 주어 장소 세포가 해당 변화를 어떻게 반영하는지 질문하였다. 그 결과로, 해마의 하위 영역 CA1에서 기존 환경에 대한 표상을 유지하는 집단과, 특정 환경에 변화가 가해진 사건에 의해 새로운 표상을 유지하는 집단이 동시다발적으로 나뉜다는 현상을 관찰하였다. 반면, 해마 하위 영역인 CA3에서는 환경에 변화가 이루어졌음에도 불구하고 대부분의 장소 세포들이 기존 환경에 대한 표상을 유지하였다. 이러한 결과를 토대로 해마 하위 영역인 CA3은 기존에 알고 있던 환경에 대한 기억을 안정적으로 유지하는 역할을 수행하는 반면, 해마 하위 영역인 CA1은 변화하는 환경 내에서도 이전의 기억과 새로운 기억을 독립적으로 구분하여 새로운 정보를 유연하게 학습하도록 하는 가능성을 제시하고자 한다.Any events or experiences in the given space and time are stitched together as an episode. The hippocampus has been widely acknowledged for its role in episodic memory for decades. At the same time, the rodent hippocampus exhibits the salient feature where its principal neurons are active in a spatially selective pattern (i.e., place cell). The place cells change their firing patterns as there are changes in the environments. Until now, we have been interpreting these firing changes, also known as "remapping," to have a functional significance in episodic memory by i) slightly modifying the old map to retrieve subtle changes from the previous memory or ii) forming the new map to reflect any major changes. In the real world, place cells receive complex sensory information from multiple sources, including multimodal sensory inputs and idiothetic information, making it even more challenging to interpret place cell activity from the intermingled sensory inputs fed into the hippocampal system. Taking advantage of the virtual reality (VR) system, I investigated how the hippocampal subregions CA1 and CA3 networks reflect environmental change. Thereby, I parametrically manipulated the environment by adding visual noise (i.e., virtual fog) in the VR environment and examined how hippocampal place cells in the CA1 and CA3 responded as visual noises were added to the environment in a quantified manner. Prior studies have suggested that CA3 forms a discrete map of the modified environments, presumably by performing either pattern separation or pattern completion. However, place cells in CA1 exhibit less coherent responses to environmental changes compared to CA3. This discrepancy between the CA1 and CA3 subregions is puzzling because CA3 output must pass through the CA1 area before reaching cortical areas. Furthermore, the functional roles of the CA1 in processing the environmental changes still need to be investigated due to the heterogeneous neural outputs with mixed yet conflicting findings. I first questioned whether our VR system reliably induced the place cells from both hippocampal subregions CA1 and CA3. As a result, I observed that the firing properties of hippocampal place cells are equivalent to that reported in the previous studies. Once I confirmed that visual environments in our VR system dominantly controlled the place cells, I examined how place cells in the CA1 and CA3 subregions responded to various levels of changes made to the visual environment. As visual noise was introduced to the familiar environment, I found that place cells in CA1 split simultaneously into two subpopulations: In one, place cells with old maps while changing their firing rate to reflect noise levels (i.e., rate remapping); in another, place cells with new maps to differentiate the dynamically changing environment from an old stable environment (i.e., global remapping). The place cells in CA3 mainly sustained the old map and reflected noise levels by rate remapping. Suppose one considers the rate remapping class of place cells as pattern-completing cells and the global remapping class as pattern-separating cells. In that case, the CA1 can manifest both pattern separation and pattern completion classes of neurons at the environmental change. My dissertation suggests that CA1 can simultaneously form an orthogonal map of the same environment to remember new episodes without interfering with the old memory.Background 1 Anatomical structures of the Hippocampal system and their proposed roles 2 The remapping properties of Hippocampal place cell 7 The usage of the virtual reality (VR) system for rodents in studying the hippocampus 16 Chapter 1. Visual scene stimulus exerts dominant control over the place fields 19 Introduction 20 Materials and methods 22 Results 37 Discussion 53 Chapter 2. The functional role of the CA1 and CA3 in processing the visually modified environment 56 Introduction 57 Materials and methods 59 Results 63 Discussion 94 General Discussion 98 Bibliography 111 국문초록 137박

The hippocampus and cerebellum in adaptively timed learning, recognition, and movement

The concepts of declarative memory and procedural memory have been used to distinguish two basic types of learning. A neural network model suggests how such memory processes work together as recognition learning, reinforcement learning, and sensory-motor learning take place during adaptive behaviors. To coordinate these processes, the hippocampal formation and cerebellum each contain circuits that learn to adaptively time their outputs. Within the model, hippocampal timing helps to maintain attention on motivationally salient goal objects during variable task-related delays, and cerebellar timing controls the release of conditioned responses. This property is part of the model's description of how cognitive-emotional interactions focus attention on motivationally valued cues, and how this process breaks down due to hippocampal ablation. The model suggests that the hippocampal mechanisms that help to rapidly draw attention to salient cues could prematurely release motor commands were not the release of these commands adaptively timed by the cerebellum. The model hippocampal system modulates cortical recognition learning without actually encoding the representational information that the cortex encodes. These properties avoid the difficulties faced by several models that propose a direct hippocampal role in recognition learning. Learning within the model hippocampal system controls adaptive timing and spatial orientation. Model properties hereby clarify how hippocampal ablations cause amnesic symptoms and difficulties with tasks which combine task delays, novelty detection, and attention towards goal objects amid distractions. When these model recognition, reinforcement, sensory-motor, and timing processes work together, they suggest how the brain can accomplish conditioning of multiple sensory events to delayed rewards, as during serial compound conditioning.Air Force Office of Scientific Research (F49620-92-J-0225, F49620-86-C-0037, 90-0128); Advanced Research Projects Agency (ONR N00014-92-J-4015); Office of Naval Research (N00014-91-J-4100, N00014-92-J-1309, N00014-92-J-1904); National Institute of Mental Health (MH-42900

Neural Dynamics of Autistic Behaviors: Cognitive, Emotional, and Timing Substrates

What brain mechanisms underlie autism and how do they give rise to autistic behavioral symptoms? This article describes a neural model, called the iSTART model, which proposes how cognitive, emotional, timing, and motor processes may interact together to create and perpetuate autistic symptoms. These model processes were originally developed to explain data concerning how the brain controls normal behaviors. The iSTART model shows how autistic behavioral symptoms may arise from prescribed breakdowns in these brain processes.Air Force Office of Scientific Research (F49620-01-1-0397); Office of Naval Research (N00014-01-1-0624

How informative are spatial CA3 representations established by the dentate gyrus?

In the mammalian hippocampus, the dentate gyrus (DG) is characterized by sparse and powerful unidirectional projections to CA3 pyramidal cells, the so-called mossy fibers. Mossy fiber synapses appear to duplicate, in terms of the information they convey, what CA3 cells already receive from entorhinal cortex layer II cells, which project both to the dentate gyrus and to CA3. Computational models of episodic memory have hypothesized that the function of the mossy fibers is to enforce a new, well separated pattern of activity onto CA3 cells, to represent a new memory, prevailing over the interference produced by the traces of older memories already stored on CA3 recurrent collateral connections. Can this hypothesis apply also to spatial representations, as described by recent neurophysiological recordings in rats? To address this issue quantitatively, we estimate the amount of information DG can impart on a new CA3 pattern of spatial activity, using both mathematical analysis and computer simulations of a simplified model. We confirm that, also in the spatial case, the observed sparse connectivity and level of activity are most appropriate for driving memory storage and not to initiate retrieval. Surprisingly, the model also indicates that even when DG codes just for space, much of the information it passes on to CA3 acquires a non-spatial and episodic character, akin to that of a random number generator. It is suggested that further hippocampal processing is required to make full spatial use of DG inputs.Comment: 19 pages, 11 figures, 1 table, submitte