シンポジウム（Symposium）

Symposium Neuronal Substrates of Episodic Memory ~ from physiology to circuits シンポジウムエピソード記憶の神経基盤~神経回路とその生理~

7月25日（木）16:55～17:13　第3会場（朱鷺メッセ　2F　メインホールB） 1S03e-1 Cortical Sensory Modulation of Hippocampal Activity and Spatial Representation Jayeeta Basu（Basu Jayeeta），Olesia Bilash（Bilash Olesia），Roland Zemla（Zemla Roland） New York University Neuroscience Institute, New York, USA Functional interaction between entorhinal cortex (EC) and hippocampus supports episodic memory and spatial navigation. EC projects multimodal sensory information namely, spatial (position, boundary, head-direction) from medial entorhinal cortex and non-spatial contextual (objects, novelty, odor) from lateral entorhinal cortex (LEC) to distal dendrites of hippocampal CA1 pyramidal neurons. Active integration of cortico-hippocampal inputs defines powerful learning rules. Yet, we know little about circuit-level functional interactions between EC, especially LEC and hippocampus. To understand circuit mechanisms underlying context-dependent memory representation, we examined how direct inputs from LEC interact with CA1 local microcircuitry to shape dendritic integration, and spatial representation during contextual learning. Using optogenetic circuit mapping with electrophysiology we defined how LEC sculpts CA1 somato-dendritic output through dynamic gating of excitation, inhibition and disinhibiton. In parallel, we developed in vivo two photon imaging of CA1 place cells during a novel odor context dependent learning paradigm to test how LEC influences place cell properties and behavior itself. We propose a new model for cortico-hippocampal processing where LEC inputs promote supralinear dendritic integration in hippocampal CA1 to modulate plasticity of place cells, thus challenging the canonical view that LEC is strictly involved in non-spatial sensory processing.		7月25日（木）17:13～17:31　第3会場（朱鷺メッセ　2F　メインホールB） 1S03e-2 マウス脳における嗅内皮質ー海馬間の記憶回路ダイナミクス Jun Yamamoto（山本純） Dept Psychiatry Neurosci Div, Univ Texas Southwestern Medical Ctr, Dallas, Texas, USA Working memory is an ability to briefly store and utilize selected information to guide behavior and usually works at the timescale of seconds to minutes. This memory function is extremely crucial for goal-directed behavior that involves planning, applying rules, and making decisions. By nature, working memory does not work alone but often works with other types of memory functions, such as long-term semantic memory or episodic memory. Among those types of memory, successful memory encoding and retrieval is one of the most important memory functions. Further investigation is required to better understand how our memory system works and how it is altered in various brain diseases. Little is known about how specific memories are accessed and formed into meaningful episodic memories to accomplish cognitive memory tasks, especially at the systems level. Numerous studies have shown that hippocampal-entorhinal (HPC-EC) circuits play crucial roles in encoding and retrieval of specific episodic memories. Many human patients who suffer from Alzheimer's disease, dementia and broad spectrum of psychosis, including schizophrenia, show various ranges of memory deficits along with the HPC-EC damage. However, little is known about how specific memories are accessed and formed into meaningful memories to accomplish given tasks, especially at the systems level. In this talk, I will focus on the neural dynamics for successful memory access and retrieval during episodic working memory tasks to elucidate the neural circuit mechanism in the hippocampal-cortical (HPC-CTX) network. I have previously demonstrated two forms of memory access in the HPC-EC circuits that are crucial during episodic memory tasks. The first form is called `gamma phase synchrony', which was observed during the running period of a spatial working memory task when the animal was about to make turns at the junction point of a T-maze (Yamamoto et al, Cell, 2014). The second form is called an `extended interregional ripple burst', a memory replay event that is made of alternating chains of burst activities within HPC-EC network during quiet awake or stopping periods on a large running maze (Yamamoto & Tonegawa, Neuron, 2017). I will discuss these two forms of memory access that turned out to be crucial for subsequent spatial working memory behavior.

7月25日（木）17:31～17:49　第3会場（朱鷺メッセ　2F　メインホールB） 1S03e-3 Dentate granule cells recruit feedforward inhibition to govern engram maintenance and remote memory generalization Nannan Guo（Guo Nannan）^1,2，Marta E Soden（Soden Marta E）³，Charlotte Herber（Herber Charlotte）^1,2，Michale Kim（Kim Michale）^1,2，Antoine Besnard（Besnard Antoine）^1,2，Paoyan Lin（Lin Paoyan）^1,2，Constance L Cepko（Cepko Constance L）⁴，Larry S Zweifel（Zweifel Larry S）³，Amar Sahay（Sahay Amar）^1,2,5 ¹Harvard Medical School, Boston ²Center for Regenerative Medicine, Massachusetts General Hospital, Boston ³Department of Pharmacology, Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle ⁴Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston ⁵BROAD Institute of Harvard and MIT, Cambridge Memories generalize over time as memory traces re-organize in hippocampal-cortical networks. Although engram-bearing dentate granule cells (eDGCs) are thought to encode memories, how DGC connectivity governs engram properties and remote memory precision is poorly understood. We show that learning increases connectivity of eDGCs with stratum lucidum inhibitory interneurons (SLINs). We identify a hippocampal mossy fiber terminal localized cytoskeletal factor, actin-binding LIM protein 3 (abLIM3) whose levels decrease upon learning. Viral downregulation of abLIM3 in DGCs increased DGC-SLIN connectivity, parvalbumin (PV)-SLIN activation, enhanced DGC recruitment of inhibition onto CA3 and maintained a fear memory engram in the dentate gyrus (DG) over time. Furthermore, abLIM3 downregulation in DGCs conferred conditioned context-specific reactivation of memory traces in hippocampal-cortical networks and the basolateral amygdala (BLA) and decreased fear memory generalization at remote timepoints. Consistent with age-related hyperactivity in CA3, learning failed to increase DGC-SLIN connectivity in aged mice. abLIM3 downregulation in DG of aged mice was sufficient to restore DGC-SLIN connectivity, increase PV-SLIN activation and improved remote memory precision. These studies exemplify a connectivity-based strategy targeting a molecular brake of inhibition in DG-CA3 that may be harnessed to decrease remote memory generalization in post-traumatic stress disorder and improve memory precision in aging.		7月25日（木）17:49～18:07　第3会場（朱鷺メッセ　2F　メインホールB） 1S03e-4 異なる情報をコードする海馬の記憶痕跡 Kazumasa Z Tanaka（田中和正）¹，Hongshen He（He Hongshen）^1,2，Anupratap Tomar（Tomar Anupratap）¹，Kazue Niisato（Niisato Kazue）¹，Arthur J.Y. Huang（Huang J.Y. Arthur）¹，Thomas McHugh（McHugh J. Thomas）^1,2 ¹理研CBS 神経回路・行動生理学 ²東京大院総合文化研 The hippocampus encodes memories for past events, but the nature of the hippocampal code subserving this function remains unclear. A prevailing idea, strongly supported by hippocampal physiology, is the Cognitive Map Theory (O'Keefe & Nadel, 1978). In this view, episodic memories are anchored to spatial domains, or allocentric frameworks, of experiences, and the hippocampus support these memories by providing a stable representation of external space. On the other hand, recent studies using Immediate Early Genes (IEGs) as a proxy of neuronal activation support the Memory Index Theory (Teyler & DiScenna, 1986). This idea posits that the hippocampal memory trace serves as an index for a cortical representation of memory (a map for internal representation) and hypothesizes the primary hippocampal function is to reinstate the pattern of cortical activity present during encoding. Although the Cognitive Map Theory and Memory Index Theory are not mutually exclusive, it still remained unclear on how to reconcile them. Our recent findings provide a unitary view on these two fundamentally different theories (Tanaka et al., 2018). In the hippocampal CA1 region, the activity of c-Fos expressing pyramidal neurons reliably reflects the identity of the context the animal is experiencing in an index-like fashion, while spikes from other active pyramidal cells provide spatial information that is stable over a long period of time. These two distinct ensembles of hippocampal neurons suggest heterogeneous roles for subsets of hippocampus neurons in memory.

7月25日（木）18:07～18:25　第3会場（朱鷺メッセ　2F　メインホールB） 1S03e-5 Emergence of memory engrams in the rodent hippocampus Marlene Bartos（Bartos Marlene） University of Freiburg During our daily life, we depend on memories of past experiences to plan future behaviour. These memories are represented by the activity of specific neuronal groups or 'engrams'. Neuronal engrams are assembled during learning by synaptic modification, and engram reactivation represents the memorized experience. Engrams of conscious memories are initially stored in the hippocampus for several days and then transferred to cortical areas. In the dentate gyrus of the hippocampus, granule cells transform rich inputs from the entorhinal cortex into a sparse output, which is forwarded to the highly interconnected pyramidal cell network in hippocampal area CA3. This process is thought to support pattern separation CA3 pyramidal neurons projecting to CA1, the hippocampal output region. Although engrams in CA1 and CA2 do not stabilize over times, reactivation of engrams in the dentate gyrus can induce recall of artificial memories even after weeks. Reconciliation of this apparent paradox we recorded from dentate gyrus granule cells throughout learning, which has so far not been performed for more than a single day. We use chronic two-photon calcium imaging in head-fixed mice performing a multiple-day spatial memory task in a virtual environment to record neuronal activity in all major hippocampal subfields. Pyramidal neurons in CA1-CA3 showed precise and highly context-specific, but continuously changing, representations of the learned spatial sceneries in our behavioral paradigm. In contrast, granule cells in the dentate gyrus had a spatial code that was stable over many days, with low place- or context-specificity. Our results suggest that synaptic weights along the hippocampal trisynaptic loop are constantly reassigned to support the formation of dynamic representations in downstream hippocampal areas based on a stable code provided by the dentate gyrus.		7月25日（木）18:25～18:43　第3会場（朱鷺メッセ　2F　メインホールB） 1S03e-6 Hippocampal circuit mechanisms for self-recognition Takashi Kitamura（北村貴司），Jun Yokose（横瀬淳） University of Texas Southwestern Medical Center In humans and animals, episodic memory requires the concerted association of objects, space, time and individuals. Our question is how the brain spatially and temporally encodes and associates these diverse set of information (what, where, when and who) in a single episode. Using advanced mouse genetics combined with viral tracing, in vitro and in vivo electrophysiology, in vivo calcium imaging and optogenetics, we have identified specific neural circuits for the representation of space and time. For example, tri-synaptic pathway from the layer II of the entorhinal cortex to hippocampal dentate gyrus and hippocampal CA3 is crucial for contextual memory, while direct inputs from the layer II/III of the entorhinal cortex to hippocampal CA1 are essential for temporal aspect of episodic memory. Here, we focus on how the brain represents the self in episodes. One of features in the formation of episodic memory is autobiographical; requires own experience accompanied with self-representation and preserves at a first-person viewpoint. In the hippocampus, dorsal CA1 neurons represent a spatial location of the self as well as that of others. Both hippocampal CA2 neurons and ventral CA1 neurons are crucial for social memory to recognize other individuals. However, it remains unknown how hippocampal networks represent the self and distinguish the self from others. In our talk, we will present cellular and neural circuit mechanisms behind the processing in self-recognition for episodic memory formation.