海馬-嗅内皮質系における認知記憶情報のダイナミクス Dynamics of memory and cognitive representations in the hippocampal-entorhinal network
S1-2-2-1 The transfer of spatial and memory information from entorhinal cortex to hippocampus ○Stefan Leutgeb1,2, Magdalene I Schlesiger1, Jena B Hales1, Mark P Brandon1, Alice L Blackshear1, Robert E Clark3,4, Jill K Leutgeb1 Neurobiol Section and Ctr for Circuits and Behavior, Div Biol Sci, Univ of California, San Diego1, Kavli Institute for Brain and Mind, University of California, San Diego2, Department of Psychiatry, University of California, San Diego3, VAMCSD, San Diego, CA4 Because specialized hippocampal circuitry is necessary for many forms of memory, we investigated the computations that are performed in a local circuitry that consists of medial entorhinal inputs to the hippocampus and hippocampal outputs to the medial entorhinal cortex. In particular, our research asks which mechanisms generate hippocampal spatial firing patterns and how spatial firing patterns contribute to spatial memory. The input layers of the medial entorhinal cortex to hippocampus contain many cell types with precise spatial firing patterns, including cells with tesselating firing fields (i.e., grid cells). We found that silencing the neuronal activity in the medial septal area abolishes theta oscillations and grid-like firing patterns in entorhinal cortex. Even though precise spatial firing patterns of grid cells in entorhinal cortex were disrupted, we found that the hippocampal spatial firing patterns in familiar environments were retained after septal inactivation. We therefore asked whether entorhinal grid cells may be particularly important for generating new spatial maps, but found that hippocampal place cells can rapidly emerge in new environments without grid cell input. We then asked whether abolishing all spatial firing in the medial entorhinal cortex would substantially diminish hippocampal spatial firing. We found that hippocampal spatial firing patterns were retained after medial entorhinal lesions, but that spatial representations were no longer stable over long time periods. Spatial memory acquisition was nonetheless only transiently impaired. These findings have important implications for understanding the brain circuits for spatial processing and for network function in neurodegenerative diseases such as Alzheimer's disease.	S1-2-2-2 AMPA受容体のシナプス移行により決定される海馬場所細胞の時空間発火パターン Spatiotemporal firing patterns of hippocampal place cells determined by synaptic delivery of AMPA receptor ○田代歩1,2,3 ○Ayumu Tashiro1,2,3 南洋理工大学・生物科学学院・ウォーリックNTU神経科学研究プログラム1, ウォーリック大学・生命科学部・ウォーリックNTU神経科学研究プログラム2, カヴリ統合神経科学研究所・ノルウェー科学技術大学3 Warwick-NTU Neuroscience Research Programme, School of Biological Sciences, Nanyang Technological University, Singapore1, Warwick-NTU Neuroscience Research Programme, School of Life Sciences, University of Warwick, Coventry, UK2, Kavli Institue for Systems Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway3 Characterizing neuronal activity in freely behaving animals helps elucidate information processing in the brain. Although cellular mechanisms underlying the neuronal activity have been investigated with conventional pharmacological and transgenic methods, these approaches face a difficulty in distinguishing whether observed changes in firing are caused directly by the interference of cellular machinery or indirectly by the systemic cognitive impairments induced by the manipulations. One way to overcome this limitation is to manipulate cellular machinery in a small population of neurons so that we can monitor firing of manipulated neurons without systemic changes of the brain functions. To achieve this, we devised a multi-unit recording combined with viral vector-mediated local genetic manipulation. Using this approach, we asked whether synaptic plasticity regulates hippocampal place cell activity, by overexpressing the GluR1-c-tail gene which is known to block long-term potentiation by inhibiting synaptic delivery of AMPA receptors. Recombinant adeno-associated viral vectors achieved local, efficient, and pyramidal-cell selective transduction in the rat hippocampus. We found that GluR1-c-tail expression delays rapid formation of spatial firing when animals explore a novel environment while keeping previously formed spatial firing pattern intact. Furthermore, GluR1-c-tail expression impaired a temporal firing pattern along slow, but not fast, gamma oscillations that are thought to originate from the CA3 area and the medial entorhinal cortex, respectively. These results indicate that local synaptic plasticity determines precise spatial and temporal firing of CA1 place cells. Rapid acquisition of spatial information into CA1 place cells may be mediated by synaptic plasticity in CA3-CA1 synapses during slow gamma oscillation.
S1-2-2-3 海馬-嗅内皮質-前頭前皮質間の脳波同期パターンの学習依存的変化 Learning-related changes in oscillatory coupling between the hippocampus, lateral entorhinal, and medial prefrontal cortices ○竹原-西内可織1 ○Kaori Takehara-Nishiuchi1 Department of Psychology, University of Toronto1 Memories are thought to be encoded as a distributed representation in the neocortex, which are initially bound together by the hippocampus (HPC). Accumulating evidence suggests that over the course of consolidation processes the medial prefrontal cortex (mPFC) may take over the binding function from the hippocampus. Yet, mechanisms by which the HPC and mPFC access the distributed representation in the neocortex remain unknown. One possibility is that the HPC and mPFC may modulate neocortical representations through their interaction with the entorhinal cortex, an area that is reciprocally connected with many neocortical regions. We addressed this possibility by applying behavioral and electrophysiological approaches to rat trace eyeblink conditioning. First, we found that reversible inactivation of lateral portions of the entorhinal cortex (LEC) equally impaired the expression of new (i.e., 1-day-old) and old (i.e., 1-month-old) memory, and that the disconnection of the LEC from the mPFC impaired the expression of old memory. Second, by recording local field potentials in the LEC, HPC, and mPFC during learning and expression of old memory, we found that theta oscillations in the LEC and mPFC became strongly synchronized following the presentation of paired stimuli. Furthermore, the strength of mPFC-LEC theta synchronization was correlated with memory performance during the late stage of learning and later expression. LEC theta oscillations also synchronized with HPC theta oscillations upon the stimulus presentation; however, LEC-HPC theta synchronization became weak with learning. Together, our results suggest that functional connectivity between the LEC and mPFC is strengthened with learning and consolidation whereas that between the LEC and HPC is concomitantly weakened. Thus, consolidation may involve changes in LEC-mPFC connections that are necessary and potentially sufficient for maintaining initially hippocampus-dependent associations over long time periods.	S1-2-2-4 生体における海馬神経回路活動の可視化 Visualizing the dynamics of hippocampal circuit activity in vivo ○佐藤正晃1,2, 水田恒太郎1, 河野真子1, 竹川高志1, イスラムタンビル1, 山川宏1, 山口陽子1, 深井朋樹1, 大倉正道3, 中井淳一3, 林康紀1,3 ○Masaaki Sato1,2, Kotaro Mizuta1, Masako Kawano1, Takashi Takekawa1, Tanvir Islam1, Hiroshi Yamakawa1, Yoko Yamaguchi1, Tomoki Fukai1, Masamichi Ohkura3, Junichi Nakai3, Yasunori Hayashi1,3 理化学研究所脳科学総合研究センター1, JSTさきがけ2, 埼玉大学・脳科学融合研究センター3 RIKEN Brain Science Institute1, JST PRESTO2, Brain Sci. Inst., Saitama Univ, Saitama3 The hippocampus plays a crucial role in the formation of memories for place and events. In vivo two-photon calcium imaging has great potential for monitoring dynamic properties of neural circuit activity underlying these processes at cellular and subcellular resolution. Towards this goal, we have developed a set of new technologies that allow imaging of large neuronal populations in hippocampus of behaving mice. We have generated transgenic mice that express a new variant of the G-CaMP calcium indicator (Ohkura et al., PLoS One, 2012) under the neuron-specific thy1 promoter or the tetracycline response element. Following a unilateral craniotomy and implantation of an imaging window, activity of hundreds of dorsal CA1 pyramidal neurons can be imaged simultaneously with a fast resonant scanning two-photon microscope while these mice perform spatial memory tasks in an immersive virtual reality system. Time-varying fluorescence intensities of individual cells are extracted from images using a novel automated analysis software based on a non-negative matrix factorization algorithm. Using these techniques, we can image specific cellular responses to various attributes of behavior as exemplified by intermingled representations of virtual place fields within local CA1 circuits. Future work will investigate how specific patterns of neural activity evolve during learning.
S1-2-2-5 海馬歯状回顆粒細胞の記憶形成と想起における役割 The role of dentate gyrus granule cells in pattern separation and pattern completion ○仲柴俊昭1, 利根川進1 ○Toshiaki Nakashiba1, Thomas McHugh1, Chris McBain2, Michael Fanselow3, Susumu Tonegawa1 , アメリカ国立衛生研究所2, カリフォルニア大学ロサンゼルス校3 The Picower Institute for Learning and Memory at MIT, RIKEN-MIT Center for Neural Circuit Genetics1, National Institutes of Health, Bethesda, MD, USA2, University of California, Los Angeles, CA, USA3 Previous theoretical and experimental studies have suggested that dentate gyrus granule cells (DG GCs) subserve pattern separation, or the ability to distinguish between similar events. DG GCs are continuously generated throughout adult life and constitute a small fraction of GCs in the DG. Adult-born GCs have distinct electrophysiological properties when they are young and later become indistinguishable from the vast majority of old GCs (i.e., those born developmentally and older adult-born GCs). Although recent studies have indicated the necessity of adult neurogenesis in pattern separation, whether old GCs play a role in this phenomenon remains unclear. To address these issues, we generated a transgenic mouse in which synaptic transmission from old GCs was selectively inhibited while keeping synaptic transmission from young GCs intact. Mutant mice failed to exhibit a deficit in pattern separation between similar contexts or between similar spatial locations; however, ablation of young adult-born GCs led to a deficit in pattern separation. Moreover, these mice exhibited deficits in the rapid recall of memories through pattern completion, or the ability to retrieve an entire memory with partial cues. Thus, contrary to the long standing idea of the DG's role in pattern separation, the vast majority of GCs at older ages are dispensable for pattern separation but are required for rapid pattern completion, whereas young adult-born GCs are required for pattern separation. Our data suggest that adult-born GCs may shift their function from pattern separation to rapid pattern completion as they age.

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