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シンポジウム 30 Novel Aspects of Hippocampal Function: Molecules, Cells and Circuits 座長：McHugh Thomas John（CBS） 2022年7月2日　9:00～9:25　沖縄コンベンションセンター 劇場棟　第1会場 3S01m-01 Population dynamics underlying associative learning in the dorsal and ventral hippocampus *Mazen Kheirbek(1) 1. Weill Institute for Neurosciences, Dept of Psychiatry and Behavioral Sciences, San Francisco, CA, USA Keyword: hippocampus, associative learning, ventral CA1 Animals associate cues with outcomes and continually update these associations as new information is presented. The hippocampus is crucial for this, yet how neurons track changes in cue-outcome associations remains unclear. Here I will present work using high resolution 2-photon calcium imaging, where we tracked the same neurons in dCA1 and vCA1 across multiple days across different stages of learning to determine how responses evolve a during odor-outcome learning. We find that, initially, odors elicited robust responses in dCA1 where single neurons responded robustly to odorants, and the identity of the presented odorant could be accurately decoded from the population activity. However, this was not the case in vCA1, where odorants elicited minimal responses and the identity of the odorant presented could not be decoded from the population how activity. However, in vCA1 responses emerged after associative learning, independent of the nature of the unconditioned stimulus (reward or shock). These representations were broad, responses stretched across the cue, trace, and outcome periods. Population dynamics in both regions rapidly reorganized with learning, then stabilized into ensembles that stored odor representations for many days, even after extinction or pairing with a different outcome. Finally, we found stable, robust signals across CA1 when anticipating reward, but not when anticipating inescapable shock. These results identify how the hippocampus encodes, stores, and updates learned associations, and illuminates the unique contributions of dorsal and ventral hippocampus. 2022年7月2日　9:25～9:50　沖縄コンベンションセンター 劇場棟　第1会場 3S01m-02 Dysregulation of hippocampal adult-born neurons disrupts a brain-wide network for spatial memory Hechen Bao(1), Zhiqiang Hu(2), Sung-ho Lee(1), Tzu-Hao Harry Chao(1), Yan-Jia Luo(1), Yen-Yu Ian Shih(1), *Juan Song(1) 1. University of North Carolina, Chapel Hill, 2. University of California, Berkeley Keyword: adult hippocampal neurogenesis, neural circuits, spatial memory , dentate gyrus Mounting evidence suggests that cognitive deficits associated with various neurological disorders may arise in part from dysregulated adult-born neurons in the dentate gyrus (DG). It remains unknown how dysregulated adult-born neurons contribute to brain-wide network maladaptation and subsequent cognitive deficits. Using an established mouse model with dysregulated adult-born immature neurons and spatial memory deficits, we performed resting state functional magnetic resonance imaging and found that approximately 500 deficient adult-born neurons (<0.1% of total DG granule neurons) are sufficient to induce a significant decrease in the functional connectivity between DG and insular cortex (IC), two brain regions without direct anatomical connections. Furthermore, using a combination of rabies-based retrograde tracing and in vivo fiber photometry recording, we demonstrated that dysregulated adult-born neurons induce aberrant activity in local hippocampal CA3 and CA1 regions, as well as distal medial-dorsal thalamus and IC regions during a spatial memory process. These results suggest that a small number of dysregulated adult-born neurons can impact brain-wide network dynamics across several anatomically discrete regions and collectively contribute to impaired memory. 2022年7月2日　9:50～10:15　沖縄コンベンションセンター 劇場棟　第1会場 3S01m-03 Endoplasmic Reticulum Chaperone Genes Encode Effectors of Long-Term Memory *Abel Ted(1) *Ted Abel(1) 1. Iowa Neuroscience Institute, University of Iowa Keyword: memory loss, ARDR, Nr4a proteins , long-term memory The mechanisms underlying memory loss associated with Alzheimer’s disease and related dementias (ADRD) remain unclear, and no effective treatments exist. Fundamental studies have shown that a set of transcriptional regulatory proteins of the nuclear receptor 4a (Nr4a) family serve as molecular switches for long-term memory. Here, we show that Nr4a proteins regulate the transcription of genes encoding chaperones that localize to the endoplasmic reticulum (ER). These chaperones fold and traffic plasticity-related proteins to the cell surface during long lasting forms of synaptic plasticity and memory. Dysregulation of Nr4a transcription factors and ER chaperones are linked to ADRD, and overexpressing Nr4a1 or the chaperone Hspa5 ameliorates long-term memory deficits in a tau-based mouse model of ADRD, pointing towards novel therapeutic approaches for treating memory loss. Our findings establish a novel molecular concept underlying long-term memory and provide novel insights into the mechanistic basis of cognitive deficits in dementia. 2022年7月2日　10:15～10:40　沖縄コンベンションセンター 劇場棟　第1会場 3S01m-04 Astrocytes Render Memory Flexible by Releasing D-Serine and Regulating NMDA Receptor Tone in the Hippocampus *C Justin Lee Lee(1) 1. IBS (Institute for Basic Sciences) Center for Cognition and Sociality Keyword: astrocyte-neuron interaction, reversal learning, norepinephrine, autism spectrum disorder NMDA receptor (NMDAR) hypofunction has been implicated in several psychiatric disorders with impairment of cognitive flexibility. However, the molecular mechanism of how NMDAR hypofunction with decreased NMDAR tone causes the impairment of cognitive flexibility has been minimally understood. Furthermore, it has been unclear whether hippocampal astrocytes regulate NMDAR tone and cognitive flexibility. We employed cell type–specific genetic manipulations, ex vivo electrophysiological recordings, sniffer patch recordings, cutting-edge biosensor for norepinephrine, and behavioral assays to investigate whether astrocytes can regulate NMDAR tone by releasing D-serine and glutamate. Subsequently, we further investigated the role of NMDAR tone in heterosynaptic long-term depression, metaplasticity, and cognitive flexibility. We found that hippocampal astrocytes regulate NMDAR tone via BEST1-mediated corelease of D-serine and glutamate. Best1 knockout mice exhibited reduced NMDAR tone and impairments of homosynaptic and a1 adrenergic receptor–dependent heterosynaptic long-term depression, which leads to defects in metaplasticity and cognitive flexibility. These impairments in Best1 knockout mice can be rescued by hippocampal astrocyte-specific BEST1 expression or enhanced NMDAR tone through D-serine supplement. D-serine injection in Best1 knockout mice during initial learning rescues subsequent reversal learning. These findings indicate that NMDAR tone during initial learning is important for subsequent learning, and hippocampal NMDAR tone regulated by astrocytic BEST1 is critical for heterosynaptic long-term depression, metaplasticity, and cognitive flexibility. 2022年7月2日　10:40～11:00　沖縄コンベンションセンター 劇場棟　第1会場 3S01m-05 The role of noncanonical hippocampal circuits in memory *Thomas McHugh(1) 1. RIKEN Center for Brain Science Keyword: hippocampus, memory, replay The human hippocampus plays a crucial role in episodic memory; the who, what, where memories that define our lives. In the rodent, well-defined anatomy and physiology make the structure an ideal model system; amenable to circuit manipulations and observations designed to test hypotheses concerning how memories are formed and used. Here I will present our recent work in mice which combines anatomical characterization, genetic interventions and in vivo recording to address how noncononical inputs and outputs influence information flow in the hippocampus. I will highlight connectivity between the hippocampal area CA2, the medial septum and the hypothalamus, which together form reciprocal loops that influence both the oscillations and spiking activity neccessary for the encoding, and consolidation of memory.