認知機能向上及び障害のメカニズムー分子、細胞、回路レベルの解析から Enhancement and dysfunction of cognitive function at the molecular, cellular and circuit levels
S1-4-3-1 Molecular mechanisms of memory consolidation and enhancement ○Cristina Alberini1 The Center for Neural Science, New York University1 Emotionally relevant events become long-lasting memories through a process known as memory consolidation through which newly learned information Become stronger and stored as a long-lasting memory. Consolidation requires an initial phase of gene expression that in the hippocampus lasts for more than 24 hours but less than 48 hours. We are interested in understanding which molecular changes mediate memory consolidation and whether these mechanisms can be manipulated to promote memory enhancement and persistence. We have found that, in rats, the hippocampal activation of the CREB-C/EBP-dependent of gene cascade is required for the consolidation inhibitory avoidance memory, in which the animals remember a context previously associated with a foot shock. A C/EBPβ-regulated target gene that increases after learning and plays an essential role during memory consolidation is insulin-like growth factor 2 (lGF-z). We also found that this mitogenic polypeptide that belongs to the IGF system acts as a potent memory enhancer. Specifically, IGF-2 bilaterally injected into the rat hippocampus immediately after training enhances inhibitory avoidance memory and also prolongs its persistence. The effect is temporally restricted and can be re-enacted by reactivating the memory with retrieval. Inhibitory avoidance is known to require an intact hippocampus and amygdala, as it processes contextual fear conditioning information. Similar effects of IGF-2 in memory enhancement were found on contextual fear conditioning. However, no enhancing effect was seen on auditory fear conditioning, a task that is known to be amygdala- but not hippocampal-dependent. We also found that IGF-2 is not effective when injected into the basolateral amygdala, indicating that the IGF-2-dependent effects are targeting hippocampal mechanisms and relative memories. Investigations on other members of the IGF system and of systemic IGF-II treatments will be discussed.	S1-4-3-2 Genomic landscape of histone acetylation and gene expression in the adult hippocampus: contribution to neuronal plasticity and memory Genomic landscape of histone acetylation and gene expression in the adult hippocampus: contribution to neuronal plasticity and memory ○Angel Barco1 Instituto de Neurociencias de Alicante, Universidad Miguel Hernández1 Molecular Neurobiology, Institute of Neuroscience (UMH-CSIC)1 The acetylation of histone tails is an epigenetic modification of the chromatin associated with active loci and thought to favor transcription. The process is regulated by the opposing activities of lysine acetyltransferase (KAT) and histone deacetylase (HDAC) enzymes and plays a relevant role in neuronal plasticity, learning and memory. This view is based on three independent lines of evidence. First, correlative evidence indicates that histone acetylation is dynamically regulated during memory formation. Second, the reduction of neuronal KAT activity has been associated with impaired intellectual abilities both in humans and mice, whereas reductions in specific HDACs have been associated with enhanced cognitive performance. Third, HDAC inhibitors (HDACi), drugs that increase histone acetylation, have been shown to potentiate memory and synaptic plasticity in wild type animals and to ameliorate cognitive deficits and neurodegeneration in animal models of different neurological conditions. However, the mechanisms that underlie the specificity and beneficial effects of HDACi in the nervous system remain largely unknown. We used chromatin immunoprecipitation coupled to deep sequencing (ChIPseq) and microarray technologies to determine genome-wide histone acetylation and gene expression profiles in the adult mouse hippocampus of animals with normal, reduced or increased levels of histone acetylation. The combination of differential expression and histone acetylation screenings clarified the role of histone acetylation in neuronal gene expression as well as the mechanism of action and main targets of HDACi in neural tissue. Both questions are of great interest for the development of new therapeutic strategies to treat neuropsychiatric disorders.
S1-4-3-3 Molecular, cellular, systems and behavioral mechanisms of memory allocation in neuronal networks ○Alcino J. Silva1 Departments of Neurobiology, Psychiatry, and Psychology, UCLA1 Although memory allocation is a subject of active research in computer science, little is known about how the brain allocates information within neural circuits. Until recently, however, the mechanisms that determine how specific cells and synapses (and not their neighbors) within a neural circuit are recruited during learning have received little attention. Recent findings from our laboratory suggest that memory allocation is not random, but rather specific mechanisms regulate where information is stored within a neural circuit. Our laboratory used a range of single cell manipulation (i.e., optogenetics) and recording (i.e., imaging) techniques to demonstrate that CREB activity regulates neuronal excitability and consequently the allocation of fear memory to specific cells in lateral amygdala. Our studies suggest that some of the mechanisms involved in the consolidation of one memory (e.g., CREB activation) affect the allocation of the next memory. Importantly, we also showed direct evidence for the behavioral impact of memory allocation mechanisms. The findings show that memory allocation mechanisms strengthen and connect independent memories.	S1-4-3-4 Enhancing, Erasing, and Tracing Long-term Memories by Targeting PKMzeta ○Todd C. Sacktor1 Physiology, Pharmacology, and Neurology, SUNY Downstate Medical Center1 Most molecular targets for the manipulation of memory focus on the signaling events that initiate memory formation during the brief time window of memory consolidation, or following the reactivation of memory, during reconsolidation. Targets for maintaining the long-term memory trace after consolidation have been largely unknown. Recently, however, the persistently active atypical PKC isoform, PKMzeta, has been identified as a potential component of the molecular mechanism maintaining the long-term memory trace. Pharmacological or genetic inhibition decreasing PKMzeta activity disrupts both new and established long-term memories, whereas increasing PKMzeta enhances both new and established memories. The genetic deletion of PKMzeta performed conditionally in adult mice prevents late-LTP and long-term memory. In contrast, constitutive knock-out mice show compensation with the PKM form of the other atypical PKC, PKCiota/lambda and have normal memory, thus confirming the essential role of a PKM form of atypical PKC in brain function. In wild-type rats and mice, localizing the increases of PKMzeta within specific circuits of the brain days to weeks after memory consolidation gives the first indication of how the physical trace of long-term memories are stored and can be erased and enhanced.
S1-4-3-5 シナプスから核へ、そして核からシナプスへのシグナリング Signaling from the synapses to the nucleus and from the nucleus back to the synapses ○尾藤晴彦1,2, 川島尚之1, 野中美応1,2, 金亮1,2, 井上昌俊1,2, 藤井哉1,2, 竹本-木村さやか1,3, 奥野浩行1,2 ○Haruhiko Bito1,2, Takashi Kawashima1, Mio Nonaka1,2, Ryang Kim1,2, Masatoshi Inoue1,2, Hajime Fujii1,2, Sayaka Takemoto-Kimura1,3, Hiroyuki Okuno1,2 東京大院・医・神経生化1, PRESTO-JST, Kawaguchi, Japan3 Dept Neurochem, Univ of Tokyo Grad Sch Med1, CREST-JST, Tokyo, Japan2, PRESTO-JST3 Over the past years, we have systematically investigated the molecular basis of the signaling from synapses to the nucleus and from the nucleus back to the synapses, during synaptic plasticity. We thus uncovered an activity-dependent protein kinase cascade CaMKK-CaMKIV that critically controls the amplitude and time course of phosphorylation of a nuclear transcription factor CREB downstream of synaptic activity, thereby activating a plethora of adaptive transcriptional responses within a neuronal circuit. We further identified a potent synaptic activity-responsive element (SARE) on the promoter of one of the most prominent neuronal activity-induced genes, namely Arc/Arg3.1. Strikingly, the SARE of Arc gene consisted of a unique cluster of binding sites for CREB, MEF2 and SRF/TCF, each of which significantly contributing to converting synaptic responses into a transcriptional one. We recently succeeded in long-term imaging of Arc induction and its synaptic targeting in plasticity-induced neurons. Contrary to previous views, we found that Arc protein was targeted to inactive, weak synapses, rather than to active, strong synapses, with significant impact on the synaptic expression of surface glutamate receptors. Because the number of glutamate receptors directly determines the efficacy of synaptic connections between neurons in the brain, these results demonstrate that one critical role of Arc may be to keep weak synapses weak, while allowing strong, essential synapses to remain strong and capable of memory storage. These experiments shed light on the intricate and interactive relationship between the information encoded into the genome and the ongoing synaptic activity during long-term memory formation in the brain.	S1-4-3-6 BMAL1による記憶想起のサーカディアン制御 Circadian regulation of memory retrieval by BMAL1 ○喜田聡1,2 ○Satoshi Kida1,2 東京農業大学応用生物科学部バイオサイエンス学科1 Department of Bioscience, Tokyo University of Agriculture1, CREST, JST, JAPAN2 bHLH-PAS transcription factor BMAL1 has been shown to play essential roles in circadian transcriptional rhythm. Importantly, BMAL1 ubiquitously expresses in the brain and other peripheral tissues, thereby regulating circadian transcription rhythms in not only the SCN but also other cells including neurons in the forebrain. In this study, we have tried to understand roles of BMAL1 in the forebrain in learning and memory. To do this, we have derived conditional mutant mice that enable to induce the inhibition of BMAL1 function in the forebrain by regulating expression of a dominant negative mutant of BMAL1 (BMAL1 R91A; dnBMAL1; Hosoda et al, 2004). Biochemical analyses showed that dnBMAL1 mice exhibit disruptions of circadian expression cycle of BAML1-target genes in the forebrain, but not in the hypothalamus. In addition, dnBMAL1 mice displayed normal circadian rhythms at the behavioral level. These results indicated that inhibition of BMAL1 activity forebrain-specifically impairs circadian transcription rhythms without affecting behavioral circadian rhythms. Behavioral analyses using social recognition, novel object recognition and contextual fear conditioning tasks showed that these mutant mice exhibited impairments of memory retrieval tested at ZT10 in a dnBMAL1 expression-dependent manner, while these mutant mice displayed normal memory retrieval tested at ZT4, 16, or 22. Furthermore, similar impairments of memory retrieval in these mutant mice were also observed in constant dark (CT) conditions. Importantly, dnBMAL1 mice also displays a deficit in c-fos induction in the hippocampus when contextual fear memory was tested at ZT10, suggesting that hippocampal activation associated with memory retrieval is impaired at ZT10 in these mutant mice. These findings indicate that CLOCK/BMAL1 in the forebrain contributes to circadian regulation of memory retrieval.

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