|松尾 直毅（まつお なおき）||データ更新日：2022.04.28|
教授 ／ 理学研究院 生物科学部門 動態生物学講座
|1.||Naoki Matsuo, Shoko Kawamoto, Kenichi Matsubara, Kousaku Okubo, Cloning of a cDNA encoding a novel sugar transporter expressed in the neonatal mouse hippocampus, Biochemical and Biophysical Research Communications, 10.1006/bbrc.1997.7252, 238, 1, 126-129, 1997.09, [URL], While analyzing active genes in the neonatal mouse hippocampus, we observed several novel genes that were abundantly expressed in this tissue. We report here cloning and sequencing of one of these tran scripts, HiAT1 (Hippocampus Abundant Gene Transcript 1). The mRNA was 2.7 Kb in length, and the deduced amino acid sequence consisted of 490 amino acids with characteristics typical of members of the sugar transporter family. However, its overall sequence homology to known transporter cDNAs was only about 30%, suggesting strongly that it represents a novel sugar transporter gene. Northern hybridization analyses showed this transcript is detected in adult and embryonic brains, as well as in other tissues..|
|2.||Naoki Matsuo, Shoko Kawamoto, Kenichi Matsubara, Kousaku Okubo, A novel SCG10-related gene uniquely expressed in the nervous system, Gene, 10.1016/S0378-1119(98)00324-2, 215, 2, 477-481, 1998.07, [URL], We have isolated a novel cDNA (HiAT3: hippocampus abundant transcript 3) in the course of screening for genes that are preferentially expressed in neonatal mouse hippocampus using random 3'-directed cDNA sequencing approach. It encodes a 180-aa protein that has high similarity to SCG10, a neuron-specific negative regulator of microtubule dynamics during neurite outgrowth. The expression of HiAT3 is limited to neurons and peaks about 1 week after birth. The identification of HiAT3 suggests that there may be an elaborate destabilizing regulation for microtubule dynamics in neurons in addition to the stabilizing effect of multiple microtubule-associated proteins (MAPs)..|
|3.||Naoki Matsuo, Shoko Kawamoto, Kenichi Matsubara, Kousaku Okubo, Cloning and developmental expression of the murine homolog of doublecortin, Biochemical and Biophysical Research Communications, 10.1006/bbrc.1998.9698, 252, 3, 571-576, 1998.11, [URL], While analyzing active genes in neonatal mouse hippocampus by quantitative 3'-cDNA collection, we identified a highly conserved murine homolog of doublecortin, the causative gene of X-linked lissencephaly (XLIS) and subcortical laminar heterotopia (SCLH) syndrome. The m-doublecortin cDNA contains nearly 8 kb 3' UTR homologous to hs-doublecortin. and it was mapped to the X chromosome. The expression of m-doublecortin is limited to the developing CNS, especially the cortical plate, supporting that XLIS/SCLH syndrome is associated with an arrest of neuronal migration in the cerebral cortex. The m-doublecortin mRNA was absent in the ventricular zone where neuronal precursors proliferate, and interestingly it was found in various brain structures that are not typically affected in patients with this syndrome..|
|4.||Naoki Matsuo, Mikio Hoshino, Masato Yoshizawa, Yo Ichi Nabeshima, Characterization of STEF, a guanine nucleotide exchange factor for Rac1, required for neurite growth, Journal of Biological Chemistry, 10.1074/jbc.M106186200, 277, 4, 2860-2868, 2002.01, [URL], Accumulating evidence suggests that Rho family GTPases play critical roles in the organization of the nervous system. We previously identified a guanine nucleotide exchange factor of Rac1, STEF (SIF and Tiam 1-like exchange factor), which can induce ruffling membrane in KB cells and is predominantly expressed in the brain during development. Here, we characterize the molecular nature of STEF and its involvement in neurite growth. Deletion analyses revealed distinct roles for individual domains: PHnTSS for membrane association, DH for enzymatic activity, and PHc for promoting catalytic activity. Ectopic expression of STEF in NIE-115 neuroblastoma cells induced neurite-like processes containing F-actin, βIII tubulin, MAP2, and GAP43 in a Rac1-dependent manner even under the serum-containing neurite-inhibiting conditions. We further found that a PHnTSS STEF fragment specifically inhibited the function of both STEF and Tiam1, a closely related Rac1 guanine nucleotide exchange factor. Suppression of endogenous STEF and Tiam1 activities in N1E-115 cells by ectopically expressed PHnTSS STEF resulted in inhibition of neurite outgrowth in serum-starved conditions, which usually induce neurite formation. Furthermore, these inhibitory effects were rescued by exogenously expressed STEF or Tiam1, suggesting that STEF and Tiaml are involved in neurite formation through the activation of Rac1 and successive cytoskeletal reorganization of neuronal cells during development..|
|5.||Masato Yoshizawa, Masaki Sone, Naoki Matsuo, Takahiro Nagase, Osamu Ohara, Yo Ichi Nabeshima, Mikio Hoshino, Dynamic and coordinated expression profile of dbl-family guanine nucleotide exchange factors in the developing mouse brain, Gene Expression Patterns, 10.1016/S1567-133X(03)00002-4, 3, 3, 375-381, 2003.06, [URL], Dbl-family guanine nucleotide exchange factors (Dbl-GEFs) act as activators of Rho-like small G proteins such as Rac1, Cdc42 and RhoA. Recently, some GEFs have been suggested to play important roles in the development of the nervous system. Here, we report a comprehensive expression profile analysis of 20 Dbl-GEFs that have yet to be well investigated. Northern analyses of murine mRNAs from brains of E13, E17, P7 and adult mice revealed expression of 18 out of 20 GEFs in some or all stages. In addition, we found that three human GEFs were highly expressed in the brain. Examination of the spatial expression patterns of five GEFs in embryos or neonatal brain by in situ hybridization revealed distinct patterns for each GEF. Our study reveals the dynamic and coordinated expression profiles of the Dbl-GEFs and provides a basic framework for understanding the function of GEFs in neural development..|
|6.||Naoki Matsuo, Mami Terao, Yo Ichi Nabeshima, Mikio Hoshino, Roles of STEF/Tiam1, guanine nucleotide exchange factors for Rac1, in regulation of growth cone morphology, Molecular and Cellular Neuroscience, 10.1016/S1044-7431(03)00122-2, 24, 1, 69-81, 2003.09, [URL], Rho family GTPases are suggested to be pivotal for growth cone behavior, but regulation of their activities in response to environmental cues remains elusive. Here, we describe roles of STEF and Tiam1, guanine nucleotide exchange factors for Rac1, in neurite growth and growth cone remodeling. We reveal that, in primary hippocampal neurons, STEF/Tiam1 are localized within growth cones and essential for formation of growth cone lamellipodia, eventually contributing to neurite growth. Furthermore, experiments using a dominant-negative form demonstrate that STEF/Tiam1 mediate extracellular laminin signals to activate Rac1, promoting neurite growth in N1E-115 neuroblastoma cells. STEF/Tiam1 are revealed to mediate Cdc42 signal to activate Rac1 during lamellipodial formation. We also show that RhoA inhibits the STEF/Tiam1-Rac1 pathway. These data are used to propose a model that extracellular and intracellular information is integrated by STEF/Tiam1 to modulate the balance of Rho GTPase activities in the growth cone and, consequently, to control growth cone behavior..|
|7.||Mikio Hoshino, Shoko Nakamura, Kiyoshi Mori, Takeshi Kawauchi, Mami Terao, Yoshiaki V. Nishimura, Akihisa Fukuda, Toshimitsu Fuse, Naoki Matsuo, Masaki Sone, Masahiko Watanabe, Haruhiko Bito, Toshio Terashima, Christopher V.E. Wright, Yoshiya Kawaguchi, Kazuwa Nakao, Yo Ichi Nabeshima, Ptf1a, a bHLH transcriptional gene, defines GABAergic neuronal fates in cerebellum, Neuron, 10.1016/j.neuron.2005.06.007, 47, 2, 201-213, 2005.07, [URL], The molecular machinery governing glutamatergic-GABAergic neuronal subtype specification is unclear. Here we describe a cerebellar mutant, cerebelless, which lacks the entire cerebellar cortex in adults. The primary defect of the mutant brains was a specific inhibition of GABAergic neuron production from the cerebellar ventricular zone (VZ), resulting in secondary and complete loss of external germinal layer, pontine, and olivary nuclei during development. We identified the responsible gene, Ptf1a, whose expression was lost in the cerebellar VZ but was maintained in the pancreas in cerebelless. Lineage tracing revealed that two types of neural precursors exist in the cerebellar VZ: Ptf1a-expressing and -nonexpressing precursors, which generate GABAergic and glutamatergic neurons, respectively. Introduction of Ptf1a into glutamatergic neuron precursors in the dorsal telencephalon generated GABAergic neurons with representative morphological and migratory features. Our results suggest that Ptf1a is involved in driving neural precursors to differentiate into GABAergic neurons in the cerebellum..|
|8.||Leon G. Reijmers, Brian L. Perkins, Naoki Matsuo, Mark Mayford, Localization of a stable neural correlate of associative memory, Science, 10.1126/science.1143839, 317, 5842, 1230-1233, 2007.08, [URL], Do learning and retrieval of a memory activate the same neurons? Does the number of reactivated neurons correlate with memory strength? We developed a transgenic mouse that enables the long-lasting genetic tagging of c-fos-active neurons. We found neurons in the basolateral amygdala that are activated during Pavlovian fear conditioning and are reactivated during memory retrieval. The number of reactivated neurons correlated positively with the behavioral expression of the fear memory, indicating a stable neural correlate of associative memory. The ability to manipulate these neurons genetically should allow a more precise dissection of the molecular mechanisms of memory encoding within a distributed neuronal network..|
|9.||Rie Nagaoka-Yasuda, Naoki Matsuo, Brian Perkins, Klara Limbaeck-Stokin, Mark Mayford, An RNAi-based genetic screen for oxidative stress resistance reveals retinol saturase as a mediator of stress resistance, Free Radical Biology and Medicine, 10.1016/j.freeradbiomed.2007.05.008, 43, 5, 781-788, 2007.09, [URL], Oxidative stress has been implicated in the pathogenesis of numerous late-onset diseases as well as organismal longevity. Nevertheless, the genetic components that affect cellular sensitivity to oxidative stress have not been explored extensively at the genome-wide level in mammals. Here we report an RNA interference (RNAi) screen for genes that increase resistance to an organic oxidant, tert-butylhydroperoxide (tert-BHP), in cultured fibroblasts. The loss-of-function screen allowed us to identify several short hairpin RNAs (shRNAs) that elevated the cellular resistance to tert-BHP. One of these shRNAs strongly protected cells from tert-BHP and H2O2 by specifically reducing the expression of retinol saturase, an enzyme that converts all-trans-retinol (vitamin A) to all-trans-13,14-dihydroretinol. The protective effect was well correlated with the reduction in mRNA level and was observed in both primary fibroblasts and NIH3T3 cells. The results suggest a novel role for retinol saturase in regulating sensitivity to oxidative stress and demonstrate the usefulness of large-scale RNAi screening for elucidating new molecular pathways involved in stress resistance..|
|10.||Naoki Matsuo, Leon Reijmers, Mark Mayford, Spine-type-specific recruitment of newly synthesized AMPA receptors with learning, Science, 10.1126/science.1149967, 319, 5866, 1104-1107, 2008.02, [URL], The stabilization of long-term memories requires de novo protein synthesis. How can proteins, synthesized in the soma, act on specific synapses that participate in a given memory? We studied the dynamics of newly synthesized AMPA-type glutamate receptors (AMPARs) induced with learning using transgenic mice expressing the GluR1 subunit fused to green fluorescent protein (GFP-GluR1) under control of the c-fos promoter. We found learning-associated recruitment of newly synthesized GFP-GluR1 selectively to mushroom-type spines in adult hippocampal CA1 neurons 24 hours after fear conditioning. Our results are consistent with a "synaptic tagging" model to allow activated synapses to subsequently capture newly synthesized receptor and also demonstrate a critical functional distinction in the mushroom spines with learning..|
|11.||Naoki Matsuo, Koichi Tanda, Kazuo Nakanishi, Nobuyuki Yamasaki, Keiko Toyama, Keizo Takao, Hiroshi Takeshima, Tsuyoshi Miyakawa, Comprehensive behavioral phenotyping of ryanodine receptor type 3 (RyR3) knockout mice
Decreased social contact duration in two social interaction tests, Frontiers in Behavioral Neuroscience, 10.3389/neuro.08.003.2009, 3, MAY, 2009.05, [URL], Dynamic regulation of the intracellular Ca2+ concentration is crucial for various neuronal functions such as synaptic transmission and plasticity, and gene expression. Ryanodine receptors (RyRs) are a family of intracellular calcium release channels that mediate calcium-induced calcium release from the endoplasmic reticulum. Among the three RyR isoforms, RyR3 is preferentially expressed in the brain especially in the hippocampus and striatum. To investigate the behavioral effects of RyR3 deficiency, we subjected RyR3 knockout (RyR3-/-) mice to a battery of behavioral tests. RyR3-/- mice exhibited significantly decreased social contact duration in two different social interaction tests, where two mice can freely move and make contacts with each other. They also exhibited hyperactivity and mildly impaired prepulse inhibition and latent inhibition while they did not show significant abnormalities in motor function and working and reference memory tests. These results indicate that RyR3 has an important role in locomotor activity and social behavior..
|12.||Koichi Tanda, Akinori Nishi, Naoki Matsuo, Kazuo Nakanishi, Nobuyuki Yamasaki, Tohru Sugimoto, Keiko Toyama, Keizo Takao, Tsuyoshi Miyakawa, Abnormal social behavior, hyperactivity, impaired remote spatial memory, and increased D1-mediated dopaminergic signaling in neuronal nitric oxide synthase knockout mice, Molecular Brain, 10.1186/1756-6606-2-19, 2, 1, 2009.08, [URL], Background. Neuronal nitric oxide synthase (nNOS) is involved in the regulation of a diverse population of intracellular messenger systems in the brain. In humans, abnormal NOS/nitric oxide metabolism is suggested to contribute to the pathogenesis and pathophysiology of some neuropsychiatric disorders, such as schizophrenia and bipolar disorder. Mice with targeted disruption of the nNOS gene exhibit abnormal behaviors. Here, we subjected nNOS knockout (KO) mice to a battery of behavioral tests to further investigate the role of nNOS in neuropsychiatric functions. We also examined the role of nNOS in dopamine/DARPP-32 signaling in striatal slices from nNOS KO mice and the effects of the administration of a dopamine D1 receptor agonist on behavior in nNOS KO mice. Results. nNOS KO mice showed hyperlocomotor activity in a novel environment, increased social interaction in their home cage, decreased depression-related behavior, and impaired spatial memory retention. In striatal slices from nNOS KO mice, the effects of a dopamine D1 receptor agonist, SKF81297, on the phosphorylation of DARPP-32 and AMPA receptor subunit GluR1 at protein kinase A sites were enhanced. Consistent with the biochemical results, intraperitoneal injection of a low dose of SKF81297 significantly decreased prepulse inhibition in nNOS KO mice, but not in wild-type mice. Conclusion. These findings indicate that nNOS KO upregulates dopamine D1 receptor signaling, and induces abnormal social behavior, hyperactivity and impaired remote spatial memory. nNOS KO mice may serve as a unique animal model of psychiatric disorders..|
|13.||Naoki Matsuo, Nobuyuki Yamasaki, Koji Ohira, Keizo Takao, Keiko Toyama, Megumi Eguchi, Shun Yamaguchi, Tsuyoshi Miyakawa, Neural activity changes underlying the working memory defi cit in alpha-CaMKII heterozygous knockout mice, Frontiers in Behavioral Neuroscience, 10.3389/neuro.08.020.2009, 3, SEP, 2009.09, [URL], The alpha-isoform of calcium/calmodulin-dependent protein kinase II (α-CaMKII) is expressed abundantly in the forebrain and is considered to have an essential role in synaptic plasticity and cognitive function. Previously, we reported that mice heterozygous for a null mutation of α-CaMKII (α-CaMKII+/-) have profoundly dysregulated behaviors including a severe working memory deficit, which is an endophenotype of schizophrenia and other psychiatric disorders. In addition, we found that almost all the neurons in the dentate gyrus (DG) of the mutant mice failed to mature at molecular, morphological and electrophysiological levels. In the present study, to identify the brain substrates of the working memory deficit in the mutant mice, we examined the expression of the immediate early genes (IEGs), c-Fos and Arc, in the brain after a working memory version of the eight-arm radial maze test. c-Fos expression was abolished almost completely in the DG and was reduced significantly in neurons in the CA1 and CA3 areas of the hippocampus, central amygdala, and medial prefrontal cortex (mPFC). However, c-Fos expression was intact in the entorhinal and visual cortices. Immunohistochemical studies using arc promoter driven dVenus transgenic mice demonstrated that arc gene activation after the working memory task occurred in mature, but not immature neurons in the DG of wild-type mice. These results suggest crucial insights for the neural circuits underlying spatial mnemonic processing during a working memory task and suggest the involvement of α-CaMKII in the proper maturation and integration of DG neurons into these circuits..|
|14.||Naoki Matsuo, Molecular basis of long-term memory, Seikagaku, 81, 7, 610-614, 2009.09.|
|15.||Naoki Matsuo, Keizo Takao, Kazuo Nakanishi, Nobuyuki Yamasaki, Koichi Tanda, Tsuyoshi Miyakawa, Behavioral profiles of three C57BL/6 substrains, Frontiers in Behavioral Neuroscience, 10.3389/fnbeh.2010.00029, 4, 2010.01, [URL], C57BL/6 inbred strains of mice are widely used in knockout and transgenic research. To evaluate the loss-of-function and gain-of-function effects of the gene of interest, animal behaviors are often examined. However, an issue of C57BL/6 substrains that is not always appreciated is that behaviors are known to be strongly influenced by genetic background. To investigate the behavioral characteristics of C57BL/6 substrains, we subjected C57BL/6J, C57BL/6N, and C57BL/6C mice to a behavior test battery. We performed both a regular-scale analysis, in which experimental conditions were tightly-controlled, and large-scale analysis from large number of behavioral data that we have collected so far through the comprehensive behavioral test battery applied to 700-2,200 mice in total. Significant differences among the substrains were found in the results of various behavioral tests, including the open field, rotarod, elevated plus maze, prepulse inhibition, Porsolt forced swim, and spatial working memory version of the 8-arm radial maze. Our results show a divergence of behavioral performance in C57BL/6 substrains, which suggest that small genetic differences may have a great influence on behavioral phenotypes. Thus, the genetic background of different substrains should be carefully chosen, equated, and considered in the interpretation of mutant behavioral phenotypes..|
|16.||Naoya Takahashi, Kazuo Kitamura, Naoki Matsuo, Mark Mayford, Masanobu Kano, Norio Matsuki, Yuji Ikegaya, Locally synchronized synaptic inputs, Science, 10.1126/science.1210362, 335, 6066, 353-356, 2012.01, [URL], Synaptic inputs on dendrites are nonlinearly converted to action potential outputs, yet the spatiotemporal patterns of dendritic activation remain to be elucidated at single-synapse resolution. In rodents, we optically imaged synaptic activities from hundreds of dendritic spines in hippocampal and neocortical pyramidal neurons ex vivo and in vivo. Adjacent spines were frequently synchronized in spontaneously active networks, thereby forming dendritic foci that received locally convergent inputs from presynaptic cell assemblies. This precise subcellular geometry manifested itself during N-methyl-D-aspartate receptor - dependent circuit remodeling. Thus, clustered synaptic plasticity is innately programmed to compartmentalize correlated inputs along dendrites and may reify nonlinear synaptic integration..|
|17.||Naoki Matsuo, Irreplaceability of neuronal ensembles after memory allocation, Cell Reports, 10.1016/j.celrep.2015.03.042, 11, 3, 351-357, 2015.04, [URL], Lesion studies suggest that an alternative system can compensate for damage to the primary region employed when animals acquire a memory. However, it is unclear whether functional compensation occurs at the cellular ensemble level. Here, we inhibited the activities of a specific subset of neurons activated during initial learning by utilizing a transgenic mouse that expresses tetanus toxin (TeNT) under the control of the c-fos promoter. Notably, suppression interfered with relearning while sparing the ability to acquire and express fear memory for a distinct context. These results suggest that the activity of the initial ensemble is preferentially dedicated to the same learning and that it is not replaceable once it is allocated. Our results provide substantial insights into the machinery underlying how the brain allocates individual memories todiscrete neuronal ensembles and how it ensures that repetitive learning strengthens memory by reactivating the same neuronal ensembles..|
|18.||Tatsuya Hattori, Takuya Osakada, Ayaka Matsumoto, Naoki Matsuo, Sachiko Haga-Yamanaka, Takaya Nishida, Yuji Mori, Kazutaka Mogi, Kazushige Touhara, Takefumi Kikusui, Self-Exposure to the Male Pheromone ESP1 Enhances Male Aggressiveness in Mice, Current Biology, 10.1016/j.cub.2016.03.029, 26, 9, 1229-1234, 2016.05, [URL], Exocrine gland-secreting peptide 1 (ESP1) released into male tear fluids is a male pheromone that stimulates sexually receptive behavior in female mice via the vomeronasal sensory system. ESP1 also induces c-Fos expression in male brain regions distinct from those in females. However, behavior in males following ESP1 exposure has not been examined. In the present study, we show that ESP1, in conjunction with unfamiliar male urine, enhances male aggression via the specific vomeronasal receptor V2Rp5. In addition, male mice that secrete ESP1 but lack V2Rp5 exhibit a lower level of aggressiveness than do mice that express V2Rp5. These results suggest that ESP1 not only acts as a male pheromone in both sexes but also serves as an auto-stimulatory factor that enhances male aggressiveness by self-exposure. Finally, re-activation of ESP1-induced c-Fos-positive neurons by using the designer receptor exclusively activated by designer drug (DREADD) approach resulted in enhancement of sexual and aggressive behaviors in female and male mice, respectively, indicating that sexually dimorphic activation in the brain is a neural basis for the sex-specific behavioral responses to ESP1..|
|19.||Naoki Matsuo, Dynamic changes in hippocampal ensemble activities associated with contextual fear memory generalization, Folia Pharmacologica Japonica, 10.1254/fpj.148.185, 148, 4, 185-189, 2016.01, [URL].|
|20.||Marie Yokoyama, Naoki Matsuo, Loss of ensemble segregation in dentate gyrus, but not in somatosensory cortex, during contextual fear memory generalization, Frontiers in Behavioral Neuroscience, 10.3389/fnbeh.2016.00218, 10, NOV, 2016.11, [URL], The details of contextual or episodic memories are lost and generalized with the passage of time. Proper generalization may underlie the formation and assimilation of semantic memories and enable animals to adapt to ever-changing environments, whereas overgeneralization of fear memory evokes maladaptive fear responses to harmless stimuli, which is a symptom of anxiety disorders such as post-traumatic stress disorder (PTSD). To understand the neural basis of fear memory generalization, we investigated the patterns of neuronal ensemble reactivation during memory retrieval when contextual fear memory expression is generalized using transgenic mice that allowed us to visualize specific neuronal ensembles activated during memory encoding and retrieval. We found preferential reactivations of neuronal ensembles in the primary somatosensory cortex (SS), when mice were returned to the conditioned context to retrieve their memory 1 day after conditioning. In the hippocampal dentate gyrus (DG), exclusively separated ensemble reactivation was observed when mice were exposed to a novel context. These results suggest that the DG as well as the SS were likely to distinguish the two different contexts at the ensemble activity level when memory is not generalized at the behavioral level. However, 9 days after conditioning when animals exhibited generalized fear, the unique reactivation pattern in the DG, but not in the SS, was lost. Our results suggest that the alternations in the ensemble representation within the DG, or in upstream structures that link the sensory cortex to the hippocampus, may underlie generalized contextual fear memory expression..|
|21.||Takefumi Kikusui, Mayu Kajita, Natsumi Otsuka, Tatsuya Hattori, Kanako Kumazawa, Akiyuki Watarai, Miho Nagasawa, Ayumu Inutsuka, Akihiro Yamanaka, Naoki Matsuo, Herbert E. Covington, Kazutaka Mogi, Sex differences in olfactory-induced neural activation of the amygdala, Behavioural Brain Research, 10.1016/j.bbr.2017.11.034, 346, 96-104, 2018.07, [URL], Olfactory signals, including the scent of urine, are thought to be processed by specific brain regions, such as the medial amygdala (Me), and regulate sexual behavior in a sex-dependent manner. We aimed to reveal the sex-specific neural circuit from the accessory olfactory bulb (AOB) to Me by using a transgenic mouse. We quantified the long-lasting green fluorescent protein (GFP) expression profile, which was controlled by the c-fos promotor in a sex-dependent manner by the scent of urine. Female urine predominantly activated neurons of the posterodorsal medial amygdala (MePD) in male mice and the posteroventral medial amygdala (MePV) in female mice. Male urine, in contrast, generated the opposite pattern of activation in the Me. Secondary, the selective artificial activation of these circuits was used to examine their specific behavioral function, by using a dual Cre-loxP viral infection. AAV-hSyn-FLEX-hM3Dq-EGFP–the designer receptor exclusively activated by a designer drug–was infused into the AOB after infection with trans-synaptic AAV(DJ)-CMV-mCherry-2A-Cre-TTC into either the MePD or the MePV. Double virus-transfected mice were injected with hM3Dq activator and their sexual behavior was monitored. However, selective activation of sex-dependent circuits, i.e., the AOB-MePD or AOB-MePV, did not significantly alter mounting or attack behavior in male mice. There were clear sex differences in the pheromone conveying circuits in the AOB-Me of mice. The sex-dependent functional activation of the Me, however, no effect on behavior. This suggests that a diverse number of nuclei and brain areas are likely to function in concert to successfully facilitate sexual and aggressive behaviors..|
|22.||Takahiro Yoshii, Hiroshi Hosokawa, Naoki Matsuo, Pharmacogenetic reactivation of the original engram evokes an extinguished fear memory, Neuropharmacology, 10.1016/j.neuropharm.2016.09.012, 113, 1-9, 2017.02, [URL], Fear memory extinction has several characteristic behavioral features, such as spontaneous recovery, renewal, and reinstatement, suggesting that extinction training does not erase the original association between the conditioned stimulus (CS) and the unconditioned stimulus (US). However, it is unclear whether reactivation of the original physical record of memory (i.e., memory trace) is sufficient to produce conditioned fear response after extinction. Here, we performed pharmacogenetic neuronal activation using transgenic mice expressing hM3Dq DREADD (designer receptor exclusively activated by designer drug) under the control of the activity-dependent c-fos gene promoter. Neuronal ensembles activated during fear-conditioned learning were tagged with hM3Dq and subsequently reactivated after extinction training. The mice exhibited significant freezing, even when the fear memory was no longer triggered by external CS, indicating that the artificial reactivation of a specific neuronal ensemble was sufficient to evoke the extinguished fear response. This freezing was not observed in non-fear-conditioned mice expressing hM3dq in the same brain areas. These results directly demonstrated that at least part of the original fear memory trace remains after extinction, and such residual plasticity might reflect the persistent memory..|
|23.||Takuma Kitanishi, Naoki Matsuo, Organization of the claustrum-to-entorhinal cortical connection in mice, Journal of Neuroscience, 10.1523/JNEUROSCI.1360-16.2016, 37, 2, 269-280, 2017.01, [URL], The claustrum, a subcortical structure situated between the insular cortex and striatum, is reciprocally connected with almost all neocortical regions. Based on this connectivity, the claustrum has been postulated to integrate multisensory information and, in turn, coordinate widespread cortical activity. Although studies have identified how sensory information is mapped onto the claustrum, the function of individual topographically arranged claustro-cortical pathways has been little explored. Here, we investigated the organization and function of identified claustro-cortical pathways in mice using multiple anatomical and optogenetic techniques. Retrograde and anterograde tracing demonstrated that the density of anterior claustrum-to-cortical projection differs substantially depending on the target cortical areas. One of the major targets was the medial entorhinal cortex (MEC) and the MEC-projecting claustral neurons were largely segregated from the neurons projecting to primary cortices M1, S1, or V1. Exposure to a novel environment induced c-Fos expression in a substantial number of MEC-projecting claustral neurons and some M1/S1/V1-projecting claustral neurons. Optogenetic silencing of the MEC-projecting claustral neurons during contextual fear conditioning impaired later memory retrieval without affecting basal locomotor activity or anxiety-related behavior. These results suggest that the dense, anterior claustro-MEC pathway that is largely separated from other claustrocortical pathways is activated by novel context and modulates the MEC function in contextual memory..|
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