リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

リケラボ 全国の大学リポジトリにある学位論文・教授論文を一括検索するならリケラボ論文検索大学・研究所にある論文を検索できる

リケラボ 全国の大学リポジトリにある学位論文・教授論文を一括検索するならリケラボ論文検索大学・研究所にある論文を検索できる

大学・研究所にある論文を検索できる 「Phosphorylation of Npas4 by MAPK Regulates Reward-Related Gene Expression and Behaviors」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。
リケラボ

コピーが完了しました

URLをコピーしました

論文の公開元へ論文の公開元へ
書き出し

Phosphorylation of Npas4 by MAPK Regulates Reward-Related Gene Expression and Behaviors

Anthony Israel Ariza Andrade 名古屋大学

2020.06.01

概要

【Introduction】
　Dopamine (DA) is important for motor function, motivation, working memory, and the reward system (Girault and Greengard, 2004; Phillips et al., 2008). Functional deficits in DA signaling have been implicated in various neuropsychological diseases, including Parkinson’s disease, drug addiction, compulsive behavior, autism spectrum disorders, and schizophrenia (Carlsson Carlsson, 2001; Hyman et al., 2006; Iversen and Iversen, 2007; Koob and Volkow, 2010; Swanson et al., 2007). Experiencing reward and using various drugs of abuse, such as cocaine or methamphetamine, activate intracellular pathways in the brain reward system, including the ventral tegmental area (VTA), the nucleus accumbens (NAc), and the prefrontal cortex (Rogge and Wood, 2013). These pathways regulate the expression of genes that are essential for long-lasting forms of synaptic plasticity, memory processes, and drug-induced neuronal and behavioral changes (McClung and Nestler, 2008; Renthal and Nestler, 2008). Despite this knowledge, our current understanding of the mechanisms by which some transcriptional factors (TFs) are stimulated by DA and how they regulate several genes that are important for synaptic plasticity remains incomplete. It is even less well-understood how the changes that occur at the intracellular level manifest in behavioral changes.

　The principal target of DA is medium spiny neurons (MSNs), which are a special type of GABAergic inhibitory cell that comprises 90% of the neurons within the striatum, including the NAc. The MSNs in the NAc receive inputs from the dopaminergic neurons of the VTA and the glutamatergic neurons of the hippocampus, amygdala, and medial prefrontal cortex. There are two distinct classes of spatially intermixed MSNs that express dopamine type 1 or 2 receptors (D1R MSNs or D2R-MSNs, respectively; Smith et al., 2013). D1R-MSN and D2R-MSN subpopulations were also originally characterized as direct and indirect pathways in the dorsal striatum. D1R is coupled to adenylate cyclase through Golf (Gs) and activates protein kinase A (PKA), whereas D2R inhibits adenylate cyclase through Gi (Herve´ et al., 1993; Stoof and Kebabian, 1984). We previously found that DA stimulates Rap1 GEF (Rasgrp2) phosphorylation via PKA in D1R-MSNs, thereby activating Rap1, and then Rap1 regulates neuronal excitability and behavioral responses to cocaine reward through mitogen-activated protein kinase 1/3 (MAPK1/3), also known as extracellular-signal-regulated kinase 1/2 (ERK1/2) (Nagai et al., 2016). MAPK1/3 also may phosphorylate several nuclear TFs that are involved in gene expression, long-term synaptic plasticity, and memory formation. However, it remains unclear how MAPK1/3 regulates gene expression and memory formation downstream of the D1R/PKA/Rap1 pathway.

　TFs such as c-Fos, FosB, and cyclic AMP response element (CRE) binding protein (CREB) are activated by DA and mediate the expression of genes that are involved in synaptic plasticity (Hyman and Malenka, 2001; Nestler, 2001; Robinson and Kolb, 1999). A variety of protein kinases, including PKA, RSK, and CaMKII, activate CREB via serine- 133 (S133) phosphorylation (Choe and McGinty, 2000, 2001; Dash et al., 1991; Montminy et al., 1990; Sheng et al., 1991; Xing et al., 1996, 1998). The phosphorylation of CREB at S133 recruits CREB-binding protein (CBP) to promote transcription. CBP and its homolog p300 are essential transcriptional coactivators for many TFs (Karamouzis et al., 2007; Vo and Goodman, 2001). CBP/p300 can also act as a scaffold protein, stabilizing the transcription complex by simultaneously binding to other proteins. CBP also regulates transcription during memory and synaptic plasticity (Barrett and Wood, 2008). The deletion of CBP in the NAc correlates with impairments in cocaine sensitivity and reward- related learning and memory (Malvaez et al., 2011; Rogge and Wood, 2013). However, how CBP cooperates with many TFs during reward-related memory processing is not fully understood.

【Methods and Results】
　We isolated and concentrated TFs from the mouse striatum using affinity beads coated with CBP, which acts as a transcriptional coactivator. We used a fragment of CBP that we called CBP-N-TAD (Figure 1A) to pull down nuclear proteins. This method combined with a LC-MS/MS analysis identified more than 400 CBP-interacting proteins, including Neuronal Per Arnt Sim domain protein 4, Npas4 (Figure 1B). Using an in vitro kinase assay we found that MAPK phosphorylates Npas4 downstream of PKA, increasing the Npas4-CBP interaction and the transcriptional activity of Npas4 at the brain-derived neurotrophic factor (BDNF) promoter. Because Npas4 and its phosphorylation were required for cocaine-induced CPP, our findings raise the possibility that Npas4 and its phosphorylation regulate BDNF expression to form long-term reward-related memory. It has been reported that the expression of Bdnf is upregulated in the NAc of animals conditioned in a CPP task (Tian et al., 2016) and that the expression of lentivirus-BDNF and TrkB enhanced cocaine-induced CPP (Bahi et al., 2008). In addition to BDNF, Npas4 can regulate the expression of several genes that are important for neuronal survival and synaptic plasticity, such as c-Fos, Zif268, Arc/Arg3.1, and Homer1a (Lin et al., 2008; Pruunsild et al., 2011; Shan et al., 2018; Spiegel et al., 2014; Yoshihara et al., 2014).

　We also found that Npas4 was mainly expressed in D1R-MSNs after CPP training. To analyze D1R-specific Npas4 function, Npas4-DN was expressed in the NAc under the control of the D1R or Adora2a promoter using AAV-mediated conditional transgenic techniques (Figure 2 A-B). The rewarding effects of cocaine were markedly potentiated in mice that expressed Npas4-DN in D1R-MSNs, but not in D2R-MSNs, of the NAc (Figure 2C). We also administered AAV-SP-Cre into the NAc of homozygous floxed Npas4 mice (Npas4 fl/fl). The D1R-specific knockout of Npas4 notably diminished cocaine-induced CPP. This deficit in mice with local knockout of Npas4 was restored by the expression of Npas4-WT, but not Npas4-6A, indicating that Npas4 phosphorylation in D1R-MSNs is important for reward-related learning and memory (Figure 2 D-E).

【Conclusions】
　In this study we reported that MAPK phosphorylates Npas4 downstream of PKA, increasing the Npas4-CBP interaction and the transcriptional activity of Npas4 at the BDNF promoter. Additionally, the deletion of Npas4 in D1R-expressing MSNs impairs cocaine-induced place preference, which is rescued by Npas4-wild-type, but not by a phospho-deficient Npas4 mutant. These observations suggest that MAPK phosphorylates Npas4 in D1R-MSNs and increases transcriptional activity to enhance reward-related learning and memory.

論文の公開元へ

この論文で使われている画像

関連論文

関連論文をもっと見る

参考文献

Amano, M., Hamaguchi, T., Shohag, M.H., Kozawa, K., Kato, K., Zhang, X., Yura, Y., Matsuura, Y., Kataoka, C., Nishioka, T., and Kaibuchi, K. (2015). Ki- nase-interacting substrate screening is a novel method to identify kinase sub- strates. J. Cell Biol. 209, 895–912.

Bahi, A., Boyer, F., Chandrasekar, V., and Dreyer, J.L. (2008). Role of accum- bens BDNF and TrkB in cocaine-induced psychomotor sensitization, condi- tioned-place preference, and reinstatement in rats. Psychopharmacology (Berl.) 199, 169–182.

Barrett, R.M., and Wood, M.A. (2008). Beyond transcription factors: the role of chromatin modifying enzymes in regulating transcription required for memory. Learn. Mem. 15, 460–467.

Bekinschtein, P., Cammarota, M., Katche, C., Slipczuk, L., Rossato, J.I., Goldin, A., Izquierdo, I., and Medina, J.H. (2008). BDNF is essential to promote persis- tence of long-term memory storage. Proc. Natl. Acad. Sci. USA 105, 2711–2716.

Bertran-Gonzalez, J., Bosch, C., Maroteaux, M., Matamales, M., Herve´ , D., Valjent, E., and Girault, J.A. (2008). Opposing patterns of signaling activation in dopamine D1 and D2 receptor-expressing striatal neurons in response to cocaine and haloperidol. J. Neurosci. 28, 5671–5685.

Betley, J.N., and Sternson, S.M. (2011). Adeno-associated viral vectors for mapping, monitoring, and manipulating neural circuits. Hum. Gene Ther. 22, 669–677.

Bin Saifullah, M.A., Nagai, T., Kuroda, K., Wulaer, B., Nabeshima, T., Kaibuchi, K., and Yamada, K. (2018). Cell type-specific activation of mitogen-activated protein kinase in D1 receptor-expressing neurons of the nucleus accumbens potentiates stimulus-reward learning in mice. Sci. Rep. 8, 14413.

Bloodgood, B.L., Sharma, N., Browne, H.A., Trepman, A.Z., and Greenberg, M.E. (2013). The activity-dependent transcription factor NPAS4 regulates domain-specific inhibition. Nature 503, 121–125.

Caffino, L., Racagni, G., and Fumagalli, F. (2011). Stress and cocaine interact to modulate Arc/Arg3.1 expression in rat brain. Psychopharmacology (Berl.) 218, 241–248.

Carlezon, W.A., Jr., Thome, J., Olson, V.G., Lane-Ladd, S.B., Brodkin, E.S., Hiroi, N., Duman, R.S., Neve, R.L., and Nestler, E.J. (1998). Regulation of cocaine reward by CREB. Science 282, 2272–2275.

Carlsson, A. (2001). A paradigm shift in brain research. Science 294, 1021– 1024.

Choe, E.S., and McGinty, J.F. (2000). N-Methyl-D-aspartate receptors and p38 mitogen-activated protein kinase are required for cAMP-dependent cyclase response element binding protein and Elk-1 phosphorylation in the striatum. Neuroscience 101, 607–617.

Choe, E.S., and McGinty, J.F. (2001). Cyclic AMP and mitogen-activated pro- tein kinases are required for glutamate-dependent cyclic AMP response element binding protein and Elk-1 phosphorylation in the dorsal striatum in vivo. J. Neurochem. 76, 401–412.

Choy, F.C., Klaric´, T.S., Koblar, S.A., and Lewis, M.D. (2015). The role of the neuroprotective factor Npas4 in cerebral ischemia. Int. J. Mol. Sci. 16, 29011–29028.

Chrivia, J.C., Kwok, R.P., Lamb, N., Hagiwara, M., Montminy, M.R., and Goodman, R.H. (1993). Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature 365, 855–859.

Coutellier, L., Beraki, S., Ardestani, P.M., Saw, N.L., and Shamloo, M. (2012). Npas4: a neuronal transcription factor with a key role in social and cognitive functions relevant to developmental disorders. PLoS ONE 7, e46604.

Cowan, C.W., Shao, Y.R., Sahin, M., Shamah, S.M., Lin, M.Z., Greer, P.L., Gao, S., Griffith, E.C., Brugge, J.S., and Greenberg, M.E. (2005). Vav family GEFs link activated Ephs to endocytosis and axon guidance. Neuron 46, 205–217.

Dash, P.K., Karl, K.A., Colicos, M.A., Prywes, R., and Kandel, E.R. (1991). cAMP response element-binding protein is activated by Ca2+/calmodulin- as well as cAMP-dependent protein kinase. Proc. Natl. Acad. Sci. USA 88, 5061–5065.

Datko, M.C., Hu, J.H., Williams, M., Reyes, C.M., Lominac, K.D., von Jon- quieres, G., Klugmann, M., Worley, P.F., and Szumlinski, K.K. (2017). Behav- ioral and neurochemical phenotyping of mice incapable of Homer1a induction. Front. Behav. Neurosci. 11, 208.

Filip, M., Faron-Go´ recka, A., Ku´smider, M., Go1da, A., Frankowska, M., and Dziedzicka-Wasylewska, M. (2006). Alterations in BDNF and trkB mRNAs following acute or sensitizing cocaine treatments and withdrawal. Brain Res. 1071, 218–225.

Funahashi, Y., Namba, T., Fujisue, S., Itoh, N., Nakamuta, S., Kato, K., Shi- mada, A., Xu, C., Shan, W., Nishioka, T., and Kaibuchi, K. (2013). ERK2-medi- ated phosphorylation of Par3 regulates neuronal polarization. J. Neurosci. 33, 13270–13285.

Giordano, G., Sa´ nchez-Pe´ rez, A.M., Montoliu, C., Berezney, R., Malyavan- tham, K., Costa, L.G., Calvete, J.J., and Felipo, V. (2005). Activation of NMDA receptors induces protein kinase A-mediated phosphorylation and degradation of matrin 3. Blocking these effects prevents NMDA-induced neuronal death. J. Neurochem. 94, 808–818.

Girault, J.A., and Greengard, P. (2004). The neurobiology of dopamine signaling. Arch. Neurol. 61, 641–644.

Gong, S., Zheng, C., Doughty, M.L., Losos, K., Didkovsky, N., Schambra, U.B., Nowak, N.J., Joyner, A., Leblanc, G., Hatten, M.E., and Heintz, N. (2003). A gene expression atlas of the central nervous system based on bacterial artifi- cial chromosomes. Nature 425, 917–925.

Gong, S., Doughty, M., Harbaugh, C.R., Cummins, A., Hatten, M.E., Heintz, N., and Gerfen, C.R. (2007). Targeting Cre recombinase to specific neuron popu- lations with bacterial artificial chromosome constructs. J. Neurosci. 27, 9817– 9823.

Herve´ , D., Le´ vi-Strauss, M., Marey-Semper, I., Verney, C., Tassin, J.P., Glo- winski, J., and Girault, J.A. (1993). G(olf) and Gs in rat basal ganglia: possible involvement of G(olf) in the coupling of dopamine D1 receptor with adenylyl cyclase. J. Neurosci. 13, 2237–2248.

Hikida, T., Kimura, K., Wada, N., Funabiki, K., and Nakanishi, S. (2010). Distinct roles of synaptic transmission in direct and indirect striatal pathways to reward and aversive behavior. Neuron 66, 896–907.

Huang da, W., Sherman, B.T., and Lempicki, R.A. (2009a). Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 37, 1–13.

Huang da, W., Sherman, B.T., and Lempicki, R.A. (2009b). Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44–57.

Hyman, S.E., and Malenka, R.C. (2001). Addiction and the brain: the neurobi- ology of compulsion and its persistence. Nat. Rev. Neurosci. 2, 695–703.

Hyman, S.E., Malenka, R.C., and Nestler, E.J. (2006). Neural mechanisms of addiction: the role of reward-related learning and memory. Annu. Rev. Neuro- sci. 29, 565–598.

Ishikawa, M., Nishijima, N., Shiota, J., Sakagami, H., Tsuchida, K., Mizukoshi, M., Fukuchi, M., Tsuda, M., and Tabuchi, A. (2010). Involvement of the serum response factor coactivator megakaryoblastic leukemia (MKL) in the activin- regulated dendritic complexity of rat cortical neurons. J. Biol. Chem. 285, 32734–32743.

Iversen, S.D., and Iversen, L.L. (2007). Dopamine: 50 years in perspective. Trends Neurosci. 30, 188–193.

Kalita, K., Kuzniewska, B., and Kaczmarek, L. (2012). MKLs: co-factors of serum response factor (SRF) in neuronal responses. Int. J. Biochem. Cell Biol. 44, 1444–1447.

Karamouzis, M.V., Konstantinopoulos, P.A., and Papavassiliou, A.G. (2007). Roles of CREB-binding protein (CBP)/p300 in respiratory epithelium tumori- genesis. Cell Res. 17, 324–332.

Kelz, M.B., Chen, J., Carlezon, W.A., Jr., Whisler, K., Gilden, L., Beckmann, A.M., Steffen, C., Zhang, Y.J., Marotti, L., Self, D.W., et al. (1999). Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine. Nature 401, 272–276.

Kinoshita, E., Kinoshita-Kikuta, E., Takiyama, K., and Koike, T. (2006). Phos- phate-binding tag, a new tool to visualize phosphorylated proteins. Mol. Cell. Proteomics 5, 749–757.

Koob, G.F., and Volkow, N.D. (2010). Neurocircuitry of addiction. Neuropsy- chopharmacology 35, 217–238.

Leong, W.K., Klaric, T.S., Lin, Y., Lewis, M.D., and Koblar, S.A. (2013). Upre- gulation of the neuronal Per-Arnt-Sim domain protein 4 (Npas4) in the rat cor- ticolimbic system following focal cerebral ischemia. Eur. J. Neurosci. 37, 1875–1884.

Lin, Y., Bloodgood, B.L., Hauser, J.L., Lapan, A.D., Koon, A.C., Kim, T.K., Hu, L.S., Malik, A.N., and Greenberg, M.E. (2008). Activity-dependent regulation of inhibitory synapse development by Npas4. Nature 455, 1198–1204.

Malvaez, M., Mhillaj, E., Matheos, D.P., Palmery, M., and Wood, M.A. (2011). CBP in the nucleus accumbens regulates cocaine-induced histone acetylation and is critical for cocaine-associated behaviors. J. Neurosci. 31, 16941– 16948.

McClung, C.A., and Nestler, E.J. (2008). Neuroplasticity mediated by altered gene expression. Neuropsychopharmacology 33, 3–17.

Montminy, M.R., Gonzalez, G.A., and Yamamoto, K.K. (1990). Regulation of cAMP-inducible genes by CREB. Trends Neurosci. 13, 184–188.

Nagai, T., Nakamuta, S., Kuroda, K., Nakauchi, S., Nishioka, T., Takano, T., Zhang, X., Tsuboi, D., Funahashi, Y., Nakano, T., et al. (2016). Phosphoproteo- mics of the dopamine pathway enables discovery of Rap1 activation as a reward signal in vivo. Neuron 89, 550–565.

Nestler, E.J. (2001). Molecular basis of long-term plasticity underlying addic- tion. Nat. Rev. Neurosci. 2, 119–128.

Nestler, E.J., Kelz, M.B., and Chen, J. (1999). DeltaFosB: a molecular mediator of long-term neural and behavioral plasticity. Brain Res. 835, 10–17.

Ooe, N., Saito, K., Mikami, N., Nakatuka, I., and Kaneko, H. (2004). Identifica- tion of a novel basic helix-loop-helix-PAS factor, NXF, reveals a Sim2 compet- itive, positive regulatory role in dendritic-cytoskeleton modulator drebrin gene expression. Mol. Cell. Biol. 24, 608–616.

Ooe, N., Kobayashi, K., Motonaga, K., Saito, K., and Kaneko, H. (2009). Dy- namic regulation of bHLH-PAS-type transcription factor NXF gene expression and neurotrophin dependent induction of the transcriptional control activity. Biochem. Biophys. Res. Commun. 378, 761–765.

Parker, D., Ferreri, K., Nakajima, T., LaMorte, V.J., Evans, R., Koerber, S.C., Hoeger, C., and Montminy, M.R. (1996). Phosphorylation of CREB at Ser- 133 induces complex formation with CREB-binding protein via a direct mech- anism. Mol. Cell. Biol. 16, 694–703.

Patil, S.T., Zhang, L., Martenyi, F., Lowe, S.L., Jackson, K.A., Andreev, B.V., Avedisova, A.S., Bardenstein, L.M., Gurovich, I.Y., Morozova, M.A., et al. (2007). Activation of mGlu2/3 receptors as a new approach to treat schizo- phrenia: a randomized Phase 2 clinical trial. Nat. Med. 13, 1102–1107.

Phillips, A.G., Vacca, G., and Ahn, S. (2008). A top-down perspective on dopa- mine, motivation and memory. Pharmacol. Biochem. Behav. 90, 236–249.

Pruunsild, P., Sepp, M., Orav, E., Koppel, I., and Timmusk, T. (2011). Identifi- cation of cis-elements and transcription factors regulating neuronal activity- dependent transcription of human BDNF gene. J. Neurosci. 31, 3295–3308.

Ramamoorthi, K., Fropf, R., Belfort, G.M., Fitzmaurice, H.L., McKinney, R.M., Neve, R.L., Otto, T., and Lin, Y. (2011). Npas4 regulates a transcriptional program in CA3 required for contextual memory formation. Science 334, 1669–1675.

Renthal, W., and Nestler, E.J. (2008). Epigenetic mechanisms in drug addic- tion. Trends Mol. Med. 14, 341–350.

Robinson, T.E., and Kolb, B. (1999). Alterations in the morphology of dendrites and dendritic spines in the nucleus accumbens and prefrontal cortex following repeated treatment with amphetamine or cocaine. Eur. J. Neurosci. 11, 1598– 1604.

Rogge, G.A., and Wood, M.A. (2013). The role of histone acetylation in cocaine-induced neural plasticity and behavior. Neuropsychopharmacology 38, 94–110.

Salton, M., Elkon, R., Borodina, T., Davydov, A., Yaspo, M.L., Halperin, E., and Shiloh, Y. (2011). Matrin 3 binds and stabilizes mRNA. PLoS ONE 6, e23882.

Shan, W., Nagai, T., Tanaka, M., Itoh, N., Furukawa-Hibi, Y., Nabeshima, T., Sokabe, M., and Yamada, K. (2018). Neuronal PAS domain protein 4 (Npas4) controls neuronal homeostasis in pentylenetetrazole-induced epi- lepsy through the induction of Homer1a. J. Neurochem 145, 19–33.

Sheng, M., Thompson, M.A., and Greenberg, M.E. (1991). CREB: a Ca(2+)- regulated transcription factor phosphorylated by calmodulin-dependent ki- nases. Science 252, 1427–1430.

Smith, R.J., Lobo, M.K., Spencer, S., and Kalivas, P.W. (2013). Cocaine- induced adaptations in D1 and D2 accumbens projection neurons (a dichot- omy not necessarily synonymous with direct and indirect pathways). Curr. Opin. Neurobiol. 23, 546–552.

Sooksawate, T., Isa, K., Matsui, R., Kato, S., Kinoshita, M., Kobayashi, K., Wa- tanabe, D., Kobayashi, K., and Isa, T. (2013). Viral vector-mediated selective and reversible blockade of the pathway for visual orienting in mice. Front. Neu- ral Circuits 7, 162.

Speckmann, T., Sabatini, P.V., Nian, C., Smith, R.G., and Lynn, F.C. (2016). Npas4 transcription factor expression is regulated by calcium signaling path- ways and prevents tacrolimus-induced cytotoxicity in pancreatic beta cells. J. Biol. Chem. 291, 2682–2695.

Spiegel, I., Mardinly, A.R., Gabel, H.W., Bazinet, J.E., Couch, C.H., Tzeng, C.P., Harmin, D.A., and Greenberg, M.E. (2014). Npas4 regulates excitatory- inhibitory balance within neural circuits through cell-type-specific gene pro- grams. Cell 157, 1216–1229.

Stoof, J.C., and Kebabian, J.W. (1984). Two dopamine receptors: biochem- istry, physiology and pharmacology. Life Sci. 35, 2281–2296.

Swanson, J.M., Kinsbourne, M., Nigg, J., Lanphear, B., Stefanatos, G.A., Vol- kow, N., Taylor, E., Casey, B.J., Castellanos, F.X., and Wadhwa, P.D. (2007). Etiologic subtypes of attention-deficit/hyperactivity disorder: brain imaging, molecular genetic and environmental factors and the dopamine hypothesis. Neuropsychol. Rev. 17, 39–59.

Taniguchi, M., Carreira, M.B., Cooper, Y.A., Bobadilla, A.C., Heinsbroek, J.A., Koike, N., Larson, E.B., Balmuth, E.A., Hughes, B.W., Penrod, R.D., et al. (2017). HDAC5 and its target gene, Npas4, function in the nucleus accumbens to regulate cocaine-conditioned behaviors. Neuron 96, 130–144.e6.

Tian, W., Wang, J., Zhang, K., Teng, H., Li, C., Szyf, M., Sun, Z.S., and Zhao, M. (2016). Demethylation of c-MYB binding site mediates upregulation of Bdnf IV in cocaine-conditioned place preference. Sci. Rep. 6, 22087.

Tsai, L.N., Ku, T.K., Salib, N.K., and Crowe, D.L. (2008). Extracellular signals regulate rapid coactivator recruitment at AP-1 sites by altered phosphorylation of both CREB binding protein and c-jun. Mol. Cell. Biol. 28, 4240–4250.

Tyssowski, K.M., DeStefino, N.R., Cho, J.H., Dunn, C.J., Poston, R.G., Carty, C.E., Jones, R.D., Chang, S.M., Romeo, P., Wurzelmann, M.K., et al. (2018). Different neuronal activity patterns induce different gene expression pro- grams. Neuron 98, 530–546.e11.

Tzschentke, T.M. (2007). Measuring reward with the conditioned place prefer- ence (CPP) paradigm: update of the last decade. Addict. Biol. 12, 227–462.

Vialou, V., Feng, J., Robison, A.J., Ku, S.M., Ferguson, D., Scobie, K.N., Mazei- Robison, M.S., Mouzon, E., and Nestler, E.J. (2012). Serum response factor and cAMP response element binding protein are both required for cocaine in- duction of DFosB. J. Neurosci. 32, 7577–7584.

Vo, N., and Goodman, R.H. (2001). CREB-binding protein and p300 in tran- scriptional regulation. J. Biol. Chem. 276, 13505–13508.

Xing, J., Ginty, D.D., and Greenberg, M.E. (1996). Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science 273, 959–963.

Xing, J., Kornhauser, J.M., Xia, Z., Thiele, E.A., and Greenberg, M.E. (1998). Nerve growth factor activates extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways to stimulate CREB serine 133 phosphorylation. Mol. Cell. Biol. 18, 1946–1955.

Yoshihara, S., Takahashi, H., Nishimura, N., Kinoshita, M., Asahina, R., Kitsuki, M., Tatsumi, K., Furukawa-Hibi, Y., Hirai, H., Nagai, T., et al. (2014). Npas4 reg- ulates Mdm2 and thus Dcx in experience-dependent dendritic spine develop- ment of newborn olfactory bulb interneurons. Cell Rep. 8, 843–857.

Yoshimura, T., Kawano, Y., Arimura, N., Kawabata, S., Kikuchi, A., and Kaibu- chi, K. (2005). GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity. Cell 120, 137–149.

Yun, J., Koike, H., Ibi, D., Toth, E., Mizoguchi, H., Nitta, A., Yoneyama, M., Ogita, K., Yoneda, Y., Nabeshima, T., et al. (2010). Chronic restraint stress im- pairs neurogenesis and hippocampus-dependent fear memory in mice: possible involvement of a brain-specific transcription factor Npas4. J. Neurochem. 114, 1840–1851.

Yun, J., Nagai, T., Furukawa-Hibi, Y., Kuroda, K., Kaibuchi, K., Greenberg, M.E., and Yamada, K. (2013). Neuronal Per Arnt Sim (PAS) domain protein 4 (NPAS4) regulates neurite outgrowth and phosphorylation of synapsin I. J. Biol. Chem. 288, 2655–2664.

参考文献をもっと見る