{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T09:25:00Z","timestamp":1785835500689,"version":"3.56.0"},"reference-count":65,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,7,10]],"date-time":"2015-07-10T00:00:00Z","timestamp":1436486400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,7,10]],"date-time":"2015-07-10T00:00:00Z","timestamp":1436486400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Phosphodiesterase 4 (PDE4) has four isoforms (PDE4A-D) with at least 25 splice variants. PDE4 subtype nonselective inhibitors produce potent antidepressant-like and cognition-enhancing effects via increased intracellular cyclic AMP (cAMP) signaling in the brain. Our previous data have demonstrated that long-form PDE4Ds appear to be involved in these pharmacological properties of PDE4 inhibitors in the normal animals. However, it is not clear whether long-form PDE4Ds are critical for the behaviors and related cellular signaling\/neuronal plasticity\/neuroendocrine alterations in the depressed animals. In the present study, animals exposed to the chronic unpredictable stress (CUS), a rodent model of depression, exhibited elevated corticosterone, depressive-like behavior, memory deficits, accompanied with decreased cAMP-PKA-CREB and cAMP-ERK1\/2-CREB signaling and neuroplasticity. These alterations induced by CUS were reversed by RNA interference (RNAi)-mediated prefrontal cortex long-form PDE4Ds (especially PDE4D4 and PDE4D5) knock-down, similar to the effects of the PDE4 subtype nonselective inhibitor rolipram. Furthermore, these effects of RNAi were not enhanced by rolipram. These data indicate a predominant role of long-form PDE4Ds in the pharmacotherapies of PDE4 inhibitors for depression and concomitant memory deficits. Long-form PDE4Ds, especially PDE4D4 and PDE4D5, appear to be the promising targets for the development of antidepressants with high therapeutic indices.<\/jats:p>","DOI":"10.1038\/srep11332","type":"journal-article","created":{"date-parts":[[2015,7,10]],"date-time":"2015-07-10T12:47:50Z","timestamp":1436532470000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Phosphodiesterase-4D Knock-down in the Prefrontal Cortex Alleviates Chronic Unpredictable Stress-Induced Depressive-Like Behaviors and Memory Deficits in Mice"],"prefix":"10.1038","volume":"5","author":[{"given":"Zhen-Zhen","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Xing","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"You-Zhi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Qin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven P.","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M.","family":"O'Donnell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han-Ting","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Feng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,7,10]]},"reference":[{"key":"BFsrep11332_CR1","doi-asserted-by":"crossref","first-page":"e5","DOI":"10.1126\/stke.2252004re5","volume":"2004","author":"DS Charney","year":"2004","unstructured":"Charney, D. S. & Manji, H. K. Life stress, genes and depression: Multiple pathways lead to increased risk and new opportunities for intervention. Sci STKE 2004, e5 (2004).","journal-title":"Sci STKE"},{"key":"BFsrep11332_CR2","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.psychres.2005.11.011","volume":"145","author":"J Jaeger","year":"2006","unstructured":"Jaeger, J., Berns, S., Uzelac, S. & Davis-Conway, S. Neurocognitive deficits and disability in major depressive disorder. Psychiatry Res 145, 39\u201348 (2006).","journal-title":"Psychiatry Res"},{"key":"BFsrep11332_CR3","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1007\/s002130050456","volume":"134","author":"P Willner","year":"1997","unstructured":"Willner, P. Validity, reliability and utility of the chronic mild stress model of depression: A 10-year review and evaluation. Psychopharmacology (Ber l) 134, 319\u2013329 (1997).","journal-title":"Psychopharmacology (Ber"},{"key":"BFsrep11332_CR4","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1111\/j.1472-8206.2012.01049.x","volume":"27","author":"MJ Liao","year":"2013","unstructured":"Liao, M. J. et al. Daphnetin prevents chronic unpredictable stress-induced cognitive deficits. Fundam Clin Pharmacol 27, 510\u2013516 (2013).","journal-title":"Fundam Clin Pharmacol"},{"key":"BFsrep11332_CR5","doi-asserted-by":"publisher","first-page":"2404","DOI":"10.1038\/npp.2009.66","volume":"34","author":"YF Li","year":"2009","unstructured":"Li, Y. F. et al. Antidepressant- and anxiolytic-like effects of the phosphodiesterase-4 inhibitor rolipram on behavior depend on cyclic AMP response element binding protein-mediated neurogenesis in the hippocampus. Neuropsychopharmacol 34, 2404\u20132419 (2009).","journal-title":"Neuropsychopharmacol"},{"key":"BFsrep11332_CR6","doi-asserted-by":"publisher","first-page":"1688","DOI":"10.2174\/138161209788168092","volume":"15","author":"HT Zhang","year":"2009","unstructured":"Zhang, H. T. Cyclic AMP-specific phosphodiesterase-4 as a target for the development of antidepressant drugs. Curr Pharm Des 15, 1688\u20131698 (2009).","journal-title":"Curr Pharm Des"},{"key":"BFsrep11332_CR7","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1016\/S0893-133X(00)00108-1","volume":"23","author":"HT Zhang","year":"2000","unstructured":"Zhang, H. T., Crissman, A. M., Dorairaj, N. R., Chandler, L. J. & O'Donnell, J. M. Inhibition of cyclic AMP phosphodiesterase (PDE4) reverses memory deficits associated with NMDA receptor antagonism. Neuropsychopharmacol 23, 198\u2013204 (2000).","journal-title":"Neuropsychopharmacol"},{"key":"BFsrep11332_CR8","doi-asserted-by":"publisher","first-page":"1432","DOI":"10.1038\/sj.npp.1300440","volume":"29","author":"HT Zhang","year":"2004","unstructured":"Zhang, H. T. et al. Inhibition of the phosphodiesterase 4 (PDE4) enzyme reverses memory deficits produced by infusion of the MEK inhibitor U0126 into the CA1 subregion of the rat hippocampus. Neuropsychopharmacol 29, 1432\u20131439 (2004).","journal-title":"Neuropsychopharmacol"},{"key":"BFsrep11332_CR9","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1007\/s002130000414","volume":"150","author":"HT Zhang","year":"2000","unstructured":"Zhang, H. T. & O'Donnell, J. M. Effects of rolipram on scopolamine-induced impairment of working and reference memory in the radial-arm maze tests in rats. Psychopharmacology (Berl) 150, 311\u2013316 (2000).","journal-title":"Psychopharmacology (Berl)"},{"key":"BFsrep11332_CR10","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1007\/s00213-008-1273-x","volume":"202","author":"OA Reneerkens","year":"2009","unstructured":"Reneerkens, O. A., Rutten, K., Steinbusch, H. W., Blokland, A. & Prickaerts, J. Selective phosphodiesterase inhibitors: A promising target for cognition enhancement. Psychopharmacology (Berl) 202, 419\u2013443 (2009).","journal-title":"Psychopharmacology (Berl)"},{"key":"BFsrep11332_CR11","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1523\/JNEUROSCI.5236-10.2011","volume":"31","author":"YF Li","year":"2011","unstructured":"Li, Y. F. et al. Phosphodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling. J Neurosci 31, 172\u2013183 (2011).","journal-title":"J Neurosci"},{"key":"BFsrep11332_CR12","doi-asserted-by":"publisher","first-page":"16877","DOI":"10.1073\/pnas.0908706106","volume":"106","author":"DL Smith","year":"2009","unstructured":"Smith, D. L., Pozueta, J., Gong, B., Arancio, O. & Shelanski, M. Reversal of long-term dendritic spine alterations in Alzheimer disease models. Proc Natl Acad Sci U S A 106, 16877\u201316882 (2009).","journal-title":"Proc Natl Acad Sci U S A"},{"key":"BFsrep11332_CR13","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1038\/87865","volume":"7","author":"HK Manji","year":"2001","unstructured":"Manji, H. K., Drevets, W. C. & Charney, D. S. The cellular neurobiology of depression. Nat Med 7, 541\u2013547 (2001).","journal-title":"Nat Med"},{"key":"BFsrep11332_CR14","doi-asserted-by":"publisher","first-page":"7507","DOI":"10.1523\/JNEUROSCI.6410-09.2010","volume":"30","author":"D Dumitriu","year":"2010","unstructured":"Dumitriu, D. et al. Selective changes in thin spine density and morphology in monkey prefrontal cortex correlate with aging-related cognitive impairment. J Neurosci 30, 7507\u20137515 (2010).","journal-title":"J Neurosci"},{"key":"BFsrep11332_CR15","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1038\/bjp.2008.307","volume":"155","author":"D Spina","year":"2008","unstructured":"Spina, D. PDE4 inhibitors: Current status. Br J Pharmacol 155, 308\u2013315 (2008).","journal-title":"Br J Pharmacol"},{"key":"BFsrep11332_CR16","doi-asserted-by":"publisher","first-page":"5493","DOI":"10.1074\/jbc.R200029200","volume":"278","author":"M Conti","year":"2003","unstructured":"Conti, M. et al. Cyclic AMP-specific PDE4 phosphodiesterases as critical components of cyclic AMP signaling. J Biol Chem 278, 5493\u20135496 (2003).","journal-title":"J Biol Chem"},{"key":"BFsrep11332_CR17","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1016\/j.tips.2004.01.003","volume":"25","author":"JM O'Donnell","year":"2004","unstructured":"O'Donnell, J. M. & Zhang, H. T. Antidepressant effects of inhibitors of cAMP phosphodiesterase (PDE4). Trends Pharmacol Sci 25, 158\u2013163 (2004).","journal-title":"Trends Pharmacol Sci"},{"key":"BFsrep11332_CR18","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1111\/j.1601-183X.2012.00796.x","volume":"11","author":"TL Schaefer","year":"2012","unstructured":"Schaefer, T. L. et al. A new model of Pde4d deficiency: Genetic knock-down of PDE4D enzyme in rats produces an antidepressant phenotype without spatial cognitive effects. Genes Brain Behav 11, 614\u2013622 (2012).","journal-title":"Genes Brain Behav"},{"key":"BFsrep11332_CR19","first-page":"587","volume":"27","author":"HT Zhang","year":"2002","unstructured":"Zhang, H. T. et al. Antidepressant-like profile and reduced sensitivity to rolipram in mice deficient in the PDE4D phosphodiesterase enzyme. Neuropsychopharmacol 27, 587\u2013595 (2002).","journal-title":"Neuropsychopharmacol"},{"key":"BFsrep11332_CR20","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1111\/j.1476-5381.2012.02225.x","volume":"168","author":"ZZ Wang","year":"2013","unstructured":"Wang, Z. Z. et al. RNA interference-mediated phosphodiesterase 4D splice variants knock-down in the prefrontal cortex produces antidepressant-like and cognition-enhancing effects. Br J Pharmacol 168, 1001\u20131014 (2013).","journal-title":"Br J Pharmacol"},{"key":"BFsrep11332_CR21","doi-asserted-by":"publisher","first-page":"2054","DOI":"10.1111\/j.1476-5381.2011.01524.x","volume":"164","author":"O Bruno","year":"2011","unstructured":"Bruno, O. et al. GEBR-7b, a novel PDE4D selective inhibitor that improves memory in rodents at non-emetic doses. Br J Pharmacol 164, 2054\u20132063 (2011).","journal-title":"Br J Pharmacol"},{"key":"BFsrep11332_CR22","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1038\/nbt.1598","volume":"28","author":"AB Burgin","year":"2010","unstructured":"Burgin, A. B. et al. Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety. Nat Biotechnol 28, 63\u201370 (2010).","journal-title":"Nat Biotechnol"},{"key":"BFsrep11332_CR23","doi-asserted-by":"publisher","first-page":"269","DOI":"10.3233\/JAD-122236","volume":"38","author":"C Zhang","year":"2014","unstructured":"Zhang, C. et al. RNA interference-mediated knock-down of long-form phosphodiesterase-4D (PDE4D) enzyme reverses amyloid-beta42-induced memory deficits in mice. J Alzheimers Dis 38, 269\u2013280 (2014).","journal-title":"J Alzheimers Dis"},{"key":"BFsrep11332_CR24","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1172\/JCI0215506","volume":"110","author":"A Robichaud","year":"2002","unstructured":"Robichaud, A. et al. Deletion of phosphodiesterase 4D in mice shortens alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis. J Clin Invest 110, 1045\u20131052 (2002).","journal-title":"J Clin Invest"},{"key":"BFsrep11332_CR25","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1002\/(SICI)1096-9861(19990503)407:2<287::AID-CNE9>3.0.CO;2-R","volume":"407","author":"JA Cherry","year":"1999","unstructured":"Cherry, J. A. & Davis, R. L. Cyclic AMP phosphodiesterases are localized in regions of the mouse brain associated with reinforcement, movement and affect. J Comp Neurol 407, 287\u2013301 (1999).","journal-title":"J Comp Neurol"},{"key":"BFsrep11332_CR26","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1523\/JNEUROSCI.14-02-00871.1994","volume":"14","author":"AD Miller","year":"1994","unstructured":"Miller, A. D. & Ruggiero, D. A. Emetic reflex arc revealed by expression of the immediate-early gene c-fos in the cat. J Neurosci 14, 871\u2013888 (1994).","journal-title":"J Neurosci"},{"key":"BFsrep11332_CR27","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.bbr.2004.04.008","volume":"155","author":"S Pothion","year":"2004","unstructured":"Pothion, S., Bizot, J. C., Trovero, F. & Belzung, C. Strain differences in sucrose preference and in the consequences of unpredictable chronic mild stress. Behav Brain Res 155, 135\u2013146 (2004).","journal-title":"Behav Brain Res"},{"key":"BFsrep11332_CR28","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.1038\/npp.2011.319","volume":"37","author":"JD Sun","year":"2012","unstructured":"Sun, J. D., Liu, Y., Yuan, Y. H., Li, J. & Chen, N. H. Gap junction dysfunction in the prefrontal cortex induces depressive-like behaviors in rats. Neuropsychopharmacol 37, 1305\u20131320 (2012).","journal-title":"Neuropsychopharmacol"},{"key":"BFsrep11332_CR29","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1001\/archpsyc.1983.01790010081010","volume":"40","author":"J Fawcett","year":"1983","unstructured":"Fawcett, J., Clark, D. C., Scheftner, W. A. & Gibbons, R. D. Assessing anhedonia in psychiatric patients. Arch Gen Psychiatry 40, 79\u201384 (1983).","journal-title":"Arch Gen Psychiatry"},{"key":"BFsrep11332_CR30","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.metabol.2005.01.008","volume":"54","author":"BSGlucocorticoids McEwen","year":"2005","unstructured":"McEwen, B. S. Glucocorticoids, depression and mood disorders: Structural remodeling in the brain. Metabolism 54, 20\u201323 (2005).","journal-title":"Metabolism"},{"key":"BFsrep11332_CR31","doi-asserted-by":"publisher","first-page":"1357","DOI":"10.1016\/j.psyneuen.2008.07.010","volume":"33","author":"Y Ibarguen-Vargas","year":"2008","unstructured":"Ibarguen-Vargas, Y., Surget, A., Touma, C., Palme, R. & Belzung, C. Multifaceted strain-specific effects in a mouse model of depression and of antidepressant reversal. Psychoneuroendocrino 33, 1357\u20131368 (2008).","journal-title":"Psychoneuroendocrino"},{"key":"BFsrep11332_CR32","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.bbr.2008.04.021","volume":"193","author":"I Yalcin","year":"2008","unstructured":"Yalcin, I., Belzung, C. & Surget, A. Mouse strain differences in the unpredictable chronic mild stress: A four-antidepressant survey. Behav Brain Res 193, 140\u2013143 (2008).","journal-title":"Behav Brain Res"},{"key":"BFsrep11332_CR33","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1080\/10253890802506383","volume":"12","author":"ML Palumbo","year":"2009","unstructured":"Palumbo, M. L., Zorrilla, Z. M., Cremaschi, G. A. & Genaro, A. M. Different effect of chronic stress on learning and memory in BALB\/c and C57BL\/6 inbred mice: Involvement of hippocampal NO production and PKC activity. Stress 12, 350\u2013361 (2009).","journal-title":"Stress"},{"key":"BFsrep11332_CR34","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/j.bbr.2008.10.039","volume":"198","author":"K Henningsen","year":"2009","unstructured":"Henningsen, K. et al. Cognitive deficits in the rat chronic mild stress model for depression: Relation to anhedonic-like responses. Behav Brain Res 198, 136\u2013141 (2009).","journal-title":"Behav Brain Res"},{"key":"BFsrep11332_CR35","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.physbeh.2005.06.027","volume":"86","author":"AM Gouirand","year":"2005","unstructured":"Gouirand, A. M. & Matuszewich, L. The effects of chronic unpredictable stress on male rats in the water maze. Physiol Behav 86, 21\u201331 (2005).","journal-title":"Physiol Behav"},{"key":"BFsrep11332_CR36","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/0031-9384(95)02256-2","volume":"60","author":"P Willner","year":"1996","unstructured":"Willner, P., Moreau, J. L., Nielsen, C. K., Papp, M. & Sluzewska, A. Decreased hedonic responsiveness following chronic mild stress is not secondary to loss of body weight. Physiol Behav 60, 129\u2013134 (1996).","journal-title":"Physiol Behav"},{"key":"BFsrep11332_CR37","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1007\/BF00187257","volume":"93","author":"P Willner","year":"1987","unstructured":"Willner, P., Towell, A., Sampson, D., Sophokleous, S. & Muscat, R. Reduction of sucrose preference by chronic unpredictable mild stress and its restoration by a tricyclic antidepressant. Psychopharmacology (Berl) 93, 358\u2013364 (1987).","journal-title":"Psychopharmacology (Berl)"},{"key":"BFsrep11332_CR38","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1002\/da.22063","volume":"30","author":"RS McIntyre","year":"2013","unstructured":"McIntyre, R. S. et al. Cognitive deficits and functional outcomes in major depressive disorder: Determinants, substrates and treatment interventions. Depress Anxiety 30, 515\u2013527 (2013).","journal-title":"Depress Anxiety"},{"key":"BFsrep11332_CR39","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1017\/S0033291711001097","volume":"42","author":"R Kerestes","year":"2012","unstructured":"Kerestes, R. et al. Abnormal prefrontal activity subserving attentional control of emotion in remitted depressed patients during a working memory task with emotional distracters. Psychol Med 42, 29\u201340 (2012).","journal-title":"Psychol Med"},{"key":"BFsrep11332_CR40","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1016\/j.biopsych.2010.12.015","volume":"69","author":"N Li","year":"2011","unstructured":"Li, N. et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 69, 754\u2013761 (2011).","journal-title":"Biol Psychiatry"},{"key":"BFsrep11332_CR41","doi-asserted-by":"publisher","first-page":"832","DOI":"10.1021\/cn3000907","volume":"3","author":"A Garcia-Osta","year":"2012","unstructured":"Garcia-Osta, A., Cuadrado-Tejedor, M., Garcia-Barroso, C., Oyarzabal, J. & Franco, R. Phosphodiesterases as therapeutic targets for Alzheimer's disease. ACS Chem Neurosci 3, 832\u2013844 (2012).","journal-title":"ACS Chem Neurosci"},{"key":"BFsrep11332_CR42","first-page":"168","volume":"43C","author":"WN Marsden","year":"2012","unstructured":"Marsden, W. N. Synaptic plasticity in depression: Molecular, cellular and functional correlates. Prog Neuropsychopharmacol Biol Psychiatry 43C, 168\u2013184 (2012).","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"key":"BFsrep11332_CR43","doi-asserted-by":"publisher","first-page":"14172","DOI":"10.1523\/JNEUROSCI.2122-11.2011","volume":"31","author":"K Schutsky","year":"2011","unstructured":"Schutsky, K., Ouyang, M., Castelino, C. B., Zhang, L. & Thomas, S. A. Stress and glucocorticoids impair memory retrieval via beta2-adrenergic, Gi\/o-coupled suppression of cAMP signaling. J Neurosci 31, 14172\u201314181 (2011).","journal-title":"J Neurosci"},{"key":"BFsrep11332_CR44","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1038\/sj.npp.1301574","volume":"33","author":"C Pittenger","year":"2008","unstructured":"Pittenger, C. & Duman, R. S. Stress, depression and neuroplasticity: A convergence of mechanisms. Neuropsychopharmacol 33, 88\u2013109 (2008).","journal-title":"Neuropsychopharmacol"},{"key":"BFsrep11332_CR45","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1046\/j.1471-4159.2001.00300.x","volume":"77","author":"Y Dwivedi","year":"2001","unstructured":"Dwivedi, Y. et al. Reduced activation and expression of ERK1\/2 MAP kinase in the post-mortem brain of depressed suicide subjects. J Neurochem 77, 916\u2013928 (2001).","journal-title":"J Neurochem"},{"key":"BFsrep11332_CR46","doi-asserted-by":"publisher","first-page":"e431","DOI":"10.1371\/journal.pone.0000431","volume":"2","author":"U Boer","year":"2007","unstructured":"Boer, U. et al. CRE\/CREB-driven up-regulation of gene expression by chronic social stress in CRE-luciferase transgenic mice: Reversal by antidepressant treatment. PLoS One 2, e431 (2007).","journal-title":"PLoS One"},{"key":"BFsrep11332_CR47","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/j.pnpbp.2012.08.001","volume":"40","author":"A Chandran","year":"2013","unstructured":"Chandran, A. et al. Reduced phosphorylation of the mTOR signaling pathway components in the amygdala of rats exposed to chronic stress. Prog Neuropsychopharmacol Biol Psychiatry 40, 240\u2013245 (2013).","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"key":"BFsrep11332_CR48","doi-asserted-by":"publisher","first-page":"1312","DOI":"10.1046\/j.1471-4159.2003.01770.x","volume":"85","author":"SD Kuipers","year":"2003","unstructured":"Kuipers, S. D., Trentani, A., Den Boer, J. A. & Ter Horst, G. J. Molecular correlates of impaired prefrontal plasticity in response to chronic stress. J Neurochem 85, 1312\u20131323 (2003).","journal-title":"J Neurochem"},{"key":"BFsrep11332_CR49","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.ijdevneu.2011.02.006","volume":"29","author":"AF Arnsten","year":"2011","unstructured":"Arnsten, A. F. Prefrontal cortical network connections: Key site of vulnerability in stress and schizophrenia. Int J Dev Neurosci 29, 215\u2013223 (2011).","journal-title":"Int J Dev Neurosci"},{"key":"BFsrep11332_CR50","doi-asserted-by":"publisher","first-page":"16609","DOI":"10.1074\/jbc.275.22.16609","volume":"275","author":"SJ MacKenzie","year":"2000","unstructured":"MacKenzie, S. J., Baillie, G. S., McPhee, I., Bolger, G. B. & Houslay, M. D. ERK2 mitogen-activated protein kinase binding, phosphorylation and regulation of the PDE4D cAMP-specific phosphodiesterases. The involvement of COOH-terminal docking sites and NH2-terminal UCR regions. J Biol Chem 275, 16609\u201316617 (2000).","journal-title":"J Biol Chem"},{"key":"BFsrep11332_CR51","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1093\/emboj\/18.4.893","volume":"18","author":"R Hoffmann","year":"1999","unstructured":"Hoffmann, R., Baillie, G. S., MacKenzie, S. J., Yarwood, S. J. & Houslay, M. D. The MAP kinase ERK2 inhibits the cyclic AMP-specific phosphodiesterase HSPDE4D3 by phosphorylating it at Ser579. Embo J 18, 893\u2013903 (1999).","journal-title":"Embo J"},{"key":"BFsrep11332_CR52","doi-asserted-by":"publisher","first-page":"1503","DOI":"10.1016\/S1359-6446(05)03622-6","volume":"10","author":"MD Houslay","year":"2005","unstructured":"Houslay, M. D., Schafer, P. & Zhang, K. Y. Keynote review: Phosphodiesterase-4 as a therapeutic target. Drug Discov Today 10, 1503\u20131519 (2005).","journal-title":"Drug Discov Today"},{"key":"BFsrep11332_CR53","doi-asserted-by":"publisher","first-page":"1186","DOI":"10.1042\/bst0311186","volume":"31","author":"MD Houslay","year":"2003","unstructured":"Houslay, M. D. & Baillie, G. S. The role of ERK2 docking and phosphorylation of PDE4 cAMP phosphodiesterase isoforms in mediating cross-talk between the cAMP and ERK signalling pathways. Biochem Soc Trans 31, 1186\u20131190 (2003).","journal-title":"Biochem Soc Trans"},{"key":"BFsrep11332_CR54","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1101\/lm.461407","volume":"14","author":"T Nagai","year":"2007","unstructured":"Nagai, T. et al. Dopamine D1 receptors regulate protein synthesis-dependent long-term recognition memory via extracellular signal-regulated kinase 1\/2 in the prefrontal cortex. Learn Mem 14, 117\u2013125 (2007).","journal-title":"Learn Mem"},{"key":"BFsrep11332_CR55","doi-asserted-by":"publisher","first-page":"1395","DOI":"10.1111\/j.1745-7254.2006.00429.x","volume":"27","author":"YF Li","year":"2006","unstructured":"Li, Y. F. et al. Agmatine increases proliferation of cultured hippocampal progenitor cells and hippocampal neurogenesis in chronically stressed mice. Acta Pharmacol Sin 27, 1395\u20131400 (2006).","journal-title":"Acta Pharmacol Sin"},{"key":"BFsrep11332_CR56","doi-asserted-by":"publisher","first-page":"3842","DOI":"10.1210\/endo.138.9.5395","volume":"138","author":"HC Atkinson","year":"1997","unstructured":"Atkinson, H. C. & Waddell, B. J. Circadian variation in basal plasma corticosterone and adrenocorticotropin in the rat: Sexual dimorphism and changes across the estrous cycle. Endocrinology 138, 3842\u20133848 (1997).","journal-title":"Endocrinology"},{"key":"BFsrep11332_CR57","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1016\/j.biopsych.2008.02.022","volume":"64","author":"A Surget","year":"2008","unstructured":"Surget, A. et al. Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal. Biol Psychiatry 64, 293\u2013301 (2008).","journal-title":"Biol Psychiatry"},{"key":"BFsrep11332_CR58","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1097\/00008877-200605000-00008","volume":"17","author":"T Strekalova","year":"2006","unstructured":"Strekalova, T., Gorenkova, N., Schunk, E., Dolgov, O. & Bartsch, D. Selective effects of citalopram in a mouse model of stress-induced anhedonia with a control for chronic stress. Behav Pharmacol 17, 271\u2013287 (2006).","journal-title":"Behav Pharmacol"},{"key":"BFsrep11332_CR59","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1111\/j.1601-183X.2011.00691.x","volume":"10","author":"GS Kirshenbaum","year":"2011","unstructured":"Kirshenbaum, G. S. et al. Decreased neuronal Na+, K+ -ATPase activity in Atp1a3 heterozygous mice increases susceptibility to depression-like endophenotypes by chronic variable stress. Genes Brain Behav 10, 542\u2013550 (2011).","journal-title":"Genes Brain Behav"},{"key":"BFsrep11332_CR60","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1503\/jpn.120050","volume":"38","author":"AL Takatsu-Coleman","year":"2013","unstructured":"Takatsu-Coleman, A. L. et al. Short-term social isolation induces depressive-like behaviour and reinstates the retrieval of an aversive task: Mood-congruent memory in male mice? J Psychiatry Neurosci 38, 259\u2013268 (2013).","journal-title":"J Psychiatry Neurosci"},{"key":"BFsrep11332_CR61","first-page":"275","volume":"30","author":"M Bourin","year":"2005","unstructured":"Bourin, M., Masse, F. & Hascoet, M. Evidence for the activity of lamotrigine at 5-HT(1A) receptors in the mouse forced swimming test. J Psychiatry Neurosci 30, 275\u2013282 (2005).","journal-title":"J Psychiatry Neurosci"},{"key":"BFsrep11332_CR62","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1038\/297681a0","volume":"297","author":"RG Morris","year":"1982","unstructured":"Morris, R. G., Garrud, P., Rawlins, J. N. & O'Keefe, J. Place navigation impaired in rats with hippocampal lesions. Nature 297, 681\u2013683 (1982).","journal-title":"Nature"},{"key":"BFsrep11332_CR63","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1016\/j.neuroscience.2005.02.021","volume":"133","author":"G Flores","year":"2005","unstructured":"Flores, G. et al. Alterations in dendritic morphology of prefrontal cortical and nucleus accumbens neurons in post-pubertal rats after neonatal excitotoxic lesions of the ventral hippocampus. Neuroscience 133, 463\u2013470 (2005).","journal-title":"Neuroscience"},{"key":"BFsrep11332_CR64","first-page":"387","volume":"87","author":"DA Sholl","year":"1953","unstructured":"Sholl, D. A. Dendritic organization in the neurons of the visual and motor cortices of the cat. J Anat 87, 387\u2013406 (1953).","journal-title":"J Anat"},{"key":"BFsrep11332_CR65","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.brainres.2009.10.047","volume":"1308","author":"ZZ Wang","year":"2010","unstructured":"Wang, Z. Z. et al. Chemokine-like factor 1, a novel cytokine, induces nerve cell migration through the non-extracellular Ca2+-dependent tyrosine kinases pathway. Brain Res 1308, 24\u201334 (2010).","journal-title":"Brain Res"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep11332.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep11332","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep11332.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T18:05:09Z","timestamp":1672941909000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep11332"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,7,10]]},"references-count":65,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,9,1]]}},"alternative-id":["BFsrep11332"],"URL":"https:\/\/doi.org\/10.1038\/srep11332","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,7,10]]},"assertion":[{"value":"7 January 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 May 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 July 2015","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"11332"}}