{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:17:25Z","timestamp":1790698645407,"version":"4.1.0"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,2,1]],"date-time":"2017-02-01T00:00:00Z","timestamp":1485907200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,2,1]],"date-time":"2017-02-01T00:00:00Z","timestamp":1485907200000},"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":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Impaired motivation is present in a variety of neurological disorders, suggesting that decreased motivation is caused by broad dysfunction of the nervous system across a variety of circuits. Based on evidence that impaired motivation is a major symptom in the early stages of Huntington\u2019s disease, when dopamine receptor type 2-expressing striatal medium spiny neurons (D2-MSNs) are particularly affected, we hypothesize that degeneration of these neurons would be a key node regulating motivational status. Using a progressive, time-controllable, diphtheria toxin-mediated cell ablation\/dysfunction technique, we find that loss-of-function of D2-MSNs within ventrolateral striatum (VLS) is sufficient to reduce goal-directed behaviours without impairing reward preference or spontaneous behaviour. Moreover, optogenetic inhibition and ablation of VLS D2-MSNs causes, respectively, transient and chronic reductions of goal-directed behaviours. Our data demonstrate that the circuitry containing VLS D2-MSNs control motivated behaviours and that VLS D2-MSN loss-of-function is a possible cause of motivation deficits in neurodegenerative diseases.<\/jats:p>","DOI":"10.1038\/ncomms14304","type":"journal-article","created":{"date-parts":[[2017,2,1]],"date-time":"2017-02-01T13:27:07Z","timestamp":1485955627000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Dysfunction of ventrolateral striatal dopamine receptor type 2-expressing medium spiny neurons impairs instrumental motivation"],"prefix":"10.1038","volume":"8","author":[{"given":"Iku","family":"Tsutsui-Kimura","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Takiue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keitaro","family":"Yoshida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryutaro","family":"Yano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1816-7912","authenticated-orcid":false,"given":"Hiroyuki","family":"Ohta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Nishida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youcef","family":"Bouchekioua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideyuki","family":"Okano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motokazu","family":"Uchigashima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiko","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norio","family":"Takata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Drew","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromi","family":"Sano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaru","family":"Mimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji F.","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,2,1]]},"reference":[{"key":"BFncomms14304_CR1","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1212\/WNL.46.1.130","volume":"46","author":"MS Mega","year":"1996","unstructured":"Mega, M. S., Cummings, J. L., Fiorello, T. & Gornbein, J. The spectrum of behavioral changes in Alzheimer's disease. Neurology 46, 130\u2013135 (1996).","journal-title":"Neurology"},{"key":"BFncomms14304_CR2","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1016\/j.jalz.2011.05.2410","volume":"7","author":"CG Lyketsos","year":"2011","unstructured":"Lyketsos, C. G. et al. Neuropsychiatric symptoms in Alzheimer's disease. Alzheimers Dement. 7, 532\u2013539 (2011).","journal-title":"Alzheimers Dement."},{"key":"BFncomms14304_CR3","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1002\/mds.26208","volume":"30","author":"MG den Brok","year":"2015","unstructured":"den Brok, M. G. et al. Apathy in Parkinson's disease: A systematic review and meta-analysis. Mov. Disord. 30, 759\u2013769 (2015).","journal-title":"Mov. Disord."},{"key":"BFncomms14304_CR4","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1016\/S0140-6736(07)60111-1","volume":"369","author":"FO Walker","year":"2007","unstructured":"Walker, F. O. Huntington's disease. Lancet 369, 218\u2013228 (2007).","journal-title":"Lancet"},{"key":"BFncomms14304_CR5","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1176\/appi.neuropsych.11030057","volume":"24","author":"JC Thompson","year":"2012","unstructured":"Thompson, J. C. et al. Longitudinal evaluation of neuropsychiatric symptoms in Huntington's disease. J. Neuropsychiatry Clin. Neurosci. 24, 53\u201360 (2012).","journal-title":"J. Neuropsychiatry Clin. Neurosci."},{"key":"BFncomms14304_CR6","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1002\/mds.25872","volume":"29","author":"JR Burrell","year":"2014","unstructured":"Burrell, J. R., Hodges, J. R. & Rowe, J. B. Cognition in corticobasal syndrome and progressive supranuclear palsy: a review. Mov. Disord. 29, 684\u2013693 (2014).","journal-title":"Mov. Disord."},{"key":"BFncomms14304_CR7","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1111\/j.1479-8301.2011.00358.x","volume":"11","author":"S Hama","year":"2011","unstructured":"Hama, S., Yamashita, H., Yamawaki, S. & Kurisu, K. Post-stroke depression and apathy: interactions between functional recovery, lesion location, and emotional response. Psychogeriatrics 11, 68\u201376 (2011).","journal-title":"Psychogeriatrics"},{"key":"BFncomms14304_CR8","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1159\/000346076","volume":"35","author":"L Caeiro","year":"2013","unstructured":"Caeiro, L., Ferro, J. M. & Costa, J. Apathy secondary to stroke: a systematic review and meta-analysis. Cerebrovasc. Dis. 35, 23\u201339 (2013).","journal-title":"Cerebrovasc. Dis."},{"key":"BFncomms14304_CR9","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1176\/ajp.147.1.22","volume":"147","author":"RS Marin","year":"1990","unstructured":"Marin, R. S. Differential diagnosis and classification of apathy. Am. J. Psychiatry. 147, 22\u201330 (1990).","journal-title":"Am. J. Psychiatry."},{"key":"BFncomms14304_CR10","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1176\/jnp.3.3.243","volume":"3","author":"RS Marin","year":"1991","unstructured":"Marin, R. S. Apathy: a neuropsychiatnc syndrome. J. Neuropsychiatry Clin. Neurosci. 3, 243\u2013254 (1991).","journal-title":"J. Neuropsychiatry Clin. Neurosci."},{"key":"BFncomms14304_CR11","doi-asserted-by":"publisher","first-page":"1437","DOI":"10.1111\/j.1460-9568.2008.06422.x","volume":"28","author":"HH Yin","year":"2008","unstructured":"Yin, H. H., Ostlund, S. B. & Balleine, B. W. Reward-guided learning beyond dopamine in the nucleus accumbens: the integrative functions of cortico-basal ganglia networks. Eur. J. Neurosci. 28, 1437\u20131448 (2008).","journal-title":"Eur. J. Neurosci."},{"key":"BFncomms14304_CR12","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1093\/brain\/117.4.859","volume":"117","author":"KP Bhatia","year":"1994","unstructured":"Bhatia, K. P. & Marsden, C. D. The behavioural and motor consequences of focal lesions of the basal ganglia in man. Brain 117, (Pt 4): 859\u2013876 (1994).","journal-title":"Brain"},{"key":"BFncomms14304_CR13","doi-asserted-by":"publisher","first-page":"5733","DOI":"10.1073\/pnas.85.15.5733","volume":"85","author":"A Reiner","year":"1988","unstructured":"Reiner, A. et al. Differential loss of striatal projection neurons in Huntington disease. Proc. Natl Acad. Sci. USA 85, 5733\u20135737 (1988).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms14304_CR14","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1002\/ana.410310412","volume":"31","author":"RL Albin","year":"1992","unstructured":"Albin, R. L. et al. Preferential loss of striato-external pallidal projection neurons in presymptomatic Huntington's disease. Ann. Neurol. 31, 425\u2013430 (1992).","journal-title":"Ann. Neurol."},{"key":"BFncomms14304_CR15","doi-asserted-by":"publisher","first-page":"5547","DOI":"10.1073\/pnas.89.12.5547","volume":"89","author":"M Gossen","year":"1992","unstructured":"Gossen, M. & Bujard, H. Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc. Natl Acad. Sci. USA 89, 5547\u20135551 (1992).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms14304_CR16","doi-asserted-by":"publisher","first-page":"11371","DOI":"10.1073\/pnas.95.19.11371","volume":"95","author":"P Lee","year":"1998","unstructured":"Lee, P. et al. Conditional lineage ablation to model human diseases. Proc. Natl Acad. Sci. USA 95, 11371\u201311376 (1998).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms14304_CR17","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1038\/emboj.2011.400","volume":"31","author":"PF Durieux","year":"2012","unstructured":"Durieux, P. F., Schiffmann, S. N. & de Kerchove d'Exaerde, A. Differential regulation of motor control and response to dopaminergic drugs by D1R and D2R neurons in distinct dorsal striatum subregions. EMBO J. 31, 640\u2013653 (2012).","journal-title":"EMBO J."},{"key":"BFncomms14304_CR18","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/S0891-0618(99)00009-5","volume":"16","author":"HJ Groenewegen","year":"1999","unstructured":"Groenewegen, H. J., Galis-de Graaf, Y. & Smeets, W. J. Integration and segregation of limbic cortico-striatal loops at the thalamic level: an experimental tracing study in rats. J. Chem. Neuroanat. 16, 167\u2013185 (1999).","journal-title":"J. Chem. Neuroanat."},{"key":"BFncomms14304_CR19","doi-asserted-by":"publisher","first-page":"9539","DOI":"10.1523\/JNEUROSCI.18-22-09539.1998","volume":"18","author":"N Maurice","year":"1998","unstructured":"Maurice, N., Deniau, J. M., Glowinski, J. & Thierry, A. M. Relationships between the prefrontal cortex and the basal ganglia in the rat: physiology of the corticosubthalamic circuits. J. Neurosci. 18, 9539\u20139546 (1998).","journal-title":"J. Neurosci."},{"key":"BFncomms14304_CR20","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1007\/s00213-002-1154-7","volume":"163","author":"TW Robbins","year":"2002","unstructured":"Robbins, T. W. The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry. Psychopharmacology 163, 362\u2013380 (2002).","journal-title":"Psychopharmacology"},{"key":"BFncomms14304_CR21","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1097\/FBP.0b013e3283305e65","volume":"20","author":"I Tsutsui-Kimura","year":"2009","unstructured":"Tsutsui-Kimura, I. et al. The effects of serotonin and\/or noradrenaline reuptake inhibitors on impulsive-like action assessed by the three-choice serial reaction time task: a simple and valid model of impulsive action using rats. Behav. Pharmacol. 20, 474\u2013483 (2009).","journal-title":"Behav. Pharmacol."},{"key":"BFncomms14304_CR22","doi-asserted-by":"publisher","first-page":"1267","DOI":"10.1126\/science.1137073","volume":"315","author":"JW Dalley","year":"2007","unstructured":"Dalley, J. W. et al. Nucleus accumbens D2\/3 receptors predict trait impulsivity and cocaine reinforcement. Science 315, 1267\u20131270 (2007).","journal-title":"Science"},{"key":"BFncomms14304_CR23","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1038\/nn.3369","volume":"16","author":"R Bock","year":"2013","unstructured":"Bock, R. et al. Strengthening the accumbal indirect pathway promotes resilience to compulsive cocaine use. Nat. Neurosci. 16, 632\u2013638 (2013).","journal-title":"Nat. Neurosci."},{"key":"BFncomms14304_CR24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/0165-0270(95)00153-0","volume":"66","author":"NR Richardson","year":"1996","unstructured":"Richardson, N. R. & Roberts, D. C. Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J. Neurosci. Methods 66, 1\u201311 (1996).","journal-title":"J. Neurosci. Methods"},{"key":"BFncomms14304_CR25","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.bbr.2013.05.021","volume":"255","author":"T Tsunematsu","year":"2013","unstructured":"Tsunematsu, T. et al. Long-lasting silencing of orexin\/hypocretin neurons using archaerhodopsin induces slow-wave sleep in mice. Behav. Brain Res. 255, 64\u201374 (2013).","journal-title":"Behav. Brain Res."},{"key":"BFncomms14304_CR26","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1038\/nn.2286","volume":"12","author":"PF Durieux","year":"2009","unstructured":"Durieux, P. F. et al. D2R striatopallidal neurons inhibit both locomotor and drug reward processes. Nat. Neurosci. 12, 393\u2013395 (2009).","journal-title":"Nat. Neurosci."},{"key":"BFncomms14304_CR27","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1002\/cne.903160305","volume":"316","author":"HW Berendse","year":"1992","unstructured":"Berendse, H. W., Galis-de Graaf, Y. & Groenewegen, H. J. Topographical organization and relationship with ventral striatal compartments of prefrontal corticostriatal projections in the rat. J. Comp. Neurol. 316, 314\u2013347 (1992).","journal-title":"J. Comp. Neurol."},{"key":"BFncomms14304_CR28","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1093\/cercor\/bhj043","volume":"16","author":"R Levy","year":"2006","unstructured":"Levy, R. & Dubois, B. Apathy and the functional anatomy of the prefrontal cortex-basal ganglia circuits. Cereb. Cortex 16, 916\u2013928 (2006).","journal-title":"Cereb. Cortex"},{"key":"BFncomms14304_CR29","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1016\/j.neuron.2005.08.008","volume":"47","author":"CM Kuhnen","year":"2005","unstructured":"Kuhnen, C. M. & Knutson, B. The neural basis of financial risk taking. Neuron 47, 763\u2013770 (2005).","journal-title":"Neuron"},{"key":"BFncomms14304_CR30","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.neuron.2006.11.010","volume":"53","author":"B Knutson","year":"2007","unstructured":"Knutson, B., Rick, S., Wimmer, G. E., Prelec, D. & Loewenstein, G. Neural predictors of purchases. Neuron 53, 147\u2013156 (2007).","journal-title":"Neuron"},{"key":"BFncomms14304_CR31","doi-asserted-by":"publisher","first-page":"14080","DOI":"10.1523\/JNEUROSCI.2752-10.2010","volume":"30","author":"C Pr\u00e9vost","year":"2010","unstructured":"Pr\u00e9vost, C., Pessiglione, M., M\u00e9t\u00e9reau, E., Cl\u00e9ry-Melin, M. L. & Dreher, J. C. Separate valuation subsystems for delay and effort decision costs. J. Neurosci. 30, 14080\u201314090 (2010).","journal-title":"J. Neurosci."},{"key":"BFncomms14304_CR32","doi-asserted-by":"publisher","first-page":"6170","DOI":"10.1523\/JNEUROSCI.6459-11.2012","volume":"32","author":"MT Treadway","year":"2012","unstructured":"Treadway, M. T. et al. Dopaminergic mechanisms of individual differences in human effort-based decision-making. J. Neurosci. 32, 6170\u20136176 (2012).","journal-title":"J. Neurosci."},{"key":"BFncomms14304_CR33","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1016\/j.celrep.2012.06.011","volume":"2","author":"KF Tanaka","year":"2012","unstructured":"Tanaka, K. F. et al. Expanding the repertoire of optogenetically targeted cells with an enhanced gene expression system. Cell Rep. 2, 397\u2013406 (2012).","journal-title":"Cell Rep."},{"key":"BFncomms14304_CR34","doi-asserted-by":"publisher","first-page":"7583","DOI":"10.1523\/JNEUROSCI.4932-12.2013","volume":"33","author":"H Sano","year":"2013","unstructured":"Sano, H., Chiken, S., Hikida, T., Kobayashi, K. & Nambu, A. Signals through the striatopallidal indirect pathway stop movements by phasic excitation in the substantia nigra. J. Neurosci. 33, 7583\u20137594 (2013).","journal-title":"J. Neurosci."},{"key":"BFncomms14304_CR35","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1176\/jnp.4.2.134","volume":"4","author":"SE Starkstein","year":"1992","unstructured":"Starkstein, S. E. et al. Reliability, validity, and clinical correlates of apathy in Parkinson's disease. J. Neuropsychiatry Clin. Neurosci. 4, 134\u2013139 (1992).","journal-title":"J. Neuropsychiatry Clin. Neurosci."},{"key":"BFncomms14304_CR36","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1016\/S1474-4422(15)00019-8","volume":"14","author":"J Pagonabarraga","year":"2015","unstructured":"Pagonabarraga, J., Kuliseky, J., Strafella, A. P. & Krack, P. Apathy in Parkinson's disease: clinical features, neural substrates, diagnosis, and treatment. Lancet Neurol. 14, 518\u2013531 (2015).","journal-title":"Lancet Neurol."},{"key":"BFncomms14304_CR37","doi-asserted-by":"publisher","first-page":"2395","DOI":"10.1098\/rstb.2012.0038","volume":"367","author":"KF Tanaka","year":"2012","unstructured":"Tanaka, K. F., Samuels, B. A. & Hen, R. Serotonin receptor expression along the dorsal-ventral axis of mouse hippocampus. Philos. Trans. R. Soc. Lond. B Biol. Sci. 367, 2395\u20132401 (2012).","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"BFncomms14304_CR38","doi-asserted-by":"publisher","first-page":"1661","DOI":"10.1162\/089976604774201631","volume":"16","author":"RQ Quiroga","year":"2004","unstructured":"Quiroga, R. Q., Nadasdy, Z. & Ben-Shaul, Y. Unsupervised spike detection and sorting with wavelets and superparamagnetic clustering. Neural Comput. 16, 1661\u20131687 (2004).","journal-title":"Neural Comput."},{"key":"BFncomms14304_CR39","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1016\/j.neubiorev.2005.04.017","volume":"29","author":"AP Carobrez","year":"2005","unstructured":"Carobrez, A. P. & Bertoglio, L. J. Ethological and temporal analyses of anxiety-like behaviour: the elevated plus-maze model 20 years on. Neurosci. Biobehav. Rev. 29, 1193\u20131205 (2005).","journal-title":"Neurosci. Biobehav. Rev."},{"key":"BFncomms14304_CR40","doi-asserted-by":"publisher","first-page":"7604","DOI":"10.1523\/JNEUROSCI.1575-07.2007","volume":"27","author":"M Niwa","year":"2007","unstructured":"Niwa, M. et al. A novel molecule \"shati\" is involved in methamphetamine-induced hyperlocomotion, sensitization, and conditioned place preference. J. Neurosci. 27, 7604\u20137615 (2007).","journal-title":"J. Neurosci."},{"key":"BFncomms14304_CR41","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1038\/266730a0","volume":"266","author":"RD Porsolt","year":"1977","unstructured":"Porsolt, R. D., Le Pichon, M. & Jalfre, M. Depression: a new animal model sensitive to antidepressant treatments. Nature 266, 730\u2013732 (1977).","journal-title":"Nature"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/ncomms14304.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms14304","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms14304.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T23:58:37Z","timestamp":1671753517000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/ncomms14304"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,2,1]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,4,28]]}},"alternative-id":["BFncomms14304"],"URL":"https:\/\/doi.org\/10.1038\/ncomms14304","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,2,1]]},"assertion":[{"value":"21 April 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 December 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 February 2017","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":"14304"}}