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Timing and Intertemporal Choice Behavior in the Valproic Acid Rat Model of Autism Spectrum Disorder

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Abstract

Recently it has been proposed that impairments related to autism spectrum disorder (ASD) may reflect a more fundamental disruption in time perception. Here, we examined whether in utero exposure to valproic acid (VPA) can generate specific behavioral deficits related to ASD and time perception. Pups from control and VPA groups were tested using fixed-interval (FI) temporal bisection, peak interval, and intertemporal choice tasks. In addition, the rats were assessed on motor function, perseverative and exploratory behavior, anxiety, and memory. The VPA group displayed a leftward shift in timing functions. VPA rats displayed no deficits on the motor and memory tasks, but were significantly different from controls on measures of perseveration and anxiety.

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References

  • Acosta, J., Campolongo, M. A., Höcht, C., Depino, A. M., Golombek, D. A., & Agostino, P. V. (2018). Deficits in temporal processing in mice prenatally exposed to valproic acid. European Journal of Neuroscience, 47(6), 619–630.

    Article  PubMed  Google Scholar 

  • Allman, M. J. (2011). Deficits in temporal processing associated with autistic disorder. Frontiers in Integrative Neuroscience, 5, 2. https://doi.org/10.3389/fnint.2011.00002/full

    Article  PubMed  PubMed Central  Google Scholar 

  • Allman, M. J., & Falter, C. M. (2015). Abnormal timing and time perception in autism spectrum disorder? A review of the evidence. In A. Vatakis & M. J. Allman (Eds.), Time distortions in mind (pp. 37–56). BRILL.

    Google Scholar 

  • Allman, M. J., & Mareschal, D. (2016). Possible evolutionary and developmental mechanisms of mental time travel (and implications for autism). Current Opinion in Behavioral Sciences, 8, 220–225.

    Article  PubMed  PubMed Central  Google Scholar 

  • Allman, M. J., & Meck, W. H. (2012). Pathophysiological distortions in time perception and timed performance. Brain: A Journal of Neurology, 135(Pt 3), 656–677. https://doi.org/10.1093/brain/awr210

    Article  Google Scholar 

  • Allman, M. J., DeLeon, I. G., & Wearden, J. H. (2011). Psychophysical assessment of timing in individuals with autism. American Journal on Intellectual and Developmental Disabilities, 116(2), 165–178. https://doi.org/10.1352/1944-7558-116.2.165

    Article  PubMed  PubMed Central  Google Scholar 

  • Allman, M. J., Teki, S., Griffiths, T. D., & Meck, W. H. (2014a). Properties of the internal clock: First- and second-order principles of subjective time. Annual Review of Psychology, 65(1), 743–771. https://doi.org/10.1146/annurev-psych-010213-115117

    Article  PubMed  Google Scholar 

  • Allman, M. J., Yin, B., & Meck, W. H. (2014b). Time in the psychopathological mind. In V. Arstila & D. Lloyd (Eds.), Subjective time: The philosophy, psychology, and neuroscience of temporality (pp. 637–654). American Psychological Association.

    Google Scholar 

  • American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders: DSM-5. American Psychiatric Association.

    Book  Google Scholar 

  • Anshu, K., Nair, A. K., Kumaresan, U. D., Kutty, B. M., Srinath, S., & Laxmi, T. R. (2017). Altered attentional processing in male and female rats in a prenatal valproic acid exposure model of autism spectrum disorder. Autism Research, 10(12), 1929–1944.

    Article  PubMed  Google Scholar 

  • Balci, F., Freestone, D., & Gallistel, C. R. (2009). Risk assessment in man and mouse. Proceedings of the National Academy of Sciences, 106(7), 2459–2463.

    Article  Google Scholar 

  • Balci, F., Papachristos, E. B., Gallistel, C. R., Brunner, D., Gibson, J., & Shumyatsky, G. P. (2008). Interval timing in genetically modified mice: A simple paradigm. Genes, Brain and Behavior, 7(3), 373–384.

    Article  Google Scholar 

  • Bambini-Junior, V., Zanatta, G., Flora Nunes, D. G., de Melo, M. G., Michels, M., Fontes-Dutra, M., et al. (2014). Resveratrol prevents social deficits in animal model of autism induced by valproic acid. Neuroscience Letters, 583, 176–181. https://doi.org/10.1016/j.neulet.2014.09.039

    Article  PubMed  Google Scholar 

  • Banji, D., Banji, O. J. F., Abbagoni, S., Hayath, S., Kambam, S., & Chiluka, V. L. (2011). Amelioration of behavioral aberrations and oxidative markers by green tea extract in valproate induced autism in animals. Brain Research, 1410, 141–151. https://doi.org/10.1016/j.brainres.2011.06.063

    Article  PubMed  Google Scholar 

  • Bares, M., Apps, R., Avanzino, L., Breska, A., D’Angelo, E., Filip, P., et al. (2019). Consensus paper: Decoding the contributions of the cerebellum as a time machine from neurons to clinical applications. Cerebellum (london, England), 18(2), 266–286. https://doi.org/10.1007/s12311-018-0979-5

    Article  Google Scholar 

  • Baron-Cohen, S., Leslie, A. M., & Frith, U. (1985). Does the autistic child have a “theory of mind”? Cognition, 21(1), 37–46.

    Article  PubMed  Google Scholar 

  • Becker, E. B., & Stoodley, C. J. (2013). Autism spectrum disorder and the cerebellum. International Review of Neurobiology, 113, 1–34. https://doi.org/10.1016/B978-0-12-418700-9.00001-0

    Article  PubMed  Google Scholar 

  • Brumback, A. C., Ellwood, I. T., Kjaerby, C., Iafrati, J., Robinson, S., Lee, A. T., et al. (2018). Identifying specific prefrontal neurons that contribute to autism-associated abnormalities in physiology and social behavior. Molecular Psychiatry, 23(10), 2078–2089. https://doi.org/10.1038/mp.2017.213

    Article  PubMed  Google Scholar 

  • Buhusi, C. V., & Meck, W. H. (2005). What makes us tick? functional and neural mechanisms of interval timing. Nature Reviews. Neuroscience, 6(10), 755–765.

    Article  PubMed  Google Scholar 

  • Buonomano, D. V. (2014). Neural dynamics based timing in the subsecond to seconds range. Advances in Experimental Medicine and Biology, 829, 101–117. https://doi.org/10.1007/978-1-4939-1782-2_6

    Article  PubMed  Google Scholar 

  • Cassidy, S., Hannant, P., Tavassoli, T., Allison, C., Smith, P., & Baron-Cohen, S. (2016). Dyspraxia and autistic traits in adults with and without autism spectrum conditions. Molecular Autism, 7(1), 48.

    Article  PubMed  PubMed Central  Google Scholar 

  • Chadman, K. K., Fernandes, S., DiLiberto, E., & Feingold, R. (2019). Do animal models hold value in autism spectrum disorder (ASD) drug discovery? Expert Opinion on Drug Discovery, 14, 727.

    Article  PubMed  Google Scholar 

  • Chomiak, T., Turner, N., & Hu, B. (2013a). What we have learned about autism spectrum disorder from valproic acid. Pathology Research International, 2013, 712758–712768. https://doi.org/10.1155/2013/712758

    Article  PubMed  PubMed Central  Google Scholar 

  • Chomiak, T., Turner, N., & Bin, Hu. (2013b). What we have learned about autism spectrum disorder from valproic acid. Pathology Research International, 2013, 712758–712768. https://doi.org/10.1155/2013/712758

    Article  PubMed  PubMed Central  Google Scholar 

  • Christensen, D. L., Maenner, M. J., Bilder, D., Constantino, J. N., Daniels, J., Durkin, M. S., et al. (2019). Prevalence and characteristics of autism spectrum disorder among children aged 4 years—Early autism and developmental disabilities monitoring network, seven sites, United States, 2010, 2012, and 2014. Morbidity and Mortality Weekly Report. Surveillance Summaries, 68(2), 1–19. https://doi.org/10.15585/mmwr.ss6802a1

    Article  PubMed  PubMed Central  Google Scholar 

  • Church, R. M., Meck, W. H., & Gibbon, J. (1994). Application of scalar timing theory to individual trials. Journal of Experimental Psychology: Animal Behavior Processes, 20, 135–155.

    PubMed  Google Scholar 

  • Clayton-Smith, J., & Donnai, D. (1995). Fetal valproate syndrome. Journal of Medical Genetics, 32(9), 724.

    Article  PubMed  PubMed Central  Google Scholar 

  • Coull, J. T., Cheng, R., & Meck, W. H. (2011). Neuroanatomical and neurochemical substrates of timing. Neuropsychopharmacology, 36(1), 3–25. https://doi.org/10.1038/npp.2010.113

    Article  PubMed  Google Scholar 

  • Daniels, C. W., Fox, A. E., Kyonka, E. G., & Sanabria, F. (2015). Biasing temporal judgments in rats, pigeons, and humans. International Journal of Comparative Psychology. https://doi.org/10.46867/ijcp.2015.28.02.07

    Article  Google Scholar 

  • Delehanty, A. D., Stronach, S., Guthrie, W., Slate, E., & Wetherby, A. M. (2018). Verbal and nonverbal outcomes of toddlers with and without autism spectrum disorder, language delay, and global developmental delay. Autism & Developmental Language Impairments, 3, 2396941518764764.

    Article  Google Scholar 

  • Demetriou, E. A., Lampit, A., Quintana, D. S., Naismith, S. L., Song, Y., Pye, J. E., et al. (2018). Autism spectrum disorders: A meta-analysis of executive function. Molecular Psychiatry, 23(5), 1198.

    Article  PubMed  Google Scholar 

  • Di Martino, A., Kelly, C., Grzadzinski, R., Zuo, X. N., Mennes, M., Mairena, M. A., et al. (2011). Aberrant striatal functional connectivity in children with autism. Biological Psychiatry, 69(9), 847–856. https://doi.org/10.1016/j.biopsych.2010.10.029

    Article  PubMed  Google Scholar 

  • Dziuk, M. A., Larson, J. G., Apostu, A., Mahone, E. M., Denckla, M. B., & Mostofsky, S. H. (2007). Dyspraxia in autism: Association with motor, social, and communicative deficits. Developmental Medicine & Child Neurology, 49(10), 734–739.

    Article  Google Scholar 

  • Edalatmanesh, M. A., Nikfarjam, H., Vafaee, F., & Moghadas, M. (2013). Increased hippocampal cell density and enhanced spatial memory in the valproic acid rat model of autism. Brain Research, 1526, 15–25.

    Article  PubMed  Google Scholar 

  • Ellenbroek, B. A., August, C., & Youn, J. (2016). Does prenatal valproate interact with a genetic reduction in the serotonin transporter? A rat study on anxiety and cognition. Frontiers in Neuroscience, 10, 424.

    Article  PubMed  PubMed Central  Google Scholar 

  • Emmons, E. B., De Corte, B. J., Kim, Y., Parker, K. L., Matell, M. S., & Narayanan, N. S. (2017). Rodent medial frontal control of temporal processing in the dorsomedial striatum. The Journal of Neuroscience, 37(36), 8718–8733. https://doi.org/10.1523/JNEUROSCI.1376-17.2017

    Article  PubMed  PubMed Central  Google Scholar 

  • Ergaz, Z., Weinstein-Fudim, L., & Ornoy, A. (2016). Genetic and non-genetic animal models for autism spectrum disorders (ASD). Reproductive Toxicology, 64, 116–140.

    Article  PubMed  Google Scholar 

  • Falter, C. M., Noreika, V., Wearden, J. H., & Bailey, A. J. (2012). More consistent, yet less sensitive: Interval timing in autism spectrum disorders. Quarterly Journal of Experimental Psychology, 65(11), 2093–2107. https://doi.org/10.1080/17470218.2012.690770

    Article  Google Scholar 

  • Fatemi, S. H., Aldinger, K. A., Ashwood, P., Bauman, M. L., Blaha, C. D., Blatt, G. J., et al. (2012). Consensus paper: Pathological role of the cerebellum in autism. Cerebellum (london, England), 11(3), 777–807. https://doi.org/10.1007/s12311-012-0355-9

    Article  Google Scholar 

  • Favre, M. R., Barkat, T. R., Lamendola, D., Khazen, G., Markram, H., & Markram, K. (2013). General developmental health in the VPA-rat model of autism. Frontiers in Behavioral Neuroscience, 7, 88. https://doi.org/10.3389/fnbeh.2013.00088/full

    Article  PubMed  PubMed Central  Google Scholar 

  • Fontes-Dutra, M., Nunes, G. D., Santos-Terra, J., Souza-Nunes, W., Bauer-Negrini, G., Hirsch, M. M., et al. (2019). Abnormal empathy-like pro-social behaviour in the valproic acid model of autism spectrum disorder. Behavioural Brain Research, 364, 11–18.

    Article  PubMed  Google Scholar 

  • Fox, A. E., & Kyonka, E. G. E. (2013). Pigeon responding in fixed-interval and response-initiated fixed-interval schedules of reinforcement. Journal of the Experimental Analysis of Behavior, 100(2), 187–197. https://doi.org/10.1002/jeab.38

    Article  PubMed  Google Scholar 

  • Fox, A. E., & Kyonka, E. G. (2015). Timing in response-initiated fixed intervals. Journal of the Experimental Analysis of Behavior, 103(2), 375–392. https://doi.org/10.1002/jeab.120

    Article  PubMed  Google Scholar 

  • Fox, A. E., & Kyonka, E. G. E. (2016). Effects of signaling on temporal control of behavior in response-initiated fixed intervals. Journal of the Experimental Analysis of Behavior, 106, 210–224.

    Article  PubMed  Google Scholar 

  • Fox, A. E., Prue, K. E., & Kyonka, E. G. (2016). What is timed in a fixed-interval temporal bisection procedure? Learning & Behavior, 44(4), 366–377.

    Article  Google Scholar 

  • Fox, A. E., Caramia, S. R., Haskell, M. M., Ramey, A. L., & Singha, D. (2017). Stimulus control in two rodent models of attention-deficit/hyperactivity disorder. Behavioural Processes, 135, 16–24.

    Article  PubMed  Google Scholar 

  • Fox, A. E., Visser, E. J., & Nicholson, A. M. (2019). Interventions aimed at changing impulsive choice in rats: Effects of immediate and relatively long delay to reward training. Behavioural Processes, 158, 126–136.

    Article  PubMed  Google Scholar 

  • Friedman, S. D., Shaw, D. W., Artru, A. A., Dawson, G., Petropoulos, H., & Dager, S. R. (2006). Gray and white matter brain chemistry in young children with autism. Archives of General Psychiatry, 63(7), 786–794.

    Article  PubMed  Google Scholar 

  • Fukuchi, M., Nii, T., Ishimaru, N., Minamino, A., Hara, D., Takasaki, I., et al. (2009). Valproic acid induces up- or down-regulation of gene expression responsible for the neuronal excitation and inhibition in rat cortical neurons through its epigenetic actions. Neuroscience Research, 65(1), 35–43. https://doi.org/10.1016/j.neures.2009.05.002

    Article  PubMed  Google Scholar 

  • Gadad, B. S., Hewitson, L., Young, K. A., & German, D. C. (2013). Neuropathology and animal models of autism: Genetic and environmental factors. Autism Research and Treatment. https://doi.org/10.1155/2013/731935

    Article  PubMed  PubMed Central  Google Scholar 

  • Gao, J., Wu, H., Cao, Y., Liang, S., Sun, C., Wang, P., et al. (2016). Maternal DHA supplementation protects rat offspring against impairment of learning and memory following prenatal exposure to valproic acid. The Journal of Nutritional Biochemistry, 35, 87–95.

    Article  PubMed  Google Scholar 

  • Gogolla, N., Leblanc, J. J., Quast, K. B., Sudhof, T. C., Fagiolini, M., & Hensch, T. K. (2009). Common circuit defect of excitatory-inhibitory balance in mouse models of autism. Journal of Neurodevelopmental Disorders, 1(2), 172–181. https://doi.org/10.1007/s11689-009-9023-x

    Article  PubMed  PubMed Central  Google Scholar 

  • Guilhardi, P., & Church, R. M. (2005). Dynamics of temporal discrimination. Learning and Behavior, 33, 399–416.

    Article  PubMed  Google Scholar 

  • Habib, A., Harris, L., Pollick, F., & Melville, C. (2019). A meta-analysis of working memory in individuals with autism spectrum disorders. PLoS ONE, 14(4), e0216198.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hamilton, P. J., Campbell, N. G., Sharma, S., Erreger, K., Herborg Hansen, F., Saunders, C., et al. (2013). De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder. Molecular Psychiatry, 18(12), 1315–1323. https://doi.org/10.1038/mp.2013.102

    Article  PubMed  PubMed Central  Google Scholar 

  • Haznedar, M. M., Buchsbaum, M. S., Hazlett, E. A., LiCalzi, E. M., Cartwright, C., & Hollander, E. (2006). Volumetric analysis and three-dimensional glucose metabolic mapping of the striatum and thalamus in patients with autism spectrum disorders. The American Journal of Psychiatry, 163(7), 1252–1263.

    Article  PubMed  Google Scholar 

  • Heilbronner, S. R., & Meck, W. H. (2014). Dissociations between interval timing and intertemporal choice following administration of fluoxetine, cocaine, or methamphetamine. Behavioural Processes, 101, 123–134. https://doi.org/10.1016/j.beproc.2013.09.013

    Article  PubMed  Google Scholar 

  • Hertz-Picciotto, I., Schmidt, R. J., & Krakowiak, P. (2018). Understanding environmental contributions to autism: Causal concepts and the state of science. Autism Research, 11(4), 554–586.

    Article  PubMed  Google Scholar 

  • Isaksson, S., Salomäki, S., Tuominen, J., Arstila, V., Falter-Wagner, C. M., & Noreika, V. (2018). Is there a generalized timing impairment in autism spectrum disorders across time scales and paradigms? Journal of Psychiatric Research, 99, 111–121.

    Article  PubMed  Google Scholar 

  • Juybari, K. B., Sepehri, G., Meymandi, M. S., Shahrbabaki, S. S. V., Moslemizadeh, A., Saeedi, N., et al. (2020). Sex dependent alterations of resveratrol on social behaviors and nociceptive reactivity in VPA-induced autistic-like model in rats. Neurotoxicology and Teratology, 81, 106905.

    Article  PubMed  Google Scholar 

  • Kaiser, D. H. (2008). The proportion of fixed interval trials to probe trials affects acquisition of the peak procedure fixed interval timing task. Behavioural Processes, 77(1), 100–108.

    Article  PubMed  Google Scholar 

  • Kemper, T. L., & Bauman, M. (1998). Neuropathology of infantile autism. Journal of Neuropathology and Experimental Neurology, 57(7), 645–652. https://doi.org/10.1097/00005072-199807000-00001

    Article  PubMed  Google Scholar 

  • Kerr, D. M., Downey, L., Conboy, M., Finn, D. P., & Roche, M. (2013). Alterations in the endocannabinoid system in the rat valproic acid model of autism. Behavioural Brain Research, 249, 124–132. https://doi.org/10.1016/j.bbr.2013.04.043

    Article  PubMed  Google Scholar 

  • Kim, J. W., Seung, H., Kwon, K. J., Ko, M. J., Lee, E. J., Oh, H. A., et al. (2014). Subchronic treatment of donepezil rescues impaired social, hyperactive, and stereotypic behavior in valproic acid-induced animal model of autism. PLoS ONE, 9(8), e104927. https://doi.org/10.1371/journal.pone.0104927

    Article  PubMed  PubMed Central  Google Scholar 

  • Kim, K. C., Choi, C. S., Kim, J., Han, S., Cheong, J. H., Ryu, J. H., & Shin, C. Y. (2016). MeCP2 modulates sex differences in the postsynaptic development of the valproate animal model of autism. Molecular Neurobiology, 53(1), 40–56.

    Article  PubMed  Google Scholar 

  • Kim, K. C., Kim, P., Go, H. S., Choi, C. S., Park, J. H., Kim, H. J., et al. (2013). Male-specific alteration in excitatory post-synaptic development and social interaction in pre-natal valproic acid exposure model of autism spectrum disorder. Journal of Neurochemistry, 124(6), 832–843.

    Article  PubMed  Google Scholar 

  • Kim, K. C., Kim, P., Go, H. S., Choi, C. S., Yang, S., Cheong, J. H., et al. (2011). The critical period of valproate exposure to induce autistic symptoms in Sprague-Dawley rats. Toxicology Letters, 201(2), 137–142. https://doi.org/10.1016/j.toxlet.2010.12.018

    Article  PubMed  Google Scholar 

  • Knopf, A. (2018). Autism rates increase slightly: CDC. The Brown University Child and Adolescent Behavior Letter, 34(6), 4–5.

    Article  Google Scholar 

  • Kuo, H. Y., & Liu, F. C. (2017). Valproic acid induces aberrant development of striatal compartments and corticostriatal pathways in a mouse model of autism spectrum disorder. FASEB Journal, 31(10), 4458–4471. https://doi.org/10.1096/fj.201700054R

    Article  PubMed  Google Scholar 

  • Lambrechts, A., Falter-Wagner, C. M., & van Wassenhove, V. (2018). Diminished neural resources allocation to time processing in autism spectrum disorders. NeuroImage: Clinical, 17, 124–136.

    Article  Google Scholar 

  • Langen, M., Leemans, A., Johnston, P., Ecker, C., Daly, E., Murphy, C. M., et al. (2012). Fronto-striatal circuitry and inhibitory control in autism: Findings from diffusion tensor imaging tractography. Cortex: A Journal Devoted to the Study of the Nervous System and Behavior, 48(2), 183–193. https://doi.org/10.1016/j.cortex.2011.05.018

    Article  Google Scholar 

  • Lauber, E., Filice, F., & Schwaller, B. (2016). Prenatal valproate exposure differentially affects parvalbumin-expressing neurons and related circuits in the cortex and striatum of mice. Frontiers in Molecular Neuroscience, 9, 150. https://doi.org/10.3389/fnmol.2016.00150

    Article  PubMed  PubMed Central  Google Scholar 

  • Lawson, W. (2001). Understanding and working with the spectrum of autism: An insider’s view. Jessica Kingsley Publishers.

    Google Scholar 

  • Leigh, J. P., & Du, J. (2015). Brief report: Forecasting the economic burden of autism in 2015 and 2025 in the united states. Journal of Autism and Developmental Disorders, 45(12), 4135–4139.

    Article  PubMed  Google Scholar 

  • Lewis, G. J., Shakeshaft, N. G., & Plomin, R. (2018). Face identity recognition and the social difficulties component of the autism-like phenotype: Evidence for phenotypic and genetic links. Journal of Autism and Developmental Disorders, 48(8), 2758–2765.

    Article  PubMed  PubMed Central  Google Scholar 

  • Mabunga, D. F. N., Gonzales, E. L. T., Kim, J., Kim, K. C., & Shin, C. Y. (2015). Exploring the validity of valproic acid animal model of autism. Experimental Neurobiology, 24(4), 285–300.

    Article  PubMed  PubMed Central  Google Scholar 

  • MacDonald, M., Lord, C., & Ulrich, D. A. (2014). Motor skills and calibrated autism severity in young children with autism spectrum disorder. Adapted Physical Activity Quarterly, 31(2), 95–105.

    Article  PubMed  Google Scholar 

  • Macdonald, C. J., Cheng, R., & Meck, W. H. (2012). Acquisition of “start” and “stop” response thresholds in peak-interval timing is differentially sensitive to protein synthesis inhibition in the dorsal and ventral striatum. Frontiers in Integrative Neuroscience, 6, 10.

    Article  PubMed  PubMed Central  Google Scholar 

  • Main, S. L., & Kulesza, R. J. (2017). Repeated prenatal exposure to valproic acid results in cerebellar hypoplasia and ataxia. Neuroscience, 340, 34–47.

    Article  PubMed  Google Scholar 

  • Malapani, C., Dubois, B., Rancurel, G., & Gibbon, J. (1998). Cerebellar dysfunctions of temporal processing in the seconds range in humans. NeuroReport, 9(17), 3907–3912.

    Article  PubMed  Google Scholar 

  • Marinho, V., Oliveira, T., Rocha, K., Ribeiro, J., Magalhaes, F., Bento, T., et al. (2018). The dopaminergic system dynamic in the time perception: A review of the evidence. The International Journal of Neuroscience, 128(3), 262–282. https://doi.org/10.1080/00207454.2017.1385614

    Article  PubMed  Google Scholar 

  • Markram, K., Rinaldi, T., La Mendola, D., Sandi, C., & Markram, H. (2008). Abnormal fear conditioning and amygdala processing in an animal model of autism. Neuropsychopharmacology, 33(4), 901–912. https://doi.org/10.1038/sj.npp.1301453

    Article  PubMed  Google Scholar 

  • Martin, J. S., Poirier, M., & Bowler, D. M. (2010). Brief report: Impaired temporal reproduction performance in adults with autism spectrum disorder. Journal of Autism and Developmental Disorders, 40(5), 640–646. https://doi.org/10.1007/s10803-009-0904-3

    Article  PubMed  Google Scholar 

  • Meck, W. H. (2006a). Neuroanatomical localization of an internal clock: A functional link between mesolimbic, nigrostriatal, and mesocortical dopaminergic systems. Brain Research, 1109(1), 93–107.

    Article  PubMed  Google Scholar 

  • Meck, W. H. (2006b). Temporal memory in mature and aged rats is sensitive to choline acetyltransferase inhibition. Brain Research, 1108(1), 168–175.

    Article  PubMed  Google Scholar 

  • Moore, S. J., Turnpenny, P., Quinn, A., Glover, S., Lloyd, D. J., Montgomery, T., & Dean, J. (2000). A clinical study of 57 children with fetal anticonvulsant syndromes. Journal of Medical Genetics, 37(7), 489–497.

    Article  PubMed  PubMed Central  Google Scholar 

  • Motanis, H., Seay, M. J., & Buonomano, D. V. (2018). Short-term synaptic plasticity as a mechanism for sensory timing. Trends in Neurosciences, 41(10), 701–711.

    Article  PubMed  PubMed Central  Google Scholar 

  • Muller, C. L., Anacker, A. M. J., & Veenstra-Vanderweele, J. (2015). The serotonin system in autism spectrum disorder: From biomarker to animal models. Neuroscience, 321, 24–41. https://doi.org/10.1016/j.neuroscience.2015.11.010

    Article  PubMed  Google Scholar 

  • Mychasiuk, R., Richards, S., Nakahashi, A., Kolb, B., & Gibb, R. (2012). Effects of rat prenatal exposure to valproic acid on behaviour and neuro-anatomy. Developmental Neuroscience, 34(2–3), 268–276. https://doi.org/10.1159/000341786

    Article  PubMed  Google Scholar 

  • Narayanan, N. S., Land, B. B., Solder, J. E., Deisseroth, K., & DiLeone, R. J. (2012). Prefrontal D1 dopamine signaling is required for temporal control. Proceedings of the National Academy of Sciences of the United States of America, 109(50), 20726–20731. https://doi.org/10.1073/pnas.1211258109

    Article  PubMed  PubMed Central  Google Scholar 

  • Nelson, S. B., & Valakh, V. (2015). Excitatory/inhibitory balance and circuit homeostasis in autism spectrum disorders. Neuron, 87(4), 684–698. https://doi.org/10.1016/j.neuron.2015.07.033

    Article  PubMed  PubMed Central  Google Scholar 

  • Olexova, L., Stefanik, P., & Krskova, L. (2016). Increased anxiety-like behaviour and altered GABAergic system in the amygdala and cerebellum of VPA rats—An animal model of autism. Neuroscience Letters, 629, 9–14.

    Article  PubMed  Google Scholar 

  • Petter, E. A., Lusk, N. A., Hesslow, G., & Meck, W. H. (2016). Interactive roles of the cerebellum and striatum in sub-second and supra-second timing: Support for an initiation, continuation, adjustment, and termination (ICAT) model of temporal processing. Neuroscience and Biobehavioral Reviews, 71, 739–755.

    Article  PubMed  Google Scholar 

  • R Core Team. (2019). R: A language and environment for statistical computing. R Core Team.

    Google Scholar 

  • Ranger, P., & Ellenbroek, B. A. (2016). Perinatal influences of valproate on brain and behaviour: An animal model for autism. Current Topics in Behavioral Neurosciences, 29, 363–386. https://doi.org/10.1007/7854_2015_404

    Article  PubMed  Google Scholar 

  • Reynard, J. (2011). The impact of environmental enrichment on neurogenesis in an animal model of autism Available from Dissertations & Theses Europe Full Text: Science & Technology. Retrieved from https://search.proquest.com/docview/1238010355

  • Rogge, N., & Janssen, J. (2019). The economic costs of autism spectrum disorder: A literature review. Journal of Autism and Developmental Disorders, 49, 2873.

    Article  PubMed  Google Scholar 

  • Rubenstein, J. L., & Merzenich, M. M. (2003). Model of autism: Increased ratio of excitation/inhibition in key neural systems. Genes, Brain, and Behavior, 2(5), 255–267.

    Article  PubMed  PubMed Central  Google Scholar 

  • Sathyanesan, A., Zhou, J., Scafidi, J., Heck, D. H., Sillitoe, R. V., & Gallo, V. (2019). Emerging connections between cerebellar development, behaviour and complex brain disorders. Nature Reviews. Neuroscience, 20(5), 298–313. https://doi.org/10.1038/s41583-019-0152-2

    Article  PubMed  PubMed Central  Google Scholar 

  • Schneider, T., & Przewlocki, R. (2005). Behavioral alterations in rats prenatally exposed to valproic acid: Animal model of autism. Neuropsychopharmacology, 30(1), 80–89. https://doi.org/10.1038/sj.npp.1300518

    Article  PubMed  Google Scholar 

  • Schneider, T., Roman, A., Basta-Kaim, A., Kubera, M., Budziszewska, B., Schneider, K., & Przewłocki, R. (2008). Gender-specific behavioral and immunological alterations in an animal model of autism induced by prenatal exposure to valproic acid. Psychoneuroendocrinology, 33(6), 728–740.

    Article  PubMed  Google Scholar 

  • Schneider, T., Turczak, J., & Przewlocki, R. (2006). Environmental enrichment reverses behavioral alterations in rats prenatally exposed to valproic acid: Issues for a therapeutic approach in autism. Neuropsychopharmacology, 31(1), 36–46. https://doi.org/10.1038/sj.npp.1300767

    Article  PubMed  Google Scholar 

  • Schuck, R. K., Flores, R. E., & Fung, L. K. (2019). Brief report: Sex/gender differences in symptomology and camouflaging in adults with autism spectrum disorder. Journal of Autism and Developmental Disorders, 49(6), 2597–2604.

    Article  PubMed  PubMed Central  Google Scholar 

  • Simonoff, E., Pickles, A., Charman, T., Chandler, S., Loucas, T., & Baird, G. (2008). Psychiatric disorders in children with autism spectrum disorders: Prevalence, comorbidity, and associated factors in a population-derived sample. Journal of the American Academy of Child & Adolescent Psychiatry, 47(8), 921–929.

    Article  Google Scholar 

  • Soares, S., Atallah, B. V., & Paton, J. J. (2016). Midbrain dopamine neurons control judgment of time. Science (new York, n.y.), 354(6317), 1273–1277.

    Article  Google Scholar 

  • Stoodley, C. J. (2016). The cerebellum and neurodevelopmental disorders. Cerebellum (london, England), 15(1), 34–37. https://doi.org/10.1007/s12311-015-0715-3

    Article  Google Scholar 

  • Tosun, T., Gür, E., & Balcı, F. (2016). Mice plan decision strategies based on previously learned time intervals, locations, and probabilities. Proceedings of the National Academy of Sciences, 113(3), 787–792. https://doi.org/10.1073/pnas.1518316113

    Article  Google Scholar 

  • Underwood, J. F., Kendall, K. M., Berrett, J., Anney, R., Van Den Bree, M., & Hall, J. (2018). ASD diagnosis in adults: Phenotype and genotype findings from a clinically-derived cohort. bioRxiv, 215, 647.

    Google Scholar 

  • Vogel, D., Falter-Wagner, C. M., Schoofs, T., Krämer, K., Kupke, C., & Vogeley, K. (2019). Interrupted time experience in autism spectrum disorder: Empirical evidence from content analysis. Journal of Autism and Developmental Disorders, 49(1), 22–33.

    Article  PubMed  Google Scholar 

  • Wang, R., Tan, J., Guo, J., Zheng, Y., Han, Q., So, K. F., et al. (2018). Aberrant development and synaptic transmission of cerebellar cortex in a VPA induced mouse autism model. Frontiers in Cellular Neuroscience, 12, 500. https://doi.org/10.3389/fncel.2018.00500

    Article  PubMed  PubMed Central  Google Scholar 

  • Warrier, V., & Baron-Cohen, S. (2018). Genetic contribution to ‘theory of mind’in adolescence. Scientific Reports, 8(1), 3465.

    Article  PubMed  PubMed Central  Google Scholar 

  • Williams, G., King, J., Cunningham, M., Stephan, M., Kerr, B., & Hersh, J. H. (2001). Fetal valproate syndrome and autism: Additional evidence of an association. Developmental Medicine and Child Neurology, 43(3), 202–206.

    Article  PubMed  Google Scholar 

  • Wilson, C. E., Murphy, C. M., McAlonan, G., Robertson, D. M., Spain, D., Hayward, H., et al. (2016). Does sex influence the diagnostic evaluation of autism spectrum disorder in adults? Autism, 20(7), 808–819.

    Article  PubMed  PubMed Central  Google Scholar 

  • Wiśniowiecka-Kowalnik, B., & Nowakowska, B. A. (2019). Genetics and epigenetics of autism spectrum disorder—Current evidence in the field. Journal of Applied Genetics, 60(1), 37–47.

    Article  PubMed  PubMed Central  Google Scholar 

  • Wittmann, M., Carter, O., Hasler, F., Cahn, B. R., Grimberg, U., Spring, P., et al. (2007). Effects of psilocybin on time perception and temporal control of behaviour in humans. Journal of Psychopharmacology (Oxford, England), 21(1), 50–64. https://doi.org/10.1177/0269881106065859

    Article  Google Scholar 

  • Wu, H. F., Chen, Y. J., Chu, M. C., Hsu, Y. T., Lu, T. Y., Chen, I. T., et al. (2018). Deep brain stimulation modified autism-like deficits via the serotonin system in a valproic acid-induced rat model. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms19092840

    Article  PubMed  PubMed Central  Google Scholar 

  • Young, M. E. (2017). Discounting: A practical guide to multilevel analysis of indifference data. Journal of the Experimental Analysis of Behavior, 108(1), 97–112.

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors thank the following undergraduate students at St. Lawrence University for assistance with data collection, analysis, and presentation of results at scholarly conferences: Elina Breton, Rebecca Briggs, Meghan Demers-Peel, Laura Goldhar, Joe Licata, Emma Morgan, Alycia Nicholson, Sejla Palic, Joe Parise, Cole Poulin, Alea Robinson, Sumra Sikandar, Depika Singha, Emily Viehl, and Emma Visser. We also thank St. Lawrence University for funding this research.

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    William E. DeCoteau & Adam E. Fox

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  1. William E. DeCoteau
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Both authors contributed to the study conceptualization and design, interpretation of data, drafting the manuscript, and approval of the final manuscript. AEF collected and analyzed operant chamber task data. WED collected and analyzed the other behavioral task data.

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Correspondence to Adam E. Fox.

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DeCoteau, W.E., Fox, A.E. Timing and Intertemporal Choice Behavior in the Valproic Acid Rat Model of Autism Spectrum Disorder. J Autism Dev Disord 52, 2414–2429 (2022). https://doi.org/10.1007/s10803-021-05129-y

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