Interstimulus interval (ISI) discrimination of the conditioned eyeblink response in a rodent model of autism

Department of Psychology, University of Delaware, Newark, DE 19716, USA.
Behavioural brain research (Impact Factor: 3.03). 11/2008; 196(2):297-303. DOI: 10.1016/j.bbr.2008.09.020
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Rats exposed to valproic acid (VPA) on gestational day 12 (GD12) have been advanced as a rodent model of autism [Arndt TL, Stodgell, Rodier PM. The teratology of autism. Int J Dev Neurosci 2005;23: 189-99.]. These rats show cerebellar anomalies and alterations in eyeblink conditioning that are associated with autism. Autistic humans and VPA-exposed rats show normal responses to conditioned and unconditioned stimuli, but they show marked differences from comparison groups in acquisition, magnitude, and timing of the conditioned response (CR). This study examined VPA-induced eyeblink CR timing differences by training rats on an interstimulus interval (ISI) discrimination task, in which two distinct conditioned stimuli (CS; tone and light) are paired with the same unconditioned stimulus (US; periocular shock) at two distinct CS-US intervals. Previous findings suggest that this task would produce abnormally large and prematurely timed CRs for VPA-exposed rats relative to controls. Adult male Long-Evans rats that were exposed to either VPA or saline on GD 12.5 were trained on an ISI discrimination task [Brown KL, Pagani JH, Stanton ME. The ontogeny of interstimulus interval (ISI) discrimination of the conditioned eyeblink response in rats. Behav Neurosci 2006;120: 1057-70.]. In support of earlier findings, we observed early acquisition and enhanced magnitude of the CR in VPA rats compared with controls on long CS trials. VPA rats also showed prematurely timed CRs to long- CS trials, but not to short- CS trials. The ISI discrimination procedure used in the current study reveals differential timed responses in this animal model of autism not previously seen.

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Available from: Nathen J Murawski, Apr 10, 2015
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    • "The main finding is that only 9% (3/34) of studies correctly identified the experimental unit and thus made valid inferences from the data. One study used a nested design [44], the second mentioned that litter was the experimental unit [45], and the third used one animal from each litter, thus bypassing the issue [46]. In fourteen studies (41%) it was not possible to determine the number of dams that were used (i.e. the sample size) and in four studies (12%) the number of offspring used were not indicated. "
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    ABSTRACT: Background Animals from the same litter are often more alike compared with animals from different litters. This litter-to-litter variation, or “litter effects”, can influence the results in addition to the experimental factors of interest. Furthermore, sometimes an experimental treatment can only be applied to whole litters rather than to individual offspring. An example is the valproic acid (VPA) model of autism, where VPA is administered to pregnant females thereby inducing the disease phenotype in the offspring. With this type of experiment the sample size is the number of litters and not the total number of offspring. If such experiments are not appropriately designed and analysed, the results can be severely biased as well as extremely underpowered. Results A review of the VPA literature showed that only 9% (3/34) of studies correctly determined that the experimental unit (n) was the litter and therefore made valid statistical inferences. In addition, litter effects accounted for up to 61% (p <0.001) of the variation in behavioural outcomes, which was larger than the treatment effects. In addition, few studies reported using randomisation (12%) or blinding (18%), and none indicated that a sample size calculation or power analysis had been conducted. Conclusions Litter effects are common, large, and ignoring them can make replication of findings difficult and can contribute to the low rate of translating preclinical in vivo studies into successful therapies. Only a minority of studies reported using rigorous experimental methods, which is consistent with much of the preclinical in vivo literature.
    BMC Neuroscience 03/2013; 14(1):37. DOI:10.1186/1471-2202-14-37 · 2.67 Impact Factor
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    • "However, it is still not clear which period of valproate exposure is critical to induce autism-like behaviors. A number of different time points have been used to treat valproic acid on pregnant rats from embryonic day 9 (Dufour- Rainfray et al., 2010; Kuwagata et al., 2009; Miyazaki et al., 2005; Nakasato et al., 2008; Narita et al., 2002, 2010; Tsujino et al., 2007), 11.5 (Rinaldi et al., 2007, 2008a,b), 12 (Murawski et al., 2009; Stanton et al., 2007) or 12.5 (Dufour-Rainfray et al., 2010; Markram et al., 2008; Schneider and Przewlocki, 2005; Schneider et al., 2006, 2007, 2008). "
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    ABSTRACT: Prenatal exposure to valproic acid (VPA) induces neural tube defects and impairment in social behaviors related to autistic spectrum disorder in newborns, which make it a useful animal model of autism. In this study, we compared the effects of different time window of prenatal valproic acid exposure for inducing the altered social behaviors relevant to autism from embryonic day 7 to embryonic day 15 in Sprague-Dawley rats to determine the critical periods for the impairment. Compared to E7, E9.5 and E15 exposure, VPA exposure at E12 showed most significant changes in behaviors over control animals with reduced sociability and social preference. E9.5 exposure to valproic acid showed strong reproductive toxicity including decrease in the number of live birth. In general, exposure at E15 showed only marginal effects on reproduction and social behaviors. Finally, VPA-exposed rats at E12 were more sensitive to electric shock than VPA-exposed rats at any other periods. These results suggested that E12 is the critical period in rats when valproate exposure has prominent effects for inducing the altered social behavior similar to human autistic behavior.
    Toxicology Letters 03/2011; 201(2):137-42. DOI:10.1016/j.toxlet.2010.12.018 · 3.26 Impact Factor
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    • "In addition, a variety of rodent models, designed to test for the effects of specific environmental or genetic manipulations on the development of ASD endophenotypes, coincidentally include altered serotonergic homestasis. One of the most longstanding ASD models, gestational exposure to valproic acid (VPA), shows altered development of afferent serotonergic innervation to the forebrain, along with behavioral manifestations such as increased stereotopies, altered sensory responsiveness and altered eye-blink reflexes ( Miyazaki et al. , 2005 ; Schneider and Przewlocki, 2005 ; Stanton et al. , 2007 ; Murawski et al. , 2009 "
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    ABSTRACT: This chapter provides a review of basic research as well as clinical literature in support of the idea that altered serotonergic homeostasis is prominently involved in the pathogenesis of Autism Spectrum Disorder (ASD). Animal models of cortical serotonergic effects in development and plasticity are reviewed and juxtaposed to neuropathological and clinical findings in ASD. Based on the emerging conceptualization of ASD as a developmental disorder of cortical connectivity, we present a hypothesis about the role of serotonin in altered cortical network formation, as a substrate for altered cognitive function. Investigations into the role of serotonin in immune regulation, and particularly neuroimmune regulation, support a role for serotonin in a variety of homeostatic functions that may be impaired in ASD and can contribute to altered brain development and function. A unified hypothesis such as proposed here could provide an avenue towards early identification of biomarkers as well as therapeutic strategies. We hope to provide an impetus for new investigations into a ‘serotonergic hypothesis’ for ASD.
    01/2010; Elsevier., ISBN: 978-0-12-374634-4
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