Interstimulus interval (ISI) discrimination of the conditioned eyeblink response in a rodent model of autism
ABSTRACT 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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ABSTRACT: Autism spectrum disorders (ASD) is diagnosed in males at a much higher rate than females. For this reason, the majority of autism research has used male subjects exclusively. However; more recent studies using genetic sex as a factor find that the development of the male and female brain is differentially affected by ASD. That is, the natural sex-specific differences that exist between male and female brains lead to sexually dimorphic expressions of autism. Here we investigate the putative sexual dimorphism that exists in the deep cerebellar nuclei of male and female rats exposed to valproic acid (VPA) on embryological day 12.5. We find natural sex-specific differences in adult nucleus area, length, and estimated cell populations. Therefore VPA exposure during embryology creates some sex-specific deficits such as higher cell counts in the VPA males and lower cell counts in the VPA females. At the same time, some effects of VPA exposure occur regardless of sex. That is, smaller nucleus area and length lead to truncated nuclei in both VPA males and females. These deficits are more pronounced in the VPA males suggesting that genetic sex could play a role in teratogenic susceptibility to VPA. Taken together our results suggests that VPA exposure induces sexually dimorphic aberrations in morphological development along a mediolateral gradient at a discrete region of the hindbrain approximate to rhombomere (R) 1 and 2. Sex-specific disruption of the local and long-range projections emanating from this locus of susceptibility could offer a parsimonious explanation for the brain-wide neuroanatomical variance reported in males and females with ASD. Published by Elsevier Ltd.International Journal of Developmental Neuroscience 10/2014; 40C:15-23. DOI:10.1016/j.ijdevneu.2014.10.003 · 2.92 Impact Factor
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ABSTRACT: Autism is unique among other disorders in that acquisition of conditioned eyeblink responses is enhanced in children, occurring in a fraction of the trials required for control participants. The timing of learned responses is, however, atypical. Two animal models of autism display a similar phenotype. Researchers have hypothesized that these differences in conditioning reflect cerebellar abnormalities. The present study used computer simulations of the cerebellar cortex, including inhibition by the molecular layer interneurons, to more closely examine whether atypical cerebellar processing can account for faster conditioning in individuals with autism. In particular, the effects of inhibitory levels on delay eyeblink conditioning were simulated, as were the effects of learning-related synaptic changes at either parallel fibers or ascending branch synapses from granule cells to Purkinje cells. Results from these simulations predict that whether molecular layer inhibition results in an enhancement or an impairment of acquisition, or changes in timing, may depend on (1) the sources of inhibition, (2) the levels of inhibition, and (3) the locations of learning-related changes (parallel vs. ascending branch synapses). Overall, the simulations predict that a disruption in the balance or an overall increase of inhibition within the cerebellar cortex may contribute to atypical eyeblink conditioning in children with autism and in animal models of autism.Cognitive Affective & Behavioral Neuroscience 03/2014; DOI:10.3758/s13415-014-0263-1 · 3.87 Impact Factor
Recent Advances in Autism Spectrum Disorders - Volume I, Edited by Michael Fitzgerald, 03/2013: chapter Valproic Acid in Autism Spectrum Disorder: From an Environmental Risk Factor to a Reliable Animal Model: pages 143-163; INTECH.