Discrimination learning and reversal of the conditioned eyeblink reflex in a rodent model of autism

Abstract

Offspring of rats exposed to valproic acid (VPA) on Gestational Day (GD) 12 have been advocated as a rodent model of autism because they show neuron loss in brainstem nuclei and the cerebellum resembling that seen in human autistic cases [20,37]. Studies of autistic children have reported alterations in acquisition of classical eyeblink conditioning [40] and in reversal of instrumental discrimination learning [9]. Acquisition of discriminative eyeblink conditioning depends on known brainstem-cerebellar circuitry whereas reversal depends on interactions of this circuitry with the hippocampus and prefrontal cortex. In order to explore behavioral parallels of the VPA rodent model with human autism, the present study exposed pregnant Long-Evans rats to 600 mg/kg VPA on GD12 [cf. 37] and tested their offspring from PND26-31 on discriminative eyeblink conditioning and reversal. VPA rats showed faster eyeblink conditioning, consistent with studies in autistic children [40]. This suggests that previously reported parallels between human autism and the VPA rodent model with respect to injury to brainstem-cerebellar circuitry [37] are accompanied by behavioral parallels when a conditioning task engaging this circuitry is used. VPA rats also showed impaired reversal learning, but this likely reflected "carry-over" of enhanced conditioning during acquisition rather than a reversal learning deficit like that seen in human autism. Further studies of eyeblink conditioning in human autism and in various animal models may help to identify the etiology of this developmental disorder. KeywordsEyeblink Conditioning; Gestational Valproate Exposure; Discrimination Reversal; Cerebellum; Hippocampus; Development The purpose of this article is to use a developmental rodent model of eyeblink conditioning to gather evidence bearing on the hypothesis that early gestational injury to the brainstem plays a role in the etiology of autism [3,37,39]. Evidence for this hypothesis arises from a disparate set of findings that show remarkable convergence [39]. The first clues came from reports of an association between autism and early gestational exposure to thalidomide and misoprostol [27]. Knowledge concerning the teratology of thalidomide permits inferences concerning the timing of thalidomide exposure based on the presence of craniofacial defects (ear anomolies). When thalidomide cases involving exposure specifically between 20-24 days post-conception were considered, autism occurred at a staggering rate (~30%, [39]). It was subsequently

The Cerebellum Is Involved in Reward-based Reversal Learning

“…The most remarkable finding in the present study was impaired reward-based reversal learning in the cerebellar lesion group, a deficit which has previously been documented in rodents with cerebellar damage [50]. The present data extend previous findings which related reward-based reversal learning to the ventral PFC [10] and the ventral [9] and dorsal striatum [8].…”

Pre-clinical models of neurodevelopmental disorders: focus on the cerebellum

“…Acquisition of discriminative eyeblink conditioning depends on the brainstem-cerebellar circuitry whereas reversal learning involves long-range interactions between the cerebellum and the hippocampus and prefrontal cortex. VPA exposed rats exhibited faster eyeblink conditioning, in line with the findings in autistic children (Stanton et al, 2007). In a series of cognitive tests, prenatally VPA-treated rats had changes in the delayed non-match-to-sample task, novel object recognition, activity box, and Whishaw tray reaching task.…”

Environmental Factors in the Aetiology of Autism – Lessons from Animals Prenatally Exposed to Valproic Acid

“…Those results confirm existence of similarities between the observed pattern of aberrations in VPA rats and features of disturbed behaviour in autistic patients. Noteworthy, VPA rats express a very specific pattern of aberration in eye-blink conditioning test (Murawski et al, 2009;Stanton et al, 2007), which is similar to that reported by Sears and colleagues (1994) in autistic patients, i.e., normal basic sensory and motor function, but exaggerated amplitude of conditioned blinks, and altered timing of conditioned blinks. One difference between children with autism and the VPA-exposed rats was that the animals did not display a higher rate of acquisition of conditioned responses.…”