The Role of Prenatal Hormone Exposure on Associative Learning in a Rat Model of Autism Spectrum Disorder

Abstract

Approximately 1 in 68 children are diagnosed with an autism spectrum disorder (ASD), and lifetime costs in the U.S. per child are estimated at $2.3 million. While the precise causes for abnormal brain development in ASD are not known, environmental contributions from endocrine disrupting chemicals (EDCs) – particularly androgens and estrogens - may play an adverse role. Prenatal hormone exposure (PHE) may affect hippocampal and cerebellar function, but the underlying mechanisms of disruption are not well-understood. In this study, we examined whether PHE affected two variations of eyeblink classical conditioning (ECC), each of which is mediated by the hippocampus (trace) or cerebellum (delay). Because neuron number is an important indicator of behavioral function, the possible link between changes in neuron number and alterations in associative learning were correlated. Pregnant Sprague-Dawley rats received daily injections of either dihydrotestosterone propionate (8 mg/kg), estradiol benzoate (50 µg/kg), or corn oil (vehicle) from embryonic days 15-19. Their offspring were tested as adults (postnatal day 90+) using trace or delay ECC. Neuron number was quantified using unbiased stereology within hippocampal cell layer CA1 (which supports trace ECC) and cerebellar regions that support delay ECC (interpositus nucleus and Purkinje cells). Preliminary results indicate altered learning in PHE rats. Learning was enhanced in animals that received trace ECC and impaired in those that received delay ECC, providing support for the idea that the hippocampus undergoes reorganization to mediate cellular activities that improve hippocampal function in humans with ASD (e.g., greater spatial reasoning) but at the cost of simple motor-related function served by the cerebellum. EDCs may produce organizational brain changes that underlie certain forms of ASD, as evidenced by neurobehavioral alterations in associative learning. Findings from this study may help elucidate the link between cellular changes and ASDs, so that treatments targeted at enhancing cellular function can be implemented.