Fetal Alcohol Spectrum Disorder (FASD) is a leading cause of intellectual and developmental disabilities that continues to be a significant public health problem worldwide. An important feature of FASD is impairment of "executive function," an umbrella term for a range of prefrontal-cortex-dependent cognitive processes such as attention, working memory, conceptual set shifting, and inhibitory learning (Fryer et al., 2007;Mattson et al., 2011;Rasmussen, 2005). For example, children and adults with FASD are impaired on the Wisconsin Card Sorting Task, a well-known neuropsychological assessment of attentional set shifting and inhibitory control in humans (reviewed in Mattson et al., 2011). These emerging findings on executive function in FASD have stimulated some recent rodent model research showing that developmental alcohol exposure targets the prefrontal cortex (Hamilton, Whitcher &Klintsova, 2010;Otero et al;2012;Smith et al., 2012;Whitcher &Klintsova, 2008). However, the search for behavioral correlates of this prefrontal targeting in rodents has failed to use assessments that specifically measure prefrontal or executive function (Smith et al., 2012). To address this gap in current knowledge, this R03 Small Research Grant proposal seeks to determine whether a well characterized, widely accepted, and highly specific test of prefrontal executive function in rodents---the attentional set shifting task (ASST)---is impaired by developmental alcohol exposure. The proposal combines the PI's experience with a well-established rodent model of third-trimester equivalent alcohol exposure (e.g., Murawski &Stanton, 2010;Hamilton et al, 2011) with the Co-PI's experience with the attention set shifting task (Cain, Wasserman, Waterhouse &McGaughy, 2011;Newman &McGaughy, 2011). The proposal uses an alcohol exposure scenario that targets prefrontal cortex (Whitcher &Klintsova, 2008).
In Aim 1, male and female Long-Evans rats will either receive intubations of 5.25g/kg/day alcohol (EtOH), sham intubation (SI) or will be left undisturbed (UD) from Postnatal Days (PD) 4-9 and then tested on the ASST in adulthood (PD70-90).
In Aim 2, dose-response effects on adult ASST performance will be examined by comparing groups of male and female rats receiving 0 (SI), 2.75, 4, and 5.25 g/kg/day of alcohol on PD4-9. The ASST paradigm includes components---Discrimination, Reversal, Intradimensional Shift, and Extradimensional Shift---that each probe specific cognitive processes that depend on different prefrontal subregions in the rat. If successful, these experiments will lay the foundation for a future R01 proposal that will use attentional set shifting to study mechanisms and interventions related to impaired executive function in a rodent model of FASD that has direct translational application to the human disorder.
This R03 Small Research Grant application by Mark E. Stanton and Jill McGaughy requests support to gather feasibility data on a domain of prefrontal-dependent executive function---Attentional Set Shifting---in a rodent model of Fetal Alcohol Spectrum Disorder (FASD). FASD represents a range of adverse behavioral and neural effects of developmental alcohol exposure that remains a leading preventable cause of intellectual and developmental disabilities. Impairment of executive function is well established in human FASD but it has not yet been documented in rodent models. The research in this proposal will begin to address that gap in current knowledge. If successful, it will provide foundational data for a large proposal that will advance research on animal models of FASD in a manner that can facilitate the development of interventions in human populations that suffer from this disorder.