Jill McGaughy - US grants

DESCRIPTION (provided by applicant): We will utilize our previous experience in attentional testing to provide evidence of how the executive functions of adolescents differ from adults. Specifically, we will explore the functional significance of developmental changes in cortical noradrenergic systems and how these changes influence the ontogeny of attention. Moreover, we will investigate the proposed hypothesis that developmental changes in norepinephrine transporters (NET) are critical to specific forms of executive function including affective and attentional set shifts. Our laboratory and others have shown that noradrenergic deafferentation of the prelimbic cortex produces impairments in attentional set-shifting. These impairments can be attenuated by the administration of atomoxetine, a drug that selectively blocks NET and increases extracellular norepinephrine (NE). Recent data from our laboratory has also shown that noradrenergic deafferentation of orbitofrontal cortex produces selective impairments in reversal learning larger than those produced by serotonergic dysfunction in the same region. In pilot studies, we have found the performance of adolescent rats on tests of attentional set shifting and affective shifts (reversal learning) to be similar to adult rats after prefrontal, noradrenergic lesions. Recent analyses of NET density in the prefrontal cortex shows that noradrenergic transporter (NET), but not dopamine transporter (DAT), density is much lower in the frontal cortices of PND 50 than PND25 rats. We hypothesize the higher density of NET at ages younger than PND 50 removes NE from the extracellular space so efficiently that it produces a functional hypoactivity of this system thereby producing behavior in young, adolescent rats similar to that of adult rats with noradrenergic lesions of prefrontal subregions. In Specific Aim 1, we will investigate executive function at the early and late stages of adolescence as well as in young adulthood. This will provide novel data about the ontogeny of executive functions including affective and attentional set-shifting to determine the basis of the differential performance of adolescent and adult rats. We hypothesize that the higher densities of NET in the prelimbic cortex of PND 40 rats relative to PND 50 rats will result in less efficient shifts of attentional set in the younger adolescent rats. Higher densities of NET in orbitofrontal cortex in rats at PND 40 than PND 50 are hypothesized to produce less efficient performance in tests of affective shifts in the younger adolescent rats. In Specific Aim 2, we will assess the effects of drugs that block NET on the performance of young adolescent rats with high levels of NET. If NET blockade can alter adolescent attentional performance so that it is similar to that of adults, it will provide support for the hypothesis that attentional differences between adults and adolescents are due to changes in the densities of NET in prefrontal cortices between early and late adolescence. These studies will be novel in assessing adolescent executive function and the involvement of the prefrontal noradrenergic system in mediating these behaviors. PUBLIC HEALTH RELEVANCE: Executive functions include the ability to plan and sequence behavior, to filter irrelevant information, to learn contingencies that predict reward have changed and to redirect attention when previously irrelevant stimuli become relevant to current learning. Data from humans, primates and rodents suggest that these behaviors and the parts of the brain that control them are still developing in adolescents and young adults. The current application is designed to understand how chemical transmitters in the brain are critical to this development to provide insight into normal and pathological development of executive functions, to assist in improving education of normal adolescents and to improve treatment of neuropsychiatric diseases that impair executive functions.

DESCRIPTION (provided by applicant): 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.