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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21MH087921-01
Application #
7772810
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Rossi, Andrew
Project Start
2010-05-14
Project End
2012-02-28
Budget Start
2010-05-14
Budget End
2011-02-28
Support Year
1
Fiscal Year
2010
Total Cost
$220,805
Indirect Cost
Name
University of New Hampshire
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
111089470
City
Durham
State
NH
Country
United States
Zip Code
03824
Chu, Richard; Shumsky, Jed; Waterhouse, Barry D (2016) Differentiation of rodent behavioral phenotypes and methylphenidate action in sustained and flexible attention tasks. Brain Res 1641:306-19
Chandler, Daniel J (2016) Evidence for a specialized role of the locus coeruleus noradrenergic system in cortical circuitries and behavioral operations. Brain Res 1641:197-206
Bradshaw, Sarah E; Agster, Kara L; Waterhouse, Barry D et al. (2016) Age-related changes in prefrontal norepinephrine transporter density: The basis for improved cognitive flexibility after low doses of atomoxetine in adolescent rats. Brain Res 1641:245-57
Newman, Lori A; Creer, David J; McGaughy, Jill A (2015) Cognitive control and the anterior cingulate cortex: how conflicting stimuli affect attentional control in the rat. J Physiol Paris 109:95-103
Bhattacharya, Shevon E; Shumsky, Jed S; Waterhouse, Barry D (2015) Attention enhancing effects of methylphenidate are age-dependent. Exp Gerontol 61:1-7
Chandler, Daniel J; Lamperski, Carolyn S; Waterhouse, Barry D (2013) Identification and distribution of projections from monoaminergic and cholinergic nuclei to functionally differentiated subregions of prefrontal cortex. Brain Res 1522:38-58
Agster, Kara L; Mejias-Aponte, Carlos A; Clark, Brian D et al. (2013) Evidence for a regional specificity in the density and distribution of noradrenergic varicosities in rat cortex. J Comp Neurol 521:2195-207
Berridge, Craig W; Shumsky, Jed S; Andrzejewski, Matt E et al. (2012) Differential sensitivity to psychostimulants across prefrontal cognitive tasks: differential involvement of noradrenergic ?? - and ??-receptors. Biol Psychiatry 71:467-73
Newman, Lori A; McGaughy, Jill (2011) Adolescent rats show cognitive rigidity in a test of attentional set shifting. Dev Psychobiol 53:391-401
Newman, Lori A; McGaughy, Jill (2011) Attentional effects of lesions to the anterior cingulate cortex: how prior reinforcement influences distractibility. Behav Neurosci 125:360-71

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