Cortical Norepinephrine and Adolescent Executive Function

皮质去甲肾上腺素和青少年执行功能

• 批准号: 7772810
• 负责人: Jill Ann McGaughy
• 金额: $ 22.08万
• 依托单位: UNIVERSITY OF NEW HAMPSHIRE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-14 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7772810
• 关键词: Acute; Adolescence; Adolescent; Adult; Affect; Affective; Age; Animals; Attention; Attention deficit hyperactivity disorder; Attentional deficit; Attenuated; Behavior; Behavioral; Bipolar Disorder; Brain; Chemicals; Cognition; Data; Deafferentation procedure; Development; Disease; Dopamine; Dose; Education; Extracellular Space; Fiber; Figs - dietary; Functional disorder; Future; Growth; Human; Impairment; Laboratories; Lateral; Learning; Lesion; Life; Mediating; Mental Depression; Mental disorders; Methylphenidate; Norepinephrine; Performance; Pharmaceutical Preparations; Pilot Projects; Prefrontal Cortex; Primates; Rattus; Relative (related person); Reversal Learning; Rewards; Rodent; Role; Schizophrenia; Staging; Stimulus; Synapses; System; Testing; Time; Training; Translational Research; Varicosity; Work; atomoxetine; base; density; design; dopamine transporter; executive function; experience; extracellular; frontal lobe; human data; improved; insight; mind control; neurochemistry; neuropsychiatry; noradrenaline transporter; noradrenergic; novel; public health relevance; research study; response; safety education; young adult

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): 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.