Cortical Norepinephrine and Adolescent Executive Function

描述（由申请人提供）：我们将利用我们以前在注意力测试方面的经验来提供证据，证明青少年的执行功能与成年人的不同。具体来说，我们将探讨皮质去肾上腺素能系统发育变化的功能意义，以及这些变化如何影响注意的个体发生。此外，我们将研究提出的假设，即去甲肾上腺素转运蛋白（NET）的发育变化对特定形式的执行功能（包括情感和注意力集中转移）至关重要。我们的实验室和其他研究人员已经证明，前边缘皮层的去肾上腺素能性神经分化会对注意力转移造成损害。这些损伤可以通过使用托莫西汀来减轻，这是一种选择性阻断NET并增加细胞外去甲肾上腺素（NE）的药物。我们实验室最近的数据也表明，眶额皮质的去甲肾上腺素能神经传递障碍在逆向学习中产生的选择性损伤比在同一区域由血清素能功能障碍产生的损伤更大。在初步研究中，我们发现青春期大鼠在注意力集中转移和情感转移（反向学习）测试中的表现与前额叶去肾上腺素能损伤后的成年大鼠相似。最近对PND 50大鼠额叶皮质内去甲肾上腺素能转运体（NET）密度的分析表明，与PND25大鼠相比，PND 50大鼠额叶皮质内的去甲肾上腺素能转运体（NET）密度明显降低，而多巴胺转运体（DAT）密度不明显。我们假设，小于PND 50的年龄的NET密度较高，可以有效地将NE从细胞外空间移除，从而产生该系统的功能减退，从而在年轻的青春期大鼠中产生与前额叶亚区去肾上腺素能损伤的成年大鼠相似的行为。在具体目标1中，我们将研究青春期早期和晚期以及成年早期的执行功能。这将提供关于执行功能个体发生的新数据，包括情感和注意力设置转移，以确定青少年和成年大鼠差异表现的基础。我们假设，相对于PND 50大鼠，PND 40大鼠的前边缘皮层中NET的密度更高，将导致年轻的青春期大鼠的注意力集中转移效率较低。假设处于PND 40的大鼠眶额叶皮层的NET密度比处于PND 50的大鼠高，会在年轻的青春期大鼠的情感转换测试中产生较低的效率。在具体目标2中，我们将评估阻断NET的药物对具有高水平NET的年轻青春期大鼠的表现的影响。如果NET阻断可以改变青少年的注意力表现，使其与成年人的注意力表现相似，那么它将支持成年人和青少年之间的注意力差异是由于青春期早期和晚期前额叶皮层中NET密度的变化造成的假设。这些研究将是评估青少年执行功能和参与调解这些行为的前额叶去肾上腺素能系统的新颖。

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.