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。具体地说，我们将探索皮质去甲肾上腺素系统发育变化的功能意义，以及这些变化如何影响注意力的个体发生。此外，我们将调查提出的假设，即去甲肾上腺素转运体(NET)的发育变化对包括情感和注意力定势转移在内的特定形式的执行功能至关重要。我们的实验室和其他人已经证明，去甲肾上腺素能去传入大脑皮层会导致注意定势转移的损害。这些损害可以通过给予托莫西汀来减轻，托莫西汀是一种选择性地阻断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还表明，去甲肾上腺素能去传入眼眶前额叶皮质在逆转学习中产生的选择性损害比同一区域的5-羟色胺能障碍产生的更大。在初步研究中，我们发现青春期大鼠在注意定势转移和情感转移(反转学习)测试中的表现与成年大鼠在前额叶去甲肾上腺素能损伤后的表现相似。最近对前额叶皮质净密度的分析表明，去甲肾上腺素转运体(Net)，而不是多巴胺转运体(DAT)，在PND50大鼠的额叶皮质中的密度比PND25大鼠低得多。我们假设，年龄小于PND 50的较高密度的Net可以如此有效地将NE从细胞外空间中移除，从而产生该系统的功能低下，从而在幼年、青少年大鼠中产生类似于成年大鼠的行为，这些大鼠患有前额亚区去甲肾上腺素能损伤。在具体目标1中，我们将研究青春期早期和晚期以及青春期的执行功能。这将提供关于执行功能个体发育的新数据，包括情感和注意力定势转移，以确定青春期和成年大鼠不同表现的基础。我们推测，与PND 50大鼠相比，PND 40大鼠大脑皮层中Net的密度较高，将导致青春期幼鼠注意定势的转移效率较低。PND 40的大鼠眼眶前额叶皮质的净密度高于PND 50的密度，假设在测试较年轻的青春期大鼠的情感转移时，会产生较低的效率。在具体目标2中，我们将评估阻断Net的药物对高Net水平的青春期幼鼠表现的影响。如果网络阻断可以改变青少年的注意表现，使其与成人的注意表现相似，这将支持成人和青少年之间的注意差异是由于青春期早期和晚期前额叶皮质中网络密度的变化所致。这些研究将在评估青少年执行功能和前额叶去甲肾上腺素系统参与调节这些行为方面具有新颖性。 公共卫生相关性：执行功能包括对行为进行计划和排序、过滤不相关的信息、学习预测奖励已发生变化的偶发事件以及在以前不相关的刺激与当前学习相关时重新引导注意力。来自人类、灵长类动物和啮齿动物的数据表明，这些行为以及大脑中控制它们的部分仍在青少年和年轻人中发育。目前的应用旨在了解大脑中的化学递质如何对这种发育至关重要，为执行功能的正常和病理发展提供洞察，帮助改善正常青少年的教育，并改进损害执行功能的神经精神疾病的治疗。

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.