Factors Regulating NE Transporter Localization in PFC

PFC 中 NE 转运蛋白定位的调节因素

• 批准号: 7331455
• 负责人: Susan R. Sesack
• 金额: $ 26万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-15 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7331455
• 关键词: Acute; Affect; Affective; Anatomy; Animals; Antidepressive Agents; Attention deficit hyperactivity disorder; Axon; Cell membrane; Cell surface; Characteristics; Chronic; Chronic stress; Cognitive; Complex; Cytoplasm; Diffusion; Disease; Documentation; Dopamine; Electrons; Enzymes; Event; Exhibits; Exposure to; Figs - dietary; Functional disorder; In Vitro; Knowledge; Lesion; Light; Localized; Membrane; Membrane Transport Proteins; Mental Depression; Mental disorders; Microscopic; Minority; Modeling; Neuromodulator; Neurons; Norepinephrine; Pathology; Pharmaceutical Preparations; Population; Positioning Attribute; Post-Traumatic Stress Disorders; Prefrontal Cortex; Range; Rattus; Recycling; Relative (related person); Role; Stimulus; Stress; Surface; System; Testing; Therapeutic; Tyrosine 3-Monooxygenase; Ventral Tegmental Area; Work; base; cognitive function; design; extracellular; immunocytochemistry; immunoreactivity; locus ceruleus structure; monoamine; nerve supply; neuronal cell body; noradrenaline transporter; norepinephrine system; protein expression; response; reuptake; stressor; synthetic enzyme; trait; transmission process; uptake

DESCRIPTION (provided by applicant): The norepinephrine (NE) innervation to the prefrontal cortex (RFC) is involved in complex cognitive functioning, and pathologies in this system are implicated in mental health disorders including depression, post-traumatic stress disorder, and attention deficit hyperactivity disorder. NE transmission in the RFC is regulated in part by uptake through its plasma membrane transporter (NET). In the first ultrastructural immunocytochemical study of its type, we showed that most NE terminals in the RFC of naive rats contain NET primarily within the cytoplasm (i.e. not on the membrane) and lack detectable levels of the synthetic enzyme tyrosine hydroxylase (TH). Only a minority of NE terminals express appreciable plasmalemmal NET and detectable levels of TH. The basis for the predominantly cytoplasmic localization of NET and lack of TH in the majority of RFC NE terminals is not known. However, we hypothesize that these factors are influenced by the level of activity in the NE system as well as the availability of extracellular dopamine (DA), a precursor for NE. In support of this hypothesis, we have demonstrated that exposure to chronic cold stress, a treatment that persistently activates the locus coeruleus (LC) NE system, increases both the plasmalemmal localization of NET and the expression of detectable TH within the RFC. In the proposed functional anatomical studies, we will further examine the factors that regulate the subcellular distribution of NET and expression of TH in the rat RFC using immunocytochemistry and electron microscopic analysis. In Aim 1, we will study the effects of acutely altering the activity of the LC and its RFC projections using electrical or pharmacological stimulation. In Aims 2 and 3, we will examine the impact of chronic treatment with antidepressant drugs that selectively block NET, both in naive rats (Aim 2) and in animals simultaneously exposed to chronic cold stress. Finally, given the known ability of NET to transport DA, we hypothesize that NE terminals in the RFC utilize extracellular DA to synthesize NE in the absence of TH. Hence, in Aim 4, we will examine how the availability of extracellular DA affects NET distribution and TH expression in RFC NE terminals by lesioning the DA cell bodies in the ventral tegmental area. The findings from these studies will provide valuable information regarding the normal functions of the central NE system and its role in the pathophysiology and treatment of mental disorders.

描述（由申请人提供）：对前额叶皮层（RFC）的去甲肾上腺素（NE）神经涉及复杂的认知功能，该系统中的病理学与精神健康障碍有关，包括抑郁症，创伤后应激障碍和注意力缺陷多动障碍。 RFC中的NE传输部分通过其质膜转运蛋白（NET）的吸收来部分调节。在首次对其类型的超微结构免疫细胞化学研究中，我们表明，天真大鼠RFC中的大多数NE末端主要含有细胞质内的NET（即不在膜上），并且缺乏可检测到的合成酶酪氨酸酪氨酸羟化酶（TH）的合成水平。只有少数NE末端表达可观的纤溶酶网和TH的可检测水平。在大多数RFC NE终端中，主要是细胞质定位和缺乏TH的基础尚不清楚。但是，我们假设这些因素受NE系统活性水平以及细胞外多巴胺（DA）的可用性的影响，NE。为了支持这一假设，我们已经证明了暴露于慢性冷应激，这种治疗持续激活了基因座（LC）NE系统，从而增加了NET的血浆定位和RFC中可检测到的TH的表达。在拟议的功能解剖学研究中，我们将进一步研究使用免疫细胞化学和电子显微镜分析在大鼠RFC中调节净和Th的亚细胞分布的因素。在AIM 1中，我们将研究使用电或药理刺激急性改变LC及其RFC投影的作用。在目标2和3中，我们将检查抗抑郁药的慢性治疗，这些药物在天真的大鼠（AIM 2）和同时暴露于慢性冷应激的动物中有选择性地阻断净的净净。最后，鉴于净运输DA的已知能力，我们假设RFC中的NE终端利用细胞外DA在没有TH的情况下合成NE。因此，在AIM 4中，我们将研究细胞外DA的可用性如何通过在腹侧段区域的DA细胞体上生出RFC NE末端的净分布和Th表达。这些研究的发现将提供有关中央NE系统正常功能及其在病理生理学和精神障碍治疗中的作用的宝贵信息。