Factors Regulating NE Transporter Localization in PFC

PFC 中 NE 转运蛋白定位的调节因素

• 批准号: 7994764
• 负责人: Susan R. Sesack
• 金额: $ 25.74万
• 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 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7994764
• 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; Functional disorder; In Vitro; Knowledge; Lesion; Light; 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; 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）：前额皮质（RFC）的去甲肾上腺素（NE）神经支配涉及复杂的认知功能，该系统中的病理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症。 RFC 中的 NE 传输部分通过其质膜转运蛋白 (NET) 的摄取来调节。在该类型的第一个超微结构免疫细胞化学研究中，我们表明，幼鼠 RFC 中的大多数 NE 末端主要在细胞质内（即不在细胞膜上）含有 NET，并且缺乏可检测水平的合成酶酪氨酸羟化酶 (TH)。只有少数 NE 终端表达明显的质膜 NET 和可检测水平的 TH。大多数 RFC NE 终端中 NET 主要定位于细胞质且缺乏 TH 的基础尚不清楚。然而，我们假设这些因素受到 NE 系统的活动水平以及细胞外多巴胺 (DA)（NE 的前体）的可用性的影响。为了支持这一假设，我们已经证明，暴露于慢性冷应激（一种持续激活蓝斑（LC）NE系统的治疗方法）可以增加NET的质膜定位和RFC内可检测到的TH的表达。在拟议的功能解剖学研究中，我们将使用免疫细胞化学和电子显微镜分析进一步研究调节大鼠 RFC 中 NET 亚细胞分布和 TH 表达的因素。在目标 1 中，我们将研究使用电刺激或药理刺激急剧改变 LC 活性及其 RFC 预测的效果。在目标 2 和 3 中，我们将研究选择性阻断 NET 的抗抑郁药物长期治疗对幼稚大鼠（目标 2）和同时暴露于慢性冷应激的动物的影响。最后，考虑到 NET 运输 DA 的已知能力，我们假设 RFC 中的 NE 终端在没有 TH 的情况下利用细胞外 DA 合成 NE。因此，在目标 4 中，我们将通过损伤腹侧被盖区的 DA 细胞体来研究细胞外 DA 的可用性如何影响 RFC NE 末端的 NET 分布和 TH 表达。这些研究的结果将为中枢 NE 系统的正常功能及其在精神障碍的病理生理学和治疗中的作用提供有价值的信息。