Thalamocortical Boundary Markers and the Influence of Serotonin

丘脑皮质边界标记和血清素的影响

• 批准号: 7585745
• 负责人: ROBERT W RHOADES
• 金额: $ 28.28万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7585745
• 关键词: Address; Agonist; Amphetamines; Animals; Antisense Oligonucleotides; Area; Axon; Binding; Blur; Brain; Cells; Chimeric Proteins; Class; Cues; Development; Developmental Delay Disorders; Disease; Elevation; Eph Family Receptors; EphA1 Receptor; Ephrin-A2; Ephrins; Family; Family member; Fiber; Goals; Growth; Growth Cones; Immunohistochemistry; In Situ Hybridization; Individual; Invaded; Knowledge; Laboratories; Lead; Ligands; Localized; Maintenance; Maps; Mediating; Membrane; Messenger RNA; Methods; Morphology; Neuropil; Neurotransmitters; Pattern; Pattern Formation; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Positioning Attribute; Process; Proteins; Rattus; Receptor Protein-Tyrosine Kinases; Regulation; Reporting; Research; Research Personnel; Rodent; Role; Septal Area; Serotonin; Signal Transduction; Somatosensory Cortex; Structure; Testing; Thalamic structure; Time; Trigeminal System; Vibrissae; Week; axon growth; axon guidance; base; day; environmental agent; loss of function; neonate; postnatal; prevent; programs; protein expression; receptor; receptor expression; research study; somatosensory

Development of the cortex is regulated by both intrinsic and extrinsic factors, including guidance molecules and neurotransmitters, that may be impacted by pharmacological or other environmental agents. The Eph receptors are members of the family of receptor tyrosine kinases which interact with ligand proteins, the ephrins, to mediate patterning of brain structures, in particular the axons that project from the thalamus to cortex, the thalamocortical afferents (TCAs). These molecules are good candidates for involvement in postnatal boundary formation and possibly in correcting errors induced in TCA patterns. Our previous results showed that TCA patterns are disrupted by excessive fiber outgrowth in neonate rats by elevated levels of the transmitter serotonin (5-HT), and yet these patterns become normalized during the second postnatal week, despite continued elevation of 5-HT. Moreover, there are spatial limits to TCA outgrowth induced by 5-HT. The existence of boundaries limiting abnormal growth and processes that remove axons from inappropriate regions may depend on repulsive molecular interactions, and expression of Eph/ephrin family molecules are consistent with their involvement with either or both of these mechanisms. The goal of the proposed research is to investigate the potential role of Ephs/ephrins in cortical boundary formation and to test whether these molecules redirect axons to normalize TCA patterns when these are perturbed, for example by drugs that alter cortical 5-HT levels (amphetamines, SSRIs). The specific aims are: 1. Examine the distribution of Eph/ephrin protein and mRNA in and surrounding somatosensory cortex (S-l) and ventrobasal thalamus (VB). Expression patterns of these molecules will be visualized by immunohistochemistry and in situ hybridization. 2. Examine the influence of Eph/ephrin molecules on TCA patterns and arbors of individual TCA axons. Gain and loss of function experiments are used to test to test if TCAs are influenced by local changes in ephrin distributions.. 3. Determine the role of Eph/ephrin molecules in normalizing fused TCA patterns resultant from elevation of cortical 5-HT levels. Changes in Eph/ephrin distributions and function during the period of pattern normalization will be investigated. The knowledge gained by these studies will expand our understanding of how one class of endogenous guidance cues helps to define cortical boundaries and participates in early brain plasticity induced by the alteration of a cortical transmitter which is susceptible to widely utilized pharmaceutical agents..

皮质的发育受内在和外在因素的调节，包括导向分子 和神经递质，可能受到药理学或其他环境因素的影响。所述Eph 受体是与配体蛋白相互作用的受体酪氨酸激酶家族的成员， 肝配蛋白，以介导大脑结构的模式，特别是从丘脑投射到 皮质，丘脑皮质传入神经（TCAs）。这些分子是参与 出生后边界的形成，并可能在纠正错误引起的TCA模式。我们以前的 结果表明，TCA模式被新生大鼠中过度的纤维生长所破坏， 5-羟色胺（5-HT）的水平，但这些模式在第二个过程中变得正常化。 出生后一周，尽管5-HT持续升高。此外，三氯乙酸的副产物也有空间限制 5-HT诱导。存在限制异常生长和移除轴突的过程的边界 从不适当的区域可能取决于排斥分子相互作用，和表达Eph/ephrin 家族分子与它们参与这些机制中的一种或两种是一致的。的目标 拟开展的研究旨在探讨Ephs/ephrins在皮层边界形成中的潜在作用， 为了测试这些分子是否会改变轴突的方向，使其在受到干扰时使TCA模式正常化， 例如改变皮质5-HT水平的药物（安非他明，SSRI）。具体目标是： 1.检测Eph/ephrin蛋白和mRNA在肝组织及其周围的分布 躯体感觉皮层（S-l）和腹基底丘脑（VB）。这些基因的表达模式 分子将通过免疫组织化学和原位杂交显现。 2.检测Eph/ephrin分子对个体TCA模式和动脉的影响 TCA轴突。使用功能增益和功能损失实验来测试TCA是否受到以下因素的影响： 肝配蛋白分布的局部变化。 3.确定Eph/ephrin分子在使融合的TCA模式正常化中的作用， 皮质5-羟色胺水平升高所致Eph/ephrin分布和功能的变化 将研究图案归一化的周期。 这些研究所获得的知识将扩大我们对一类内源性 引导线索有助于定义皮层边界，并参与由大脑皮层引起的早期大脑可塑性。 对广泛使用的药剂敏感的皮层递质的改变。