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: 7760926
• 负责人: ROBERT W RHOADES
• 金额: $ 28.33万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7760926
• 关键词: Address; Agonist; Amphetamines; Animals; Antisense Oligonucleotides; Area; Axon; Binding; Brain; Cells; Chimeric Proteins; Cues; Development; Developmental Delay Disorders; Disease; Eph Family Receptors; Ephrin-A2; Ephrins; Family; Family member; Fiber; Goals; Growth; Growth Cones; Immunohistochemistry; In Situ Hybridization; Individual; Invaded; Knowledge; Laboratories; Lead; Ligands; Maintenance; Maps; Mediating; Membrane; Messenger RNA; Methods; Molecular; 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; axon growth; axon guidance; base; 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..

皮质的发育受到内在和外在因素的调节，包括引导分子 和神经递质，可能受到药理或其他环境因素的影响。以弗所 受体是受体酪氨酸激酶家族的成员，其与配体蛋白相互作用， 肝配蛋白，介导大脑结构的模式，特别是从丘脑投射到 皮层，丘脑皮质传入神经（TCA）。这些分子是参与的良好候选分子 出生后边界的形成以及可能纠正 TCA 模式中引起的错误。我们之前的 结果表明，TCA 模式因新生大鼠中纤维过度生长而被破坏， 递质血清素 (5-HT) 的水平，但这些模式在第二个过程中变得正常化 产后一周，尽管 5-HT 持续升高。此外，TCA 的增长存在空间限制 由5-HT诱导。限制异常生长和去除轴突的过程的边界的存在 来自不适当区域的可能取决于排斥性分子相互作用以及 Eph/ephrin 的表达 家族分子与它们参与其中一种或两种机制一致。目标是 拟议的研究旨在调查 Ephs/ephrins 在皮质边界形成中的潜在作用和 测试这些分子是否会在轴突受到干扰时重定向轴突以使 TCA 模式正常化，例如 例如改变皮质 5-HT 水平的药物（安非他明、SSRIs）。具体目标是： 1. 检查Eph/ephrin蛋白和mRNA在及其周围的分布 体感皮层（S-l）和腹基底丘脑（VB）。这些的表达模式 分子将通过免疫组织化学和原位杂交可视化。 2. 检查Eph/ephrin分子对个体TCA模式和乔木的影响 TCA 轴突。功能获得和丧失实验用于测试 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 分子在标准化融合 TCA 模式所得结果中的作用 皮质 5-HT 水平升高。 Eph/ephrin 分布和功能的变化 将研究模式标准化的时期。 通过这些研究获得的知识将扩大我们对一类内源性因素如何产生影响的理解。 指导线索有助于定义皮质边界并参与早期大脑可塑性 改变对广泛使用的药剂敏感的皮质递质。