Axon, Testosterone and Mental Health during Adolescence

轴突、睾酮和青春期心理健康

• 批准号: 8488259
• 负责人: Tomas Paus
• 金额: $ 17.29万
• 依托单位: BAYCREST CENTRE FOR GERIATRIC CARE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8488259
• 关键词: 18 year old; 20 year old; Adolescence; Adolescent; Affect; Age; Androgen Receptor; Animal Model; Animals; Axon; Axonal Transport; Back; Birth; Brain; CAG repeat; Caliber; Castration; Cell Communication; Cells; Child; Childhood; Codon Nucleotides; Cognitive; Communication; Development; Disease; Dose; Electron Microscopy; England; Ensure; Enzymes; Evaluation; Genes; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Impairment; Indium; Individual; Leucine; Longitudinal Studies; Magnetic Resonance Imaging; Male Adolescents; Measures; Mental Depression; Mental Health; Mental disorders; Metabolism; Modeling; Myelin; Myelin Sheath; NIH Program Announcements; Nervous system structure; Neurosciences; Neurosecretory Systems; Organelles; Parents; Participant; Pattern; Phenotype; Placebos; Population; Principal Investigator; Process; Property; Proteins; Psychopathology; Puberty; Rattus; Receptor Gene; Relative (related person); Research; Risk; Risk Assessment; Scanning; Schizophrenia; Series; Sexual Maturation; Signal Transduction; Stanolone; Supplementation; Synapses; Testing; Testosterone; Testosterone 5-alpha-Reductase; Thick; Time; Valine; Variant; Work; base; cholestenone 5 alpha-reductase; cohort; early onset; emerging adult; in vivo; indexing; male; neurodevelopment; neuronal cell body; older men; population based; programs; public health relevance; receptor; relating to nervous system; research study; response; white matter; young adult

DESCRIPTION (provided by applicant): This application is submitted in response to the Program Announcement "Neurodevelopment and Neuroendocrine signalling in Adolescence: Relevance to Mental Health " (PA-09-008). The primary objective of our research is to understand how rising levels of testosterone during male adolescence affect the axon. The secondary objective is to evaluate the possible impact of such effects on the risk of psychopathology during male adolescence. The focus on the axon, a key element in long-range cell-to- cell communication in the nervous system, is motivated by the known impairment of neural connectivity in disorders emerging during adolescence and young adulthood, including depression and schizophrenia. To reach our goal, the proposed research sets the following four specific aims. (1) To evaluate whether or not the timing & dynamics of sexual maturation during early and mid-adolescence predicts structural properties of white matter during late adolescence. To achieve this aims, we will employ multi-modal magnetic-resonance imaging (MRI) of white matter in a large number (n=500) of 18-year old male adolescents selected from a unique longitudinal birth-cohort established in England in early 1990's, namely the Avon Longitudinal Study of Parents and Children (ALSPAC). The timing & dynamics of sexual maturation will be indexed by the age of puberty onset and changes in testosterone levels throughout adolescence, i.e. using information collected in this cohort over the past 10 years. (2) To evaluate the moderating effects of genes involved in testosterone signalling and/or metabolism on the predicted relationship between testosterone levels and structural & functional propertise of white matter. This aim will be achieved by genotyping the 500 male adolescents for functional polymorphisms in the androgen-receptor (AR) gene and the 5-alpha reductase gene; (3) To evaluate whether experimental manipulations of testosterone levels during puberty affect functional and morphological properties of the axon. This aim will be achieved by studying male rats following real or sham castration, with or without supplementation of testosterone. In this animal model, we will measure two main phenotypes: (a) axonal transport using in vivo Mn++ MR imaging at 7 T; and (b) axonal caliber and myelin thickness assessed ex vivo with electron microscopy; and (4) We will evaluate possible relationship between the timing & dynamics of sexual maturation and the risk of psychopathology and assess whether puberty-related changes in white matter modulate this relationship. This aim will be achieved using the existing longitudinal information about puberty and psychopathology collected in the last 10 years in the ALSPAC participants, and by an assessment of the risk of psychopathology at the time of an MR acquisition, i.e. at the age of 18 years. The above research program integrates population neuroscience (Aims 1, 2 & 4) with experimental neuroscience (Aim 3), with the ultimate goal to understand how inter-individual variations in the maturation of white matter during male adolescence might affect mental health. PUBLIC HEALTH RELEVANCE: The white matter of a 20-year old man contains a staggering 176,000 km of myelinated axons. Axons ensure smooth communication throughout the brain in two important ways: by conducting electrical impulses and also by transporting various molecules, organelles and proteins from the cell body to the synapse and back. Given the critical importance of neural connectivity for brain functioning, it is very likely that processes influencing maturation of the axon during childhood and adolescence will impact the child's cognitive development and mental health. The proposed research will combine two approaches: population and experimental neuroscience. Taking advantage of an existing cohort of adolescents, we will investigate the relationship between testosterone trajectories during adolescence and structural properties of white matter. We will also test experimentally the effect of testosterone treatment on structural and functional properties of white matter in experimental animals (rats). Altogether, we believe that the proposed series of population-based and experimental studies will provide an integrative answer to our single question: how does testosterone affect the axon and with what consequences? As such, this work is likely to open up new and uncharted avenues into studies of the neural underpinnings of psychiatric disorders that emerge during male adolescence.

描述（由申请人提供）：该申请是根据计划公告“青春期神经发育和神经内分泌信号传导：与心理健康相关的”（PA-09-008）。我们研究的主要目的是了解男性青春期期间睾丸激素水平的上升如何影响轴突。次要目标是评估这种影响对男性青春期心理病理风险的可能影响。对轴突的关注是神经系统中远程细胞通信的关键要素，是由已知的青春期和年轻成年后出现的疾病中神经连通性的已知损害，包括抑郁症和精神分裂症。为了实现我们的目标，拟议的研究设定了以下四个特定目标。 （1）评估早期和青春期期间性成熟的时间和动态是否预测青春期后白质的结构特性。为了实现这一目标，我们将在1990年代初期在英格兰建立的独特的纵向出生怪胎中选出的大量（n = 500）的白质（n = 500）的白质（n = 500）中，我们将采用多模式的磁性成像（MRI），这是我们将采用多模式的磁振荡成像（MRI）。性成熟的时机和动态将由青春期的年龄和整个青春期的睾丸激素水平的变化索引，即使用过去10年中此同类中收集的信息。 （2）评估与睾丸激素信号传导和/或代谢有关睾丸激素水平与白质结构和功能特性之间预测关系的基因的调节作用。通过将500名男性青少年用于雄激素受体（AR）基因和5-α还原酶基因中的功能多态性，可以实现这一目标； （3）评估青春期期间睾丸激素水平的实验性操纵是否影响轴突的功能和形态学特性。在实际或假cast割后研究雄性大鼠，有或不补充睾丸激素，可以实现这一目标。在该动物模型中，我们将测量两种主要表型：（a）使用体内MN ++ MR成像在7 T时使用轴突转运； （b）用电子显微镜在体内评估的轴突口径和髓磷脂厚度； （4）我们将评估性成熟的时机和动态之间的可能关系，并评估白质中与青春期相关的变化是否在调节这种关系之间。使用有关在ALSPAC参与者中收集的有关青春期和精神病理学的现有纵向信息以及通过评估MR收购时的精神病理风险，即18岁时，将实现此目标。上述研究计划将人群神经科学（目标1、2和4）与实验性神经科学（AIM 3）结合在一起，并最终的目标是了解男性青春期期间白质成熟的个体差异如何影响心理健康。 公共卫生相关性：一名20岁男子的白质包含惊人的176,000公里的骨髓轴突。轴突以两种重要的方式确保整个大脑的平稳通信：通过进行电脉冲，以及通过将各种分子，细胞器和蛋白质从细胞体传输到突触和背部。鉴于神经连通性对大脑功能的重要性至关重要，因此在儿童期和青春期影响轴突成熟的过程很可能会影响孩子的认知发展和心理健康。拟议的研究将结合两种方法：种群和实验性神经科学。利用现有的青少年队列，我们​​将研究青春期睾丸激素轨迹与白质结构特性之间的关系。我们还将通过实验测试睾丸激素治疗对实验动物（大鼠）白质结构和功能特性的影响。总而言之，我们认为拟议的一系列基于人群的和实验研究将为我们的单一问题提供一个综合的答案：睾丸激素如何影响轴突以及如何影响？因此，这项工作可能会为对男性青春期中出现的精神疾病神经基础的研究开放新的和未知的途径。