Axon, Testosterone and Mental Health during Adolescence

轴突、睾酮和青春期心理健康

基本信息

批准号：
8660075
负责人：
Tomas Paus
金额：
$ 10.93万
依托单位：
BAYCREST CENTRE FOR GERIATRIC CARE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8660075
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

项目摘要

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.

描述（由申请人提供）：本申请是为了响应计划公告“青春期神经发育和神经内分泌信号传导：与心理健康的相关性”（PA-09-008）而提交的。我们研究的主要目的是了解男性青春期睾酮水平的升高如何影响轴突。第二个目标是评估这种影响对男性青春期精神病理学风险的可能影响。对轴突的关注是神经系统中远程细胞间通讯的关键要素，其动机是由于青春期和青年期出现的疾病（包括抑郁症和精神分裂症）中已知的神经连接受损。为了实现我们的目标，拟议的研究设定了以下四个具体目标。 (1) 评估青春期早期和中期性成熟的时间和动态是否可以预测青春期后期白质的结构特性。为了实现这一目标，我们将对大量 (n = 500) 18 岁男性青少年进行白质多模态磁共振成像 (MRI)，这些青少年是从英格兰早期建立的独特纵向出生队列中选出的。 20世纪90年代，即雅芳父母和儿童纵向研究（ALSPAC）。性成熟的时间和动态将通过青春期开始的年龄和整个青春期睾酮水平的变化来索引，即使用过去 10 年在该队列中收集的信息。 (2) 评估参与睾酮信号传导和/或代谢的基因对睾酮水平与白质结构和功能特性之间的预测关系的调节作用。这一目标将通过对 500 名男性青少年的雄激素受体 (AR) 基因和 5-α 还原酶基因的功能多态性进行基因分型来实现； (3) 评估青春期睾酮水平的实验操作是否影响轴突的功能和形态特性。这一目标将通过研究真实或假去势后补充或不补充睾酮的雄性大鼠来实现。在此动物模型中，我们将测量两种主要表型：(a) 使用 7 T 体内 Mn++ MR 成像进行轴突运输； (b) 用电子显微镜离体评估轴突直径和髓磷脂厚度； (4)我们将评估性成熟的时间和动态与精神病理学风险之间可能的关系，并评估青春期相关的白质变化是否调节这种关系。这一目标将利用过去 10 年在 ASPAC 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，并通过评估 MR 采集时（即 18 岁时）的精神病理学风险来实现。上述研究计划将群体神经科学（目标 1、2 和 4）与实验神经科学（目标 3）相结合，最终目标是了解男性青春期白质成熟的个体间差异如何影响心理健康。