Mechanisms underlying sexually differentiated brain remodeling during adolescence

青春期性别分化大脑重塑的机制

基本信息

批准号：
8225239
负责人：
Lydia L DonCarlos
金额：
$ 37.25万
依托单位：
LOYOLA UNIVERSITY CHICAGO
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 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8225239
关键词：
Address Adolescence Adolescent Adolescent Development Adult Affect Age Amygdaloid structure Animals Area Astrocytes Behavior Behavioral Biological Assay Birth Brain Cell Cycle Cell Death Cell Nucleus Cell Proliferation Cell Survival Cells Cellular Morphology Confocal Microscopy Coupled Deoxyuridine Development Developmental Process Disease Eating Embryo Estradiol Etiology Female Female Adolescents Functional disorder Goals Gonadal Hormones Gonadotropins Hormonal Hormones Human Hypothalamic structure Immediate-Early Genes Immunohistochemistry Injection of therapeutic agent Knowledge Label Laboratories Life Light Link Maintenance Medial Mental disorders Moods Neonatal Neurobiology Neuroglia Neurons Neurophysiology - biologic function Ovarian hormone Ovary Phenotype Physiology Population Predisposition Prevention Production Progesterone Progesterone Receptors Proteins Puberty Rattus Research Rodent Role Schizophrenia Sex Bias Sex Characteristics Shapes Structure Structure of terminal stria nuclei of preoptic region Synapses Testicular Hormones Testis Testosterone Time Tracer Undifferentiated Uridine brain remodeling brain tissue clinically relevant critical period dimorphism functional outcomes male myelination neural circuit new therapeutic target postnatal prepuberty public health relevance research study sex sexual dimorphism synaptogenesis time use young man young woman

项目摘要

DESCRIPTION (provided by applicant): Adolescence has only recently been recognized as a protracted period of extensive brain remodeling. This critical period of development is associated with the emergence of sex differences in susceptibility to and manifestation of several mental illnesses, including eating, mood, and conduct disorders, and schizophrenia. Thus, the etiology of these illnesses is likely to be impacted by how pubertal hormones influence the remodeling of sexually differentiated behavioral circuits during adolescence. The longstanding view has been that sexual differentiation of the brain occurs during late embryonic or early postnatal brain development, and that these sex differences are passively maintained throughout adolescence and into adulthood. Recent findings from the PIs' laboratories overturn this view by providing evidence in rats for active maintenance of sexual dimorphisms during puberty via active and hormonally modulated cell addition in sexually differentiated cell groups during puberty. This finding represents a fundamental shift in the understanding of how and when sexual dimorphisms in the brain are established and maintained in the mammalian brain. This newly discovered developmental process may be an active mechanism for either maintaining structural and functional sexual dimorphisms in the face of remodeling of the adolescent brain or for creating new sex differences that emerge during adolescent development. Using timed injections of bromo-deoxyuridine (BrdU) coupled with immunohistochemistry for markers of neurons and glial cells, as well as functional assays, the mechanisms underlying this addition of new cells to the adolescent brain will be determined. The questions to be addressed are: 1) Do gonadal hormones modulate the pubertal addition of cells to the adolescent brain in cell groups that are either male-biased or female-biased by increasing cell proliferation, survival, or both? 2) Is addition of new cells a pubertal or a life-long mechanism for maintenance of structural sexual dimorphisms? 3) What are the fates and functional outcomes of cells that are added to the adolescent brain during puberty? These studies will generate new knowledge and potentially new therapeutic targets to explain and appropriately treat sex-biased mental illnesses that are associated with puberty and adolescence. PUBLIC HEALTH RELEVANCE: Mechanisms of sexually differentiated brain remodeling during adolescence. Adolescence is a critical period of development associated with the emergence of sex differences in susceptibility to, and manifestation of, several mental illnesses, including eating, mood, and conduct disorders, and schizophrenia. We have recently discovered that new cells are added to the adolescent brain, and that hormones produced by the ovaries and testes alter the addition of new cells to different cell groups in the brain, producing sexually differentiated brain circuitry. The goal of these studies is to understand precisely how hormones affect this remodeling of brain circuitry in an effort to shed light on the etiology and progression, and ultimately treatment and prevention, of mental illnesses that emerge during adolescence and affect young men and women differently.

描述（由申请人提供）：青春期直到最近才被公认为是大脑重塑的旷日持久的时期。这个关键的发展时期与几种精神疾病的敏感性和表现（包括饮食，情绪和引起疾病和精神分裂症）的性别差异的出现有关。因此，这些疾病的病因可能会受到青春期在青春期的重塑行为回路的重塑的影响。长期以来的观点是，大脑的性别分化发生在胚胎晚期或早期的大脑发育期间，并且这些性别差异在整个青春期和成年期都被动地维持。 PIS的实验室的最新发现推翻了这种观点，该观点通过在青春期通过活跃和荷尔蒙调节的细胞在青春期期间通过活跃和荷尔蒙调制的细胞添加在青春期期间积极维持性二态性的证据来推翻这种观点。这一发现代表了对在哺乳动物大脑中建立和维持大脑中的性二态性如何以及何时的理解的根本转变。这个新发现的发育过程可能是一种积极的机制，可以在面对青少年大脑的重塑时保持结构和功能性二态性，或者在青少年发展过程中产生新的性别差异。使用对神经元和神经胶质细胞标志物的免疫组织化学以及功能分析的免疫组织化学的定时注射，以及将这种新细胞添加到青春期大脑中的机制。要解决的问题是：1）性腺激素是否会在细胞群中调节青少年大脑的青春期添加，而细胞群会因增加细胞增殖，存活还是同时增加雄性偏见或雌性偏见？ 2）新细胞的添加是一个青春期还是终身维持结构性二态性的机制？ 3）青春期中添加到青少年大脑中的细胞的命运和功能结果是什么？这些研究将产生新的知识和潜在的新治疗靶标，以解释和适当治疗与青春期和青春期相关的性偏见的精神疾病。公共卫生相关性：青春期性别分化的大脑重塑的机制。青春期是与几种精神疾病（包括饮食，情绪和引起疾病和精神分裂症）的易感性和表现性的性别差异和表现相关的至关重要的发展。我们最近发现，新细胞被添加到青春期大脑中，卵巢和睾丸产生的激素改变了向大脑中不同细胞组添加的新细胞，从而产生性别分化的脑回路。这些研究的目的是精确地了解激素如何影响脑电路的这种重塑，以阐明对青春期中出现的精神疾病的病因和进展，最终治疗和预防，并以不同的方式影响年轻人。