Mechanisms underlying sexually differentiated brain remodeling during adolescence

描述（由申请人提供）：青春期只是最近才被认为是一个长期的广泛的大脑重塑。这一关键的发展时期与几种精神疾病的易感性和表现形式的性别差异有关，包括饮食，情绪和行为障碍以及精神分裂症。因此，这些疾病的病因可能受到青春期激素如何影响青春期性分化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出生后早期的大脑发育过程中，这些性别差异在整个青春期和成年期被动地保持着。PI实验室的最新发现推翻了这一观点，提供了大鼠在青春期期间通过性分化细胞群中的主动和经神经调节的细胞添加来主动维持性二态性的证据。这一发现代表了对大脑中的性二态性是如何以及何时在哺乳动物大脑中建立和维持的理解的根本转变。这个新发现的发展过程可能是一个积极的机制，无论是在面对青少年大脑的重塑，或为创造新的性别差异，出现在青少年发展过程中，保持结构和功能的性二态性。使用定时注射溴脱氧尿苷（BrdU），再加上免疫组织化学标记的神经元和神经胶质细胞，以及功能测定，这种新的细胞添加到青少年大脑的机制将被确定。要解决的问题是：1）性腺激素是否通过增加细胞增殖、存活或两者兼而有之来调节青春期向青春期大脑中添加的细胞，这些细胞群要么是男性偏向的，要么是女性偏向的？2)新细胞的增加是青春期的还是维持结构性两性异形的终生机制？3)在青春期被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的治疗目标，以解释和适当治疗与青春期和青春期有关的性别偏见精神疾病。 公共卫生相关性：青春期性分化脑重塑的机制。 青春期是一个关键的发展时期，与出现的性别差异的易感性，并表现出，几种精神疾病，包括饮食，情绪和行为障碍，精神分裂症。我们最近发现，青春期的大脑中增加了新的细胞，卵巢和睾丸产生的激素改变了大脑中不同细胞群中新细胞的增加，产生了性别分化的大脑回路。这些研究的目标是准确地了解激素如何影响大脑回路的这种重塑，以阐明青春期出现的精神疾病的病因和进展，并最终治疗和预防，并以不同的方式影响年轻男性和女性。

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.