Mechanisms underlying sexually differentiated brain remodeling during adolescence

描述（由申请人提供）：青春期直到最近才被认为是一个长期的广泛的大脑重塑时期。这一发育的关键时期与几种精神疾病的易感性和表现的性别差异的出现有关，包括饮食、情绪、行为障碍和精神分裂症。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别分化行为电路重塑的影响。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都是被动维持的。pi实验室最近的发现推翻了这一观点，他们在大鼠身上提供了证据，证明青春期性别分化细胞群中通过活跃的激素调节细胞增加，积极维持了青春期性别二态性。这一发现代表了对哺乳动物大脑中两性异形是如何以及何时建立和维持的理解的根本转变。这个新发现的发育过程可能是一个积极的机制，在面对青少年大脑重塑时维持结构和功能上的两性异形，或者在青少年发育过程中产生新的性别差异。通过定时注射溴脱氧尿苷（BrdU），结合神经元和神经胶质细胞标记物的免疫组织化学，以及功能测定，将确定这种向青少年大脑添加新细胞的机制。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，来调节青春期细胞在男性或女性偏向的细胞群中向青少年大脑中添加的细胞？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身机制？3)青春期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靶点，以解释和适当治疗与青春期和青春期相关的性别偏见精神疾病。

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.