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广泛的大脑重塑的漫长时期。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，这些疾病包括进食、情绪和行为障碍以及精神分裂症。因此，这些疾病的病因很可能受到青春期激素如何影响青春期性分化行为回路重塑的影响。长期以来的观点认为，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期间，这些性别差异在整个青春期和成年期都被被动地保持着。PIs实验室的最新发现推翻了这一观点，为大鼠在青春期通过在性分化细胞群中主动和受激素调节的细胞添加来积极维持性二型提供了证据。这一发现代表着对大脑中性别二态如何以及何时在哺乳动物大脑中建立和维持的理解发生了根本性的转变。这一新发现的发育过程可能是一种积极的机制，既可以在青少年大脑重塑的情况下保持结构和功能上的性别二态，也可以创造青少年发展过程中出现的新的性别差异。通过定时注射溴脱氧尿苷(BrdU)，结合免疫组织化学标记神经元和神经胶质细胞，以及功能分析，将确定这种新细胞添加到青少年大脑的机制。要解决的问题是：1)性腺激素是否通过增加细胞增殖、存活率或两者兼而有之来调节青春期细胞群中青春期细胞向青春期大脑的增加？2)新细胞的增加是青春期或终生维持结构性性别二型性的机制？3)青春期添加到青春期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，以解释和适当地治疗与青春期和青春期有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.