Adolescence neurogenesis mechanisms of antipsychotic sensitization and tolerance

 青春期是大脑和各种心理功能经历戏剧性转变的时期。这也是各种严重精神障碍症状经常出现的时候。近年来，患有精神分裂症和其他严重精神疾病的儿童和青少年使用抗精神病药物的人数显著增加（约6倍）。然而，关于抗精神病药物暴露对大脑和行为发育的长期影响的研究还缺乏。由于抗精神病药物治疗的精神疾病患者，有必要评估可能的短期和长期的影响，抗精神病药物对心理功能和其他方面的大脑成熟在不同的年龄使用一个有效的临床前疾病模型的精神分裂症。PI的长期目标是了解青春期抗精神病药物治疗对整个发育过程中行为和神经生物学功能的影响。PI实验室的既往工作表明，奥氮平重复间歇给药在成年和青春期大鼠的条件性回避反应模型中诱导致敏样（幅度增加）效应，而氯氮平重复间歇给药诱导耐受样（幅度降低）效应。临床前研究还表明，反复抗精神病药物治疗改变青少年海马神经发生。R 03项目将在这些发现的基础上评估奥氮平致敏（目标1）和氯氮平耐受性（目标2）及其与青春期大鼠神经发生改变的可能联系，这些大鼠出生于暴露于多胞苷酸：聚肌苷酸（PolyI：C）的大鼠母亲-一种经验证的精神分裂症大鼠母体免疫激活（MIA）模型。此外，该项目将揭示MIA和抗精神病药物诱导的神经发生模式变化之间可能的相互作用。一般的方法是用PolyI：C在妊娠雌性大鼠体内产生免疫激活，然后通过连续给药诱导青春期子代奥氮平致敏或氯氮平耐受，待动物成年后检测其表达。合成核苷溴脱氧尿苷（BrdU）将用于确定抗精神病药物治疗后神经元存活的区域。最后，使用NeuN或神经胶质细胞酸性蛋白抗体对抗BrdU进行双标记，以进一步确认在抗精神病药物治疗的影响下产生的细胞的分化。这个项目不仅将增加我们对抗精神病药物作用的行为和神经生物学机制的理解，而且还允许详细研究这种暴露对神经元发育的长期影响。该项目具有重要意义，因为它将对精神药物评价，未来药物开发和临床实践产生影响。

 DESCRIPTION: Adolescence is a period in which the brain and various psychological functions undergo dramatic transitions. It is also the time when symptoms of a variety of severe mental disorders often manifest. In recent years, there has been a significant increase (~6 folds) in antipsychotic use in children and adolescents with schizophrenia and other severe mental illnesses. However, research on the long-term consequences of antipsychotic exposure on the brain and behavioral developments is lacking. As antipsychotic treatment is administered to patients of psychiatric illnesses, there is a need to evaluate the possible short-term and long-term impacts of antipsychotic medications on psychological functions and other aspects of brain maturation at various ages using a validated preclinical disease model of schizophrenia. The PI's long-term goal is to understand the impacts of antipsychotic treatment during adolescence on the behavioral and neurobiological functions throughout development. Previous work from the PI's laboratory shows that repeated intermittent administration of olanzapine induces a sensitization-like (increase in magnitude) effect in a conditioned avoidance response model in both adult and adolescent rats, whereas repeated intermittent administration of clozapine induces a tolerance- like (decrease in magnitude) effect. Preclinical studies also suggest that repeated antipsychotic treatment alters adolescent neurogenesis in the hippocampus. This R03 project will build upon these findings to assess olanzapine sensitization (Aim 1) and clozapine tolerance (Aim 2) and their possible link to alterations in neurogenesis in adolescent rats born from rat mothers that have been exposed to polycytidilic:polyinosinic acid (PolyI:C) - a validated rat maternal immune activation (MIA) model of schizophrenia. In addition, the project will reveal possible interactions between MIA and antipsychotic-induced changes in patterns of neurogenesis. The general approach is to generate immune activation in pregnant female rats using PolyI:C, then induce olanzapine sensitization or clozapine tolerance in the adolescent offspring through continuous drug administration, then test its expression after the animals become adults. The synthetic nucleoside bromodeoxyuridine (BrdU) will be used to identify regions of neuronal survival following antipsychotic treatments. Finally, double labeling of anti-BrdU with NeuN or glial fibrillary acidic protein antibodies is used to further confirm the differentiation of cells generated under the influence of antipsychotic treatment. This project wil not only increase our understanding of the behavioral and neurobiological mechanisms of antipsychotic action, but also allow a detailed study of the long-term impacts of such exposure on neuronal development. This project is significant as it will have implications for psychotropic drug evaluation, future drug development, and clinical practice.