Antidepressant Effect on Hippocampal Synaptogenesis

对海马突触发生的抗抑郁作用

• 批准号: 7033517
• 负责人: TIBOR HAJSZAN
• 金额: $ 27.87万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7033517
• 关键词: age difference; animal old age; antidepressants; behavioral /social science research tag; cholinergic agents; clinical depression; dendrites; dentate gyrus; estrogens; fluoxetine; gender difference; hippocampus; immature animal; laboratory rat; mental disorder chemotherapy; neural plasticity; neurogenesis; ovariectomy; psychopharmacology; serotonin inhibitor; stress; synaptogenesis

DESCRIPTION (provided by applicant): Depression is one of the most common neurological disorders in the United States, affecting approximately 17% of the population with a clear sex difference. According to a current hypothesis, efficacy of antidepressant drugs depends on increased hippocampal neurogenesis, elicited after prolonged antidepressant medication. Since rapid changes in mood state that occur, e.g., at the onset of individual depressive episodes cannot be reconciled with slowly evolving neurogenetic alterations, an argument has been raised recently that antidepressant treatment might also involve a more rapid cellular plasticity mechanism that affects the integrity of the hippocampal neuronal circuitry. We have discovered that treatment of ovariectomized female rats with fluoxetine for 5 days elicits a robust increase in the density of dendritic spine synapses in the CA 1 hippocampal area and dentate gyrus, while spine synapse density increases of similar magnitude in the CAS area can be observed only after 14-day treatment. These spine synapse changes in CA 1 and dentate gyrus occur long before the first indications of increased dentate gyrus neurogenesis. Based on these data, we hypothesize that the mechanism of antidepressant action involves the induction of spine synapse formation in the hippocampus, leading to the restoration of the hippocampal neuronal circuitry and behavioral improvement. Since this same neuronal circuit is also a major target of gonadal steroid action, this mechanism may not only be associated with rapid changes in mood state, but also may provide an explanation for the sex and age differences in rates of depression and responses to antidepressant treatment. To test this hypothesis, we propose a combination of morphological and behavioral experiments in the rat that will investigate (a) the sequence and behavioral correlates of fluoxetine-induced hippocampal spine synapse changes; (b) the hippocampal synaptogenetic potential of several classes of antidepressants; (c) the neuronal substrates of the hippocampal synaptogenetic effect of several antidepressants; and (d) the possible sex and age differences in fluoxetine-induced hippocampal spine synapse changes. The experiments proposed in this application represent the first step in our effort to understand the role and significance of hippocampal synaptic remodeling in the neurobiology of depression and antidepressant therapy.

描述（由申请人提供）：抑郁症是美国最常见的神经系统疾病之一，影响约 17% 的人口，且存在明显的性别差异。根据目前的假设，抗抑郁药物的疗效取决于长期抗抑郁药物治疗后海马神经发生的增加。由于情绪状态的快速变化（例如，在个体抑郁发作时）无法与缓慢发展的神经遗传改变相协调，因此最近有人提出抗抑郁治疗可能还涉及更快速的细胞可塑性机制，从而影响神经遗传的完整性。海马神经元回路。我们发现，用氟西汀治疗切除卵巢的雌性大鼠 5 天后，CA 1 海马区和齿状回的树突棘突触密度显着增加，而 CAS 区域的树突棘突触密度也有类似程度的增加。仅在14天的治疗后。 CA 1 和齿状回中的这些棘突触变化早在齿状回神经发生增加的第一个迹象出现之前就发生了。基于这些数据，我们假设抗抑郁作用的机制涉及诱导海马体中棘突触的形成，从而导致海马体神经元回路的恢复和行为的改善。由于同一神经元回路也是性腺类固醇作用的主要目标，因此这种机制不仅可能与情绪状态的快速变化有关，而且还可以解释抑郁症发生率和抗抑郁治疗反应的性别和年龄差异。为了检验这一假设，我们提出在大鼠中进行形态学和行为学实验相结合，以研究（a）氟西汀诱导的海马棘突触变化的序列和行为相关性； (b) 几类抗抑郁药的海马突触发生潜力； (c) 几种抗抑郁药的海马突触发生作用的神经元底物； （d）氟西汀引起的海马棘突触变化可能存在性别和年龄差异。本申请中提出的实验代表了我们努力了解海马突触重塑在抑郁症和抗抑郁治疗的神经生物学中的作用和意义的第一步。