Necessity of Neurogenesis for Antidepressant Efficacy

神经发生对于抗抑郁功效的必要性

• 批准号: 8369866
• 负责人: TARIQUE DHYAN PERERA
• 金额: $ 37.97万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-06 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8369866
• 关键词: Ablation; Accounting; Acute; Address; Adult; Adverse effects; Age; Animals; Anterior; Antidepressive Agents; Anxiety; Anxiety Disorders; Attenuated; Beginning of Human Life; Behavior; Behavioral; Brain; Cephalic; Chronic; Chronic stress; Clinical; Control Groups; Data; Derivation procedure; Economic Burden; Electroconvulsive Therapy; Elements; Endogenous depression; Fluoxetine; Generations; Hippocampus (Brain); Human; Hyperplasia; Laboratories; Lead; Learning; Location; Macaca radiata; Major Depressive Disorder; Mammals; Mediating; Memory impairment; Mental Depression; Modeling; Monkeys; Moods; Morbidity - disease rate; Mus; Neural Pathways; Neurobiology; Neurons; Pathogenesis; Patients; Pharmaceutical Preparations; Predisposing Factor; Prevalence; Prevention; Process; Production; Property; Recruitment Activity; Regulation; Resistance; Risk; Rodent; Role; Simulate; Speed; Staging; Stimulus; Stress; Syndrome; Testing; Therapeutic; Therapeutic Effect; base; clinically relevant; depressive symptoms; design; expectation; irradiation; mortality; nerve stem cell; neural circuit; neurobiological mechanism; neurogenesis; pre-clinical; prevent; public health relevance; regional difference; response; social

DESCRIPTION (provided by applicant): Antidepressant medications are the principal treatment for major depression and chronic anxiety disorders, two syndromes with significant morbidity and mortality. The ultimate neurobiological target of antidepressants is unknown. Although these treatments are highly beneficial in many cases, shortcomings in others include limited efficacy, delayed onset of action, and undesirable side effects. The quest to identify basic mechanisms has yielded the hypothesis that neurogenesis in the adult hippocampus is central to antidepressant efficacy. Tests of this hypothesis, while not definitive, have been supportive. We showed that a non-pharmacological model of antidepressant therapy produces a dramatic increase in hippocampal neurogenesis. We have also obtained preliminary evidence that fluoxetine stimulates hippocampal neurogenesis and prevents depressive behavior and that both effects are abolished by preventing hippocampal neurogenesis. We propose a larger study that will establish the significance of these preliminary findings and will extend them to models that better parallel applications in humans. Three unresolved questions will be addressed: Our pilot data shows that chronic stress induces depression-like behaviors and is accompanied by reduced neurogenesis rates but the relationship between these two processes is unknown. Aim 1 will determine whether suppression of neurogenesis is sufficient to produce a depressive state under ambient conditions or increases risk of depressive behavior during chronic stress. All studies of antidepressants and depressive behavior in mammals have been modeled on prevention; none have addressed the role of antidepressants in reversing depressive behavior, although this is clearly more relevant to clinical antidepressant therapy. Aim 2 will determine whether fluoxetine can attenuate or eliminate depressive behavior and whether this is associated with hippocampal neurogenesis. We will then determine whether this improvement with treatment is prevented by blocking hippocampal neurogenesis. We suspect that neurogenesis is necessary for maintaining antidepressant response but not for immediate behavioral effects, because they seem to occur before new neurons can be integrated into neural pathways. Finally, although studies have shown that neurogenesis is necessary for delayed contextual learning, there is inadequate data to suggest any mechanism by which newly generated neurons may reverse depressive behaviors. Aim 3 seeks to identify the maturational stage and anatomical location where new neurons are preferentially activated with therapeutic response to treatment.

描述（由申请人提供）：抗抑郁药是严重抑郁症和慢性焦虑症的主要治疗方法，两种综合症具有明显的发病率和死亡率。抗抑郁药的最终神经生物学靶标尚不清楚。尽管这些治疗方法在许多情况下是非常有益的，但其他治疗方法包括有限的功效，延迟发作和不良的副作用。识别基本机制的追求提出了这样一种假设，即成年海马中的神经发生对于抗抑郁药疗效至关重要。对该假设的检验虽然不是确定的，但却是支持的。我们表明，抗抑郁药治疗的非药物模型可显着增加海马神经发生。我们还获得了初步证据，表明氟西汀刺激海马神经发生并防止抑郁行为，并且通过预防海马神经发生来消除这两种作用。我们提出了一项更大的研究，该研究将确定这些初步发现的重要性，并将其扩展到更好地在人类中平行应用的模型。将解决三个未解决的问题：我们的试点数据表明，慢性应激会导致抑郁症样行为，并伴有降低的神经发生率，但是这两个过程之间的关系尚不清楚。 AIM 1将确定神经发生的抑制是否足以在环境条件下产生抑郁状态或增加慢性应激期间抑郁行为的风险。 所有抗抑郁药和哺乳动物抑郁行为的研究均以预防进行建模。尽管这显然与临床抗抑郁药疗法更相关，但没有人能解决抗抑郁药在逆转抑郁行为中的作用。 AIM 2将确定氟西汀是否可以减弱或消除抑郁行为，以及这是否与海马神经发生有关。然后，我们将通过阻断海马神经发生来确定是否可以预防治疗的这种改善。我们怀疑神经发生对于维持抗抑郁反应而不是立即行为效应是必要的，因为它们似乎在将新神经元整合到神经途径中之前就发生。 最后，尽管研究表明，神经发生对于延迟上下文学习是必要的，但数据不足以暗示新产生的神经元可能会逆转抑郁行为的任何机制。 AIM 3试图确定成熟阶段和解剖位置，其中新神经元优先激活了对治疗的治疗反应。