Neurocircuitry underlying ketamine-induced antidepressant effects during adolescence.

青春期氯胺酮诱导的抗抑郁作用的神经回路。

• 批准号: 8835921
• 负责人: Eric Michael Parise
• 金额: $ 3.77万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-23 至 2016-09-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8835921
• 关键词: AMPA Receptors; Address; Adolescence; Adolescent; Adult; Adverse effects; Affect; Age; Antidepressive Agents; Anxiety; Area; Attention; Behavioral; Biochemical; Brain; Brain region; Child; Childhood; Clinical Research; Data; Disease; Disease remission; Effectiveness; Environment; Exposure to; Fluoxetine; Functional disorder; Health; Hippocampus (Brain); Infusion procedures; Investigation; Ketamine; Life; Major Depressive Disorder; Male Adolescents; Mediating; Methods; Mitogen-Activated Protein Kinases; Modeling; Molecular; Moods; Motivation; N-Methyl-D-Aspartate Receptors; Neurobiology; Optics; Pathway interactions; Pharmaceutical Preparations; Play; Population; Prefrontal Cortex; Proto-Oncogene Proteins c-akt; Public Health; Rattus; Recurrence; Relapse; Resistance; Rewards; Risk; Role; Safety; Selective Serotonin Reuptake Inhibitor; Self-Injurious Behavior; Sirolimus; Stress; Substance abuse problem; Suicide; Suicide attempt; Therapeutic; Therapeutic Effect; Time; Training; Ventral Tegmental Area; Work; Youth; alternative treatment; base; behavior influence; brain pathway; burden of illness; child depression; cost; depressive symptoms; design; disability; dopaminergic neuron; effective therapy; evidence base; insight; mTOR protein; neural circuit; neurobiological mechanism; neuronal circuitry; novel; optogenetics; receptor density; relating to nervous system; research study; response; therapy development

As one of the leading causes of disease burden and disability in the world, Major Depressive Disorder (MDD) is a persistent and ever expanding financial and public health concern. Sadly, MDD is quite prevalent in children and adolescents with life-long negative consequences including increased risk for conduct and substance abuse disorders, self-harm as well as suicide, and up to 75% risk of recurrent depressive episodes in adulthood. Although there are treatments available for MDD, they lack in effectiveness, and have a potential for enduing negative side effects. These observations, combined with the realization that decisions involving antidepressant treatment in children and adolescents are primarily based on data from adults, it is critically important to develop more effective treatments to be characterized in “age-appropriate” models. Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, has recently shown great promise as a rapid-acting and long-lasting treatment for MDD. Therefore, it is conceivable that ketamine could serve as an ideal therapeutic for pediatric MDD. Unfortunately, the efficacy, functionality, and biochemical consequences of ketamine exposure during periods prior to adulthood are not known. Preliminary data presented here suggests that ketamine is an effective antidepressant in adolescents, however the neurobiological underpinning(s) mediating these effects are unknown. To complicate matters, the neural circuits involved in MDD are poorly understood, although studies indicate that the mesolimbic brain pathway plays an essential role in MDD. This neural circuit includes the ventral tegmental area (VTA), prefrontal cortex (PFC), and hippocampus, all of which are known to be sensitive to the effects of stress. Recent evidence has shown that ketamine reverses the deficits associated with stress in the PFC and hippocampus, however its effects in the VTA as well as the neural circuitry involved are unknown. Therefore, to start addressing gaps in our basic understanding, the experiments outlined in this proposal are designed to examine the neurobiological underpinnings of ketamine’s antidepressant effects in adolescent males. This will be accomplished within the framework of the following specific aims: 1) assess the specific contribution(s) of the VTA to the antidepressant-like effects observed after ketamine exposure during adolescence, and 2) determine the neuronal circuitry underlying ketamine’s effects, specifically the neural projection from the VTA to the PFC. I hypothesize that infusing ketamine directly into the VTA will elicit antidepressant-like responses similar to those observed with systemic administration of the drug; and that optical stimulation of VTA-to-PFC pathway will produce antidepressant-like responses in the absence of ketamine. Data derived from this work will reveal novel insight(s) into ketamine’s functional effects in the immature brain, and neural substrates and circuitry underlying its effects on mood-and motivation-related brain areas in a grossly understudied period prior to adulthood, while providing advanced training in behavioral and molecular methods in an exceptional environment.

作为世界上疾病烧伤和残疾的主要原因之一，重度抑郁症（MDD）是一种持续的且不断扩大的财务和公共卫生问题。可悲的是，MDD在具有终身负面后果的儿童和青少年中非常普遍，包括增加行为和药物滥用障碍的风险，自我伤害和自杀，以及成年后复发性抑郁发作的风险高达75％。尽管有用于MDD的治疗方法，但它们缺乏有效性，并且有可能消除副作用。这些观察结果，加上以下意识到，涉及儿童和青少年抗抑郁药治疗的决策主要基于成人的数据，至关重要的是，开发更有效的治疗方法以在“适合年龄”模型中表征的更有效的治疗方法。氯胺酮是一种非竞争性的N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，最近显示出对MDD的快速作用和持久治疗的巨大希望。因此，可以想象氯胺酮可以作为小儿MDD的理想疗法。不幸的是，尚不清楚氯胺酮在成年之前的氯胺酮暴露的有效性，功能和生化后果。此处提供的初步数据表明，氯胺酮在青少年中是一种有效的抗抑郁药，但是介导这些作用的神经生物学基础是未知的。对于复杂的问题，尽管研究表明中唇脑途径在MDD中起着至关重要的作用，但涉及MDD的神经元回路的理解很少。该神经元电路包括腹侧对盖区（VTA），前额叶皮层（PFC）和海马，所有这些都对应激的影响敏感。最近的证据表明，氯胺酮逆转了与PFC和Hippocampus压力相关的定义，但是其在VTA中的作用以及所涉及的神经记录的作用尚不清楚。因此，为了开始解决我们的基本理解中的差距，该提案中概述的实验旨在检查氯胺酮在青少年男性中抗抑郁作用的神经生物学基础。这将在以下特定目的的框架内完成：1）评估VTA对青少年期间氯胺酮暴露后观察到的抗抑郁药样效应的特定贡献，以及2）确定氯胺酮作用的神经元电路，特别是来自VTA对PFC的神经元投射。我假设将氯胺酮直接注入VTA中会引起类似抗抑郁药样的反应，类似于系统的药物给药。 VTA-TO-PFC途径的光学刺激在没有氯胺酮的情况下会产生抗抑郁药样反应。从这项工作中得出的数据将揭示出对氯胺酮在未成熟大脑中功能效应的新见解，以及在成年期间在广泛理解的时期内对情绪相关的大脑区域的影响的神经材料和电路，同时在非凡的环境中提供了行为和分子方法的先进训练。