Neurogenesis, BMP signaling, and mechanisms of Ketamine's antidepressant effects

神经发生、BMP 信号传导以及氯胺酮抗抑郁作用的机制

• 批准号: 10326367
• 负责人: Radhika Rawat
• 金额: $ 5.18万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10326367
• 关键词: Acute; Adult; Adverse effects; Affect; Antidepressive Agents; Anxiety; Autopsy; BMP4; Behavior; Behavioral; Bone Morphogenetic Proteins; Cells; Chronic; Clinical; Clozapine; Cytoplasmic Granules; Development; Disease remission; Dose; Exposure to; Fluoxetine; Generations; Genes; Goals; Hippocampus (Brain); Hour; Human; Immunohistochemistry; Impairment; Injections; Ketamine; Label; Laboratories; Major Depressive Disorder; Measures; Mediating; Mental Depression; Modeling; Molecular; Morbidity - disease rate; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Newborn Infant; Oxides; Pathogenesis; Patients; Pharmaceutical Preparations; Process; Recurrence; Research; Risk; Rodent Model; Role; Signaling Protein; Stress; Tamoxifen; Techniques; Therapeutic; Therapeutic Effect; Time; Tissues; Work; addiction; antagonist; antidepressant effect; behavior measurement; behavioral response; clinically relevant; dentate gyrus; designer receptors exclusively activated by designer drugs; disability; drinking water; early onset; environmental enrichment for laboratory animals; inducible gene expression; inhibitor; mouse model; neurogenesis; newborn neuron; novel therapeutics; progenitor; relating to nervous system; serotonin receptor; stem; stem cells; suicidal behavior; suicidal risk; treatment responders; Acute; Adult; Adverse effects; Affect; Antidepressive Agents; Anxiety; Autopsy; BMP4; Behavior; Behavioral; Bone Morphogenetic Proteins; Cells; Chronic; Clinical; Clozapine; Cytoplasmic Granules; Development; Disease remission; Dose; Exposure to; Fluoxetine; Generations; Genes; Goals; Hippocampus (Brain); Hour; Human; Immunohistochemistry; Impairment; Injections; Ketamine; Label; Laboratories; Major Depressive Disorder; Measures; Mediating; Mental Depression; Modeling; Molecular; Morbidity - disease rate; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Newborn Infant; Oxides; Pathogenesis; Patients; Pharmaceutical Preparations; Process; Recurrence; Research; Risk; Rodent Model; Role; Signaling Protein; Stress; Tamoxifen; Techniques; Therapeutic; Therapeutic Effect; Time; Tissues; Work; addiction; antagonist; antidepressant effect; behavior measurement; behavioral response; clinically relevant; dentate gyrus; designer receptors exclusively activated by designer drugs; disability; drinking water; early onset; environmental enrichment for laboratory animals; inducible gene expression; inhibitor; mouse model; neurogenesis; newborn neuron; novel therapeutics; progenitor; relating to nervous system; serotonin receptor; stem; stem cells; suicidal behavior; suicidal risk; treatment responders

Major Depressive Disorder (MDD) is one of the top three causes of disability worldwide, but only 60-70% of patients with MDD respond to first-line therapies, and responders have lasting impairments and recurrences. Thus, further research into the molecular basis of depression and antidepressant action is needed. Using chemogenetic techniques, our lab has established a causal relationship between changes in adult hippocampal neurogenesis and anxiety/depression-like behavior in mice. Further, we have shown that acutely increasing new neuron activity without an increase in neurogenesis is sufficient to rapidly induce antidepressant effects. The behavioral consequences of increasing new neuron activity occur within hours, whereas the effects of increasing the number of new neurons and their integration into the hippocampal Dentate Gyrus (DG) takes weeks. Most antidepressants have a therapeutic lag of weeks in patients, but earlier onset of antidepressant effects correlates with decreased suicidal behavior and increased likelihood of remission, making rapid-acting antidepressants desirable. At subanesthetic doses, the NMDA receptor antagonist ketamine exerts antidepressant effects within hours and has sustained therapeutic effects lasting weeks. Understanding its mechanism may inform new antidepressants with minimal therapeutic lag and fewer significant adverse effects. The neurogenic niche is necessary for ketamine's sustained effects and a single dose of ketamine accelerates neurogenesis. I have found that ketamine increases both neurogenesis in the DG and the activity of DG neurons. Here, I propose that effects of ketamine on newborn neuron activity mediate ketamine’s rapid behavioral effect, whereas effects on neurogenesis underlie its longer-term behavioral effect. In Aim 1, I will determine the contribution of newborn neuron activity to ketamine’s acute behavioral effects. I will define how silencing new neurons alters ketamine’s acute effects in naïve mice and mice exposed to unpredictable chronic mild stress (UCMS). To inducibly and specifically silence new neurons, I will use Cre-inducible expression of an inhibitory Designer Receptor Exclusively Activated by Designer Drugs (DREADD) in neural stem/progenitor cells and their progeny. I will administer ketamine and determine how new neuron silencing alters ketamine’s effect on mouse anxiety/depression-like behavior. In Aim 2, I will examine mechanisms of ketamine’s sustained effects on neurogenesis and behavior and determine if they depend on a reduction in BMP signaling. Neurogenesis in the DG is inhibited by BMP signaling, and inhibition of BMP signaling increases neurogenesis and exerts an antidepressant effect. The behavioral effects of the Selective Serotonin Receptor Inhibitor (SSRI) fluoxetine are mediated by decreased BMP signaling, and I have found that ketamine treatment similarly reduces BMP signaling. I will maintain high BMP signaling in naïve mice and mice exposed to UCMS, administer ketamine, and measure behavioral effects. While ketamine use poses its own risks, understanding the mechanisms of its antidepressant effects may inform a new generation of rapid-acting antidepressant medications.

主要抑郁症（MDD）是全球残疾的三大原因之一，但只有60-70％ MDD患者对一线疗法有反应，响应者持续损害和回报。 这需要进一步研究抑郁症和抗抑郁作用的分子基础。使用 化学发生技术，我们的实验室已经建立了成人海马变化之间的因果关系 小鼠的神经发生和动画/抑郁症行为。此外，我们已经表明，新的 神经元的活性没有神经发生的增加足以迅速诱导抗抑郁作用。这 增加新神经元活动的行为后果发生在数小时之内，而增加的影响 新神经元的数量及其整合到海马齿状回（DG）中需要数周。最多 抗抑郁药的患者具有数周的治疗滞后，但抗抑郁作用的发作早期相关 自杀行为减少并增加了缓解可能性，使快速作用抗抑郁药 理想。在下动剂剂量时，NMDA受体拮抗剂氯胺酮在内部执行抗抑郁作用 小时，并持续了几周的治疗作用。了解其机制可能会为新的信息提供信息 抗抑郁药具有最小的治疗滞后和较少的显着不利影响。神经源性的生态位是 氯胺酮的持续作用和单剂量氯胺酮所必需的加速神经发生。我有 发现氯胺酮在DG和DG神经元的活性中增加了神经发生。在这里，我建议 氯胺酮对新生神经元活动培养基的快速行为效应的影响，而对 神经发生其长期行为效应。在AIM 1中，我将确定新生儿的贡献 神经元活性对氯胺酮的急性行为作用。我将定义沉默的新神经元如何改变氯胺酮的 暴露于不可预测的慢性轻度应激（UCMS）的幼稚小鼠和小鼠的急性作用。诱导和 特别是沉默的新神经元，我将使用抑制性设计器受体的CRE诱导表达 在神经茎/祖细胞及其后代中专门激活设计师药物（Dreadd）。我会 管理氯胺酮，并确定新的神经元沉默如何改变氯胺酮对小鼠的影响 动画/抑郁症行为。在AIM 2中，我将研究氯胺酮对持续影响的机制 神经发生和行为，并确定它们是否取决于BMP信号的降低。神经发生 BMP信号传导抑制DG，而BMP信号传导的抑制会增加神经发生并发挥作用 抗抑郁作用。选择性5-羟色胺受体抑制剂（SSRI）氟西汀的行为效应是 通过下降BMP信号传导介导，我发现氯胺酮治疗类似地降低了BMP 信号。我将在幼稚的小鼠和暴露于UCMS的小鼠中保持高BMP信号传导，给予氯胺酮， 并衡量行为效应。氯胺酮的使用会带来自身的风险，但了解其机制 抗抑郁作用可能会为新一代快速作用抗抑郁药提供信息。