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

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.

重度抑郁症（MDD）是世界范围内导致残疾的三大原因之一，但只有60-70%的人 MDD患者对一线治疗有反应，而反应者有持久的损伤和复发。 因此，需要进一步研究抑郁症和抗抑郁作用的分子基础。使用 化学遗传学技术，我们的实验室已经建立了成人海马变化之间的因果关系， 神经发生和焦虑/抑郁样行为。此外，我们已经表明，急剧增加的新 神经元活性而不增加神经发生足以快速诱导抗抑郁作用。的 增加新神经元活动的行为后果在数小时内发生，而增加神经元活动的影响在数小时内发生。 新生神经元的数量和它们整合到海马齿状回（DG）需要数周时间。最 抗抑郁药在患者中有数周的治疗滞后，但抗抑郁作用的早期发作与 自杀行为减少，缓解的可能性增加，使速效抗抑郁药 令人向往在亚麻醉剂量，NMDA受体拮抗剂氯胺酮发挥抗抑郁作用， 小时，并具有持续数周的治疗效果。了解其机制可以为新的 具有最小治疗滞后和较少显著副作用的抗抑郁药。神经原生态位是 氯胺酮的持续作用和单剂量氯胺酮加速神经发生所必需的。我有 发现氯胺酮增加DG的神经发生和DG神经元的活性。在此，我提议， 氯胺酮对新生神经元活动的影响介导氯胺酮的快速行为效应，而对新生神经元活动的影响介导氯胺酮的快速行为效应。 神经发生是其长期行为效应的基础。在目标1中，我将确定新生儿 神经元活动与氯胺酮的急性行为效应之间的关系我会解释沉默新的神经元是如何改变氯胺酮的 对未处理小鼠和暴露于不可预测的慢性轻度应激（UCMS）的小鼠的急性效应。以诱导和 为了特异性地沉默新的神经元，我将使用抑制性设计受体的Cre诱导表达 在神经干/祖细胞及其后代中的设计药物独家激活（DREADD）。我会 给药氯胺酮并确定新的神经元沉默如何改变氯胺酮对小鼠的作用 焦虑/抑郁样行为。在目标2中，我将研究氯胺酮的持续作用机制， 神经发生和行为，并确定它们是否依赖于BMP信号传导的减少。神经发生 DG被BMP信号抑制，BMP信号的抑制增加神经发生，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 通过减少BMP信号传导介导，我发现氯胺酮治疗类似地减少BMP 信号我将在未处理小鼠和暴露于UCMS的小鼠中维持高BMP信号传导，给予氯胺酮， 并测量行为效应。虽然氯胺酮的使用有其自身的风险，但了解其机制， 抗抑郁作用可能会为新一代速效抗抑郁药物提供信息。