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）是全球悬浮性的最高，但只有60-70％ MDD患者对一线疗法有反应，响应者患有持久的障碍和递归。 因此，需要进一步研究剥夺和抗抑郁药的分子基础。 化学发生技术 小鼠的神经发生和焦虑/抑郁样行为。 神经元的活性无需增加神经发生，足以迅速诱导indidepressions效应 增加神经元活性的行为后果发生在数小时内，而增加的影响 新神经元的数量以及在海马齿状回（DG）中的整合需要数周。 抗抑郁药在患者中具有数周的治疗滞后，但较早的ontidepressssants效应相关联。 随着自杀行为的降低和缓解可能性增加，使快速抗抑郁药 可取的。 小时并持续了几周的治疗作用。 具有最小治疗滞后的抗抑郁药和较少的显着不良反应。 氯胺酮的持续作用和单剂量的氯胺酮加速了神经发生 发现氯胺酮在DG和DG神经元的活性中增加了神经发生。 氯胺酮对新生神经元活性介体快速行为效应的影响，而对 神经发生是其长期行为效应。 神经元活性促进氯胺酮的加强行为作用。 暴露于不可预测的慢性应激（UCM）的幼稚小鼠和小鼠的急性作用 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）。 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 在AIM 2中，焦虑/抑郁症的行为，我将检查氯胺酮的持续影响 神经发生和行为，并确定它们是否依赖 BMP信号传导抑制了DG，而BMP信号的不可自行性会增加神经发生并发挥作用 抗抑郁作用。 通过降低BMP信号传导介导，我发现氯胺酮治疗类似地降低了BMP 信号。 并衡量行为影响，而氯胺酮使用会带来自身的风险 抗抑郁作用可能会为新一代快速抗抑郁药提供信息。