Depression is a complex psychiatric disorder that is a major burden on society, with only ~33% of depressed patients attaining remission upon initial monotherapy with a selective serotonin reuptake inhibitor (SSRI). In preclinical studies using rodents, chronic stress paradigms, such as chronic corticosterone and social instability stress, are used to induce avoidance behaviors associated with negative affective states. Chronic fluoxetine (FLX; an SSRI) treatment reverses these chronic stress-induced behavioral changes in some, but not all mice, permitting stratification of mice into behavioral responders and non-responders to FLX. We previously reported that 5-HT_1A receptors, which are Gi-coupled inhibitory receptors, on mature granule cells (GCs) in the dentate gyrus (DG) are necessary and sufficient for the behavioral, neurogenic, and neuroendocrine response to chronic SSRI treatment. Since inhibition of mature DG GCs through cell autonomous Gi-coupled receptors is critical for mounting an antidepressant response, we assessed the relationship between behavioral response to FLX and DG GC activation in FLX responders, non-responders, and stress controls in both male and female mice. Intriguingly, using disparate stress paradigms, we found that male and female behavioral FLX responders show decreased DG GC activation (as measured by cFos immunostaining) relative to non-responders and stress controls. We then show in both sexes that chronic inhibition of ventral DG GCs (through usage of Gi-DREADDs) results in a decrease in maladaptive avoidance behaviors, while ventral DG GCs stimulation with Gq-DREADDs increases maladaptive behaviors. Finally, we were able to bidirectionally control the behavioral response to FLX through modulation of DG GCs. Chronic inhibition of ventral DG GCs with Gi-DREADDs converted FLX non-responders into responders, while activation of ventral DG GCs with Gq-DREADDs converted FLX responders into non-responders. This study illustrates ventral DG GC activity is a major modulator of the behavioral response to FLX in both male and female mice.

抑郁症是一种复杂的精神疾病，是社会的主要负担，只有约33％的抑郁症患者在最初的单一疗法中使用选择性5-羟色胺再摄取抑制剂（SSRI）才能获得缓解。在使用啮齿动物的临床前研究中，慢性应激范例（例如慢性皮质酮和社会不稳定应激）被用来诱发与负面情感状态相关的回避行为。慢性氟西汀（FLX; SSRI）治疗可逆转某些但不是全部小鼠中的这些慢性应激诱导的行为变化，从而允许将小鼠分层为FLX的行为反应者和非反应者。我们之前曾报道过5-HT _1A齿状回（DG）中成熟颗粒细胞（GC）上的Gi偶联受体是Gi偶联的抑制性受体，对于行为，神经源性和神经内分泌对慢性SSRI治疗的反应是必要和充分的。由于通过细胞自主的Gi偶联受体抑制成熟的DG GC对于产生抗抑郁反应至关重要，因此我们评估了FLX响应者，无反应者中对FLX的行为响应和DG GC激活之间的关系，以及男性和女性的压力控制老鼠。有趣的是，使用不同的压力范例，我们发现男性和女性行为FLX响应者相对于无响应者和压力控制者，DG GC激活降低（通过cFos免疫染色测量）。然后，我们在男女中均显示，通过使用Gi-DREADDs来抑制腹部DG GC会导致慢性适应不良回避行为的减少，而使用Gq-DREADDs刺激腹侧DG GC则会加剧适应不良的行为。最后，我们能够通过调制DG GC双向控制对FLX的行为响应。带有Gi-DREADDs的腹侧DG GC的慢性抑制将FLX无反应者转化为响应者，而带有Gq-DREADDs的腹侧DG GC的激活将FLX响应者转化为非反应者。这项研究表明，腹部DG GC活性是雄性和雌性小鼠对FLX行为反应的主要调节剂。我们能够通过调制DG GC双向控制对FLX的行为响应。带有Gi-DREADDs的腹侧DG GC的慢性抑制将FLX无反应者转化为响应者，而带有Gq-DREADDs的腹侧DG GC的激活将FLX响应者转化为非反应者。这项研究表明，腹部DG GC活性是雄性和雌性小鼠对FLX行为反应的主要调节剂。我们能够通过调制DG GC双向控制对FLX的行为响应。带有Gi-DREADDs的腹侧DG GC的慢性抑制将FLX无反应者转化为响应者，而带有Gq-DREADDs的腹侧DG GC的激活将FLX响应者转化为非反应者。这项研究表明，腹部DG GC活性是雄性和雌性小鼠对FLX行为反应的主要调节剂。