Behavioral response to fluoxetine in both female and male mice is modulated by dentate gyrus granule cell activity.
Behavioral response to fluoxetine in both female and male mice is modulated by dentate gyrus granule cell activity.
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雌性和雄性小鼠对氟西汀的行为反应均受齿状回颗粒细胞活性的调节。
DOI：
10.1016/j.ynstr.2020.100257
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发表时间：
2020-11
影响因子：
5
通讯作者：
Samuels BA
中科院分区：
文献类型：
--
作者：
Yohn CN;Dieterich A;Maita I;Bazer AS;Diethorn E;Ma D;Gergues MM;Hu P;Samuels BA
抑郁症是一种复杂的精神障碍，是社会的主要负担，只有33%的抑郁症患者在最初使用选择性5-羟色胺再摄取抑制剂(SSRI)进行单一治疗后获得缓解。在啮齿动物的临床前研究中，慢性应激范式，如慢性皮质酮和社会不稳定应激，被用来诱导与负面情感状态相关的回避行为。慢性氟西汀(Flx；一种SSRI)治疗逆转了部分(但不是所有)小鼠的这些慢性应激诱导的行为变化，允许将小鼠分为对Flx有反应和无反应的小鼠。我们先前报道，齿状回(DG)成熟颗粒细胞(GC)上的5-HT1A受体是慢性SSRI治疗的行为、神经源性和神经内分泌反应所必需的和充分的，是GI偶联抑制受体。由于通过细胞自主GI偶联受体抑制成熟的DG GC是启动抗抑郁反应的关键，我们评估了对Flx的行为反应与Flx应答者、无应答者和应激控制雄性和雌性小鼠的DG GC激活之间的关系。有趣的是，使用不同的应激范式，我们发现男性和女性行为Flx应答者与无应答者和应激对照组相比，DG GC激活(通过CFOS免疫染色测量)减少。我们随后发现，在两性中，长期抑制腹侧DG GC(通过使用GI-DREADDS)导致不良适应回避行为的减少，而GQ-DREADD刺激腹侧DG GCs会增加不良适应行为。最后，我们能够通过调节DG-GC来双向控制对氟尿嘧啶的行为反应。GI-DREADD对腹侧DG GC的慢性抑制将FLX无反应者转化为应答者，而GQ-DREADD激活腹侧DG GC将FLX应答者转化为无反应者。这项研究表明，腹侧DGGC活性是雄性和雌性小鼠对氟尿嘧啶行为反应的主要调节因素。
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-HT1A 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.
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影响因子：
25
作者：
Samuels BA;Anacker C;Hu A;Levinstein MR;Pickenhagen A;Tsetsenis T;Madroñal N;Donaldson ZR;Drew LJ;Dranovsky A;Gross CT;Tanaka KF;Hen R
通讯作者：
Hen R
影响因子：
56.9
作者：
Santarelli, L;Saxe, M;Hen, R
通讯作者：
Hen, R
影响因子：
56.9
作者：
Luna, Victor M.;Anacker, Christoph;Hen, Rene
通讯作者：
Hen, Rene
影响因子：
3.5
作者：
Lacefield, Clay O.;Itskov, Vladimir;Reardon, Thomas;Hen, Rene;Gordon, Joshua A.
通讯作者：
Gordon, Joshua A.
影响因子：
4.6
作者：
Manvich DF;Webster KA;Foster SL;Farrell MS;Ritchie JC;Porter JH;Weinshenker D
通讯作者：
Weinshenker D