Btbd3 expression regulates compulsive-like and exploratory behaviors in mice.
Btbd3 expression regulates compulsive-like and exploratory behaviors in mice.
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Btbd3 表达调节小鼠的强迫样行为和探索行为。
DOI：
10.1038/s41398-019-0558-7
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发表时间：
2019
影响因子：
6.8
通讯作者：
Dulawa,StephanieC
中科院分区：
文献类型：
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作者：
Thompson,SummerL;Welch,AmandaC;Ho,EmilyV;Bessa,JoãoM;Portugal-Nunes,Carlos;Morais,Mónica;Young,JaredW;Knowles,JamesA;Dulawa,StephanieC
在首次强迫症（OCD）全基因组关联研究中，BTB/POZ结构域3 （BTBD3）被确定为潜在风险基因。BTBD3是一种被认为与初级感觉皮层发育过程中树突修剪有关的转录因子。我们评估了BTBD3是否也调节小鼠边缘皮质-纹状体-丘脑-皮质回路中的神经回路形成和与强迫症相关的行为。与强迫症相关的行为表型在动物身上是可测量的，包括强迫行为和减少探索。我们测试了dbtbd3野生型、杂合型和基因敲除型小鼠的强迫行为，包括在笼子里给同伴拔毛、过度跑动轮子、重复运动模式、在概率学习任务（PLT）中目标导向行为的减少，以及在开阔场地、挖掘和埋大理石测试中的探索行为。btbd3杂合和敲除小鼠在PLT中表现出过度的剃毛、滚轮跑、目标导向行为受损以及探索减少。此外，氟西汀而非地西帕明的慢性治疗减少了btbd3野生型和杂合型小鼠的脱发，但没有减少基因敲除小鼠的脱发。相比之下，btbd3的表达并没有改变焦虑样、抑郁样或感觉运动行为。我们还量化了btbd3高表达区域前扣带皮层、丘脑中背侧和海马的树突形态。令人惊讶的是，btbd3基因敲除小鼠仅显示出前扣带脊柱密度的适度增加，而其他部位的树突形态没有改变。最后，在新生儿发育过程中，我们病毒性地敲低了整个海马或海马背侧的btbd3表达，并评估了成年期的行为。整个海马btbd3敲除，但不包括背侧，重现了btbd3敲除表型。我们的研究结果表明，海马btbd3的表达选择性地调节强迫行为和探索行为。
BTB/POZ domain-containing 3 (BTBD3) was identified as a potential risk gene in the first genome-wide association study of obsessive-compulsive disorder (OCD). BTBD3 is a putative transcription factor implicated in dendritic pruning in developing primary sensory cortices. We assessed whether BTBD3 also regulates neural circuit formation within limbic cortico-striato-thalamo-cortical circuits and behaviors related to OCD in mice. Behavioral phenotypes associated with OCD that are measurable in animals include compulsive-like behaviors and reduced exploration. We testedBtbd3wild-type, heterozygous, and knockout mice for compulsive-like behaviors including cage-mate barbering, excessive wheel-running, repetitive locomotor patterns, and reduced goal-directed behavior in the probabilistic learning task (PLT), and for exploratory behavior in the open field, digging, and marble-burying tests.Btbd3heterozygous and knockout mice showed excessive barbering, wheel-running, impaired goal-directed behavior in the PLT, and reduced exploration. Further, chronic treatment with fluoxetine, but not desipramine, reduced barbering inBtbd3wild-type and heterozygous, but not knockout mice. In contrast,Btbd3expression did not alter anxiety-like, depression-like, or sensorimotor behaviors. We also quantified dendritic morphology within anterior cingulate cortex, mediodorsal thalamus, and hippocampus, regions of highBtbd3expression. Surprisingly,Btbd3knockout mice only showed modest increases in spine density in the anterior cingulate, while dendritic morphology was unaltered elsewhere. Finally, we virally knocked downBtbd3expression in whole, or just dorsal, hippocampus during neonatal development and assessed behavior during adulthood. Whole, but not dorsal, hippocampalBtbd3knockdown recapitulatedBtbd3knockout phenotypes. Our findings reveal that hippocampalBtbd3expression selectively modulates compulsive-like and exploratory behavior.