Prefrontal cortex-dependent innate behaviors are altered by selective knockdown of Gad1 in neuropeptide Y interneurons.
Prefrontal cortex-dependent innate behaviors are altered by selective knockdown of Gad1 in neuropeptide Y interneurons.
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DOI：
10.1371/journal.pone.0200809
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Dobrunz LE
中科院分区：
文献类型：
--
作者：
Corder KM;Cortes MA;Bartley AF;Lear SA;Lubin FD;Dobrunz LE
gaba能功能障碍与多种神经和精神疾病有关，包括焦虑症。焦虑症是青春期最常见的精神疾病。焦虑中GABA能传递不足，通过药物手段增强GABA传递可减少焦虑行为。gad67——一种产生GABA的酶——与焦虑症有关。一类gaba能中间神经元，神经肽Y （NPY）表达细胞，大量存在于大脑中与焦虑和恐惧学习相关的区域，包括前额皮质、海马和杏仁核。此外，NPY本身已被证明具有抗焦虑作用，NPY+中间神经元的缺失会增强焦虑行为。先前的一项研究表明，从NPY+细胞中敲除Gad1可以减少成年小鼠的焦虑行为。然而，从NPY+中间神经元释放GABA在青少年焦虑中的作用尚不清楚。在这里，我们使用了一种转基因小鼠，通过敲除Gad1来降低NPY+细胞中的GAD67 (NPYGAD1-TG)，并测试了对青春期小鼠行为的影响。青少年NPYGAD1-TG小鼠表现出增强的焦虑样行为和运动活动的性别依赖性变化。我们还发现，另外两项先天行为任务——筑巢和社会支配——也有增强。相比之下，恐惧学习没有变化。因为我们看到了依赖于前额皮质和海马体的行为任务的变化，我们研究了GAD67在这些区域的下调程度。免疫组织化学显示，前额皮质NPY+细胞中GAD67降低40%，表明GAD67明显但不完全下调。相比之下，海马NPY+细胞中GAD67未见减少。与此一致的是，海马的抑制性突触传递没有变化。我们的研究结果显示了细胞特异性中间神经元功能障碍的行为影响，并表明NPY+细胞释放GABA对调节青少年先天前额叶皮层依赖行为很重要。
GABAergic dysfunction has been implicated in a variety of neurological and psychiatric disorders, including anxiety disorders. Anxiety disorders are the most common type of psychiatric disorder during adolescence. There is a deficiency of GABAergic transmission in anxiety, and enhancement of GABA transmission through pharmacological means reduces anxiety behaviors. GAD67—the enzyme responsible for GABA production–has been linked to anxiety disorders. One class of GABAergic interneurons, Neuropeptide Y (NPY) expressing cells, is abundantly found in brain regions associated with anxiety and fear learning, including prefrontal cortex, hippocampus and amygdala. Additionally, NPY itself has been shown to have anxiolytic effects, and loss of NPY+ interneurons enhances anxiety behaviors. A previous study showed that knockdown of Gad1 from NPY+ cells led to reduced anxiety behaviors in adult mice. However, the role of GABA release from NPY+ interneurons in adolescent anxiety is unclear. Here we used a transgenic mouse that reduces GAD67 in NPY+ cells (NPYGAD1-TG) through Gad1 knockdown and tested for effects on behavior in adolescent mice. Adolescent NPYGAD1-TG mice showed enhanced anxiety-like behavior and sex-dependent changes in locomotor activity. We also found enhancement in two other innate behavioral tasks, nesting construction and social dominance. In contrast, fear learning was unchanged. Because we saw changes in behavioral tasks dependent upon prefrontal cortex and hippocampus, we investigated the extent of GAD67 knockdown in these regions. Immunohistochemistry revealed a 40% decrease in GAD67 in NPY+ cells in prefrontal cortex, indicating a significant but incomplete knockdown of GAD67. In contrast, there was no decrease in GAD67 in NPY+ cells in hippocampus. Consistent with this, there was no change in inhibitory synaptic transmission in hippocampus. Our results show the behavioral impact of cell-specific interneuron dysfunction and suggest that GABA release by NPY+ cells is important for regulating innate prefrontal cortex-dependent behavior in adolescents.
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影响因子：
2.7
作者：
Davis, Matthew J.;Haley, Tammie;Duvoisin, Robert M.;Raber, Jacob
通讯作者：
Raber, Jacob
影响因子：
3.8
作者：
Bicks LK;Koike H;Akbarian S;Morishita H
通讯作者：
Morishita H
影响因子：
1.7
作者：
Beesdo, Katja;Knappe, Susanne;Pine, Daniel S.
通讯作者：
Pine, Daniel S.
DOI：
10.1073/pnas.95.9.5335
发表时间：
1998-04-28
影响因子：
11.1
作者：
Caldji, C;Tannenbaum, B;Meaney, MJ
通讯作者：
Meaney, MJ
影响因子：
168.9
作者：
Cipriani, Andrea;Zhou, Xinyu;Xie, Peng
通讯作者：
Xie, Peng