Cortical-amygdalar circuit dysfunction in a genetic mouse model of serotonin deficiency.
Cortical-amygdalar circuit dysfunction in a genetic mouse model of serotonin deficiency.
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DOI：
10.1523/jneurosci.4891-12.2013
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发表时间：
2013-03-06
期刊：
影响因子：
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通讯作者：
Nicolelis MA
中科院分区：
文献类型：
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作者：
Dzirasa K;Kumar S;Sachs BD;Caron MG;Nicolelis MA
虽然大多数一线抗抑郁药增加脑5-羟色胺和罕见的多态性色氨酸羟化酶-2（Tph 2），在脑5-羟色胺合成途径中的限速酶，已被确定在队列中的受试者患有重度抑郁症，电路水平的改变，从多巴胺能功能减退症的结果仍然知之甚少。在这里，我们使用慢性多回路神经生理学记录来表征小鼠大脑皮层和边缘回路的功能相互作用，这些小鼠被设计为表达人类功能丧失型抑郁等位基因Tph 2-（R441 H）[Tph 2敲入（Tph 2KI）]。我们的研究结果表明，Tph 2KI小鼠表现出增加内侧前额叶皮层（mPFC）和基底杏仁核（AMY）内的网络同步性和增加这两个大脑网络之间的网络间同步性。此外，我们证明，氟西汀的长期治疗逆转了Tph 2KI小鼠内观察到的几个电路改变。总之，我们的研究结果建立了功能性神经功能减退和改变mPFC-AMY网络动力学之间的功能联系。
Although the majority of first-line antidepressants increase brain serotonin and rare polymorphisms in tryptophan hydroxlase-2 (Tph2), the rate-limiting enzyme in the brain serotonin synthesis pathway, have been identified in cohorts of subjects with major depressive disorder, the circuit level alterations that results from serotonergic hypofunction remain poorly understood. Here we use chronic multicircuit neurophysiological recordings to characterize functional interactions across cortical and limbic circuits in mice engineered to express a human loss-of-function depression allele Tph2-(R441H) [Tph2 knockin (Tph2KI)]. Our results show that Tph2KI mice exhibit increased intra-network synchrony within medial prefrontal cortex (mPFC) and basal amygdala (AMY) and increased internetwork synchrony between these two brain networks. Moreover, we demonstrate that chronic treatment with fluoxetine reverses several of the circuit alterations observed within Tph2KI mice. Together, our findings establish a functional link between functional hyposerotonergia and altered mPFC–AMY network dynamics.