Dysregulation of the Synaptic Cytoskeleton in the PFC Drives Neural Circuit Pathology, Leading to Social Dysfunction.
Dysregulation of the Synaptic Cytoskeleton in the PFC Drives Neural Circuit Pathology, Leading to Social Dysfunction.
复制标题
PFC中突触细胞骨架的失调驱动神经回路病理学，导致社会功能障碍。
DOI：
10.1016/j.celrep.2020.107965
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发表时间：
2020-07-28
期刊：
影响因子：
8.8
通讯作者：
Soderling SH
中科院分区：
文献类型：
--
作者：
Kim IH;Kim N;Kim S;Toda K;Catavero CM;Courtland JL;Yin HH;Soderling SH
精神疾病是高度遗传的神经回路功能改变的病理。然而，基因突变如何导致行为中断的特定神经回路异常仍不清楚。使用电路选择性转基因工具和适应不良的社会行为（ArpC 3突变）的小鼠模型，我们确定了一个神经回路机制驱动功能失调的社会行为。我们证明，电路选择性敲除（ctKO）的ArpC 3基因的前额叶皮质神经元，项目的基底外侧杏仁核提高了电路神经元的兴奋性，导致社会诱发的神经活动的中断，并导致异常的社会行为。野生型小鼠中该回路的光遗传激活重现了ArpC 3突变小鼠中观察到的社会功能障碍。最后，ctKO小鼠的适应不良社交性通过光遗传学沉默该回路内的神经元来拯救。这些结果突出了基因-神经回路相互作用如何驱动改变的社会行为的机制，这是几种精神疾病的常见表型。Kim等人在体内利用回路选择性基因操作方法特异性敲除PFC-BLA回路中的ArpC 3，并发现回路中的神经元活动中断，导致异常的社会行为。光遗传学PFC-BLA回路激活破坏了正常小鼠的社交能力，而光遗传学回路沉默则挽救了回路敲除小鼠的异常社交能力。
Psychiatric disorders are highly heritable pathologies of altered neural circuit functioning. How genetic mutations lead to specific neural circuit abnormalities underlying behavioral disruptions, however, remains unclear. Using circuit-selective transgenic tools and a mouse model of maladaptive social behavior (ArpC3 mutant), we identify a neural circuit mechanism driving dysfunctional social behavior. We demonstrate that circuit-selective knockout (ctKO) of the ArpC3 gene within prefrontal cortical neurons that project to the basolateral amygdala elevates the excitability of the circuit neurons, leading to disruption of socially evoked neural activity and resulting in abnormal social behavior. Optogenetic activation of this circuit in wild-type mice recapitulates the social dysfunction observed in ArpC3 mutant mice. Finally, the maladaptive sociability of ctKO mice is rescued by optogenetically silencing neurons within this circuit. These results highlight a mechanism of how a gene-to-neural circuit interaction drives altered social behavior, a common phenotype of several psychiatric disorders. Kim et al. exploit circuit-selective gene manipulation approaches in vivo to specifically knock out ArpC3 in the PFC-BLA circuit and find disrupted neuronal activities in the circuit, leading to abnormal social behavior. Optogenetic PFC-BLA circuit activation disrupts sociability of normal mice, while optogenetic circuit silencing rescues the abnormal sociability in the circuit knockout mice.
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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：
11
作者：
Durand CM;Perroy J;Loll F;Perrais D;Fagni L;Bourgeron T;Montcouquiol M;Sans N
通讯作者：
Sans N
影响因子：
2.5
作者：
CASSELL, MD;CHITTICK, CA;WRIGHT, DJ
通讯作者：
WRIGHT, DJ
DOI：
10.1523/jneurosci.0005-12.2012
发表时间：
2012-04-04
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Bossert JM;Stern AL;Theberge FR;Marchant NJ;Wang HL;Morales M;Shaham Y
通讯作者：
Shaham Y
影响因子：
64.5
作者：
Gore F;Schwartz EC;Brangers BC;Aladi S;Stujenske JM;Likhtik E;Russo MJ;Gordon JA;Salzman CD;Axel R
通讯作者：
Axel R