Anxiety disorder (AD) is characterized by the development of maladaptive neuronal circuits and changes to the excitatory/inhibitory (E/I) balance of the central nervous system. Although AD is considered to be heritable, specific genetic markers remain elusive. Recent genome-wide association studies (GWAS) studies have identified non-catalytic region of tyrosine kinase adaptor protein 1 (NCK1), a gene that codes for an intracellular adaptor protein involved in actin dynamics, as an important gene in the regulation of mood. Using a murine model in which NCK1 is inactivated, we show that male, but not female, mice display increased levels of context-dependent anxiety-like behaviors along with an increase in circulating serum corticosterone relative to control. Treatment of male NCK1 mutant mice with a positive allosteric modulator of the GABA_A receptor rescued the anxiety-like behaviors implicating NCK1 in regulating neuronal excitability. These defects are not attributable to apparent defects in gross brain structure or in axon guidance. However, when challenged in an approach-avoidance conflict paradigm, male NCK1-deficient mice have decreased neuronal activation in the prefrontal cortex (PFC), as well as decreased activation of inhibitory interneurons in the basolateral amygdala (BLA). Finally, NCK1 deficiency results in loss of dendritic spine density in principal neurons of the BLA. Taken together, these data implicate NCK1 in the control of E/I balance in BLA. Our work identifies a novel role for NCK1 in the regulation of sex-specific neuronal circuitry necessary for controlling anxiety-like behaviors. Further, our work points to this animal model as a useful preclinical tool for the study of novel anxiolytics and its significance towards understanding sex differences in anxiolytic function.

焦虑症（AD）的特征是适应不良的神经元回路的发展以及中枢神经系统兴奋/抑制（E / I）平衡的变化。尽管AD被认为是可遗传的，但是具体的遗传标记仍然难以捉摸。最近的全基因组关联研究（GWAS）研究已确定酪氨酸激酶衔接蛋白1（NCK1）的非催化区域，该基因编码参与肌动蛋白动力学的细胞内衔接蛋白，是调节情绪的重要基因。使用其中NCK1的鼠模型灭活后，我们显示雄性而非雌性小鼠表现出与情景相关的焦虑样行为水平升高，以及相对于对照的循环血清皮质酮水平升高。用GABA _A的正变构调节剂治疗雄性NCK1突变小鼠受体挽救了NCK1参与调节神经元兴奋性的焦虑样行为。这些缺陷不能归因于总体大脑结构或轴突引导中的明显缺陷。但是，当在避免进近冲突的范式中受到挑战时，雄性NCK1缺陷型小鼠的前额叶皮层（PFC）中的神经元激活降低，而基底外侧杏仁核（BLA）中的抑制性中间神经元激活降低。最后，NCK1缺乏导致BLA主要神经元的树突棘密度降低。综上所述，这些数据意味着NCK1参与了BLA中E / I平衡的控制。我们的工作确定了NCK1的新角色在控制焦虑样行为所需的性别特异性神经元回路的调节中。此外，我们的工作指出这种动物模型是研究新型抗焦虑药的有用的临床前工具，并且对理解抗焦虑功能的性别差异具有重要意义。