A strong animal survival instinct is to approach objects and situations that are of benefit and to avoid risk. In humans, a large proportion of mental disorders are accompanied by impairments in risk avoidance. One of the most important genes involved in mental disorders is disrupted-in-schizophrenia-1 (DISC1), and animal models in which this gene has some level of dysfunction show emotion-related impairments. However, it is not known whether DISC1 mouse models have an impairment in avoiding potential risks. In the present study, we used DISC1-N terminal truncation (DISC1-N^TM) mice to investigate risk avoidance and found that these mice were impaired in risk avoidance on the elevated plus maze (EPM) and showed reduced social preference in a three-chamber social interaction test. Following EPM tests, c-Fos expression levels indicated that the nucleus accumbens (NAc) was associated with risk-avoidance behavior in DISC1-N^TM mice. In addition, in vivo electrophysiological recordings following tamoxifen administration showed that the firing rates of fast-spiking neurons (FS) in the NAc were significantly lower in DISC1-N^TM mice than in wild-type (WT) mice. In addition, in vitro patch clamp recording revealed that the frequency of action potentials stimulated by current injection was lower in parvalbumin (PV) neurons in the NAc of DISC1-N^TM mice than in WT controls. The impairment of risk avoidance in DISC1-N^TM mice was rescued using optogenetic tools that activated NAc^PV neurons. Finally, inhibition of the activity of NAc^PV neurons in PV-Cre mice mimicked the risk-avoidance impairment found in DISC1-N^TM mice during tests on the elevated zero maze. Taken together, our findings confirm an impairment in risk avoidance in DISC1-N^TM mice and suggest that reduced excitability of NAc^PV neurons is responsible.

一种强烈的动物求生本能是接近有益的物体和情况并避免风险。在人类中，很大一部分精神障碍伴随着风险规避能力受损。与精神障碍有关的最重要基因之一是精神分裂症中断 1 ( DISC1 )，该基因具有一定程度功能障碍的动物模型显示出与情绪相关的障碍。然而，尚不清楚DISC1小鼠模型在规避潜在风险方面是否存在障碍。在本研究中，我们使用了DISC1-N末端截断 ( DISC1-N ^TM) 小鼠来研究风险规避，发现这些小鼠在高架十字迷宫 (EPM) 上的风险规避能力受损，并在三室社交互动测试中表现出降低的社会偏好。在 EPM 测试之后，c-Fos 表达水平表明伏隔核 (NAc) 与DISC1-N ^TM小鼠的风险规避行为相关。此外，他莫昔芬给药后的体内电生理记录表明，DISC1-N ^TM小鼠中NAc 中快速尖峰神经元 (FS) 的放电率显着低于野生型 (WT) 小鼠。此外，体外膜片钳记录显示，在DISC1-N ^TM小鼠NAc 中的小清蛋白 (PV) 神经元中，电流注射刺激的动作电位频率低于 WT 对照。使用激活 NAc ^PV神经元的光遗传学工具挽救了DISC1-N ^TM小鼠的风险规避障碍。最后，PV-Cre 小鼠中 NAc ^PV神经元活性的抑制模拟了在高架零迷宫测试期间在DISC1-N ^TM小鼠中发现的风险规避障碍。总之，我们的研究结果证实了DISC1-N ^TM小鼠的风险规避受损，并表明 NAc ^{PV 的}兴奋性降低 神经元负责。