Abstract：
Closed head injury is a prevalent form of traumatic brain injury with poorly understood effects on cortical neural circuits. Given the emotional and behavioral impairments linked to closed head injury, it is vital to uncover brain functional deficits and their driving mechanisms. In this study, we employed a robust viral tracing technique to identify the alteration of the neural pathway connecting the medial prefrontal cortex to the basolateral amygdala, and we observed the disruptions in neuronal projections between the medial prefrontal cortex and the basolateral amygdala following closed head injury. Remarkably, our results highlight that ZL006, an inhibitor targeting PSD-95/nNOS interaction, stands out for its ability to selectively reverse these aberrations. Specifically, ZL006 effectively mitigates the disruptions in neuronal projections from the medial prefrontal cortex to basolateral amygdala induced by closed head injury. Furthermore, using chemogenetic approaches, we elucidate that activating the medial prefrontal cortex projections to the basolateral amygdala circuit produces anxiolytic effects, aligning with the therapeutic potential of ZL006. Additionally, ZL006 administration effectively mitigates astrocyte activation, leading to the restoration of medial prefrontal cortex glutamatergic neuron activity. Moreover, in the context of attenuating anxiety-like behaviors through ZL006 treatment, we observe a reduction in closed head injury-induced astrocyte engulfment, which may correlate with the observed decrease in dendritic spine density of medial prefrontal cortex glutamatergic neurons.
摘要：
闭合性颅脑损伤是创伤性脑损伤的一种常见形式，对皮质神经回路的影响知之甚少。鉴于与闭合性头部损伤相关的情绪和行为障碍，发现大脑功能缺陷及其驱动机制至关重要。在这项研究中,我们采用了一种强大的病毒追踪技术来识别连接内侧前额叶皮质和基底外侧杏仁核的神经通路的改变，我们观察到闭合性颅脑损伤后内侧前额叶皮质和基底外侧杏仁核之间的神经元投射中断。值得注意的是,我们的结果强调了ZL006，一种靶向PSD-95/nNOS相互作用的抑制剂，以其选择性逆转这些畸变的能力而脱颖而出。具体来说,ZL006有效地减轻了闭合性颅脑损伤引起的内侧前额叶皮质到基底外侧杏仁核的神经元投射的破坏。此外，使用化学遗传学方法，我们阐明，激活内侧前额叶皮质投射到基底外侧杏仁核回路产生抗焦虑作用，与ZL006的治疗潜力一致。此外,ZL006给药有效缓解星形胶质细胞活化，导致内侧前额叶皮质谷氨酸能神经元活动的恢复。此外，在通过ZL006治疗减轻焦虑样行为的背景下，我们观察到闭合性颅脑损伤引起的星形胶质细胞吞噬减少，这可能与所观察到的内侧前额叶皮质谷氨酸能神经元的树突脊柱密度降低有关。
