Visual experience-dependent expression of Fn14 is required for retinogeniculate refinement (Fn14 KO RNA-Seq)

Sensory experience influences the establishment of neural connectivity through molecular mechanisms that remain unclear. Here, we employ single-nucleus RNA-sequencing to investigate the contribution of sensory-driven gene expression to synaptic refinement in the dorsal lateral geniculate nucleus of the thalamus, a region of the brain that processes visual information. We find that visual experience induces the expression of the cytokine receptor Fn14 in excitatory thalamocortical neurons. By combining electrophysiological and structural techniques, we show that Fn14 is dispensable for early phases of refinement mediated by spontaneous activity, but that Fn14 is essential for refinement during a later, experience-dependent period of development. Refinement deficits in mice lacking Fn14 are associated with functionally weaker and structurally smaller retinogeniculate inputs, indicating that Fn14 mediates both functional and anatomical rearrangements in response to sensory experience. These findings identify Fn14 as a molecular link between sensory-driven gene expression and vision-sensitive refinement in the brain. Whole-transcriptome RNA-sequencing was performed on microdissected dLGN tissue from male and female Fn14 KO and WT littermates at P27. Differential gene expression analysis was used to compare KO to WT.

感官经验通过尚未阐明的分子机制调控神经连接的建立。本研究采用单细胞核RNA测序（single-nucleus RNA-sequencing），探究感官驱动的基因表达对丘脑背外侧膝状体核（dorsal lateral geniculate nucleus, dLGN）突触精细化的调控作用——该脑区负责视觉信息的处理。研究发现，视觉经验可诱导兴奋性丘脑皮层神经元中细胞因子受体Fn14的表达。结合电生理与结构学技术，我们证实：Fn14对于自发活动介导的突触精细化早期阶段并非必需，但在发育后期依赖感官经验的精细化阶段中，Fn14发挥不可或缺的作用。缺失Fn14的小鼠存在突触精细化缺陷，该缺陷与视网膜-膝状体传入纤维的功能减弱、结构萎缩相关，表明Fn14可介导感官经验诱导的功能与解剖学重塑。本研究证实Fn14是感官驱动的基因表达与大脑视觉敏感性突触精细化之间的分子关联因子。研究人员于出生后第27天（postnatal day 27, P27），对雌雄Fn14基因敲除（KO）与野生型（WT）同窝小鼠的显微切割dLGN组织开展全转录组RNA测序，并通过差异基因表达分析比较KO组与WT组的基因表达差异。