Vision-dependent specification of cell types and function in the developing cortex

The role of postnatal experience in sculpting cortical circuitry, while long appreciated, is poorly understood at the level of cell types. We explore this in the mouse primary visual cortex (V1) using single-nucleus RNA-sequencing, visual deprivation, genetics, and functional imaging. We find that vision selectively drives the specification of glutamatergic cell types in upper layers (L) (L2/3/4), while deeper-layer glutamatergic, GABAergic, and non-neuronal cell types are established prior to eye opening. L2/3 cell types form an experience-dependent spatial continuum defined by the graded expression of ~200 genes, including regulators of cell adhesion and synapse formation. One of these, Igsf9b, a vision-dependent gene encoding an inhibitory synaptic cell adhesion molecule, is required for the normal development of binocular responses in L2/3. In summary, vision preferentially regulates the development of upper-layer glutamatergic cell types through the regulation of cell type-specific gene expression programs. Single-nucleus transcriptomics of P8, P14, P17, P21, P28, and P38 normally reared mice and P28 dark-reared, P38 dark-reared, and P28 dark-light reared mice. Each of the nine datasets was obtained from 30 mice.尽管学界早已认识到产后经验在塑造大脑皮层环路中的重要作用，但在细胞类型层面的具体调控机制仍未被充分阐释。本研究以小鼠初级视觉皮层（V1）为模型，采用单细胞核RNA测序（single-nucleus RNA-sequencing）、视觉剥夺、遗传学操控及功能成像技术对此展开研究。研究发现，视觉信号可选择性地驱动上层皮层（L2/3/4层）谷氨酸能（glutamatergic）细胞类型的特化；而深层皮层的谷氨酸能、GABA能（GABAergic）及非神经元细胞类型则在小鼠睁眼发育阶段前就已确立。L2/3层的细胞类型形成了一个经验依赖的空间连续体，其特征由约200个基因的梯度表达所界定，这些基因涵盖细胞黏附与突触形成的调控因子。其中Igsf9b作为视觉依赖型基因，编码一种抑制性突触细胞黏附分子，其对于L2/3层双眼反应的正常发育至关重要。综上，视觉信号可通过调控细胞类型特异性基因表达程序，优先调控上层皮层谷氨酸能细胞类型的发育进程。本研究对正常饲养的出生后第8（P8）、14（P14）、17（P17）、21（P21）、28（P28）及38（P38）天小鼠，以及P28暗饲养、P38暗饲养、P28暗-光交替饲养的小鼠开展单细胞核转录组学（single-nucleus transcriptomics）分析。本研究的9个数据集均来源于30只小鼠。