Conservation and alteration of mammalian striatal interneurons

Mammalian brains vary in size, structure, and function, but the extent to which evolutionarily novel cell types contribute to this variation remains unresolved. Recent studies suggest there is a primate-specific population of striatal inhibitory interneurons, the TAC3 interneurons. However, broader taxonomic and developmental characterization is required to address novelty in cell type evolution. Here, we examine gene expression in inhibitory neurons across 11 mammalian species, spanning 160 million years divergence from primates. We find that the initial class of newborn TAC3 interneurons specified during development represents an ancestral, MGE-derived striatal population also present in pig and ferret cortex. This discovery prompted a reexamination of the Glire clade, including mice which are thought to lack the TAC3 type. Targeted enrichment of MGE precursors in mice reveals conservation of the TAC3 initial class, camouflaged by reduced expression of Tac2 (the mouse ortholog of TAC3) and a gain of Th expression. Extending our analysis to the adult striatum further supports the homology of primate TAC3 and mouse Th striatal interneurons, while uncovering a rare Tac2 subpopulation in mouse ventromedial striatum. This study suggests that initial classes of telencephalic inhibitory neurons are largely conserved and that during evolution, neuronal types in the mammalian brain change through redistribution and fate refinement, rather than by derivation of novel precursors early in development.哺乳动物的大脑在尺寸、结构与功能上均存在差异，但进化上新颖的细胞类型对这种差异的贡献程度仍未明确。近期研究发现一类灵长类特异性的纹状体抑制性中间神经元（striatal inhibitory interneurons），即TAC3中间神经元（TAC3 interneurons）。然而，要阐明细胞类型进化的新颖性，仍需开展更广泛的分类学与发育特征研究。本研究对11种哺乳动物的抑制性神经元进行基因表达分析，这些物种与灵长类的分化时间跨度达1.6亿年。我们发现，发育过程中特化的新生TAC3中间神经元初始类群，实则为一类祖先性的、源自内侧神经节隆起（Medial Ganglionic Eminence，MGE）的纹状体细胞群，该类群同样存在于猪与雪貂的皮层中。这一发现促使我们重新审视Glire演化支（Glire clade）——其中包括此前被认为缺乏TAC3型神经元的小鼠。对小鼠内侧神经节隆起前体细胞的靶向富集实验显示，TAC3初始类群在小鼠中仍具有保守性，只是其特征被Tac2（TAC3在小鼠中的同源基因）表达水平下调以及酪氨酸羟化酶（Tyrosine Hydroxylase，Th）表达上调所掩盖。将分析拓展至成年纹状体后，进一步证实了灵长类TAC3中间神经元与小鼠Th纹状体中间神经元的同源性，同时还在小鼠腹内侧纹状体中发现了一个罕见的Tac2亚群。本研究表明，端脑抑制性神经元的初始类群在很大程度上具有保守性；在演化过程中，哺乳动物大脑的神经元类型并非通过发育早期产生全新前体细胞的方式演化，而是通过细胞类型的重分布与命运细化实现改变。