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We begin by performing cross-species analysis of developing initial classes of both striatal and cortical inhibitory neuron populations by integrating single cell sequencing data from 8 mammals, spanning from primates to marsupials.

Through integrative analysis, we find that initial classes of inhibitory neurons are conserved across placental mammals. Surprisingly, this conservation includes the MGE-derived TAC3 initial class, which was previously thought to be a primate-specific striatal interneuron population

Although the TAC3 initial class is conserved to marsupials (opossum and sugar glider), we observe turnover of signaling pathway genes across multiple timescales, and an additional migratory destination in Laurasiatherian (pig and ferret) cortex

Given the conservation of this initial class in Laurasiatherians and marsupials, we next investigate the Glire lineage (rabbit, naked mole rat, rat, mouse), as the population was reported missing in mouse.

Surprisingly, we find that the population was hiding in plain sight, but disguised by the loss of TAC3 (called Tac2 in mouse) and gain of Th expression, indicating an unappreciated homology between rodent Th and mammalian TAC3 striatal interneurons.

Through integrated analysis of adult mouse, marmoset, and human striatal inhibitory neurons, we confirmed the homology of Th interneurons in adult mouse and TAC3 interneurons in the adult primate.

In adult mouse, we identified a rare subpopulation of Th interneurons which expresses residual Tac2 (TAC3). Using the Allen institute’s Merscope data, we find this rare Tac2-expressing population is spatially restricted to the ventromedial striatum.

Together, we conclude the TAC3 initial class is conserved across placental mammals, but modifies its gene expression and distribution throughout evolution.

Collectively, the broad pattern of inhibitory neuron conservation suggests that, on the mammalian timescale, evolution modifies the brain by ‘teaching old cells new tricks’, rather than inventing novel cell types early in development.

7/11/25, 6:06 pm1 repost3 likes