The ubiquitous presence of inhibitory interneurons in the thalamus of primates contrasts with the sparsity of interneurons reported in mice. Here, we identify a larger than expected complexity and distribution of interneurons across the mouse thalamus, where all thalamic interneurons can be traced back to two developmental programs: one specified in the midbrain and the other in the forebrain. Interneurons migrate to functionally distinct thalamocrtical nuclei depending on their origin: the abundant, midbrain-generated class populates the first and higher order sensory thalamus while the rarer, forebrain-generated class is restricted to some higher order associative regions. We also observe that markers for the midbrain-born class are abundantly expressed throughout the thalamus of the New World monkey marmoset. These data therefore reveal that, despite the broad variability in interneuron density across mammalian species, the blueprint of the ontogenetic organisation of thalamic interneurons of larger-brained mammals exists and can be studied in mice.

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Precise spatiotemporal control of gene expression in the developing brain is critical for neural circuit formation, and comprehensive expression mapping in the developing primate brain is crucial to understand brain function in health and disease. Here, we developed an unbiased, automated, large-scale, cellular-resolution in situ hybridization (ISH)–based gene expression profiling system (GePS) and companion analysis to reveal gene expression patterns in the neonatal New World marmoset cortex, thalamus, and striatum that are distinct from those in mice. Gene-ontology analysis of marmoset-specific genes revealed associations with catalytic activity in the visual cortex and neuropsychiatric disorders in the thalamus. Cortically expressed genes with clear area boundaries were used in a three-dimensional cortical surface mapping algorithm to delineate higher-order cortical areas not evident in two-dimensional ISH data. GePS provides a powerful platform to elucidate the molecular mechanisms underlying primate neurobiology and developmental psychiatric and neurological disorders.

12The proportion and distribution of local inhibitory neurons (interneurons) in the thalamus 13 varies widely across mammals. This is reflected in the structure of thalamic local circuits, 14which is more complex in primates compared to smaller-brained mammals like rodents. 15An increase in the number of thalamic interneurons could arise from addition of novel 16 interneuron types or from elaboration of a plesiomorphic ontogenetic program, common to 17 all mammals. The former has been proposed for the human brain, with migration of 18 interneurons from the ventral telencephalon into higher order thalamus as one of its unique 19 features (Letinic and Rakic, 2001). 20Here, we identify a larger than expected complexity and distribution of interneurons across 21 the mouse thalamus. All thalamic interneurons can be traced back to two developmental 22 programs: one specified in the midbrain and the other in the forebrain. Interneurons migrate 23 to functionally distinct thalamic nuclei, where the midbrain-derived cells populate the sensory 24 thalamus, and forebrain-generated interneurons only the higher order regions. The latter 25 interneuron type may be homologous to the one previously considered to be human-specific, 26while we also observe that markers for the midbrain-born class are abundantly expressed in 27 the primate thalamus. These data therefore point to a shared ontogenetic organization of 28 thalamic interneurons across mammals. 29 30

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