Deciphering the transcriptomic signatures, physiology, and connectivity of the specialized morphotypes in macaque insular cortex

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Abstract Since Ramon y Cajal, neuroscientists have speculated that even the most complex brain functions might even- tually be understood at the level of neuronal cell types and their connections. More recently, while we have be- gun to understand cell types and their wiring principles in cortical circuits of rodents, we are still in infancy in understanding the circuit organization of the primate cortex at the level of cell types and their connections, slowing progress toward a circuit-level mechanistic understanding of complex cognitive capabilities of pri- mates. For instance, the human cortex houses two unique morphotypes, von Economo neurons (VENs) and fork cells, which are concentrated in the cortical regions that support complex social cognitive abilities and self- awareness. For a long time, the VENs and fork cells are believed to be unique to human and great apes, and thus are hypothesized to be the neural correlate of consciousness and human-like complex social behaviors. Despite their importance, their functions are deemed to be experimentally intractable given their exclusive re- striction to hominids. A recent study, however, provides compelling evidence that these unique morphotypes are also present in the anterior insula (AI) of macaque monkeys, providing an unprecedented opportunity for functional characterization of these novel neurons in the laboratory. Here, by partnering with a Chinese primate research laboratory to leverage the abundant macaque resources and lower cost of single-cell RNA- sequencing (scRNA-seq) in China, we propose to take this opportunity to dissect out the cortical circuit of mon- key AI and characterize these novel cell types in terms of electrophysiology, morphology, transcriptome, and connectivity. By taking advantage of a novel set of cost-effective, high-throughput approaches, including large- scale droplet-based scRNA-seq, Patch-seq, and multi-cell patch recordings, we aim to identify and character- ize all the cell types that comprise monkey AI with molecular, spatial and functional annotations. Particularly, this comprehensive interrogation of macaque cortical circuit will lead to a detailed, functional characterization of VENs and FCs for the first time. Importantly, by complementing the strength and unique resources of two collaborating labs in USA and in China, we expect to accomplish this otherwise infeasible, costly primate re- search at this scale within a reasonable budget and time period, providing unprecedented knowledge and re- source for the field to understand the emergence of human-like social intelligence and related neuropsychiatric disorders. Particularly, identifying the specific marker genes for those novel cell types will promote the field to develop genetically targeted tools for studying human-like social cognitive abilities in the context of behaviors. With all information and tools available, our understanding of human intelligence, previously perceived as ex- perimentally intractable and largely speculative, will finally gain solid ground and are ready to take off in the near future.