Much of our unique abilities can be attributed to the cerebral cortex, which integrates sensory inputs, commands motor activity, and facilitates complex cognitive tasks. Through evolution, both its size and intricacy have expanded, particularly in primates and notably in humans. Cross-species comparisons enable the identification of species-specific changes in neural circuits, including those unique to humans. When tracing these changes through development, it can offer deeper mechanistic insights into the formation and function of the neural circuits that underpin our distinct mental abilities (see our review in Curr Opin Neurobiol 2023). Our lab is dedicated to harnessing multimodal cross-species comparisons (transcriptomics, epigenomics, etc), and utilizing models such as mice, primates, and organoids to decipher the molecular and cellular mechanisms underlying brain development, evolution, and dysfunctions.  

1. Molecular and Cellular mechanisms underlying primate and human brain specializations 

The expansion and evolutionary specializations of the cerebral cortex are thought to underlie the rich and complex nature of cognition in humans and other primates. The molecular and cellular mechanisms governing these processes, however, are not fully understood. Our recent comparative transcriptomic study of dorsolateral prefrontal cortex across adult humans, chimpanzees, macaques, and marmosets has shed light on species differences (Science 2022). While most transcriptomically-defined cell types are conserved, we identified species-specific cell subtypes and observed species divergence in the heterogeneity and abundance of certain intratelencephalic projection neurons. Within homologous cell types, we also unraveled notable molecular changes, characterized by the species-specific employment of neurotransmitters (e.g., dopamine and somatostatin) in certain interneurons, and the primate- and human-specific expression of the language gene FOXP2 in layer 4 granular neurons and microglia, respectively. Continuing with comparative studies, our lab seeks to map species-specific genomic and gene expression regulation to cellular functions, connectivity, and neural circuit, thereby deepening our understanding of human brain organization and cognitive function.  

2. Developmental and evolutionary mechanisms governing primate cortical arealization 

The human cerebral cortex is divided into numerous areas, each with distinct anatomical, functional and connectivity characteristics, a level of heterogeneity not readily comparable in other species. However, the developmental and evolutionary mechanisms contributing to the formation of such diverse cell types, gene expression profiles, and circuits in the human cerebral cortex are less understood. The Protomap hypothesis indicates that intrinsic mechanisms seeded in early neural stem cells establish regional identities, while the Protocortex hypothesis hinted that cell identities undergo further refinement through extrinsic mechanisms, particularly thalamocortical projections. Our recent research has provided a comprehensive molecular landscape of macaque cortical arealization and identified key region-specific signatures attributed to intrinsic or extrinsic mechanisms (Science 2023). In addition, we discovered a primate-specific activation of GALP signaling, selectively involved in the patterning of frontal regions and promoting frontal neural stem cell proliferation, thus potentially contributing to primate frontal cortex specialization. Leveraging non-human primate research and developing region-specific organoid models, we are committed to further exploring how intrinsic and extrinsic mechanisms develop, integrate, and evolve to shape primate cortical arealization.   

3. Genetic and molecular mechanisms underlying species and regional differences in disease vulnerability 

The expanded complexity and heterogeneity of the cerebral cortex are believed to underpin our intricate cognitive functions, yet they also increase vulnerability to neuropsychiatric and neurological disorders, many of which display region-specific associations. In line with this, our research has revealed that multiple brain disease risk genes are differentially employed across cortical regions in developing brains (Science 2023). Notably, we highlighted the primate-specific METTL7B expression, which defines subregion-specific cells in hippocampus and implicates in Alzheimer’s disease (Neuron 2022). Despite of these findings, a clear understanding of how cortical region patterning and species specializations relate to the vulnerability of neuropsychiatric and neurological diseases, including their underlying genetic and molecular mechanisms, remain elusive. In our lab, we will continue to explore these questions through integrating comparative studies and the development of disease models in mice, non-human primates, and organoids.