Meeting Abstract
Comparing with non-human primates, we evolved unique cognitive abilities which have been attributed to high volume of human brain especially the expansion of prefrontal cortex (PFC). To understand gene regulatory mechanism underlying human brain specialization, a comparison of cortical transcriptomes between human and closely related primates revealed that human CLOCK (huCLK) is up-regulated in human PFC. However, how huCLK results in human brain specializations? To address the question, we firstly generated humanized (HU) mice which overexpress huCLK in CLK-knockout mice to mimic relative expression of CLK in human versus other primates. Through a battery of cognitive tests, we found that HU mice showed similar activity, anxiety, and general learning abilities as wildtype (WT) mice, while HU mice outperformed WT mice in social learning and cognitive flexibility both of which are PFC dependent cognitive abilities. We then leveraged immunohistochemistry to compared neuroanatomical characteristics of PFC between genotypes. Results show that HU mice did not alter cortical thickness and lamination while they possessed higher density of neuron and oligodendrocyte than WT mice. To understand gene regulatory mechanism behind the alternations of HU mice, we did single-nuclei RNA-Seq in PFC of young adult mice (8 weeks). Preliminary analysis shows that nuclei of HU mice are enriched in an interneuron cluster and an oligodendrocyte cluster. More results, such as differential expression and pathway analysis are in progress. In summary, we found that overexpression of huCLK resulted in improved cognitive flexibility, higher neuron and oligodendrocyte density, and alternation of cell composition in PFC. These results suggest that huCLK might play an important role in proliferation and differentiation of cortical cells under the evolution of human brain.
