The molecular mechanisms underlying the significant co-morbidity of sleep and circadian disturbances in patients with autism spectrum disorder remain unknown. There is mounting evidence for genetic and genomic alteration to core circadian factors in autism. The transcription factor CLOCK has been well-studied for its role in circadian function within the suprachiasmatic nucleus, but its role in other parts of the brain are not well known. We have observed that the human neocortex has a significant increase in CLOCK expression and altered CLOCK coexpression compared to other primates. We therefore hypothesize that CLOCK-mediated transcriptional networks specific to the human neocortex are involved in circadian and cognitive function and are disrupted in cognitive disorders such as ASD. To test this hypothesis, we propose to identify the transcriptional networks regulated by CLOCK specifically in human neurons. We will determine transcriptional targets of human CLOCK using three systems: primary human neural progenitors and their differentiated neurons, human neocortical post-mortem tissue, and mice expressing human CLOCK together with its regulatory elements. This novel approach of using evolutionary data to inform cognitive disease directed functional studies should provide important new insights into aspects of human brain evolution that are most at risk in cognitive disorders with a circadian component.
Patients with cognitive disorders such as autism and bipolar disorder exhibit symptoms relevant to disturbances in sleep and overall circadian function. Very little is known about the role of core circadian components in human cortex, especially as they might relate to autism or other disorders. This proposal aims to identify the transcriptional networks regulated by a core circadian transcription factor, CLOCK, in human neocortex and to determine the role of these networks in diseases such as autism.
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