Human CLOCK enhances neocortical function.

Area of Science:

• Neuroscience
• Genetics
• Chronobiology

Background:

• The transcription factor CLOCK is vital for circadian rhythms.
• Human neocortical CLOCK expression suggests additional, specialized functions beyond circadian regulation.
• Understanding CLOCK's role in the human brain is key to deciphering cognitive evolution.

Purpose of the Study:

• To investigate the functional consequences of human-specific CLOCK expression in the mouse neocortex.
• To explore the molecular mechanisms underlying CLOCK's potential role in cognitive functions.
• To determine if altered CLOCK expression impacts neuronal structure and connectivity.

Main Methods:

• Generation of a humanized CLOCK mouse model (HU mice) with human cortical expression patterns.
• Cell-type-specific genomic profiling in HU mice to identify affected gene networks.
• Assessment of neuronal morphology (dendritic complexity, spine density) and synaptic function (ePSCs) in HU mice.
• Analysis of CLOCK knockout in human induced pluripotent stem cell-derived neurons.

Main Results:

• HU mice exhibit enhanced cognitive flexibility.
• Genomic profiling revealed upregulated genes associated with dendritic growth and spine formation in HU mouse excitatory neurons.
• Excitatory neurons in HU mice displayed increased dendritic complexity, spine density, and excitatory postsynaptic current frequency.
• CLOCK knockout in human iPSC-derived neurons led to reduced dendritic complexity and presynaptic puncta density.

Conclusions:

• Altered spatiotemporal gene expression of CLOCK may confer evolved, brain-relevant functions.
• CLOCK's enhanced functions in the human brain could contribute to unique human cognitive specializations.
• CLOCK plays a significant role in regulating neuronal structure and connectivity, impacting cognitive abilities.