Human CLOCK Gene Promotes Neural Connectivity and Cognitive Flexibility in Mice, Study Reveals

Recent research has shed light on the role of the human CLOCK gene beyond its established function in regulating circadian rhythms. CLOCK genes are crucial in orchestrating the body's internal 24-hour clock, influencing sleep-wake cycles and various hormonal processes. The study, conducted by scientists at UT Southwestern Medical Center, focused on how the expression of the CLOCK gene in the human neocortex impacts cognitive functions.

Using innovative genetic modification techniques, researchers created a humanized mouse model that mimics the human pattern of CLOCK gene expression in the brain. This model allowed them to explore the gene's influence on neural connectivity and behavior. Notably, the expression of CLOCK in the neocortex, a brain region vital for reasoning, language, and decision-making, suggested potential roles beyond circadian regulation.

The team discovered that in these humanized mice, the CLOCK gene enhances the formation of neural connections, resulting in increased dendritic growth and synaptic complexity. These neural modifications correlated with improved performance in cognitive flexibility tasks, specifically in rule-based learning sets such as set-shifting procedures. Importantly, this indicates that CLOCK contributes to higher-order cognitive processes.

Comparative genomic analyses reveal that the human neocortex exhibits higher activity of the CLOCK gene compared to non-human primates, highlighting its evolutionary significance. The gene's elevated expression in cortical neurons—distinct from its circadian functions—points toward a unique role in human brain evolution. The researchers observed that the gene's activity during development potentially influences neurogenesis, increasing cell density in the cortex.

Further investigations involved advanced techniques such as immunohistochemistry, single-nucleus RNA sequencing, and electrophysiology, to identify when and where CLOCK is active in the brain. The findings showed that human CLOCK governs the expression of genes related to excitatory neurons, thus fostering the development of intricate neural networks that likely underpin cognitive flexibility.

Moreover, validation experiments using stem cell models confirmed that human-specific CLOCK expression impacts neuronal structures, such as dendritic spines. The study's implications suggest that CLOCK's functions have evolved to support complex brain capabilities that distinguish humans from other primates.

This groundbreaking research not only broadens our understanding of CLOCK’s role in the brain but also provides valuable resources, including humanized mouse models and CRISPR-edited human stem cells, for future studies. It offers compelling evidence that genes involved in circadian regulation may have been co-opted during evolution to enhance neural plasticity and cognitive abilities, contributing to human brain development.

The findings highlight the importance of exploring how circadian genes may influence other aspects of brain function and evolution, paving the way for potential therapeutic insights into cognitive disorders and neurodevelopmental conditions.

Source: https://medicalxpress.com/news/2025-07-human-clock-gene-brain-mental.html