Environmental Enrichment and Estrogen Upregulate Beta-Hydroxybutyrate Underlying Functional Improvement

Area of Science:

• Neuroscience
• Metabolic Science
• Behavioral Science

Background:

• Environmental enrichment (EE) shows therapeutic potential for metabolic and neuronal health.
• The sex-specific mechanisms of EE's effects are not fully understood.
• Estrogen's role in EE-induced neuroplasticity and metabolic changes requires further investigation.

Purpose of the Study:

• To investigate the sex-specific effects of long-term EE on metabolism, body composition, and behavior.
• To elucidate the molecular mechanisms, including beta-hydroxybutyrate (βHB) and its related pathways, underlying EE's impact.
• To determine the role of estrogen in mediating EE's benefits in female mice.

Main Methods:

• Mice were exposed to EE for 8 weeks.
• Metabolic parameters, body composition, and behavioral phenotypes were assessed.
• Levels of βHB, histone deacetylases (HDAC), and brain-derived neurotrophic factor (BDNF) were measured.
• Ovariectomized mice models were used to confirm the role of estrogen.

Main Results:

• EE induced metabolic changes and reduced fat mass.
• EE increased βHB levels and enhanced BDNF expression, while reducing HDAC, particularly in the cerebral cortex and hippocampus.
• Significant improvements in motor and cognitive behaviors were observed in female mice, linked to estrogen levels.
• Estrogen treatment in ovariectomized mice confirmed EE's upregulation of βHB and BDNF.

Conclusions:

• Long-term EE alters metabolism, potentially via βHB regulation, and enhances neuroplasticity by modulating HDAC and BDNF expression.
• EE's beneficial effects on metabolism and behavior are sex-dependent and influenced by estrogen levels.
• EE represents a promising non-invasive strategy for improving metabolic and neuronal health, with potential therapeutic applications.