Corticosterone Impairs Hippocampal Neurogenesis and Behaviors through p21-Mediated ROS Accumulation

Area of Science:

• Neuroscience
• Molecular Biology
• Stress Research

Background:

• Stress induces negative effects on adult hippocampal neurogenesis (AHN) and behavior.
• Glucocorticoids (GCs) mediate stress responses, with the hippocampus being rich in GC receptors.
• The hippocampus plays a crucial role in regulating mood and cognitive functions.

Purpose of the Study:

• To investigate the molecular mechanisms underlying stress-induced hippocampal alterations and anxiety-like behaviors.
• To identify key genes and pathways involved in the stress response within the hippocampus.
• To explore potential therapeutic targets for stress-related anxiety disorders.

Main Methods:

• RNA-sequencing (RNA-seq) analysis of hippocampal tissue after corticosterone (CORT) exposure.
• Overexpression of the p21 gene in the hippocampal dentate gyrus.
• Assessment of reactive oxygen species (ROS) levels, AHN, dendritic morphology, and anxiety-like behaviors.
• Inhibition of ROS to evaluate its rescue effects.

Main Results:

• RNA-seq identified a central regulatory role for the p21 gene (Cdkna1a) and its interaction with oxidative stress pathways.
• p21 overexpression mimicked CORT-induced phenotypes: increased ROS, reduced AHN, dendritic atrophy, and anxiety.
• Inhibiting ROS partially rescued anxiety-like behaviors and hippocampal changes induced by both p21 overexpression and CORT.

Conclusions:

• The p21 gene is a key mediator of stress-induced hippocampal damage and anxiety.
• Oxidative stress, indicated by ROS accumulation, is a critical component of these stress-related effects.
• Targeting p21 or ROS in the hippocampus offers a promising therapeutic strategy for anxiety disorders linked to chronic stress.