Early weaning increases anxiety via brain-derived neurotrophic factor signaling in the mouse prefrontal cortex

Area of Science:

• Neuroscience
• Developmental Psychology
• Molecular Biology

Background:

• Maternal care deprivation during early development significantly impacts emotional development, with underlying neuromolecular mechanisms requiring further elucidation.
• Early life stress, such as disrupted mother-infant relationships leading to early weaning in mice, results in long-term increases in corticosterone, anxiety, and stress responses in adulthood.
• Understanding these mechanisms is crucial for addressing mental health issues stemming from childhood adversity.

Purpose of the Study:

• To investigate the neuromolecular mechanisms by which early weaning affects anxiety and stress responses.
• To identify the role of corticosterone and brain-derived neurotrophic factor (BDNF) signaling in the prefrontal cortex (PFC) in mediating these effects.
• To explore potential therapeutic targets for ameliorating anxiety caused by early life stress.

Main Methods:

• Utilized a mouse model of disrupted mother-infant relationship (early weaning).
• Assessed anxiety levels using the plus maze test.
• Administered corticosterone, a glucocorticoid receptor antagonist, BDNF, and a BDNF receptor agonist.
• Measured corticosterone levels and gene/protein expression of BDNF and associated mRNAs in the PFC.

Main Results:

• Normalizing circulating corticosterone levels, either post-weaning or in adulthood, ameliorated anxiety in early-weaned mice.
• Targeting the PFC with a glucocorticoid receptor antagonist reversed early weaning-induced anxiety, while corticosterone administration increased anxiety.
• Early-weaned mice exhibited reduced BDNF expression in the PFC, and anxiety was alleviated by BDNF or its receptor agonist.
• These findings implicate dysregulated glucocorticoid and BDNF signaling in the PFC as key mediators of anxiety following early life stress.

Conclusions:

• Early weaning induces long-lasting anxiety by disrupting glucocorticoid and BDNF signaling pathways within the PFC.
• The PFC serves as a critical target brain region for corticosterone's effects on anxiety.
• Targeting BDNF signaling in the PFC offers a potential therapeutic strategy for anxiety disorders linked to early life adversity.