Perineuronal Nets Alterations Contribute to Stress-Induced Anxiety-Like Behavior

Area of Science:

• Neuroscience
• Molecular Psychiatry
• Behavioral Neuroscience

Background:

• Anxiety disorders affect nearly 30% of adults globally, yet their molecular underpinnings remain largely unknown.
• Chronic restraint stress (CRS) is a validated model for inducing anxiety-like behaviors in rodents.
• Perineuronal nets (PNNs) are extracellular matrix structures that regulate neuronal plasticity and function.

Purpose of the Study:

• To investigate the role of PNNs in the medial prefrontal cortex (mPFC) in the development of anxiety-like behaviors.
• To explore the impact of chronic stress on PNNs and aggrecan (ACAN) expression.
• To determine if pharmacological interventions targeting PNNs or stress-induced changes can ameliorate anxiety-like phenotypes.

Main Methods:

• Mice were subjected to chronic restraint stress (CRS) to induce anxiety-like behavior.
• Wisteria Floribunda agglutinin (WFA) staining was used to assess PNNs expression in the mPFC.
• Messenger RNA (mRNA) and protein levels of aggrecan (ACAN) were quantified.
• Enzymatic digestion of PNNs using Chondroitinase ABC (chABC) and treatment with Fluoxetine (FXT) were performed.

Main Results:

• CRS mice displayed increased anxiety-like behavior and reduced synaptic transmission in the mPFC.
• CRS led to a significant decrease in PNNs and ACAN expression in the mPFC.
• Enzymatic digestion of PNNs mimicked anxiety-like behavior, while FXT treatment reversed stress-induced behavioral and molecular deficits.
• FXT treatment prevented the reduction of PNNs and ACAN caused by CRS.

Conclusions:

• Reduced PNNs expression in the mPFC is implicated in the pathophysiology of anxiety disorders.
• Maintaining adequate PNNs levels is crucial for normal brain function and anxiety regulation.
• Targeting PNNs or mitigating stress-induced PNN loss may represent novel therapeutic strategies for anxiety disorders.