Dynamic Behavioral and Molecular Changes Induced by Chronic Restraint Stress Exposure in Mice

Area of Science:

• Neuroscience
• Molecular Biology
• Behavioral Science

Background:

• Chronic stress (CRS) is a significant risk factor for mood disorders like depression, contributing to brain changes and behavioral alterations such as anxiety and anhedonia.
• The precise sequence and early molecular alterations in the brain resulting from chronic stress remain poorly understood.

Purpose of the Study:

• To investigate the temporal dynamics of behavioral changes and molecular alterations in the prefrontal cortex induced by chronic restraint stress (CRS) in mice.
• To identify specific molecular markers in synaptic, GABAergic, and astroglial compartments that correlate with anxiety-like and anhedonia-like behaviors.
• To explore potential sex differences in the underlying molecular pathologies driven by CRS.

Main Methods:

• Utilized the chronic restraint stress (CRS) model in mice, exposing them to stress for 0 to 35 days.
• Assessed anxiety-like behaviors using the PhenoTyper test and anhedonia-like behaviors via the sucrose consumption test.
• Analyzed molecular changes in the prefrontal cortex using Western blot and quantitative polymerase chain reaction (qPCR) for synaptic, GABAergic, and astroglial markers.

Main Results:

• Anxiety-like behaviors emerged after 7 days of CRS, while anhedonia-like deficits were observed only after 35 days.
• CRS gradually reduced protein and RNA levels of synaptic (PSD95, SYN1, VGLUT1, GPHN), GABAergic (SST, PV, GAD67, VIP), and astroglial (GFAP, GLT1, GS) markers.
• Astroglial markers correlated negatively with anhedonia, SYN1 and GPHN with anxiety, and GLT1, VGLUT1, SYN1, and GAD67 with emotionality scores, with sex-specific patterns observed in network analyses.

Conclusions:

• CRS induces progressive behavioral and molecular changes in the brain, with distinct temporal profiles for anxiety and anhedonia.
• Molecular alterations in synaptic, GABAergic, and astroglial pathways are associated with stress-induced behavioral deficits.
• Despite similar behavioral outcomes, male and female mice may exhibit different underlying molecular pathologies in response to chronic stress.