Dynamic contrast-enhanced MRI reveals glymphatic dysfunction in mice with depressive-like behavior

Area of Science:

• Neuroscience
• Biomedical Imaging
• Psychiatry

Background:

• The glymphatic system clears waste from the brain, and its dysfunction is implicated in neurological disorders.
• Depression is associated with neuroinflammation and altered brain function, but glymphatic involvement is not fully understood.

Purpose of the Study:

• To investigate glymphatic system dysfunction in a mouse model of chronic unpredictable mild stress (CUMS)-induced depression.
• To explore the association between glymphatic alterations, aquaporin-4 (AQP4) expression, and astrocyte changes.
• To utilize dynamic contrast-enhanced MRI (DCE-MRI) for assessing glymphatic dynamics.

Main Methods:

• Thirty-eight mice underwent a 28-day CUMS protocol or served as controls.
• Depressive-like behaviors were assessed using sucrose preference, forced swim, and tail suspension tests.
• DCE-MRI with Gd-DTPA and ex vivo tracer imaging evaluated cerebrospinal fluid (CSF) influx and efflux.
• Immunofluorescence quantified AQP4 polarization and GFAP expression in key brain regions.

Main Results:

• CUMS mice displayed significant depressive-like behaviors.
• DCE-MRI revealed altered contrast agent distribution and accumulation in CUMS mice, indicating impaired glymphatic transport.
• Ex vivo imaging confirmed reduced CSF influx in CUMS mice.
• Immunofluorescence showed decreased AQP4 expression and polarization, along with reduced GFAP levels in CUMS mice.

Conclusions:

• CUMS-induced depression is associated with significant glymphatic system dysfunction, including impaired CSF influx and efflux.
• Downregulation of AQP4 and astrocyte alterations are linked to this glymphatic impairment.
• DCE-MRI clustering analysis offers novel insights into the spatiotemporal characteristics of glymphatic abnormalities in depression, suggesting potential therapeutic targets.