Related Experiment Video
Updated: May 12, 2026
Applying Stereotactic Injection Technique to Study Genetic Effects on Animal Behaviors
Published on: May 10, 2015
Dynamic contrast-enhanced MRI reveals glymphatic dysfunction in mice with depressive-like behavior
1Department of Psychiatry, Affiliated Hospital of Guizhou Medical University, Guiyang, China.
Objective:
This study aimed to investigate glymphatic system dysfunction in chronic unpredictable mild stress (CUMS)-induced depressive-like mice and its association with aquaporin-4 (AQP4) and astrocyte alterations using dynamic contrast-enhanced MRI (DCE-MRI).
Methods:
Thirty-eight C57BL/6 mice were randomized into CUMS (28-day stress protocol) and control groups. Behavioral tests (sucrose preference, forced swim, tail suspension) assessed depressive phenotypes. DCE-MRI with Gd-DTPA cisterna magna injection was performed to evaluate glymphatic dynamics via hierarchical and k-means clustering of time-signal curves. Ex vivo Texas Red-dextran-3 tracer imaging quantified cerebrospinal fluid (CSF) influx. Immunofluorescence measured AQP4 polarization and GFAP expression in the hippocampus, prefrontal cortex, and hypothalamic regions. Statistical analyses included independent t-tests.
Results:
CUMS mice exhibited reduced sucrose preference (0.71 vs. 0.81, t = 2.113, P = 0.0418) and prolonged immobility in forced swim tests (176.6 vs. 156.4 s, t = 2.200, P = 0.0343). DCE-MRI revealed a statistically significant intergroup difference in contrast agent signal intensity distribution within the Right Cortical Amygdala(Cortical amygdalar-R), (t = 2.641, P = 0.0247, P < 0.05). Simultaneously, CUMS mice exhibited significant contrast agent accumulation in the thalamus. Hierarchical clustering identified enhanced Gd-DTPA influx but delayed peak timing in CUMS clusters, while k-means analysis showed reduced efflux in CSF-dense regions (P < 0.01). Ex vivo tracer influx was reduced in CUMS (24.64 %vs.39.09 %, t = 5.440, P = 0.0003). Immunofluorescence revealed reduced AQP4 expression in CUMS hippocampus (t = 2.697, P = 0.027) and prefrontal cortex (t = 4.543, P = 0.0007), decreased polarization (t = 2.308, P = 0.0396), and diminished GFAP expression (t = 10.08, P < 0.0001).
Conclusions:
CUMS-induced depressive-like behavior is linked to glymphatic dysfunction, characterized by impaired CSF influx/efflux and AQP4/astrocyte downregulation. DCE-MRI clustering analysis provides novel insights into spatiotemporal glymphatic abnormalities, highlighting potential therapeutic targets for depression.
Insights
Chronic unpredictable mild stress (CUMS) causes depressive-like behavior linked to impaired glymphatic system function, reduced aquaporin-4 (AQP4), and astrocyte changes. Dynamic contrast-enhanced MRI (DCE-MRI) reveals these glymphatic abnormalities in depression models.
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.
