Chronic Corticosterone Intake Induces Fatigue-like Behaviors and Alteration of CSF Influx

다국어 초록 (Multilingual Abstract)

Background: Chronic glucocorticoids exposure is closely associated with various neurological disorders. CSF dynamics are tightly governed by circadian mechanisms, and their disruption has been associated with impaired brain homeostasis. In this study, we investigated whether chronic corticosterone excess impairs the brain’s clearance system by altering cerebrospinal fluid (CSF) dynamics.
Methods: Male C57BL/6N mice (8 weeks old) received corticosterone (200 μg/mL) in their drinking water for 4 weeks. Three weeks after administration, behavioral assessments were performed to assess central fatigue. CSF inflow was analyzed as the primary outcome via tracer injection into the intracisternal magna. Additionally, we specifically investigated glymphatic system regulators and neuronal activity through histological analysis.
Results: Chronic corticosterone (CORT) administration induced a fatigue-like behaviors, characterized by reduced voluntary activity, impaired cognitive performance, and increased depressive- and anxiety-like behaviors, without overt neuromuscular weakness. Concurrently, CSF influx was markedly increased and accompanied by alterations in the glial component of the glymphatic system. Specifically, chronic CORT increased AQP4 expression predominantly in GFAP-negative astrocytes, while overall astrocyte abundance, as indicated by ALDH1L1 expression, remained unchanged. Increased CSF influx was also associated with reduced neuronal activity, as evidenced by decreased c-Fos and PSD95 expression.
Conclusion: These neural alterations were accompanied by behavioral impairment, indicating that chronic glucocorticoid excess can disrupt brain function in parallel with altered CSF dynamics. Collectively, these findings identify excessive glucocorticoid signaling as a key modulator of brain fluid homeostasis and link chronic stress hormone exposure to neurobehavioral dysfunction.

목차 (Table of Contents)

• Abstract 01
• Ⅰ. Introduction 02
• Ⅱ. Materials and Methods 04
• 1. Materials and reagents 04
• 2. Corticosterone drink preparation 05
• 3. Animal and experimental design 06
• 4. Home cage activity test 07
• 5. Rota-rod test 08
• 6. Treadmill fatigue test 09
• 7. Grip strength test 10
• 8. Open field test 11
• 9. Tail suspension test 12
• 10. Forced swimming test 13
• 11. Novel object test 14
• 12. Sample preparation 15
• 13. Determination of corticosterone 17
• 14. Immunohistology staining analysis 18
• 15. Western blot analysis 19
• 16. Statistical analysis 20
• Ⅲ. Results 21
• 1. Suppressed serum corticosterone levels following chronic corticosterone intake 21
• 2. Chronic corticosterone intake induced fatigue-like behavior 23
• 3. CSF influx surge caused by chronic corticosterone intake 27
• 4. Chronic corticosterone increased AQP4, but decreased GFAP in PFC and Hippo. 31
• 5. No change in GR activation and total astrocyte number, but increased AQP4 expression in PFC 33
• 6. Decreased GR activation without changes in total astrocyte number, but increased AQP4 expression in the hippocampus 35
• 7. No change in neuronal number but reduced neuronal activation and synaptic plasticity in the PFC 37
• 8. No change in neuronal number but reduced neuronal activation and synaptic plasticity in the Hippo. 39
• Ⅳ. Discussion 41
• References 45
• Abstract in Korean 48