Inulin alleviates vascular cognitive impairment by restoring prefrontal GABAergic function via...

Area of Science:

• Neuroscience
• Microbiology
• Pharmacology

Background:

• Vascular cognitive impairment (VCI) affects medial prefrontal cortex (mPFC) function, which depends on GABAergic transmission.
• Prebiotics may help VCI by altering gut microbiota, but mechanisms are unclear.
• This study explores if inulin can improve VCI by restoring mPFC GABAergic function via the gut-brain axis.

Purpose of the Study:

• To investigate the effect of the prebiotic inulin on VCI.
• To determine if inulin restores GABAergic function in the mPFC.
• To elucidate the role of the gut-brain axis and short-chain fatty acids (SCFAs) in inulin's effects on VCI.

Main Methods:

• Used a mouse model of VCI induced by bilateral carotid artery stenosis (BCAS).
• Administered inulin and assessed cognitive and anxiety-like behaviors.
• Analyzed gut microbiota composition, mPFC GABAergic transmission, GABA levels, and SCFA receptor expression (GPR41/43).
• Utilized antibiotic depletion, shRNA knockdown, and pharmacological blockade (bicuculline) to confirm mechanisms.

Main Results:

• Inulin ameliorated cognitive deficits and anxiety in VCI mice, reshaping gut microbiota towards SCFA producers.
• Inulin reversed VCI-induced reductions in mPFC GABAergic transmission and GABA levels, correlating with increased SCFA levels.
• SCFA receptor GPR41/43 upregulation and presynaptic restoration were key mechanisms; blocking these receptors abolished inulin's benefits.
• GABAergic function was identified as the final pathway for inulin's cognitive and anti-inflammatory effects.

Conclusions:

• Inulin alleviates VCI by increasing gut-derived SCFAs that activate GPR41/43 in the mPFC, restoring GABAergic function.
• This study establishes a gut-mPFC pathway mediated by the microbiota-SCFA-GABA axis.
• Inulin shows therapeutic potential for cognitive disorders by targeting this axis.