Kynurenines increase MRS metabolites in basal ganglia and decrease resting-state connectivity in frontostriatal...

Area of Science:

• Neuroscience
• Psychiatry
• Biochemistry

Background:

• Inflammation is linked to anhedonia in major depression (MD).
• The precise brain mechanisms connecting inflammation to anhedonia remain unclear.
• The kynurenine pathway (KP) is activated by inflammation and influences brain chemistry.

Purpose of the Study:

• To investigate how plasma and cerebrospinal fluid (CSF) KP metabolites affect brain chemistry and neural function in depressed individuals.
• To explore the relationship between KP metabolites, brain imaging markers, and anhedonia severity.

Main Methods:

• Utilized multimodal neuroimaging in 49 depressed subjects.
• Measured KP metabolites in plasma and CSF.
• Assessed brain chemistry (glutamate, myo-inositol) using magnetic resonance spectroscopy (MRS) in the basal ganglia.
• Analyzed resting-state functional MRI for regional homogeneity (ReHo) and functional connectivity.
• Quantified anhedonia using the Inventory for Depressive Symptoms-Self Report Version (IDS-SR).

Main Results:

• Elevated plasma KYN/TRP ratio and CSF 3HK correlated with increased basal ganglia myo-inositol.
• Plasma KYNA and KYNA/QA were linked to decreased basal ganglia glutamate, while QA was linked to increased glutamate.
• Plasma and CSF KP metabolites were associated with reduced ReHo in basal ganglia and DMPFC, and impaired functional connectivity between these regions.
• DMPFC-basal ganglia connectivity mediated the impact of KP on anhedonia.

Conclusions:

• Dysregulation of the kynurenine pathway significantly impacts brain chemistry and neural function in depression.
• KP metabolites contribute to inflammatory behaviors like anhedonia by altering basal ganglia and DMPFC function.
• These findings elucidate a key pathway linking inflammation to anhedonia in major depression.