Chronic Ketamine Exposure Causes White Matter Microstructural Abnormalities in Adolescent Cynomolgus Monkeys

Area of Science:

• Neuroscience
• Pharmacology
• Psychiatry

Background:

• Ketamine exposure mimics schizophrenia symptoms, especially cognitive deficits.
• Chronic ketamine use is crucial for modeling schizophrenia's cognitive aspects.
• Long-term effects of ketamine on brain circuits and white matter integrity remain unclear.

Purpose of the Study:

• To investigate the causal effects of repeated ketamine exposure on white matter integrity.
• To examine microstructural changes in white matter tracts using a non-human primate model.
• To enhance understanding of schizophrenia neuropathology.

Main Methods:

• Intravenous administration of ketamine or saline to adolescent male cynomolgus monkeys for 3 months.
• Diffusion tensor imaging (DTI) for brain imaging.
• Tract-based spatial statistics (TBSS) for data analysis and fractional anisotropy (FA) quantification.

Main Results:

• Ketamine group showed significantly reduced FA in key white matter tracts compared to controls.
• Affected tracts include the sagittal striatum, posterior thalamic radiation (PTR), retrolenticular limb of the internal capsule (RLIC), and superior longitudinal fasciculus (SLF).
• Reductions were observed in both fronto-thalamo-temporal and striato-thalamic connections.

Conclusions:

• Chronic ketamine exposure causes significant white matter microstructural changes in primates.
• Findings support the role of altered white matter integrity in schizophrenia pathophysiology.
• This primate model offers translational insights for schizophrenia research and treatment development.