Assessing post-stroke cognition in pre-clinical models: lessons and recommendations from a multi-center study

Area of Science:

• Neuroscience
• Translational Medicine
• Animal Models

Background:

• Cognitive decline is a major consequence of stroke, yet effective treatments are lacking.
• Developing therapies requires reliable methods to detect post-stroke cognitive impairment in preclinical models.

Purpose of the Study:

• To establish a robust multi-site method for detecting cognitive performance deficits after ischemic stroke in mice.
• To evaluate the efficacy of Novel Object Recognition (NOR) and Barnes Maze (BM) tests in assessing post-stroke cognitive function.

Main Methods:

• Ischemic stroke was induced in mice using three models: distal middle cerebral artery occlusion (dMCAO), dMCAO with hypoxia, and transient middle cerebral artery occlusion.
• Cognitive function was assessed using NOR and BM tests at baseline, sub-acute (1-2 weeks), and chronic (8 weeks) post-stroke.
• Histology, immunostaining, and plasma neurofilament light quantification were used to evaluate brain damage and neuronal loss.

Main Results:

• The Novel Object Recognition test did not reliably detect cognitive deficits following stroke.
• The Barnes Maze showed a promising signal for detecting cognitive impairment, though tested at a single site.
• Histological analyses confirmed varying degrees of infarct size and neuronal damage across stroke models.

Conclusions:

• Detecting cognitive impairment in preclinical stroke models presents significant challenges, impacting therapy development.
• The Barnes Maze may offer a more sensitive measure of post-stroke cognitive deficits than NOR in certain contexts.
• Recommendations are provided for optimizing the design and execution of multi-site preclinical stroke cognition studies.