Cognitive Dysfunction and Anxiety Resulting from Synaptic Downscaling, Hippocampal Atrophy, and Ventricular Enlargement with Intracerebroventricular Streptozotocin Injection in Male Wistar Rats.

Abstract

Insulin-resistant brain state is proposed to be the early sign of Alzheimer's disease (AD), which can be studied in the intracerebroventricular streptozotocin (ICV-STZ) rodent model. ICV-STZ is reported to induce sporadic AD with the majority of the disease hallmarks as phenotype. On the other hand, available experimental evidence has used varying doses of STZ (< 1 to 3mg/kg) and studied its effect for different study durations, ranging from 14 to 270days. Though these studies suggest 3mg/kg of ICV-STZ to be the optimum dose for progressive pathogenesis, the reason for such is elusive.Here, we sought to investigate the mechanism of action of 3mg/kg ICV-STZ on cognitive and non-cognitive aspects at a follow-up interval of 2weeks for 2months. On the 60th day, we examined the layer thickness, cell density, ventricular volume, spine density, protein expression related to brain metabolism, and mitochondrial function by histological examination. The findings suggest a progressive loss of a spatial, episodic, and avoidance memory with an increase in anxiety in a span of 2months. Furthermore, hippocampal neurodegeneration, ventricular enlargement, diffused amyloid plaque deposition, loss of spine in the dentate gyrus, and imbalance in energy homeostasis were found on the 60th day post-injection. Interestingly, AD rats showed a uniform fraction of time spent in four quadrants of the water maze with a change in strategy when they were exposed to height. Our findings reveal that ICV-STZ injection at a dose of 3mg/kg can cause cognitive and neuropsychiatric abnormalities due to structural loss both at the neuronal as well as the synaptic level, which is tightly associated with the change in neuronal metabolism.