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 3 mg/kg) and studied its effect for different study durations, ranging from 14 to 270 days. Though these studies suggest 3 mg/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 3 mg/kg ICV-STZ on cognitive and non-cognitive aspects at a follow-up interval of 2 weeks for 2 months. 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 2 months. 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 3 mg/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.
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Raw data analyzed in the present study will be available with a request to lead contact.
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Acknowledgements
We acknowledge Mr. Sanjeev Beniwal for his assistance in the behavioral experiment and Dr. Priyanka Kumari, Department of Physiology, All India Institute of Medical Sciences, New Delhi, for his assistance in histology.
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This work was supported by the institutional fund from All India Institute of Medical Sciences, Indian Institute of Technology-PhD assistantship and Indian Council for Medical Research (IR-594/2019/RS).
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Avishek Roy and Suman Jain conceived the idea and planned the experiment; Avishek Roy wrote the manuscript with suggestions from Suman Jain and Tapas Chandra Nag; Jantinder Katyal and Yogendra Kumar Gupta supervised the cognitive behavioral testing and drug administration, and dose selection; Tapas Chandra Nag supervised the histological experiment; Sakshi Sharma has conducted the Dirichlet distribution and kinoscope analysis with suggestions from Avishek Roy; the experiments were carried out and the data were curated by Avishek Roy and Sakshi Sharma; Avishek Roy performed the stereotaxic surgeries and tissue isolation, and immunostaining; histometric and other image analysis were performed by Avishek Roy. The authors read and approved the final manuscript.
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The experiments were conducted following the guidelines of the Institutional Animal Ethical Committee at All India Institute of Medical Sciences, New Delhi, vide 937/IAEC/PhD-2016.
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Roy, A., Sharma, S., Nag, T.C. et al. Cognitive Dysfunction and Anxiety Resulting from Synaptic Downscaling, Hippocampal Atrophy, and Ventricular Enlargement with Intracerebroventricular Streptozotocin Injection in Male Wistar Rats. Neurotox Res 40, 2179–2202 (2022). https://doi.org/10.1007/s12640-022-00563-x
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DOI: https://doi.org/10.1007/s12640-022-00563-x