engleski

Too nervous to sleep? Novel behavioral aspects of the intracerebroventricular streptozotocin- induced rat model of sporadic Alzheimer’s disease

Introduction: Alzheimer’s disease (AD) has been described more than 115 years ago, however, its etiopathogenesis remains unknown to date. Consequently, modeling of the disease in laboratory animals remains a challenge and the development of novel treatment solutions have been unsuccessful so far. Cognitive impairment is the most pronounced behavioral alteration present in both patients and animal models of the disease, nevertheless accompanying neuropsychiatric symptoms such as anxiety are often neglected and the behavioral complexity of current AD models remains largely unexplored. Considering neurobehavioral phenomena provide a unique insight into the pathophysiology of the central nervous system, acknowledgment of subtle behavioral changes may provide additional information indispensable for understanding the development of neuropathology in animal models. The present aim was to explore behavioral alterations accompanying deficits of learning and memory in the widely used intracerebroventricular streptozotocin (STZ-icv)- induced rat model of sporadic AD with a special focus directed to circadian alterations, stress response, and attention/impulsivity recently recognized as neglected behavioral and psychological symptoms often present in the early stage of the disease. Materials and methods: Independent cohorts of male Wistar rats treated with STZ-icv (3 mg/kg) and vehicle-treated controls have been studied. Acute and sub-acute circadian changes have been assessed by a custom- made circadian tracker—multi-cage infra-red open- source locomotor activity viewer (MIROSLAV). Acoustic startle and prepulse inhibition sensorimotor gating have been examined using the custom-made griPASTA platform. Open field test, social preference, novel object recognition, and passive avoidance have been used for assessment of general (anxiety, cognition, social preference, recognition memory, and associative learning) and subtle (attention dynamics, hesitancy/impulsivity) behavioral patterns. Results: Preliminary evidence suggests STZ-icv rats suffer from pronounced circadian dysrhythmia that develops already upon administration of the first dose of STZ-icv. Apart from well-known cognitive deficits, STZ-icv rats suffer from increased acoustic startle response with unaltered prepulse inhibition sensorimotor gating, increased anxiety accompanied by paradoxically increased exploration drive, and increased social preference. Furthermore, analysis of subtle behavioral patterns uncovers increased attention shifting and impulsivity in the STZ-icv rats. Conclusion: Deficits of learning and memory are well-known behavioral alterations present in the STZ-icv rats. Nevertheless, thorough exploration of the behavioral phenotype uncovers a complex pattern characterized by overlapping neurobehavioral phenomena that might provide a unique insight into the etiopathogenesis of STZ- icvinduced neurodegeneration with anxiety, altered stress response, and circadian dysrhythmia indicating the potential importance of the hypothalamus. Furthermore, acknowledgment of the behavioral complexity may uncover potential sources of bias and significantly contribute to the robustness and reliability of the results from the experiments exploiting the STZ-icv rat model of AD. This work was funded by the Croatian Science Foundation (IP-2018-01-8938). Research was co-financed by the Scientific Centre of Excellence for Basic, Clinical and Translational Neuroscience (project ‘‘Experimental and clinical research of hypoxic-ischemic damage in perinatal and adult brain’’ ; GA KK01.1.1.01.0007 funded by the European Union through the European Regional Development Fund).

Alzheimer's disease ; streptozotocin ; circadian rhytm ; behavioral phenotype

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