Behavioral phenotyping of rodents using neurodegeneration models has received much research attention over the past three decades. However, some difficulties still exist in understanding the variability of behavior caused by genetic, environmental, and biological factors, human intervention and poorly standardized experimental protocols, which can negatively affect the interpretation of the results obtained. In this article, we discuss factors that have a negative impact on the performance of behavioral testing of laboratory animals, modern approaches to overcome them, as well as new technologies, such as visualization of neuronal activity using ion-dependent fluorescent indicators (optogenetics), which expand the boundaries of the study of neuronal networks responsible for behavior by evaluating neuronal function at both the cellular and population levels. Ultimately, this will increase the reliability of the results obtained and provide an opportunity to take a fresh look at the ethological paradigms of a particular transgenic mouse model.