Abstract
With the appreciation that behavior represents the integration and complexity of the nervous system, neurobehavioral phenotyping and assessment has seen a renaissance over the last couple of decades, resulting in a robust database on rodent performance within various testing paradigms, possible associations with human disorders, and therapeutic interventions. The interchange of data across behavior and other test modalities and multiple model systems has advanced our understanding of fundamental biology and mechanisms associated with normal functions and alterations in the nervous system. While there is a demonstrated value and power of neurobehavioral assessments for examining alterations due to genetic manipulations, maternal factors, early development environment, the applied use of behavior to assess environmental neurotoxicity continues to come under question as to whether behavior represents a sensitive endpoint for assessment. Why is rodent behavior a sensitive tool to the neuroscientist and yet, not when used in pre-clinical or chemical neurotoxicity studies? Applying new paradigms and evidence on the biological basis of behavior to neurobehavioral testing requires expertise and refinement of how such experiments are conducted to minimize variability and maximize information. This review presents relevant issues of methods used to conduct such test, sources of variability, experimental design, data analysis, interpretation, and reporting. It presents beneficial and critical limitations as they translate to the in vivo environment and considers the need to integrate across disciplines for the best value. It proposes that a refinement of behavioral assessments and understanding of subtle pronounced differences will facilitate the integration of data obtained across multiple approaches and to address issues of translation.
Highlights
The nervous system is comprised of a dynamic interactive circuitry involving communication between neurons, glia, neurovascular and neurolymphatic systems for which temporal and spatial regulation are critical factors
5.4.2 Morris Water Maze The Morris Water Maze (MWM) is a common method used for assessing rodent spatial learning and memory (Morris, 1984; Vorhees and Williams, 2006; Terry, 2009; Vorhees and Williams, 2014b)
Examples of data to collect and presentation are provided for motor activity (Table 1; Figure 2), startle and Prepulse startle inhibition (PPI) (Table 2; Figure 3), and Morris Water Maze (Table 3; Figure 4)
Summary
The nervous system is comprised of a dynamic interactive circuitry involving communication between neurons, glia, neurovascular and neurolymphatic systems for which temporal and spatial regulation are critical factors. Identifying the benefits and limitations of each approach, developing a strategy for integrating in vivo and in vitro studies and findings, inclusion of mechanistic endpoints, and providing validation to support translation to in vivo, and prediction to an adverse health outcome are necessary to fully advance the field and to ensure a level of confidence in the data for human health risk assessment (Carlson et al, 2020; Payne-Sturges et al, 2021) One step in this process is to undertake an honest consideration of various pitfalls and missed opportunities of the rodent behavioral studies and to learn from this to minimize similar “failures” in any future approaches, in vivo or in vitro. How they can identify potential target cells and enhance and embellish our understanding of modes of action for neurotoxicity
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