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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.

Keywords: suicidality; Black Box; activation syndrome; behavioral toxicity; antidepressants EN suicidality Black Box activation syndrome behavioral toxicity antidepressants 1 3 3 05/05/20 20200430 NES 200430 In a recent issue of Frontiers in Psychiatry, Spielmans et al. ([1]) defend the 2004 decision of the Food and Drug Administration (FDA) to issue a Black Box warning on the potential risk of suicidality in youth being administered antidepressant medications. As various neural correlates (e.g., amygdala connectivity) have predicted attenuated antidepressant treatment response ([9], [10]), it is possible that such developmental alterations in brain maturation also relate to increased possibility of SSRI-induced behavioral side effects. [Extracted from the article]