Evaluating Neuropsychiatric Disease in Mouse Models of Systemic Lupus Erythematosus.

Primary neuropsychiatric manifestations in systemic lupus erythematosus (NPSLE) affect 20% to 40% of patients, significantly impacting quality of life and patient prognosis. However, the complex pathophysiology underlying these manifestations remains incompletely understood, partly due to challenges in distinguishing direct disease effects from secondary complications. Animal models are essential for investigating these mechanisms, but their effective utilization requires standardized behavioral assessment protocols, an area where the field currently lacks sufficient consensus. This article presents seven validated behavioral paradigms optimized for NPSLE mouse models, covering four key behavioral domains: activity levels (open field test); anxiety-like behavior (open field test, dark-light box, elevated plus maze); depression-like behavior (tail suspension test, Porsolt swim test); and cognitive function (novel objects, Barnes maze). We provide detailed protocols for each test, including equipment specifications, procedural steps, parameter measurements, and troubleshooting guidance specifically tailored for NPSLE research. Special considerations for NPSLE mouse models, including potential confounding factors like light sensitivity, motor impairments, and stress sensitivity, are addressed throughout. Additionally, we offer strategic recommendations for test selection based on specific research objectives, emphasizing the importance of test sequencing, proper habituation, and consistent handling techniques. We additionally recommend correlating behavioral outcomes with immunological markers to establish relationships between immune dysfunction and neuropsychiatric manifestations. By standardizing behavioral assessment methodologies in NPSLE research, these protocols enable more reliable cross-laboratory comparisons, enhance reproducibility, and ultimately improve translational relevance. The rigorous behavioral phenotyping approaches detailed herein will facilitate more accurate modeling of neuropsychiatric manifestations in lupus, advance our understanding of underlying disease mechanisms, and accelerate the development of targeted therapeutic interventions for this challenging aspect of SLE. © 2025 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Open field test: Assessment of locomotor activity and anxiety-like behavior Basic Protocol 2: Novel object assays: Assessment of learning and memory Basic Protocol 3: Dark-light box: Assessment of anxiety-like behavior Basic Protocol 4: Elevated plus maze: Assessment of anxiety-like behavior Basic Protocol 5: Barnes maze: Assessment of spatial learning and memory Basic Protocol 6: Tail suspension test: Assessment of depression-like behavior Basic Protocol 7: Porsolt swim test: Assessment of depression-like behavior.