Large-Scale Validation of the Paddling Pool Task in the Clockmaze for Studying Hippocampus-Based Spatial Cognition in...

Rationally designed behavioral tests are important tools to assess the function of specific brain regions. The hippocampus is a crucial neural substrate for spatial cognition, and many studies have linked hippocampal dysfunction with defects on spatial learning and memory in neurological conditions ranging from Alzheimer's disease to autoimmune syndromes, such as neuropsychiatric lupus. While our understanding of hippocampal function, from the molecular to the system levels, has increased dramatically over the last decades, this effort has not yet translated into efficacious therapies for cognitive impairment. We think that the availability of highly validated behavioral paradigms to measure cognition in mouse models is likely to enhance the potential success of preclinical therapeutic modalities. Here, we present an extensive study of the paddling pool task (PPT), first reported by Deacon and Rawlins, in which mice learn to escape from shallow water through a peripheral exit in a circular arena dubbed the clockmaze. We show that the PPT provides highly reliable results when assaying spatial cognition in C57/BL6 mice (120 males, 40 females) and BALB/c mice (40 males, 90 females). Additionally, we develop a robust algorithm for the assessment of escape strategies with clearly quantifiable readouts, enabling fine-granular phenotyping. Notably, the use of spatial strategy increases linearly across trials in the PPT. In a separate cohort of mice, we apply muscimol injections to silence the dorsal CA1 region of the hippocampus and show that the use of the spatial strategy in the PPT relies on the integrity of the dorsal hippocampus. Additionally, we compare directly the PPT and the Morris water maze (MWM) task in C57/BL6 mice (20 males, 20 females) and BALB/c mice (20 males, 20 females) and we find that the PPT induces significantly lower anxiety, exhaustion and hypothermia than the MWM. We conclude that the PPT provides a robust assessment of spatial cognition in mice, which can be applied in conjunction with other tests, to facilitate hypothesis testing and drug development to combat cognitive impairment.