Abstract
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.
Highlights
The hippocampus is a brain region that integrates large numbers of cortical and subcortical inputs and contributes to the neural substrate of episodic learning and memory, spatial navigation, contextual recall and emotional memory (Eichenbaum, 2000; Morris, 2007; O’Keefe, 2007; Fanselow and Dong, 2010; Hartley et al, 2014; Calhoon and Tye, 2015; Moscovitch et al, 2016)
We studied the rate of escape strategy misclassification when a given parameter was omitted in a classification and regression tree’’ (CART) model and found that exclusion of the number of errors yielded a misclassification score of 12.7%, omission of the escape latency gave a misclassification of 15.8%, whereas exclusion of both the escape latency and the number of errors increased the misclassification to 35.8% (Figure 5A)
This study has described a large-scale validation of the paddling pool task (PPT) as a robust paradigm to test spatial cognition in two strains of mice, C57 and BALB/c
Summary
The hippocampus is a brain region that integrates large numbers of cortical and subcortical inputs and contributes to the neural substrate of episodic learning and memory, spatial navigation, contextual recall and emotional memory (Eichenbaum, 2000; Morris, 2007; O’Keefe, 2007; Fanselow and Dong, 2010; Hartley et al, 2014; Calhoon and Tye, 2015; Moscovitch et al, 2016). It is clear that hippocampal dysfunction is a core syndrome in an array of neurodegenerative and immunological disorders, such as Alzheimer’s, chronic depression, schizophrenia, epilepsy, hypertension, Cushing’s disease, head injury, post-traumatic stress disorder, brain inflammation, cerebral hypoxia, neuropsychiatric lupus, and severe sepsis (Terry et al, 1991; Starkman et al, 1992; Aleman et al, 1999; Capuron et al, 1999; Austin et al, 2001; O’Brien et al, 2003; Elger et al, 2004; Appenzeller et al, 2006; Reitz et al, 2007; Iwashyna et al, 2010; Omalu et al, 2010; Yaffe et al, 2010; Davydow et al, 2013) All of these conditions are known to produce cognitive impairment of varying degree and long-term disability in patients. Genetic engineering has facilitated the creation of transgenic mouse models of human diseases for which cognitive impairment is an expected behavioral phenotype (Lipp and Wolfer, 1998; D’Hooge and De Deyn, 2001; Janus, 2004; Chang et al, 2006; Lindgren and Dunnett, 2012; Jankowsky and Zheng, 2017; Honeycutt and Garcia, 2018)
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