The location discrimination reversal task in mice is sensitive to deficits in performance caused by aging, pharmacological and other challenges

Deficits in hippocampal-mediated pattern separation are one aspect of cognitive function affected in schizophrenia (SZ) or Alzheimer's disease (AD). To develop novel therapies, it is beneficial to explore this specific aspect of cognition preclinically. The location discrimination reversal (LDR) task is a hippocampal-dependent operant paradigm that evaluates spatial learning and cognitive flexibility using touchscreens. Here we assessed baseline performance as well as multimodal disease-relevant manipulations in mice. Mice were trained to discriminate between the locations of two images where the degree of separation impacted performance. Administration of putative pro-cognitive agents was unable to improve performance at narrow separation. Furthermore, a range of disease-relevant manipulations were characterized to assess whether performance could be impaired and restored. Pertinent to the cholinergic loss in AD, scopolamine (0.1 mg/kg) produced a disruption in LDR, which was attenuated by donepezil (1 mg/kg). Consistent with NMDA hypofunction in cognitive impairment associated with SZ, MK-801 (0.1 mg/kg) also disrupted performance; however, this deficit was not modified by rolipram. Microdeletion of genes associated with SZ (22q11) resulted in impaired performance, which was restored by rolipram (0.032 mg/kg). Since aging and inflammation affect cognition and are risk factors for AD, these aspects were also evaluated. Aged mice were slower to acquire the task than young mice and did not reach the same level of performance. A systemic inflammatory challenge (lipopolysaccharide (LPS), 1 mg/kg) produced prolonged (7 days) deficits in the LDR task. These data suggest that LDR task is a valuable platform for evaluating disease-relevant deficits in pattern separation and offers potential for identifying novel therapies.