Hippocampal scrapie infection impairs operant DRL performance in mice

In differential reinforcement of low rates of responding (DRL) tasks, animals are trained to respond for rewards that become available only after some set time has elapsed since the animal's previous response. DRL performance is impaired by hippocampal lesions regardless of their precise location, and can be measured using automated operant equipment, whereas spatial tasks are selectively impaired by dorsal, but not ventral hippocampal lesions, and are typically conducted by hand. Earlier studies of prion infection following dorsal hippocampal microinjections of scrapie have shown clear impairments of spatial alternation, but these occurred significantly later than dysfunction in hippocampus-dependent domestic tasks such as nesting or burrowing. In the present experiment, mice were trained to respond on an automated DRL schedule prior to dorsal hippocampal ME7 scrapie injection. Postoperative DRL performance was monitored, along with performance on domestic and other tests, which provided additional measures of disease progression. Animals with scrapie developed a clear DRL deficit at approximately the same time as their deficits on the other tests became apparent, and long before clinical signs were detectable. DRL deficits thus appeared earlier in the sequence of disease progression than previously reported for spatial alternation, suggesting that early signs of scrapie infection are caused in part by neuronal dysfunction extending beyond the dorsal hippocampal region of initial infection