Delay-dependent impairment of reversal learning in rats treated with trimethyltin

Recent theories of hippocampal function focus on its role in the formation of associations in the temporal domain. A reversal learning paradigm based on leverpress automaintenance was developed to vary the CS-US relationship along two independent dimensions, one temporal and one not: CS(+)-US delay and the probability of reinforcement [P(RFT)] following the CS+. Eight male hooded Long-Evans rats were trained to reverse these automaintained discriminations repeatedly, until stable performance was achieved. The neurotoxicant trimethyltin (TMT) was used to induce lesions in the CNS, including the CA3-4 region of Ammon's Horn in dorsal hippocampus. Following iv injection of 7 mg/kg TMT to half the rats, reversal learning was assessed under varying conditions of delay and P(RFT). After recovery from the acute effects of TMT (1-2 weeks), treated rats reversed normally when no delay separated the CS+ and US; with delays of 2 to 4 s, they reversed less completely within a session than did controls. Changing P(RFT) did not affect reversal learning in either group, but reduced response rates similarly in both groups. Morphological damage was quantified by measuring the length of the remaining pyramidal cell line in sections of dorsal hippocampus. The degree of behavioral impairment correlated significantly with hippocampal damage only at nonzero CS(+)-US delays. These results indicate that TMT impaired ability of rats to integrate temporal relationships between stimulus events, and are consistent with theories of hippocampal mediation of temporal associations.