Uncovering the Role of the Hippocampus in the Transitive Inference Task Utilizing Pharmacological and Genetic Manipulations: Implications for Patients with Schizophrenia

Abstract

Patients with schizophrenia show a number of cognitive deficits that may be related to abnormal hippocampal physiology and function. One such cognitive deficit is in transitive inference. Simply stated, transitive inference is the ability to infer A > C after directly learning A > B and B > C. The hippocampus has been implicated in transitive inference as lesions of the hippocampus in C57BL/6 mice after initial training and testing impairs transitive inference. Likewise, lesions of the hippocampus in rats prior to training also impair transitive inference. However, lesions of the whole hippocampus are not able to specifically examine the role of the dorsal versus ventral hippocampus in this task. This is important because studies suggest that the dorsal and ventral poles of the hippocampus may be functionally different. The present experiment used reversible inactivation of the dorsal and ventral hippocampus to examine the role of these structures in transitive inference. Mice were trained to learn that A>B, B>C, C>D, and D>E during training phases and then were tested to show if they learned that A>E (the novel control pairing) and that B>D (the novel pairing which requires transitive inference) during test sessions. Following these test sessions, cannulae were inserted into the hippocampus and the mice were allowed 5 days to recover. After the recovery period, mice underwent 4 more test sessions. The GABAA agonist muscimol or saline was infused into the dorsal or ventral hippocampus thirty minutes before each test session. The mice which received muscimol infusion into the dorsal hippocampus performed similarly to controls on the novel control pairing (A>E) but were significantly impaired on the novel pairing (B>D) which required transitive inference. The DBA/2 strain of mice have altered hippocampal function and has been used to model schizophrenia. The study also compared performance of DBA/2J and C57BL/6J inbred mice in TI, and foreground and background fear conditioning, which both involve the hippocampus. Separate mice were then trained with two different fear conditioning paradigms. For background fear conditioning, mice are trained with two paired presentations of a conditioned stimulus (CS, 30 second, 85 dB white noise) and an unconditioned stimulus (US, 2 second, 0.57 mA foot shock). Mice are then tested the next day for both freezing to the training context. Foreground fear conditioning differed in that the mice were presented with only the shocks during training. DBA/2J mice performed significantly worse than the C57BL/6J in both foreground and background fear conditioning and transitive inference. These results provide further support for the role of the dorsal hippocampus in transitive inference. Moreover, these results may help provide a better understanding of the cognitive deficits associated with schizophrenia.