Cognitive flexibility: modulation of prefrontal-hippocampal network activation.

Cognitive flexibility refers to the ability to adjust one’s behaviour adaptively in response to changes in the environment. An adaptive response involves different concomitant components, including attention to contingency changes, inhibition of previous responses, and acquisition of new strategies. In this thesis, we aimed to broaden the general neurochemical and neuroanatomical knowledge of cognitive flexibility. To achieve this purpose, we conducted a series of pharmacological and anatomical studies in mice.

In a first study, we investigated the role of NMDA receptors in flexibility by administrating NMDA receptor antagonist MK-801 (dizocilpine). The effect of MK-801 on flexibility was examined in a non-spatial visual discrimination task and in a spatial Morris water maze task. Results showed that blocking NMDA receptors affected reversal learning, a behavioural readout of cognitive flexibility, in both tasks. Further analyses indicated that these deficits appeared to be caused by perseverative errors, and could not be attributed to other non-mnemonic factors (e.g. anxiety, motivation).

In a second pharmacological study, we examined the effect of post-training scopolamine administration. Scopolamine is a muscarinic receptor antagonist that blocks the activity of muscarinic acetylcholine receptors. Here, we assessed the effect of scopolamine in three different tasks: odour discrimination in a digging paradigm, visual discrimination in a touchscreen setup, and spatial learning in the Morris water maze. Results showed that post-training administration of scopolamine facilitated performance in the reversal learning phase in odour and visual discrimination, by decreasing perseverance. However, performance in the spatial Morris water maze task was not affected. Further analyses indicated it is unlikely that these results can be explained by non-mnemonic factors or peripheral side-effects (e.g. mydriasis).

Finally, we investigated the interaction between the orbitofrontal cortex (OFC) and ventral hippocampus (vHC) in flexibility, using a disconnection model. In this model, lesions were made in left OFC and right vHC (contralateral), left OFC and left vHC (ipsilateral), left and right OFC, or left and right vHC. As there is one functional OFC-vHC unit left in the ipsilateral group, but none in the contralateral group, we hypothesized that performance in reversal learning would be affected more severely in the contralateral group. Results showed that early phase reversal learning was indeed impaired in the contralateral group, compared to the control group. Performance in other lesion groups was similar to the control group. Additional non-mnemonic tests showed that these results can not be attributed to motoric, motivational or anxiety-related factors. These data support a role for the interaction between the OFC and vHC during reversal learning.

Taken together, these three studies provide further knowledge with regard to the neurochemical and neuroanatomical basis of cognitive flexibility. In the first and second pharmacological study, evidence was provided for a modulatory role of NMDA receptors and muscarinic acetylcholine receptors, respectively. Finally, in a neuroanatomical lesion study, we presented data that suggests a role for OFC-vHC interaction in behavioural flexibility.