Delay-dependent impairment of a matching-to-place task with chronic and intrahippocampal infusion of the NMDA-antagonist D-AP5

Hippocampal Neural Disinhibition Causes Attentional and Memory Deficits

“…Nevertheless, the control data from the misplaced electrodes support that picrotoxin effects were largely restricted to the hippocampus. This is consistent with autoradiographic studies showing that intra-hippocampally infused radiolabelled AP-5, even at the relatively high infusion volume of 1 µl (in the present study, we used 0.5 µl), does not substantially spread across the medial and lateral boundaries of the hippocampus, probably because of the densely packed fiber bundles surrounding the hippocampus (Morris et al 1989;Steele and Morris 1999).…”

“…Second, we analyzed which proportion of trial-1 time spent in these 8 zones was spent in the zone containing the platform location on the pevious day ('previous day's zone'). Intact rats typically spend more time in the previous day's zone than expected based on chance (12.5 %), indicating place memory for the previous day's correct location acquired during the 4 trials completed on the previous day (Steele and Morris, 1999). If picrotoxin-infused rats spent more time in the previous day's zone during trial 1, this could be taken to reflect perseverative behavior, which might interfere with learning of the new location.…”

“…The watermaze DMP task requires rats to learn rapidly, within one trial, the daily changing place of a hidden platform in order to escape efficiently from a circular pool of water (Steele and Morris 1999). The task, especially in our new modification measuring search preference on probe trials to assess one-trial place memory, is highly sensitive to disruption of hippocampal function (Bast et al 2009;Pezze and Bast 2012).…”

“…If picrotoxin-infused rats spent more time in the previous day's zone during trial 1, this could be taken to reflect perseverative behavior, which might interfere with learning of the new location. If they spent less time, this could reflect impaired retrieval/expression of place memory acquired during the 4 trials of the previous day (Steele and Morris, 1999). However, there was no significant effect of infusion on the percentage of time spent in the previous day's zone during trial 1 [(time in previous day's zone/total time in all 8 zones)X100%, mean+SEM: Saline, 25.3+3.0%; 75 ng picrotoxin, 24.9+3.0%; 150 ng picrotoxin, 17.7+2.7%; F 2,26 =2.3, P=0.12).…”

“…To test for attentional deficits, we used the 5-choice-serial-reaction-time (5CSRT) task, which has high validity to measure prefrontal-dependent sustained attention, as impaired in several cognitive disorders, including schizophrenia and agerelated cognitive decline (Chudasama and Robbins 2006;Lustig et al 2013;Romberg et al 2013), and requires balanced prefrontal activity . To test for memory deficits, we used the watermaze delayed-matching-to-place (DMP) task, which requires rats to learn rapidly (within one trial) new place information every day and is highly dependent on hippocampal function (Steele and Morris 1999;Bast et al 2009;Pezze and Bast 2012), including function of the temporal to intermediate hippocampus (presumably because these regions feature functional connectivity to frontal and subcortical sites necessary to translate hippocampal learning into performance; Bast et al 2009;Bast 2011). The task resembles the everyday problem of remembering new places and routes, and similar human tests using virtual or real-space analogues of the watermaze reveal marked deficits in schizophrenia and age-related cognitive decline (Hort et al 2007;Fajnerova et al .…”