Suppression of Neurotoxic Lesion-Induced Seizure Activity: Evidence for a Permanent Role for the Hippocampus in Contextual Memory

Abstract

Damage to the hippocampus (HPC) using the excitotoxin N-methyl-D-aspartate (NMDA) can cause retrograde amnesia for contextual fear memory. This amnesia is typically attributed to loss of cells in the HPC. However, NMDA is also known to cause intense neuronal discharge (seizure activity) during the hours that follow its injection. These seizures may have detrimental effects on retrieval of memories. Here we evaluate the possibility that retrograde amnesia is due to NMDA-induced seizure activity or cell damage per se. To assess the effects of NMDA induced activity on contextual memory, we developed a lesion technique that utilizes the neurotoxic effects of NMDA while at the same time suppressing possible associated seizure activity. NMDA and tetrodotoxin (TTX), a sodium channel blocker, are simultaneously infused into the rat HPC, resulting in extensive bilateral damage to the HPC. TTX, co-infused with NMDA, suppresses propagation of seizure activity. Rats received pairings of a novel context with foot shock, after which they received NMDA-induced, TTX+NMDA-induced, or no damage to the HPC at a recent (24 hours) or remote (5 weeks) time point. After recovery, the rats were placed into the shock context and freezing was scored as an index of fear memory. Rats with an intact HPC exhibited robust memory for the aversive context at both time points, whereas rats that received NMDA or NMDA+TTX lesions showed a significant reduction in learned fear of equal magnitude at both the recent and remote time points. Therefore, it is unlikely that observed retrograde amnesia in contextual fear conditioning are due to disruption of non-HPC networks by propagated seizure activity. Moreover, the memory deficit observed at both time points offers additional evidence supporting the proposition that the HPC has a continuing role in maintaining contextual memories.

Hippocampus and medial prefrontal cortex contributions to trace and contextual fear memory expression over time

“…As was observed in Experiment 1, there was no remote memory impairment for trace tone freezing following hippocampus damage, yet the context freezing deficit was maintained in these same animals (at least for VH lesioned rats). The functional differences found here between DH and VH lesioned rats in the context test may help explain the dichotomy in the field with some studies showing temporal gradients and others showing absence of gradients for contextual fear (Kim and Fanselow 1992;Frankland and Bontempi 2005;Sutherland et al 2008Sutherland et al , 2010Sparks et al 2011). It may be possible in the case of contextual, but not trace, fear that the larger VH lesion size, compared to the DH lesions, contributes to a greater deficit.…”

Memory Consolidation

“…Thus, one group has repeatedly failed to find a temporal gradient (Lehmann et al 2007;Sutherland et al 2008;Sparks et al 2011). Another group found no temporal gradient despite systematic manipulation of potentially relevant parameters: lesion method, lesion size, single trial training, and massed and spaced multitrial training (Broadbent and Clark 2013).…”

Adult Hippocampal Neurogenesis, Fear Generalization, and Stress

“…As a consequence, interference between indexes (hippocampal ensembles) determines whether overlapping memory traces in the cortex are activated and the extent to which cortical traces are consolidated. The continued involvement of the hippocampus in maintenance of precision of remote contextual memories (Sutherland et al, 2008;Wang et al, 2009;Wiltgen et al, 2010;Goshen et al, 2011;Sparks et al, 2011) suggests that hippocampal-cortical systems consolidation of remote memories may require the maintenance of hippocampal indexes.…”