Bilateral CA1 Research Articles

Mechanisms in the development of limbic status epilepticus and hippocampal neuron loss: an experimental study in a model of status epilepticus induced by kindling-like electrical stimulation of the deep prepyriform cortex in rats.

A new model of status epilepticus (SE), which was induced by intermittent electrical stimulation (20 Hz for 20 sec every min for 180 min) of the deep prepyriform cortex, has been developed in the conscious rat. SE was induced in 9 of 16 rats in the drug-free group. The number of stimulation trains required to induce SE in this status subgroup was 125.6 +/- 12.7 (mean +/- SEM) and the mean duration of self-sustained seizure activity (SSSA) occurring after cessation of the stimulation session was 295.4 +/- 111.4 min. Some animals showed secondary generalized seizures. Significant cell loss was observed in the hippocampal CA3 pyramidal cell layer ipsilateral to the stimulation site and bilateral CA1 areas in the status subgroup compared with the group subjected to sham operation. In addition, there was a significant negative correlation between the duration of SSSA subsequent to the stimulation session and the total number of intact pyramidal neurons observed in the bilateral CA1 and ipsilateral CA3 subfields of the status subgroup. There were significant differences between the status and non-status subgroups with respect to the number of afterdischarges (ADs) and the total AD duration during the stimulation session. Pretreatment with phenobarbital (30 mg/kg) prevented the development of SE and hippocampal cell loss completely. Pretreatment with MK-801, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist (0.25 or 1 mg/kg), also prevented hippocampal cell loss, although it did not block SE generation completely, which suggests dissociation of the mechanisms underlying the development of SE and hippocampal damage. These results indicate that prolonged SSSA actually causes hippocampal damage and it is critically dependent upon NMDA receptor participation.

Preoperative training modifies radial maze performance in rats with ischemic hippocampal injury.

Rats exposed to 30 minutes of four-vessel occlusion reliably develop severe bilateral CA1 hippocampal injury; under certain conditions of radial maze training, such rats perform the reference memory component as well as controls yet perform the working memory component worse than controls. Reference memory is thought to depend on invariable and working memory on variable spatial information. We assessed the effect of training before ischemia. In Experiment 1, rats trained for 36 trials on 12-arm radial mazes before ischemia demonstrated a persistent impairment on the working memory task but eventually performed the reference memory task comparable to controls. Ischemic rats made more working memory errors as the number of choices increased. This pattern of working memory errors was similar to that in controls except, as expected, ischemic rats made many more errors. In Experiment 2, training for 80 trials before ischemia in rats decreased the severity of both the working and the reference memory impairment. Ischemia did not affect motor behavior in either experiment. These results characterize the working memory deficit in ischemic rats and demonstrate the importance of experimental factors, particularly in the design of treatment strategies to reduce functional impairments caused by ischemia.

Increased vulnerability of the midly traumatized rat brain to cerebral ischemia: the use of controlled secondary ischemia as a research tool to identify common or different mechanisms contributing to mechanical and ischemic brain injury

Fasted Wistar rats were subjected to either a mild mechanical injury, 6 min of transient forebrain ischemia, or a mild mechanical injury followed 1 h later by 6 min of forebrain ischemia. EEG and evoked potentials were assessed intermittently and morphological analyses were performed after 7 das postinjury survival. In all groups complete qualitative recovery of electrical activity and general behavior was observed with 7-day survival. However, rats subjected to combined concussion and ischemia displayed EEG spike activity and a delayed return of EEG and evoked potentials during acute recovery not evident in other groups. No overt neuronal cells loss was seen in trauma alone and was minimal or absent in ischemia alone. However, extensive bilateral CA1 and subicular pyramidal cell loss was found in the septal and mid-dorsal hippocampi in the combined trauma and ischemia group. In contrast, no overt axonal injury was found in any group. We conclude that even mild mechanical injury can potentiate selective ischemic hippocampal neuronal necrosis in the absence of overt axonal injury. This potentiation also occurs in conjunction with more generalized electrophysiological disturbances such as EEG evidence of postischemic neuronal hyperactivity suggesting that mild concussion may also decrease the threshold for post-ischemic neuronal excitation. These results suggest the potential of this model for examining common or different injury mechanisms in mechanical and ischemic brain injury.

Modified T-maze training demonstrates dissociated memory loss in rats with ischemic hippocampal injury

Rats were trained for 20 days on a modified T-maze which required discrimination of a stem choice that was invariant and a goal choice that alternated. Animals were then exposed to 30 min of transient severe forebrain ischemia (postischemic, PI animals), 30 min of less severe ischemia (non-criterion ischemic, NCI animals), or sham operations (controls). After 30 postoperative days, all animals were returned to the maze for an additional 30 trials. PI rats demonstrated a dissociated performance on stem and goal choice. Specifically, the PI animals were significantly impaired on discrimination of a goal choice, yet performed comparably to controls on discrimination of a stem choice. Impaired goal choice for PI animals was not due to differential run times, proactive interference, or interaction between goal and stem choice. Histopathologic analysis of PI animals revealed bilateral destruction of the pyramidal neurons in the dorsal CA1 region of the hippocampus and lesser damage in the anterodorsal subiculum and the dorsolateral caudate. NCI animals had patchy variable ischemic neuronal damage. These data suggest that ischemic-induced bilateral CA1 pyramidal neuron loss is sufficient to cause dissociated performance in trained animals on a T-maze, but that less severe ischemia does not cause reproducible hippocampal neuron damage or functional deficits. Further, the data extends the development of reliable behavioral measures for an animal model of the amnesic syndrome that may occur in humans after cardiac arrest.