Seizures are often followed by sensory, cognitive or motor impairments during the postictal phase that show striking similarity to transient hypoxic/ischemic attacks. Here we show that seizures result in a severe hypoxic attack confined to the postictal period. We measured brain oxygenation in localized areas from freely-moving rodents and discovered a severe hypoxic event (pO2 < 10 mmHg) after the termination of seizures. This event lasted over an hour, is mediated by hypoperfusion, generalizes to people with epilepsy, and is attenuated by inhibiting cyclooxygenase-2 or L-type calcium channels. Using inhibitors of these targets we separated the seizure from the resulting severe hypoxia and show that structure specific postictal memory and behavioral impairments are the consequence of this severe hypoperfusion/hypoxic event. Thus, epilepsy is much more than a disease hallmarked by seizures, since the occurrence of postictal hypoperfusion/hypoxia results in a separate set of neurological consequences that are currently not being treated and are preventable.DOI: http://dx.doi.org/10.7554/eLife.19352.001
We present evidence that certain learning parameters can make a memory, even a very recent one, become independent of the hippocampus. We confirm earlier findings that damage to the hippocampus causes severe retrograde amnesia for context memories, but we show that repeated learning sessions create a context memory that is not vulnerable to the damage. The findings demonstrate that memories normally dependent on the hippocampus are incrementally strengthened in other memory networks with additional learning. The latter provides a new account for patterns of hippocampal retrograde amnesia and how memories may become independent of the hippocampus.
It is generally believed that the hippocampus is not required for simple discrimination learning. However, a small number of studies have shown that hippocampus damage impairs retention of a previously learned visual discrimination task. We propose that, although simple discrimination learning may proceed in the absence of the hippocampus, it plays an important role in this type of learning when it is intact. In order to test the role of the hippocampus in simple discrimination learning, we performed a series of experiments utilizing a two-choice picture discrimination task. Our experiments confirm that rats readily learn simple two-choice picture discriminations after hippocampus damage. However, if such discriminations are first learned while the hippocampus is intact, subsequent hippocampus damage causes severe retrograde amnesia for the discriminations. Furthermore, retrograde amnesia for simple picture discriminations was equally severe when the interval between training and damage was 1 d or 60 d; remote picture memories are not spared. Similarly, the rule or schema underlying a recently or remotely acquired picture discrimination learning set was lost after hippocampus damage. The severity of retrograde amnesia for simple picture discriminations is negatively correlated with the volume of spared hippocampus tissue. Thus, the hippocampus plays an essential role in long-term memories supporting simple picture discriminations.Much of what is known about the role of the hippocampus in learning and memory comes from studies of anterograde amnesia after hippocampus damage. There is a consensus that the ability to learn simple discrimination tasks typically is not affected by anterograde amnesia (Broadbent et al. 2007). In simple discrimination tasks, usually involving many trials of training, one stimulus is reinforced and another is not. As such, simple discriminations are among the class of problems that have linear solutions (i.e., during training, S+ acquires greater excitatory associative strength than S.)מ Numerous experiments have confirmed that anterograde amnesia after hippocampus damage does not affect simple discrimination problems (Sutherland and Rudy 1989;Whishaw and Tomie 1991;Alvarado and Rudy 1995). Thus, data from studies of anterograde amnesia after hippocampus damage support the conclusions that the hippocampus is not necessary for simple discrimination learning and that neural systems outside the hippocampus are capable of encoding, storing, and retrieving memories supporting simple discrimination learning.One might conclude from the foregoing that the learning systems that support simple discriminations also function
Chronic adrenalectomy (ADX) causes a gradual and selective loss of granule cells in the dentate gyrus (DG) of the rat. Here, we administered replacement corticosterone to rats beginning 10 wk after ADX. We then tested them in three discrimination tasks based on object novelty, location, or object/context association. Only during testing of the object/context association did ADX rats demonstrate deficits. These findings add to a body of evidence that the hippocampus is necessary when contextual information is important. We also confirm that memory deficits after chronic adrenalectomy are not a result of loss of corticosterone per se.Research with rats (Sutherland and McDonald 1990;Kim and Faneslow 1992;Anagnostaras et al. 2001;Lehmann et al. 2009), nonhuman primates (Machado and Bachevalier 2006;Pascalis et al. 2009), and humans (Alvarez et al. 2008;Marschner et al. 2008) shows that hippocampal damage can disrupt the ability to recall or express information about context. Furthermore, several reports suggest that the hippocampus is important for creating flexible representations of context and object associations. Studies in rats (Mumby et al. 2002;O'Brien et al. 2006) and humans (Pascalis et al. 2009) show that lesions specific to the hippocampus produce deficits in object recognition only when contextual information is altered.Within the hippocampus, the dentate gyrus (DG) is important for certain aspects of memory (Xavier et al. 1999;Garthe et al. 2009). Chronic adrenalectomy (ADX) causes a gradual and selective loss of granule cells in the DG of the rat (Sloviter et al. 1989). This loss of cells is attributed to a lack of circulating corticosterone (CORT) (Sloviter et al. 1989;Woolley et al. 1991). Behavioral deficits as a result of chronic ADX have been reported in the Morris water task (Armstrong et al. 1993;Roozendaal et al. 1998;Spanswick et al. 2007) and open-field task (Islam et al. 1995). There has been debate as to whether the deficits experienced by ADX rats are a result of lost CORT or due to the depletion of the granule cell layer itself. Conrad and Roy (1995) and McCormick et al. (1997) report that acute CORT replacement is sufficient to alleviate some of the deficits in spatial tasks associated with chronic ADX. These findings have led some to conclude that the removal of CORT is responsible for the behavioral deficits experienced by ADX rats and not the loss of granule cells per se. In direct contrast to these findings, Spanswick et al. (2007) report that administration of CORT after 6 wk of ADX does not alleviate spatial deficits in a moving-platform version of the Morris water task. Also in opposition to Conrad and Roy (1995) and McCormick et al. (1997), studies utilizing colchicine as a method to remove granule cells report spatial deficits as a result of cell loss (Sutherland et al. 1983;Xavier et al. 1999;Jeltsch et al. 2001).Here, we show using three versions of a novelty-preference task (novel object, novel place, and object/context mismatch) that lesions limited to the granule cell layer...
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