[Show abstract][Hide abstract] ABSTRACT: Repeated electrical stimulation results in development of seizures and a permanent increase in seizure susceptibility (kindling). The permanence of kindling suggests that chronic changes in gene expression are involved. Kindling at different sites produces specific effects on interictal behaviors such as spatial cognition and anxiety, suggesting that causal changes in gene expression might be restricted to the stimulated site. We employed focused microarray analysis to characterize changes in gene expression associated with amygdaloid and hippocampal kindling. Male Long-Evans rats received 1 s trains of electrical stimulation to either the amygdala or hippocampus once daily until five generalized seizures had been kindled. Yoked control rats carried electrodes but were not stimulated. Rats were euthanized 14 days after the last seizures, both amygdala and hippocampus dissected, and transcriptome profiles compared. Of the 1,200 rat brain-associated genes evaluated, 39 genes exhibited statistically significant expression differences between the kindled and non-kindled amygdala and 106 genes exhibited statistically significant differences between the kindled and non-kindled hippocampus. In the amygdala, subsequent ontological analyses using the GOMiner algorithm demonstrated significant enrichment in categories related to cytoskeletal reorganization and cation transport, as well as in gene families related to synaptic transmission and neurogenesis. In the hippocampus, significant enrichment in gene expression within categories related to cytoskeletal reorganization and cation transport was similarly observed. Furthermore, unique to the hippocampus, enrichment in transcription factor activity and GTPase-mediated signal transduction was identified. Overall, these data identify specific and unique neurochemical pathways chronically altered following kindling in the two sites, and provide a platform for defining the molecular basis for the differential behaviors observed in the interictal period.
[Show abstract][Hide abstract] ABSTRACT: The kindling of seizures with stimulation of brainstem sites has been reported inconsistently in the literature. The characteristics of the kindling observed, involving high intensities of stimulation and immediate onset of generalized tonic-clonic convulsions, raise questions regarding the nature of kindling from these sites.
We implanted chronic electrodes in either the nucleus reticularis pontis oralis (RPO), mesencephalic reticular formation (MRF), dorsal periaqueductal gray (dPAG), or ventrolateral periaqueductal gray (vlPAG) in male Long-Evans rats, with a recording electrode in the amygdala. Rats received conventional high-frequency kindling stimulation once daily for 30 days. To test for transfer, we kindled the amygdala beginning 7 weeks after the last brainstem kindling trial.
Tonic-clonic seizures were evoked by stimulation from all brainstem sites. Seizures were brief and were associated with characteristic low-amplitude high-frequency afterdischarge (AD). Kindling of the dPAG resulted in the development of classic AD and increased AD duration. Prior kindling of the dPAG facilitated subsequent kindling of the amygdala; however, no transfer was observed with prekindling of other brainstem sites.
The variability in the response to kindling stimulation suggests that certain brainstem sites are resistant to kindling, whereas other sites are more susceptible to kindling but are still relatively resistant in comparison to sites in the forebrain. The development of classic AD in later trials of dPAG stimulation suggests that epileptogenesis can occur even in the initial absence of classic AD when low-amplitude high-frequency AD is present.
[Show abstract][Hide abstract] ABSTRACT: Kindling in rats produces enduring behavioral changes that parallel the psychobehavioral disturbances frequently accompanying temporal lobe epilepsy. Some evidence suggests that the site of kindling is an important determinant of the type of behavioral changes observed following kindling, although this variable has not been systematically investigated. In the present experiments, the effects of amygdaloid kindling were assessed on a battery of behavioral tests we used previously to assess the effects of kindling in dorsal hippocampus or perirhinal cortex. Three generalized seizures were kindled with stimulation in or near the basolateral amygdala. One week later, rats were tested successively on measures of anxiety, activity, object recognition memory, and spatial working memory over a period of 3 weeks. Amygdaloid kindling produced increased anxiety, but spared all other behaviors assessed. This pattern of results is partially distinct from the previously described effects of perirhinal cortical kindling, which increases anxiety but also impairs object recognition memory, and is completely distinct from dorsal hippocampal kindling, which selectively increases activity and impairs spatial working memory. The observations suggest that kindling of distinct highly interconnected temporal lobe sites produces distinct patterns of behavioral comorbidity. The underlying mechanisms are thus most likely localized to intrinsic circuits at the site of seizure origination.
[Show abstract][Hide abstract] ABSTRACT: Rats received 45 pairings of kindling or sham stimulation in distinctive contexts before a conditioned place preference/aversion test, to determine whether the stimulation and seizures were rewarding or punishing. After more pairings, rats received kindling stimulation in each context (switch test). Ictal measures in this test included afterdischarge duration, clonus duration, latency to clonus, class of convulsion and falls. After more pairings, afterdischarge threshold was measured in each context. On every fourth day of pairings, the rats' behaviour in the prestimulation interval was recorded, to measure conditioned anticipatory defensive behaviour. We partially replicated the finding of Barnes et al. (2001, Behav. Neurosci., 115, 1065-1072) that conditioned anticipatory responses and conditioned place aversion are associated with the kindling environment. However, there were no conditioned effects on any ictal measures, including afterdischarge threshold. Our results fail to support the hypothesis that conditioning is a universal mechanism for kindling.
European Journal of Neuroscience 02/2008; 27(1):169-76. DOI:10.1111/j.1460-9568.2007.05977.x · 3.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Various studies of hippocampus and medial thalamus (MT) suggest that these brain areas play a crucial, marginal, or no essential role in spatial navigation. These divergent views were examined in experiments using electrolytic Lesions of fimbria-fornix (FF) or radiofrequency or neurotoxic Lesions of MT of rats subsequently trained to find a stable visible (experiment 1) or hidden platform (experiments 2 and 3) in a water maze (WM) pool. Rats with electrolytic Lesions of FF or radiofrequency Lesions of MT were impaired in swimming to a stable visible platform, particularly the MT Lesion Group, suggesting impairment of WM strategies acquisition. Additional Lesioned rats were then tested in a hidden platform version of the WM task. Some rats were given Morris's nonspatial pretraining prior to Lesioning to provide them with training in the required WM behavioral strategies. Nonspatially Pretrained rats with FF Lesions eventually were able to navigate to the hidden platform, but the accuracy of place responding was impaired. This impairment occurred without problems in the motoric control of swimming or the use of WM behavioral strategies, suggesting that these rats had a spatial mapping impairment. Radiofrequency MT Lesions blocked acquisition of WM behavioral strategies by Naive rats throughout 3 days of training, severely impairing performance on all aspects of the hidden platform task. Nonspatially Pretrained rats given the same MT Lesions readily learned the hidden platform location and were indistinguishable from controls throughout spatial training. Rats given neurotoxic Lesions of MT for removal of cells were only mildly impaired and improved considerably during training, suggesting an important role for fibers of passage in WM strategies learning. The results provide a clear dissociation between a role for MT in learning WM behavioral strategies and the hippocampal formation in spatial mapping and memory. This is the first identification of a brain area, MT, that is essential for learning behavioral strategies that by themselves do not constitute the solution to the task but are necessary for the successful use of an innate learning ability: place response learning using spatial mapping.
Behavioural Brain Research 07/2006; 170(2):241-56. DOI:10.1016/j.bbr.2006.02.023 · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The mechanisms underlying brain seizure tolerance, a phenomenon in which brief periods of seizures protect brain against the lethal effects of subsequent sustained seizures, are poorly understood. Because brain seizure tolerance and brain ischemia tolerance likely share certain common mechanisms, the recent evidence that activation of extracellular regulated kinase (ERK) and p38 kinase pathways plays a critical role in ischemic preconditioning suggests that a similar mechanism may underlie brain seizure tolerance. We investigated the hypothesis in a rat kainic acid preparation of seizure preconditioning and tolerance, which was established by induction of one episode of priming epileptic status lasting for 20 min on the first day and another episode of sustained epileptic status lasting for 2 hr on the second day. We observed that acute seizures lead to a rapid activation of ERK and p38 in the hippocampal CA3 area, the brain region most susceptible to the lethal effects of epileptic status. Pretreatment with the ERK inhibitor PD98059 and the p38 inhibitor SB203580 selectively reduces seizure-elicited activation of ERK and p38, respectively, and significantly reduces priming seizure-induced protection of CA3 neurons. These findings indicate that, similar to brain ischemia tolerance, brain seizure tolerance also involves the ERK and p38 signaling pathways.
Journal of Neuroscience Research 08/2005; 81(4):581-8. DOI:10.1002/jnr.20566 · 2.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Temporal lobe epilepsy (TLE) is frequently accompanied by memory impairments and, although their bases are unknown, most research has focused on the hippocampus. The present study investigated the importance of another medial temporal lobe structure, the perirhinal cortex (Prh), in changes in memory in TLE using kindling as a model. Rats were kindled twice daily with anterior Prh stimulation until three fully generalized seizures were evoked. Beginning 7 days later and on successive days, rats were tested in an elevated plus maze, a large circular open field, an open field object exploration task and a delayed-match-to-place task in a water maze in order to assess anxiety-related and exploratory behaviour, object recognition memory and spatial cognition. Kindling increased anxiety-related behaviour in both the elevated plus and open field mazes and disrupted spontaneous object recognition but spared all other behaviours tested. These results are consistent with other findings indicating a greater role for the Prh in object memory and emotional behaviour than in spatial memory and contrast with the selective disruption of spatial memory produced by dorsal hippocampal kindling. The site-selectivity of the behavioural disruptions produced by kindling indicates that such effects are probably mediated by changes particular to the site of seizure initiation rather than to changes in the characteristic circuitry activated by limbic seizure generalization. Further investigation of the behavioural effects of Prh kindling may be useful for studying the mechanisms of mnemonic and affective dysfunction associated with TLE and offer insights into bases for variability in such dysfunction across patients.
European Journal of Neuroscience 03/2005; 21(4):1081-90. DOI:10.1111/j.1460-9568.2005.03938.x · 3.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Characterizing the differences in kindling rates and associated convulsive behaviors following kindling of various structures
may aid in understanding the structural and functional mechanisms of epileptogenesis. Overall, the structures and pathways
that are critical to kindling are largely unknown. The results of recent research suggest a role for the CLA, namely that
the CLA may be part of a network of structures involved in seizure generalization. The anterior CLA is highly susceptible
to kindling, involving a pattern of dual-phase seizure development.1
[Show abstract][Hide abstract] ABSTRACT: Epilepsy is a chronic disorder defined by the recurrence of spontaneous seizures affecting ∼2% of the population in North
America.1 There are a variety of distinct subtypes of the disorder with the most common, temporal lobe epilepsy (TLE), accounting for
about 55% of all cases.1, 2 While the seizures themselves can be significantly debilitating, the clinical impact of TLE is exacerbated by the fact that
about half of all sufferers exhibit serious disturbances of affect and/or memory function.3–6 At present, the mechanisms of these TLE-associated psychological impairments are unknown and, although recent studies have
begun to explore the potential effectiveness of behavioral interventions,7,8 there is no treatment currently available. Consequently, these problems are often neglected clinically and have a significant
adverse effect on patient quality of life.9 There is a clear need, then, for research to provide a better understanding of the bases for epilepsy-associated psychological
disturbances and to develop effective treatment strategies. Clinical studies, however, are challenging because of the large
number of potentially relevant but difficult to control variables. Thus, progress relies heavily on work with suitable animal
models. The present chapter reviews studies on one such model — kindling in rats, and describes characteristics of spatial
memory changes in this model, their relation to kindling-related variables, and potential mediating mechanisms.
[Show abstract][Hide abstract] ABSTRACT: For millennia there has been interest in the potential therapeutic effects of marijuana (cannabis), including its potential
antiepileptic effects. A flurry of research on cannabis and seizures occurred in the 1970s, when purified tetrahydrocannabinol
(THC) became available for research. The results demonstrated that a variety of seizures, including kindled seizures can be
suppressed by THC, but typically at toxic doses.1–3 It was also reported that prophylactic administration of THC can delay limbic kindling in rats2 and cats.3 In contrast, other studies that received less attention described proepileptic or proconvulsant effects of a variety of cannabinoids,
including THC.4–6 Because of a lack of knowledge about the mechanisms of cannabis’s effects oh the brain, research on cannabis and epilepsy
declined to a very low level in the 1980s.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to determine whether N-palmitoylethanolamide (PEA), a putative endocannabinoid, would be effective against kindled amygdaloid seizures. For a comparison with earlier work, we also tested the effectiveness of PEA against pentylenetetrazol (PTZ)-induced convulsions.
Kindling electrodes were implanted bilaterally in the amygdala in 32 Long-Evans rats. After the kindling of generalized (stage 5) seizures, the effects of PEA administration [i.p.; 1, 10, 100 mg/kg in dimethylsulfoxide (DMSO)] were evaluated for anticonvulsant activity. PEA (40 mg/kg, i.p. in DMSO) also was tested for anticonvulsant activity against PTZ-induced convulsions (75 mg/kg, i.p.).
After i.p. administration of PEA, kindled rats displayed an increased latency to clonus at the 1-mg/kg dose. No other dose-dependent effects were noted. When tested against PTZ-induced convulsions, PEA protected against tonic convulsions and prolonged the latency between convulsive episodes.
PEA produces antiepileptic effects, but does not completely suppress seizures. The mechanism of action of PEA remains to be defined.
[Show abstract][Hide abstract] ABSTRACT: Dorsal hippocampal kindling impairs subsequent performance on spatial tasks. The relation between this effect and the extent of kindling achieved prior to testing has not been clearly established. Thus, the present study investigated the effects of dorsal hippocampal kindling on performance of a delayed-match-to-place (DMTP) task in the Morris water maze by assessing performance after each of series of different points in the kindling process including 1, 6, 11, and 16 afterdischarges, 1 stage 1 seizure, and 1 stage 5 seizure. We found that kindling produced a deficit that was apparent very early into kindling in terms of both direct swim (by 1 AD) and escape distance (by 6 ADs) measures but that did not clearly change in severity with further kindling. These results illustrate that kindling of even a few localized hippocampal seizures can disrupt spatial cognition and suggest that the mechanisms mediating memory disruption either do not change substantially as kindling progresses or that compensatory processes are engaged across training that mitigate any further kindling-related deteriorations in performance.
Epilepsy Research 03/2004; 58(2-3):145-54. DOI:10.1016/j.eplepsyres.2004.01.004 · 2.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The anatomy of the claustrum (CLA) has been well characterized, but its functional role remains uncertain. The results of recent research suggest that the CLA may be part of a network of structures involved in seizure generalization, and we set out to test this idea. To test persistence, seizures were kindled in the anterior CLA. Following a 14-day suspension of kindling, all rats required only one stimulation to evoke a stage 5 seizure. In another experiment, groups of rats received bilateral lesions of the anterior CLA before and after amygdaloid kindling. We found that small lesions of the anterior CLA retard amygdaloid kindling, but do not block the expression of generalized seizures. Lesions produced after amygdaloid kindling resulted in a shorter seizure duration, but had no marked effect on seizure expression. Another group of rats was tested for transfer of kindling between the anterior CLA and contralateral amygdala. We found an asymmetrical transfer of kindling to the CLA from the amygdala wherein amygdaloid kindling facilitated subsequent kindling of the CLA but kindling of the anterior CLA failed to facilitate kindling of the amygdala. The results add support to the notion that the CLA contributes to the development of generalized limbic seizures.
[Show abstract][Hide abstract] ABSTRACT: Temporal lobe epilepsy, the most common type of epilepsy in adult humans, is characterized clinically by the progressive development of spontaneous recurrent seizures of temporal lobe origin and pathologically by hippocampal neuronal loss and mossy fiber sprouting. In this study, we sought to test the prominent hypothesis that neuronal loss and mossy fiber sprouting play a critical role in the genesis and progression of temporal lobe epilepsy. Rats receiving a single kainic acid injection experienced a single sustained episode of epileptic status with massive neuronal loss and mossy fiber sprouting, whereas rats receiving triple kainic acid injections experienced two priming episodes and one sustained episode of epileptic status with no detectable neuronal loss and mossy fiber sprouting. Early in the process of chronic seizure development, primed rats that failed to show detectable neuronal loss and mossy fiber sprouting exhibited a starting date and a frequency of spontaneous recurrent seizures similar to those of nonprimed rats that showed massive neuronal loss and mossy fiber sprouting. However, nonprimed rats displayed significantly prolonged episodes of spontaneous recurrent seizures over the whole process of chronic seizure development and more frequent severe seizures later in the process. Similar results were observed in both Fischer-344 and Wistar rats as well as in the rat pilocarpine preparation of temporal lobe epilepsy. These results fail to reveal a relation between neuronal loss-mossy fiber sprouting and the genesis of temporal lobe epilepsy but suggest that neuronal loss, mossy fiber sprouting, or both contribute to the intensification of chronic seizures.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 08/2002; 22(14):6052-61. · 6.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Kindling produces enduring neural changes that are subsequently manifest in enhanced susceptibility to seizure-evoking stimuli and alterations in some types of behavior. The present study investigated the effects of dorsal hippocampal (dHPC) kindling on a variety of behaviors to clarify the nature of previously reported effects on spatial task performance. Rats were kindled twice daily with dHPC stimulation until three fully generalized seizures were evoked. Beginning 7 d later and on successive days, rats were tested in an elevated plus maze, a large circular open field, an open field object exploration task, and a delayed-match-to-place (DMTP) task in a water maze to assess anxiety-related and activity-related behavior (tasks 1 and 2), object recognition memory (task 3), and spatial cognition (task 4). Kindling disrupted performance on the DMTP task in a manner that was not delay dependent and produced a mild enhancement of activity-related behaviors in the open field task but not the elevated plus maze. All other aspects of testing were spared. These findings indicate that dHPC kindling produces enduring and selective effects on behavior that are consistent with a restricted disruption of hippocampally mediated functions. Possible bases for these effects are changes in local NMDA receptor function and/or changes in local inhibition, which might alter the optimal conditions for experience-dependent induction of intrahippocampal plasticity. This preparation may be useful for studying the mechanisms of mnemonic dysfunction associated with temporal lobe epilepsy and may offer unique insights into the mechanisms underlying normal hippocampal function.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 07/2001; 21(12):4443-50. · 6.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The claustrum has been implicated in the kindling of generalized seizures from limbic sites. We examined the susceptibility of the anterior claustrum itself to kindling and correlated this with an anatomical investigation of its afferent and efferent connections. Electrical stimulation of the anterior claustrum resulted in a pattern of rapid kindling with two distinct phases. Early kindling involved extremely rapid progression to bilaterally generalized seizures of short duration. With repeated daily kindling stimulations, early-phase generalized seizures abruptly became more elaborate and prolonged, resembling limbic-type seizures as triggered from the amygdala. We suggest that the rapid rate of kindling from the anterior claustrum is an indication that the claustrum is functionally close to the mechanisms of seizure generalization. In support of our hypothesis, we found significant afferent, efferent, and often reciprocal connections between the anterior claustrum and areas that have been implicated in the generation of generalized seizures, including frontal and motor cortex, limbic cortex, amygdala, and endopiriform nucleus. Additional connections were found with various other structures, including olfactory areas, nucleus accumbens, midline thalamus, and brainstem nuclei including the substantia nigra and the dorsal raphe nucleus. The anatomical connections of the anterior claustrum are consistent with its very high susceptibility to kindling and support the view that the claustrum is part of a forebrain network of structures participating in the generalization of seizures.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 06/2001; 21(10):3674-87. · 6.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The perirhinal cortex has recently been implicated in the kindling of limbic generalized seizures. The following experiments in rats tested the selectivity of the perirhinal cortex's epileptogenic properties by comparing its kindling profile with those of the adjacent insular cortex, posterior (dorsolateral) claustrum and amygdala. The first experiment examined the kindling and EEG profiles, and found that both the claustrum and insular cortex demonstrated rapid epileptogenic properties similar to the perirhinal cortex, including very rapid kindling rates and short latencies to convulsion. Furthermore, electrical stimulation of all three structures led to a two-phase progression through stage-5 seizures which had characteristics of both neocortical and amygdaloid kindling. In a second experiment rats were suspended in a harness to allow for more detailed documentation of both forelimb and hindlimb convulsions. With this procedure we were able to detect subtle yet unique differences in convulsion characteristics from each of the kindled sites and stage-5 seizure phases. Some of these convulsive parameters were correlated with changes in FosB/DeltaFosB protein and BDNF mRNA expression measured two hours after the last convulsion. Overall, it appears that the perirhinal cortex is not unique in its property of rapid epileptogenesis. Moreover, the posterior claustrum exhibited the fastest kindling and most vigorous patterns of clonus, suggesting that it may be even more intimately associated with the motor substrates responsible for limbic seizure generalization than is the perirhinal cortex.
European Journal of Neuroscience 05/2001; 13(8):1501-19. DOI:10.1046/j.0953-816x.2001.01532.x · 3.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Kindling with electrical stimulation of the dorsal hippocampus has been shown to disrupt spatial task performance in rats. The present study investigated the specificity of this effect in terms of the possible contribution of nonmnemonic effects, the presence of a more general mnemonic deficit, and the involvement of learning/short-term memory and/or long-term memory processes. Rats were fully kindled with stimulation of the dorsal hippocampus and subsequently tested for acquisition, 7-day retention, and 28-day retention of a hidden platform (HP) location in the Morris water maze and an object discrimination problem in a modified water maze. To control for nonmnemonic behavioral impairments, testing on both tasks was preceded by training on visible platform control tasks. Kindling impaired acquisition of the HP location but spared performance on all other aspects of testing, indicating a specific impairment of spatial learning/short-term memory. These results suggest that epileptogenesis induced by hippocampal stimulation is indeed associated with a selective disruption of the mechanisms mediating spatial learning/short-term memory.
[Show abstract][Hide abstract] ABSTRACT: Kindling produces enduring changes in the brain that are evident in not only enhanced susceptibility to seizure-evoking stimuli but also alterations in non-epileptic behaviors or functions. The present review examines the effects of kindling on one class of non-epileptic functions, learning and memory, and explores the dependence of these effects on variables such as the site of kindling, extent of kindling, and interval between kindling and testing. Current research shows that kindling is capable of altering performance on a variety of tasks including those that require spatial cognition, aversive conditioning, and object-related cognition and that non-mnemonic effects are unlikely, in at least some cases, to underlie these effects. Consideration of the conditions under which these effects are observed indicates a distinct relation between specific mnemonic effects and both the site and extent of kindling. Continued characterization of the mnemonic effects of kindling should provide a theoretical framework to guide discovery of their underlying mechanisms, which, in turn, may lead to rational therapy for mnemonic dysfunction associated with epilepsy and insights into the mechanisms of learning and memory.