Amygdala kindling disrupts trace and delay fear conditioning with parallel changes in Fos protein expression throughout the limbic brain.

Amygdala kindling is well known to increase unconditioned fear and anxiety. However, relatively little is known about whether this form of kindling causes functional changes within the neural circuitry that mediates fear learning and the retrieval of fear memories. To address this issue, we examined the effect of short- (i.e., 30 stimulations) and long-term (i.e., 99 stimulations) amygdala kindling in rats on trace and delay fear conditioning, which are aversive learning tasks that rely predominantly on the hippocampus and amygdala, respectively. After memory retrieval, we analyzed the pattern of neural activity with Fos, the protein product of the immediate early gene c-fos. We found that kindling had no effect on acquisition of the trace fear conditioning task but it did selectively impair retrieval of this fear memory. In contrast, kindling disrupted both acquisition and retrieval of fear memory in the delay fear conditioning task. We also found that kindling-induced impairments in memory retrieval were accompanied by decreased Fos expression in several subregions of the hippocampus, parahippocampus, and amygdala. Interestingly, decreased freezing in the trace conditioning task was significantly correlated with dampened Fos expression in hippocampal and parahippocampal regions whereas decreased freezing in the delay conditioning task was significantly correlated with dampened Fos expression in hippocampal, parahippocampal, and amygdaloid circuits. Overall, these results suggest that amygdala kindling promotes functional changes in brain regions involved in specific types of fear learning and memory.

The effect of amygdala kindling on hippocampal neurogenesis coincides with decreased reelin and DISC1 expression in the adult dentate gyrus.

Temporal lobe seizures can induce the proliferation and abnormal migration of newly generated dentate granule cells, but little is known about the molecular mechanisms that govern these pathological events. Reelin and DISC1 (disrupted-in-schizophrenia 1) are proteins that play a regulatory role in the maturation and integration of new neurons in the developing and adult brain. In this study, we examined whether amygdala kindling results in aberrant neurogenesis and altered expression of reelin and DISC1 in the adult dentate gyrus. Using doublecortin immunohistochemistry, we found that short-term kindling (i.e., 30 electrical stimulations) significantly increased the number of immature neurons in the dentate subgranular zone (SGZ), whereas long-term kindling (i.e., 99 electrical stimulations) did not. However, doublecortin-labeled neurons in long-term kindled rats showed greater dendritic complexity than they did in short-term kindled or control rats. We also found that long-term kindling decreased the number of reelin-positive cells and decreased DISC1 expression in the dentate granule cell layer and subgranular zone. Interestingly, kindling-induced changes in reelin and DISC1 expression coincided with the appearance of ectopically located Prox1-labeled granule cells in the hilus. These effects occurred independently of alterations in granule cell layer length, dentate volume, or the number of hilar neurons. Taken together, these findings suggest a novel role for DISC1 in the pathophysiology of temporal lobe epilepsy and further suggest that changes in reelin and DISC1 expression may contribute to aberrant neurogenesis in the kindling model.

Profound hypothermia determines the anticonvulsant and neuroprotective effects of swim stress.

In contrast to most stressors that appear to be proconvulsant in nature, forced swimming (or swim stress) produces substantial anticonvulsant effects. Here we describe a series of experiments designed to identify the specific factors of swim stress (e.g., duration, swimming behavior, water temperature, and frequency of exposure) that are essential for the emergence of anticonvulsant effects in the rat. Our results revealed that the anticonvulsant effect of swim stress against lithium-pilocarpine convulsions occurred only when swim durations were at least 5 min in length and in water temperatures of 20 degrees C or less. Moreover, this anticonvulsant effect was not associated with habituation even after 10 days of repeated swimming. Treatment with lithium-pilocarpine coupled with 10 degrees C or 20 degrees C swim stress for 10 min caused pronounced hypothermia (10 to 15 degrees C reduction in body temperature) that required at least 12 h to return to baseline. One day after seizures were induced, swim stressed rats showed significantly fewer degenerating neurons in the hippocampus as revealed by Fluoro-Jade B staining. These results suggest that dramatically lowered body temperature could be the critical factor that produces the anticonvulsive and neuroprotective effects of swim stress.

Impaired social cognition 30 years after hemispherectomy for intractable epilepsy: the importance of the right hemisphere in complex social functioning.

Clinical research with individuals following hemispherectomy typically quantifies the success of surgical outcomes by focusing primarily on the achievement of seizure control and the preservation of general brain functions, such as movement, sensation, language, and memory. In addition to these outcomes, careful study of individuals following hemispherectomy also has the potential to contribute to our understanding of functional brain asymmetries involving other complex cognitive behaviors. In this study, we report preliminary evidence for the lateralization of social perception. We administered a series of neuropsychological tests that were developed to assess emotional recognition and the formation of social inferences and advanced social cognitive judgments, as they occur in everyday situations, to two adult participants who underwent complete anatomic left- or right-sided hemispherectomy. Our results show that despite a 30-year postsurgical period of recovery and consistent and high levels of family support and social engagement, distinct cognitive profiles are still evident between our right- and left-sided participants. In particular, participant S.M., who underwent an anatomic right hemispherectomy, showed the most severe impairments in identifying negative emotional expressions and conversational exchanges involving lies and sarcasm and in "mentalizing" the intent of others. In contrast, participant J.H., who underwent an anatomic left hemispherectomy was highly skilled interpersonally, despite evident language-related limitations, and showed only mild difficulties when asked to identify emotional expressions involving disgust and anger. These results suggest that the right hemisphere plays a particularly important role in social cognitive functioning and reasoning. Further examination of the extent of social perceptual difficulties prior to and following surgical intervention for epilepsy may guide the development of effective social skills training programs that can improve quality of life beyond seizure control.

Alpha2-adrenergic inhibition prevents the accompanied anticonvulsant effect of swim stress on behavioral convulsions induced by lithium and pilocarpine.

There has been much debate regarding the potential influence of stress on epilepsy. Many studies have reported that stress can affect seizure susceptibility through eliciting either proconvulsant or anticonvulsant effects within the nervous system. In this study, we investigated the potential anticonvulsant effect of a 10-min swim stress on convulsions induced by a single systemic injection of lithium chloride followed 4 h later with pilocarpine. Rats pretreated with lithium chloride and exposed to a 10-min swim stressor prior to pilocarpine injection displayed a significant delay to seizure onset compared to unstressed rats or rats exposed to swim stress 10 min after lithium chloride, 2 h after lithium chloride, or immediately after pilocarpine injection. We then determined whether administration of a glucocorticoid antagonist (mifepristone; 10 or 50 mg/kg), an alpha(2)-adrenergic antagonist (yohimbine; 2 or 5 mg/kg), or a nonspecific opioid blocker (naloxone; 0.2 or 1 mg/kg) could prevent the anticonvulsant effect of swim stress. Only the high dose of yohimbine was capable of inhibiting the anticonvulsant effect of swim stress on lithium-pilocarpine seizures. Our findings highlight the importance of an endogenous noradrenergic-dependent anticonvulsant system in mediating the effects of swim stress on seizures. Further studies exploring the benefits of treatments with noradrenergic acting drugs in epilepsy is well warranted.

Geophysical variables and behavior: C. Increased geomagnetic activity on days of commercial air crashes attributed to computer or pilot error but not mechanical failure.

Global geomagnetic activity (aa values) for the days of crashes of airplanes and for each of the three days before and after the crashes were compared for 373 events (years 1940 through 2002) attributed to unknown factors, mechanical errors, electronic/computer failures or pilot errors. Interactions between days and classifications of the crashes were due to the significantly greater geomagnetic activity on the days of crashes attributed to pilot or computer error but not to mechanical or unknown factors. Successive temporal analyses indicated that the elevated activity on the days of crashes attributed to pilot error have not changed over time, but there was an increase in those attributed to electronic errors after 1965. No more than 9% of the variance in geomagnetic activity on the days of the crashes was associated with the type of crash. These results are consistent with our hypothesis that some factor or factors associated with relative increases in geomagnetic activity may affect complex electronic systems composed of either silica (computer) or carbon (brain) aggregates.

Chronic administration of the L-type calcium channel blocker nimodipine can facilitate the acquisition of sequence learning in a radial-arm maze.

Nimodipine, a dihydropyridine L-type voltage-gated calcium-channel blocker, was examined for its potential effect on the acquisition of a complex-arm sequence task in an automated radial maze. Young (60-day-old) male Wistar rats were injected with saline or nimodipine (5 mg/kg) 15 min prior to radial maze training, or immediately following the radial maze testing. The results of the learning task (over 7 days of testing) showed that rats injected with nimodipine each training session acquired the task more quickly and more efficiently compared to saline-treated animals. There were no significant differences for rats that were pre-/post-treated with nimodipine during the maze-learning task. The number of incorrect arm entries and number of additional lever presses in the same arm were found to be significantly lower in rats treated with nimodipine compared to saline-injected controls. The beneficial effect of nimodipine treatment occurred only in rats that were acquiring the task, and not in rats that had already learned the arm sequence paradigm. There were no potential non-specific influences on locomotor activity or appetite caused by chronic nimodipine treatments. These results strongly suggest that nimodipine can facilitate the acquisition of a complex learning task.

The neuromatrix and the epileptic brain: behavioral and learning preservation in limbic epileptic rats treated with ketamine but not acepromazine.

Conceiving the organization of the brain as a "neuromatrix" could provide significant insights into how different injuries to the nervous system could result in very distinct changes in behavior. The use of different pharmacological treatments to combat the deleterious consequences of such injuries is common practice. However, such treatments may have the capacity to alter the configurations of various neuronal circuits that contribute to the "neuromatrix" by selectively preventing damage to some pathways while facilitating the spread of destruction along others. The choice of pharmacological treatment may have profound consequences on the recovery of normal functioning following injury. We examined the behavior of rats treated with one of two potentially neuroprotective agents, the N-methyl-D-aspartate antagonist ketamine and the atypical neuroleptic acepromazine, on seizures induced by lithium-pilocarpine. Rats treated with ketamine following seizure onset were virtually indistinguishable from nonepileptic controls on a variety of behavioral tasks that included tests on learning, memory, and anxiety. In contrast, acepromazine-treated rats showed marked deficits on all learning and behavioral measures tested. These results suggest that administration of ketamine relatively soon after the emergence of epilepsy can prevent many of the cognitive deficits that are commonly found in rats subjected to lithium-pilocarpine-induced seizures. Further clinical testing investigating ketamine as a potential adjunct treatment for epilepsy may be well warranted.

Learning and memory in agmatine-treated rats.

Agmatine, a noncompetitive N-methyl-D-aspartate (NMDA) antagonist, was examined for its role in water maze place learning, contextual and auditory-cued (discrete) fear learning and conditioned taste aversion learning, when administered systemically. Male Wistar rats were given saline or 1, 5, 10 or 50 mg/kg agmatine ip 20 min prior to or 30 min following daily training sessions in a hidden-platform (place learning) water maze task. Agmatine did not affect latencies to find the hidden platform or preference for the training quadrant during probe trials. When administered 20 min prior to contextual or auditory-cued fear-conditioning sessions, these doses of agmatine evoked a linear dose-dependent impairment in the magnitude of learned fear to the contextual stimuli when assessed during extinction trials 24 h later, but had no effect on the magnitude of learned fear to the auditory stimulus. Inferences of baseline motor activity and ability to respond to the presentation of footshock stimuli were not affected by the treatment. Injections of 50 mg/kg agmatine concurrently with a malaise-evoking agent following presentations to a novel sucrose solution abolished learned taste aversions; this agent did not evoke conditioned taste aversions alone. These studies indicate that systemically administered agmatine selectively impairs behavioral inferences of specific types of learning and memory.