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Objective: Growing evidence shows a critical role of network disturbances in the pathogenesis of migraine. Unilateral pattern of neurological symptoms of aura suggests disruption of interhemispheric interactions during the early phase of a migraine attack. Using local field potentials data from the visual and motor cortices, this study explored effects of unilateral cortical spreading depression, the likely pathophysiological mechanism of migraine aura, on interhemispheric functional connectivity in freely behaving rats. Methods: Temporal evolution of the functional connectivity was evaluated using mutual information and phase synchronization measures applied to local field potentials recordings obtained in homotopic points of the motor and visual cortices of the two hemispheres in freely behaving rats after induction of a single unilateral cortical spreading depression in the somatosensory S1 cortex and sham cortical stimulation. Results: Cortical spreading depression was followed by a dramatic broadband loss of interhemispheric functional connectivity in the visual and motor regions of the cortex. The hemispheric disconnection started after the end of the depolarization phase of cortical spreading depression, progressed gradually, and terminated by 5 min after initiation of cortical spreading depression. The network impairment had region- and frequency-specific characteristics and was more pronounced in the visual cortex than in the motor cortex. The period of impaired neural synchrony coincided with post-cortical spreading depression electrographic aberrant activation of the ipsilateral cortex and abnormal behavior. Conclusion: The study provides the first evidence that unilateral cortical spreading depression induces a reversible loss of functional hemispheric connectivity in the cortex of awake animals. Given a critical role of long-distance cortical synchronization in sensory processing and sensorimotor integration, the post-cortical spreading depression breakdown of functional connectivity may contribute to neuropathological mechanisms of aura generation. [ABSTRACT FROM AUTHOR]

Abstract Transient postictal behavioral impairments in patients with epilepsy provide clues to seizure localization, but no attempt has been made previously to study the localization/lateralization value of postseizure motor disturbances in experimental models of epilepsy. The present study investigated relation of postictal motor deficit to seizure localization in the rat model of sound-induced reflex epilepsy. Sound-induced motor seizures started with a focal brainstem seizure (running) and progressed to a secondarily generalized seizure. Depending on innate or acquired seizure susceptibility of rats, focal brainstem seizures secondarily generalized within the brainstem (brainstem-generalized seizures) or spread to the forebrain (focal or generalized forebrain seizures). All sound-induced seizures were followed by catalepsy and abnormal limb posturing. The duration of the postictal catalepsy and the pattern of the posture abnormality depended on brainstem or forebrain localization of secondarily generalized seizures. Brainstem-driven seizures induced long-lasting whole-body catalepsy and cataleptic limb posture in the postictal period. Secondary seizure generalization to the forebrain led to shortening postictal catalepsy and development of rigid limb posturing. Asymmetric limb posturing was always observed after focal forebrain seizures, and the postictal asymmetry was closely linked to ictal asymmetry of the earliest running seizure phase, predicting lateralization of the seizure-onset side. This is the first demonstration of circuit-specific postictal behavioral impairments and their localization and lateralization values in epileptic rats. Highlights • Postictal catalepsy and abnormal limb posture reliably follow audiogenic seizures in rats. • Brainstem-driven seizures are critical for triggering postictal catalepsy. • Forebrain-driven seizures antagonize the catalepsy induced by brainstem seizures. • Focal seizures are followed by asymmetric postictal limb posture. • The postictal asymmetry closely relates to ictal asymmetry of initial focal seizure. [ABSTRACT FROM AUTHOR]

Background Cortical spreading depression (SD) is thought to underlie migraine aura but mechanisms of triggering SD in the structurally normal, well-nourished cortex of migraine patients remain unknown. Synaptic and network dysfunctions appear to underlie episodic neurological disorders, including migraine. The narrative review summarizes old and recent experimental evidence for triggering SD by synaptic/network mechanisms and discusses the relevance of the data to migraine pathogenesis. Our hypothesis is that under some conditions synaptic/network hyperactivity may reliably ignite SD, and this mechanism may underlie triggering migraine aura in patients. Findings High-frequency tetanic stimulation of the cortex reliably triggers SD in synaptically connected regions; SD is a reliable cortical response to acute hyperexcitability (epileptic seizures), though chronic epilepsy prevents triggering SD; in the hyperexcitable cortex, SD may be triggered by sensory stimulation; compromised glutamatergic transmission plays the critical role in triggering SD. Conclusion SD may be triggered by dynamic network instability produced by dysfunction of calcium-dependent glutamate release. Synaptic drive from subcortical sensory processing structures (brainstem and/or thalamocortical networks) is able to evoke depolarization of hyperexcitable cortical neurons sufficient to initiate the regenerative SD process. Studying SD initiation by synaptic/network hyperexcitability may provide insights into basic mechanisms underlying SD generation in migraine brain. [ABSTRACT FROM AUTHOR]

Human epilepsy is usually considered to result from cortical pathology, but animal studies show that the cortex may be secondarily involved in epileptogenesis, and cortical seizures may be triggered by extracortical mechanisms. In the audiogenic kindling model, recurrent subcortical (brainstem-driven) seizures induce secondary epileptic activation of the cortex. The present review focuses on behavioral and electrographic features of the subcortico-cortical epileptogenesis: (1) behavioral expressions of traditional and mild paradigms of audiogenic kindling produced by full-blown (generalized) and minimal (focal) audiogenic seizures, respectively; (2) electrographic manifestations of secondary epileptic activation of the cortex — cortical epileptic discharge and cortical spreading depression; and (3) persistent individual asymmetry of minimal audiogenic seizures and secondary cortical events produced by their repetition. The characteristics of audiogenic kindling suggest that this model represents a unique experimental approach to studying cortical epileptogenesis and network aspects of epilepsy. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic". [ABSTRACT FROM AUTHOR]

Purpose Spike-and-wave discharges (SWDs) recorded in the cortical EEGs of WAG/Rij rats are the hallmark for absence epilepsy in this model. Although this type of epilepsy was long regarded as a form of primary generalized epilepsy, it is now recognized that there is an initiation zone — the perioral region of the somatosensory cortex. However, networks involved in spreading the seizure are not yet fully known. Previously, the dynamics of coupling between different layers of the perioral cortical region and between these zones and different thalamic nuclei was studied in time windows around the SWDs, using nonlinear Granger causality. The aim of the present study was to investigate, using the same method, the coupling dynamics between different regions of the cortex and between these regions and the hippocampus. Methods Local field potentials were recorded in the frontal, parietal, and occipital cortices and in the hippocampus of 19 WAG/Rij rats. To detect changes in coupling reliably in a short time window, in order to provide a good temporal resolution, the innovative adapted time varying nonlinear Granger causality method was used. Mutual information function was calculated in addition to validate outcomes. Results of both approaches were tested for significance. Results The SWD initiation process was revealed as an increase in intracortical interactions starting from 3.5 s before the onset of electrographic seizure. The earliest preictal increase in coupling was directed from the frontal cortex to the parietal cortex. Then, the coupling became bidirectional, followed by the involvement of the occipital cortex (1.5 s before SWD onset). There was no driving from any cortical region to hippocampus, but a slight increase in coupling from hippocampus to the frontoparietal cortex was observed just before SWD onset. After SWD onset, an abrupt drop in coupling in all studied pairs was observed. In most of the pairs, the decoupling rapidly disappeared, but driving force from hippocampus and occipital cortex to the frontoparietal cortex was reduced until the SWD termination. Conclusion Involvement of multiple cortical regions in SWD initiation shows the fundamental role of corticocortical feedback loops, forming coupling architecture and triggering the generalized seizure. The results add to the ultimate aim to construct a complete picture of brain interactions preceding and accompanying absence seizures in rats. [ABSTRACT FROM AUTHOR]

It is now recognized that both generalized and focal seizures may originate in subcortical structures. The well-known types of focal subcortically-driven seizures are gelastic seizures in patients with the hypothalamic hamartoma and sound-induced seizures in rodents with audiogenic epilepsy. The seizures are generated by subcortical intrinsically epileptogenic focus, the hamartoma in humans and the inferior colliculus (IC) in rodents. In patients with gelastic epilepsy additional seizure types may develop with time that are supposed to result from secondary epileptogenesis and spreading of epileptic discharges to the cortex. Repeated audiogenic seizures can also lead to development of additional seizure behavior and secondary epileptic activation of the cortex. This process, named audiogenic kindling, may be useful for studying secondary subcortico-cortical epileptogenesis. Using intracollicular and intracortical recordings, we studied an ictal electrographic pattern of focal subcortical seizures induced by repeated sound stimulation in Wistar audiogenic-susceptible rats. The audiogenic seizures, representing brief attacks of paroxysmal unidirectional running, were accompanied by epileptiform abnormalities in the IC, mostly on the side ipsilateral to run direction, and enhanced rhythmic 8–9 Hz activity in the cortex. With repetition of the subcortical seizures and kindling development, a secondary cortical discharge began to follow the IC seizure. The secondary discharge initially involved the cortex homolateral to the side of dominant subcortical epileptiform abnormalities and behaviorally expressed as limbic (partial) clonus. Kindling progression was associated with bilateralization of the secondary cortical discharge, an increase in its amplitude and duration, intensification of associated behavioral seizures (from partial clonus to generalized tonic–clonic convulsions). Thus, ictal recordings during brief audiogenic running seizures showed their focal subcortical origin. Repetition of the subcortical seizures may result in secondary subcortico-cortical epileptogenesis manifested by emergence and progressive intensification of epileptiform discharges in the cortex. [ABSTRACT FROM AUTHOR]

Background: Migraine and epilepsy are highly co-morbid neurological disorders associated with episodic dysfunction of both cortical and subcortical networks. The study examined the interrelation between cortical spreading depression, the electrophysiological correlate of migraine aura and seizures triggered at cortical and brainstem levels by repeated sound stimulation in rats with acoustic hypersensitivity (reflex audiogenic epilepsy).Method: In awake, freely moving rats with innate audiogenic epilepsy, 25 episodes of running seizure (brainstem seizures) were induced by repeated sound stimulation. Spreading depression and seizures were recorded using implanted cortical electrodes.Results: The first sound-induced brainstem seizures evoked neither spreading depression nor seizures in the cortex. With repetition, brainstem seizures began to be followed by a single cortical spreading depression wave and an epileptiform discharge. Spreading depression was more frequent an early cortical event than seizures: spreading depression appeared after 8.4 ± 1.0 repeated stimulations in 100% rats (n = 24) while cortical seizures were recorded after 12.9 ± 1.2 tests in 46% rats. Brainstem seizure triggered unilateral long-latency spreading depression. Bilateral short-latency cortical spreading depression was recorded only after intense cortical seizures.Conclusion: These data show that episodic brainstem activation is a potent trigger of unilateral cortical spreading depression. Development of intense seizures in the cortex leads to initiation of spreading depression in multiple cortical sites of both hemispheres. [ABSTRACT FROM AUTHOR]

Summary: Endocannabinoid system and its CB1 receptors are suggested to provide endogeneous protection against seizures. The present study examines whether CB1 receptors contribute to resistance to seizures and kindling epileptogenesis in a model of audiogenic epilepsy. Three groups of Wistar rats were used: rats unsusceptible to audiogenic seizures, rats with acquired resistance to audiogenic seizures and rats with reproducible audiogenic running seizures. Chronic treatment with the CB1 receptor antagonist SR141716 (5 daily dosing of 30mg/kg) did not change innate resistance to audiogenic seizures in non-epileptic rats but reverted acquired seizure resistance in rats which lost their epileptic sensitivity with repeated testing. In the latter rats, audiogenic running seizures reappeared for at least two weeks after the end of treatment. In rats with reproducible seizure response, acutely, SR lengthened audiogenic seizures due to prolongation or appearance, de novo, of post-running limbic clonus without any effect on running seizure per se. This limbic component mimicked audiogenic kindling and indicated propagation of sound-induced brainstem seizure to the limbic forebrain. After chronic SR administration the incidence of the limbic clonus remained to be increased for at least two weeks. The present study supports the hypothesis about a role of CB1 receptors in endogeneous anticonvulsive mechanisms of the brain. [Copyright &y& Elsevier]

Abstract: Audiogenic kindling (AK) represents a model of naturally occurring epileptogenesis in which intensification of repeatedly induced audiogenic seizures results from propagation of epileptic activity from the brainstem to forebrain. Previously it has been shown that unilateral cortical spreading depression (SD) is a reliable earliest manifestation of mild AK produced by repetition of minimal audiogenic seizures (running) in Wistar rats. The unilateral triggering SD suggests the existence of asymmetry in the forebrain recruitment during the kindling and the present study examined whether epileptogenesis produced by this mild AK paradigm is a lateralized process. Twenty five running episodes were induced by brief sound stimulation in Wistar rats susceptible to audiogenic seizures. Behavioral and EEG correlates of AK development were assessed. Running behavior elicited by brief sound stimulation had an asymmetrical pattern with profound preference for one direction. Most rats expressing leftward running displayed full kindling development whereas the majority of rats with rightward running were resistant to AK. The EEG marker of AK, a cortical epileptiform discharge, was recorded only in rats with leftward running and the first discharge appeared in the left cortex. Cortical SD was recorded after repeated running seizures in all rats with reproducible audiogenic response irrespective of the running lateralization and propensity to kindling. Until the late kindling stages, SD was triggered unilaterally in the cortex ipsilateral to the running direction. These findings indicate intrinsically determined lateralization of epileptogenic process in the mild AK model and enhanced vulnerability of the left hemisphere to epileptogenesis. [Copyright &y& Elsevier]

Abstract: Cortical spreading depression (SD) is thought to underlie the migraine aura but the mechanisms of triggering SD in the human cortex remain unknown. Because growing evidence points to a key role of brainstem circuits in initiating migraine attacks, the present study examined whether recurrent episodes of brainstem activation in rats could induce cortical SD. Explosive running elicited by sounds in rodents with inherited hypersensitivity to acoustic stimuli (reflex audiogenic epilepsy), is known to reflect a transient aberrant activation of the brainstem. Repeated induction of such audiogenic responses enhances the excitability of the cortex, culminating in its epileptic activation (audiogenic kindling). In Wistar rats with inherited hypersensitivity to sounds, 15 brief episodes of running were induced by sound stimulation, and slow potential shifts as well as the EEG were recorded in the cortex. Single unilateral SD began to occur in the cortex following a running episode after the 5th to 15th test (mean 9.4±1.2). Once appeared, SD was regularly recorded in subsequent tests. The side of the SD initiation closely correlated with the direction of running. Triggering SD was not associated with epileptic activation of the cortex in most rats. The present findings suggest that the sensory-induced brainstem excitation could be a potent trigger of SD in the hyperexcitable cortex, providing an experimental evidence of a possible causative role of the brainstem activation in initiating the migraine aura. [Copyright &y& Elsevier]

Audiogenic kindling (AK) is a model of naturally occurring epileptogenesis triggered by repeated sound stimulation of rats genetically prone to audiogenic seizures. It is accepted that limbic seizure networks underlie progressive changes in behavioral seizure pattern during AK. The present study investigated AK progression in rats susceptible and unsusceptible to absence seizures. Progression of AK as indicated by an appearance and intensification of limbic clonus was examined in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats with genetic absence epilepsy and in Wistar rats. Subpopulations of kindling-prone and kindling-resistant rats were found in both Wistar and WAG/Rij strains. Despite identical seizure responses to the first sound stimulation, AK progression dramatically differed between the two subpopulations. AK-prone rats exhibited rapid kindling development up to maximal stage-5 severity. In AK-resistant rats, limbic clonus did not appear after 30 stimulations or if it appeared, it did not progress beyond stage 2. The proportions of AK-prone and AK-resistant animals within Wistar and WAG/Rij strains were similar. Comparison of Wistar and WAG/Rij rats within the kindling-prone and kindling-resistant groups did not reveal a significant strain effect on AK progression. However, within the WAG/Rij strain, a significantly higher incidence of absence seizures was found in AK-resistant rats compared to AK-prone rats. The present study demonstrates that sensitivity to sound-induced epileptogenesis differs dramatically within Wistar and WAG/Rij strains, whereas genetic susceptibility to absence seizures does not change AK progression significantly. It is supposed that an increased incidence of nonconvulsive seizures and resistance to kindling result from a common seizure modulating mechanism. [ABSTRACT FROM AUTHOR]

To study anticonvulsive and antiepileptogenic effects of singe levetiracetam (LEV) administration in the model of audiogenic kindling. Rats of Krushinsky-Molodkina (KM) strain genetically susceptible to severe audiogenic seizures received one intraperitoneal injection of saline, low (6 mg/kg) or high (50 mg/kg) dose of LEV before or after audiogenic kindling. One hour postinjection, an audiogenic seizure was induced to assess anticonvulsive effect of LEV in nonkindled and kindled rats. To examine antiepileptogenic activity of LEV, nonkindled rats injected with the drug or saline were kindled with repeated sound stimulations. Audiogenic kindling development manifested in an appearance and progressive prolongation of an additional seizure phase, post-tonic–clonus. The latency and duration of audiogenic seizures and the duration of every seizure phase (running, tonic, post-tonic–clonic) were measured. One hour posttreatment, LEV dose-dependently lengthened the latency and reduced the duration of audiogenic seizures in both nonkindled and kindled rats. The seizure shortening resulted from selective suppression of tonic and kindled post-tonic–clonic phases. The dose of 50 mg/kg completely blocked tonic and clonic convulsions 1 h postinjection. The anticonvulsive effect of LEV was more pronounced in kindled than in nonkindled rats. Single LEV injection in the dose of 50 mg/kg prior audiogenic kindling significantly suppressed subsequent kindling progression indicating profound antiepileptogenic potency of the drug. The present study shows that LEV exerts both short-lasting anticonvulsive effect on audiogenic seizures and very long-lasting antiepileptogenic effect on audiogenic kindling. Remarkably, a single injection of LEV is enough to significantly suppress kindling progression in KM rats. [ABSTRACT FROM AUTHOR]

Abstract: Explosive running is a reliable initial component of audiogenic seizures (AS) induced by acoustic stimulation in genetically prone rodents. This profound locomotor activation is usually considered as a convulsive manifestation of AS although some studies attribute running to a panic-like response. Increase in central histamine activity has been shown to suppress clonic and tonic seizures. The present study examined the involvement of histaminergic mechanisms in the expression of running component of AS. Metoprine, an inhibitor of histamine-N-methyltransferase, was used to increase brain histamine level. Running was induced 4 and 24 h after intraperitoneal injection of metoprine or vehicle in rats of different strains. A brief sound stimulation elicited running followed by clonic–tonic convulsions in Krushinsky–Molodkina (KM) rats or running alone in AS-prone Wistar and WAG/Rij rats. In KM rats, metoprine exerted opposite effects on the main phases of AS. It increased the duration of running and decreased the duration and severity of clonic–tonic convulsions. In Wistar rats, metoprine produced a remarkable aggravation of running leading to its 2- to 3-fold prolongation. In WAG/Rij rats with mixed seizures (absence and audiogenic), the drug caused either aggravation or suppression of running behavior. These results suggest specific role for histaminergic system in the expression of behavioral components of AS. Suppressive role of histamine in clonic–tonic seizures is associated with facilitation of running suggesting specific effects of histamine on brainstem neuronal networks underlying these phases of AS. Possible roles of histaminergic mechanisms in seizure, motor and aversive aspects of sound-induced running are discussed. [Copyright &y& Elsevier]

Abstract: Spreading depression (SD), a self-propagating wave of reversible cellular depolarization, is thought to play an important role in brain pathophysiology. SD and seizures are closely related events but little is known about involvement of SD in chronic epileptogenesis. Here we show that cortical SD is the first and highly reproducible manifestation of audiogenic kindling induced by repeated sound stimulation of WAG/Rij rats with genetic audiogenic and absence epilepsy. Repetition of sound-induced running seizures in freely moving rats led to an appearance and gradual intensification of post-running facial and forelimb clonic convulsions coupled with afterdischarge in the fronto-parietal cortex. Before the development of these traditional manifestations of audiogenic kindling, an unilateral cortical SD wave began to be triggered by audiogenic seizures. Once cortical SD appeared, it became a permanent component of subsequent seizures. SD was always recorded in the hemisphere ipsilateral to the running direction. Only at the late stages of audiogenic kindling SD developed bilaterally. To estimate the contribution of SD in postictal effects of audiogenic seizures, we compared cortical activity after seizures induced SD or not. It was found that only seizures with cortical SD were followed by postictal suppression of spontaneous spike-wave discharges displayed by WAG/Rij rats. The results show that (1) cortical SD is readily triggered by brief sensory-induced seizures in awake animals; (2) SD may be responsible for postictal changes in cortical activity; (3) unilateral initiation of SD suggests asymmetrical recruitment of the cortex into seizure network during audiogenic kindling. [Copyright &y& Elsevier]

Background: Neurogenic meningeal inflammation is regarded as a key driver of migraine headache. Multiple evidence show importance of inflammatory processes in the dura mater for pain generation but contribution of the leptomeninges is less clear. We assessed effects of cortical spreading depolarization (CSD), the pathophysiological mechanism of migraine aura, on expression of inflammatory mediators in the leptomeninges. Methods: A single CSD event was produced by a focal unilateral microdamage of the cortex in freely behaving rats. Three hours later intact cortical leptomeninges and parenchyma of ipsi-lesional (invaded by CSD) and sham-treated contra-lesional (unaffected by CSD) hemispheres were collected and mRNA levels of genes associated with inflammation (Il1b, Tnf, Ccl2; Cx3cl1, Zc3h12a) and endocannabinoid CB2 receptors (Cnr2) were measured using qPCR. Results: Three hours after a single unilateral CSD, most inflammatory factors changed their expression levels in the leptomeninges, mainly on the side of CSD. The meninges overlying affected cortex increased mRNA expression of all proinflammatory cytokines (Il1b, Tnf, Ccl2) and anti-inflammatory factors Zc3h12a and Cx3cl1. Upregulation of proinflammatory cytokines was found in both meninges and parenchyma while anti-inflammatory markers increased only meningeal expression. Conclusion: A single CSD is sufficient to produce pronounced leptomeningeal inflammation that lasts for at least three hours and involves mostly meninges overlying the cortex affected by CSD. The prolonged post-CSD inflammation of the leptomeninges can contribute to mechanisms of headache generation following aura phase of migraine attack. [ABSTRACT FROM AUTHOR]

Background: Spreading depolarization (SD), underlying mechanism of migraine aura and potential activator of pain pathways, is known to elicit transient local silencing cortical activity. Sweeping across the cortex, the electrocorticographic depression is supposed to underlie spreading negative symptoms of migraine aura. Main information about the suppressive effect of SD on cortical oscillations was obtained in anesthetized animals while ictal recordings in conscious patients failed to detect EEG depression during migraine aura. Here, we investigate the suppressive effect of SD on spontaneous cortical activity in awake animals and examine whether the anesthesia modifies the SD effect. Methods: Spectral and spatiotemporal characteristics of spontaneous cortical activity following a single unilateral SD elicited by amygdala pinprick were analyzed in awake freely behaving rats and after induction of urethane anesthesia. Results: In wakefulness, SD transiently suppressed cortical oscillations in all frequency bands except delta. Slow delta activity did not decline its power during SD and even increased it afterwards; high-frequency gamma oscillations showed the strongest and longest depression under awake conditions. Unexpectedly, gamma power reduced not only during SD invasion the recording cortical sites but also when SD occupied distant subcortical/cortical areas. Contralateral cortex not invaded by SD also showed transient depression of gamma activity in awake animals. Introduction of general anesthesia modified the pattern of SD-induced depression: SD evoked the strongest cessation of slow delta activity, milder suppression of fast oscillations and no distant changes in gamma activity. Conclusion: Slow and fast cortical oscillations differ in their vulnerability to SD influence, especially in wakefulness. In the conscious brain, SD produces stronger and spatially broader depression of fast cortical oscillations than slow ones. The frequency-specific effects of SD on cortical activity of awake brain may underlie some previously unexplained clinical features of migraine aura. [ABSTRACT FROM AUTHOR]

Abstract Mood and anxiety disorders, as well as memory impairments, are important factors affecting quality of life in patients with epilepsy and can influence the antiepileptic therapy. Clinical studies of psychiatric comorbidities are quite complicated to design and interpret, so animal studies of behavioral impairments associated with seizures can be of use. We investigated the effect of early administration of endocannabinoid receptor agonist WIN-55,212-2 on the development of spontaneous seizures, long-term behavioral and memory impairments, and neurodegeneration in the hippocampus on the lithium–pilocarpine model of status epilepticus (SE). We also studied the role of spontaneous seizures in the development of pathologic consequences of the SE. Our results showed that behavioral impairments found in the elevated plus maze test depended mostly on the consequences of SE itself and not on the development of spontaneous seizures while hyperactivity in the open-field test and light–dark chamber was more prominent in rats with spontaneous seizures. Administration of WIN-55,212-2 decreased emotional behavior in the elevated plus maze but did not affect hyperactive behavior in the open-field test. Spatial memory impairment developed both in the presence or absence of spontaneous seizures and was not affected by administration of WIN-55,212-2. Both administration of endocannabinoid receptor agonist WIN-55,212-2 and the presence of spontaneous seizures affected SE-induced neuronal loss in the hippocampus. Highlights • Behavior in elevated plus maze test depends mostly on the consequences of SE. • Hyperactivity in open field depends on the development of spontaneous seizures. • Early post-SE endocannabinoid activation modulates emotional behavior. • Early post-SE endocannabinoid activation does not prevent epileptogenesis. [ABSTRACT FROM AUTHOR]

Cortical spreading depolarization (CSD) is the neuronal correlate of migraine aura and the reliable consequence of acute brain injury. The role of CSD in triggering headaches that follow migraine aura and brain injury remains to be uncertain. We examined whether a single CSD occurring in awake animals modified the expression of proinflammatory cytokines (Il1b, TNF, and Il6) and endogenous mediators of nociception/neuroinflammation-pannexin 1 (Panx1) channel and calcitonin gene-related peptide (CGRP), transforming growth factor beta (TGFb) in the cortex. Unilateral microinjury of the somatosensory cortex triggering a single CSD was produced in awake Wistar rats. Three hours later, tissue samples from the lesioned cortex, intact ipsilesional cortex invaded by CSD, and homologous areas of the contralateral sham-treated cortex were harvested and analyzed using qPCR. Three hours post-injury, intact CSD-exposed cortexes increased TNF, Il1b, Panx1, and CGRP mRNA levels. The strongest upregulation of proinflammatory cytokines was observed at the injury site, while CGRP and Panx1 were upregulated more strongly in the intact cortexes invaded by CSD. A single CSD is sufficient to produce low-grade parenchymal neuroinflammation with simultaneous overexpression of Panx1 and CGRP. The CSD-induced molecular changes may contribute to pathogenic mechanisms of migraine pain and post-injury headache. [ABSTRACT FROM AUTHOR]

• Bilateral micro-injury of the amygdala was done 1 h after memory reactivation. • The injury induced a bilateral/unilateral wave of spreading depolarization (SD) or no SD. • Irrespectively of triggering SD, the injury did not affect fear expression 24 h later. • But the amygdala injury has delayed effect on fear extinction. • The effect of amygdala injury on fear extinction depended on whether SD was triggered. Spreading depolarization (SD), a self-propagating wave of near-complete breakdown of the transmembrane ion gradients with water influx, regularly occurs in traumatized human brain. Here, we investigated long-term neurobehavioral consequences of injury-triggered SDs. Recently, we revealed that SD is reliably triggered by micro-injury of the amygdala, a key brain structure involved in fear processing. Using the classical Pavlovian fear conditioning paradigm, we investigated effects of the post-retrieval amygdala micro-injury and associated SD on fear memory in rats. We found that neither SD nor micro-injury alone affect fear response 24 h later but profoundly change it in subsequent extinction phase. If bilateral injury of the amygdala did not induce SD, fear extinction was severely impaired, while conditioned fear in rats with the identical amygdala injury triggering SD was successfully extinguished similarly to naïve rats. Our study provides first experimental evidence for involvement of injury-induced SD in extinction of traumatic fear memory. [ABSTRACT FROM AUTHOR]

The problem of n-butanol ‒ water separation arises from the widespread interest to the search for alternative energy sources. To solve the problem by membrane technique, pervaporation membranes were developed on the basis of polyphenyleneisophthalamide modified with hybrid star macromolecules containing six arms of polystyrene and six arms of poly-tert-butyl methacrylate on the fullerene (C60) core. The structure was studied by scanning electron microscopy that reveal a tendency to form domains in the membranes modified by star macromolecules. Modification of the membrane by star fullerene (C60)-containing macromolecules led to a sharp increase in the selectivity and permeability of the membrane. Transport properties of novel membranes were studied in pervaporation of n-butanol‒water mixtures to separate n-butanol from water admixture for further use of this alcohol as industrial solvent and biofuel. It was found that introduction up to 5 wt% star modifier increases the separation efficiency of membranes in dehydration of n-butanol (water content in the permeate reaches 99.9 wt% while pervaporation separation index comes up to 400 kg/m2h), which allows obtaining high-purity n-butanol. [ABSTRACT FROM AUTHOR]

We studied spatiotemporal features of acute transcriptional inflammatory response induced by a focal brain injury in distant uninjured neuronal tissue and a role of endocannabinoid (eCB) system in its control. A focal excitotoxic lesion was induced by a unilateral injection of kainate in the dorsal hippocampus of awake Wistar rats. During acute post-injury period (3 h and 24 h post-injection), mRNA levels of genes associated with neuroinflammation (Il1b , Il6 , Tnf , Ccl2; Cx3cl1 , Zc3 h12a , Tgfb1) and eCB receptors of CB1 and CB2 types (Cnr1 and Cnr2) in intact regions of the hippocampus and neocortex were measured using qPCR. Occurrence of acute symptomatic seizures was controlled electrographically. To modulate eCB signaling during injury and acute post-injury period, antagonists (AM251, AM630) and agonist (WIN55–212-2) of eCB receptors were administered before the injury induction. Local intrahippocampal injury triggered widespread time- and region-dependent neuroinflammation in undamaged brain regions remote from the lesion site. The distant areas of the hippocampus and hippocampal meninges exhibited early (3 h) transient upregulation of pro- and anti-inflammatory cytokines simultaneously with occurrence of acute symptomatic seizures. The neocortex and its meninges showed minor neuroinflammation early after injury (3 h) but later (24 h) significantly upregulated several genes, mainly with anti-inflammatory properties. Focal lesion also changed expression of eCB receptors in the distant extra-lesional regions – CB1 receptors at 3 h and both CB1 and CB2 receptors at 24 h. Within the hippocampus, significant regional differences in constitutive and post-injury expression CB1 receptors were found. Pharmacological blockade of eCB receptors during injury and early post-injury period lengthened hippocampal neuroinflammation and reversed upregulation of anti-inflammatory molecules in the neocortex. The findings show that focal brain injury rapidly triggers widespread parenchymal and extraparenchymal neuroinflammation. The early injury-induced response is likely to represent neurogenic neuroinflammation produced by network hyperexcitability (acute symptomatic seizures). Activation of eCB signaling during acute phase of the brain injury is important for initiation of adaptive anti-inflammatory processes and prevention of chronic pathologic neuroinflammation in distant uninjured structures. However, the beneficial role of injury-induced eCB activity appears to depend on many factors including time, brain region, eCB tone etc. [Display omitted] • Focal brain injury triggers fast parenchymal/extraparenchymal neuroinflammation (NI). • Early NI in uninjured sites is produced by acute network hyperexcitability (seizures). • Activation of endocannabinoid (eCB) system during brain injury controls the acute NI. • Injury-induced eCB activity promotes anti-NI processes and dampens pro-NI events. [ABSTRACT FROM AUTHOR]

Functional connectivity analysis is gaining more interest due to its promising clinical applications. To study network mechanisms underlying seizure termination and postictal depression, we explore dynamics of interhemispheric functional connectivity near the offset of focal and bilateral seizures in the experimental model of reflex audiogenic epilepsy. In the model, seizures and spreading depression are induced by sound stimulation of genetically predisposed rodents. We characterize temporal evolution of seizure-associated coupling dynamics in the frontoparietal cortex during late ictal, immediate postictal and interictal resting states, using two measures applied to local field potentials recorded in awake epileptic rats. Signals were analyzed with mean phase coherence index in delta (1–4 Hz), theta (4–10 Hz) beta (10–25 Hz) and gamma (25–50 Hz) frequency bands and mutual information function. The study shows that reflex seizures elicit highly dynamic changes in interhemispheric functional coupling with seizure-, region- and frequency-specific patterns of increased and decreased connectivity during late ictal and immediate postictal periods. Also, secondary generalization of recurrent seizures (kindling) is associated with pronounced alterations in resting-state functional connectivity – an early wideband decrease and a subsequent beta-gamma increase. The findings show that intracortical functional connectivity is dynamically modified in response to seizures on short and long timescales, suggesting the existence of activity-dependent plastic network alterations that may promote or prevent seizure propagation within the cortex and underlie postictal behavioral impairments. • Audiogenic seizures change interhemispheric functional coupling (IFC) in the cortex. • Late ictal and postictal IFC shows seizure-, region- and frequency-specific dynamics. • Animals expressing focal cortical seizures show reduced resting-state IFC. • But bilateralization of the seizures is associated with enhanced beta-gamma resting-state IFC. [ABSTRACT FROM AUTHOR]

The role of the hippocampus (Hp) in absence epileptic networks and the effect of endocannabinoid system on this network remain enigmatic. Here, using adapted nonlinear Granger causality, we compared the differences in network strength in four intervals (baseline or interictal, preictal, ictal and postictal) in two hours before (Epoch 1) and six hours (epochs 2, 3 and 4) after the administration of three different doses of the endocannabinoid agonist WIN55,212–2 (WIN) or solvent. Local field potentials were recorded for eight hours in 23 WAG/Rij rats in the Frontal (FC), Parietal PC), Occipital Cortex (OC) and in the hippocampus (Hp). The four intervals were visually marked by an expert neurophysiologist and the strength of couplings between electrode pairs were calculated in both directions. Ictally, a strong decrease in coupling strength was found between Hp and FC, as well as a large increase bidirectionally between PC and FC and unidirectionally from FC and PC to OC, and from FC to Hp over all epochs. The highest dose of WIN increased the couplings strength from FC to Hp and from OC to PC during 4 and 2 hr respectively in all intervals, and decreased the FC to PC coupling strength postictally in epoch 2. A single rat showed generalized convulsive seizures after the highest dose: this rat shared not only coupling changes with the other rats in the same condition, but showed many more. WIN reduced SWD number in epoch 2 and 3, their mean duration increased in epochs 3 and 4. Conclusions:during SWDs FC and PC are strongly coupled and drive OC, while at the same time the influence of Hp to FC is diminished. The first is in agreement with the cortical focus theory, the latter demonstrates an involvement of the hippocampus in SWD occurrence and that ictally the hippocampal control of the cortico-thalamo-cortical system is lost. WIN causes dramatic network changes which have major consequences for the decrease of SWDs, the occurrence of convulsive seizures, and the normal cortico-cortical and cortico-hippocampal interactions. [Display omitted] • Ictally, a strong coupling decrease was found between hippocampus and frontal cortex. • High WIN55212-2 doses increase the couplings from frontal cortex to hippocampus. • WIN55212-2 reduces number of spike-wave discharges for 4 h after administration. • Mean discharge duration largely increases 2 h after WIN55212-2 administration. • One rat showed generalized convulsive seizures after the highest dose of WIN55212-2. [ABSTRACT FROM AUTHOR]

An acute brain insult can cause a spectrum of primary and secondary pathologies including increased risk for epilepsy, mortality and neurodegeneration. The endocannabinoid system, involved in protecting the brain against network hyperexcitability and excitotoxicity, is profoundly dysregulated by acute brain insults. We hypothesize that post-insult dysregulation of the endocannabinoid signaling may contribute to deleterious effects of an acute brain injury and potentiation of endocannabinoid transmission soon after an insult may reduce its pathological outcomes. Effects of an acute post-insult administration of the endocannabinoid receptor agonist WIN55,212-2 on early seizure occurrence, animal mortality and hippocampal cell loss were studied in the lithium–pilocarpine status model. A single dose of WIN55,212-2 (5 mg/kg) administered four hours after the end of status epilepticus (SE) reduced the incidence of early seizures during the first two post-SE days though did not change their duration and latency. Brief 4–6-Hz spike–wave discharges appeared de novo in the latent post-SE period and the acute administration of WIN55,212-2 also reduced the incidence of the epileptiform events. A single dose of WIN55,212-2 administered soon after SE improved survival of animals and reduced cell loss in the dentate hilus but did not prevent appearance of spontaneous recurrent seizures in the chronic period. Thus, a brief pharmacological stimulation of the endocannabinoid system soon after a brain insult exerts beneficial effects on its pathological outcome though does not prevent epileptogenesis. [ABSTRACT FROM AUTHOR]