Induction Of Spreading Depression Research Articles

Atogepant - an orally-administered CGRP antagonist - attenuates activation of meningeal nociceptors by CSD.

This study investigated the mechanism of action of atogepant, a small-molecule CGRP receptor antagonist recently approved for the preventive treatment of episodic migraine, by assessing its effect on activation of mechanosensitive C- and Aδ-meningeal nociceptors following cortical spreading depression. Single-unit recordings of trigeminal ganglion neurons (32 Aδ and 20 C-fibers) innervating the dura was used to document effects of orally administered atogepant (5 mg/kg) or vehicle on cortical spreading depression-induced activation in anesthetized male rats. Bayesian analysis of time effects found that atogepant did not completely prevent the activation of nociceptors at the tested dose, but it significantly reduced response amplitude and probability of response in both the C- and the Aδ-fibers at different time intervals following cortical spreading depression induction. For C-fibers, the reduction in responses was significant in the early phase (first hour), but not delayed phase of activation, whereas in Aδ-fibers, significant reduction in activation was apparent in the delayed phase (second and third hours) but not early phase of activation. These findings identify differences between the actions of atogepant, a small molecule CGRP antagonist (partially inhibiting both Aδ and C-fibers) and those found previously for fremanezumab, a CGRP-targeted antibody (inhibiting Aδ fibers only) and onabotulinumtoxinA (inhibiting C-fibers only)- suggesting that these agents differ in their mechanisms for the preventive treatment of migraine.

Hypoxia Tolerance Declines with Age in the Absence of Methionine Sulfoxide Reductase (MSR) in Drosophila melanogaster.

Unlike the mammalian brain, Drosophila melanogaster can tolerate several hours of hypoxia without any tissue injury by entering a protective coma known as spreading depression. However, when oxygen is reintroduced, there is an increased production of reactive oxygen species (ROS) that causes oxidative damage. Methionine sulfoxide reductase (MSR) acts to restore functionality to oxidized methionine residues. In the present study, we have characterized in vivo effects of MSR deficiency on hypoxia tolerance throughout the lifespan of Drosophila. Flies subjected to sudden hypoxia that lacked MSR activity exhibited a longer recovery time and a reduced ability to survive hypoxic/re-oxygenation stress as they approached senescence. However, when hypoxia was induced slowly, MSR deficient flies recovered significantly quicker throughout their entire adult lifespan. In addition, the wildtype and MSR deficient flies had nearly 100% survival rates throughout their lifespan. Neuroprotective signaling mediated by decreased apoptotic pathway activation, as well as gene reprogramming and metabolic downregulation are possible reasons for why MSR deficient flies have faster recovery time and a higher survival rate upon slow induction of spreading depression. Our data are the first to suggest important roles of MSR and longevity pathways in hypoxia tolerance exhibited by Drosophila.

Optogenetic Spreading Depression Elicits Trigeminal Pain and Anxiety Behavior

Cortical spreading depression (SD) is an intense depolarization underlying migraine aura. Despite the weight of evidence linking SD to the pain phase of migraine, controversy remains over a causal role of SD in cephalgia because of the invasive nature of previous SD induction methods. To overcome this problem, we used a novel minimally invasive optogenetic SD induction method and examined the effect of SD on behavior. Optogenetic SD was induced as a single event or repeatedly every other day for 2 weeks. End points, including periorbital and hindpaw mechanical allodynia, mouse grimace, anxiety, and working memory, were examined in male and female mice. A single SD produced bilateral periorbital mechanical allodynia that developed within 1 hour and resolved within 2 days. Sumatriptan prevented periorbital allodynia when administered immediately after SD. Repeated SDs also produced bilateral periorbital allodynia that lasted 4 days and resolved within 2 weeks after the last SD. In contrast, the hindpaw withdrawal thresholds did not change after repeated SDs suggesting that SD-induced allodynia was limited to the trigeminal region. Moreover, repeated SDs increased mouse grimace scores 2 days after the last SD, whereas a single SD did not. Repeated SDs also increased thigmotaxis scores as a measure of anxiety. In contrast, neither single nor repeated SDs affected visuospatial working memory. We did not detect sexual dimorphism in any end point. Altogether, these data show a clinically congruent causal relationship among SD, trigeminal pain, and anxiety behavior, possibly reflecting SD modulation of hypothalamic, thalamic, and limbic mechanisms. ANN NEUROL 2021;89:99-110.

Optogenetic induction of cortical spreading depression in anesthetized and freely behaving mice

Cortical spreading depression, which plays an important role in multiple neurological disorders, has been studied primarily with experimental models that use highly invasive methods. We developed a relatively non-invasive optogenetic model to induce cortical spreading depression by transcranial stimulation of channelrhodopsin-2 ion channels expressed in cortical layer 5 neurons. Light-evoked cortical spreading depression in anesthetized and freely behaving mice was studied with intracortical DC-potentials, multi-unit activity and/or non-invasive laser Doppler flowmetry, and optical intrinsic signal imaging. In anesthetized mice, cortical spreading depression induction thresholds and propagation rates were similar for invasive (DC-potential) and non-invasive (laser Doppler flowmetry) recording paradigms. Cortical spreading depression-related vascular and parenchymal optical intrinsic signal changes were similar to those evoked with KCl. In freely behaving mice, DC-potential and multi-unit activity recordings combined with laser Doppler flowmetry revealed cortical spreading depression characteristics comparable to those under anesthesia, except for a shorter cortical spreading depression duration. Cortical spreading depression resulted in a short increase followed by prolonged reduction of spontaneous active behavior. Motor function, as assessed by wire grip tests, was transiently and unilaterally suppressed following a cortical spreading depression. Optogenetic cortical spreading depression induction has significant advantages over current models in that multiple cortical spreading depression events can be elicited in a non-invasive and cell type-selective fashion.

Altered inhibition in the hippocampal neural networks after spreading depression.

Prolonged neuronal depression after spreading depression (SD) is followed by a late cellular and synaptic hyperexcitability. Intra- and extracellular recordings of bioelectrical activities were performed in the rodent hippocampus to investigate the role of γ-aminobutyric acid (GABA)-mediated inhibition in the late hyperexcitable state of SD. The effect of KCl-induced negative DC potential shifts was investigated on extracellularly recorded paired-pulse depression (PPD) and bicuculline-induced afterdischarges as well as intracellularly recorded inhibitory post synaptic potentials (IPSPs) in the hippocampal CA1 area. The results revealed that SD decreased the degree of PPD, enhanced the number and duration of bicuculline-induced afterdischarges, and reduced the amplitude and duration of IPSPs. Application of low concentrations of bicuculline before the induction of SD enhanced the inhibitory effect of SD on IPSPs. Data indicate the contribution of GABA-mediated inhibition to SD-induced delayed hyperexcitability. Modulation of GABA function in the late hyperexcitability phase of SD may play a role in therapeutic management of SD-related neurological disorders.

Temporal profiles of high-mobility group box 1 expression levels after cortical spreading depression in mice.

Cortical spreading depression (CSD) has recently been shown to induce the release of the nuclear protein termed high-mobility group box 1 from neurons, causing activation of the trigeminovascular system. Here, we explored the effects of single and multiple cortical spreading depression inductions on high-mobility group box 1 (HMGB1) transcriptional activity relative to high-mobility group box 1 protein expression levels and intracellular localization in cortical neurons and astrocytes. Single or multiple cortical spreading depression inductions were achieved by KCl application to the mouse cerebral cortex. The animals were sacrificed at 30 minutes, 3 hours and 24 hours after cortical spreading depression induction. High-mobility group box 1 expression levels were explored with in situ hybridization, Western blotting and immunostaining. Cortical spreading depression up-regulated high-mobility group box 1 transcriptional activity in neurons at 3 hours in a manner that was dependent on the number of cortical spreading depression inductions. At 24 hours, the high-mobility group box 1 transcriptional activity had returned to basal levels. Cortical spreading depression induced a reduction in high-mobility group box 1 protein expression at 3 hours, which was also dependent on the number of cortical spreading depression inductions. Following cortical spreading depression, the release of high-mobility group box 1 from the nucleus was observed in a small proportion of neurons, but not in astrocytes. Cortical spreading depression induced translocation of high-mobility group box 1 from neuronal nuclei, driving transcriptional up-regulation of high-mobility group box 1 to maintain protein levels.

Role of Spreading Depression On Memory Consolidation in Developmental Animal Model of Schizophrenia

Background Schizophrenia is a complex disorder, characterized by both genetic and environmental factors and their interactions. Post weaning social isolation (SI) has been proposed as a model of Schizophrenia. Glutamate hypothesis in schizophrenia produce analogous symptoms. In this regards, reduction in NMDA receptor activity has been hypothesized for induction of schizophrenia in clinical studies. Furthermore, NMDA receptors activation play role in various neurodegenerative diseases including phenomenon of spreading depression (SD). SD plays a pivotal role in glutamate release and its action on the NMDA receptor. Method and material In the present study 24Wistar juvenile rats (65-80 gr) were used. Animals were classified in three groups as SD treated with Social isolation, social isolation, and sham groups. SI was induced by six week post weaning social isolation of puppies, which followed by four consecutive weeks SD induction in SD-social isolation group. Prepulse inhibition (PPI) test and passive avoidance by shuttle box test have been done at the end of experiment. Results Our result from behavioral test suggested that SD induction during for week after six week social isolation may be able to help to ameliorate schizophrenia symptoms. Significant changes in cognition tests were seen in SD induced group in comparison with social isolation group. Conclusion data from present study revealed that glutamate level in extracellular space which followed by NMDA receptor activation as well as its expression following SD induction perhaps decrease some neurological characteristics of schizophrenia, which could reveal NMDA protective role on schizophrenic patient.

Spreading Depression Mimics the Behavioral Features of Schizophrenia

Spreading depression (SD) known as an evoked neuronal activity and changes in ionic, metabolic and hemodynamic characteristics of the brain. From a clinical perspective SD plays a pathophysiological role in several neurological disorders, e.g., migraine, epilepsy, and spinal cord disease. Pronounced release of dopamine in mesolimbic pathway, remarkably in nucleus accumbens during SD and the noted role of increased dopamine in schizophrenia suggests that SD could be a predisposing factor for the occurrence of schizophrenia. To test this hypothesis, male Wistar rats (60-80gr) randomly chosen in 3 groups. For induction of repetitive SD, 3 mol/L KCl was injected four times in rats during 4 weeks. After 4 weeks rats’ anxiety were evaluated using elevated plus-maze. Furthermore, all three groups of rats spent comparable times in social contact in order to determine social interaction. In the present study, we also tested the possible effect of SD induction on prepulse inhibition (PPI). SD induced rats had decreased threshold of anxiety in comparison with control group. The percentage of aggressive behavior was also increased in SD induced rats. Finally, the amount of prepulse inhibition was decreased significantly in SD group of animals. The results suggest that SD can mimic some behavioral features of schizophrenia and might be a useful animal model in the study of this disease. We conclude that Spreading depression potentiates to be a kind of useful way for making a new model of schizophrenia and this can used in different basic and clinical researches in the field of schizophrenia.

A voxel-based analysis of brain activity in high-order trigeminal pathway in the rat induced by cortical spreading depression

Cortical spreading depression (SD) is a self-propagating wave of depolarization that is thought to be an underling mechanism of migraine aura. Growing evidence demonstrates that cortical SD triggers neurogenic meningeal inflammation and contributes to migraine headaches via subsequent activation of trigeminal afferents. Although direct and indirect evidence shows that cortical SD activates the trigeminal ganglion (peripheral pathway) and the trigeminal nucleus caudalis (TNC, the first central site of the trigeminal nociceptive pathway), it is not yet known whether cortical SD activates the high-order trigeminal nociceptive pathway in the brain. To address this, we induced unilateral cortical SD in rats, and then examined brain activity using voxel-based statistical parametric mapping analysis of FDG-PET imaging. The results show that approximately 40h after the induction of unilateral cortical SD, regional brain activity significantly increased in several regions, including ipsilateral TNC, contralateral ventral posteromedial (VPM) and posterior thalamic nuclei (Po), the trigeminal barrel-field region of the primary somatosensory cortex (S1BF), and secondary somatosensory cortex (S2). These results suggest that cortical SD is a noxious stimulus that can activate the high-order trigeminal nociceptive pathway even after cortical SD has subsided, probably due to prolonged meningeal inflammation.

EHMTI-0094. Effect of nifedipine on memory impairment induced by repetitive spreading depression

Spreading depression (SD) is known by transient loss of spontaneous and evoked neuronal activity and changes in ionic, metabolic and hemodynamic characteristics of the brain. It has been shown that repetitive SD produced memory deficits in juvenile rats. Furthermore, the role of Ca2+channels on induction and propagation of SD was investigated by several scientists. The aim of the present study was to study the role of a Ca2+channel-blocker, nifedipine, on memory deficits induced by repetitive SD.

Microfabricated solid-state ion-selective electrode probe for measuring potassium in the living rodent brain: Compatibility with DC-EEG recordings to study spreading depression

There is considerable need in neuroscience research to reliably measure concentrations of extracellular ions in the living brain as the dynamics of ion levels increasingly is considered to play a key role in the pathophysiology of many brain disorders. Unfortunately, most probes currently used for direct measurement of extracellular ion concentrations in living brain tissue in experimental animals have considerable limitations. They are custom-made glass capillary ion-selective microelectrodes that are fragile, time-consuming to prepare, and can practically only be used to measure at one depth and one location in the brain. We here present the design and fabrication of a novel type of miniaturized probe that can simultaneously measure, in the brain of a living animal, multiple parameters relevant to the neurological phenomenon of spreading depression (SD) at multiple depths and locations. SD is characterized by a slowly propagating wave of initial neuronal and glial cell depolarization that is followed by depression of activity. SD is accompanied by a massive redistribution of ions, including K+, between intracellular and extracellular compartments and is considered important in brain diseases such as stroke, traumatic brain injury, and migraine with aura. This work focuses on the functionalization of fabricated probes for measuring changes in extracellular K+ concentration (and its associated changes in neuronal activity) using an ion-selective potentiometric sensor. We show that the choice of conductive polymer and the method of electro-deposition is critical to obtain low cross-sensitivity for pH and O2. The sensor's response to K+ is approximately linear between 2 and 40mM with a voltage-response of 39mV/log[K+]. Proof-of-principle in vivo brain recordings were performed in the cortex of a wild-type mouse during induction of cortical SD. We reliably measured the theoretically expected rise and fall of brain tissue K+ levels during a locally induced cortical SD. We envisage that our probe can be of great use to reliably measure K+, without being affected by pH or O2 changes, in the living brain and be widely applicable in neuroscience research.

Familial hemiplegic migraine and spreading depression.

Familial hemiplegic migraine (FHM) is an autosomal dominantly inherited subtype of migraine with aura, characterized by transient neurological signs and symptoms. Typical hemiplegic migraine attacks start in the first or second decade of life. Some patients with FHM suffer from daily recurrent attacks since childhood. Results from extensive studies of cellular and animal models have indicated that gene mutations in FHM increase neuronal excitability and reduce the threshold for spreading depression (SD). SD is a transient wave of profound neuronal and glial depolarization that slowly propagates throughout the brain tissue and is characterized by a high amplitude negative DC shift. After induction of SD, S218L mutant mice exhibited neurological signs highly reminiscent of clinical attacks in FHM type 1 patients carrying this mutation. FHM1 with ataxia is attributable to specific mutations that differ from mutations that cause pure FHM1 and have peculiar consequences on cerebellar Cav2.1 currents that lead to profound Purkinje cell dysfunction and neuronal loss with atrophy. SD in juvenile rats produced neuronal injury and death. Hormonal factors involved in FHM affect SD initiation and propagation. The data identify SD as a possible target of treatment of FHM. In addition, FHM is a useful model to explore the mechanisms of more common types of migraine.

Spreading depression triggers ictaform activity in partially disinhibited neuronal tissues

There is unequivocal electrophysiological evidence that spreading depression (SD) can trigger epileptiform field potentials. In vitro experiments on human brain tissues indicated that γ-aminobutyric acid (GABA)-mediated inhibition prevented this process. Intra- and extracellular recordings of bioelectrical activities were performed in the rodent neocortex, hippocampus and amygdala after perfusion of low concentrations of the GABAA antagonist bicuculline and induction of SD by KCl application. Induction of SD in combined amygdala–hippocampus–cortex slices pre-treated with low concentration of bicuculline triggered epileptiform burst discharges in cortical as well as subcortical brain structures. Propagation of SD significantly depolarized the membrane, decreased the amplitude and duration of action potentials (APs) and after-hyperpolarization as well as the neuronal membrane input resistance and the amplitude of threshold potentials. Ten to twenty minutes after induction of SD, the pattern of APs changed from regular firing to a series of APs riding on an underlying paroxysmal depolarization shift before the appearance of typical ictaform activities. Changes of characteristic features of APs occurred after SD persisted during the appearance of epileptiform activities. These results indicate that SD increases neuronal excitability and facilitates synchronization of neuronal discharges in the presence of partial disinhibition of neuronal tissues. Our findings might explain the occurrence of seizures in neurological disorders with partial impairment of inhibitory tone, such as brain ischemia and epilepsy.

Dexamethasone multifunctional role in spreading depression

Spreading depression (SD) is a neural hyperexc/INS;itabi/INS;lity, which spreads/INS; to adjoining area of brain cortical; slowly continues/INS; through the brain and changes /INS;neural electrical and metabolic activity. It has been proved that SD plays/INS; a dramatic role in some neurological disorder through the changes it causes/INS;. Previous studies applied various types of drugs through diverse pharmacological aspects to relieve /INS;SD wave distribution. However most have been abort due to their unpleasant side effects. In the present study we seek for dexamethasone's (Dex) multifunctional properties in order to protect cellular damage and/INS; then prevent even other neurological disorder accuracy following SD. Animals/INS; were /INS;randomly divided into five groups/INS; including /INS;CTRLs, sham, spreading depression and dexamethasone treatment group. Animals/INS; were anesthetized and a /INS;cannula as well as an /INS;electrode was /INS;established above the brain cortex. Intracerebral KCl was used to induce repetitive cortical SD for 4 continuous week. Following each induction memory retrieval tests/INS; (T-maze) were done. The brains were removed after 4 weeks. Histopathologically estimation was used to testify dexamethasone effect. In addition dexamethasone effects on blood brain barer (BBB) to facilitate /INS;substance recovery in cerebral fluid were tested by Evans blue. By repetitive SD memory retrieval was impaired due to increscent of dark neural seen in several regions of juvenile rat brain. Besides/INS; that brain electrical activity determination showed slake of neural activity after SD induction. Neural cell recoveries after SD due to increscent of substance passage through BBB were promoted/INS;.

Memory improvement after spreading depression by NMDA blocker as memory destructor

Spreading depression (SD) is transient neural hyperexitablity followed by depolarization wave, which propagates/INS; through the brain and modulate electrical gradient and synaptic activity. Data have shown that SD wave distributes/INS; coincidence between neural activity and behavioral activity/INS;. Neural activity and electrical potential effect on memory retrieval have been demonstrated. Inhibitory effect of NMDA receptors in SD procedure can control memory impairment caused by SD. However, the /INS;negative effect of NMDA receptor blockage on memory has/INS; been proven in previous studies. In the present study the /INS;effect of NMDA receptors blockage (MK801) used to evaluate its efficiency in subsiding of SD negative influence on memory. /INS;Wistar rats/INS; (60–/INS;80 g/INS;) were /INS;randomly chosen in 6 groups and (NMDA blocker0.63–/INS;1 mg/kg) were administrated after 3 mol/L KCl injection for induction of repetitive/INS; SD in rat. The groups were evaluated by T-maze test and SD groups /INS;were compared with control groups, including (NMDA blocker 1–/INS;0.63 mg/kg /INS;controls) and sham group. T-maze data have showed that repeated SD could significantly alter memory/INS; retrieval performance. However, in the second week memory enhancement was/INS; induced by SD induction. Repeated SD induction during other weeks indicated/INS; impairment in memory. Application of NMDA blocker showed significantly enhanced /INS;memory retrieval and/INS; could /INS;potentially control memory impairment after SD. /INS;The studies indicated that NMDA blocker may decrease memory performance/INS;, on the other hand the /INS;effect of MK801 on inhibition of SD propagation may somehow weaken memory improvement due to its memory destruction effects.

Neuronal death by repetitive cortical spreading depression in juvenile rat brain

Spreading depression (SD) is an intrinsic bioelectrical property of the human central nervous system, which plays a key role in neurological disorders. In the present study, we investigated whether experimentally induced repetitive SD caused neuronal death in cortical and subcortical regions of the juvenile rat brain. The animals were anesthetized and the electrodes as well as a cannula were implanted over the brain. Repetitive cortical SD events were induced by KCl injection. The brains were removed after 4weeks. Repetitive SD enhanced the production of dark neurons, reduced the mean volume of normal neurons, increased the number of apoptotic neurons, and enhanced expression of the NR2B subunit of NMDA receptors as well as the GluR1 subunit of AMPA receptors in various regions of the juvenile rat brain. In addition, induction of repetitive SD enhanced long-term potentiation in CA1 hippocampal area. We observed a correlation between cell injury/neuronal death induced by repetitive SD and changes in glutamate receptor expression. The data indicate that repetitive cortical SD in juvenile rats causes neuronal damage in both cortical and subcortical areas of the brain. This may play an important role in the pathophysiology of SD-related neurological disorders, especially in children.

Epigenetic chromatin modifications in the cortical spreading depression

Preconditioning with Cortical Spreading Depression induces a sort of tolerance to a subsequent episode of ischemia. The mechanism of this tolerance is not clear. We studied if such treatment induces epigenetic chromatin modifications on the hemispheres of rats preconditioned by Cortical Spreading Depression. The contralateral hemispheres were used as control. We determined the level of H3K4 and H3K9 methylation and the mRNA amounts for the two well known H3K4 methyltransferases (MLL and SET7) in rats 24°h after the Cortical Spreading Depression induction. Western blotting experiments have been performed using three different types of primary antibodies against mono-, di- and tri-methyl H3K4 and primary antibody anti-dimethyl H3K9. In the same samples we checked if the H3 histones were replaced by the H3.3 histone variants that could be an additional marker of chromatin modifications. The level of mono- and di-methyl H3K4 was significantly lower in samples of the treated hemispheres than those of the contralateral hemispheres (40% and about 60%, respectively) while the level of tri-methylation remained unchanged. The level of di-methyl H3K9 was almost 60% higher in the treated hemispheres than the contralateral hemispheres. The treatment for Cortical Spreading Depression affected also the level of expression of H3K4 histone methyltransferase MLL and SET7 that decreased in the treated hemispheres in comparison to the control hemispheres (80% and 40%, respectively). The treatment for Cortical Spreading Depression instead had no effects on the overall amounts of mRNA for H3 and H3.3 histones. In conclusion epigenetic chromatin modifications are evident in rats 24°h after the Cortical Spreading Depression induction.

Patterns of neurotransmitter receptor distributions following cortical spreading depression

Spreading depression (SD), a self-propagating depolarization of neurons and glia, is believed to play a role in different neurological disorders including migraine aura and acute brain ischaemia. Initiation and propagation of SD modulate excitability of neuronal network. A brief period of excitation heralds SD which is immediately followed first by prolonged nerve cell depression and later by an excitatory phase. The aim of the present study was to characterize local and remote transmitter receptor changes after propagation of cortical SD. Quantitative receptor autoradiography was used to asses 16 transmitter receptor types in combined striatum-hippocampus–cortex slices of the rat 1 h after induction of cortical SD. In neocortical tissues, local increases of glutamate NMDA, AMPA, and kainate receptor binding sites were observed. In addition to up-regulation of ionotropic glutamate receptors, receptor binding sites of GABAA, muscarinic M1 and M2, adrenergic α1 and α2, and serotonergic 5-HT2 receptors were increased in the hippocampus. Cortical SD also upregulated NMDA, AMPA, kainate, GABAA, serotonergic 5-HT2, adrenergic α2 and dopaminergic D1 receptor binding sites in the striatum. These findings indicate selective changes in several receptors binding sites both in cortical and subcortical regions by SD which may explain delayed excitatory phase after SD. Mapping of receptor changes by cortical SD increases our understanding of the mechanism of SD action in associated neurological disorders.

Effect of cortical spreading depression on basal forebrain neurons

During natural sleep and anesthesia, rhythmic hypo- and hyperpolarizations alternate in cortical pyramidal cells and are reflected as slow (<1 Hz) cortical rhythm at the level of the electroencephalogram (EEG). Membrane potential changes in pyramidal neurons were initially attributed to the rhythmic fluctuation of the cholinergic input as the basal forebrain (BF) neurons fire in synchrony with cortical waves, but a more recent proposal suggested that the slow rhythm was of cortical origin. In the present experiments, interaction between the cortex and the BF was examined in urethane-anesthetized rats. BF neuronal activity was inhibited by local infusion of lidocaine into the substantia innominata in one group of rats, while in another group, the slow cortical rhythm was blocked by inducing spreading depression (SD) in the cortex. Slow cortical rhythm persisted after unilateral lidocaine injection, but rhythmic firing in BF neurons disappeared following SD induction. These findings support the view that slow cortical rhythm is generated in the cortex and transmitted to the BF through descending fibers. According to anatomical data, these fibers can excite cholinergic cells only indirectly as they terminate on non-cholinergic neurons. Thus, timing of activity changes in BF neurons during the slow cortical rhythm might give some clue regarding their transmitter specificity.

Audiogenic seizures associated with a cortical spreading depression wave suppress spike-wave discharges in rats

To study the role of the cortex and sub-cortical structures in the generation of epileptic spike-wave discharges in more detail, cortical and striatal activity was eliminated by the induction of spreading depression in a non-invasive way. EEG and DC potentials were recorded from the cortex and striatum of WAG/Rij rats. Several of these rats show two forms of generalised epilepsy: spontaneously occurring non-convulsive absence seizures, together with convulsive audiogenic seizures. The latter can be evoked by a brief sound stimulation, provoking a fit of wild running, which is regarded as the first phase of an audiogenic seizure. In a majority of fits the cortical DC potential does not show main changes, while the spontaneously occurring spike-wave discharges are briefly suppressed for some minutes. In a minority of fits, however, audiogenic seizures are associated with a spreading depression wave, clearly expressed in the cortical DC potential. This wave is bilaterally initiated in the cortex and propagates to the caudate nucleus of the striatum. In these cases spontaneously occurring spike-wave discharges are fully suppressed for about 1 h. It is suggested that cortical spreading depression, triggered by a short audiogenic seizure, induces a long-lasting suppression of spike-wave discharges. These results are in line with the concept that spike-wave discharges are originally initiated in the cortex, as proposed by the ‘cortical focus’ theory. The precise role of the striatum remains less clear, although this structure seems not to play a pivotal role in spike-wave generation.