Retrosplenial Cortex Contributes to Network Changes during Seizures in the GAERS Absence Epilepsy Rat Model.
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ABSTRACT:
SUBMITTER: Wachsmuth L
PROVIDER: S-EPMC8263073 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveGeneralized epilepsy syndromes often confer multiple types of seizures, but it is not known if these seizures activate separate or overlapping brain networks. Recently, we reported that mice with a juvenile myoclonic epilepsy mutation (Gabra1[A322D]) exhibited both absence and myoclonic generalized seizures. Here, we determined the time course of sensorimotor cortex activation and the spatial distribution of spike voltage during these two seizures.MethodsWe implanted Gabra1+/A322D mice with multiple electroencephalography (EEG) electrodes over bilateral somatosensory cortex barrel fields (S1) and anterior (aM1) and posterior (pM1) motor cortices and recorded absence seizures/spike-wave discharges (SWDs) and myoclonic seizures. We used nonlinear-association analyses and cross-correlation calculations to determine the strength, leading regions, and time delays of cortical coupling from the preictal to ictal states and within the spike and interspike periods. The distribution of spike voltage was also measured in SWDs and myoclonic seizures.ResultsEEG connectivity among all electrode pairs increased at the onset of both SWDs and myoclonic seizures. Surprisingly, during spikes of both seizure types, S1 led M1 with similar delay times. Myoclonic seizure spikes started more focally than SWD spikes, with a significant majority appearing first only in S1 electrodes, whereas a substantial fraction of SWD spikes were detected first in S1 and at least one M1 electrode. The absolute voltage of myoclonic seizure spikes was significantly higher than that of SWD spikes, and there was a greater relative voltage over M1 during myoclonic seizure spikes than in the first one to two SWD spikes.SignificanceThe leading sites in S1 and similar delay times suggest both SWDs and myoclonic seizures activate overlapping networks in sensorimotor cortex and thus, therapeutically targeting of this network could potentially treat both seizures. Spike focality, absolute voltage, and voltage distribution provide insight into neuronal activation during these two seizure types.
| S-EPMC5056152 | biostudies-literature
Project description:Childhood absence epilepsy seizures arise in the cortico-thalamocortical network due to multiple cellular and molecular mechanisms, which are still under investigation. Understanding the precise mechanisms is imperative given that treatment fails in ~30% of patients while adverse neurological sequelae remain common. Impaired GABAergic neurotransmission is commonly reported in research models investigating these mechanisms. Recently, we reported a region-specific reduction in the whole-tissue and synaptic GABAA receptor (GABAAR) α1 subunit and an increase in whole-tissue GAD65 in the primary somatosensory cortex (SoCx) of the adult epileptic stargazer mouse compared with its non-epileptic (NE) littermate. The current study investigated whether these changes occurred prior to the onset of seizures on postnatal days (PN) 17-18, suggesting a causative role. Synaptic and cytosolic fractions were biochemically isolated from primary SoCx lysates followed by semiquantitative Western blot analyses for GABAAR α1 and GAD65. We found no significant changes in synaptic GABAAR α1 and cytosolic GAD65 in the primary SoCx of the stargazer mice at the critical developmental stages of PN 7-9, 13-15, and 17-18. This indicates that altered levels of GABAAR α1 and GAD65 in adult mice do not directly contribute to the initial onset of absence seizures but are a later consequence of seizure activity.
| S-EPMC9856073 | biostudies-literature
Project description:Using the gamma-butyrolactone (GBL) model of absence seizures in Long-Evans rats, this study investigated if 2.5-6 Hz paroxysmal discharges (PDs) induced by GBL were synchronized among the thalamocortical system and the hippocampus, and whether inactivation of the hippocampus affected PDs.Local field potentials were recorded by chronically implanted depth electrodes in the neocortex (frontal, parietal, visual), ventrolateral thalamus and dorsal hippocampal CA1 area. In separate experiments, multiple unit recordings were made at the hippocampal CA1 pyramidal cell layer, or the mid-septotemporal hippocampus was inactivated by local infusion of GABAA receptor agonist muscimol.As PDs developed following GBL injection, coherence of local field potentials at 2.5-6 Hz increased between the hippocampus and thalamus, and between the hippocampus and the neocortex. Hippocampal theta rhythm was disrupted when GBL induced immobility in the rats. The probability of hippocampal multiple unit firing significantly increased at 40-80 ms prior to the negative peak of thalamic PDs. Coherence between hippocampal multiple unit activity and thalamic field potentials at 2.5-6 Hz was significantly increased after GBL injection. Muscimol infusion to inactivate the mid-septotemporal hippocampus, as compared to saline infusion, significantly decreased the peak frequency of the PDs induced by GBL, decreased 30-120 Hz hippocampal gamma power, and hastened the transition of PDs to 1-2 Hz slow waves.During GBL induced 2.5-6 Hz PDs, a hallmark of absence seizure, increased synchronization between the hippocampus and the thalamocortical network was indicated by frequency and temporal correlation analysis. These results suggest that the hippocampus was entrained by thalamocortical activity in the present model of absence seizures. Prolonged synchronization of the hippocampus may result in synaptic alterations that may explain the cognitive and memory deficits in some patients with absence seizures and absence status epilepticus.
| S-EPMC4942264 | biostudies-literature
Project description:The rodent retrosplenial cortex is known to be vital for spatial cognition, but evidence has also pointed to a role in processing nonspatial information. It has been suggested that the retrosplenial cortex may serve as a site of integration of incoming sensory information. To examine this proposal, the current set of experiments assessed the impact of excitotoxic lesions in the retrosplenial cortex on two behavioral tasks that tax animals' ability to process multiple and overlapping environmental stimuli. In Experiment 1, rats with retrosplenial lesions acquired a negative patterning discrimination, a form of configural learning that can be solved only by learning the conjunction of cues. Subsequent transfer tests confirmed that both the lesion and control animals had solved the task by using configural representations. Furthermore, in Experiment 2, a 2nd cohort of retrosplenial lesion animals successfully acquired conditioned inhibition. Nevertheless, the same animals failed a subsequent summation test that assesses the ability to transfer what has been learned about one stimulus to another stimulus in the absence of reinforcement. Taken together, these results suggest that in the nonspatial domain, the retrosplenial cortex is not required for forming associations between multiple or overlapping environmental stimuli and, consequently, retrosplenial engagement in such processes is more selective than was previously envisaged. (PsycINFO Database Record (c) 2018 APA, all rights reserved).
| S-EPMC6188469 | biostudies-literature
Project description:It has been proposed that the retrosplenial cortex forms part of a 'where/when' information network. The present study focussed on the related issue of whether retrosplenial cortex also contributes to 'what/when' information, by examining object recency memory. In Experiment 1, rats with retrosplenial lesions were found to be impaired at distinguishing the temporal order of objects presented in a continuous series ('Within-Block' condition). The same lesioned rats could, however, distinguish between objects that had been previously presented in one of two discrete blocks ('Between-Block' condition). Experiment 2 used intact rats to map the expression of the immediate-early gene c-fos in retrosplenial cortex following performance of a between-block, recency discrimination. Recency performance correlated positively with levels of c-fos expression in both granular and dysgranular retrosplenial cortex (areas 29 and 30). Expression of c-fos in the granular retrosplenial cortex also correlated with prelimbic cortex and ventral subiculum c-fos activity, the latter also correlating with recency memory performance. The combined findings from both experiments reveal an involvement of the retrosplenial cortex in temporal order memory, which includes both between-block and within-block problems. The current findings also suggest that the rat retrosplenial cortex comprises one of a group of closely interlinked regions that enable recency memory, including the hippocampal formation, medial diencephalon and medial frontal cortex. In view of the well-established importance of the retrosplenial cortex for spatial learning, the findings support the notion that, with its frontal and hippocampal connections, retrosplenial cortex has a key role for both what/when and where/when information.
| S-EPMC5488228 | biostudies-literature
Project description:We investigated how environment symmetry shapes the neural processing of direction by recording directionally tuned retrosplenial neurons in male Lister hooded rats exploring multicompartment environments that had different levels of global rotational symmetry. Our hypothesis built on prior observations of twofold symmetry in the directional tuning curves of rats in a globally twofold-symmetric environment. To test whether environment symmetry was the relevant factor shaping the directional responses, here we deployed the same apparatus (two connected rectangular boxes) plus one with fourfold symmetry (a 2 × 2 array of connected square boxes) and one with onefold symmetry (a circular open-field arena). Consistent with our hypothesis we found many neurons with tuning curve symmetries that mirrored these environment symmetries, having twofold, fourfold, or onefold symmetric tuning, respectively. Some cells expressed this pattern only globally (across the whole environment), maintaining singular tuning curves in each subcompartment. However, others also expressed it locally within each subcompartment. Because multidirectionality has not been reported in naive rats in single environmental compartments, this suggests an experience-dependent effect of global environment symmetry on local firing symmetry. An intermingled population of directional neurons were classic head direction cells with globally referenced directional tuning. These cells were electrophysiologically distinct, with narrower tuning curves and a burstier firing pattern. Thus, retrosplenial directional neurons can simultaneously encode overall head direction and local head direction (relative to compartment layout). Furthermore, they can learn about global environment symmetry and express this locally. This may be important for the encoding of environment structure beyond immediate perceptual reach.SIGNIFICANCE STATEMENT We investigated how environment symmetry shapes the neural code for space by recording directionally tuned neurons from the retrosplenial cortex of rats exploring single- or multicompartment environments having onefold, twofold, or fourfold rotational symmetry. We found that many cells expressed a symmetry in their head direction tuning curves that matched the corresponding global environment symmetry, indicating plasticity of their directional tuning. They were also electrophysiologically distinct from canonical head directional cells. Notably, following exploration of the global space, many multidirectionally tuned neurons encoded global environment symmetry, even in local subcompartments. Our results suggest that multidirectional head direction codes contribute to the cognitive mapping of the complex structure of multicompartmented spaces.
| S-EPMC9761682 | biostudies-literature
Project description:Objective: With increasing efforts devoted to investigating the generation and propagation mechanisms of spontaneous spike and wave discharges (SWDs), little attention has been paid to network mechanisms associated with termination patterns of SWDs to date. In the current study, we aimed to identify the frequency-dependent neural network dynamics during the offset of absence seizures. Methods: Fifteen drug-naïve patients with childhood absence epilepsy (CAE) were assessed with a 275-Channel Magnetoencephalography (MEG) system. MEG data were recorded during and between seizures at a sampling rate of 6,000 Hz and analyzed in seven frequency bands. Source localization was performed with accumulated source imaging. Granger causality analysis was used to evaluate effective connectivity networks of the entire brain at the source level. Results: At the low-frequency (1-80 Hz) bands, activities were predominantly distributed in the frontal cortical and parieto-occipito-temporal junction at the offset transition periods. The high-frequency oscillations (HFOs, 80-500 Hz) analysis indicated significant source localization in the medial frontal cortex and deep brain areas (mainly thalamus) during both the termination transition and interictal periods. Furthermore, an enhanced positive cortico-thalamic effective connectivity was observed around the discharge offset at all of the seven analyzed bands, the direction of which was primarily from various cortical regions to the thalamus. Conclusions: Seizure termination is a gradual process that involves both the cortices and the thalamus in CAE. Cortico-thalamic coupling is observed at the termination transition periods, and the cerebral cortex acts as the driving force.
| S-EPMC6626921 | biostudies-literature
Project description:Cohorts of rats with excitotoxic retrosplenial cortex lesions were tested on four behavioural tasks sensitive to dysfunctions in prelimbic cortex, anterior cingulate cortex, or both. In this way the study tested whether retrosplenial cortex has nonspatial functions that reflect its anatomical interactions with these frontal cortical areas. In Experiment 1, retrosplenial cortex lesions had no apparent effect on a set-shifting digging task that taxed intradimensional and extradimensional attention, as well as reversal learning. Likewise, retrosplenial cortex lesions did not impair a strategy shift task in an automated chamber, which involved switching from visual-based to response-based discriminations and, again, included a reversal (Experiment 2). Indeed, there was evidence that the retrosplenial lesions aided the initial switch to response-based selection. No lesion deficit was found on an automated cost-benefit task that pitted size of reward against effort to achieve that reward (Experiment 3). Finally, while retrosplenial cortex lesions affected matching-to-place task in a T-maze, the profile of deficits differed from that associated with prelimbic cortex damage (Experiment 4). When the task was switched to a nonmatching design, retrosplenial cortex lesions had no apparent effect on performance. The results from the four experiments show that many frontal tasks do not require the retrosplenial cortex, highlighting the specificity of their functional interactions. The results show how retrosplenial cortex lesions spare those learning tasks in which there is no mismatch between the internal and external representations used to guide behavioural choice. In addition, these experiments further highlight the importance of the retrosplenial cortex in solving tasks with a spatial component.
| S-EPMC5597037 | biostudies-literature
Project description:Hippocampal (HPC) theta oscillation during post-training rapid eye movement (REM) sleep supports spatial learning. Theta also modulates neuronal and oscillatory activity in the retrosplenial cortex (RSC) during REM sleep. To investigate the relevance of theta-driven interaction between these two regions to memory consolidation, we computed the Granger causality within theta range on electrophysiological data recorded in freely behaving rats during REM sleep, both before and after contextual fear conditioning. We found a training-induced modulation of causality between HPC and RSC that was correlated with memory retrieval 24 h later. Retrieval was proportional to the change in the relative influence RSC exerted upon HPC theta oscillation. Importantly, causality peaked during theta acceleration, in synchrony with phasic REM sleep. Altogether, these results support a role for phasic REM sleep in hippocampo-cortical memory consolidation and suggest that causality modulation between RSC and HPC during REM sleep plays a functional role in that phenomenon.
| S-EPMC8219679 | biostudies-literature
Project description:Absence epilepsy is a common childhood disorder featuring frequent cortical spike-wave seizures with a loss of awareness and behavior. Using the calcium indicator GCaMP6 with in vivo 2-photon cellular microscopy and simultaneous electrocorticography, we examined the collective activity profiles of individual neurons and surrounding neuropil across all layers in V1 during spike-wave seizure activity over prolonged periods in stargazer mice. We show that most (~80%) neurons in all cortical layers reduce their activity during seizures, whereas a smaller pool activates or remains neutral. Unexpectedly, ictal participation of identified single-unit activity is not fixed, but fluctuates on a flexible time scale from seizure to seizure. Pairwise correlation analysis of calcium activity reveals a surprising lack of synchrony among neurons and neuropil patches in all layers during seizures. Our results demonstrate asynchronous suppression of visual cortex during absence seizures, with potential implications for understanding cortical network function during EEG states of reduced awareness.
| S-EPMC5955878 | biostudies-literature