Interictal electroencephalogram (EEG) patterns, including high-frequency oscillations (HFOs), interictal spikes (ISs), and slow wave activities (SWAs), are defined as specific oscillations between seizure events. These interictal oscillations reflect specific dynamic changes in network excitability and play various roles in epilepsy. In this review, we briefly describe the electrographic characteristics of HFOs, ISs, and SWAs in the interictal state, and discuss the underlying cellular and network mechanisms. We also summarize representative evidence from experimental and clinical epilepsy to address their critical roles in ictogenesis and epileptogenesis, indicating their potential as electrophysiological biomarkers of epilepsy. Importantly, we put forwards some perspectives for further research in the field.
Abstract Aims Epilepsy, frequently comorbid with depression, easily develops drug resistance. Here, we investigated how dorsal raphe (DR) and its 5‐HTergic neurons are implicated in epilepsy. Methods In mouse hippocampal kindling model, using immunochemistry, calcium fiber photometry, and optogenetics, we investigated the causal role of DR 5‐HTergic neurons in seizure of temporal lobe epilepsy (TLE). Further, deep brain stimulation (DBS) of the DR with different frequencies was applied to test its effect on hippocampal seizure and depressive‐like behavior. Results Number of c‐fos + neurons in the DR and calcium activities of DR 5‐HTergic neurons were both increased during kindling‐induced hippocampal seizures. Optogenetic inhibition, but not activation, of DR 5‐HTergic neurons conspicuously retarded seizure acquisition specially during the late period. For clinical translation, 1‐Hz‐specific, but not 20‐Hz or 100‐Hz, DBS of the DR retarded the acquisition of hippocampal seizure. This therapeutic effect may be mediated by the inhibition of DR 5‐HTergic neurons, as optogenetic activation of DR 5‐HTergic neurons reversed the anti‐seizure effects of 1‐Hz DR DBS. However, DBS treatment had no effect on depressive‐like behavior. Conclusion Inhibition of hyperactivity of DR 5‐HTergic neuron may present promising anti‐seizure effect and the DR may be a potential DBS target for the therapy of TLE.
Cognitive deficit is a common comorbidity in temporal lobe epilepsy (TLE) and is not well controlled by current therapeutics. Currently, how epileptic seizure affects cognitive performance is still largely unclear, leading to a situation that lacks precise treatment. Here, we used an activity-dependent labeling technique to tag seizure-activated neurons in the subiculum (SUB), a region that plays a pivotal role in cognition and TLE. Combined with chemogenetics, and Ca2+ fiber photometry approaches, we sought to reveal the role of these neurons in cognitive impairment in epilepsy. We found that chemogenetic inhibition of subicular seizure-tagged fos+ neurons, a part of CaMKIIα+ neurons, showed a considerable protective effect on seizures generalization and improved the behavioral outcomes in both episodic memory and spatial memory of hippocampal-kindled mice. While, chemogenetic inhibition of the whole subicular CaMKIIα+ neuron impaired episodic memory and spatial memory and did not protect against seizures. Notably, Ca2+ fiber photometry data showed that subicular CaMKIIα+ neurons selectively increased the activity to the new location and new object in normal conditions, whereas seizure-tagged neurons in epileptic mice lost responsive activity during cognitive tasks. Histological and electrophysiological data indicated that inhibition of subicular seizure-tagged fos+ neurons enhanced the recruitment of cognition-tagged fos+ neurons via increasing neural excitability from synaptic integration. Our results suggest the subicular seizure-activated fos+ neurons contribute to cognitive impairment in epilepsy, and support that seizure-tagged fos+ neurons as the potential target to alleviate cognitive impairment in TLE.Funding Information: This project was supported by grants from the National Key R&D program of China (2021ZD0202803 and 2020YFA0803902), the National Natural Science Foundation of China (82022071), and the Natural Science Foundation of Zhejiang Province (LD22H310003).Declaration of Interests: No conflicts to report.Ethics Approval Statement: All experiments were carried out following the National Institutes of Health guidelines, and all procedures were approved by the local ethics review committee of Zhejiang Chinese Medical University.
Predatory hunting is an innate appetite-driven and evolutionarily conserved behavior essential for animal survival, integrating sequential behaviors including searching, pursuit, attack, retrieval, and ultimately consumption. Nevertheless, neural circuits underlying hunting behavior with different features remain largely unexplored. Here, we deciphered a novel function of lateral hypothalamus (LH) calcium/calmodulin-dependent protein kinase II α (CaMKII α + ) neurons in hunting behavior and uncovered upstream/downstream circuit basis. LH CaMKII α + neurons bidirectionally modulate novelty-seeking behavior, predatory attack, and eating in hunting behavior. LH CaMKII α + neurons integrate hunting-related novelty-seeking information from the medial preoptic area (MPOA) and project to the ventral periaqueductal gray (vPAG) to promote predatory eating. Our results demonstrate that LH CaMKII α + neurons are the key hub that integrate MPOA-conveyed novelty-seeking signals and encode predatory eating in hunting behavior, which enriched the neuronal substrate of hunting behavior.
Epileptic networks are characterized as having two states, seizures or more prolonged interictal periods. However, cellular mechanisms underlying the contribution of interictal periods to ictal events remain unclear. Here, we use an activity-dependent labeling technique combined with genetically encoded effectors to characterize and manipulate neuronal ensembles recruited by focal seizures (FS-Ens) and interictal periods (IP-Ens) in piriform cortex, a region that plays a key role in seizure generation. Ca2+ activities and histological evidence reveal a disjointed correlation between the two ensembles during FS dynamics. Optogenetic activation of FS-Ens promotes further seizure development, while IP-Ens protects against it. Interestingly, both ensembles are functionally involved in generalized seizures (GS) due to circuit rearrangement. IP-Ens bidirectionally modulates FS but not GS by controlling coherence with hippocampus. This study indicates that the interictal state may represent a seizure-preventing environment, and the interictal-activated ensemble may serve as a potential therapeutic target for epilepsy.
Abstract Epilepsy is considered a circuit-level dysfunction associated with imbalanced excitation-inhibition, it is therapeutically necessary to identify key brain regions and related circuits in epilepsy. The subiculum is an essential participant in epileptic seizures, but the circuit mechanism underlying its role remains largely elusive. Here we deconstruct the diversity of subicular circuits in a mouse model of epilepsy. We find that excitatory subicular pyramidal neurons heterogeneously control the generalization of hippocampal seizures by projecting to different downstream regions. Notably, anterior thalamus-projecting subicular neurons bidirectionally mediate seizures, while entorhinal cortex-projecting subicular neurons act oppositely in seizure modulation. These two subpopulations are structurally and functionally dissociable. An intrinsically enhanced hyperpolarization-activated current and robust bursting intensity in anterior thalamus-projecting neurons facilitate synaptic transmission, thus contributing to the generalization of hippocampal seizures. These results demonstrate that subicular circuits have diverse roles in epilepsy, suggesting the necessity to precisely target specific subicular circuits for effective treatment of epilepsy.
Epileptic networks are characterized by two states, seizures or more prolonged interictal periods. Here, we present the procedure for labeling seizure-activated and interictal-activated neuronal ensembles in mouse hippocampal kindling model using an enhanced-synaptic-activity-responsive element. We describe the seizure model establishment, tamoxifen induction, electrical stimulation, and calcium signal recording of labeled ensembles. This protocol has demonstrated dissociated calcium activities in the two ensembles during focal seizure dynamics and can be applied to other animal models of epilepsy. For complete details on the use and execution of this protocol, please refer to Lai et al. (2022).1.
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