Interictal-period-activated neuronal ensemble in piriform cortex retards further seizure development

Lai, Nanxi; Cheng, Heming; Li, Zhisheng; Wang, Xia; Ruan, Yuanyuan; Qi, Yingbei; Yang, Lin; Fei, Fan; Dai, Sijie; Chen, Liying; Zheng, Yang; Xu, Cenglin; Jiang, Fang; Wang, Shuang; Chen, Zhong; Wang, Yi

doi:10.1016/j.celrep.2022.111798

Cited by 13 publications

(8 citation statements)

References 75 publications

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“…Some of these findings were corroborated by a recent study by Lai et al. (2022). Thus, targeted inhibition of pyramidal neurons in the PC may be an attractive therapeutic approach from both the functional and clinical perspectives.…”

Section: Discussionsupporting

confidence: 75%

“…We used chemogenetic and optogenetic modulation of these cells, demonstrating the potential efficacy of these powerful tools for the treatment of epilepsy (Rajasethupathy et al, 2016). Some of these findings were corroborated by a recent study by Lai et al (2022). Thus, targeted inhibition of pyramidal neurons in the PC may be an attractive therapeutic approach from both the functional and clinical perspectives.…”

Section: Discussionmentioning

confidence: 63%

“…Seizures can cause a variety of transient or persistent changes in the PC, including smaller structural volume (Goncalves Pereira et al, 2005), neuronal loss (Chen & Buckmaster, 2005;Roch et al, 2002;Scholl et al, 2013) and changes in neuronal excitability (Chang et al, 2018;Maciejak et al, 2010;Wei et al, 2017;Xu & Luo, 2018). Importantly, in rodent models, pharmacological interventions (Namvar et al, 2008;Rezvani et al, 2007;Schwabe et al, 2004a), lesions (Kelly et al, 2002;Myhrer et al, 2008;Racine et al, 1988) and other manipulations (Lai et al, 2022) targeting the PC can reduce the risk of epilepsy and significantly delay the development of seizures, suggesting that the PC plays a key role in seizure control and might act as a promising therapeutic target for epilepsy therapy. However, the cell types involved and the specific functional role of the PC in controlling epilepsy remain elusive.…”

Section: Introductionmentioning

confidence: 99%

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Principal neurons in the olfactory cortex mediate bidirectional modulation of seizures

Liu

Geng

et al. 2023

The Journal of Physiology

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Although the piriform cortex (PC) has been previously implicated as a critical node for seizure generation and propagation, the underlying neural mechanism has remained unclear. Here, we found increased excitability in PC neurons during amygdala kindling acquisition. Optogenetic or chemogenetic activation of PC pyramidal neurons promoted kindling progression, whereas inhibition of these neurons retarded seizure activities induced by electrical kindling in the amygdala. Furthermore, chemogenetic inhibition of PC pyramidal neurons alleviated the severity of kainic acid‐induced acute seizures. These results demonstrate that PC pyramidal neurons bidirectionally modulate seizures in temporal lobe epilepsy, providing evidence for the efficacy of PC pyramidal neurons as a potential therapeutic target for epileptogenesis. imageKey points While the piriform cortex (PC) is an important olfactory centre critically involved in olfactory processing and plays a crucial role in epilepsy due to its close connection with the limbic system, how the PC regulates epileptogenesis is largely unknown. In this study, we evaluated the neuronal activity and the role of pyramidal neurons in the PC in the mouse amygdala kindling model of epilepsy. PC pyramidal neurons are hyperexcited during epileptogenesis. Optogenetic and chemogenetic activation of PC pyramidal neurons significantly promoted seizures in the amygdala kindling model, whereas selective inhibition of these neurons produced an anti‐epileptic effect for both electrical kindling and kainic acid‐induced acute seizures. The results of the present study indicate that PC pyramidal neurons bidirectionally modulate seizure activity.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Principal neurons in the olfactory cortex mediate bidirectional modulation of seizures

Liu

Geng

et al. 2023

The Journal of Physiology

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“…When a circuit-informed bridging neuroprosthesis is not feasible, interictal discharges may still present the key for an effective closed-loop DBS, as they reflect the propensity of the epileptic brain to generate seizures [48][49][50]. Nonetheless, the concept of an interictal-informed closed-loop DBS has only recently emerged [51,52] and the direct exploitation of interictal discharges to drive the closed-loop stimulation has never been considered prior to the present work. This is because a clear definition of their pro-ictogenic versus anti-ictogenic role is still a matter of debate due to the general assumption that the two roles are mutually exclusive.…”

Section: Discussionmentioning

confidence: 99%

Biohybrid restoration of the hippocampal loop re-establishes the non-seizing state in an in vitro model of limbic seizures

et al. 2023

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Objective. The compromise of the hippocampal loop is a hallmark of mesial temporal lobe epilepsy (MTLE), the most frequent epileptic syndrome in the adult population and the most often refractory to medical therapy. Hippocampal sclerosis is found in >50% of drug-refractory MTLE patients and primarily involves the CA1, consequently disrupting the hippocampal output to the entorhinal cortex (EC). Closed-loop deep brain stimulation (DBS) is the latest frontier to improve drug-refractory MTLE; however, current approaches do not restore the functional connectivity of the hippocampal loop, they are designed by trial-and-error and heavily rely on seizure detection or prediction algorithms. The objective of this study is to evaluate the anti-ictogenic efficacy and robustness of an artificial bridge restoring the dialog between hippocampus and EC. Approach. In mouse hippocampus-EC slices treated with 4-aminopyridine and in which the Schaffer Collaterals are severed, we established an artificial bridge between hippocampus and EC wherein interictal discharges originating in the CA3 triggered stimulation of the subiculum so to entrain EC networks. Combining quantification of ictal activity with tools from information theory, we addressed the efficacy of the bridge in controlling ictogenesis and in restoring the functional connectivity of the hippocampal loop.Main results. The bridge significantly decreased or even prevented ictal activity and proved robust to failure; when operating at 100% of its efficiency (i.e., delivering a pulse upon each interictal event), it recovered the functional connectivity of the hippocampal loop to a degree similar to what measured in the intact circuitry. The efficacy and robustness of the bridge stem in mirroring the adaptive properties of the CA3, which acts as biological neuromodulator.Significance. This work is the first stepping stone toward a paradigm shift in the conceptual design of stimulation devices for epilepsy treatment, from function control to functional restoration of the salient brain circuits.

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“…79 Chimeric CreERT2 driven by enhanced synaptic activity-responsive element was recently used to label the neuronal ensemble activated during focal seizures, and separately, the neural ensemble, activated during interictal periods in mouse anterior piriform cortex. 80 The optokindling as well as electrokindling processes potentiated synaptic transmission and promoted neural circuit rearrangement, which increases the intensity and number of seizures. Using a sophisticated combination of opto-and chemogenetic, electrophysiological, histological, and behavioral methods, it was shown that a strictly determined population of neurons is responsible for the formation of epileptic seizures.…”

Section: Epilepsy Models Based On Optokindlingmentioning

confidence: 99%

Neurophotonic methods in approach to in vivo animal epileptic models: Advantages and limitations

Tsytsarev,

Sopova,

Leonova

et al. 2024

Epilepsia

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Neurophotonic technology is a rapidly growing group of techniques that are based on the interactions of light with natural or genetically modified cells of the neural system. New optical technologies make it possible to considerably extend the tools of neurophysiological research, from the visualization of functional activity changes to control of brain tissue excitability. This opens new perspectives for studying the mechanisms underlying the development of human neurological diseases. Epilepsy is one of the most common brain disorders; it is characterized by recurrent seizures and affects >1% of the world's population. However, how seizures occur, spread, and terminate in a healthy brain is still unclear. Therefore, it is extremely important to develop appropriate models to accurately explore the causal relationship of epileptic activity. The use of neurophotonic technologies in epilepsy research falls into two broad categories: the visualization of neural epileptic activity, and the direct optical influence on neurons to induce or suppress epileptic activity. An optogenetic variant of the classical kindling model of epileptic seizures, in which activatable cells are genetically defined, is called optokindling. Research is also underway concerning the application of neurophotonic techniques for suppressing epileptic activity, aiming to bring these methods into clinical practice. This review aims to systematize and describe new approaches that use combinations of different neurophotonic methods to work with in vivo models of epilepsy. These approaches overcome many of the shortcomings associated with classical animal models of epilepsy and thus increase the effectiveness of developing new diagnostic methods and antiepileptic therapy.

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Interictal-period-activated neuronal ensemble in piriform cortex retards further seizure development

Cited by 13 publications

References 75 publications

Principal neurons in the olfactory cortex mediate bidirectional modulation of seizures

Principal neurons in the olfactory cortex mediate bidirectional modulation of seizures

Biohybrid restoration of the hippocampal loop re-establishes the non-seizing state in an in vitro model of limbic seizures

Neurophotonic methods in approach to in vivo animal epileptic models: Advantages and limitations

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