Search

Abstract Fear memory is essential for survival and adaptation, yet excessive fear memories can lead to emotional disabilities and mental disorders. Despite previous researches have indicated that histamine H1 receptor (H1R) exerts critical and intricate effects on fear memory, the role of H1R is still not clarified. Here, we show that deletion of H1R gene in medial septum (MS) but not other cholinergic neurons selectively enhances contextual fear memory without affecting cued memory by differentially activating the dentate gyrus (DG) neurons in mice. H1R in cholinergic neurons mediates the contextual fear retrieval rather than consolidation by decreasing acetylcholine release pattern in DG. Furthermore, selective knockdown of H1R in the MS is sufficient to enhance contextual fear memory by manipulating the retrieval-induced neurons in DG. Our results suggest that H1R in MS cholinergic neurons is critical for contextual fear retrieval, and could be a potential therapeutic target for individuals with fear-related disorders.

Abstract Ample evidence has suggested the stress etiology of depression, but the underlying mechanism is not fully understood yet. Here, we report that chronic social defeat stress (CSDS) attenuates the excitatory output of the claustrum (CLA) to the prelimbic cortex (PL) through the dynorphin/κ-opioid receptor (KOR) signaling, being critical for depression-related behaviors in male mice. The CSDS preferentially impairs the excitatory output from the CLA onto the parvalbumin (PV) of the PL, leading to PL micronetwork dysfunction by disinhibiting pyramidal neurons (PNs). Optogenetic activation or inhibition of this circuit suppresses or promotes depressive-like behaviors, which is reversed by chemogenetic inhibition or activation of the PV neurons. Notably, manipulating the dynorphin/KOR signaling in the CLA-PL projecting terminals controls depressive-like behaviors that is suppressed or promoted by optogenetic activation or inhibition of CLA-PL circuit. Thus, this study reveals both mechanism of the stress etiology of depression and possibly therapeutic interventions by targeting CLA-PL circuit.

Background: Managing refractory epilepsy presents a significant a substantial clinical challenge. Deep brain stimulation (DBS) has emerged as a promising avenue for addressing refractory epilepsy. However, the optimal stimulation targets and effective parameters of DBS to reduce seizures remian unidentified. Objectives: This study endeavors to scrutinize the therapeutic potential of DBS within the zona incerta (ZI) across diverse seizure models and elucidate the associated underlying mechanisms. Methods: We evaluated the therapeutic potential of DBS with different frequencies in the ZI on kainic acid (KA)-induced TLE model or M1-cortical seizures model, pilocarpine-induced M1-cortical seizure models, and KA-induced epilepsy model. Further, employing calcium fiber photometry combined with cell-specific ablation, we sought to clarified the causal role of ZI GABAergic neurons in mediating the therapeutic effects of DBS. Results: Our findings reveal that DBS in the ZI alleviated the severity of seizure activities in the KA-induced TLE model. Meanwhile, DBS attenuated seizure activities in KA- or pilocarpine-induced M1-cortical seizure model. In addition, DBS exerts a mitigating influence on KA induced epilepsy model. DBS in the ZI showed anti-seizure effects at low frequency spectrum, with 5 Hz exhibiting optimal efficacy. The low-frequency DBS significantly increased the calcium activities of ZI GABAergic neurons. Furthermore, selective ablation of ZI GABAergic neurons with taCasp3 blocked the anti-seizure effect of low-frequency DBS, indicating the anti-seizure effect of DBS is mediated by the activation of ZI GABAergic neurons. Conclusion: Our results demonstrate that low-frequency DBS in the ZI attenuates seizure via driving GABAergic neuronal activity. This suggests that the ZI represents a potential DBS target for treating both hippocampal and cortical seizure through the activation of GABAergic neurons, thereby holding therapeutic significance for seizure treatment.

Interictal epileptiform discharges (IEDs) often co-occur across spatially-separated cortical regions, forming IED networks. However, the factors prompting IED propagation remain unelucidated. We hypothesized that slow oscillations (SOs) might facilitate IED propagation. Here, the amplitude and phase synchronization of SOs preceding propagating and non-propagating IEDs were compared in 22 patients with focal epilepsy undergoing intracranial electroencephalography (EEG) evaluation. Intracranial channels were categorized into the irritative zone (IZ) and normal zone (NOZ) regarding the presence of IEDs. During wakefulness, we found that pre-IED SOs within the IZ exhibited higher amplitudes for propagating IEDs than non-propagating IEDs (delta band: p = 0.001, theta band: p

Abstract Temporal lobe epilepsy (TLE), one common type of medically refractory epilepsy, is accompanied with altered adult-born dentate granule cells (abDGCs). However, the causal role of abDGCs in recurrent seizures of TLE is not fully understood. Here, taking advantage of optogenetic and chemogenetic tools to selectively manipulate abDGCs in a reversible manner, combined with Ca2+ fiber photometry, trans-synaptic viral tracing, in vivo/vitro electrophysiology approaches, we aimed to test the role of abDGCs born at different period of epileptogenic insult in later recurrent seizures in mouse TLE models. We found that abDGCs were functionally inhibited during recurrent seizures. Optogenetic activation of abDGCs significantly extended, while inhibition curtailed, the seizure duration. This seizure-modulating effect was attributed to specific abDGCs born at a critical early phase after kindled status, which experienced specific type of circuit re-organization. Further, abDGCs extended seizure duration via local excitatory circuit with early-born granule cells (ebDGCs). Repeated modulation of “abDGC-ebDGC” circuit may easily induce a change of synaptic plasticity, and achieve long-term anti-seizure effects in both kindling and kainic acid-induced TLE models. Together, we demonstrate that abDGCs born at a critical period of epileptogenic insult maintain seizure duration via local aberrant excitatory circuits, and inactivation of these aberrant circuits can long-termly alleviate severity of seizures. This provides a deeper and more comprehensive understanding of the potential pathological changes of abDGCs circuit and may be helpful for the precise treatment in TLE.

Abstract Seizures due to cortical dysplasia are notorious for their poor prognosis even with medications and surgery, likely due to the widespread seizure network. Previous studies have primarily focused on the disruption of dysplastic lesions, rather than remote regions such as the hippocampus. Here, we first quantified the epileptogenicity of the hippocampus in patients with late-stage cortical dysplasia. We further investigated the cellular substrates leading to the epileptic hippocampus, using multiscale tools including calcium imaging, optogenetics, immunohistochemistry and electrophysiology. For the first time, we revealed the role of hippocampal somatostatin-positive interneurons in cortical dysplasia-related seizures. Somatostatin-positive were recruited during cortical dysplasia-related seizures. Interestingly, optogenetic studies suggested that somatostatin-positive interneurons paradoxically facilitated seizure generalization. By contrast, parvalbumin-positive interneurons retained an inhibitory role as in controls. Electrophysiological recordings and immunohistochemical studies revealed glutamate-mediated excitatory transmission from somatostatin-positive interneurons in the dentate gyrus. Taken together, our study reveals a novel role of excitatory somatostatin-positive neurons in the seizure network and brings new insights into the cellular basis of cortical dysplasia.

The raphe nuclei, the primary resource of forebrain 5-HT, play an important but heterogeneous role in regulating subcortical excitabilities. Fundamental circuit organizations of different median raphe (MR) subsystems are far from completely understood. In the present study, using cell-specific viral tracing, Ca2+ fiber photometry and epilepsy model, we map out the forebrain efferent and afferent of different MR Pet+ subpopulations and their divergent roles in epilepsy. We found that PetMR neurons send both collateral and parallel innervations to different downstream regions through different subpopulations. Notably, CA3-projecting PetMR subpopulations are largely distinct from habenula (Hb)-projecting PetMR subpopulations in anatomical distribution and topological organization, while majority of the CA3-projecting PetMR subpopulations are overlapped with the medial septum (MS)-projecting PetMR subpopulations. Further, using Ca2+ fiber photometry, we monitor activities of PetMR neurons in hippocampal-kindling seizure, a classical epilepsy model with pathological mechanisms caused by excitation-inhibition imbalance. We found that soma activities of PetMR neurons are heterogeneous during different periods of generalized seizures. These divergent activities are contributed by different projection-defined PetMR subpopulations, manifesting as increased activities in CA3 but decreased activity in Hb resulting from their upstream differences. Together, our findings provide a novel framework of MR subsystems showing that projection-defined MR Pet+ subpopulations are topologically heterogenous with divergent circuit connections and are diversely implicated in seizures. This may help in the understanding of heterogeneous nature of MR 5-HTergic subsystems and the paradox roles of 5-HTergic systems in epilepsy.

Neocortical epilepsy is resistant to current treatments. Zhao et al. report that optogenetic stimulation of astrocytes effectively attenuates seizures via driving Na+-K+-ATPase, indicating a potential treatment strategy for intractable epilepsy.

The subiculum is known to contribute to seizures in epilepsy. Here the authors investigate the circuit mechanism by which the subiculum contributes to initiation and propagation of hippocampal seizures in a mouse model.

Epilepsy, one of the most common neurological disorders, often is not well controlled by current pharmacological and surgical treatments. Sensory neuromodulation, including multi-sensory stimulation, auditory stimulation, olfactory stimulation, is a kind of novel noninvasive mind-body intervention and receives continued attention as complementary safe treatment of epilepsy. In this review, we summarize the recent advances of sensory neuromodulation, including enriched environment therapy, music therapy, olfactory therapy, other mind-body interventions, for the treatment of epilepsy based on the evidence from both clinical and preclinical studies. We also discuss their possible anti-epileptic mechanisms on neural circuit level and propose perspectives on possible research directions for future studies.

The ATP1A3 gene, which encodes the Na+/K+-ATPase α3 catalytic subunit, plays a crucial role in both physiological and pathological conditions in the brain, and mutations in this gene have been associated with a wide variety of neurological diseases by impacting the whole infant development stages. Cumulative clinical evidence suggests that some severe epileptic syndromes have been linked to mutations in ATP1A3, among which inactivating mutation of ATP1A3 has been intriguingly found to be a candidate pathogenesis for complex partial and generalized seizures, proposing ATP1A3 regulators as putative targets for the rational design of antiepileptic therapies. In this review, we introduced the physiological function of ATP1A3 and summarized the findings about ATP1A3 in epileptic conditions from both clinical and laboratory aspects at first. Then, some possible mechanisms of how ATP1A3 mutations result in epilepsy are provided. We think this review timely introduces the potential contribution of ATP1A3 mutations in both the genesis and progression of epilepsy. Taken that both the detailed mechanisms and therapeutic significance of ATP1A3 for epilepsy are not yet fully illustrated, we think that both in-depth mechanisms investigations and systematic intervention experiments targeting ATP1A3 are needed, and by doing so, perhaps a new light can be shed on treating ATP1A3-associated epilepsy.

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.

Summary: Epilepsy is a circuit-level brain disorder characterized by hyperexcitatory seizures with unclear mechanisms. Here, we investigated the causal roles of calretinin (CR) neurons in the posterior intralaminar thalamic nucleus (PIL) in hippocampal seizures. Using c-fos mapping and calcium fiber photometry, we found that PIL CR neurons were activated during hippocampal seizures in a kindling model. Optogenetic activation of PIL CR neurons accelerated seizure development, whereas inhibition retarded seizure development. Further, viral-based circuit tracing verified that PIL CR neurons were long-range glutamatergic neurons, projecting toward various downstream regions. Interestingly, selective inhibition of PIL-lateral amygdala CR circuit attenuated seizure progression, whereas inhibition of PIL-zona incerta CR circuit presented an opposite effect. These results indicated that CR neurons in the PIL play separate roles in hippocampal seizures via distinct downstream circuits, which complements the pathogenic mechanisms of epilepsy and provides new insight for the precise medicine of epilepsy.

Social impairment and anhedonia are common negative symptoms in patients with schizophrenia. Here, the authors show that the histamine H1 receptor in cholinergic neurons in the basal forebrain has a critical role in sensorimotor gating, social behaviour, and anhedonia-like behaviour in mice.

The neural circuits through which the substantia nigra pars reticulata (SNr) exerts its role in epilepsy control are not known. Here the authors reveal that a long-range SNr-parafascicular nucleus disinhibitory circuit participates in regulating seizures in temporal lobe epilepsy and inhibition of this circuit can alleviate severity of epileptic seizures.

Secondary epileptogenesis is a common phenomenon in epilepsy, characterized by epileptiform discharges from the regions outside the primary focus. It is one of the major reasons for pharmacoresistance and surgical failure. Compared with primary epileptogenesis, the mechanism of secondary epileptogenesis is usually more complex and diverse. In this review, we aim to summarize the characteristics of secondary epileptogenesis from both clinical and laboratory studies in a historical view. Mechanisms of secondary epileptogenesis in molecular, cellular, and circuity levels are further presented. Potential treatments targeting the process are discussed as well. At last, we highlight the importance of circuitry studies, which would further illustrate precise treatments of secondary epileptogenesis in the future.

Summary: Complex febrile seizures (FSs) lead to a high risk of intractable temporal lobe epilepsy during adulthood, yet the pathological process of complex FSs is largely unknown. Here, we demonstrate that activated microglia extensively associated with glutamatergic neuronal soma displace surrounding GABAergic presynapses in complex FSs. Patch-clamp electrophysiology establishes that the microglial displacement of GABAergic presynapses abrogates a complex-FS-induced increase in GABAergic neurotransmission and neuronal excitability, whereas GABA exerts an excitatory action in this immature stage. Pharmacological inhibition of microglial displacement of GABAergic presynapses or selective ablation of microglia in CD11bDTR mice promotes the generation of complex FSs. Blocking or deleting the P2Y12 receptor (P2Y12R) reduces microglial displacement of GABAergic presynapses and shortens the latency of complex FSs. Together, microglial displacement of GABAergic presynapses, regulated by P2Y12R, reduces neuronal excitability to mitigate the generation of complex FSs. Microglial displacement is a protective event during the pathological process of complex FSs.

The relationship between circadian rhythm and epilepsy has been recognized for decades. Yet many questions underlying the complex mechanisms of their interaction remain elusive. A better understanding on this topic allows the development of accurate seizure-detection algorithm and alternative precise therapeutic strategies. Preclinical laboratory studies based on epileptic animal models, with controllable epileptogenic pathology and an array of intervention strategies, shed light on the bidirectional effects between circadian rhythm and epileptic seizures as well as their underlying mechanisms. Here, we reviewed findings on the interaction between circadian rhythm and epileptic seizures in the preclinical setting. We present the possible mechanisms at molecular, cellular and circuitry levels. We propose that future experimental designs should take into account the relationship between circadian rhythm and epilepsy as well as the underlying mechanisms in different types of animal models, which may have a translational significance as stepping stones for clinical benefits.

Temporal lobe epilepsy (TLE) is the most common type of epilepsy and is often medically refractory. Previous studies suggest that selective pharmaco-genetic inhibition of pyramidal neurons has therapeutic value for the treatment of epilepsy, however there is a risk of disrupting normal physical functions. Here, we test whether pharmaco-genetic activation of parvalbumin neurons, which are transgenetically transduced with the modified muscarinic receptor hM3Dq can attenuate TLE. We found that pharmaco-genetic activation of hippocampal parvalbumin neurons in epileptogenic zone not only significantly extends the latency to different seizure stages and attenuates seizure activities in acute seizure model, but also greatly alleviates the severity of seizure onsets in two chronic epilepsy models. This manipulation did not affect the normal physical function evaluated in various cognitive tasks. Further, the activation of parvalbumin neurons produced an inhibition on parts of surrounding pyramidal neurons, and the direct inactivation of pyramidal neurons via the viral expression of a modified muscarinic receptor hM4Di produced a similar anti-ictogenic effect. Interestingly, pharmaco-genetic inactivation of pyramidal neurons was more sensitive to impair cognitive function. Those data demonstrated that pharmaco-genetic seizure attenuation through targeting parvalbumin neurons rather than pyramidal neurons may be a novel and relatively safe approach for treating refractory TLE.

Abstract Positive transfer of secondary focus (PTS) refers to new epileptogenesis outside the primary focus and is minimally controlled by existing treatments. Low-frequency stimulation (LFS) has benefits on the onset of epilepsy and epileptogenesis. However, it’s unclear whether LFS can retard the PTS in epilepsy. Here we found that PTS at both contralateral amygdala and ipsilateral hippocampus were promoted after the primary focus was fully kindled in rat kindling model. The promotion of PTS at the mirror focus started when the primary kindling acquisition reached focal seizures. LFS retarded the promotion of PTS when it was applied at the primary focus during its kindling acquisition, while it only slightly retarded the promotion of PTS when applied after generalized seizures. Meanwhile, we found the expression of potassium chloride cotransporter 2 (KCC2) decreased during PTS, and LFS reversed this. Further, the decreased expression of KCC2 was verified in patients with PTS. These findings suggest that LFS may be a potential therapeutic approach for PTS in epilepsy.

Environmental exposure early in development plays a role in susceptibility to disease in later life. Here, we demonstrate that prolonged febrile seizures induced by exposure of rat pups to a hyperthermic environment enhance seizure susceptibility not only in these hyperthermia-treated rats but also in their future offspring, even if the offspring never experience febrile seizures. This transgenerational transmission was intensity-dependent and was mainly from mothers to their offspring. The transmission was associated with DNA methylation. Thus, our study supports a “Lamarckian”-like mechanism of pathogenesis and the crucial role of epigenetic factors in neurological conditions.