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The cerebellum contributes to generalized seizures by altering activity in the ventral posteromedial nucleus.

ABSTRACT: Thalamo-cortical networks are central to seizures, yet it is unclear how these circuits initiate seizures. We test whether a facial region of the thalamus, the ventral posteromedial nucleus (VPM), is a source of generalized, convulsive motor seizures and if convergent VPM input drives the behavior. To address this question, we devise an in vivo optogenetic mouse model to elicit convulsive motor seizures by driving these inputs and perform single-unit recordings during awake, convulsive seizures to define the local activity of thalamic neurons before, during, and after seizure onset. We find dynamic activity with biphasic properties, raising the possibility that heterogenous activity promotes seizures. Virus tracing identifies cerebellar and cerebral cortical afferents as robust contributors to the seizures. Of these inputs, only microinfusion of lidocaine into the cerebellar nuclei blocks seizure initiation. Our data reveal the VPM as a source of generalized convulsive seizures, with cerebellar input providing critical signals.

SUBMITTER: Beckinghausen J

PROVIDER: S-EPMC10349834 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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The cerebellum contributes to generalized seizures by altering activity in the ventral posteromedial nucleus.

Beckinghausen Jaclyn J Ortiz-Guzman Joshua J Lin Tao T Bachman Benjamin B Salazar Leon Luis E LE Liu Yu Y Heck Detlef H DH Arenkiel Benjamin R BR Sillitoe Roy V RV

Communications biology 20230715 1

Thalamo-cortical networks are central to seizures, yet it is unclear how these circuits initiate seizures. We test whether a facial region of the thalamus, the ventral posteromedial nucleus (VPM), is a source of generalized, convulsive motor seizures and if convergent VPM input drives the behavior. To address this question, we devise an in vivo optogenetic mouse model to elicit convulsive motor seizures by driving these inputs and perform single-unit recordings during awake, convulsive seizures ...[more]

PMID: 37454228

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Project description:BackgroundAs the relay centre for processing sensory information, the thalamus may involve in the abnormal sensory procedure caused by cortical spreading depression (CSD). However, few studies have focused on the transient response of thalamus during CSD. Our study aimed to investigate the neuronal activity of mouse thalamus ventral posteromedial nucleus (VPM) during CSD by in vivo micro-endoscopic fluorescence imaging of the genetic calcium probe GCaMP6s expressed in excitatory glutamatergic neurons.MethodsThirty-four transgenic VGluT2-GCaMP6s mice were used in the experiments. An endoscope was inserted into the VPM for image acquisition. CSD was induced by KCl topically applied unilaterally on the cranial dura. Data were acquired in awake (ipsilateral or contralateral VPM, saline instead of KCl, MK-801 treatment) and anaesthetized (isoflurane, pentobarbital) states. Statistical analysis was performed using analysis of variance (ANOVA) by SPSS.ResultsWe found that after CSD induced in ipsilateral motor cortex, the neuronal activity increased and propagated from the posterior-lateral to the anterior-medial part of the VPM with an average speed of 3.47 mm/min. When CSD was induced in visual cortex, the response propagated in opposite direction, from the anterior-medial to the posterior-lateral part of the VPM. Aanaesthetics resulted in the suppression of VPM activation induced by CSD. No significant VPM activation was detected when CSD was induced in contralateral cortex or KCl was replaced by saline. When 5 mM MK-801 was applied to the dura, the electrode failed to record the DC shift of CSD, and there was no significant VPM activation after KCl application.ConclusionCSD induced propagating activation of the ipsilateral VPM in awake mice. The response might correlate to the cortical location where CSD was induced and might be affected by anaesthetics. No significant VPM activation was detected in saline and mk801 experiment results indicated that this VPM activation is due to CSD rather than mouse motion or direct effect of the KCl applying to the intact dura. This finding suggests the potential involvement of thalamus in the migraine auras.

Project description:ObjectivePatients with generalized epilepsy exhibit different epileptiform events including asymptomatic interictal spikes (IS), absence seizures with spike-wave discharges (SWDs), and myoclonic seizures (MS). Our objective was to determine the spatiotemporal patterns of cortical activation in SWDs, IS, and MS in the Gabra1+/A322D juvenile myoclonic epilepsy mouse.MethodsWe fabricated affordable, flexible high-density electroencephalography (HdEEG) arrays and recorded spontaneous SWD, IS, and MS with video/HdEEG. We determined differences among the events in amplitude spectral density (ASD) in the δ/θ/α/β/γ frequency bands at baseline (3.5-4.0 seconds before the first spike time, t0 ) and the prespike period (0.1-0.5 seconds before t0 ), and we elucidated the spatiotemporal activation during the t0 spike.ResultsAll three events had an increase in ASD between baseline and prespike in at least one frequency band. During prespike, MS had the largest δ-band ASD, but SWD had the greatest α/β/γ band ASD. For all three events, the ASD was largest in the anterior regions. The t0 spike voltage was also greatest in the anterior regions for all three events and IS and MS had larger voltages than SWD. From 7.5 to 17.5 msec after t0 , MS had greater voltage than IS and SWD, and maximal voltage was in the posterior parietal region.SignificanceChanges in spectral density from baseline to prespike indicate that none of these generalized events are instantaneous or entirely unpredictable. Prominent engagement of anterior cortical regions during prespike and at t0 suggest that common anterior neural circuits participate in each event. Differences in prespike ASD signify that although the events may engage similar brain regions, they may arise from distinct proictal states with different neuronal activity or connectivity. Prolonged activation of the posterior parietal area in MS suggests that posterior circuits contribute to the myoclonic jerk. Together, these findings identify brain regions and processes that could be specifically targeted for further recording and modulation.

Dataset Information

The cerebellum contributes to generalized seizures by altering activity in the ventral posteromedial nucleus.

Publications

The cerebellum contributes to generalized seizures by altering activity in the ventral posteromedial nucleus.

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