Presubiculum stimulation in vivo evokes distinct oscillations in superficial and deep entorhinal cortex layers in chronic epileptic rats

The characteristic cell loss in layer III of the medial entorhinal area (MEA-III) in human mesial temporal lobe epilepsy is reproduced in the rat kainate model of the disease. To understand how this cell loss affects the functional properties of the MEA, we investigated whether projections from the presubiculum (prS), providing a main input to the MEA-III, are altered in this epileptic rat model. Injections of an anterograde tracer in the prS revealed bilateral projection fibers mainly to the MEA-III in both control and chronic epileptic rats. We further examined the prS-MEA circuitry using a 16-channel electrode probe covering the MEA in anesthetized control and chronic epileptic rats. With a second 16-channel probe, we recorded signals in the hippocampus. Current source density analysis indicated that, after prS double-pulse stimulation, afterdischarges in the form of oscillations (20-45 Hz) occurred that were confined to the superficial layers of the MEA in all epileptic rats displaying MEA-III neuronal loss. Slower oscillations (theta range) were occasionally observed in the deep MEA layers and the dentate gyrus. This kind of oscillation was never observed in control rats. We conclude that dynamical changes occur in an extensive network within the temporal lobe in epileptic rats, manifested as different kinds of oscillations, the characteristics of which depend on local properties of particular subareas. These findings emphasize the significance of the entorhinal cortex in temporal lobe epilepsy and suggest that the superficial cell layers could play an important role in distributing oscillatory activity.status: publishe

Migraine-relevant sex-dependent activation of mouse meningeal afferents by TRPM3 agonists

Background Migraine is a common brain disorder that predominantly affects women. Migraine pain seems mediated by the activation of mechanosensitive channels in meningeal afferents. Given the role of transient receptor potential melastatin 3 (TRPM3) channels in mechanical activation, as well as hormonal regulation, these channels may play a role in the sex difference in migraine. Therefore, we investigated whether nociceptive firing induced by TRPM3 channel agonists in meningeal afferents was different between male and female mice. In addition, we assessed the relative contribution of mechanosensitive TRPM3 channels and that of mechanosensitive Piezo1 channels and transient receptor potential vanilloid 1 (TRPV1) channels to nociceptive firing relevant to migraine in both sexes. Methods Ten- to 13-week-old male and female wildtype (WT) C57BL/6 J mice were used. Nociceptive spikes were recorded directly from nerve terminals in the meninges in the hemiskull preparations. Results Selective agonists of TRPM3 channels profoundly activated peripheral trigeminal nerve fibres in mouse meninges. A sex difference was observed for nociceptive firing induced by either PregS or CIM0216, both agonists of TRPM3 channels, with the induced firing being particularly prominent for female mice. Application of Yoda1, an agonist of Piezo1 channels, or capsaicin activating TRPV1 channels, although also leading to increased nociceptive firing of meningeal fibres, did not reveal a sex difference. Cluster analyses of spike activities indicated a massive and long-lasting activation of TRPM3 channels with preferential induction of large-amplitude spikes in female mice. Additional spectral analysis revealed a dominant contribution of spiking activity in the alpha- and beta-ranges following TRPM3 agonists in female mice. Conclusions Together, we revealed a specific mechanosensitive profile of nociceptive firing in females and suggest TRPM3 channels as a potential novel candidate for the generation of migraine pain, with particular relevance to females.Functional Genomics of Muscle, Nerve and Brain Disorder

Migraine-relevant sex-dependent activation of mouse meningeal afferents by TRPM3 agonists

Background Migraine is a common brain disorder that predominantly affects women. Migraine pain seems mediated by the activation of mechanosensitive channels in meningeal afferents. Given the role of transient receptor potential melastatin 3 (TRPM3) channels in mechanical activation, as well as hormonal regulation, these channels may play a role in the sex difference in migraine. Therefore, we investigated whether nociceptive firing induced by TRPM3 channel agonists in meningeal afferents was different between male and female mice. In addition, we assessed the relative contribution of mechanosensitive TRPM3 channels and that of mechanosensitive Piezo1 channels and transient receptor potential vanilloid 1 (TRPV1) channels to nociceptive firing relevant to migraine in both sexes. Methods Ten- to 13-week-old male and female wildtype (WT) C57BL/6 J mice were used. Nociceptive spikes were recorded directly from nerve terminals in the meninges in the hemiskull preparations. Results Selective agonists of TRPM3 channels profoundly activated peripheral trigeminal nerve fibres in mouse meninges. A sex difference was observed for nociceptive firing induced by either PregS or CIM0216, both agonists of TRPM3 channels, with the induced firing being particularly prominent for female mice. Application of Yoda1, an agonist of Piezo1 channels, or capsaicin activating TRPV1 channels, although also leading to increased nociceptive firing of meningeal fibres, did not reveal a sex difference. Cluster analyses of spike activities indicated a massive and long-lasting activation of TRPM3 channels with preferential induction of large-amplitude spikes in female mice. Additional spectral analysis revealed a dominant contribution of spiking activity in the alpha- and beta-ranges following TRPM3 agonists in female mice. Conclusions Together, we revealed a specific mechanosensitive profile of nociceptive firing in females and suggest TRPM3 channels as a potential novel candidate for the generation of migraine pain, with particular relevance to females.Functional Genomics of Muscle, Nerve and Brain Disorder

Headache in people with epilepsy

Epidemiological estimates indicate that individuals with epilepsy are more likely to experience headaches, including migraine, than individuals without epilepsy. Headaches can be temporally unrelated to seizures, or can occur before, during or after an episode; seizures and migraine attacks are mostly not temporally linked. The pathophysiological links between headaches (including migraine) and epilepsy are complex and have not yet been fully elucidated. Correct diagnoses and appropriate treatment of headaches in individuals with epilepsy is essential, as headaches can contribute substantially to disease burden. Here, we review the insights that have been made into the associations between headache and epilepsy over the past 5 years, including information on the pathophysiological mechanisms and genetic variants that link the two disorders. We also discuss the current best practice for the management of headaches co-occurring with epilepsy and highlight future challenges for this area of research.Paroxysmal Cerebral Disorder

Funnel-freezing versus heat-stabilization for the visualization of metabolites by mass spectrometry imaging in a mouse stroke model

Functional Genomics of Muscle, Nerve and Brain Disorder

EEG-based visual deviance detection in freely behaving mice

The mouse is widely used as an experimental model to study visual processing. To probe how the visual system detects changes in the environment, functional paradigms in freely behaving mice are strongly needed. We developed and validated the first EEG-based method to investigate visual deviance detection in freely behaving mice. Mice with EEG implants were exposed to a visual deviant detection paradigm that involved changes in light intensity as standard and deviant stimuli. By subtracting the standard from the deviant evoked waveform, deviant detection was evident as bi-phasic negativity (starting around 70 ms) in the difference waveform. Additionally, deviance-associated evoked (beta/gamma) and induced (gamma) oscillatory responses were found. We showed that the results were stimulus-independent by applying a "flip-flop " design and the results showed good repeatability in an independent measurement. Together, we put forward a validated, easy-to-use paradigm to measure visual deviance processing in freely behaving mice.Functional Genomics of Muscle, Nerve and Brain Disorder

Impaired theta-gamma coupling indicates inhibitory dysfunction and seizure risk in a Dravet syndrome mouse model

Dravet syndrome (DS) is an epileptic encephalopathy that still lacks biomarkers for epileptogenesis and its treatment. Dysfunction of Na(V)1.1 sodium channels, which are chiefly expressed in inhibitory interneurons, explains the epileptic phenotype. Understanding the network effects of these cellular deficits may help predict epileptogenesis. Here, we studied theta-gamma coupling as a potential marker for altered inhibitory functioning and epileptogenesis in a DS mouse model. We found that cortical theta-gamma coupling was reduced in both male and female juvenile DS mice and persisted only if spontaneous seizures occurred. theta-gamma Coupling was partly restored by cannabidiol (CBD). Locally disrupting Na(V)1.1 expression in the hippocampus or cortex yielded early attenuation of theta-gamma coupling, which in the hippocampus associated with fast ripples, and which was replicated in a computational model when voltage-gated sodium currents were impaired in basket cells (BCs). Our results indicate attenuated theta-gamma coupling as a promising early indicator of inhibitory dysfunction and seizure risk in DS.Functional Genomics of Muscle, Nerve and Brain Disorder

Current understanding of cortical structure and function in migraine

Objective To review and discuss the literature on the role of cortical structure and function in migraine. Discussion Structural and functional findings suggest that changes in cortical morphology and function contribute to migraine susceptibility by modulating dynamic interactions across cortical and subcortical networks. The involvement of the cortex in migraine is well established for the aura phase with the underlying phenomenon of cortical spreading depolarization, while increasing evidence suggests an important role for the cortex in perception of head pain and associated sensations. As part of trigeminovascular pain and sensory processing networks, cortical dysfunction is likely to also affect initiation of attacks. Conclusion Morphological and functional changes identified across cortical regions are likely to contribute to initiation, cyclic recurrence and chronification of migraine. Future studies are needed to address underlying mechanisms, including interactions between cortical and subcortical regions and effects of internal (e.g. genetics, gender) and external (e.g. sensory inputs, stress) modifying factors, as well as possible clinical and therapeutic implications.Paroxysmal Cerebral Disorder