Studying neuronal circuits during seizure generation

Epilepsy is a common disorder affecting 50 million people globally and is caused by an imbalance of synchronous activity in the brain, characterized by recurrent convulsions or seizures and hyperactive brain activity. Currently, there are several treatments for epileptic seizures and also drugs to abort an active seizure, but as the exact neurophysiological mechanisms underlying epilepsy are still not fully understood, only a fraction of epilepsy patients can be treated and early prediction or prevention of seizures is still technically challenging. The aim of my PhD project is to characterize and understand the dynamical behavior of brain circuits during the epileptogenesis by combining the state of the art brain activity imaging techniques with applied mathematical tools, in a small vertebrate, the zebrafish. My proposed project will consist of an experimental part where large sets of neural data will be collected with high spatial and temporal resolution from the brains of living zebrafish that displays epilepsy. Later I will develop and use applied mathematical tools for analyzing complex neural data and to build a mathematical model of brain networks undergoing epileptogenesis. The final goal my project is to use all the above information from neural data and theoretical modeling to understand neural mechanisms underlying epileptogenesis, which will allow me to predict epileptic seizures and silence them before they occur in the brain. I expect that the results of my PhD project will inspire novel approaches in diagnosis and treatment of epilepsy in humans. We hope that my PhD project will provide a high-throughput environment to test and identify novel drugs or technologies in collaboration with industrial partners.status: publishe

Past, present and future of zebrafish in epilepsy research

Animal models contribute greatly to our understanding of brain development and function as well as its dysfunction in neurological diseases. Epilepsy research is a very good example of how animal models can provide us with a mechanistic understanding of the genes, molecules, and pathophysiological processes involved in disease. Over the course of the last two decades, zebrafish came in as a new player in epilepsy research, with an expanding number of laboratories using this animal to understand epilepsy and to discover new strategies for preventing seizures. Yet, zebrafish as a model offers a lot more for epilepsy research. In this viewpoint, we aim to highlight some key contributions of zebrafish to epilepsy research, and we want to emphasize the great untapped potential of this animal model for expanding these contributions. We hope that our suggestions will trigger further discussions between clinicians and researchers with a common goal to understand and cure epilepsy

Mating suppresses alarm response in zebrafish

Mating and flight from threats are innate behaviors which enhance species survival. Stimuli to these behaviors often are contemporaneous and conflicting. How such conflicts are resolved, and where in the brain such decisions are made, are both poorly understood. For teleosts, olfactory stimuli are key elements of mating and threat responses. For example, zebrafish manifest a stereotypical escape response when exposed to alarm substance released from injured conspecific skin (“skin extract”). We find that when mating, fish ignore this threatening stimulus. Water conditioned by the mating fish (“mating water”) suffices to suppress much of the alarm response behavior. By 2-photon imaging of calcium transients, we mapped the regions of the brain responding to skin extract and to mating water. In the telencephalon, we found regions where the responses overlap, and also one region (medial Dp), to be predominantly activated by skin extract, and another, Vs, to be predominantly activated by mating water. When mating water and skin extract were applied simultaneously, the alarm-specific response was suppressed, while the mating water-specific response was retained, corresponding to the dominance of mating over flight behavior. The choice made, for reproduction over escape, is opposite to that of mammals, presumably reflecting how the balance affects species survival

Mating suppresses alarm response in zebrafish

Mating and flight from threats are innate behaviors which enhance species survival. Stimuli to these behaviors often are contemporaneous and conflicting. How such conflicts are resolved, and where in the brain such decisions are made, both are poorly understood. For teleosts, olfactory stimuli are key elements of mating and threat responses. For example, zebrafish manifest a stereotypical escape response when exposed to “alarm substance” released from injured conspecific skin. We found that mating zebrafish ignore alarm substance and that a significant part of this suppression is mimicked by water primed by the mating pair. Two-photon imaging of calcium transients in single telencephalic neurons revealed a specific telencephalic region, Dp, activated by alarm substance and another, Vs, is activated by mating water (in addition to overlapping responses in Dm and Dl). When mating water and alarm substance are applied simultaneously, the alarm-specific response in Dp is suppressed while the mating water-specific telencephalic response is retained. Thus, when presented with competing olfactory stimuli, zebrafish enact the stereotypical behaviors of mating over those for alarm and response to threat, and this choice is matched by suppression of activation in the alarm-specific region of the telencephalon. The choice made, for reproduction over escape, is different from mammals, suggesting that it correlates with different a different balance of species survival advantages

Mating Suppresses Alarm Response in Zebrafish

Mating and flight from threats are innate behaviors that enhance species survival [1, 2]. Stimuli to these behaviors often are contemporaneous and conflicting [3, 4]. Both how such conflicts are resolved and where in the brain such decisions are made are poorly understood. For teleosts, olfactory stimuli are key elements of mating and threat responses [5-7]. For example, zebrafish manifest a stereotypical escape response when exposed to an alarm substance released from injured conspecific skin ("skin extract") [8, 9]. We find that when mating, fish ignore this threatening stimulus. Water conditioned by the mating fish ("mating water") suffices to suppress much of the alarm-response behavior. By 2-photon imaging of calcium transients [10], we mapped the regions of the brain responding to skin extract and to mating water. In the telencephalon, we found regions where the responses overlap, one region (medial Dp) to be predominantly activated by skin extract, and another, Vs, to be predominantly activated by mating water. When mating water and skin extract were applied simultaneously, the alarm-specific response was suppressed, while the mating-water-specific response was retained, corresponding to the dominance of mating over flight behavior. The choice made, for reproduction over escape, is opposite to that of mammals, presumably reflecting how the balance affects species survival.status: publishe

Motile-Cilia-Mediated Flow Improves Sensitivity and Temporal Resolution of Olfactory Computations

Motile cilia are actively beating hair-like structures that cover the surface of multiple epithelia. The flow that ciliary beating generates is utilized for diverse functions and depends on the spatial location and biophysical properties of cilia. Here we show that the motile cilia in the nose of aquatic vertebrates are spatially organized and stably beat with an asymmetric pattern, resulting in a robust and stereotypical flow around the nose. Our results demonstrate that these flow fields attract odors to the nose pit and facilitate detection of odors by the olfactory system in stagnant environments. Moreover, we show that ciliary beating quickly exchanges the content of the nose, thereby improving the temporal resolution of the olfactory system for detecting dynamic changes of odor plumes in turbulent environments. Altogether, our work unravels a central function of ciliary beating for generating flow fields that increase the sensitivity and the temporal resolution of olfactory computations in the vertebrate brain

Glia-neuron interactions underlie state transitions to generalized seizures

Brain activity and connectivity alter drastically during epileptic seizures. The brain networks shift from a balanced resting state to a hyperactive and hypersynchronous state. It is, however, less clear which mechanisms underlie the state transitions. By studying neural and glial activity in zebrafish models of epileptic seizures, we observe striking differences between these networks. During the preictal period, neurons display a small increase in synchronous activity only locally, while the gap-junction-coupled glial network was highly active and strongly synchronized across large distances. The transition from a preictal state to a generalized seizure leads to an abrupt increase in neural activity and connectivity, which is accompanied by a strong alteration in glia-neuron interactions and a massive increase in extracellular glutamate. Optogenetic activation of glia excites nearby neurons through the action of glutamate and gap junctions, emphasizing a potential role for glia-glia and glia-neuron connections in the generation of epileptic seizures

Glia-neuron interactions underlie state transitions to generalized seizures

Brain activity and connectivity alter drastically during epileptic seizures. The brain networks shift from a balanced resting state to a hyperactive and hypersynchronous state. It is, however, less clear which mechanisms underlie the state transitions. By studying neural and glial activity in zebrafish models of epileptic seizures, we observe striking differences between these networks. During the preictal period, neurons display a small increase in synchronous activity only locally, while the gap-junction-coupled glial network was highly active and strongly synchronized across large distances. The transition from a preictal state to a generalized seizure leads to an abrupt increase in neural activity and connectivity, which is accompanied by a strong alteration in glia-neuron interactions and a massive increase in extracellular glutamate. Optogenetic activation of glia excites nearby neurons through the action of glutamate and gap junctions, emphasizing a potential role for glia-glia and glia-neuron connections in the generation of epileptic seizures.status: publishe

Functional properties of habenular neurons are determined by developmental stage and sequential neurogenesis

The developing brain undergoes drastic alterations. Here, we investigated developmental changes in the habenula, a brain region that mediates behavioral flexibility during learning, social interactions, and aversive experiences. We showed that developing habenular circuits exhibit multiple alterations that lead to an increase in the structural and functional diversity of cell types, inputs, and functional modules. As the habenula develops, it sequentially transforms into a multisensory brain region that can process visual, olfactory, mechanosensory, and aversive stimuli. Moreover, we observed that the habenular neurons display spatiotemporally structured spontaneous activity that shows prominent alterations and refinement with age. These alterations in habenular activity are accompanied by sequential neurogenesis and the integration of distinct neural clusters across development. Last, we revealed that habenular neurons with distinct functional properties are born sequentially at distinct developmental time windows. Our results highlight a strong link between the functional properties of habenular neurons and their precise birthdate.status: publishe