How seizures emerge from the abnormal dynamics of neural networks within the epileptogenic tissue remains an enigma. Are seizures random events, or do detectable changes in brain dynamics precede them? Are mechanisms of seizure emergence identical at the onset and later stages of epilepsy? Is the risk of seizure occurrence stable, or does it change over time? A myriad of questions about seizure genesis remains to be answered to understand the core principles governing seizure genesis. The last decade has brought unprecedented insights into the complex nature of seizure emergence. It is now believed that seizure onset represents the product of the interactions between the process of a transition to seizure, long-term fluctuations in seizure susceptibility, epileptogenesis, and disease progression. During the lecture, we will review the latest observations about mechanisms of ictogenesis operating at multiple temporal scales. We will show how the latest observations contribute to the formation of a comprehensive theory of seizure genesis, and challenge the traditional perspectives on ictogenesis. Finally, we will discuss how combining conventional approaches with computational modeling, modern techniques of in vivo imaging, and genetic manipulation open prospects for exploration of yet hidden mechanisms of seizure genesis.

New memories are initially labile and have to be consolidated into stable long-term representations. Current theories assume that this is supported by a shift in the neural substrate that supports the memory, away from rapidly plastic hippocampal networks towards more stable representations in the neocortex. Rehearsal, i.e. repeated activation of the neural circuits that store a memory, is thought to crucially contribute to the formation of neocortical long-term memory representations. This may either be achieved by repeated study during wakefulness or by a covert reactivation of memory traces during offline periods, such as quiet rest or sleep. My research investigates memory consolidation in the human brain with multivariate decoding of neural processing and non-invasive in-vivo imaging of microstructural plasticity. Using pattern classification on recordings of electrical brain activity, I show that we spontaneously reprocess memories during offline periods in both sleep and wakefulness, and that this reactivation benefits memory retention. In related work, we demonstrate that active rehearsal of learning material during wakefulness can facilitate rapid systems consolidation, leading to an immediate formation of lasting memory engrams in the neocortex. These representations satisfy general mnemonic criteria and cannot only be imaged with fMRI while memories are actively processed but can also be observed with diffusion-weighted imaging when the traces lie dormant. Importantly, sleep seems to hold a crucial role in stabilizing the changes in the contribution of memory systems initiated by rehearsal during wakefulness, indicating that online and offline reactivation might jointly contribute to forming long-term memories. Characterizing the covert processes that decide whether, and in which ways, our brains store new information is crucial to our understanding of memory formation. Directly imaging consolidation thus opens great opportunities for memory research.

Using a combination of in vivo imaging of neuronal circuit functional and structural dynamics, we have investigated the mechanisms by which patterned neural activity and sensory experience alter connectivity in the developing brain. We have identified, in addition to the long-hypothesized Hebbian structural plasticity mechanisms, a kind of plasticity induced by the absence of correlated firing that we dubbed “Stentian plasticity”. In the talk I will discuss the phenomenology and some mechanistic insights regarding Stentian mechanisms in brain development. Further, I will show how glia may have a key role in circuit remodeling during development. These studies have led us to an appreciation of the importance of neuron-glia interactions in early development and the ability of patterned activity to guide circuit wiring.

The vagus nerve contains a diversity of sensory neurons that detect peripheral stimuli such as blood pressure changes at the aortic arch, lung expansion during breathing, meal-induced stomach distension, and chemotherapeutics that induce nausea. Underlying vagal sensory mechanisms are largely unresolved at a molecular level, presenting tremendously important problems in sensory biology. We charted vagal sensory neurons by single cell RNA sequencing, identifying novel cell surface receptors and classifying a staggering diversity of sensory neuron types. We then generated a collection of ires-Cre knock-in mice to target each neuron type, and adapted genetic tools for Cre-based anatomical mapping, in vivo imaging, targeted ablation, and optogenetic control of vagal neuron activity. We found different sensory neuron types that innervate the lung and exert powerful effects on breathing, others that monitor and control the digestive system, and yet others that innervate that innervate the larynx and protect the airways. Together with Ardem Patapoutian, we also identified a critical role for Piezo mechanoreceptors in the sensation of airway stretch, which underlies a classical respiratory reflex termed the Hering-Breuer inspiratory reflex, as well as in the neuronal sensation of blood pressure and the baroreceptor reflex.