A fundamental challenge for the brain is to extract relevant information from an ever changing external world. Natural odours are in a constant state of flux. Turbulent airflow shapes odours into spatiotemporally complex plumes that carry information about the olfactory scenery and provide vital clues about the location of, for example, food sources or predators. How the mammalian olfactory system extracts information about space from temporal odour dynamics, however, is still not well understood. Recent methodological advances in presenting dynamic odour stimuli, neural activity recordings and machine-vision algorithms now offer the exciting opportunity to address this fundamental question. Using a multidisciplinary approach, this project will uncover how temporally complex odour information is processed across the olfactory system and how odour dynamics give rise to behaviour. We will first investigate how temporally complex odour information is represented across key structures of the mammalian olfactory system using in vivo physiology. This will provide important groundwork for the next step, elucidating the cellular and circuit mechanisms underlying the encoding of dynamic odours in the early olfactory system. Finally, we will study which features of temporally complex odours are used for navigation behaviour by simultaneously recording and correlating the animal’s respiration sampling strategy, the dynamic odour profile encountered by the animal and neural activity from early and higher order olfactory areas in freely moving mice. By combining cellular and systems neuroscience with behavioural investigations, we aim to directly assess how mammals use olfaction to extract information about space from time. I strongly believe that this innovative research programme will generate novel and highly generalizable insights into how naturalistic sensory information is processed and that it will uncover neural mechanisms that give rise to our perception of the world.

As photo-activatable drugs (PDs) can be precisely controlled in space and time, caged and switchable photoactivatable drugs (CPDs, SPDs) are rapidly emerging as potential therapeutics for varied forms of cancer, vision loss, diabetes, or pain disorders. Despite their potential, PDs have not been exploited for epilepsy, a common, often debilitating neurological disorder. As 30% of epilepsies are medically intractable, and antiepileptic drugs often cause multi-organ side effects, PDs could break new therapeutic ground. PDs can be applied on demand, and locally activated/inactivated in single or multiple epileptic brain areas in a targeted fashion. This minimizes systemic side effects, and allows the application of potent drugs from other fields yet unthinkable in routine epileptology (e.g. general anesthetics). Importantly, being small molecules, different PDs can be combined or easily exchanged, and do not require protein expression. Using current and new PDs, we aim to control epileptic networks in vivo in a realistic epilepsy mouse model, and resected human brain tissue from patients with intractable epilepsy. Aim 1 will quantify antiepileptic potency of a range of PDs in human tissue using field potential and patch-clamp recordings, and cellular scale 2-photon imaging. In aim 2, PDs will be evaluated in vivo using wireless video-EEG, imaging and light-fiber-targeted drug photoactivation in chronically epileptic mice. Further, by use of caged immunomodulators, we will explore disease-modifying capacity of targeted PD photoactivation in epileptogenesis and chronic epilepsy. PhotoTherEpi will establish targeted photopharmacology as a versatile, and powerful new approach to control focal epilepsy, which could jumpstart a new branch of translational epilepsy research. The approach could obviate the need for resective surgery in many cases, and be used in multi-focal epilepsy. Importantly, it may be clinically tested in the foreseeable future.

The Interleukin (IL)-1 family of pro-inflammatory cytokines are among the most potent pyrogens, and their excessive production can cause several auto-inflammatory syndromes. Additionally, overabundance of IL-1 cytokines can trigger, or contribute to a range of inflammatory and metabolic disorders. The expression of the key members of the IL-1 family, such as IL-1β and IL-18, is regulated at both the transcriptional and post-transcriptional levels. IL-1β and IL-18, are produced as inactive precursors, which require activation of caspase-1 by the inflammasomes for their maturation and release by from cells, occasionally at the cost of caspase-1 mediated-cell death. We have recently discovered that inflammasomes are released into the extracellular space where they remain active after the demise of activated cells, and that extracellular inflammasomes can amplify inflammation by sustaining extracellular production of IL-1β. However, the sources of extracellular pro-IL-1β are not known. Recent advances in platelet proteomics have revealed that these non-nucleated cells are able to produce their own cytokines, including soluble IL-1β and membrane-bound IL-1α, and are able to significantly magnify IL-1 production by immune cells. As platelets outnumber leukocytes by several folds, they could potentially be the major source of extracellular inflammasomes in the body, or be a major producer of IL-1 precursors that are cleaved by extracellular inflammasomes released from dying immune cells. In this proposal, we will investigate the mechanism(s) by which platelets produce IL-1, and the specific contribution of platelet-derived IL-1 to sterile inflammation, or host resistance to bacterial and viral infection. We believe that a deeper understanding of platelet-IL-1 and their interaction with immune cells during sterile inflammation, or infection might help to uncover new targets for immune-therapies.