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.