"Chronic pain is a serious medical problem and a socioeconomic burden that severely reduces quality of life worldwide. Neural plasticity constitutes a key element of pathological pain, which can come about over various anatomical and temporal scales. Apart from functional plasticity, tremendous potential exists for changes in the structure, connectivity and representation of pain, which can account for long-term persistence of pathological pain. This grant aims to study structural plasticity processes in the somatosensory nociceptive system, test their functional significance and address underlying molecular and cellular mechanisms, a topic not adequately studied so far owing to technical constraints.On the background of our established repertoire of mouse models for chronic pain and transgenic/viral gene delivery/RNA interference approaches for molecular manipulations, two key complementary methodologies will be employed to visualize and modify structural plasticity, namely non-invasive multiphoton in vivo imaging and optogenetic reversible modulation of neuronal activity in vivo, respectively. We will dynamically study sprouting, regeneration and rewiring of sensory nerves over the progression of neuropathic and tumor-evoked pain and image invasion of tumor cells into nerves. Moreover, we will directly image remodelling of synaptic contacts in brain regions processing pain. Importantly, the impact of structural changes on function will be studied by measuring pain behavior concurrently in the same animals and via targeted molecular interventions. Secondly, optogenetic activation and reversible silencing of nociceptors or specific areas in the brain in vivo will be used to directly measure peripheral and central contributions to plasticity and chronic pain behavior.These innovative, multidisciplinary approaches promise to deliver important novel insights into mechanisms driving chronic pain and provide a basis for new ways of reversing pathological processes."