Dopamine and the basal ganglia have been conserved over more than 500 million years of evolution. They are fundamental to animal and human behaviour. Parkinson’s disease (PD) is associated with loss of dopaminergic innervation to the basal ganglia. Over 6 million people suffer from the debilitating symptoms of PD that span disturbance of emotion, cognition and movement. There is a pressing need to understand the pathogenesis of these symptoms, but an integrated account of dopamine and basal ganglia function is lacking. This constitutes a significant roadblock to scientific and therapeutic advances. To overcome this roadblock, ReinforceBG poses the novel unconventional hypothesis that loss of dopamine in PD does not impair movement per se but leads to chronic negative reinforcement of neural population dynamics. Conversely, in the healthy state, transient dopamine signals may stabilize cortex–basal ganglia activity to facilitate reentry and refinement of cortical output. To address this hypothesis, ReinforceBG will combine invasive electrocorticography and local field potential recordings with closed-loop deep brain stimulation in PD patients. Aim 1 will investigate how basal ganglia pathways coordinate neuromuscular adaptation. Aim 2 will shed light on basal ganglia reinforcement in multiple behavioural domains, including movement, gait, speech, and spatial navigation in virtual reality. Aim 3 will develop a neuroprosthetic brain-computer interface that aims to modulate basal ganglia reinforcement. ReinforceBG deviates from outdated models on pro- vs. antikinetic “Go” and “NoGo” pathways and promises a holistic-reinforcement centred view of basal ganglia function. It will leverage the unprecedented spatiotemporal precision of neuromodulation for the development of an innovative brain circuit intervention that modulates neural reinforcement in real time. This opens new horizons for the interdisciplinary treatment of brain disorders affecting the dopaminergic system.

Five out of ten diseases leading to long term-disability are related to the brain, including stroke, depression or dementia. Despite tremendous progress in neurotechnology, there is still no effective treatment option available for many brain-related disorders. A very promising approach to treat brain disorders uses transcranial electric or magnetic stimulation (TES/TMS) to directly influence brain activity related to specific symptoms. However, these methods are limited in their spatial resolution, specificity and ability to reach deep brain areas. The aim of the proposed project is to develop a technical and experimental proof-of-concept for a new non-invasive tool that allows for millimeter- and millisecond-precise modulation of neural activity in superficial and deep areas of the human brain. Capitalizing on temporal interference effects, the device will apply high carrier frequency magnetic fields through a pair of coils. By modulating their relative phase, the combined fields will induce a locally amplitude-modulated electric field in the brain. As neural tissue is insensitive to unmodulated high-frequency fields (>1kHz), but responds to low-frequency amplitude-modulated fields, only brain regions will be stimulated where the combined field is amplitude-modulated. Building on the resulting versatility of stimulation frequencies and waveforms, we aim at providing proof for cell-type specificity of such temporal interference magnetic stimulation (TIMS). Moreover, we aim at providing proof for the feasibility of targeting neural activity at millisecond-to-millisecond precision. Availability of such device offering high spatial resolution, depth selectivity, steerability, as well as closed-loop-compatibility and cell-type specificity would mark a major break-through for clinical neuroscience. Together with two partners from industry and a partner for technology transfer, we strive for fast translation of expected research results into innovative products.

Macrophage differentiation programs are critical for the outcome of immunity against infection, chronic inflammatory diseases and cancer. How diverse inflammatory signals are translated to macrophage programs in the large range of human pathologies is largely unexplored. In the last years we focused on macrophage differentiation in granulomatous diseases. These affect millions worldwide, including young adults and children and tend to run a chronic course, with a high socioeconomic burden. Their common hallmark is the formation of granulomas, macrophage-driven structures of organized inflammation that replace healthy tissue. We revealed that macrophage precursors in granulomas experience a replication block and trigger the DNA Damage Response (DDR), a fundamental cellular process activated in response to genotoxic stress. This leads to the formation of multinucleated macrophages with tissue-remodelling signatures (Herrtwich, Cell 2016). Our work unravelled an intriguing link between genotoxic stress and granuloma-specific macrophage programs. The molecular pathways regulating DDR-driven macrophage differentiation and their role in chronic inflammatory pathologies remain however a black box. We hypothesize that the DDR promotes macrophage reprogramming to inflammation-maintaining modules. Such programs operate in granulomatous diseases and in chronic arthritis. Using state-of-the art genetic models, human tissues and an array of techniques crossing the fields of immunology, cell biology and cancer biology, our goal is to unravel the macrophage-specific response to genotoxic stress as an essential regulator of chronic inflammation-induced pathologies. The anticipated results will provide the scientific community with new knowledge on the role of genotoxic stress in immune dysregulation and will carry tremendous implications for the therapeutic targeting of macrophages in the context of chronic inflammatory diseases and cancer.

Environmental and internal stimuli are constantly sensed by the body’s two large sensory units, the nervous system and the immune system. Integration of these sensory signals and translation into effector responses are essential for maintaining body homeostasis. While some of the intrinsic pathways of the immune or nervous system have been investigated, how the two sensory interfaces coordinate their responses remains elusive. We have recently investigated neuro-immune interaction at the mucosa of the intestine, which is densely innervated by the enteric nervous system (ENS). Our research has exposed a previously unrecognized pathway used by enteric neurons to shape type 2 immunity at mucosal barriers. Cholinergic enteric neurons produce the neuropeptide Neuromedin U (NMU) to elicit potent activation of type 2 innate lymphoid cells (ILC2s) via Neuromedin U receptor 1, selectively expressed by ILC2s. Interestingly, NMU stimulated protective immunity against the parasite Nippostrongylus brasiliensis but also triggered allergic lung inflammation. Therefore, the NMU-NMUR1 axis provides an excellent opportunity to study how neurons and immune cells interact to regulate immune responses and maintain body homeostasis. We propose to generate and use elegant genetic tools, which will allow us to systematically investigate the consequences of neuro-immune crosstalk at mucosal surfaces in various disease models. These tools will enable us to selectively measure and interfere with neuronal and ILC2 gene expression and function, thereby leading to an unprecedented understanding of how the components of neuro-immune crosstalk contribute to parasite immunity or allergic disease development. Furthermore, we will progress into translational aspects of NMU-regulated immune activation for human immunology. Therefore, our research has the potential to develop basic concepts of mucosal immune regulation and such discoveries could also be harnessed for therapeutic intervention.