Homeostatic plasticity in neural networks – stability drives functionality
Neural networks experience changes in their activity upon both physiological and pathological stimuli. To maintain a functional network state that enables flexible behavior, synaptic transmission and neuronal firing rates are interconnected through cell-autonomous negative feedback mechanisms. This is the concept of homeostatic synaptic plasticity, which is primarily investigated in our lab. Previous studies revealed the biological relevance of homeostatic plasticity in promoting experience-dependent plasticity as a prerequisite for flexible behavior. Therefore, pathology-driven changes in the ability for homeostatic plasticity expression might represent a hallmark for the development of clinical symptoms under various conditions, such as Alzheimer’s disease, traumatic CNS/PNS injury and neuroinflammation.
By investigating homeostatic synaptic plasticity in translational research approaches, we aim at providing insights in basic mechanisms that maintain functionality of the CNS and elucidate the role of maladaptive plasticity in disease pathogenesis. Specifically, the following points will be addressed:
- The traumatic loss of input to neural circuits in the central nervous system is frequently seen in clinical practice. Through pathway-specific lesions in tissue culture models – entorhino-hippocampal slice cultures – of laminated neural networks, we study molecular signaling pathways of lesion-induced plasticity and network reorganization. These findings will help to identify therapeutic targets that improve post-lesion network reorganization.
- Sensory deprivation is a major trigger for homeostatic synaptic plasticity that drives neural network reorganization. In humans, age-dependent hearing decline is frequently observed. Although considerable network changes can be assumed, the synaptic effects on neocortical circuits in the human brain remain widely unknown. In a cross-disciplinary approach, we will elucidate how progressive hearing loss might interfere with cortical information processing across species, including humans.
- The morphological complexity of neurons requires homeostatic plasticity expression at long distances from the soma, since it depends on de novo protein synthesis. Therefore, local protein synthesis in neurites has been established as a crucial prerequisite for synaptic plasticity. In our lab, we are studying the local regulation of local protein synthesis by retinoids, which regulate synaptic strength and promote ultrastructural reorganizations of synapses. Since retinoid metabolism represents a potential therapeutic target, the clinical potential of these signaling pathways will be evaluated.
In conclusion, this research focus will elucidate the driving or maintaining mechanisms of pathologies of the nervous system and thereby aims at enabling restorative strategies for regaining homeostasis in neural networks.
Synaptic plasticity in the human brain – personalized brain research
One of the most impressive features of our central nervous system is its ability for structural, functional and molecular adaptations to suitable stimuli, which is summarized under the term ‘synaptic plasticity’. The expression of synaptic plasticity is relevant for basic daily functions, such as temporal and spatial orientation, learning and memory consolidation but also the implementation of complex behavior. Although this topic has been extensively investigated over the last decades, little is known about synaptic transmission and plasticity in the human brain.
Within this research focus we implemented a translational and interdisciplinary strategy to assess synaptic transmission and plasticity in the human neocortex on the level of individual neurons. In an interdisciplinary team of neurosurgeons and neuroanatomists, human neocortical tissue – explanted during tumor or epilepsy surgery for medical or procedural indication – is used to investigate single-cell features in the human brain. Together with multi-dimensional data integration (single-cell and clinical data), our results will identify influential factors on neurotransmission in the human brain. Specifically, the following points will be addressed:
- Influential factors on neurotransmission and intrinsic cellular properties in the human neocortex: Which patient characteristics define structural, functional and molecular features in the adult human neocortex? Following this approach, we will investigate potential therapeutic strategies that efficiently target synaptic transmission and plasticity in the human brain.
- Structure/Function-Interrelation: Human neurons have a high morphological complexity. Using 1:1 correlations of electrophysiological properties and the post hoc analysis of neuronal and synaptic morphologies, we will provide insights in the interdependency of neuronal structure and function. Through open data reporting, we will thereby provide the basis for in silico models of the human brain that allow for predictions of adaptive processes in the human brain.
- (Reverse) Translation: By employing the parallel use of established research models and human neocortical tissues, we aim at evaluating the biological relevance of previous finding in the human CNS. Particularly, we will test if influential factors on synaptic plasticity that we identified in the human brain are evident in vivo and in cell culture models as well. With this approach, we will develop research strategies to gain insights in the human neocortex, which finally aims at refining, reducing and replacing (3R) animal experiments.
In conclusion, this research focus will elucidate the neuroanatomical basis for functional features in the human central nervous system
Neuroimmunology and Neuroinfection
The central nervous system consists of diverse cell types, such as neurons, microglia, astrocytes and oligodendrocytes that continuously interact with each other. These collaborative interactions are a prerequisite for normal brain function. If these interactions are disturbed by endogenous (e.g., metabolic changes) or exogenous (e.g., infection and trauma) stimuli, pathological network states might lead to the development of neurological or psychiatric symptoms.
Within this research focus, we will address the role of neuro-immune interactions in health and disease. Particularly, we focus on the role of microglia – the resident immune cells of the brain – in shaping the structural and functional features of other cell types in neural circuits. Microglia can interact with other immune cells entering the brain, such as lymphocytes and NK cells, which might affect microglial states. Depending on these states, microglia interact with neurons through soluble factors and/or direct physical contact sites during both resting state or inflammatory conditions. Here, neurotrophic viral infections represent a major inflammatory stimulus, which severely affects neural circuits. In this context, we will assess how both endogenous and exogenous stimuli regulate neuro-immune interactions. In an interdisciplinary effort with our collaborating partners the following points will be addressed:
- Microglia/Neuron-interactions determine the ability of neural networks to express synaptic plasticity. Although the microglial impact on synaptic transmission has been well characterized, their role in regulating cellular excitability remains widely unknown. Here, we will assess how the metabolic and inflammatory tissue state affects direct and/or indirect microglia/neuron-interactions and subsequently controls neuronal excitability and gene expression. We aim at revealing the therapeutic potential of microglia depletion on inflammation-related network defects. On the other hand, the effects of microglia depletion on the flexibility of neural networks under physiological conditions will be tested.
- Various viruses, such as HSV-1 and SARS-CoV-2, target the central nervous system and cause acute or persisting infections. Here, we investigate the neuronal effects of viral infection and persistence. Our experimental strategies will test for infection-induced plasticity defects, which presumably cause maladaptive changes in neural circuits. By unraveling the underlying mechanisms, we aim at establishing novel perspectives for therapeutic approaches in virus-related neural deficits.
- Tissue cultures are suitable in vitro models of the central nervous system that allow for experimental strategies covering long time scales. Therefore, we intend to study long-lasting effects of persistent infections, e.g. in the context of therapy-induced viral silencing. Moreover, environmental and intrinsic determinants of viral reactivation and its impact on the integrity of neural networks will be studied with respect to cellular interactions in tissue of the central nervous system.
In summary, we will elucidate the influence of acute or persisting viral infections and other inflammatory stimuli on neuronal transmission and plasticity, which ultimately aims at the implementation of novel therapeutic strategies in the treatment of inflammation-related network dysfunction, e.g. in neurodegeneration and epilepsy.
The Brain-Body-Interface: The Heart/Brain-Axis
Cardiovascular diseases are among the most common reasons for death and disabilities worldwide. Dysfunction of the cardiovascular system affects other organs and is therefore accompanied by various comorbidities. To fuel the brains metabolism, a continuous high blood supply is needed to enable normal brain function. Due to its specific anatomy, the blood/brain-barrier is crucially involved in regulating structural, functional and molecular features of neural circuits. In this research focus, we will elaborate an interdisciplinary clinical-to-basic-science approach, which aims at revealing the interrelation between the cardiovascular system and the brain’s neural circuits. The following points will be addressed:
- Heart insufficiency and neurovascular coupling: Heart insufficiency is a frequently observed clinical condition, which has been studied in various research models. Here, we will elucidate the heart insufficiency related remodeling of integral CNS parts. In addition to the assessment of ultrastructural features of the blood/brain-barrier, functional, structural and molecular changes in synaptic transmission and plasticity will be investigated. We here aim at identifying factors and signaling pathways that determine and mediate secondary CNS alterations during heart insufficiency.
- In vitro models for neuro-vascular interactions: In vitro models of neural tissue provide the opportunity for in depth assessments of neural transmission and plasticity. To improve the biological relevance of currently available in vitro models we intend to generate CNS tissue culture models, which form (1) a blood/brain-barrier and (2) allow for applying mechanical stimuli to mimic pulsatile perfusion of neural tissues. We are confident that these newly generated tools will enable large-scale in vitro screenings in neuro/vascular interactions.
- The influence of cardiovascular risk factors and diseases on human neocortical networks: Human neocortical resections are clinically required during tumor or epilepsy surgery in the brain. In these tissues, (sub)cellular features of individual neurons and other cells can be assessed. Using multimodal approaches of data integration, we will match clinical data focusing on cardiovascular risk factors, diseases and medication with neural (sub)cellular features in human subjects. Thus, the translational capacity of in vitro and other research models will be assessed by unraveling secondary alterations in neural circuits from cardiovascular disease patients.
In conclusion, the ultimate goal of this research focus is the identification of molecular heart/brain-interactions, which might mediate cognitive symptoms in cardiovascular diseases and therefore provide the biological basis for therapeutic approaches at the blood/brain-interface.
PNS/CNS-Communication – from peripheral nerve regeneration towards understanding neuropathic pain
Since many years, studies on peripheral nerve repair and regeneration represent one research focus at our institute. Peripheral nerve lesions result in impairment of quality of life with differing severity for patients, many suffer from life-long disabilities. Surgical techniques and therapeutic options have increased over the last decades, but achievable functional outcome of peripheral nerve repair is not always meeting patients expectations. In many years of research in peripheral nerve regeneration using animal models and in vitro systems, we contributed to the clinical approval of chitosan-based nerve guides and have worked on further improvement of these guides towards a replacement strategy for autologous nerve grafting. In our work, we combine material science approaches with tissue engineering attempts. The latter was originally based on genetic engineering of peripheral glia cells, Schwann cells, but has nowadays evolved to work with Schwann cells derived from human induced pluripotent stem cells (iPSCs). Such cells may represent a valuable source for upgrading otherwise cell-free or even hollow nerve guides able to support nerve repair also across large defect distances. Since the healthy and the injured peripheral nervous system communicate with the central nervous system, synaptic plasticity at the spinal cord level is an evolving field of research. Indeed, even if functionality in terms of motor function and touch sensation has been recovered to a considerable degree with successful peripheral nerve repair, patients may secondarily develop neuropathic pain. Furthermore full limb replantation approaches after amputation events, will need to consider not only conditions of the peripheral nerves inside the limb but also how the communication between the limb and the central nervous system can be recovered in a way that reduces motor impairment and limits the risk to develop neuropathic pain.
In this research focus we address questions related to peripheral nerve development and regeneration under different systemic conditions, and will enlarge our previous focus toward better understanding of the neuroanatomical basis of local pain perception and the development of neuropathic pain.
Specifically, the following points will be addressed:
- We study the “gut-peripheral nerve axis” using germ-free and gnotobiotic mice in healthy conditions and after peripheral nerve lesion. The gut microbiome and the metabolites derived from it are more and more understood to contribute to healthy or pathological conditions also of the nervous system via the “gut-brain-axis”. We perform functional, histological and molecular studies on various structures of the peripheral and the central nervous system. In this project we collaborate with the Gnotobiotic Group at the MHH-Institute for Laboratory Animal Science (Dr. Marijana Basic, Dr. Silvia Bolsega) and colleagues from Italy (Prof. Giulia Ronchi, University of Turin, Prof. Matilde Cescon, University of Padua).
- The conditions of peripheral nerves in an amputated limb of adult pigs are studied with functional, histological and molecular techniques. The aim of the project is to optimally condition peripheral nerves in amputated limbs under ex-vivo perfusion conditions for successful limb replantation (https://www.mhh.de/presse-news/hoffnung-fuer-schwerverletzte-nach-amputation-von-gliedmassen)https://www.mhh.de/presse-news/hoffnung-fuer-schwerverletzte-nach-amputation-von-gliedmassen. The investigations are carried out in close collaboration with PD Dr. Bettina Wiegmann from the MHH-Department for Cardiothoracic, Transplantation and Vascular Surgery. The work is funded by a contract of the German Armed Forces (2022-2024).
- We have recently established a protocol for deriving human Schwann cells from human iPSCs and plan to characterize them further with regard to their functional ability in vitro and in vivo towards a patient-specific application in peripheral nerve repair.
Advanced tissue culture models
Cell culture techniques and biological engineering of various organ tissues are essential components for sustainable progress in neuroscience. However, the biological relevance in translational research approaches – and thereby their potential to replace animal experiments – remains widely unknown. Using our technical core expertise, we aim at advancing the development of these resources in neuroscience research:
- Humanizing organotypic tissue cultures: Murine tissue cultures that consist of various interacting cell types, are suitable tools for translational research. Notably, similar human tissue cultures models do not exist although a variety of human CNS cell types can be differentiated from induced pluripotent stem cells (iPSCs). We intend to establish structured human tissue cultures that enable the investigation of single cell synaptic connectivity and thereby provide novel insights in patient-oriented personalized synaptic transmission.
- Self-organizing models: Self-organizing 3D-models of the central nervous system (“organoids”) have recently gained considerable interest. Based on their differentiation, complex interacting systems can be generated that mimic different brain regions (“assembloids”). We have the goal to build personalized organoids and assembloids to address specific questions in the pathophysiology of neuropsychiatric disorders.
- Ex vivo inter-organ communication: The performance of our brain relies on internal body conditions, which are regulated by a complex interplay of different organs. To improve the biological relevance of neuroscientific research approaches, it is a major challenge to model inter-organ communication ex vivo. Together with our collaborating partners, we aim at contributing to advances in this field by implementing models for gut-brain, liver-brain and heart-brain axes.
Addressing these points, our vision is to improve the translational relevance of research models in neuroscience. Simultaneously, our technical resources will help us to accelerate 3R (reduce, replace, refine) concepts in animal research.