Science is not only a disciple of reason but, also, one of romance and passion.
Our brain operates with exquisite brilliance and yet alluring mystery. Behind the main scenes, of functional hubs wiring together, numerous and meticulously organized microcircuitries talk through highly non-random synaptic connections. In sheer complexity, rather than a static and precise skeleton of connectivity, a fascinating dynamic nature of neural circuits is unveiled in response to the organism needs or to an injury. Our group delves into the secrets of brain circuits plasticity in the aftermath of an insult. We aim at advancing our understanding of the changing brain and exploit the underlying mechanisms towards brain regeneration.
Dynamic processes can alter the architecture of adult neural circuits and contribute to sculpt their activity: neurogenesis, new neurons are born at confined islets of neural stem cells and integrate into mature circuits; myelination, myelin remodels or forms de novo altering axonal conduction; and rewiring, axonal branches, boutons and spines grow or retract changing synaptic connectivity. These processes flourish in the context of an insult, presumably to counteract the dysfunction and reach a new status quo. How is such plasticity unfolded? What is its scale? Can we harness it to foster regeneration?
We seek to understand the biological principles of the brain’s internal response to a neurological dysfunction. We are fascinated by such endogenous toolbox, its circuit/cellular/molecular underpins and potential for regenerative approaches.
Towards our overarching goal, we investigate the magnitude of injury-induced plasticity. Dysfunction in one brain area can lead to partial functional recovery or functional compensation relying on the spared areas. Such extraordinary response, and transition from a local glitch to a global balance shows how imperative it is to study such a sophisticated structure as the mammalian brain as a whole, since circuits act and react ultimately en masse, not in isolation. Taking this integrative system-wide approach, we explore the structural and molecular logic behind induced plasticity, with predicted value for brain repair.
The golden era of brain connectomics has been providing incredible advances in our understanding of neural circuits in genetic model organisms like the mouse, in addition to novel resources and methodologies for nervous system research. These recent assets open now an enticing opportunity to study brain plasticity from a holistic angle. We believe that such integrative view is paramount for a genuine understanding of the potential and limits of brain plasticity, and ultimately for the design of interventions for brain functional regeneration.
We use mouse as a mammalian model system to explore the mechanisms of neural circuit plasticity. Mouse models of human disease can provide fundamental insights into processes underlying disease progression and ultimately guide the development of therapeutic interventions. Transgenic and gene targeting technology available in mice allows for the highly specific manipulation of gene expression, making these the primary mammalian species at the forefront of modern biomedical research.
We leverage cutting-edge technologies for circuit mapping and manipulation, optical clearing in tandem with whole brain imaging, genetic fate mapping, proteomics and advanced microscopy amongst others. During my postdoc I have established a pipeline to map and measure connectivity at brain-wide scale and single cell resolution, an approach I call quantitative connectomics, and that offers the opportunity for comparative circuit analysis. We use this approach to map alterations in brain connectivity upon a focal dysfunction. Furthermore, we combine our in vivo studies with in vitro experiments in cell culture or brain slices whenever a reductionist model suffices to dissect cellular details or fuel screening assays.
In a matter of seconds, brain injury can affect who we are, our ability to act, think, feel. Those can be lifelong disabilities, representing an unmet medical need. In this endeavor, expectations rose as we recognized how malleable the adult mammalian brain is. Research at our lab will provide fundamental insights into neurological disease and circuit plasticity. We believe that our findings may constitute transferable knowledge to non-model organisms and help paving the way to the development of novel therapeutic interventions for devastating neurological conditions as stroke, brain trauma or neurological disease.
Thomas, J., Martinez-Reza, MF., Thorwirth, M., Zarb, Y., Conzelmann, KK., Hauck, SM., Grade, S., Götz, M. (2022). Excessive local host-graft connectivity in aging and amyloid-loaded brain. Sci Adv. 8(23):eabg9287
Grade, S., Thomas, J., Zarb, Y., Thorwirth, M., Conzelmann, KK., Hauck, SM., Götz, M. (2022). Brain injury environment critically influences the connectivity of transplanted neurons. Sci Adv. 8(23):eabg9445
Petrik, D., Myoga, MH., Grade, S., Gerkau, NJ., Pusch, M., Rose, CR., Grothe, B., Götz, M. (2018). Epithelial Sodium Channel Regulates Adult Neural Stem Cell Proliferation in a Flow-Dependent Manner. Cell Stem Cell. 22(6):865-878.e8
Grade, S., Götz, M. (2017). Neuronal replacement therapy: previous achievements and challenges ahead. NPJ Regen Med. 2:29
Falkner, S., Grade, S., Dimou, L., Conzelmann, KK., Bonhoeffer, T., Götz, M., Hübener, M. (2016). Transplanted embryonic neurons integrate into adult neocortical circuits. Nature. 539(7628):248-253
Grade, S., Weng, YC., Snapyan, M., Kriz, J., Malva, JO., Saghatelyan, A. (2013). Brain-derived neurotrophic factor promotes vasculature-associated migration of neuronal precursors toward the ischemic striatum. PLoS One. 8(1):e55039