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The wonders and complexities of brain microstructure: Enabling biomedical engineering studies combining imaging and models
Brain microstructure plays a key role in driving the transport of drug molecules directly administered to the brain tissue as in Convection-Enhanced Delivery procedures. This study reports the first systematic attempt to characterize the cytoarchitecture of commissural, long association and projection fiber, namely: the corpus callosum, the fornix and the corona radiata. Ovine samples from three different subjects have been imaged using scanning electron microscope combined with focused ion beam milling. Particular focus has been given to the axons. For each tract, a 3D reconstruction of relatively large volumes (including a significant number of axons) has been performed. Namely, outer axonal ellipticity, outer axonal cross-sectional area and its relative perimeter have been measured. This study [1] provides useful insight into the fibrous organization of the tissue that can be described as composite material presenting elliptical tortuous tubular fibers, leading to a workflow to enable accurate simulations of drug delivery which include well-resolved microstructural features. As a demonstration of the use of these imaging and reconstruction techniques, our research analyses the hydraulic permeability of two white matter (WM) areas (corpus callosum and fornix) whose three-dimensional microstructure was reconstructed starting from the acquisition of the electron microscopy images. Considering that the white matter structure is mainly composed of elongated and parallel axons we computed the permeability along the parallel and perpendicular directions using computational fluid dynamics [2]. The results show a statistically significant difference between parallel and perpendicular permeability, with a ratio about 2 in both the white matter structures analysed, thus demonstrating their anisotropic behaviour. This is in line with the experimental results obtained using perfusion of brain matter [3]. Moreover, we find a significant difference between permeability in corpus callosum and fornix, which suggests that also the white matter heterogeneity should be considered when modelling drug transport in the brain. Our findings, that demonstrate and quantify the anisotropic and heterogeneous character of the white matter, represent a fundamental contribution not only for drug delivery modelling but also for shedding light on the interstitial transport mechanisms in the extracellular space. These and many other discoveries will be discussed during the talk." "1. https://www.researchsquare.com/article/rs-686577/v1, 2. https://www.pnas.org/content/118/36/e2105328118, 3. https://ieeexplore.ieee.org/abstract/document/9198110
Reverse engineering Hydra
Hydra is an extraordinary creature. Continuously replacing itself, it can live indefinitely, performing a stable repertoire of reasonably sophisticated behaviors. This remarkable stability under plasticity may be due to the uniform nature of its nervous system, which consists of two apparently noncommunicating nerve net layers. We use modeling to understand the role of active muscles and biomechanics interact with neural activity to shape Hydra behaviour. We will discuss our findings and thoughts on how this simple nervous system may self-organize to produce purposeful behavior.
Using Human Stem Cells to Uncover Genetic Epilepsy Mechanisms
Reprogramming somatic cells to a pluripotent state via the induced pluripotent stem cell (iPSC) method offers an increasingly utilized approach for neurological disease modeling with patient-derived cells. Several groups, including ours, have applied the iPSC approach to model severe genetic developmental and epileptic encephalopathies (DEEs) with patient-derived cells. Although most studies to date involve 2-D cultures of patient-derived neurons, brain organoids are increasingly being employed to explore genetic DEE mechanisms. We are applying this approach to understand PMSE (Polyhydramnios, Megalencephaly and Symptomatic Epilepsy) syndrome, Rett Syndrome (in collaboration with Ben Novitch at UCLA) and Protocadherin-19 Clustering Epilepsy (PCE). I will describe our findings of robust structural phenotypes in PMSE and PCE patient-derived brain organoid models, as well as functional abnormalities identified in fusion organoid models of Rett syndrome. In addition to showing epilepsy-relevant phenotypes, both 2D and brain organoid cultures offer platforms to identify novel therapies. We will also discuss challenges and recent advances in the brain organoid field, including a new single rosette brain organoid model that we have developed. The field is advancing rapidly and our findings suggest that brain organoid approaches offers great promise for modeling genetic neurodevelopmental epilepsies and identifying precision therapies.
Reverse engineering neural control of movement in Hydra
Hydra is a fascinating model organism for neuroscience. It is transparent; new genetic lines allow one to image activity in both neurons (Dupre and Yuste, 2017) and muscle cells (Szymanski and Yuste, 2019) ; it exhibits rich behavior, and it continually rebuilds itself. Hydra’s fairly simply physical structure as a two-layered fluid-filled hydrostat and the accessibility of information about neural and muscle activity opens the possibility of a complete model of neural control of behavior. This requires understanding the transformations that occur in the muscle cell layers and a biomechanical model of the body column. We show that we can use this modeling to reverse engineer how neural activity drives behavior.
Glia neuron metabolic interactions in Drosophila
To function properly, the nervous system consumes vast amounts of energy, which is mostly provided by carbohydrate metabolism. Neurons are very sensitive to changes in the extracellular fluid surrounding them, which necessitated shielding of the nervous system from fluctuating solute concentrations in circulation. This is achieved by the blood-brain barrier (BBB) that prevents paracellular diffusion of solutes into the nervous system. This in turn also means that all nutrients that are needed e.g. for sufficient energy supply need to be transported over the BBB. We use Drosophila as a model system to better understand the metabolic homeostasis in the central nervous system. Glial cells play essential roles in both nutrient uptake and neural energy metabolism. Carbohydrate transport over the glial BBB is well-regulated and can be adapted to changes in carbohydrate availability. Furthermore, Drosophila glial cell are highly glycolytic cells that support the rather oxidative metabolism of neurons. Upon perturbations of carbohydrate metabolism, the glial cells prove to be metabolically very flexible and able to adapt to changing circumstances. I will summarize what we know about carbohydrate transport at the Drosophila BBB and about the metabolic coupling between neurons and glial cells. Our data shows that many basic features of neural metabolism are well conserved between the fly and mammals.
Exploring morin hydrate's key role in LPS-induced immune response and cellular motility in macrophages
FENS Forum 2024
Investigating the neural basis of dehydration-induced anorexia
FENS Forum 2024
Temperature-driven neural and behavioural responses in Hydra vulgaris
FENS Forum 2024
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