Integrated Calendar

SARM1 is a central executor of neurodegeneration. Remarkably, neurons from SARM1 knock-out mice (which appear to be normal in many respects) show prolonged resistance for neuronal degeneration after mechanical damage, oxidative stress, and chemotherapy treatments. Mechanistically, SARM1 contains NADase activity, which, in response to nerve injury, depletes the key cellular metabolite, NAD+. To gain structural knowledge of SARM1 we use X-ray crystallography of isolated SARM1 domains and single particle EM 3D reconstruction of the intact protein. We discovered that SARM1, like other apoptotic complexes, assembles into an oligomeric ring. Structure analysis and additional experiments in cultured cells points at a surprising molecular mechanism by which SARM1 is kept inactive during homeostasis and how it becomes activated in response to metabolic and oxidative stress conditions 1,2,3.

1 Sporny, M. et al. Structural Evidence for an Octameric Ring Arrangement of SARM1. J Mol Biol
431, 3591-3605, doi:10.1016/j.jmb.2019.06.030 (2019).

2 Sporny, M. et al. Structural basis for SARM1 inhibition and activation under energetic stress. Elife 9, doi:10.7554/eLife.62021 (2020).

3.Khazma T. et al. A Duplex Structure of SARM1 Octamers Induced by a New Inhibitor. bioRxiv doi.org/10.1101/2022.03.02.482641 (2022).

Self-assembly and self-organization are two big challenges in the natural sciences. What are the rules governing the emergence of greater structures from unassuming elements? Does statistical-mechanics restrict their complexity? Biochemical processes can shape highly specific structures and function on the macro-scale using only molecular information. Although stereochemistry has been a central focus of molecular sciences since Pasteur, its synthetic province has been restricted to the nanometric scale. In my talk, I will describe how to propagate molecular information to self-assemble free-form architectures on the micron-scale and beyond. These architectures are a thousand times greater than their constituent molecules yet have a preprogrammed geometry and chirality. I will then show how to animate such synthetic microstructures into bacteria-like micro-swimmers. Previous artificial microswimmers relied on an external chemical fuel to drive their propulsion which restricted their operational concentration as they competed locally over fuel. I will demonstrate how to use material science and physical chemistry to self-assemble fuel-free micro-swimmers that are driven solely by light. The fuel independence allows the swimmers to stay active even at high densities, where they form turbulent flow structures (previously seen in living fluids), and cooperate to perform a greater task.

Decision-making requires a consideration of both costs and benefits. Although mesolimbic dopamine (DA) plays an established role in reward-related decisions, there has been longstanding controversy over its sensitivity to costs vs benefits. Manipulations of DA function imply a primary role in mediating cost calculations, while DA recordings suggest a preference for encoding benefit. These studies often confound cost and benefit by varying both simultaneously, and rarely combine correlational and causal tools to explore how encoding relates to behavior. Here we independently varied costs and benefits, studying DA's role using both recording and manipulation. We found that DA release reflects changes in both cost and benefit, although the precise relationship depended on the time within a trial and the site of DA release. Then we used behavioral economics to probe how these patterns of DA release relate to two important behavioral parameters: a mouse's preferred level of reward consumption and the amount of work it is willing to expend to maintain that consumption. We found that DA release in the nucleus accumbens core and dorsolateral striatum does not predict an animal's preferred level of consumption. It does, however, strongly reflect an animal's willingness to work for reward. Surprisingly, the more DA released for each reward, the less demand for that reward. The inverse relationship between DA release and demand held true both for natural rewards and optogenetic stimulation of DA release in both striatal targets. Our findings support an inverted-U model of dopamine and reinforcement, where a minimal level of DA release is critical to motivate behavior, but increments above that level actually reduce demand.
Link to join:
https://weizmann.zoom.us/j/95406893197?pwd=REt5L1g3SmprMUhrK3dpUDJVeHlrZz09

Meeting ID: 954 0689 3197
Password: 750421

While our world is three-dimensional (3D), spatial perception is most often studied in animals and humans navigating across 2D surfaces. I will present two cases in which the consideration of the 3D nature of the world has led us to surprising results. The first case regards the neural recording of mammalian grid cells. Grid cells that are recorded over 2D surfaces create a hexagonal-shaped repetitive lattice, which inspired many theoretical studies to investigate the pattern’s mechanism and function. Upon recording in bats flying through 3D space, we found that grid cells did not exhibit a hexagonal global lattice, but rather showed a local order – with grid-fields exhibiting fixed local distances. Our results in 3D strongly argue against most of the prevailing models of grid-cell function, and we suggest a unified model that explains the results in both 2D and 3D.  The second case regards the perception of 3D space in humans. Different behavioral studies have shown contradicting evidence of human perception of 3D space being either isotropic or vertically compressed. We addressed this question using human experts in 3D motion and navigation – fighter pilots – studied in a flight simulator. We considered two aspects of the perception of 3D space: surrounding space and travelled space. We show that different aspects of the perception of space are shaped differently with experience: whereas the perception of the 3D surrounding space was vertically compressed in both expert and non-expert subjects, fighter pilots exhibited isotropic perception of travelled space, whereas non-expert subjects retained a distorted perception.  Together, our research sheds light on the differences and similarities between the coding of 3D versus 2D space, in both animals and humans.  

Explaining organisms in terms of the jiggling and wiggling of atoms is a central goal in molecular biology. Yet, the dynamics of proteins with their sophisticated three-dimensional architectures exceeds the capabilities of
analytical theories. On the other
hand, intrinsically
disordered proteins are often well described by polymer theories of different flavors. However, these theories do not apply to proteins in which disorder and order mix. Combining structural biology with polymer theory is therefore required to understand such biomolecules. I will discuss how optical single-molecule spectroscopy allows us to probe the dynamics of (partially) disordered proteins and complexes from nanoseconds to milliseconds. I will show how many weak protein-protein interactions can cause rugged energy landscapes that slow-down dynamics by orders of magnitude. In the second part, I will discuss how we envision to bridge scales between molecules and cells at the example of a cellular phenotype switch that requires a dynamic interplay between proteins and DNA. While single-molecule tools to probe the kinetics of biomolecules are well developed, similar approaches to study the dynamics of cellular processes such as gene expression are scarce. In the final part of my talk I will therefore present a new approach to tackle this problem using single-particle tracking