Neurons interact in networks distributed throughout the brain. While much effort has focused on whole-brain calcium imaging, advances in genetically encoded voltage indicators raise the question of whether it might be possible to image neuronal voltage across entire brains. Achieving this requires a microscope with high volumetric imaging rates and signal-to-noise ratio. Here we present a remote-scanning light-sheet microscope capable of imaging genetically encoded voltage indicator-expressing neurons distributed throughout much of the brain of larval zebrafish at a volumetric rate of 200.8 Hz. We measured voltage traces from approximately one-quarter of all brain neurons. We found that neurons firing at different times during a sequence occupied different locations: visually evoked sequences mapped across the optic tectum, whereas stimulus-independent bursts were mapped across the cerebellum and medulla. Imaging voltage of neurons distributed in many brain regions may open new frontiers for understanding fundamental neural system operations.

Glucagon-like peptide 1 receptor agonists (GLP1RAs) effectively reduce body weight and improve metabolic outcomes; however, established peptide-based therapies require injections and are complex to manufacture. Small-molecule GLP1RAs promise oral bioavailability and scalable manufacturing, but their selective binding to human versus rodent receptors has limited mechanistic studies. Here we developed humanized GLP1R mouse models to investigate how small-molecule GLP1RAs influence feeding behaviour. We found that these compounds regulate both homeostatic and hedonic feeding through parallel neural circuits. Beyond engaging canonical hypothalamic and hindbrain networks that control metabolic homeostasis, GLP1RAs recruit a discrete population of Glp1r-expressing neurons in the central amygdala, which selectively suppress the consumption of palatable foods by reducing dopamine release in the nucleus accumbens. Stimulating these central amygdalar neurons curtails hedonic feeding, whereas targeted deletion of the receptor in this cell population specifically diminishes the anorectic efficacy of GLP1RAs for reward-driven intake. These findings identify a neural circuit through which small-molecule GLP1RAs modulate reward processing, with implications for the treatment of substance-use disorder and binge eating.

The integration of synaptic inputs is a fundamental function of neurons. In the traditional model, excitatory inputs are summed at the soma to generate action potentials. However, how synaptic inputs are integrated by dendrites in vivo remains poorly explored. We used intravital two-photon dendritic imaging with a genetically encoded voltage indicator (accelerated sensor of action potentials 5) together with somatic whole-cell patch clamp recordings to investigate how synaptic depolarizations are transferred to the soma in pyramidal neurons of the mouse somatosensory cortex. We studied the integration of synaptic inputs under spontaneous and sensory-evoked conditions, as well as following electrical and optogenetic stimulation. In all cases, while multiple inputs evoked measurable depolarizations in the cell body, isolated synaptic potentials were strongly attenuated. Our results suggest that isolated synaptic inputs have a minimal contribution to somatic depolarization, whereas coincident inputs within short temporal windows are more effective, indicating a regime of dendritic integration that favors coincident or clustered neuronal activity in cortical networks.

Recent advances in the field of Voltage Imaging, with a special focus on new constructs and novel implementations.

Basal Ganglia Advances is a collection highlighting research on the structure, function, and disorders of the basal ganglia. It features studies spanning neuroscience, clinical insights, and computational models, serving as a hub for advances in movement, cognition, and behavior.

Work related to place tuning, spatial navigation, orientation and direction. Mainly includes articles on connectivity in the hippocampus, retrosplenial cortex, and related areas.

Neurons interact in networks distributed throughout the brain. While much effort has focused on whole-brain calcium imaging, advances in genetically encoded voltage indicators raise the question of whether it might be possible to image neuronal voltage across entire brains. Achieving this requires a microscope with high volumetric imaging rates and signal-to-noise ratio. Here we present a remote-scanning light-sheet microscope capable of imaging genetically encoded voltage indicator-expressing neurons distributed throughout much of the brain of larval zebrafish at a volumetric rate of 200.8 Hz. We measured voltage traces from approximately one-quarter of all brain neurons. We found that neurons firing at different times during a sequence occupied different locations: visually evoked sequences mapped across the optic tectum, whereas stimulus-independent bursts were mapped across the cerebellum and medulla. Imaging voltage of neurons distributed in many brain regions may open new frontiers for understanding fundamental neural system operations.

Staphylocoagulase (SC), a crucial virulence protein secreted by several strains of the major pathogen , functions as a potent inducer of blood clotting. SC binds its zymogen target, prothrombin (ProT) with subnanomolar affinity, allosterically inducing a thrombin-like active site in the bound zymogen. The resulting SC·(Pro)T* active complexes effectively convert fibrinogen (Fbg) into clot-forming fibrin (Fbn). We previously reported crystal structures of the N-terminal SC domains, responsible for ProT binding and activation, and characterized the mechanism of cofactor-induced zymogen activation in detail. However, the lack of three-dimensional (3D) structures for the C-terminal SC region has hampered a complete understanding of its role in Fbg recognition and cleavage. Here, we present and discuss 3D models of the Fbg-binding SC region. Our results suggest that the major C-terminal domain of SC folds into a single-layer β-sheet structurally similar to the membrane occupation and recognition nexus (MORN) family of tandem repeats. We further propose a folding pathway for this C-terminal SC region that is contingent upon the presence of its substrate, Fbg. These structural and mechanistic insights are critical for understanding SC-mediated fibrin generation, which is highly relevant to heart valve vegetations and biofilm formation during infection.