Propofol is the most commonly used general anesthetic in humans. Our understanding of its mechanism of action has focused on its capacity to potentiate inhibitory systems in the brain. However, it is unknown whether other neural mechanisms are involved in general anesthesia. Here, we demonstrate that the synaptic release machinery is also a target. Using single-particle tracking photoactivation localization microscopy, we show that clinically relevant concentrations of propofol and etomidate restrict syntaxin1A mobility on the plasma membrane, whereas non-anesthetic analogs produce the opposite effect and increase syntaxin1A mobility. Removing the interaction with the t-SNARE partner SNAP-25 abolishes propofol-induced syntaxin1A confinement, indicating that syntaxin1A and SNAP-25 together form an emergent drug target. Impaired syntaxin1A mobility and exocytosis under propofol are both rescued by co-expressing a truncated syntaxin1A construct that interacts with SNAP-25. Our results suggest that propofol interferes with a step in SNARE complex formation, resulting in non-functional syntaxin1A nanoclusters.

Visual decision making in animals is influenced by innate preferences as well as experience. Interaction between hard-wired responses and changing motivational states determines whether a visual stimulus is attractive, aversive or neutral. It is, however, difficult to separate the relative contribution of nature versus nurture in experimental paradigms, especially for more complex visual parameters such as the shape of objects. We used a closed-loop virtual reality paradigm for walking Drosophila to uncover innate visual preferences for the shape and size of objects, in a recursive choice scenario allowing the flies to reveal their visual preferences over time. We found that Drosophila melanogaster display a robust attraction/repulsion profile for a range of object sizes in this paradigm, and that this visual preference profile remains evident under a variety of conditions and persists into old age. We also demonstrate a level of flexibility in this behavior: innate repulsion to certain objects could be transiently overridden if these were novel, although this effect was only evident in younger flies. Finally, we show that a neuromodulatory circuit in the fly brain, Drosophila neuropeptide F (dNPF), can be recruited to guide visual decision making. Optogenetic activation of dNPF-expressing neurons converted a visually repulsive object into a more attractive object. This suggests that dNPF activity in the Drosophila brain guides ongoing visual choices, to override innate preferences and thereby provide a necessary level of behavioral flexibility in visual decision making.

Object-based attention describes the brain’s capacity to prioritize one set of stimuli while ignoring others. Human research suggests that the binding of diverse stimuli into one attended percept requires phase-locked oscillatory activity in the brain. Even insects display oscillatory brain activity during visual attention tasks, but it is unclear if neural oscillations in insects are selectively correlated to different features of attended objects. We addressed this question by recording local field potentials in theDrosophilacentral complex, a brain structure involved in visual navigation and decision making. We found that attention selectively increased the neural gain of visual features associated with attended objects and that attention could be redirected to unattended objects by activation of a reward circuit. Attention was associated with increased beta (20- to 30-Hz) oscillations that selectively locked onto temporal features of the attended visual objects. Our results suggest a conserved function for the beta frequency range in regulating selective attention to salient visual features.

15Visual decision-making in animals is influenced by innate preferences as well as 16 experience. Interaction between hard-wired responses and changing motivational states 17 determines whether a visual stimulus is attractive, aversive, or neutral. It is however difficult 18 to separate the relative contribution of nature versus nurture in experimental paradigms, 19 especially for more complex visual parameters such as the shape of objects. We used a 20 closed-loop virtual reality paradigm for walking Drosophila flies to uncover innate visual 21 preferences for the shape and size of objects, in a recursive choice scenario allowing the 22 flies to reveal their visual preferences over time. We found that Drosophila flies display a 23 robust attraction / repulsion profile for a range of objects sizes in this paradigm, and that this 24 visual preference profile remains evident under a variety of conditions and persists into old 25 age. We also demonstrate a level of flexibility in this behavior: innate repulsion to certain 26 objects could be transiently overridden if these were novel, although this effect was only 27 evident in younger flies. Finally, we show that a reward circuit in the fly brain, Drosophila 28

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