Thursday, June 19th, 2025

Time	Event
4:19p	Gas-sensing neurons prime mitochondrial fitness to offset metabolic stress Animals integrate environmental and internal cues to maintain homeostasis and health. The mitochondrial stress response is an essential cytoprotective mechanism, and priming its activation provides a survival advantage. Here, we show that the Caenorhabditis elegans receptor guanylyl cyclase GCY-9 regulates neuropeptide signalling from carbon dioxide sensing neurons to govern a non-canonical mitochondrial stress response in the intestine. This stress response induces atypical mitochondrial chaperone transcription, confers mitochondrial stress resistance, and increases mitochondrial membrane potential and respiration. GCY-9 loss disrupts pathogen avoidance, leading to indiscriminate feeding. We show that starvation decreases GCY-9 expression and propose that the resultant cytoprotective program is launched to offset risks associated with this behaviour. Thus, environmental sensing by peripheral neurons can pre-emptively enhance systemic mitochondrial function in response to metabolic uncertainty. One-Sentence SummaryProtecting mitochondria by integrating environmental signals (Comment on this)
9:15p	Resolving synaptic events using subsynaptically targeted GCaMP8 variants While genetically encoded Ca2+ indicators are valuable for visualizing neural activity, their speed and sensitivity have had limited performance when compared to chemical dyes and electrophysiology, particularly at synaptic compartments. We addressed these limitations by engineering a suite of next-generation GCaMP8-based indicators, targeted to presynaptic boutons, active zones, and postsynaptic compartments at the Drosophila neuromuscular junction. We first validated these sensors to be superior to previous versions. Next, we developed a new Python-based analysis program, CaFire, which enables the automated quantification of evoked and spontaneous Ca2+ signals. Using CaFire, we show a ratiometric presynaptic GCaMP8m sensor accurately captures physiologically-relevant presynaptic Ca2+ changes with superior sensitivity and similar kinetics compared to chemical dyes. Moreover, we test the ability of an active zone-targeted, ratiometric GCaMP8f sensor to report differences in Ca2+ between release sites. Finally, a newly engineered postsynaptic GCaMP8m, positioned near glutamate receptors, detects quantal events with temporal and signal resolution comparable to electrophysiological recordings. These next generation indicators and analytical methods demonstrate that GCaMP8 sensors, targeted to synaptic compartments, can now achieve the speed and sensitivity necessary to resolve Ca2+ dynamics at levels previously only attainable with chemical dyes or electrophysiology. (Comment on this)
9:15p	A model investigation of short-term synaptic plasticity tuned via Unc13 isoforms. Short-term synaptic plasticity (STP) is a fundamental mechanism of neural computation supporting a variety of nervous system functions from sensory adaptation and gain control to working memory and decision making. At the presynaptic release site, an interplay between distinct (M)Unc13 protein isoforms is suggested to orchestrate depressing and facilitating components of STP. In this study, we introduce a modification of the well-established TsodyksMarkram Model (TMM) for STP. We constrain our model by in vivo intracellular recordings in the olfactory system of the fruit fly, where previous work suggested Unc13A to provide a phasic, depressing and Unc13B a tonic, facilitating release component. A combination of a facilitating and a depressing model component indeed allowed for accurate model fits. Differential knock-down experiments of the Unc13A and Unc13B gene variants provide biological model interpretation, linking the protein-specific molecular mechanisms to synaptic function and STP. Our mathematical formulation of protein-dependent STP can be readily and efficiently used to design biologically realistic spiking neural network models that feature different genetically defined synapse types. (Comment on this)
9:15p	High-speed whole-brain imaging in Drosophila Recent advances in brain-wide recordings of small animals such as worms, fish, and flies have revealed complex activity involving large populations of neurons. In the Drosophila brain, with about 140,000 neurons, brain-wide recordings have been critical to uncovering widespread sensory and motor activity. However, current limitations in volumetric imaging rates hinder the accurate capture of fast neural dynamics. To improve the speed of volumetric imaging in Drosophila, we leverage the recently introduced light beads microscopy (LBM) method. We built a microscope and a LBM module tailored to fly brain experiments and used it to record brain-wide calcium signals in adult behaving flies at 28 volumes per second and at 60 volumes per second when selecting the central brain alone. We uncover fast-timescale auditory responses that are missed with standard volumetric imaging. We also demonstrate how temporal super-resolution can be combined with LBM data to uncover responses to single Drosophila courtship song pulses. This establishes LBM as a viable tool for capturing whole-brain activity at high spatial and temporal resolution in the fly. (Comment on this)
9:15p	A genetic driver of epileptic encephalopathy impairs gating of synaptic glycolysis The brain is a disproportionately large consumer of fuel, estimated to expend [~]20% of the whole-body energy budget, and therefore it is critical to adequately control brain fuel expenditures while satisfying its on-demand needs for continued function. The brain is also metabolically vulnerable as the inability to adequately fuel cellular processes that support information transfer between cells leads to rapid neurological impairment. We show here that a genetic driver of early onset epileptic encephalopathy (EOEE), SLC13A5, a Na+/citrate cotransporter (NaCT), is critical for gating the activation of local presynaptic glycolysis. We show that SLC13A5 is in part localized to a presynaptic pool of membrane-bound organelles and acts to transiently clear axonal citrate during electrical activity, in turn activating phosphofructokinase 1. We show that loss of SLC13A5 or mistargeting to the plasma membrane results in suppressed glycolytic gating, activity dependent presynaptic bioenergetic deficits and synapse dysfunction. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=168 HEIGHT=200 SRC="FIGDIR/small/660213v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@ef96dcorg.highwire.dtl.DTLVardef@1995c90org.highwire.dtl.DTLVardef@18c0538org.highwire.dtl.DTLVardef@1aadcd9_HPS_FORMAT_FIGEXP M_FIG C_FIG (Comment on this)

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