Small fly eyes should not see fine image details. Because flies exhibit saccadic visual behaviors and their compound eyes have relatively few ommatidia (sampling points), their photoreceptors would be expected to generate blurry and coarse retinal images of the world. Here we demonstrate that Drosophila see the world far better than predicted from the classic theories. By using electrophysiological, optical and behavioral assays, we found that R1-R6 photoreceptors' encoding capacity in time is maximized to fast high-contrast bursts, which resemble their light input during saccadic behaviors. Whilst over space, R1-R6s resolve moving objects at saccadic speeds beyond the predicted motion-blur-limit. Our results show how refractory phototransduction and rapid photomechanical photoreceptor contractions jointly sharpen retinal images of moving objects in space-time, enabling hyperacute vision, and explain how such microsaccadic information sampling exceeds the compound eyes' optical limits. These discoveries elucidate how acuity depends upon photoreceptor function and eye movements.

Small fly eyes should not see fine image details. Because flies exhibit saccadic visual behaviors and their compound eyes have relatively few ommatidia (sampling points), their photoreceptors would be expected to generate blurry and coarse retinal images of the world. Here we demonstrate that Drosophila see the world far better than predicted from the classic theories. By using electrophysiological, optical and behavioral assays, we found that R1-R6 photoreceptors’ encoding capacity in time is maximized to fast high-contrast bursts, which resemble their light input during saccadic behaviors. Whilst over space, R1-R6s resolve moving objects at saccadic speeds beyond the predicted motion-blur-limit. Our results show how refractory phototransduction and rapid photomechanical photoreceptor contractions jointly sharpen retinal images of moving objects in space-time, enabling hyperacute vision, and explain how such microsaccadic information sampling exceeds the compound eyes’ optical limits. These discoveries elucidate how acuity depends upon photoreceptor function and eye movements.

Figure S1, related to Figures 3, 5, S2 and S3. Characteristic voltage-sensitive shaker and shab K + current responses of (A) wild-type, (B) dSK -, (C) dSloand (D) dSK -;;dSlo -R1-R6 photoreceptors and their HH-models to voltage commands, under whole-cell voltage-clamp conditions.

Background: Inherited mutations in the LRRK2 protein are the common causes of Parkinson’s disease, but the mechanisms by which increased kinase activity of mutant LRRK2 leads to pathological events remain to be determined. In vitro assays (heterologous cell culture, phospho-protein mass spectrometry) suggest that several Rab proteins might be directly phosphorylated by LRRK2-G2019S. An in vivo screen of Rab expression in dopaminergic neurons in young adult Drosophila demonstrated a strong genetic interaction between LRRK2-G2019S and Rab10. Objective: To determine if Rab10 is necessary for LRRK2-induced pathophysiological responses in the neurons that control movement, vision, circadian activity, and memory. These four systems were chosen because they are modulated by dopaminergic neurons in both humans and flies. Methods: LRRK2-G2019S was expressed in Drosophila dopaminergic neurons and the effects of Rab10 depletion on Proboscis Extension, retinal neurophysiology, circadian activity pattern (‘sleep’), and courtship memory determined in aged flies. Results: Rab10 loss-of-function rescued LRRK2-G2019S induced bradykinesia and retinal signaling deficits. Rab10 knock-down, however, did not rescue the marked sleep phenotype which results from dopaminergic LRRK2-G2019S. Courtship memory is not affected by LRRK2, but is markedly improved by Rab10 depletion. Anatomically, both LRRK2-G2019S and Rab10 are seen in the cytoplasm and at the synaptic endings of dopaminergic neurons. Conclusion: We conclude that, in Drosophila dopaminergic neurons, Rab10 is involved in some, but not all, LRRK2-induced behavioral deficits. Therefore, variations in Rab expression may contribute to susceptibility of different dopaminergic nuclei to neurodegeneration seen in people with Parkinson’s disease.

38Ca 2+ -activated K + channels (BK and SK) are ubiquitous in synaptic circuits, but their role in network 39 adaptation and sensory perception remains largely unknown. Using electrophysiological and 40 behavioral assays and biophysical modelling, we discover how visual information transfer in mutants 41 lacking the BK channel (dSlo -), SK channel (dSK -) or both (dSK -;;dSlo -) is shaped in the female fruit 42 fly (Drosophila melanogaster) R1-R6 photoreceptor-LMC circuits (R-LMC-R system) through 43 synaptic feedforward-feedback interactions and reduced R1-R6 Shaker and Shab K + conductances. 44 This homeostatic compensation is specific for each mutant, leading to distinctive adaptive dynamics. 45 We show how these dynamics inescapably increase the energy cost of information and promote the 1 mutants' distorted motion perception, determining the true price and limits of chronic homeostatic 2 compensation in an in vivo genetic animal model. These results reveal why Ca 2+ -activated K + 3 channels reduce network excitability (energetics), improving neural adaptability for transmitting and 4 perceiving sensory information. 5 6Significance statement: 7 In this study, we directly link in vivo and ex vivo experiments with detailed stochastically operating 8 biophysical models to extract new mechanistic knowledge of how Drosophila photoreceptor-9interneuron-photoreceptor (R-LMC-R) circuitry homeostatically retains its information sampling and 10 transmission capacity against chronic perturbations in its ion-channel composition, and what is the 11 cost of this compensation and its impact on optomotor behavior. We anticipate that this novel 12 approach will provide a useful template to other model organisms and computational neuroscience, 13 in general, in dissecting fundamental mechanisms of homeostatic compensation and deepening our 14 understanding of how biological neural networks work. 15 16 2018). Here, we study to what extent intrinsic perturbations of missing one or both of these K + 1 channels, through gene-deletion, can be neutralized by homeostatic processes trying to sustain 2 normal network functions, and what is the price of this compensation. 3 4By using electrophysiological and behavioral assays and biophysical modelling, we uncover why 5 Ca 2+ -activated K + channels improve communication between photoreceptors and Large Monopolar 6 Cells (LMCs), which in the fly eye lamina network form stereotypical columns of feedforward and 7 feedback synapses (R-LMC-R system) that process and route visual information to the fly brain. We 8show that although the loss of SK and BK channels does not diminish Drosophila photoreceptors' 9 information sampling capacity in vivo, it homeostatically reduces other K + currents and overloads 10 synaptic-feedback from the lamina network. This makes communication between the mutant 11 photoreceptors and LMCs inefficient, consuming more energy and distorting visual information flow 12 to the brain. Thus, homeostatic compensation of missing SK and BK channels within the lami...

BackgroundInherited mutations in the LRRK2 protein are the most common known cause of Parkinson’s, but the mechanisms by which increased kinase activity of mutant LRRK2 leads to pathological events remain to be determined. In vitro assays (heterologous cell culture, phospho-protein mass spectrometry) suggest that several Rab proteins might be directly phosphorylated by LRRK2-G2019S. Which Rabs interact with LRRK2 in dopaminergic neurons to facilitate normal and pathological physiological responses remains to be determined. An in vivo screen of Rab expression in dopaminergic neurons in young adult Drosophila demonstrated a strong genetic interaction between LRRK2-G2019S and Rab10. We now ask if Rab10 is required for LRRK2-induced physiological responses in DA neurons.MethodsLRRK2-G2019S was expressed in Drosophila dopaminergic neurons and the effects of Rab10 depletion on Proboscis Extension, vision, circadian activity pattern and courtship memory determined in aged flies.ResultsRab10 loss-of-function rescued bradykinesia of the Proboscis Extension Response (PER) and visual defects of aged flies expressing LRRK2-G2019S in DA neurons. Rab10 knock-down however, did not rescue the marked sleep phenotype which results from dopaminergic expression of LRRK2-G2019S. Courtship memory is not affected by LRRK2 expression, but is markedly improved by Rab10 depletion. Anatomically, both LRRK2-G2019S and Rab10 are seen in the cytoplasm and at the synaptic endings of dopaminergic neurons.ConclusionsWe conclude that, in Drosophila dopaminergic neurons, Rab10 is involved differentially in LRRK2-induced behavioral deficits. Therefore, variations in Rab expression may contribute to susceptibility of dopaminergic neurons to neurodegeneration seen in people with Parkinson’s.Graphical AbstractRab10 depletion ameliorates the proboscis extension bradykinesia and loss of synaptic signalling in the retina induced by LRRK2-G2019S expression (magenta arrows/orange crosses). Rab10 manipulation does not affect the ‘sleep’ phenotype from LRRK2-G2019S (magenta arrow). Reduction of Rab10 facilitates conditioned courtship memory, but LRRK2 has no effect (yellow arrow). All manipulations of Rab10 and G2019S in dopaminergic neurons, shown in the outline of the brain (filled cells have high levels of Rab10). We conclude that Rab10 and LRRK2 interact in some, but not all dopaminergic neurons. This may underlie differences in the susceptibility of different human striatal dopaminergic cells to Parkinson’s.

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Circadian behavioural deficits, such as increased daytime naps and reduced night-time sleep, are common in Alzheimer’s disease and other tauopathies. But it has remained unclear whether these circadian abnormalities arise from tau pathology in either the master pacemaker or downstream neurons. Here we study this question by selectively expressing different human tau proteins in specific Drosophila brain circuits and monitoring locomotor activity under light-dark (LD) and in “free-running” dark-dark (DD) conditions. We show that expressing human tau proteins in the fly brain recapitulates faithfully several behavioural changes found in tauopathies. We identify discrete neuronal subpopulations within the clock network as the primary target of distinct circadian behavioural disturbances in different environmental conditions. Specifically, we show that the PDF-positive pacemaker neurons are the main site for night-activity gain and -sleep loss, whereas the non-PDF clock-neurons are the main site of reduced intrinsic behavioural rhythmicity. Bioluminescence measurements revealed that the molecular clock is intact despite the behavioural arrhythmia. Our results establish that dysfunction in both the central clock- and afferent clock-neurons jointly contribute to the circadian locomotor activity rhythm disruption in Drosophila expressing human tau.Significance StatementThis study directly links in vivo human tau protein expression in region-specific Drosophila clock-neurons with the resulting sleep and circadian rhythm deficits to extract new knowledge of how Alzheimer’s disease and other tauopathies perturb the balance of activity and sleep. We anticipate that this novel approach will provide a useful general template for other studies of neurodegeneration in model organisms, seeking to dissect the impact of neurodegenerative disease on circadian behaviour, and further deepening our understanding of how the clock-neuron network works.