Biology subjects

Soba, P.

Publications and source records attributed to Soba, P..

15 recordsLinked to original sources

bioRxiv2025

RHODOPSIN 7: An ancient non-retinal photoreceptor for contrast vision, darkness detection, and circadian regulation

1Animals rely on light not only for vision but also to adapt behavior to their environment through non-image-forming pathways. In Drosophila, most rhodopsins mediate retinal image formation, but RHODOPSIN 7 (RH7) is widely expressed in the brain and optic lobe, acting as a non-canonical light sensor reminiscent of mammalian melanopsin. We combined expression mapping, behavioral assays, and phylogenetic comparisons to investigate its function. RH7 detects temporal changes in luminance, guiding rapid behavioral responses, and regulating daily activity patterns. Flies lacking RH7 are less active during the dark phase, while strains with constitutively active RH7 show increased activity. Phylogenetic analyses suggest that RH7 is an ancient rhodopsin present across panarthropods, representing an intermediate between G protein-coupled receptors and specialized rhodopsins, highlighting a key step in the evolution of non-visual light perception. These findings show that RH7 functions as a melanopsin-like sensor, shaping behavior, and illuminating the origins of light detection.

neuroscience↗

bioRxiv2025

Peptidergic top-down control of metabolic state-dependent behavioral decisions in a conflicting sensory context

Animals make economically beneficial behavioral decisions by integrating the external sensory environment with their internal state. The metabolic state, i.e. hunger, can shift priorities, prompting risk-taking and reducing responses to danger during foraging activities. How behavioral changes are processed in the nervous system to generate flexible responses based on needs and risks remains largely unclear. Here, we demonstrate in Drosophila larvae that the corticotropin releasing hormone (CRH) homolog diuretic hormone 44 (Dh44) and its producing neurons exert metabolic top-down control of behavioral choice in a conflicting sensory context. The metabolic state via Dh44 signaling mediates the transition from avoiding to tolerating aversive light conditions in the presence of food. In vivo imaging of neuropeptide release revealed that Dh44 regulates the acute release of Insulin-like peptide 7 (Ilp7) specifically in a conflicting context, thereby inducing light tolerance. Optogenetic activation of specific subsets of Dh44 or Ilp7 producing neurons during starvation is sufficient to shift behavior from light tolerance to avoidance by regulating light avoidance circuit responses. This top-down feedforward peptidergic circuit may represent a general mechanism that helps organisms to balance risk-taking with metabolic needs by allowing flexible adjustment of behavior in a conflicting multisensory environment.

neuroscience↗

bioRxiv2025

Multimodal characterization and optogenetic potential of the bistable Gi/o-coupled vertebrate ancient opsin from the flashlight fish Anomalops katoptron

Vertebrate ancient long opsin, or VAL opsin, is a light-sensitive protein that is found within and outside the visual system in vertebrates. In accordance with its wide distribution in the retina, brain, testis and skin, VAL is suggested to play a role in light-dependent physiological processes that are beyond vision. However, many aspects of the physiological properties and specific functions of VAL remain unclear. Here we identified and characterized the VAL opsin from the flashlight fish Anomalops katoptron (AkVAL) and show that this opsin is bistable and reversibly converts between active and inactive states by responding to cycles of green and blue/UV lights. We further show that AkVAL couples to the Gi/o pathway and controls the activity of GIRK channels in a bistable manner. In line with this, we demonstrated that AkVAL modulates neuronal activity in cerebellar Purkinje cells, where neuronal activity is reduced by UV/blue light and increased by green/red light illumination. In addition, upon the in vivo expression of AkVAL in neurons innervating body muscles of Caenorhabditis elegans the worms body movement can be bidirectionally controlled altering blue/UV and green illuminations. These data highlight the potential of AkVAL as an optogenetic tool to control cells in vitro and in vivo, in a bistable manner.

neuroscience↗

bioRxiv2024

Lipid Disbalance Affects Neuronal Dendrite Growth and Maintenance in a Human Ceramide Synthase Disease Model

The brain is susceptible to disturbances in lipid metabolism. Among the rare, genetically-linked epilepsies Progressive Myoclonic Epilepsy Type 8 (PME8), associated with the loss of Ceramide Synthase (CerS) activity, causes epileptic symptoms accompanied by neurodegenerative traits. We show that expression of a disease-causing cerS allele in Drosophila sensory neurons yielded developmental and degenerative dendrite loss. In cerS mutants, C18-C24 ceramides and membrane-forming complex sphingolipids, into which ceramides are converted, were reduced. At the same time bioactive signaling lipids including (dh)Sphingosine-1-P, deriving from the CerS substrate, were increased. To clarifying the etiology of PME8, we thus performed in vivo experiments to cell-autonomously rescue the individual metabolic alterations. We report that restoring specific long-chain ceramides while in parallel decreasing (dh)Sphingosine-1-P fully rescues the cerS mutant phenotype. Thus, despite the complex metabolic alterations, our data provide essential information about the metabolic origin of PME8 and delineate a potential therapy.

neuroscience↗

bioRxiv2024

Axon length-dependent synapse loss is mediated by neuronal cytokine-induced glial phagocytosis

Many neurodegenerative disorders (NDDs) preferentially affect neurons with long or complex axonal arbors, but our understanding of this specific vulnerability is limited. Using Drosophila larval class IV dendrite arborization (C4da) neurons, we found that neuronal activation of the integrated stress response (ISR) induces axon length-dependent degeneration (LDD). We identified the Interleukin-6 homologue unpaired 3 (upd3) as both necessary and sufficient for LDD in C4da neurons. Upd3 recruits glial cells to phagocytose presynapses preferentially on neurons with long axons, revealing an intrinsic axon length-dependent vulnerability to glia-mediated presynapse removal. Finally, we found that axon length-dependent presynapse loss in fly models of human NDDs utilized this pathway. Altogether, our studies identify inflammatory cytokine signaling from neurons to glia as a key determinant in axon length-dependent vulnerability. One-Sentence SummarySensory neurons exhibit intrinsic length-dependent vulnerability to presynapse removal driven by cytokine activation of glia.

neuroscience↗

bioRxiv2023

Neural circuits underlying context-dependent competition between defensive actions in Drosophila larva

To ensure their survival, animals must be able to respond adaptively to threats within their environment. However, the precise neural circuit mechanisms that underlie such flexible defensive behaviors remain poorly understood. Using neuronal manipulations, machine-learning-based behavioral detection, Electron Microscopy (EM) connectomics and calcium imaging in Drosophila larva, we have mapped the second-order interneurons differentially involved in the competition between different defensive actions and the main pathways to the motor side putatively involved in inhibiting startle-type behaviors and promoting escape behaviors in a context dependent manner. We found that mechanosensory stimulation modulates the nociceptive escape sequences and inhibits C-shape bends and Rolls in favor of startle-like behaviors. This suggests a competition between mechanosensory-induced startle responses and escape behaviors. Structural and functional connectivity revealed that the second order interneurons receive their main input from projection neurons that integrate mechanosensory and nociceptive stimuli. The analysis of their postsynaptic connectivity in EM revealed that they make indirect connections to the pre-motor and motor neurons. Finally, we identify a pair of descending neurons that could promote modulate the escape sequence and promote startle behaviors. Altogether, these results characterize the pathways involved in the Startle and Escape competition, modulated by the sensory context.

neuroscience↗

bioRxiv2023

A bistable inhibitory OptoGPCR for multiplexed optogenetic control of neural circuits

Information is transmitted between brain regions through the release of neurotransmitters from long-range projecting axons. Understanding how the activity of such long-range connections contributes to behavior requires efficient methods for reversibly manipulating their function. Chemogenetic and optogenetic tools, acting through endogenous G-protein coupled receptor (GPCRs) pathways, can be used to modulate synaptic transmission, but existing tools are limited in sensitivity, spatiotemporal precision, or spectral multiplexing capabilities. Here we systematically evaluated multiple bistable opsins for optogenetic applications and found that the Platynereis dumerilii ciliary opsin (PdCO) is an efficient, versatile, light-activated bistable GPCR that can suppress synaptic transmission in mammalian neurons with high temporal precision in-vivo. PdCO has superior biophysical properties that enable spectral multiplexing with other optogenetic actuators and reporters. We demonstrate that PdCO can be used to conduct reversible loss-of-function experiments in long-range projections of behaving animals, thereby enabling detailed synapse-specific functional circuit mapping.

neuroscience↗

bioRxiv2023

Optimized design and in vivo application of optogenetically functionalized Drosophila dopamine receptors

Neuromodulatory signaling via G protein-coupled receptor (GPCRs) plays a pivotal role in regulating neural network function and animal behavior. Recent efforts have led to the development of optogenetic tools to induce G protein-mediated signaling, with the promise of acute and cell type-specific manipulation of neuromodulatory signals. However, designing and deploying optogenetically functionalized GPCRs (optoXRs) with accurate specificity and activity to mimic endogenous signaling in vivo remains challenging. Here we optimized the design of optoXRs by considering evolutionary conserved GPCR-G protein interactions and demonstrate the feasibility of this approach using two Drosophila Dopamine receptors (optoDopRs). We validated these optoDopRs showing that they exhibit high signaling specificity and light sensitivity in vitro. In vivo we detected receptor and cell type-specific effects of dopaminergic signaling in various behaviors including the ability of optoDopRs to rescue loss of the endogenous receptors. This work demonstrates that OptoXRs can enable optical control of neuromodulatory receptor specific signaling in functional and behavioral studies.

neuroscience↗

bioRxiv2022

Temporally extended and reversible neuronal silencing with Aion

Optogenetic silencing allows to reveal the necessity of selected neuronal populations for various neurophysiological functions ranging from specific behaviors to neuronal network activity. An ideal optogenetic silencing tool should be switchable between active and inactive states with precise timing while preserving its activity in the absence of light until switched to an inactive state. Although bistable anion-conducting channelrhodopsins (ACRs) were previously engineered to reach this goal, their conducting state life time was limited to only a few minutes and some ACRs were not fully switchable. Here we report Aion, a bistable ACR displaying a long-lasting open state with a spontaneous closing time constant close to 15 min. Moreover, Aion can be switched between the open and closed state with millisecond precision using blue and orange light, respectively. The long conducting state enables overnight silencing of neurons with minimal light exposure. We further generated trafficking-optimized versions of Aion, which show enhanced membrane localization and allow precisely timed, long-lasting all-optical control of nociceptive responses in larvae of Drosophila melanogaster.

neuroscience↗

bioRxiv2021

Optogenetic silencing of neurotransmitter release with a naturally occurring invertebrate rhodopsin

Information is carried between brain regions through neurotransmitter release from axonal presynaptic terminals. Understanding the functional roles of defined neuronal projection pathways in cognitive and behavioral processes requires temporally precise manipulation of their activity in vivo. However, existing optogenetic tools have low efficacy and off-target effects when applied to presynaptic terminals, while chemogenetic tools are difficult to control in space and time. Here, we show that a targeting-enhanced mosquito homologue of the vertebrate encephalopsin (eOPN3) can effectively suppress synaptic transmission through the Gi/o signaling pathway. Brief illumination of presynaptic terminals expressing eOPN3 triggers a lasting suppression of synaptic output that recovers spontaneously within minutes in vitro as well as in vivo. In freely moving mice, eOPN3-mediated suppression of dopaminergic nigrostriatal afferents leads to an ipsiversive rotational bias. We conclude that eOPN3 can be used to selectively suppress neurotransmitter release at synaptic terminals with high spatiotemporal precision, opening new avenues for functional interrogation of long-range neuronal circuits in vivo.

neuroscience↗

bioRxiv2020

Discrete escape responses are generated by neuropeptide-mediated circuit logic

Animals display a plethora of escape behaviors when faced with environmental threats. Selection of the appropriate response by the underlying neuronal network is key to maximize chances of survival. We uncovered a somatosensory network in Drosophila larvae that encodes two escape behaviors through input-specific neuropeptide action. Sensory neurons required for avoidance of noxious light and escape in response to harsh touch, each converge on discrete domains of the same neuromodulatory hub neurons. These gate harsh touch responses via short Neuropeptide F, but noxious light avoidance via compartmentalized, acute Insulin-like peptide 7 action and cognate Relaxin-family receptor signaling in connected downstream neurons. Peptidergic hub neurons can thus act as central circuit elements for first order processing of converging sensory inputs to gate specific escape responses. One Sentence SummaryCompartment-specific neuropeptide action regulates sensory information processing to elicit discrete escape behavior in Drosophila larvae.

neuroscience↗

bioRxiv2020

Optogenetic delivery of trophic signals in a genetic model of Parkinson's disease

Optogenetics has been harnessed to shed new mechanistic light on current therapies and to develop future treatment strategies. This has been to date achieved by the correction of electrical signals in neuronal cells and neural circuits that are affected by disease. In contrast, the optogenetic delivery of trophic biochemical signals, which support cell survival and thereby may modify progression of degenerative disorders, has never been demonstrated in an animal disease model. Here, we reengineered the human and Drosophila melanogaster REarranged during Transfection (hRET and dRET) receptors to be activated by light, creating one-component optogenetic tools termed Opto-hRET and Opto-dRET. Upon blue light stimulation, these receptors robustly induced the MAPK/ERK proliferative signaling pathway in cultured cells. In PINK1B9 flies that exhibit loss of PTEN-induced putative kinase 1 (PINK1), a kinase associated with familial Parkinsons disease (PD), light activation of Opto-dRET suppressed mitochondrial defects, tissue degeneration and behavioral deficits. In human cells with PINK1 loss-of-function, mitochondrial fragmentation was rescued using Opto-dRET via the PI3K/NF-[kcy]B pathway. Our results demonstrate that a light-activated receptor can ameliorate disease hallmarks in a genetic model of PD. The optogenetic delivery of trophic signals is cell type-specific and reversible and thus has the potential to overcome limitations of current strategies towards a spatio-temporal regulation of tissue repair. Significance StatementThe death of physiologically important cell populations underlies of a wide range of degenerative disorders, including Parkinsons disease (PD). Two major strategies to counter cell degeneration, soluble growth factor injection and growth factor gene therapy, can lead to the undesired activation of bystander cells and non-natural permanent signaling responses. Here, we employed optogenetics to deliver cell type-specific pro-survival signals in a genetic model of PD. In Drosophila and human cells exhibiting loss of the PINK1 kinase, akin to autosomal recessive PD, we efficiently suppressed disease phenotypes using a light-activated tyrosine kinase receptor. This work demonstrates a spatio-temporally precise strategy to interfere with degeneration and may open new avenues towards tissue repair in disease models.

neuroscience↗

bioRxiv2020

Antinociceptive modulation by the adhesion-GPCR CIRL promotes mechanosensory signal discrimination

Adhesion-type G protein-coupled receptors (aGPCRs) participate in a vast range of physiological processes. Correspondingly, these receptors are associated with diverse human diseases, such as developmental disorders, defects of the nervous system, allergies and cancer. Several aGPCRs have recently been linked to mechanosensitive functions suggesting that processing of mechanical stimuli may be a common feature of this receptor family. CIRL (ADGRL/Latrophilin, LPHN), one of the oldest members of the aGPCR family, sensitizes sensory responses of larval Drosophila to gentle touch and sound by amplifying mechanosensory signal transduction in low-threshold mechanoreceptors (Scholz et al., 2015; 2017). In the present study, we show that Cirl is also expressed in high-threshold mechanical nociceptors where it adjusts nocifensive behaviour under physiological and pathophysiological conditions. Optogenetic in vivo experiments indicate that CIRL quenches cAMP levels in both mechanosensory submodalities. However, contrasting its effect in touch sensitive neurons, CIRL dampens the response of nociceptors to mechanical stimulation. Consistent with this finding, rat nociceptors display a drop in Cirl1 expression during allodynia. Taken together, these results demonstrate that CIRL exerts opposing modulatory functions in low-threshold mechanosensors and high-threshold nociceptors. This intriguing bipolar action likely facilitates the separation of mechanosensory signals carrying different physiological information.

physiology↗

bioRxiv2019

Maintenance of cell type-specific connectivity and circuit function requires Tao kinase

Sensory circuits are typically established during early development, yet how circuit specificity and function are maintained during organismal growth has not been elucidated. To gain insight we quantitatively investigated synaptic growth and connectivity in the Drosophila nociceptive network during larval development. We show that connectivity between primary nociceptors and their downstream neurons scales with animal size. We further identified the conserved Ste20-like kinase Tao as a negative regulator of synaptic growth required for maintenance of circuit specificity and connectivity. Loss of Tao kinase resulted in exuberant postsynaptic specializations and aberrant connectivity during larval growth. Using functional imaging and behavioral analysis we show that loss of Tao-induced ectopic synapses with inappropriate partner neurons are functional and alter behavioral responses in a connection-specific manner. Our data show that fine-tuning of synaptic growth by Tao kinase is required for maintaining specificity and behavioral output of the neuronal network during animal growth.

neuroscience↗

bioRxiv2017

Artificial anion-conducting channelrhodopsins with tuned spectra, modified kinetics and enhanced light sensitivity

Genetic engineering of natural light-gated ion channels has proven a powerful way to generate optogenetic tools for a wide variety of applications. In recent years, blue light-activated engineered anion conducting channelrhodopsins (eACRs) have been developed, improved, and were successfully applied in vivo. We asked whether the approaches used to create eACRs can be transferred to other well-characterized cation-conducting channelrhodopsins (CCRs) to obtain eACRs with a broad spectrum of biophysical properties. We generated 22 variants using two conversion strategies applied to 11 CCRs and screened them for membrane expression, photocurrents and anion selectivity. We obtained two novel eACRs, Phobos and Aurora, with blue-and red-shifted action spectra and photocurrents similar to existing eACRs. Furthermore, step-function mutations greatly enhanced the cellular operational light sensitivity due to a slowed-down photocycle. These bistable eACRs can be reversibly toggled between open and closed states with brief light pulses of different wavelengths. All new eACRs reliably inhibited action potential firing in pyramidal CA1 neurons. In Drosophila larvae, eACRs conveyed robust and specific light-dependent inhibition of locomotion and nociception.

neuroscience↗