Neuromodulatory signaling via G protein-coupled receptors (GPCRs) plays a pivotal role in regulating neural network function and animal behavior. The recent development of optogenetic tools to induce G protein-mediated signaling provides 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.
View Article and Find Full Text PDFDendrites are specialized neuronal compartments that sense, integrate and transfer information in the neural network. Their development is tightly controlled and abnormal dendrite morphogenesis is strongly linked to neurological disorders. While dendritic morphology ranges from relatively simple to extremely complex for a specified neuron, either requires a functional secretory pathway to continually replenish proteins and lipids to meet dendritic growth demands.
View Article and Find Full Text PDFInformation 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.
View Article and Find Full Text PDFNeurons sensing harmful mechanical forces in the larvae of fruit flies have a striking architecture of dendrites that are optimized to detect pointy objects.
View Article and Find Full Text PDFTwo-choice assays allow assessing of different behaviors including light avoidance in larvae. Typically, the readout is limited to a preference index at a specific end point. We provide a detailed protocol to set up light avoidance assays and map the temporal distribution of larvae based on analysis of larval intensities.
View Article and Find Full Text PDFOptogenetic silencing allows to reveal the necessity of selected neuronal populations for various neurophysiological functions. These range from synaptic transmission and coordinated neuronal network activity to control of specific behaviors. An ideal single-component 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.
View Article and Find Full Text PDFMicrotubule (MT) modifications are critical during axon development, with stable MTs populating the axon. How these modifications are spatially coordinated is unclear. Here, via high-resolution microscopy, we show that early developing neurons have fewer somatic acetylated MTs restricted near the centrosome.
View Article and Find Full Text PDFAnimals display selective escape behaviors when faced with environmental threats. Selection of the appropriate response by the underlying neuronal network is key to maximizing chances of survival, yet the underlying network mechanisms are so far not fully understood. Using synapse-level reconstruction of the Drosophila larval network paired with physiological and behavioral readouts, we uncovered a circuit that gates selective escape behavior for noxious light through acute and input-specific neuropeptide action.
View Article and Find Full Text PDFFly (Austin)
December 2022
Dendritic morphogenesis requires dynamic microtubules (MTs) to form a coordinated cytoskeletal network during development. Dynamic MTs are characterized by their number, polarity and speed of polymerization. Previous studies described a correlation between anterograde MT growth and terminal branch extension in dendritic arborization (da) neurons, suggesting a model that anterograde MT polymerization provides a driving force for dendritic branching.
View Article and Find Full Text PDFInformation is carried between brain regions through neurotransmitter release from axonal presynaptic terminals. Understanding the functional roles of defined neuronal projection pathways requires temporally precise manipulation of their activity. However, existing inhibitory 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.
View Article and Find Full Text PDFOptogenetics has been harnessed to shed new mechanistic light on current and future therapeutic strategies. This has been to date achieved by the regulation of ion flow and electrical signals in neuronal cells and neural circuits that are known to be affected by disease. In contrast, the optogenetic delivery of trophic biochemical signals, which support cell survival and are implicated in degenerative disorders, has never been demonstrated in an animal model of disease.
View Article and Find Full Text PDFAdhesion-type GPCRs (aGPCRs) participate in a vast range of physiological processes. Their frequent association with mechanosensitive functions suggests that processing of mechanical stimuli may be a common feature of this receptor family. Previously, we reported that the aGPCR CIRL sensitizes sensory responses to gentle touch and sound by amplifying signal transduction in low-threshold mechanoreceptors (Scholz et al.
View Article and Find Full Text PDFDendritic arborization is highly regulated and requires tight control of dendritic growth, branching, cytoskeletal dynamics, and ion channel expression to ensure proper function. Abnormal dendritic development can result in altered network connectivity, which has been linked to neurodevelopmental disorders, including autism spectrum disorders (ASDs). How neuronal growth control programs tune dendritic arborization to ensure function is still not fully understood.
View Article and Find Full Text PDFSensory 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.
View Article and Find Full Text PDFMultiple sclerosis (MS) is characterized by inflammatory insults that drive neuroaxonal injury. However, knowledge about neuron-intrinsic responses to inflammation is limited. By leveraging neuron-specific messenger RNA profiling, we found that neuroinflammation leads to induction and toxic accumulation of the synaptic protein bassoon (Bsn) in the neuronal somata of mice and patients with MS.
View Article and Find Full Text PDFDevelopmental pruning of axons and dendrites is crucial for the formation of precise neuronal connections, but the mechanisms underlying developmental pruning are not fully understood. Here, we have investigated the function of JNK signaling in dendrite pruning using class IV dendritic arborization (c4da) neurons as a model. We find that loss of JNK or its canonical downstream effectors Jun or Fos led to dendrite-pruning defects in c4da neurons.
View Article and Find Full Text PDFDendrite morphogenesis is a highly regulated process that gives rise to stereotyped receptive fields, which are required for proper neuronal connectivity and function. Specific classes of neurons, including Drosophila class IV dendritic arborization (C4da) neurons, also feature complete space-filling growth of dendrites. In this system, we have identified the substrate-derived TGF-β ligand maverick (mav) as a developmental signal promoting space-filling growth through the neuronal Ret receptor.
View Article and Find Full Text PDFA correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
View Article and Find Full Text PDFThermo-nociception, the detection and behavioral response to noxious temperatures, is a highly conserved action to avoid injury and ensure survival. Basic molecular mechanisms of thermal responses have been elucidated in several model organisms and are of clinical relevance as thermal hypersensitivity (thermos-allodynia) is common in neuropathic pain syndromes. larvae show stereotyped escape behavior upon noxious heat stimulation, which can be easily quantified and coupled with molecular genetic approaches.
View Article and Find Full Text PDFDuring differentiation, neurons require a high lipid supply for membrane formation as they elaborate complex dendritic morphologies. While glia-derived lipids support neuronal growth during development, the importance of cell-autonomous lipid production for dendrite formation has been unclear. Using Drosophila larva dendritic arborization (da) neurons, we show that dendrite expansion relies on cell-autonomous fatty acid production.
View Article and Find Full Text PDFGenetic 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.
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