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3867 Publications
Showing 121-130 of 3867 resultsMany neurons in the central nervous system produce a single primary cilium that serves as a specialized signaling organelle. Several neuromodulatory G-protein-coupled receptors (GPCRs) localize to primary cilia in neurons, although it is not understood how GPCR signaling from the cilium impacts circuit function and behavior. We find that the vertebrate ancient long opsin A (VALopA), a G-coupled GPCR extraretinal opsin, targets to cilia of zebrafish spinal neurons. In the developing 1-d-old zebrafish, brief light activation of VALopA in neurons of the central pattern generator circuit for locomotion leads to sustained inhibition of coiling, the earliest form of locomotion. We find that a related extraretinal opsin, VALopB, is also G-coupled, but is not targeted to cilia. Light-induced activation of VALopB also suppresses coiling, but with faster kinetics. We identify the ciliary targeting domains of VALopA. Retargeting of both opsins shows that the locomotory response is prolonged and amplified when signaling occurs in the cilium. We propose that ciliary localization provides a mechanism for enhancing GPCR signaling in central neurons.
Rhodamine dyes are excellent scaffolds for developing a broad range of fluorescent probes. A key property of rhodamines is their equilibrium between a colorless lactone and fluorescent zwitterion. Tuning the lactone–zwitterion equilibrium constant (KL–Z) can optimize dye properties for specific biological applications. Here, we use known and novel organic chemistry to prepare a comprehensive collection of rhodamine dyes to elucidate the structure–activity relationships that govern KL–Z. We discovered that the auxochrome substituent strongly affects the lactone–zwitterion equilibrium, providing a roadmap for the rational design of improved rhodamine dyes. Electron-donating auxochromes, such as julolidine, work in tandem with fluorinated pendant phenyl rings to yield bright, red-shifted fluorophores for live-cell single-particle tracking (SPT) and multicolor imaging. The N-aryl auxochrome combined with fluorination yields red-shifted Förster resonance energy transfer (FRET) quencher dyes useful for creating a new semisynthetic indicator to sense cAMP using fluorescence lifetime imaging microscopy (FLIM). Together, this work expands the synthetic methods available for rhodamine synthesis, generates new reagents for advanced fluorescence imaging experiments, and describes structure–activity relationships that will guide the design of future probes.
The interplay between two major forebrain structures - cortex and subcortical striatum - is critical for flexible, goal-directed action. Traditionally, it has been proposed that striatum is critical for selecting what type of action is initiated while the primary motor cortex is involved in the online control of movement execution. Recent data indicates that striatum may also be critical for specifying movement execution. These alternatives have been difficult to reconcile because when comparing very distinct actions, as in the vast majority of work to date, they make essentially indistinguishable predictions. Here, we develop quantitative models to reveal a somewhat paradoxical insight: only comparing neural activity during similar actions makes strongly distinguishing predictions. We thus developed a novel reach-to-pull task in which mice reliably selected between two similar, but distinct reach targets and pull forces. Simultaneous cortical and subcortical recordings were uniquely consistent with a model in which cortex and striatum jointly specify flexible parameters of action during movement execution.
Focal epilepsy is associated with intermittent brief population discharges (interictal spikes), which resemble sentinel spikes that often occur at the onset of seizures. Why interictal spikes self-terminate whilst seizures persist and propagate is incompletely understood. We used fluorescent glutamate and GABA sensors in an awake rodent model of neocortical seizures to resolve the spatiotemporal evolution of both neurotransmitters in the extracellular space. Interictal spikes were accompanied by brief glutamate transients which were maximal at the initiation site and rapidly propagated centrifugally. GABA transients lasted longer than glutamate transients and were maximal ∼1.5 mm from the focus where they propagated centripetally. Prior to seizure initiation GABA transients were attenuated, whilst glutamate transients increased, consistent with a progressive failure of local inhibitory restraint. As seizures increased in frequency, there was a gradual increase in the spatial extent of spike-associated glutamate transients associated with interictal spikes. Neurotransmitter imaging thus reveals a progressive collapse of an annulus of feed-forward GABA release, allowing seizures to escape from local inhibitory restraint.
Segmentation of objects in microscopy images is required for many biomedical applications. We introduce object-centric embeddings (OCEs), which embed image patches such that the spatial offsets between patches cropped from the same object are preserved. Those learnt embeddings can be used to delineate individual objects and thus obtain instance segmentations. Here, we show theoretically that, under assumptions commonly found in microscopy images, OCEs can be learnt through a self-supervised task that predicts the spatial offset between image patches. Together, this forms an unsupervised cell instance segmentation method which we evaluate on nine diverse large-scale microscopy datasets. Segmentations obtained with our method lead to substantially improved results, compared to state-of-the-art baselines on six out of nine datasets, and perform on par on the remaining three datasets. If ground-truth annotations are available, our method serves as an excellent starting point for supervised training, reducing the required amount of ground-truth needed by one order of magnitude, thus substantially increasing the practical applicability of our method. Source code is available at github.com/funkelab/cellulus.
Navigating animals continuously integrate velocity signals to update internal representations of their directional heading and spatial location in the environment. How neural circuits combine sensory and motor information to construct these velocity estimates and how these self-motion signals, in turn, update internal representations that support navigational computations are not well understood. Recent work in Drosophila has identified a neural circuit that performs angular path integration to compute the fly's head direction, but the nature of the velocity signal is unknown. Here we identify a pair of neurons necessary for angular path integration that encode the fly's rotational velocity with high accuracy using both visual optic flow and motor information. This estimate of rotational velocity does not rely on a moment-to-moment integration of sensory and motor information. Rather, when visual and motor signals are congruent, these neurons prioritize motor information over visual information, and when the two signals are in conflict, reciprocal inhibition selects either the motor or visual signal. Together, our results suggest that flies update their head direction representation by constructing an estimate of rotational velocity that relies primarily on motor information and only incorporates optic flow signals in specific sensorimotor contexts, such as when the motor signal is absent.
Lysosomes play crucial roles in maintaining cellular homeostasis and promoting organism fitness. The pH of lysosomes is a crucial parameter for their proper function, and it is dynamically influenced by both intracellular and environmental factors. Here, we present a method based on fluorescence lifetime imaging microscopy (FLIM) for quantitatively analyzing lysosomal pH profiles in diverse types of primary mammalian cells and in different tissues of the live organism Caenorhabditis elegans. This FLIM-based method exhibits high sensitivity in resolving subtle pH differences, thereby revealing the heterogeneity of the lysosomal population within a cell and between cell types. The method enables rapid measurement of lysosomal pH changes in response to various environmental stimuli. Furthermore, the FLIM measurement of pH-sensitive dyes circumvents the need for transgenic reporters and mitigates potential confounding factors associated with varying dye concentrations or excitation light intensity. This FLIM approach offers absolute quantification of lysosomal pH and highlights the significance of lysosomal pH heterogeneity and dynamics, providing a valuable tool for studying lysosomal functions and their regulation in various physiological and pathological contexts.
Foraging animals must use decision-making strategies that dynamically adapt to the changing availability of rewards in the environment. A wide diversity of animals do this by distributing their choices in proportion to the rewards received from each option, Herrnstein’s operant matching law. Theoretical work suggests an elegant mechanistic explanation for this ubiquitous behavior, as operant matching follows automatically from simple synaptic plasticity rules acting within behaviorally relevant neural circuits. However, no past work has mapped operant matching onto plasticity mechanisms in the brain, leaving the biological relevance of the theory unclear. Here we discovered operant matching in Drosophila and showed that it requires synaptic plasticity that acts in the mushroom body and incorporates the expectation of reward. We began by developing a novel behavioral paradigm to measure choices from individual flies as they learn to associate odor cues with probabilistic rewards. We then built a model of the fly mushroom body to explain each fly’s sequential choice behavior using a family of biologically-realistic synaptic plasticity rules. As predicted by past theoretical work, we found that synaptic plasticity rules could explain fly matching behavior by incorporating stimulus expectations, reward expectations, or both. However, by optogenetically bypassing the representation of reward expectation, we abolished matching behavior and showed that the plasticity rule must specifically incorporate reward expectations. Altogether, these results reveal the first synaptic level mechanisms of operant matching and provide compelling evidence for the role of reward expectation signals in the fly brain.
How memories are used by the brain to guide future action is poorly understood. In olfactory associative learning in Drosophila, multiple compartments of the mushroom body act in parallel to assign valence to a stimulus. Here, we show that appetitive memories stored in different compartments induce different levels of upwind locomotion. Using a photoactivation screen of a new collection of split-GAL4 drivers and EM connectomics, we identified a cluster of neurons postsynaptic to the mushroom body output neurons (MBONs) that can trigger robust upwind steering. These UpWind Neurons (UpWiNs) integrate inhibitory and excitatory synaptic inputs from MBONs of appetitive and aversive memory compartments, respectively. After training, disinhibition from the appetitive-memory MBONs enhances the response of UpWiNs to reward-predicting odors. Blocking UpWiNs impaired appetitive memory and reduced upwind locomotion during retrieval. Photoactivation of UpWiNs also increased the chance of returning to a location where activation was initiated, suggesting an additional role in olfactory navigation. Thus, our results provide insight into how learned abstract valences are gradually transformed into concrete memory-driven actions through divergent and convergent networks, a neuronal architecture that is commonly found in the vertebrate and invertebrate brains.
The mushroom body (MB) is the center for associative learning in insects. In Drosophila, intersectional split-GAL4 drivers and electron microscopy (EM) connectomes have laid the foundation for precise interrogation of the MB neural circuits. However, many cell types upstream and downstream of the MB remained to be investigated due to lack of driver lines. Here we describe a new collection of over 800 split-GAL4 and split-LexA drivers that cover approximately 300 cell types, including sugar sensory neurons, putative nociceptive ascending neurons, olfactory and thermo-/hygro-sensory projection neurons, interneurons connected with the MB-extrinsic neurons, and various other cell types. We characterized activation phenotypes for a subset of these lines and identified the sugar sensory neuron line most suitable for reward substitution. Leveraging the thousands of confocal microscopy images associated with the collection, we analyzed neuronal morphological stereotypy and discovered that one set of mushroom body output neurons, MBON08/MBON09, exhibits striking individuality and asymmetry across animals. In conjunction with the EM connectome maps, the driver lines reported here offer a powerful resource for functional dissection of neural circuits for associative learning in adult Drosophila.