Biology subjects

Morelli, L. G.

Publications and source records attributed to Morelli, L. G..

6 recordsLinked to original sources

bioRxiv2024

Neuronal synchronization in Drosophila

Rhythms are intrinsic to biological processes across temporal and spatial scales. In the brain, the synchronized oscillatory activity of neurons creates collective rhythms that are essential for complex functions. While this is a recognized phenomenon in the mammalian brain, information about insect neuronal synchrony and its underlying mechanisms is scarce. In the fly brain, neuronal oscillations were reported in individual lateral ventral neurons (LNvs), which play a key role in circadian and sleep behaviors. However, it is still unclear whether and how these participate in a collective rhythm. In this work, we perform thorough whole-cell patch clamp recordings of LNvs, and demonstrate consistent membrane potential oscillations. We show that oscillations degrade over time, and disappear upon exposure to an acetylcholine receptor blocker. Together with a flat phase response curve, these results suggest that oscillations are exogenously produced. Prompted by these results, we propose a generic forced oscillator theory that can account for the experimental phase response. The theory further predicts that neurons with similar properties should oscillate in synchrony with zero lags, while neurons with different properties may show coherent oscillations with non-zero lags. We confirm this prediction through simultaneous patch clamp recordings of neuronal pairs, revealing that large LNvs are consistently advanced relative to small LNvs. Additionally, we find that other neurons in the accessory medulla also exhibit coherent membrane potential oscillations, with diverse lags. Our findings suggest the intriguing possibility that brain waves may arise from collective neuronal activity within this region of the fly brain.

neuroscience↗

bioRxiv2024

Multiple Notch ligands in the synchronization of the segmentation clock

Notch signaling is a ubiquitous and versatile intercellular signaling system that drives collective behaviors and pattern formation in biological tissues. During embryonic development, Notch is involved in generation of collective biochemical oscillations that form the vertebrate body segments, and its failure results in embryonic defects. Notch ligands of the Delta family are key components of this collective rhythm, but it is unclear how different Delta ligands with distinct properties contribute to relaying information among cells. Motivated by the zebrafish segmentation clock, in this work we propose a theory describing interactions between biochemical oscillators, where Notch receptor is bound by both oscillatory and nonoscillatory Delta ligands. Based on previous in vitro binding studies, we first consider Notch activation by Delta dimers. This hypothesis is consistent with experimental observations in conditions of perturbed Notch signaling. Then we test an alternative hypothesis where Delta monomers directly bind and activate Notch, and show that this second model can also describe the experimental observations. We show that these two hypotheses assign different roles for a non-oscillatory ligand, as a binding partner or as a baseline signal. Finally, we discuss experiments to distinguish between the two scenarios. Broadly, this work highlights how a multiplicity of ligands may be harnessed by a signaling system to generate versatile responses.

developmental biology↗

bioRxiv2024

Statistical description of mobile oscillators in embryonic pattern formation

Synchronization of mobile oscillators occurs in numerous contexts, including physical, chemical, biological and engineered systems. In vertebrate embryonic development, a segmental body structure is generated by a population of mobile oscillators. Cells in this population produce autonomous gene expression rhythms, and interact with their neighbors through local signaling. These cells form an extended tissue where frequency and cell mobility gradients coexist. Gene expression kinematic waves travel through this tissue and pattern the segment boundaries. It has been shown that oscillator mobility promotes global synchronization. However, in vertebrate segment formation, mobility may also introduce local fluctuations in kinematic waves and impair segment boundaries. Here we derive a general framework for mobile oscillators that relates local mobility fluctuations to synchronization dynamics and pattern robustness. We formulate a statistical description of mobile phase oscillators in terms of a probability density. We obtain and solve diffusion equations for the average phase and variance, revealing the relationship between local fluctuations and global synchronization in a homogeneous population of oscillators. Analysis of the probability density for large mobility identifies a mean-field transition, where locally coupled oscillators start behaving as if each oscillator was coupled with all the others. We extend the statistical description to inhomogeneous systems to address the gradients present in the vertebrate segmenting tissue. The theory relates pattern stability to mobility, coupling and pattern wavelength. The general approach of the statistical description may be applied to mobile oscillators in other contexts, as well as to other patterning systems where mobility is present.

developmental biology↗

bioRxiv2023

Clock driven waves of Tbx6 expression prefigure somite boundaries

The segmented body plan of vertebrates is established during embryogenesis by periodic and sequential formation of multi-cellular structures called somites. Somitogenesis is an example of patterning by a biological oscillator, the segmentation clock, which manifests as traveling waves of oscillating Hes/Her gene expression, reiterating during the formation of each1-3. How these waves are converted into the striped Mesp gene expression pattern that prefigures morphological somite boundaries4-8 remains unclear. Here, we image this conversion in real-time at single-cell resolution in zebrafish, using light-sheet microscopy of a novel reporter of Tbx6, a key activator of Mesp expression. We observe cellular oscillations and kinematic waves of Tbx6 expression that are driven by Hes/Her genes. Tbx6 waves arrest precisely in boundary cells that eventually express Mesp, thereby prefiguring the Mesp pattern, whereas Hes/Her waves do not. Although Hes/Her oscillations began before somitogenesis9-11, the first Tbx6 wave defines the boundary cells of the anterior-most somite, forming the head-trunk interface. Our findings imply that Tbx6 acts as a genetic clutch, converting Her/Hes pacemaker waves into Mesp stripes. We propose that this clock design shields the pacemaker from external perturbations, allowing flexible and robust patterning, making it of interest for organoids and tissue-engineering.

developmental biology↗

bioRxiv2022

Adult-born granule cells improve stimulus encoding and discrimination in the dentate gyrus

Heterogeneity plays an important role in diversifying neural responses to support brain function. Adult neurogenesis provides the dentate gyrus with a heterogeneous population of granule cells (GCs) that were born and developed their properties at different times. Immature GCs have distinct intrinsic and synaptic properties than mature GCs and are needed for correct encoding and discrimination in spatial tasks. How immature GCs enhance the encoding of information to support these functions is not well understood. Here, we record the responses to fluctuating current injections of GCs of different ages to study how they encode stimuli. Immature GCs produce unreliable responses compared to mature GCs, exhibiting imprecise spike timings across repeated stimulation. We use a statistical model to describe the stimulus-response transformation performed by GCs of different ages. We fit this model to the data and obtain parameters that capture GCs encoding properties. Parameter values from this fit reflect the maturational differences of the population and indicate that immature GCs perform a differential encoding of stimuli. To study how this age heterogeneity influences encoding by a population, we perform stimulus decoding using populations that contain GCs of different ages. We find that, despite their individual unreliability, immature GCs enhance the fidelity of the signal encoded by the population and improve the discrimination of similar time dependent stimuli. Thus, the observed heterogeneity confers the population with enhanced encoding capabilities.

neuroscience↗

bioRxiv2020

Intermittent ERK oscillations downstream of FGF in mouse embryonic stem cells

Signal transduction networks process extracellular signals to guide cell fate decisions such as to divide, differentiate, or die. These networks can generate characteristic dynamic activities that are shaped by their cell-type specific architecture. The differentiation of pluripotent cells is controlled by FGF/ERK signaling. However, the dynamic activity of the FGF/ERK signaling network in this context remains unexplored. Here we use live cell sensors in wild type and Fgf4 mutant mouse embryonic stem cells to measure ERK dynamic activity in single cells, in response to defined ligand concentrations. We find that ERK activity oscillates in embryonic stem cells. Single cells can transit between oscillatory and non-oscillatory behavior, leading to heterogeneous dynamic activities in the population. Oscillations become more prevalent with increasing FGF4 dose, while maintaining a robust characteristic timescale. Our results suggest that FGF/ERK signaling operates in the vicinity of a transition point between oscillatory and non-oscillatory dynamics in embryonic stem cells.

developmental biology↗