Dra. Fernanda Ceriani
Jefa de Laboratorio
Genética del Comportamiento Versión en español
Subject
Every organism has a biological clock that regulates metabolism, physiology, and behavior so that each takes place at the optimal time across day and night. Such biological (circadian) clocks allow them not only to anticipate but also to respond to internal and external challenges. Our laboratory explores how neuronal clocks communicate within each other and with the rest of the body to stay synchronized with the environment.
Our experimental model is an invertebrate, the fruit fly Drosophila melanogaster, which displays cycles of rest and activity reminiscent of those observed in humans, which also deteriorate with aging.
The temporal organization of activity depends upon the coordinated action of about 150 clock neurons in the brain of the adult fly. Each of these neurons expresses all the genes necessary to have a functional clock; however, for a fast (flexible) and sustained response, the coordinated reaction of the entire clock network is required. Some years ago our laboratory described that an essential group of clock neurons undergoes structural remodeling of their processes (that is, the structures through which they connect with other neurons) throughout the day, showing a rare plasticity in adult brains. This finding is the basis for many questions we are actively addressing to this date; what molecular mechanisms are recruited to carry out the remodeling process on daily basis? What properties does plasticity provide to the circadian network? Is circadian structural remodeling an inherent property of a clock neuron? The observation that synaptic connectivity changes across the day suggests that the communication between pairs of neurons, mediated by the release of neurotransmitters and neuropeptides, is concomitantly changing. These fundamental questions are at the center of our research program.
But this is only part of what we do.
The biological clock depends on a complex molecular network that integrates environmental and internal cues which are essential to sustaining the organism homeostasis. To explore integration with internal keys we also explore the link between metabolism and the molecular clock, and how a progressive dysfunction of this crosstalk affects lifespan. To address this fundamental problem, a number of years ago we carried out a genetic screen which uncovered a novel gene whose dysfunction is associated with early lethality. Its biochemical characterization uncovered an essential role in the regulation of lipid catabolism. These results, in turn, enable exploring how lipid metabolism affects development and how these alterations are modulated by the central clock. Thus, understanding this interaction has become another of the central goals of our laboratory.
Approach
We combine genetic approaches and behavioral analysis with molecular tools, immunohistochemical stainings and confocal fluorescence microscopy to analyze the role of different molecules in the specific processes we are interested in. Specifically, we use genetic tools to interfere with gene expression or the function of specific cell groups through the expression of genetically encoded RNAis or probes. We take advantage of thermo and chemogenetics coupled to calcium imaging as a proxy for neuronal activity to evaluate the consequences of different genetic interventions at different levels; at the molecular level through transcriptomic analysis; at the cellular and network levels through calcium imaging or the analysis of cellular morphology, and the intact animal through behavioral assays.
Advances
The long-term goal of our laboratory is to understand the neural basis of behavior; we investigate sleep-wake cycles, found in (almost) every animal, which depend on the activity of a discrete set of clock neurons organized in a network. Thus far we have focused on understanding how clock neurons communicate with each other; we uncovered that part of the physical connections (aka ¨synapses¨) between clock neurons are remodeled on daily basis. This form of plasticity (which we named circadian structural plasticity) enables them to connect and disconnect even to neurons that do not belong to the circadian network on daily basis! We also found that some clock neurons release more than one neurotransmitter (excitatory and inhibitory). All these observations suggest an unsuspected level of complexity within the circadian neural network, which could be essential in providing an adaptive response to the challenges provided by environmental conditions (for example, in preparation for daily or seasonal changes).
Every organism has a biological clock that regulates metabolism, physiology, and behavior so that each takes place at the optimal time across day and night. Such biological (circadian) clocks allow them not only to anticipate but also to respond to internal and external challenges. Our laboratory explores how neuronal clocks communicate within each other and with the rest of the body to stay synchronized with the environment.
Our experimental model is an invertebrate, the fruit fly Drosophila melanogaster, which displays cycles of rest and activity reminiscent of those observed in humans, which also deteriorate with aging.
The temporal organization of activity depends upon the coordinated action of about 150 clock neurons in the brain of the adult fly. Each of these neurons expresses all the genes necessary to have a functional clock; however, for a fast (flexible) and sustained response, the coordinated reaction of the entire clock network is required. Some years ago our laboratory described that an essential group of clock neurons undergoes structural remodeling of their processes (that is, the structures through which they connect with other neurons) throughout the day, showing a rare plasticity in adult brains. This finding is the basis for many questions we are actively addressing to this date; what molecular mechanisms are recruited to carry out the remodeling process on daily basis? What properties does plasticity provide to the circadian network? Is circadian structural remodeling an inherent property of a clock neuron? The observation that synaptic connectivity changes across the day suggests that the communication between pairs of neurons, mediated by the release of neurotransmitters and neuropeptides, is concomitantly changing. These fundamental questions are at the center of our research program.
But this is only part of what we do.
The biological clock depends on a complex molecular network that integrates environmental and internal cues which are essential to sustaining the organism homeostasis. To explore integration with internal keys we also explore the link between metabolism and the molecular clock, and how a progressive dysfunction of this crosstalk affects lifespan. To address this fundamental problem, a number of years ago we carried out a genetic screen which uncovered a novel gene whose dysfunction is associated with early lethality. Its biochemical characterization uncovered an essential role in the regulation of lipid catabolism. These results, in turn, enable exploring how lipid metabolism affects development and how these alterations are modulated by the central clock. Thus, understanding this interaction has become another of the central goals of our laboratory.
Approach
We combine genetic approaches and behavioral analysis with molecular tools, immunohistochemical stainings and confocal fluorescence microscopy to analyze the role of different molecules in the specific processes we are interested in. Specifically, we use genetic tools to interfere with gene expression or the function of specific cell groups through the expression of genetically encoded RNAis or probes. We take advantage of thermo and chemogenetics coupled to calcium imaging as a proxy for neuronal activity to evaluate the consequences of different genetic interventions at different levels; at the molecular level through transcriptomic analysis; at the cellular and network levels through calcium imaging or the analysis of cellular morphology, and the intact animal through behavioral assays.
Advances
The long-term goal of our laboratory is to understand the neural basis of behavior; we investigate sleep-wake cycles, found in (almost) every animal, which depend on the activity of a discrete set of clock neurons organized in a network. Thus far we have focused on understanding how clock neurons communicate with each other; we uncovered that part of the physical connections (aka ¨synapses¨) between clock neurons are remodeled on daily basis. This form of plasticity (which we named circadian structural plasticity) enables them to connect and disconnect even to neurons that do not belong to the circadian network on daily basis! We also found that some clock neurons release more than one neurotransmitter (excitatory and inhibitory). All these observations suggest an unsuspected level of complexity within the circadian neural network, which could be essential in providing an adaptive response to the challenges provided by environmental conditions (for example, in preparation for daily or seasonal changes).