Nervous system reprogramming by flexible neuropeptidergic networks

Información del proyecto

FLEXPEPNET

Identificador del acuerdo de subvención: 950328

DOI

10.3030/950328

Fecha de la firma de la CE 9 Noviembre 2020

Fecha de inicio 1 Enero 2021

Fecha de finalización 31 Diciembre 2026

Financiado con arreglo a

• EXCELLENT SCIENCE - European Research Council (ERC)

Coste total

€ 1 559 807,50

Aportación de la UE

€ 1 559 807,50

Coordinado por

KATHOLIEKE UNIVERSITEIT LEUVEN
Belgium

Periodic Reporting for period 3 - FLEXPEPNET (Nervous system reprogramming by flexible neuropeptidergic networks)

Período documentado: 2024-01-01 hasta 2025-06-30

Resumen del contexto y de los objetivos generales del proyecto

Animal brains are wired according to a series of remarkable genetic programs that evolved over millions of years. Much of our behavior, however, is shaped by past experiences that influence our decisions and help us adapt to a dynamic environment. Especially environmental stressors exert profound and long-lasting effects on animal behavior. One important mechanism for dealing with such challenging circumstances is the generation of behavioral responses to avoid or even escape a harmful environment. Yet how aversive, long-term experiences are molecularly encoded in the brain and reprogram behavior remains poorly understood. This project seeks to deliver a much-needed understanding of how neuropeptidergic signaling is sculpted by persistent aversive experience and how it in turn adapts behavior. Neuropeptides are one of the largest and most diverse groups of signaling molecules in the brain. We hypothesize that long-term exposure to aversive environmental changes alters the expression and actions of these molecules to gradually adjust behavior. We are addressing this using the compact oxygen-sensing circuit of the roundworm C. elegans, which generates robust oxygen-dependent behaviors using neuropeptides. Because peptidergic networks are highly complex, such a controlled context for pioneering research on their role in coding aversive experience is preferable.
The C. elegans nervous system is exquisitely suited to study how neuropeptides adapt behavior because it counts only 302 brain cells and a map detailing all physical connections between these neurons, or “connectome”, has been established. Indeed, the diversity of neuropeptides within the animal brain results in exceedingly complex and intertwined neuropeptide signaling networks that are difficult to study in the vertebrate brain. We will first map out the neuropeptide-receptor pathways and develop tools to visualize neuropeptide signaling within the C. elegans nervous system. This will allow us to characterize plasticity in the expression of neuropeptides and their receptors induced by long-term aversive experience with unprecedented detail. We will then determine the effects of this peptidergic network on the activity of neural circuits and animal behavior. By establishing how aversive experience alters the structure of neuropeptide signaling networks and the control of behavioral states in the roundworm, we expect to boost our understanding of how neuropeptidergic plasticity governs behaviors in all sorts of animal brains, even potentially human ones.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

Neuropeptides represent a large and diverse class of signaling molecules in the brain that have important functions in experience-dependent plasticity. Understanding how experience impacts the structure and organization of this signaling network, however, is a daunting task due to the diversity and complexity of neuropeptide signaling pathways in the brain. We have reconstructed the neuropeptide network of the entire C. elegans nervous system in silico to penetrate this complexity. This “neuropeptide connectome” yields an unprecedented bird’s-eye-view on how neuropeptide signaling pathways are organized within the animal brain, in addition to having uncovered a variety of neuropeptidergic pathways that link specific brain circuits, like the oxygen-sensing circuit, to other brain areas. We have identified experience-dependent changes in neuropeptide network structure, tested animals defective for these neuropeptides and their receptors for different oxygen-dependent behaviors, and identified several neuropeptide systems that drive the behavioral adaptations following long-term exposure to aversive oxygen levels. We are now deploying tools to directly monitor neuropeptide signaling to understand which brain regions are affected upon different types of aversive experience. Specifically, we implemented a novel transcription-based activation sensor that produces a stable fluorescent readout upon neuropeptide receptor activation. The sensor allows monitoring receptor activation upon exogenous application of neuropeptide ligands, in response to optogenetically-induced neuropeptide release, and under conditions entailing endogenous neuropeptide release. Given it can be modularly applied to different neuropeptide receptors, we are validating its use for a panel of candidate receptors and circuits. Finally, we are using direct genetic manipulations and neural activity recordings to understand how the activity of target brain regions is shaped by experience-dependent changes in neuropeptide signaling, and how this ultimately affects behavior. Altogether, these findings provide a scaffold to further unravel how aversive experience influences the structure of neuropeptidergic signaling networks and mediates long-term behavioral changes. Moreover, our newly developed technologies can be used to study neuropeptide signaling in a variety of biological contexts with unprecedented detail.

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

Neuropeptides are increasingly being recognized as neural signaling molecules that provoke long-lasting changes in neural circuits and behavior. Yet, how experience shapes these signaling networks and how this in turn modifies behavior remains poorly understood. By assessing neuropeptide signaling pathways across the entire nervous system of the miniature worm C. elegans, we are delivering an unprecedented brain-wide view on the organization of neuropeptide signaling in the animal brain. This neuropeptide connectome encompasses the worm’s entire brain and connects brain regions that would otherwise not be able to exchange signals through synaptic connections alone. Using this network, we found the small and well-described oxygen sensing circuit to produce multiple neuropeptides that adjust worm behavior after prolonged exposure to aversive oxygen levels. We are developing genetically-encoded sensors for neuropeptide signaling to understand exactly which brain regions are affected by these molecules. This suggests conditional neuropeptide transmission, i.e. neuropeptides being released and exerting their function only under specific circumstances, to be an important feature shaping the structure and function of the neuropeptide connectome. As neuropeptides have ancient origins and their networks exhibit evolutionary conservation in their structure, our insights into how neuropeptide signaling and function is shaped by experience are likely to guide similar thinking about the largely uncharacterized neuropeptide networks of the mammalian brain. Furthermore, we also anticipate the technological innovation of neuropeptide GPCR sensors to spill over into many new conceptual advancements in the neuroscience field, as the newly developed tools are broadly applicable to investigate neuropeptidergic modulation of diverse brain functions, such as learning, memory, sleep and development.

Neuropeptide signaling map and activity sensors in the C. elegans nervous system