NeuroPSI – Université Paris-Saclay

Feeding state-dependent neuropeptidergic modulation of a sensorimotor circuit biases non-feeding related decisions in Drosophila larva

Résumé
Behavioral flexibility, the capacity to adapt behavior in response to changes in the environment or internal state, is a fundamental aspect of animal behavior, essential for survival and reproductive success. Notably, an animal’s feeding state strongly influences its behavior, even beyond feeding-related choices and impact even decisions unrelated to feeding. While feeding state-dependent modulation of feeding related behaviors have been extensively studied, how feeding state information modulates decision circuits not directly tied to feeding behaviors is an ongoing question in neuroscience. This project aims to shed light on the intricate relationships between physiological states, neural circuits, and behavior, crucial for comprehending brain function in health and disease.

We delve into the mechanisms of feeding-state dependent neural circuit modulation in Drosophila larvae, leveraging this model organism’s genetic tools and relatively simple nervous system to scrutinize the mechanisms of modulation of a neural circuit involved in larval sensorimotor decision-making. Specifically, this circuit orchestrates the choice between two mutually exclusive actions (hunching, a startle response and head-casting, an active avoidance response) in response to an aversive mechanical stimulation. Early in sensory processing, reciprocally connected inhibitory interneurons engaged in several sub-motifs drive the output state of this circuit, with reciprocal inhibition of inhibition implementing behavioral choice and feedback disinhibition providing positive feedback to consolidate the head-cast. Such circuit architecture allows for a flexible selection of the output behavior, which is probabilistic both between and within individuals. Starving larvae or feeding them only on sucrose, biases their decisions towards more head-casting at the expense of hunching by modulating the activity of two interconnected inhibitory interneurons.

In order to study the mechanisms of modulation of this circuit, we employ a combination of techniques including cell-specific neuropeptide manipulations, calcium imaging, behavioral analysis and connectomics. We focused on the neuropeptides NPF and sNPF, related to the mammalian NPY and known regulators of feeding behaviors. While both neuropeptides’ receptors are expressed in mechanosensory neurons, our findings show their modulation is not essential to bias larva decisions to an air puff. Instead, sNPF and NPF differentially modulate interconnected inhibitory interneurons in a feeding state-dependent manner, influencing circuit computations. We show that the projection neurons of the circuit do not express receptors for either sNPF or NPF, while the inhibitory interneurons express different combinations of receptors. This suggests that the interneurons are targets of modulation while the projection neurons relay the decision to the motor side. Indeed, reduction of sNPF signaling on these interneurons biases the choice of the larvae towards less hunching and more head-casting by oppositely regulating their activity, partially recapitulating a “sucrose-like” or “starvation-like” phenotype. Furthermore, NPF-neurons activity is increased upon sucrose feeding and starvation, and that NPF itself is necessary for the feeding state-dependent modulation of larval baseline locomotion. Moreover, NPF is responsible for an increase in the activity of specifically one of the interneurons, which suppresses hunches and promotes head-casts.

In conclusion, our data propose that this pair of interconnected inhibitory interneurons serves as an integration hub for physiological state information conveyed by neuropeptides, thus biasing behavioral choice based on the feeding state. These insights lay the groundwork for understanding state-dependent neuromodulation mechanisms in more complex brains, specifically those that and hold potential implications for treating neuropsychiatric disorders, including eating disorders.

Composition du Jury

• • Dr. Yaël Grosjean (Reviewer, Directeur de recherche, CNRS/INRAE/Université de Bourgogne, France)
  • Dr. Dennis Pauls (Reviewer, Group leader University of Leipzig, Germany)
  • Dr. Jimena Berni (Examiner, Group leader, University of Sussex, United-Kingdom)
  • Dr. Mohammed Taouis (Examiner, Professeur des universités, CNRS, Institut NeuroPSI, France)

et

• Dr. Tihana Jovanic (Group leader, CNRS Institut NeuroPSI, France)