Neural circuit mechanisms underlying context-specific halting inDrosophila

Abstract

Walking is a complex motor program involving coordinated and distributed activity across the brain and the spinal cord. Halting appropriately at the correct time is a critical but often overlooked component of walking control. While recent studies have delineated specific genetically defined neuronal populations in the mouse brainstem that drive different types of halting1–3, the underlying neural circuit mechanisms responsible for overruling the competing walking-state neural activity to generate context-appropriate halting, remain unclear. Here, we elucidate two fundamental mechanisms by whichDrosophilaimplement context-appropriate halting. The first mechanism (“walk-OFF” mechanism) relies on GABAergic neurons that inhibit specific descending walking commands in the brain, while the second mechanism (“brake” mechanism) relies on excitatory cholinergic neurons in the nerve-cord that lead to an active arrest of stepping movements. Using connectome-informed models4–6and functional studies, we show that two neuronal types that deploy the “walk-OFF” mechanism inhibit distinct populations of walking-promotion neurons, leading to differential halting of forward-walking or steering. The “brake” neurons on the other hand, override all walking commands by simultaneously inhibiting descending walking promoting pathways and increasing the resistance at the leg-joints leading to an arrest of leg movements in the stance phase of walking. We characterized two ethologically relevant behavioral contexts in which the distinct halting mechanisms were used by the animal in a mutually exclusive manner: the “walk-OFF” pathway was engaged for halting during feeding, and the “brake” pathway was engaged for halting during grooming. Furthermore, this knowledge of the neural targets and mechanisms for halting, allowed us to use connectomics to predict novel halting pathways that could be relevant in other behavioral contexts.

Presynaptic inhibition selectively suppresses leg proprioception in behavingDrosophila

“…In the female VNC connectome, some of the descending neurons presynaptic to chief 9A were recently annotated (Table S1 and Figure S8A). Three of these descending neurons are intersegmental cholinergic neurons that drive walking 37 (BDN2, oDN1) and turning 38 (DNa02), two of which (BDN2 and DNa02) were shown to be normally active during walking 37,38 . Another annotated descending neuron is a cholinergic neuron that drives front leg grooming 39 (DNg12).…”

Inhibitory control of locomotor statistics in walkingDrosophila

“…We next sought to develop a physiologically-inspired conceptual model of locomotor control that could account for the statistics we observed experimentally— in particular the shifts in statistics that occur between baseline walking and search behavior, and the changes in odor-evoked run length with baseline ground speed state. As our starting point, we considered that (1) multiple DNs contribute to both forward and angular velocity (Rayshubskiy et al 2020, Yang et al 2023, Braun et al 2023), (2) different units make different contributions to forward versus angular velocity (Rayshubskiy et al 2020, Yang et al 2023, Bresovec et al 2024, Aymanns et al, 2022), (3) bilateral activity correlates with forward velocity while activity differences between hemispheres correlate with angular velocity, both in some single neurons (Bidaye et al 2020, Yang et al 2023), and in population imaging (Bresovec et al 2024, Aymanns et al 2022), and (4) distinct sets of DNs promote stopping (Lee and Doe 2021, Sapkal et al 2023). Based on these considerations, we developed a simple model of locomotor control (Fig.…”

“…Individual DNs have been identified that generate forward walking, turning, or both, when activated (Cande et al 2018, Rayshubsky et al 2020, Bidaye et al 2020, Yang et al 2023). Other DNs promote stopping behavior (Cande et al 2018, Carreira-Rosasrio et al 2018, Lee and Doe, 2021, Sapkal et al 2023). While a small handful of DNs appear to function as “command-like neurons” and generate specific locomotor gestures, imaging studies suggest that many more DNs participate in locomotor control (Yang et al 2023, Aymanns et al 2022, Bresovec et al 2023, 2024).…”

Comparative connectomics of the descending and ascending neurons of theDrosophilanervous system: stereotypy and sexual dimorphism

“…We have established a platform for systematic neuron typing based on light-level and cross-dataset identification, which we encourage the community to utilise for studying their specific circuits of interest. Pre-publication access to our work has already benefited a number of publications ( Braun et al, 2023 ; H. S. J. Cheong et al, 2024 ; Dallmann et al, 2024 ; Lee et al, 2024 ; Lesser et al, 2024 ; Sapkal et al, 2023 ; Yang et al, 2023 ).…”