Cellular mechanisms to establish neuronal homeostatic setpoints during an embryonic critical period.
Final Report Abstract
Critical periods are transient developmental windows of heightened plasticity crucial for appropriate network function. During a critical period, networks are highly susceptible to activity perturbations, leading to lasting changes, while similar perturbations outside the critical period are less impactful. Critical periods have traditionally been studied in the mammalian visual system. Recently, they have been identified in various species and neuronal ensembles, from speech development in humans to motor behaviour in rats, fish, and insect larvae. The universality of critical periods across phyla is increasingly recognized, yet the underlying mechanisms remain complex and not fully understood. To address this, we use the nervous system of the fruit fly larva, Drosophila melanogaster, as a simpler model for studying critical periods. Despite its simplicity, Drosophila exhibits critical periods with features similar to those in mammals. The best-characterized critical period in Drosophila occurs during embryogenesis, associated with the larval locomotor network and normal crawling behaviour. Leveraging the annotated connectome of the Drosophila larval nervous system and genetic tools, we investigate cellular responses to critical period manipulations. Manipulations of neuronal activity, whether pharmacological, genetic, or optogenetic, during the critical period in Drosophila embryos, have been shown to decrease network stability, evidenced by increased recovery times from electric shock-induced seizures. Balanced network activity during critical period is necessary for forming stable, resilient networks, as supported by studies on seizure-prone parabss mutants, where transient re-balancing of activity during the critical period can permanently rescue the seizure phenotype. While perturbing neuronal activity is methodologically useful for studying critical periods, it might seem artificial. However, in poikilothermic animals like Drosophila, ambient temperature changes influence developmental speed and therefore potentially altering neuronal activity. For instance, temperature manipulation during embryonic development affects larval crawling speed and social feeding behaviour. Similarly, temperature manipulation during another critical period of Drosophila, during the end of pupariation, impacts adult neuronal wiring and behaviour. This study explores ambient temperature as an ecologically relevant critical period stimulus shaping nervous system development. Focusing on the Drosophila larval neuromuscular system, we find that different network components respond heterogeneously to transient heat stress during the critical period of locomotor network development. Increased temperature raises neuronal activity, and heat stress during the critical period leads to long-term reduced network stability, similar to activity manipulations. This includes presynaptic terminal overgrowth at the NMJ and changes in postsynaptic neurotransmitter receptor composition, while synaptic transmission remains homeostatically regulated. In central circuitry, embryonic heat stress reduces motoneuron excitability, potentially due to enhanced synaptic drive from premotor interneurons. This study provides a comprehensive analysis of how a locomotor network's interconnected elements develop differently in response to critical period perturbation by heat stress.
Publications
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Heterogeneous responses to embryonic critical period perturbations within the Drosophila larval locomotor circuit. openRxiv.
Krick, Niklas; Davies, Jacob; Coulson, Bramwell; Sobrido-Cameán, Daniel; Miller, Michael; Oswald, Matthew C. W.; Zarin, Aref A.; Baines, Richard & Landgraf, Matthias
