Neural circuits detect and process environmental changes to drive appropriate food-seeking or toxin-avoiding behaviors. However, we lack a complete understanding of the cellular and molecular mechanisms that represent chemosensory cues and generate appropriate behaviors. Furthermore, these vital sensory abilities deteriorate with age in humans and most animals, but it is unknown how aging impairs the underlying neural circuits to cause sensory behavioral declines. With powerful genetic tools, a complete connectome and robust chemosensory behaviors, the nematode Caenorhabditis elegans is ideally suited for a circuit-level analysis of these behaviors in young and aged animals. The aim of this dissertation is to identify neural signaling and circuit principles for flexibly encoding chemosensory stimuli and generating behavioral plasticity in C. elegans, which may be broadly conserved. In Chapters 2 and 3, I define a novel, sensory context- dependent and neuropeptide-regulated switch in the composition of a C. elegans salt sensory circuit. The ASE primary salt sensory neurons cleave and release insulin- like peptides in response to large but not small changes in external salt stimuli. Insulin signaling functionally switches the AWC olfactory sensory neuron into an interneuron in the high salt circuit, potentiating behavioral responses. Thus, sensory context and neuropeptide signaling act together to shape the flow of information in active neural circuits, suggesting a general mechanism for generating dynamic behavioral outputs. In Chapter 4, I identify an aging-associated decline in C. elegans olfactory behavior and map a novel underlying circuit motif. Two primary olfactory sensory neuron pairs, AWC and AWA, directly detect benzaldehyde and release insulin peptides and acetylcholine to activate two secondary neuron pairs, ASE and AWB, and drive behavioral plasticity. Interestingly, odor-evoked activity in the secondary, but not primary, neurons degrades with age. Experimental manipulations to increase primary neuron transmitter release rescue these aging-associated neuronal deficits. Furthermore, aged animals' olfactory abilities are correlated with lifespan, suggesting that olfaction may be indicative of overall health and physiology. These results show how chemosensory stimuli are encoded by a population code composed of primary and secondary neurons and suggest reduced neurotransmission as a novel mechanism driving aging-associated sensory neural activity and behavioral declines. In sum, this dissertation establishes the crucial role of peptidergic and classical neurotransmission in defining the active neural circuit configurations that regulate chemosensory behaviors

Mature behaviors emerge from neural circuits sculpted by genetic programs and spontaneous and evoked neural activity. However, how neural activity is refined to drive maturation of learned behavior remains poorly understood. Here, we explore how transient hormonal signaling coordinates a neural activity state transition and maturation of associative learning. We identify spontaneous, asynchronous activity in a Drosophila learning and memory brain region, the mushroom body. This activity declines significantly over the first week of adulthood. Moreover, this activity is generated cell-autonomously via Cacophony voltage-gated calcium channels in a single cell type, α'/β' Kenyon cells. Juvenile hormone, a crucial developmental regulator, acts transiently in α'/β' Kenyon cells during a young adult sensitive period to downregulate spontaneous activity and enable subsequent enhanced learning. Hormone signaling in young animals therefore controls a neural activity state transition and is required for improved associative learning, providing insight into the maturation of circuits and behavior.

For more than 100 years, the fruit fly Drosophila melanogaster has been one of the most studied model organisms. Here, we present a single-cell atlas of the adult fly, Tabula Drosophilae, that includes 580,000 nuclei from 15 individually dissected sexed tissues as well as the entire head and body, annotated to >250 distinct cell types. We provide an in-depth analysis of cell type-related gene signatures and transcription factor markers, as well as sexual dimorphism, across the whole animal. Analysis of common cell types between tissues, such as blood and muscle cells, reveals rare cell types and tissue-specific subtypes. This atlas provides a valuable resource for the Drosophila community and serves as a reference to study genetic perturbations and disease models at single-cell resolution.