Biology subjects

Shmueli, A.

Publications and source records attributed to Shmueli, A..

4 recordsLinked to original sources

bioRxiv2025

Cell-type-resolved RNA-seq reveals molecular engrams of sexual experience in Drosophila neuromodulatory neurons.

Flexible behavioral responses rely on the ability of neural circuits to adapt their physiology and output to changing social and environmental contexts. Neuromodulation plays a central role in this flexibility, dynamically tuning neuronal activity and gene expression to align behavior with experience and internal states. Yet how specific experiences and motivational conditions are encoded within neuromodulatory neurons remains underexplored. Here, we show that distinct motivational outcomes drive discrete, largely non-overlapping transcriptional programs across three neuromodulatory neuronal populations in male Drosophila brains. Using cell-type-resolved RNA sequencing, we profiled the transcriptomes of serotonergic (Trh), octopaminergic/tyraminergic (Tdc2), and neuropeptide F receptor (NPFR) neurons under three conditions: successful mating, sexual rejection, and the absence of social or sexual interaction. Each experience induced a unique "molecular engram" within specific neuron types. NPFR neurons exhibited the strongest transcriptional remodeling following rejection, Tdc2 neurons preferentially represented the naive-single state, and Trh neurons displayed balanced, experience-specific tuning. Shared differentially expressed genes across neuronal classes were few and often were oppositely regulated, revealing divergent circuit-specific logic. Experience triggered multilayered reprogramming across chromatin organization, RNA metabolism, translation, proteostasis and synaptic machinery, with selective recalibration of vesicle trafficking, and neuroplasticity. We further identified a compact, cross-circuit "rejection core" enriched for circadian, stress, metabolic, neuropeptidergic, and synaptic components. Together, these findings demonstrate how neuromodulatory circuits translate social experience into coordinated molecular and synaptic adaptations that enable behavioral flexibility.

neuroscience↗

bioRxiv2022

Sexual deprivation induces a CRF independent stress response and decreases resistance to stressors in Drosophila via a subpopulation of Neuropeptide F receptor-expressing neurons

Living in a changing environment composed of other behaving animals entails both opportunities and challenges to obtain resources and mating partners. Actions that promote survival and reproduction are reinforced by the brain reward systems, whereas coping with the challenges associated with obtaining these rewards are mediated by stress response pathways. The activation of the latter can impair health and shorten lifespan. Although similar responses to social opportunity and challenge exist across the animal kingdom, little is known about the mechanisms that process reward and stress under different social conditions. Here, we studied the interplay between deprivation of sexual reward and stress response in Drosophila melanogaster and discovered that repeated failures to obtain sexual reward induces a frustration-like state that is characterized by increased arousal, persistent sexual motivation, and impaired ability to cope with starvation and oxidative stressors. We show that this increased arousal and sensitivity to starvation is mediated by disinhibition of neurons that express receptors for the fly homologue of neuropeptide Y (neuropeptide F, NPF). We furthermore demonstrate the existence of an anatomical overlap between stress and reward systems in the fly brain in the form of neurons that co-express receptors for NPF (NPFR) and the corticotropin-releasing factor (CRF)-like homologue Diuretic hormone 44 (Dh44), and that deprivation of sexual reward leads to translocation of forkhead box-subgroup O (FoxO) to the cytoplasm in these neurons. Nevertheless, the activity of Dh44 neurons alone does not mediate sensitivity to starvation and aroused behavior following sexual deprivation, instead, these responses are mediated by disinhibition of ~12-16 NPFR-expressing neurons via a dynamin-independent synaptic signaling mechanism, suggesting the existence of a NPFR mediated stress pathway which is Dh44-independent. This paves the path for using simple model organisms to dissect mechanisms behind anticipation of reward, and more specifically, to determine what happens when expectations to obtain natural and drug rewards are not met.

animal behavior and cognition↗

bioRxiv2020

Transcriptome Analysis of NPFR Neurons Reveals a Connection Between proteome Diversity and Social Behavior

Complex social behaviors are mediated by the activity of highly intricate neuronal networks, the function of which is shaped by their transcriptomic and proteomic content. Contemporary advances in neurogenetics, genomics, and tools for automated behavior analysis make it possible to functionally connect the transcriptome profile of candidate neurons to their role in regulating behavior. In this study we used Drosophila melanogaster to explore the molecular signature of neurons expressing receptor for neuropeptide F (NPF), the fly homologue of neuropeptide Y (NPY). By comparing the transcription profile of NPFR neurons to those of nine other populations of neurons, we discovered that NPFR neurons exhibit a unique transcriptome, enriched with receptors for various neuropeptides and neuromodulators, as well as with genes known to regulate behavioral processes, such as learning and memory. By manipulating RNA editing and protein ubiquitination programs specifically in NPFR neurons, we demonstrate that their delicate transcriptome and proteome repertoires are required to suppress male courtship and certain features of social group interaction. Our results highlight the importance of transcriptome and proteome diversity in the regulation of complex behaviors and pave the path for future dissection of the spatiotemporal regulation of genes within highly complex tissues, such as the brain.

neuroscience↗

bioRxiv2018

Illuminating spatial A-to-I RNA editing signatures within the Drosophila brain

SummaryAdenosine-to-inosine (A-to-I) RNA editing, catalyzed by ADAR enzymes, is a ubiquitous mechanism that generates transcriptomic diversity. This process is particularly important for proper neuronal function; however, little is known about how RNA editing is dynamically regulated between the many functionally distinct neuronal populations of the brain. In this resource paper, we present a spatial RNA editing map in the Drosophila brain and show that different neuronal populations possess distinct RNA editing signatures. After purifying and sequencing RNA from genetically marked neuronal nuclei, we identified a large number of novel editing sites and compared editing levels in hundreds of transcripts across nine functionally different neuronal populations. We found distinct editing repertoires for each population, including novel sites in repeat regions of the transcriptome and differential editing in highly conserved and likely functional regions of transcripts that encode essential neuronal genes. These changes are site-specific and not driven by changes in Adar expression, suggesting a complex, targeted regulation of editing levels in key transcripts. This fine-tuning of the transcriptome between different neurons by RNA editing may account for functional differences between distinct populations in the brain.\n\nSignificance StatementA fundamental question in contemporary neuroscience is how the remarkable cellular diversity required for the intricate function of the nervous system is achieved. In this manuscript, we bridge the gap between a cellular machinery that is known to diversify the transcriptome and the existence of distinct neuronal populations that compose Drosophila brain. Adenosine-to-inosine (A-to-I) RNA-editing is a ubiquitous mechanism that generates transcriptomic diversity in cells by recoding certain adenosines within the pre-mRNA sequence into inosines. We present a spatial map of RNA editing across different neuronal populations in Drosophila brain. Each neuronal population has a distinct editing signature, with the majority of differential editing occurring in highly conserved regions of transcripts that encode ion channels and other essential neuronal genes.

neuroscience↗