Biology subjects

Butts, A. R.

Publications and source records attributed to Butts, A. R..

6 recordsLinked to original sources

bioRxiv2026

Arc capsid signaling between serotonergic and dopaminergic neurons sets sleep depth in Drosophila

Arc genes evolved from Ty3 retrotransposons and encode proteins that self-assemble into virus-like capsids that package and transfer RNA between cells. This capsid-forming property may mediate a form of intercellular signaling distinct from classical synaptic transmission, but whether it operates within a defined neuronal system to control an ongoing behavior remains unclear. Here we show that Arc-dependent capsid signaling links serotonergic and PAM neurons to set sleep depth in Drosophila melanogaster. Loss of dArc genes deepened and consolidated sleep, increasing both sleep depth and the arousal threshold to mechanical stimulation, while leaving the diurnal sleep pattern intact. dArc1 was required in serotonergic neurons and, to a lesser extent, in PAM neurons, and both the loss-of-function phenotype and its rescue depended on capsid formation. Knocking down dArc1 in Sas-expressing cells, or Ptp10D in PAM neurons, reproduced the deeper, more consolidated sleep of dArc-/-flies, implicating the Sas-Ptp10D machinery in this signaling. These results identify Arc-dependent capsid signaling as a mechanism that links two modulatory neuronal populations to regulate an ongoing homeostatic behavior.

neuroscience↗

bioRxiv2025

Connectivity biases generate a learning hierarchy in the Drosophila mushroom body

Learning and memory centers must balance maximizing coding capacity with prioritizing biologically relevant information. Expansion layers, a circuit motif common to many learning and memory centers, including the insect mushroom body, transform dense sensory representations into sparse, distributed ones, and theoretical models propose that random connectivity within these layers maximizes coding capacity by generating highly discriminable responses. Yet this solution creates a fundamental problem: purely random connectivity treats all stimuli equally, without prioritizing survival-relevant cues over neutral ones. Here, we show that the Drosophila melanogaster mushroom body resolves this capacity-selectivity trade-off through systematic biases in projection neuron-Kenyon cell connectivity. Although connectivity is random at the single-cell level, some projection neuron types connect up to 15-fold more frequently than others. These biases translate directly into function: Kenyon cell responses scales with projection neuron connectivity, and the breadth of odor-evoked responses predicts learning performance. Odors activating more than 20% of Kenyon cells drive robust associative memories, whereas those activating fewer than 10% are poorly learned. VL1 projection neurons are a notable exception: despite their weak connectivity, they elicit broad Kenyon cell activity but fail to support learning, revealing a circuit-level gate on learning. These results show that the mushroom body embeds a learning hierarchy in its connectivity architecture, prioritizing ethologically relevant odors while preserving coding capacity for diverse associations.

neuroscience↗

bioRxiv2024

dArc1 controls sugar reward valuation in Drosophila melanogaster

The Arc genes -- which include Drosophila Arc1 and Arc2 (dArc) -- evolved from Ty3 retrotransposons and encode proteins that form virus-like capsids. These capsids enable a novel form of intercellular communication by transferring RNAs between cells. However, the specific neuronal circuits and brain processes Arc intercellular signaling regulates remain unknown. Here, we show that loss of both dArc genes in Drosophila melanogaster enhances associative learning in an appetitive conditioning paradigm, where flies associate an odor with sugar rewards. This increased learning performance arises from an increased valuation of sugar rewards: unlike wild-type flies, dArc-/- flies form abnormally strong associations even when the sugar reward is small or has no caloric value. We found that the {gamma}5-dopaminergic neurons of the protocerebral anterior medial (PAM) cluster, which encode the positive valence of sugar rewards, show heightened activity in response to sucrose in dArc-/- flies. We further show that the learning phenotype of dArc-/- flies depends on the formation of capsids, underscoring a direct role for capsid-mediated Arc signaling in sugar valuation. Our findings establish dArc genes as critical regulators of reward valuation in D. melanogaster, acting through a non-cell autonomous mechanism that relies on capsid-mediated communication between cells.

neuroscience↗

bioRxiv2019

Dopaminergic learning and arousal circuits mediate opposing effects on alcohol consumption in Drosophila

The response to drugs of abuse is a combination of aversive and reinforcing reactions. While much is known about the role of dopamine in mammalian drug reinforcement, we know little about the brain circuits mediating drug aversion. Here we show that two distinct dopaminergic circuits mediate reinforcing and acute aversive responses to alcohol consumption in Drosophila. Protocerebral anterior medial dopamine neurons projecting to the mushroom bodies are required for flies to acquire alcohol preference. Conversely, a bilateral pair of dopamine neurons projecting to the dorsal fan-shaped body (dFSB) mediates acute alcohol avoidance. Alcohol consumption can be reduced by decreasing the activity of the appetitive reinforcement-circuit to the mushroom bodies, or by increasing activity in the dopamine neurons projecting to the dFSB. Thus, distinct dopaminergic pathways can be targeted to reduce the intake of harmful drugs.

neuroscience↗

bioRxiv2019

Altered actin filament dynamics in the Drosophila mushroom bodies lead to fast acquisition of alcohol consumption preference.

Alcohol use is highly prevalent in the United States and across the world, and every year millions of people suffer from alcohol use disorders (AUDs). While the genetic contribution to developing AUDs is estimated to be 50-60%, many of the underlying molecular mechanisms remain unclear. Previous studies from our lab revealed that Drosophila lacking RhoGAP18B and Ras Suppressor 1 (Rsu1) display reduced sensitivity to ethanol-induced sedation. Both Rsu1 and RhoGAP18B are negative regulators of the small Rho-family GTPase, Rac1, a modulator of actin dynamics. Here we investigate the role of Rac1 and its downstream target, the actin-severing protein cofilin, in alcohol consumption preference. We show that these two regulators of actin dynamics can alter experience-dependent alcohol preference in a bidirectional manner: expressing either activated Rac1 or dominant-negative cofilin in the mushroom bodies (MB) abolishes experience-dependent alcohol preference. Conversely, dominant-negative Rac1 or activated cofilin MB expression lead to faster acquisition of alcohol preference. Our data show that Rac1 and cofilin activity are key to determining the rate of acquisition of alcohol preference, revealing a critical role of actin dynamics regulation in the development of voluntary self-administration in Drosophila.\n\nSignificance StatementThe risks for developing an alcohol use disorder (AUD) are strongly determined by genetic factors. Understanding the genes and molecular mechanisms that contribute to that risk is therefore a necessary first step for the development of targeted therapeutic intervention. Here we show that regulators of actin cytoskeleton dynamics can bidirectionally determine the acquisition rate of alcohol self-administration, highlighting this process as a key mechanism contributing to the risk of AUD development.

neuroscience↗

bioRxiv2018

Genome-wide association and functional studies identify 46 novel loci for alcohol consumption and suggest common genetic mechanisms with neuropsychiatric disorders

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. We conducted a genome-wide association study (GWAS) of alcohol use in ~480,000 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 novel, common loci, and investigated their potential functional significance using magnetic resonance imaging data, gene expression and behavioral studies in Drosophila. Our results identify new genetic pathways associated with alcohol consumption and suggest common genetic mechanisms with several neuropsychiatric disorders including schizophrenia.

genetics↗