Where does mating drive come from?

Comment on "Asexuality in Drosophila juvenile males is organizational and independent of juvenile hormone" by Ji et al.

Beyond the symptom: the biology of fatigue.

A workshop titled "Beyond the Symptom: The Biology of Fatigue" was held virtually September 27-28, 2021. It was jointly organized by the Sleep Research Society and the Neurobiology of Fatigue Working Group of the NIH Blueprint Neuroscience Research Program. For access to the presentations and video recordings, see: https://neuroscienceblueprint.nih.gov/about/event/beyond-symptom-biology-fatigue. The goals of this workshop were to bring together clinicians and scientists who use a variety of research approaches to understand fatigue in multiple conditions and to identify key gaps in our understanding of the biology of fatigue. This workshop summary distills key issues discussed in this workshop and provides a list of promising directions for future research on this topic. We do not attempt to provide a comprehensive review of the state of our understanding of fatigue, nor to provide a comprehensive reprise of the many excellent presentations. Rather, our goal is to highlight key advances and to focus on questions and future approaches to answering them.

A gut-secreted peptide suppresses arousability from sleep.

Suppressing sensory arousal is critical for sleep, with deeper sleep requiring stronger sensory suppression. The mechanisms that enable sleeping animals to largely ignore their surroundings are not well understood. We show that the responsiveness of sleeping flies and mice to mechanical vibrations is better suppressed when the diet is protein rich. In flies, we describe a signaling pathway through which information about ingested proteins is conveyed from the gut to the brain to help suppress arousability. Higher protein concentration in the gut leads to increased activity of enteroendocrine cells that release the peptide CCHa1. CCHa1 signals to a small group of dopamine neurons in the brain to modulate their activity; the dopaminergic activity regulates the behavioral responsiveness of animals to vibrations. The CCHa1 pathway and dietary proteins do not influence responsiveness to all sensory inputs, showing that during sleep, different information streams can be gated through independent mechanisms.

Hormonal control of motivational circuitry orchestrates the transition to sexuality in Drosophila.

Newborns and hatchlings can perform incredibly sophisticated behaviors, but many animals abstain from sexual activity at the beginning of life. Hormonal changes have long been known to drive both physical and behavioral changes during adolescence, leading to the largely untested assumption that sexuality emerges from organizational changes to neuronal circuitry. We show that the transition to sexuality in male Drosophila is controlled by hormonal changes, but this regulation is functional rather than structural. In very young males, a broadly acting hormone directly inhibits the activity of three courtship-motivating circuit elements, ensuring the complete suppression of sexual motivation and behavior. Blocking or overriding these inhibitory mechanisms evokes immediate and robust sexual behavior from very young and otherwise asexual males. Similarities to mammalian adolescence suggest a general principle in which hormonal changes gate the transition to sexuality not by constructing new circuitry but by permitting activity in otherwise latent motivational circuit elements.

Daily rewiring of a neural circuit generates a predictive model of environmental light.

Behavioral responsiveness to external stimulation is shaped by context. We studied how sensory information can be contextualized, by examining light-evoked locomotor responsiveness of Drosophila relative to time of day. We found that light elicits an acute increase in locomotion (startle) that is modulated in a time-of-day-dependent manner: Startle is potentiated during the nighttime, when light is unexpected, but is suppressed during the daytime. The internal daytime-nighttime context is generated by two interconnected and functionally opposing populations of circadian neurons-LNvs generating the daytime state and DN1as generating the nighttime state. Switching between the two states requires daily remodeling of LNv and DN1a axons such that the maximum presynaptic area in one population coincides with the minimum in the other. We propose that a dynamic model of environmental light resides in the shifting connectivities of the LNv-DN1a circuit, which helps animals evaluate ongoing conditions and choose a behavioral response.

Sleep Loss Can Cause Death through Accumulation of Reactive Oxygen Species in the Gut.

The view that sleep is essential for survival is supported by the ubiquity of this behavior, the apparent existence of sleep-like states in the earliest animals, and the fact that severe sleep loss can be lethal. The cause of this lethality is unknown. Here we show, using flies and mice, that sleep deprivation leads to accumulation of reactive oxygen species (ROS) and consequent oxidative stress, specifically in the gut. ROS are not just correlates of sleep deprivation but drivers of death: their neutralization prevents oxidative stress and allows flies to have a normal lifespan with little to no sleep. The rescue can be achieved with oral antioxidant compounds or with gut-targeted transgenic expression of antioxidant enzymes. We conclude that death upon severe sleep restriction can be caused by oxidative stress, that the gut is central in this process, and that survival without sleep is possible when ROS accumulation is prevented. VIDEO ABSTRACT.

CaMKII Measures the Passage of Time to Coordinate Behavior and Motivational State.

Electrical events in neurons occur on the order of milliseconds, but the brain can process and reproduce intervals millions of times longer. We present what we believe to be the first neuronal mechanism for timing intervals longer than a few seconds. The activation and gradual relaxation of calcium-independent CaMKII measure a 6-min time window to coordinate two male-specific events during Drosophila mating: sperm transfer and a simultaneous decrease in motivation. We localize these functions to four neurons whose electrical activity is necessary only to report the conclusion of the decline in CaMKII's activity, not for the measurement of the interval. The computation of elapsed time is therefore largely invisible to standard methods of monitoring neuronal activity. Its broad conservation, ubiquitous expression, and tunable duration of activity suggest that CaMKII may time a wide variety of behavioral and cognitive processes.

Recurrent Circuitry Sustains Drosophila Courtship Drive While Priming Itself for Satiety.

Motivations intensify over hours or days, promoting goals that are achieved in minutes or hours, causing satiety that persists for hours or days. Here we develop Drosophila courtship as a system to study these long-timescale motivational dynamics. We identify two neuronal populations engaged in a recurrent excitation loop, the output of which elevates a dopamine signal that increases the propensity to court. Electrical activity within the recurrent loop accrues with abstinence and, through the activity-dependent transcription factor CREB2, drives the production of activity-suppressing potassium channels. Loop activity is decremented by each mating to reduce subsequent courtship drive, and the inhibitory loop environment established by CREB2 during high motivation slows the reaccumulation of activity for days. Computational modeling reproduces these behavioral and physiological dynamics, generating predictions that we validate experimentally and illustrating a causal link between the motivation that drives behavior and the satiety that endures after goal achievement.

Motivation, Perception, and Chance Converge to Make a Binary Decision.

We reveal a central role for chance neuronal events in the decision of a male fly to court, which can be modeled as a coin flip with odds set by motivational state. The decision is prompted by a tap of a female with the male's pheromone-receptor-containing foreleg. Each tap evokes competing excitation and inhibition onto P1 courtship command neurons. A motivating dopamine signal desensitizes P1 to the inhibition, increasing the fraction of taps that successfully initiate courtship. Once courtship has begun, the same dopamine tone potentiates recurrent excitation of P1, maintaining the courtship of highly motivated males for minutes and buffering against termination. Receptor diversity within P1 creates separate channels for tuning the propensities to initiate and sustain courtship toward appropriate targets. These findings establish a powerful invertebrate system for cue-triggered binary decisions and demonstrate that noise can be exploited by motivational systems to make behaviors scalable and flexible.

SnapShot: Circadian Clock.

Most creatures on this planet possess an ability to anticipate upcoming events in the environment, courtesy of their circadian clocks. This allows them to prepare for those changes instead of being caught by surprise, which could mean the difference between life and death. In this SnapShot, we describe the basics of how the clock ticks.

Dopaminergic Circuitry Underlying Mating Drive.

We develop a new system for studying how innate drives are tuned to reflect current physiological needs and capacities, and how they affect sensory-motor processing. We demonstrate the existence of male mating drive in Drosophila, which is transiently and cumulatively reduced as reproductive capacity is depleted by copulations. Dopaminergic activity in the anterior of the superior medial protocerebrum (SMPa) is also transiently and cumulatively reduced in response to matings and serves as a functional neuronal correlate of mating drive. The dopamine signal is transmitted through the D1-like DopR2 receptor to P1 neurons, which also integrate sensory information relevant to the perception of females, and which project to courtship motor centers that initiate and maintain courtship behavior. Mating drive therefore converges with sensory information from the female at the point of transition to motor output, controlling the propensity of a sensory percept to trigger goal-directed behavior.

Neuroscience: Suppressing One Drive for a Chance to Satisfy Another.

Food deprivation suppresses sleep, presumably to increase time available for foraging. A new study identifies a conserved gene, Translin, as a modulator of sleep in response to metabolic changes.

TARANIS Functions with Cyclin A and Cdk1 in a Novel Arousal Center to Control Sleep in Drosophila.

Sleep is an essential and conserved behavior whose regulation at the molecular and anatomical level remains to be elucidated. Here, we identify TARANIS (TARA), a Drosophila homolog of the Trip-Br (SERTAD) family of transcriptional coregulators, as a molecule that is required for normal sleep patterns. Through a forward-genetic screen, we isolated tara as a novel sleep gene associated with a marked reduction in sleep amount. Targeted knockdown of tara suggests that it functions in cholinergic neurons to promote sleep. tara encodes a conserved cell-cycle protein that contains a Cyclin A (CycA)-binding homology domain. TARA regulates CycA protein levels and genetically and physically interacts with CycA to promote sleep. Furthermore, decreased levels of Cyclin-dependent kinase 1 (Cdk1), a kinase partner of CycA, rescue the short-sleeping phenotype of tara and CycA mutants, while increased Cdk1 activity mimics the tara and CycA phenotypes, suggesting that Cdk1 mediates the role of TARA and CycA in sleep regulation. Finally, we describe a novel wake-promoting role for a cluster of ∼14 CycA-expressing neurons in the pars lateralis (PL), previously proposed to be analogous to the mammalian hypothalamus. We propose that TARANIS controls sleep amount by regulating CycA protein levels and inhibiting Cdk1 activity in a novel arousal center.

Control of sleep by cyclin A and its regulator.

How and why the brain reversibly switches from a waking to a sleep state remain among the most intriguing questions in biology. We show that cyclin A (CycA) and regulator of cyclin A1, essential cell cycle factors, function in postmitotic neurons to promote sleep in Drosophila melanogaster. Reducing the abundance of CycA in neurons delayed the wake-sleep transition, caused multiple arousals from sleep, and reduced the homeostatic response to sleep deprivation. CycA is expressed in ~40 to 50 neurons in the adult brain, most of which are intermingled with circadian clock neurons, suggesting functional interactions among neurons controlling sleep and circadian behavior.

Morphogen control of wing growth through the Fat signaling pathway.

Organ growth is influenced by organ patterning, but the molecular mechanisms that link patterning to growth have remained unclear. We show that the Dpp morphogen gradient in the Drosophila wing influences growth by modulating the activity of the Fat signaling pathway. Dpp signaling regulates the expression and localization of Fat pathway components, and Fat signaling through Dachs is required for the effect of the Dpp gradient on cell proliferation. Juxtaposition of cells that express different levels of the Fat pathway regulators four-jointed and dachsous stimulates expression of Fat/Hippo pathway target genes and cell proliferation, consistent with the hypothesis that the graded expression of these genes contributes to wing growth. Moreover, uniform expression of four-jointed and dachsous in the wing inhibits cell proliferation. These observations identify Fat as a signaling pathway that links the morphogen-mediated establishment of gradients of positional values across developing organs to the regulation of organ growth.

Regulation of cell proliferation by a morphogen gradient.

One model to explain the relationship between patterning and growth during development posits that growth is regulated by the slope of morphogen gradients. The Decapentaplegic (DPP) morphogen controls growth in the Drosophila wing, but the slope of the DPP activity gradient has not been shown to influence growth. By employing a method for spatial, temporal, and quantitative control over gene expression, we show that the juxtaposition of cells perceiving different levels of DPP signaling is essential for medial-wing-cell proliferation and can be sufficient to promote the proliferation of cells throughout the wing. Either activation or inhibition of the DPP pathway in clones at levels distinct from those in surrounding cells stimulates nonautonomous cell proliferation. Conversely, uniform activation of the DPP pathway inhibits cell proliferation in medial wing cells. Our observations provide a direct demonstration that the slope of a morphogen gradient regulates growth during development.

Genome of Xanthomonas oryzae bacteriophage Xp10: an odd T-odd phage.

Xp10 is a lytic bacteriophage of the phytopathogenic bacterium Xanthomonas oryzae. Though morphologically Xp10 belongs to the Syphoviridae family, it encodes its own single-subunit RNA polymerase characteristic of T7-like phages of the Podoviridae family. Here, we report the determination and analysis of the 44,373 bp sequence of the Xp10 genome. The genome is a linear, double-stranded DNA molecule with 3' cohesive overhangs and no terminal repeats or redundancies. Half of the Xp10 genome contains genes coding for structural proteins and host lysis functions in an arrangement typical for temperate dairy phages that are related to the Escherichia coli lambda phage. The other half of the Xp10 genome contains genes coding for factors of host gene expression shut-off, enzymes of viral genome replication and expression. The two groups of genes are transcribed divergently and separated by a regulatory region, which contains divergent promoters recognized by the host RNA polymerase. Xp10 has apparently arisen through a recombination between genomes of widely different phages. Further evidence of extensive gene flux in the evolution of Xp10 includes a high fraction (10%) of genes derived from an HNH-family endonuclease, and a DNA-dependent DNA polymerase that is closer to a homolog from Leishmania than to DNA polymerases from other phages or bacteria.