Jai Y. Yu

Cellular Organization of the Neural Circuit that Drives Drosophila Courtship Behavior

BACKGROUND Courtship behavior in Drosophila has been causally linked to the activity of the heterogeneous set of ∼1500 neurons that express the sex-specific transcripts of the fruitless (fru) gene, but we currently lack an appreciation of the cellular diversity within this population, the extent to which these cells are sexually dimorphic, and how they might be organized into functional circuits. RESULTS We used genetic methods to define 100 distinct classes of fru neuron, which we compiled into a digital 3D atlas at cellular resolution. We determined the polarity of many of these neurons and computed their likely patterns of connectivity, thereby assembling them into a neural circuit that extends from sensory input to motor output. The cellular organization of this circuit reveals neuronal pathways in the brain that are likely to integrate multiple sensory cues from other flies and to issue descending control signals to motor circuits in the thoracic ganglia. We identified 11 anatomical dimorphisms within this circuit: neurons that are male specific, are more numerous in males than females, or have distinct arborization patterns in males and females. CONCLUSIONS The cellular organization of the fru circuit suggests how multiple distinct sensory cues are integrated in the flys brain to drive sex-specific courtship behavior. We propose that sensory processing and motor control are mediated through circuits that are largely similar in males and females. Sex-specific behavior may instead arise through dimorphic circuits in the brain and nerve cord that differentially couple sensory input to motor output.

Neuronal Control of Drosophila Courtship Song

The courtship song of the Drosophila male serves as a genetically tractable model for the investigation of the neural mechanisms of decision-making, action selection, and motor pattern generation. Singing has been causally linked to the activity of the set of neurons that express the sex-specific fru transcripts, but the specific neurons involved have not been identified. Here we identify five distinct classes of fru neuron that trigger or compose the song. Our data suggest that P1 and pIP10 neurons in the brain mediate the decision to sing, and to act upon this decision, while the thoracic neurons dPR1, vPR6, and vMS11 are components of a central pattern generator that times and shapes the songs pulses. These neurons are potentially connected in a functional circuit, with the descending pIP10 neuron linking the brain and thoracic song centers. Sexual dimorphisms in each of these neurons may explain why only males sing.

Sexual Dimorphism in the Fly Brain

Summary Background Sex-specific behavior may originate from differences in brain structure or function. In Drosophila, the action of the male-specific isoform of fruitless in about 2000 neurons appears to be necessary and sufficient for many aspects of male courtship behavior. Initial work found limited evidence for anatomical dimorphism in these fru+ neurons. Subsequently, three discrete anatomical differences in central brain fru+ neurons have been reported, but the global organization of sex differences in wiring is unclear. Results A global search for structural differences in the Drosophila brain identified large volumetric differences between males and females, mostly in higher brain centers. In parallel, saturating clonal analysis of fru+ neurons using mosaic analysis with a repressible cell marker identified 62 neuroblast lineages that generate fru+ neurons in the brain. Coregistering images from male and female brains identified 19 new dimorphisms in males; these are highly concentrated in male-enlarged higher brain centers. Seven dimorphic lineages also had female-specific arbors. In addition, at least 5 of 51 fru+ lineages in the nerve cord are dimorphic. We use these data to predict >700 potential sites of dimorphic neural connectivity. These are particularly enriched in third-order olfactory neurons of the lateral horn, where we provide strong evidence for dimorphic anatomical connections by labeling partner neurons in different colors in the same brain. Conclusion Our analysis reveals substantial differences in wiring and gross anatomy between male and female fly brains. Reciprocal connection differences in the lateral horn offer a plausible explanation for opposing responses to sex pheromones in male and female flies.

Dopamine neurons modulate pheromone responses in Drosophila courtship learning

Learning through trial-and-error interactions allows animals to adapt innate behavioural ‘rules of thumb’ to the local environment, improving their prospects for survival and reproduction. Naive Drosophila melanogaster males, for example, court both virgin and mated females, but learn through experience to selectively suppress futile courtship towards females that have already mated. Here we show that courtship learning reflects an enhanced response to the male pheromone cis-vaccenyl acetate (cVA), which is deposited on females during mating and thus distinguishes mated females from virgins. Dissociation experiments suggest a simple learning rule in which unsuccessful courtship enhances sensitivity to cVA. The learning experience can be mimicked by artificial activation of dopaminergic neurons, and we identify a specific class of dopaminergic neuron that is critical for courtship learning. These neurons provide input to the mushroom body (MB) γ lobe, and the DopR1 dopamine receptor is required in MBγ neurons for both natural and artificial courtship learning. Our work thus reveals critical behavioural, cellular and molecular components of the learning rule by which Drosophila adjusts its innate mating strategy according to experience.

BrainGazer - Visual Queries for Neurobiology Research

Neurobiology investigates how anatomical and physiological relationships in the nervous system mediate behavior. Molecular genetic techniques, applied to species such as the common fruit fly Drosophila melanogaster, have proven to be an important tool in this research. Large databases of transgenic specimens are being built and need to be analyzed to establish models of neural information processing. In this paper we present an approach for the exploration and analysis of neural circuits based on such a database. We have designed and implemented \emph{BrainGazer}, a system which integrates visualization techniques for volume data acquired through confocal microscopy as well as annotated anatomical structures with an intuitive approach for accessing the available information. We focus on the ability to visually query the data based on semantic as well as spatial relationships. Additionally, we present visualization techniques for the concurrent depiction of neurobiological volume data and geometric objects which aim to reduce visual clutter. The described system is the result of an ongoing interdisciplinary collaboration between neurobiologists and visualization researchers.

Hippocampal-cortical interaction in decision making

When making a decision it is often necessary to consider the available alternatives in order to choose the most appropriate option. This deliberative process, where the pros and cons of each option are considered, relies on memories of past actions and outcomes. The hippocampus and prefrontal cortex are required for memory encoding, memory retrieval and decision making, but it is unclear how these areas support deliberation. Here we examine the potential neural substrates of these processes in the rat. The rat is a powerful model to investigate the network mechanisms underlying deliberation in the mammalian brain given the anatomical and functional conservation of its hippocampus and prefrontal cortex to other mammalian systems. Importantly, it is amenable to large scale neural recording while performing laboratory tasks that exploit its natural decision-making behavior. Focusing on findings in the rat, we discuss how hippocampal-cortical interactions could provide a neural substrate for deliberative decision making.

Human Bcl-2 cannot directly inhibit the Caenorhabditis elegans Apaf-1 homologue CED-4, but can interact with EGL-1.

Although the anti-apoptotic activity of Bcl-2 has been extensively studied, its mode of action is still incompletely understood. In the nematode Caenorhabditis elegans, 131 of 1090 somatic cells undergo programmed cell death during development. Transgenic expression of human Bcl-2 reduced cell death during nematode development, and partially complemented mutation of ced-9, indicating that Bcl-2 can functionally interact with the nematode cell death machinery. Identification of the nematode target(s) of Bcl-2 inhibition would help clarify the mechanism by which Bcl-2 suppresses apoptosis in mammalian cells. Exploiting yeast-based systems and biochemical assays, we analysed the ability of Bcl-2 to interact with and regulate the activity of nematode apoptosis proteins. Unlike CED-9, Bcl-2 could not directly associate with the caspase-activating adaptor protein CED-4, nor could it inhibit CED-4-dependent yeast death. By contrast, Bcl-2 could bind the C. elegans pro-apoptotic BH3-only Bcl-2 family member EGL-1. These data prompt us to hypothesise that Bcl-2 might suppress nematode cell death by preventing EGL-1 from antagonising CED-9, rather than by inhibiting CED-4.

Sexual behaviour: do a few dead neurons make the difference?

Why do males and females behave so differently? Sexually dimorphic neural circuitry has just been found in parts of the flys brain thought to control mating behaviour. Might this explain why males and females have such distinct sexual behaviours?

Distinct hippocampal-cortical memory representations for experiences associated with movement versus immobility

While ongoing experience proceeds continuously, memories of past experience are often recalled as episodes with defined beginnings and ends. The neural mechanisms that lead to the formation of discrete episodes from the stream of neural activity patterns representing ongoing experience are unknown. To investigate these mechanisms, we recorded neural activity in the rat hippocampus and prefrontal cortex, structures critical for memory processes. We show that during spatial navigation, hippocampal CA1 place cells maintain a continuous spatial representation across different states of motion (movement and immobility). In contrast, during sharp-wave ripples (SWRs), when representations of experience are transiently reactivated from memory, movement- and immobility-associated activity patterns are most often reactivated separately. Concurrently, distinct hippocampal reactivations of movement- or immobility-associated representations are accompanied by distinct modulation patterns in prefrontal cortex. These findings demonstrate a continuous representation of ongoing experience can be separated into independently reactivated memory representations.

Neuroscience: Hidden female talent

A male fruitfly serenades his female with a courtship song produced by vibrating one wing. The female also has the neuronal circuitry to generate a song of her own, but her brain tells her not to.