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Dopamine is synonymous with reward in mammals but associated with aversive reinforcement in insects, where reward seems to be signalled by octopamine; here it is shown that flies have discrete populations of dopamine neurons representing positive or negative values that are coordinately regulated by octopamine. Shared neuronal reward signals The neurotransmitter dopamine has been synonymous with reward in mammals, but is associated with aversive reinforcement in insects. In insects, it was thought, reward was signalled by octopamine. Now Scott Waddell and colleagues show that flies have discrete 'negative' and 'positive' populations of dopamine neurons, which are coordinately regulated by octopamine. This work reconciles previous findings with octopamine and dopamine, and suggests that reinforcement systems in flies are more like those in mammals than previously thought. Dopamine is synonymous with reward and motivation in mammals 1 , 2 . However, only recently has dopamine been linked to motivated behaviour and rewarding reinforcement in fruitflies 3 , 4 . Instead, octopamine has historically been considered to be the signal for reward in insects 5 , 6 , 7 . Here we show, using temporal control of neural function in Drosophila , that only short-term appetitive memory is reinforced by octopamine. Moreover, octopamine-dependent memory formation requires signalling through dopamine neurons. Part of the octopamine signal requires the α-adrenergic-like OAMB receptor in an identified subset of mushroom-body-targeted dopamine neurons. Octopamine triggers an increase in intracellular calcium in these dopamine neurons, and their direct activation can substitute for sugar to form appetitive memory, even in flies lacking octopamine. Analysis of the β-adrenergic-like OCTβ2R receptor reveals that octopamine-dependent reinforcement also requires an interaction with dopamine neurons that control appetitive motivation. These data indicate that sweet taste engages a distributed octopamine signal that reinforces memory through discrete subsets of mushroom-body-targeted dopamine neurons. In addition, they reconcile previous findings with octopamine and dopamine and suggest that reinforcement systems in flies are more similar to mammals than previously thought.

Plant defense compounds occur in floral nectar, but their ecological role is not well understood. We provide evidence that plant compounds pharmacologically alter pollinator behavior by enhancing their memory of reward. Honeybees rewarded with caffeine, which occurs naturally in nectar of Coffea and Citrus species, were three times as likely to remember a learned floral scent as were honeybees rewarded with sucrose alone. Caffeine potentiated responses of mushroom body neurons involved in olfactory learning and memory by acting as an adenosine receptor antagonist. Caffeine concentrations in nectar did not exceed the bees' bitter taste threshold, implying that pollinators impose selection for nectar that is pharmacologically active but not repellent. By using a drug to enhance memories of reward, plants secure pollinator fidelity and improve reproductive success.

A first ethanol exposure creates three memory-like states in Drosophila . Ethanol memory-like states appear genetically and behaviorally paralleled to the canonical learning and memory traces anesthesia-sensitive, anesthesia-resistant, and long-term memory ASM, ARM, and LTM. It is unknown if these ethanol memory-like states are also encoded by the canonical learning and memory circuitry that is centered on the mushroom bodies. We show that the three ethanol memory-like states, anesthesia-sensitive tolerance (AST) and anesthesia resistant tolerance (ART) created by ethanol sedation to a moderately high ethanol exposure, and chronic tolerance created by a longer low concentration ethanol exposure, each engage the mushroom body circuitry differently. Moreover, critical encoding steps for ethanol memory-like states reside outside the mushroom body circuitry, and within the mushroom body circuitry they are markedly distinct from classical memory traces. Thus, the first ethanol exposure creates distinct memory-like states in ethanol-specific circuits and impacts the function of learning and memory circuitry in ways that might influence the formation and retention of other memories.

Young male fruitflies learn to avoid futile courtship of non-virgin females because the latter are scented with the male pheromone cis -vaccenyl acetate; this behaviour results from an increase in the males’ innate sensitivity for the pheromone and is controlled by a small set of dopaminergic neurons. Trial-and-error learning in the fruitfly Courtship behaviour in Drosophila has become a leading model for defining the neural circuits and molecular mechanisms that underlie complex innate behaviours. Young male flies initially chase any female in the vicinity, but soon learn to avoid those perfumed with the male pheromone cis -vaccenyl acetate (cVA), which indicates loss of virginity. This study shows that this learning is not classical Pavlovian conditioning occurring through arbitrary association of cVA with rejection. Rather, it results from an increase in the males' innate sensitivity for cVA, and is controlled by a small circuit of dopaminergic neurons. The results pave the way for the study of the more sophisticated learning rules involved in sensory integration and fine decision-making. 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 1 . 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.

Pesticides that target cholinergic neurotransmission are highly effective, but their use has been implicated in insect pollinator population decline. Honeybees are exposed to two widely used classes of cholinergic pesticide: neonicotinoids (nicotinic receptor agonists) and organophosphate miticides (acetylcholinesterase inhibitors). Although sublethal levels of neonicotinoids are known to disrupt honeybee learning and behaviour, the neurophysiological basis of these effects has not been shown. Here, using recordings from mushroom body Kenyon cells in acutely isolated honeybee brain, we show that the neonicotinoids imidacloprid and clothianidin, and the organophosphate miticide coumaphos oxon, cause a depolarization-block of neuronal firing and inhibit nicotinic responses. These effects are observed at concentrations that are encountered by foraging honeybees and within the hive, and are additive with combined application. Our findings demonstrate a neuronal mechanism that may account for the cognitive impairments caused by neonicotinoids, and predict that exposure to multiple pesticides that target cholinergic signalling will cause enhanced toxicity to pollinators. Exposure to pesticides can disrupt foraging and navigation behaviour in bees. Palmer et al . use electrophysiology to show that two neonicotinoids and an organophosphate miticide cause neuronal dysfunction in the honeybee brain at environmentally relevant concentrations.

Declines in pollinator colonies represent a worldwide concern. The widespread use of agricultural pesticides is recognized as a potential cause of these declines. Previous studies have examined the effects of neonicotinoid insecticides such as imidacloprid on pollinator colonies, but these investigations have mainly focused on adult honey bees. Native stingless bees (Hymenoptera: Apidae: Meliponinae) are key pollinators in neotropical areas and are threatened with extinction due to deforestation and pesticide use. Few studies have directly investigated the effects of pesticides on these pollinators. Furthermore, the existing impact studies did not address the issue of larval ingestion of contaminated pollen and nectar, which could potentially have dire consequences for the colony. Here, we assessed the effects of imidacloprid ingestion by stingless bee larvae on their survival, development, neuromorphology and adult walking behavior. Increasing doses of imidacloprid were added to the diet provided to individual worker larvae of the stingless bee Melipona quadrifasciata anthidioides throughout their development. Survival rates above 50% were only observed at insecticide doses lower than 0.0056 µg active ingredient (a.i.)/bee. No sublethal effect on body mass or developmental time was observed in the surviving insects, but the pesticide treatment negatively affected the development of mushroom bodies in the brain and impaired the walking behavior of newly emerged adult workers. Therefore, stingless bee larvae are particularly susceptible to imidacloprid, as it caused both high mortality and sublethal effects that impaired brain development and compromised mobility at the young adult stage. These findings demonstrate the lethal effects of imidacloprid on native stingless bees and provide evidence of novel serious sublethal effects that may compromise colony survival. The ecological and economic importance of neotropical stingless bees as pollinators, their susceptibility to insecticides and the vulnerability of their larvae to insecticide exposure emphasize the importance of studying these species.

The dramatic loss of honey bees is a major concern worldwide. Previous studies have indicated that neonicotinoid insecticides cause behavioural abnormalities and have proven that exposure to sublethal doses of imidacloprid during the larval stage decreases the olfactory learning ability of adults. The present study shows the effect of sublethal doses of imidacloprid on the neural development of the honey bee brain by immunolabelling synaptic units in the calyces of mushroom bodies. We found that the density of the synaptic units in the region of the calyces, which are responsible for olfactory and visual functions, decreased after being exposed to a sublethal dose of imidacloprid. This not only links a decrease in olfactory learning ability to abnormal neural connectivity but also provides evidence that imidacloprid damages the development of the nervous system in regions responsible for both olfaction and vision during the larval stage of the honey bee.

Learning theories distinguish elemental from configural learning based on their different complexity. Although the former relies on simple and unambiguous links between the learned events, the latter deals with ambiguous discriminations in which conjunctive representations of events are learned as being different from their elements. In mammals, configural learning is mediated by brain areas that are either dispensable or partially involved in elemental learning. We studied whether the insect brain follows the same principles and addressed this question in the honey bee, the only insect in which configural learning has been demonstrated. We used a combination of conditioning protocols, disruption of neural activity, and optophysiological recording of olfactory circuits in the bee brain to determine whether mushroom bodies (MBs), brain structures that are essential for memory storage and retrieval, are equally necessary for configural and elemental olfactory learning. We show that bees with anesthetized MBs distinguish odors and learn elemental olfactory discriminations but not configural ones, such as positive and negative patterning. Inhibition of GABAergic signaling in the MB calyces, but not in the lobes, impairs patterning discrimination, thus suggesting a requirement of GABAergic feedback neurons from the lobes to the calyces for nonelemental learning. These results uncover a previously unidentified role for MBs besides memory storage and retrieval: namely, their implication in the acquisition of ambiguous discrimination problems. Thus, in insects as in mammals, specific brain regions are recruited when the ambiguity of learning tasks increases, a fact that reveals similarities in the neural processes underlying the elucidation of ambiguous tasks across species.

Alzheimer disease (AD) is one of the main causes of age-related dementia and neurodegeneration. However, the onset of the disease and the mechanisms causing cognitive defects are not well understood. Aggregation of amyloidogenic peptides is a pathological hallmark of AD and is assumed to be a central component of the molecular disease pathways. Pan-neuronal expression of Aβ 42 Arctic peptides in Drosophila melanogaster results in learning and memory defects. Surprisingly, targeted expression to the mushroom bodies, a center for olfactory memories in the fly brain, does not interfere with learning but accelerates forgetting. We show here that reducing neuronal excitability either by feeding Levetiracetam or silencing of neurons in the involved circuitry ameliorates the phenotype. Furthermore, inhibition of the Rac-regulated forgetting pathway could rescue the Aβ 42 Arctic -mediated accelerated forgetting phenotype. Similar effects are achieved by increasing sleep, a critical regulator of neuronal homeostasis. Our results provide a functional framework connecting forgetting signaling and sleep, which are critical for regulating neuronal excitability and homeostasis and are therefore a promising mechanism to modulate forgetting caused by toxic Aβ peptides.

Olfactory associative learning in Drosophila is mediated by synaptic plasticity between the Kenyon cells of the mushroom body and their output neurons. Both Kenyon cells and their inputs from projection neurons are cholinergic, yet little is known about the physiological function of muscarinic acetylcholine receptors in learning in adult flies. Here, we show that aversive olfactory learning in adult flies requires type A muscarinic acetylcholine receptors (mAChR-A), particularly in the gamma subtype of Kenyon cells. mAChR-A inhibits odor responses and is localized in Kenyon cell dendrites. Moreover, mAChR-A knockdown impairs the learning-associated depression of odor responses in a mushroom body output neuron. Our results suggest that mAChR-A function in Kenyon cell dendrites is required for synaptic plasticity between Kenyon cells and their output neurons. We can learn a surprising amount about how the brain forms memories by studying the humble fruit fly. These insects can learn to associate odors with positive or negative experiences, allowing them to then seek out ‘rewarded’ odors and avoid ‘punished’ ones. This association takes place in a brain region called the mushroom body, and it involves two types of neurons: Kenyon cells, which detect odors, and MBONs, which lead to approach or avoidance behaviors. When Kenyon cells detect an odor accompanying an unpleasant event, they weaken their connections with the MBONs that trigger approach behaviors. This prevents the fly from coming close to that odor in the future. Kenyon cells exchange signals with other neurons using a chemical called acetylcholine, which attaches onto the cells through two types of receptors: nicotinic and muscarinic. Studies in fruit fly larvae suggest that muscarinic receptors are required in Kenyon cells for the insects to learn how to associate odors with unpleasant experiences. Bielopolski et al. now show that this is also the case in adult flies. Surprisingly, while acetylcholine usually excites fly neurons, activating muscarinic receptors inhibits Kenyon cells rather than exciting them. Labeled muscarinic receptors revealed that the receptors act within the input region of Kenyon cells. Moreover, reducing the levels of muscarinic receptors inside the cells stops flies from associating an odor with a mild electric shock. This manipulation also prevents the learning experience from weakening connections from Kenyon cells onto an MBON that triggers approach behavior. This suggests that allowing these changes in connectivity might be why muscarinic receptors are important for memory. Understanding how memory works in flies can reveal basic principles that apply to many species, including humans. Such knowledge could ultimately help us improve the memory of patients with dementia, but also inspire better algorithms for artificial intelligence.