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With less than a million neurons, the western honeybee Apis mellifera is capable of complex olfactory behaviors and provides an ideal model for investigating the neurophysiology of the olfactory circuit and the basis of olfactory perception and learning. Here, we review the most fundamental aspects of honeybee’s olfaction: first, we discuss which odorants dominate its environment, and how bees use them to communicate and regulate colony homeostasis; then, we describe the neuroanatomy and the neurophysiology of the olfactory circuit; finally, we explore the cellular and molecular mechanisms leading to olfactory memory formation. The vastity of histological, neurophysiological, and behavioral data collected during the last century, together with new technological advancements, including genetic tools, confirm the honeybee as an attractive research model for understanding olfactory coding and learning.

We identified the neurons comprising the Drosophila mushroom body (MB), an associative center in invertebrate brains, and provide a comprehensive map describing their potential connections. Each of the 21 MB output neuron (MBON) types elaborates segregated dendritic arbors along the parallel axons of ∼2000 Kenyon cells, forming 15 compartments that collectively tile the MB lobes. MBON axons project to five discrete neuropils outside of the MB and three MBON types form a feedforward network in the lobes. Each of the 20 dopaminergic neuron (DAN) types projects axons to one, or at most two, of the MBON compartments. Convergence of DAN axons on compartmentalized Kenyon cell–MBON synapses creates a highly ordered unit that can support learning to impose valence on sensory representations. The elucidation of the complement of neurons of the MB provides a comprehensive anatomical substrate from which one can infer a functional logic of associative olfactory learning and memory. One of the key goals of neuroscience is to understand how specific circuits of brain cells enable animals to respond optimally to the constantly changing world around them. Such processes are more easily studied in simpler brains, and the fruit fly—with its small size, short life cycle, and well-developed genetic toolkit—is widely used to study the genes and circuits that underlie learning and behavior. Fruit flies can learn to approach odors that have previously been paired with food, and also to avoid any odors that have been paired with an electric shock, and a part of the brain called the mushroom body has a central role in this process. When odorant molecules bind to receptors on the fly's antennae, they activate neurons in the antennal lobe of the brain, which in turn activate cells called Kenyon cells within the mushroom body. The Kenyon cells then activate output neurons that convey signals to other parts of the brain. It is known that relatively few Kenyon cells are activated by any given odor. Moreover, it seems that a given odor activates different sets of Kenyon cells in different flies. Because the association between an odor and the Kenyon cells it activates is unique to each fly, each fly needs to learn through its own experiences what a particular pattern of Kenyon cell activation means. Aso et al. have now applied sophisticated molecular genetic and anatomical techniques to thousands of different transgenic flies to identify the neurons of the mushroom body. The resulting map reveals that the mushroom body contains roughly 2200 neurons, including seven types of Kenyon cells and 21 types of output cells, as well as 20 types of neurons that use the neurotransmitter dopamine. Moreover, this map provides insights into the circuits that support odor-based learning. It reveals, for example, that the mushroom body can be divided into 15 anatomical compartments that are each defined by the presence of a specific set of output and dopaminergic neuron cell types. Since the dopaminergic neurons help to shape a fly's response to odors on the basis of previous experience, this organization suggests that these compartments may be semi-autonomous information processing units. In contrast to the rest of the insect brain, the mushroom body has a flexible organization that is similar to that of the mammalian brain. Elucidating the circuits that support associative learning in fruit flies should therefore make it easier to identify the equivalent mechanisms in vertebrate animals.

The olfactory system plays crucial roles in perceiving and interacting with their surroundings. Previous studies have deciphered basic odor perceptions, but how information processing in the olfactory system is associated with learning and memory is poorly understood. In this review, we summarize recent studies on the anatomy and functional dynamics of the mouse olfactory learning pathway, focusing on how neuronal circuits in the olfactory bulb (OB) and olfactory cortical areas integrate odor information in learning. We also highlight in vivo evidence for the role of the lateral entorhinal cortex (LEC) in olfactory learning. Altogether, these studies demonstrate that brain regions throughout the olfactory system are critically involved in forming and representing learned knowledge. The role of olfactory areas in learning and memory, and their susceptibility to dysfunction in neurodegenerative diseases, necessitate further research.

The olfactory tubercle (OT) is a unique part of the olfactory cortex of the mammal brain in that it is also a component of the ventral striatum. It is crucially involved in motivational behaviors, particularly in adaptive olfactory learning. This review introduces the basic properties of the OT, its synaptic connectivity with other brain areas, and the plasticity of the connectivity associated with learning behavior. The adaptive properties of olfactory behavior are discussed further based on the characteristics of OT neuronal circuits.

Previously, we showed that adult human olfaction retains plasticity in the unilateral processing of molecular chirality (Feng and Zhou, 2019). Using a similar unilateral discrimination protocol across three experiments with human adults (n = 96; 1295 sessions), we now reveal distinct patterns of specificity, generalization, and persistence in olfactory learning, independent of adaptation or task difficulty. Training with binary odor mixtures at varying ratios consistently produced durable gains that transferred across nostrils and generalized to novel mixtures differing in both structure and perceptual quality. Conversely, training with odor enantiomers or concentration differences yielded neither transfer nor generalization, and concentration discrimination learning was short-lived. These results indicate that mixture configural quality is a distinct olfactory attribute from chirality or relative concentration, and that discrimination learning engages plasticity at different stages of olfactory processing depending on the task-relevant attribute. Moreover, they identify mixture discrimination training as a promising strategy for rehabilitating smell loss and cultivating olfactory expertise.

The GABAergic system serves as a vital negative modulator in cognitive functions, such as learning and memory, while the mechanisms governing this inhibitory system remain to be elucidated. In Drosophila, the GABAergic anterior paired lateral (APL) neurons mediate a negative feedback essential for odor discrimination; however, their activity is suppressed by learning via unknown mechanisms. In aversive olfactory learning, a group of dopaminergic (DA) neurons is activated on electric shock (ES) and modulates the Kenyon cells (KCs) in the mushroom body, the center of olfactory learning. Here we find that the same group of DA neurons also form functional synaptic connections with the APL neurons, thereby emitting a suppressive signal to the latter through Drosophila dopamine 2-like receptor (DD2R). Knockdown of either DD2R or its downstream molecules in the APL neurons results in impaired olfactory learning at the behavioral level. Results obtained from in vivo functional imaging experiments indicate that this DD2R-dependent DA-to-APL suppression occurs during odor-ES conditioning and discharges the GABAergic inhibition on the KCs specific to the conditioned odor. Moreover, the decrease in odor response of the APL neurons persists to the postconditioning phase, and this change is also absent in DD2R knockdown flies. Taken together, our findings show that DA-to-GABA suppression is essential for restraining the GABAergic inhibition during conditioning, as well as for inducing synaptic modification in this learning circuit. Such circuit mechanisms may play conserved roles in associative learning across species.

Alcohol intoxication can impact learning and this may contribute to the development of problematic alcohol use. In alcohol (ethanol)-induced state-dependent learning (SDL), information learned while an animal is intoxicated is recalled more effectively when the subject is tested while similarly intoxicated than if tested while not intoxicated. When Caenorhabditis elegans undergoes olfactory learning (OL) while intoxicated, the learning becomes state dependent such that recall of OL is only apparent if the animals are tested while intoxicated.We found that two genes known to be required for signal integration, the secreted peptide HEN-1 and its receptor tyrosine kinase, SCD-2, are required for SDL. Expression of hen-1 in the ASER neuron and scd-2 in the AIA neurons was sufficient for their functions in SDL. Optogenetic activation of ASER in the absence of ethanol during learning could confer ethanol state dependency, indicating that ASER activation is sufficient to signal ethanol intoxication to the OL circuit. To our surprise, ASER activation during testing did not substitute for ethanol intoxication, demonstrating that the effects of ethanol on learning and recall rely on distinct signals. Additionally, intoxication-state information could be added to already established OL, but state-dependent OL did not lose state information when the intoxication signal was removed. Finally, dopamine is required for state-dependent OL, and we found that the activation of ASER cannot bypass this requirement. Our findings provide a window into the modulation of learning by ethanol and suggest that ethanol acts to modify learning using mechanisms distinct from those used during memory access.

Flower-visiting social insects use a variety of cues to help them learn and recall which flowers are high-quality resources, including the flower odour. In addition, some species may learn to respond to the odours left at flowers by other insects, either to avoid flowers that have likely been depleted by recent visitors, or to identify profitable floral patches being used by competitors. For example, Australian stingless bees were observed to be more attracted to food sources recently visited, and thus odour-marked, by other stingless bees or honey bees than food sources with no prior visits. Here, we use a proboscis extension response (PER) protocol to investigate the capacity for olfactory associative learning in the Australian stingless bee, Tetragonula carbonaria . We test the ability of T. carbonaria to learn to associate a food reward with each odour in two paired sets of odours: (1) vanilla vs. lavender, and (2) linalool vs. a synthetic version of the honey bee pheromone Nasonov. After conditioning, T. carbonaria foragers demonstrated successful discrimination between the two different odours in a set, learnt to associate all four test odours with a food reward, and maintained this association for 15 min after training. In all, our results, therefore, show that PER can be used to investigate associative learning in T. carbonaria and support olfactory associative learning as a mechanism by which the odours of both flowers and other bees affect foraging decisions in this species.

O- GlcNAcylation is a dynamic post-translational modification that diversifies the proteome. Its dysregulation is associated with neurological disorders that impair cognitive function, and yet identification of phenotype-relevant candidate substrates in a brain-region specific manner remains unfeasible. By combining an O- GlcNAc binding activity derived from Clostridium perfringens OGA ( Cp OGA) with TurboID proximity labeling in Drosophila , we developed an O- GlcNAcylation profiling tool that translates O- GlcNAc modification into biotin conjugation for tissue-specific candidate substrates enrichment. We mapped the O- GlcNAc interactome in major brain regions of Drosophila and found that components of the translational machinery, particularly ribosomal subunits, were abundantly O- GlcNAcylated in the mushroom body of Drosophila brain. Hypo- O- GlcNAcylation induced by ectopic expression of active Cp OGA in the mushroom body decreased local translational activity, leading to olfactory learning deficits that could be rescued by dMyc overexpression-induced increase of protein synthesis. Our study provides a useful tool for future dissection of tissue-specific functions of O- GlcNAcylation in Drosophila , and suggests a possibility that O- GlcNAcylation impacts cognitive function via regulating regional translational activity in the brain. Newly synthesized proteins often receive further chemical modifications that change their structure and role in the cell. O -GlcNAcylation, for instance, consists in a certain type of sugar molecule being added onto dedicated protein segments. It is required for the central nervous system to develop and work properly; in fact, several neurological disorders such as Alzheimer's, Parkinson's or Huntington’s disease are linked to disruptions in O -GlcNAcylation. However, scientists are currently lacking approaches that would allow them to reliably identify which proteins require O -GlcNAcylation in specific regions of the brain to ensure proper cognitive health. To address this gap, Yu et al. developed a profiling tool that allowed them to probe O -GlcNAcylation protein targets in different tissues of fruit flies. Their approach relies on genetically manipulating the animals so that a certain brain area overproduces two enzymes that work in tandem; the first binds specifically to O -GlcNAcylated proteins, which allows the second to add a small ‘biotin’ tag to them. Tagged proteins can then be captured and identified. Using this tool helped Yu et al. map out which proteins go through O -GlcNAcylation in various brain regions. This revealed, for example, that in the mushroom body – the ‘learning center’ of the fly brain – O -GlcNAcylation occurred predominantly in the protein-building machinery. To investigate the role of O -GlcNAcylation in protein synthesis and learning, Yu et al. used an approach that allowed them to decrease the levels of O -GlcNAcylation in the mushroom body. This resulted in reduced local protein production and the flies performing poorly in olfactory learning tasks. However, artificially increasing protein synthesis reversed these deficits. Overall, the work by Yu et al. provides a useful tool for studying the tissue-specific effects of O -GlcNAcylation in fruit flies, and its role in learning. Further studies should explore how this process may be linked to cognitive function by altering protein synthesis in the brain.

Both passive exposure and active learning through reinforcement enhance fine sensory discrimination abilities. In the olfactory system, this enhancement is thought to occur partially through the integration of adult-born inhibitory interneurons resulting in a refinement of the representation of overlapping odorants. Here, we identify in mice a novel and unexpected dissociation between passive and active learning at the level of adult-born granule cells. Specifically, while both passive and active learning processes augment neurogenesis, adult-born cells differ in their morphology, functional coupling and thus their impact on olfactory bulb output. Morphological analysis, optogenetic stimulation of adult-born neurons and mitral cell recordings revealed that passive learning induces increased inhibitory action by adult-born neurons, probably resulting in more sparse and thus less overlapping odor representations. Conversely, after active learning inhibitory action is found to be diminished due to reduced connectivity. In this case, strengthened odor response might underlie enhanced discriminability.