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Sleep deprivation has marked effects on food intake, shifting food choices toward energy-dense options. Here we test the hypothesis that neural processing in central olfactory circuits, in tandem with the endocannabinoid system (ECS), plays a key role in mediating this relationship. We combined a partial sleep-deprivation protocol, pattern-based olfactory neuroimaging, and ad libitum food intake to test how central olfactory mechanisms alter food intake after sleep deprivation. We found that sleep restriction increased levels of the ECS compound 2-oleoylglycerol (2-OG), enhanced encoding of food odors in piriform cortex, and shifted food choices toward energy-dense food items. Importantly, the relationship between changes in 2-OG and food choices was formally mediated by odor-evoked connectivity between the piriform cortex and insula, a region involved in integrating feeding-related signals. These findings describe a potential neurobiological pathway by which state-dependent changes in the ECS may modulate chemosensory processing to regulate food choices. People who do not get enough sleep often start to favor sweet and fatty foods, which contributes to weight gain. While the exact mechanisms are still unknown, lack of sleep seems to change food preferences by influencing the levels of molecules that regulate food intake. In particular, it could have an effect on the endocannabinoid system, a complex network of molecules in the nervous system that controls biological processes such as appetite. The sense of smell is also tightly linked to how and what organisms choose to eat. Recent experiments indicate that in rodents, endocannabinoids enhance food intake by influencing the activity of the brain areas that process odors. However, it is still unclear whether the brain regions that process odors play a similar role in humans. To investigate, Bhutani et al. examined the impact of a four-hour night’s sleep on 25 healthy human volunteers. Blood analyses showed that after a short night, individuals had increased amounts of 2-oleoylglycerol, a molecule that is part of the endocannabinoid system. When sleep-deprived people were given the choice to eat whatever they wanted, those with greater levels of 2-oleoylglycerol preferred food higher in energy. Bhutani et al. also imaged the volunteers’ brains to examine whether these changes were connected to modifications in the way the brain processed smells. This revealed that, in people who did not sleep enough, an odor-processing region called the piriform cortex was encoding smells more strongly. The piriform cortex is connected to another region, the insula, which integrates information about the state of the body to control food intake. Lack of sleep altered this connection, and this was associated with a preference for high-energy food. In addition, further analysis showed that changes in the amounts of 2-oleoylglycerol were linked to modifications in the connection between the two brain areas. Taken together, these results suggest that sleep deprivation influences the endocannabinoid system, which in turn alters the connection between piriform and insular cortex, leading to a shift toward foods which are high in calories. In the United States alone, one in three people sleep less than six hours a night. Learning more about how sleep deprivation affects brain pathways and food choice may help scientists to develop new drugs or behavioral therapies for conditions like obesity.

Hunger arouses sensory perception, eventually leading to an increase in food intake, but the underlying mechanisms remain poorly understood. We found that cannabinoid type-1 (CB1) receptors promote food intake in fasted mice by increasing odor detection. CB1 receptors were abundantly expressed on axon terminals of centrifugal cortical glutamatergic neurons that project to inhibitory granule cells of the main olfactory bulb (MOB). Local pharmacological and genetic manipulations revealed that endocannabinoids and exogenous cannabinoids increased odor detection and food intake in fasted mice by decreasing excitatory drive from olfactory cortex areas to the MOB. Consistently, cannabinoid agonists dampened in vivo optogenetically stimulated excitatory transmission in the same circuit. Our data indicate that cortical feedback projections to the MOB crucially regulate food intake via CB1 receptor signaling, linking the feeling of hunger to stronger odor processing. Thus, CB1 receptor-dependent control of cortical feedback projections in olfactory circuits couples internal states to perception and behavior.

In the mouse, each class of olfactory receptor neurons expressing a given odorant receptor has convergent axonal projections to two specific glomeruli in the olfactory bulb, thereby creating an odour map. However, it is unclear how this map is represented in the olfactory cortex. Here we combine rabies-virus-dependent retrograde mono-trans-synaptic labelling with genetics to control the location, number and type of ‘starter’ cortical neurons, from which we trace their presynaptic neurons. We find that individual cortical neurons receive input from multiple mitral cells representing broadly distributed glomeruli. Different cortical areas represent the olfactory bulb input differently. For example, the cortical amygdala preferentially receives dorsal olfactory bulb input, whereas the piriform cortex samples the whole olfactory bulb without obvious bias. These differences probably reflect different functions of these cortical areas in mediating innate odour preference or associative memory. The trans-synaptic labelling method described here should be widely applicable to mapping connections throughout the mouse nervous system. Scent tracking In the mouse, glomeruli in the olfactory bulb receive projections from single classes of olfactory neurons, thereby forming an odour map. Information from the glomeruli is then relayed to the cortex but the projection patterns from individual glomeruli are not known. Three papers now examine the details of this projection. Luo and colleagues use a combination of genetics and retrograde mono-trans-synaptic rabies virus labelling. They trace the presynaptic connections of individual cortical neurons and find no evidence of connections supporting a stereotyped odour map in the cortex, but see systematic topographical differences in amygdala connectivity. The lack of stereotypical cortical projection is corroborated, both at the level of bulk axonal patterning and in projections of individually labelled neurons, by two papers — one from the Axel laboratory, and one from the Baldwin laboratory — that examine the anterograde projections from individual glomeruli. Together, these findings provide anatomical evidence for combinatorial processing of information from diverse glomeruli by cortical neurons and may also reflect different functions of various areas in mediating innate or learned odour preferences.

We still don't know how odors retain their identities over a range of concentrations. Working in mice, Bolding and Franks simultaneously recorded spiking activity from neurons in the olfactory bulb and piriform cortex, two important brain regions for olfaction. Odor information was transformed from a representation that was highly concentration dependent in the olfactory bulb to a representation that was largely concentration invariant in the piriform cortex. The underlying mechanism involves a “winner-takes-all” lateral inhibition. In the collateral network of the piriform cortex, the principal cells responded promptly to output from the olfactory bulb, and recurrent inhibition curtailed the intensity dependence of the signal. Science , this issue p. eaat6904 Feedback inhibition mediates the suppression of concentration-dependent sustained activity in the olfactory cortex. Animals rely on olfaction to find food, attract mates, and avoid predators. To support these behaviors, they must be able to identify odors across different odorant concentrations. The neural circuit operations that implement this concentration invariance remain unclear. We found that despite concentration-dependence in the olfactory bulb (OB), representations of odor identity were preserved downstream, in the piriform cortex (PCx). The OB cells responding earliest after inhalation drove robust responses in sparse subsets of PCx neurons. Recurrent collateral connections broadcast their activation across the PCx, recruiting global feedback inhibition that rapidly truncated and suppressed cortical activity for the remainder of the sniff, discounting the impact of slower, concentration-dependent OB inputs. Eliminating recurrent collateral output amplified PCx odor responses rendered the cortex steeply concentration-dependent and abolished concentration-invariant identity decoding.

The cortical amygdala is necessary and sufficient for processing odours that evoke aversive and attractive responses without learning. Cortical processing of odour stimuli Sensory neurons in the nose transmit information to various areas in the brain via the olfactory bulb. The roles of these different brain areas, and how they code and process odour-related information, are not well understood. Richard Axel and colleagues show that one area, the cortical amygdala, is both necessary and sufficient for processing odours that evoke aversive and attractive responses without prior learning. Such signals may play a role in shaping learned adaptive responses linking specific odours to experience. Innate behaviours are observed in naive animals without prior learning or experience, suggesting that the neural circuits that mediate these behaviours are genetically determined and stereotyped. The neural circuits that convey olfactory information from the sense organ to the cortical and subcortical olfactory centres have been anatomically defined 1 , 2 , 3 , but the specific pathways responsible for innate responses to volatile odours have not been identified. Here we devise genetic strategies that demonstrate that a stereotyped neural circuit that transmits information from the olfactory bulb to cortical amygdala is necessary for innate aversive and appetitive behaviours. Moreover, we use the promoter of the activity-dependent gene arc to express the photosensitive ion channel, channelrhodopsin, in neurons of the cortical amygdala activated by odours that elicit innate behaviours. Optical activation of these neurons leads to appropriate behaviours that recapitulate the responses to innate odours. These data indicate that the cortical amygdala plays a critical role in generating innate odour-driven behaviours but do not preclude its participation in learned olfactory behaviours.

The olfactory system is an ideal and tractable system for exploring how the brain transforms sensory inputs into behaviour. The basic tasks of any olfactory system include odour detection, discrimination and categorization. The challenge for the olfactory system is to transform the high-dimensional space of olfactory stimuli into the much smaller space of perceived objects and valence that endows odours with meaning. Our current understanding of how neural circuits address this challenge has come primarily from observations of the mechanisms of the brain for processing other sensory modalities, such as vision and hearing, in which optimized deep hierarchical circuits are used to extract sensory features that vary along continuous physical dimensions. The olfactory system, by contrast, contends with an ill-defined, high-dimensional stimulus space and discrete stimuli using a circuit architecture that is shallow and parallelized. Here, we present recent observations in vertebrate and invertebrate systems that relate the statistical structure and state-dependent modulation of olfactory codes to mechanisms of perception and odour-guided behaviour.The detection, discrimination and categorization of odours are essential for survival across the animal kingdom. In this Review, Datta and co-workers describe and compare the neural circuits that mediate the processing of olfactory information and the key principles of olfactory coding in insects and mammals.

The hippocampus is essential for representing spatiotemporal context and establishing its association with the sensory details of daily life to form episodic memories. The olfactory cortex in particular shares exclusive anatomical connections with the hippocampus as a result of their common evolutionary history. Here we selectively inhibit hippocampal projections to the anterior olfactory nucleus (AON) during behavioural tests of contextually cued odour recall. We find that spatial odour memory and temporal odour memory are independently impaired following inhibition of distinct, topographically organized hippocampal-AON pathways. Our results not only reveal a longstanding unknown function for the AON but offer new mechanistic insights regarding the representation of odours in episodic memory. Hippocampus is necessary for integrating the context with sensory cues to retrieve memory for unique episodes. Here, the authors show that inhibiting topographically organized projections from hippocampus to the anterior olfactory nucleus independently impairs spatial and temporal odour memory recall.

The evolution of animal behaviour is poorly understood 1 , 2 . Despite numerous correlations between interspecific divergence in behaviour and nervous system structure and function, demonstrations of the genetic basis of these behavioural differences remain rare 3 – 5 . Here we develop a neurogenetic model, Drosophila sechellia , a species that displays marked differences in behaviour compared to its close cousin Drosophila melanogaster 6 , 7 , which are linked to its extreme specialization on noni fruit ( Morinda citrifolia ) 8 – 16 . Using calcium imaging, we identify olfactory pathways in D. sechellia that detect volatiles emitted by the noni host. Our mutational analysis indicates roles for different olfactory receptors in long- and short-range attraction to noni, and our cross-species allele-transfer experiments demonstrate that the tuning of one of these receptors is important for species-specific host-seeking. We identify the molecular determinants of this functional change, and characterize their evolutionary origin and behavioural importance. We perform circuit tracing in the D. sechellia brain, and find that receptor adaptations are accompanied by increased sensory pooling onto interneurons as well as species-specific central projection patterns. This work reveals an accumulation of molecular, physiological and anatomical traits that are linked to behavioural divergence between species, and defines a model for investigating speciation and the evolution of the nervous system. A neurogenetic model, Drosophila sechellia —a relative of Drosophila melanogaster that has developed an extreme specialization for a single host plant—sheds light on the evolution of interspecific differences in behaviour.

Scent tracking In the mouse, glomeruli in the olfactory bulb receive projections from single classes of olfactory neurons, thereby forming an odour map. Information from the glomeruli is then relayed to the cortex but the projection patterns from individual glomeruli are not known. Three papers now examine the details of this projection. Luo and colleagues use a combination of genetics and retrograde mono-trans-synaptic rabies virus labelling. They trace the presynaptic connections of individual cortical neurons and find no evidence of connections supporting a stereotyped odour map in the cortex, but see systematic topographical differences in amygdala connectivity. The lack of stereotypical cortical projection is corroborated, both at the level of bulk axonal patterning and in projections of individually labelled neurons, by two papers — one from the Axel laboratory, and one from the Baldwin laboratory — that examine the anterograde projections from individual glomeruli. Together, these findings provide anatomical evidence for combinatorial processing of information from diverse glomeruli by cortical neurons and may also reflect different functions of various areas in mediating innate or learned odour preferences. Sensory information is transmitted to the brain where it must be processed to translate stimulus features into appropriate behavioural output. In the olfactory system, distributed neural activity in the nose is converted into a segregated map in the olfactory bulb 1 , 2 , 3 . Here we investigate how this ordered representation is transformed in higher olfactory centres in mice. We have developed a tracing strategy to define the neural circuits that convey information from individual glomeruli in the olfactory bulb to the piriform cortex and the cortical amygdala. The spatial order in the bulb is discarded in the piriform cortex; axons from individual glomeruli project diffusely to the piriform without apparent spatial preference. In the cortical amygdala, we observe broad patches of projections that are spatially stereotyped for individual glomeruli. These projections to the amygdala are overlapping and afford the opportunity for spatially localized integration of information from multiple glomeruli. The identification of a distributive pattern of projections to the piriform and stereotyped projections to the amygdala provides an anatomical context for the generation of learned and innate behaviours.

The purpose of the study was to investigate the interactions between two stimuli—menthol and nicotine—both of which activate the olfactory and the trigeminal system. More specifically, we wanted to know whether menthol at different concentrations modulates the perception of burning and stinging pain induced by nicotine stimuli in the human nose. The study followed an eightfold randomized, double-blind, cross-over design including 20 participants. Thirty phasic nicotine stimuli at one of the two concentrations (99 and 134 ng/mL) were applied during the entire experiment every 1.5 min for 1 s; tonic menthol stimulation at one of the three concentrations (0.8, 1.5 and 3.4 μg/mL) or no-menthol (placebo control conditions) was introduced after the 15th nicotine stimulus. The perceived intensities of nicotine’s burning and stinging pain sensations, as well as perceived intensities of menthol’s odor, cooling and pain sensations, were estimated using visual analog scales. Recorded estimates of stinging and burning sensations induced by nicotine initially decreased (first half of the experiment) probably due to adaptation/habituation. Tonic menthol stimulation did not change steady-state nicotine pain intensity estimates, neither for burning nor for stinging pain. Menthol-induced odor and cooling sensations were concentration dependent when combined with low-intensity nicotine stimuli. Surprisingly, this dose dependency was eliminated when combining menthol stimuli with high-intensity nicotine stimuli. There was no such nicotine effect on menthol’s pain sensation. In summary, we detected interactions caused by nicotine on menthol perception for odor and cooling but no effect was elicited by menthol on nicotine pain sensation.