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The cortex organizes sensory information to enable discrimination and generalization 1 – 4 . As systematic representations of chemical odour space have not yet been described in the olfactory cortex, it remains unclear how odour relationships are encoded to place chemically distinct but similar odours, such as lemon and orange, into perceptual categories, such as citrus 5 – 7 . Here, by combining chemoinformatics and multiphoton imaging in the mouse, we show that both the piriform cortex and its sensory inputs from the olfactory bulb represent chemical odour relationships through correlated patterns of activity. However, cortical odour codes differ from those in the bulb: cortex more strongly clusters together representations for related odours, selectively rewrites pairwise odour relationships, and better matches odour perception. The bulb-to-cortex transformation depends on the associative network originating within the piriform cortex, and can be reshaped by passive odour experience. Thus, cortex actively builds a structured representation of chemical odour space that highlights odour relationships; this representation is similar across individuals but remains plastic, suggesting a means through which the olfactory system can assign related odour cues to common and yet personalized percepts. Both piriform cortex and its sensory inputs from the olfactory bulb represent chemical odour relationships, but cortex reshapes relational information inherited from the sensory periphery to enhance odour generalization and to reflect experience.

Odor landscapes contain complex blends of molecules that each activate unique, overlapping populations of olfactory sensory neurons (OSNs). Despite the presence of hundreds of OSN subtypes in many animals, the overlapping nature of odor inputs may lead to saturation of neural responses at the early stages of stimulus encoding. Information loss due to saturation could be mitigated by normalizing mechanisms such as antagonism at the level of receptor-ligand interactions, whose existence and prevalence remains uncertain. By imaging OSN axon terminals in olfactory bulb glomeruli as well as OSN cell bodies within the olfactory epithelium in freely breathing mice, we find widespread antagonistic interactions in binary odor mixtures. In complex mixtures of up to 12 odorants, antagonistic interactions are stronger and more prevalent with increasing mixture complexity. Therefore, antagonism is a common feature of odor mixture encoding in OSNs and helps in normalizing activity to reduce saturation and increase information transfer. Odor blends contain molecules that activate unique, overlapping populations of sensory neurons (OSNs). Here, by imaging OSN axon terminals, as well as their cell bodies within the olfactory epithelium, the authors find widespread antagonistic interactions in binary and complex odor mixtures.

In comparison to that of other animals, the human sense of smell is widely considered to be weak and underdeveloped. This is, however, an unproven hypothesis. In a Review, McGann traces the origins of this false belief back to comparative 19th-century neuroanatomical studies by Broca. A modern look at the human olfactory bulb shows that it is rather large compared with those of rats and mice, which are presumed to possess a superior sense of smell. In fact, the number of olfactory bulb neurons across 24 mammalian species is comparatively similar, with humans in the middle of the pack, and our sense of smell is similar to that of other mammals. Science , this issue p. eaam7263 It is commonly believed that humans have a poor sense of smell compared to other mammalian species. However, this idea derives not from empirical studies of human olfaction but from a famous 19th-century anatomist’s hypothesis that the evolution of human free will required a reduction in the proportional size of the brain’s olfactory bulb. The human olfactory bulb is actually quite large in absolute terms and contains a similar number of neurons to that of other mammals. Moreover, humans have excellent olfactory abilities. We can detect and discriminate an extraordinary range of odors, we are more sensitive than rodents and dogs for some odors, we are capable of tracking odor trails, and our behavioral and affective states are influenced by our sense of smell.

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.

The human olfactory system comprises olfactory receptor neurons, projection neurons, and interneurons that perform remarkably sophisticated functions, including sensing, filtration, memorization, and forgetting of chemical stimuli for perception. Developing an artificial olfactory system that can mimic these functions has proved to be challenging. Herein, inspired by the neuronal network inside the glomerulus of the olfactory bulb, we present an artificial chemosensory neuronal synapse that can sense chemical stimuli and mimic the functions of excitatory and inhibitory neurotransmitter release in the synapses between olfactory receptor neurons, projection neurons, and interneurons. The proposed device is based on a flexible organic electrochemical transistor gated by the potential generated by the interaction of gas molecules with ions in a chemoreceptive ionogel. The combined use of a chemoreceptive ionogel and an organic semiconductor channel allows for a long retentive memory in response to chemical stimuli. Long-term memorization of the excitatory chemical stimulus can be also erased by applying an inhibitory electrical stimulus due to ion dynamics in the chemoresponsive ionogel gate electrolyte. Applying a simple device design, we were able to mimic the excitatory and inhibitory synaptic functions of chemical synapses in the olfactory system, which can further advance the development of artificial neuronal systems for biomimetic chemosensory applications. Developing an artificial olfactory system that can mimic the biological functions remains a challenge. Here, the authors develop an artificial chemosensory synapse based on a flexible organic electrochemical transistor gated by the potential generated by the interaction of gas molecules with ions in a chemoreceptive ionogel.

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.

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.

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.

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 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.