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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.

The nervous system flexibly processes information under different conditions. To do this, neural networks frequently rely on uniform expression of modulatory receptors by distinct classes of neurons to fine tune the computations supported by each neuronal class. Here, we explore an alternate organization in which one population of neurons in the olfactory system of Drosophila expresses all of the receptors for the modulator serotonin. We find extensive, heterogeneous receptor co-expression by ventral projection neurons (v-PNs), with many receptor combinations present. Despite overlap in glomerular innervation of v-PNs expressing each serotonin receptor, their axon terminals innervate largely distinct zones within a higher order olfactory region. Serotonin differentially modulates odor-evoked responses of v-PNs with distinct receptor expression and these v-PNs synapse upon separate sets of third order olfactory neurons. This functional organization implies that serotonin differentially modulates the responses of v-PNs that participate in divergent, downstream olfactory circuits. Jonaitis et al demonstrate that serotonin differentially modulates feedforward inhibitory neurons in the olfactory system of Drosophila which likely reflects odor categorization in higher order brain regions.

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.

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.

Olfactory neurons respond to various odorants according to which olfactory receptors, of many, they express. During development, axons from olfactory neurons that express the same olfactory receptor converge to share the same glomeruli. Nakashima et al. now show that, in mice, the neurons build these connections according to shared patterns of activity. When the olfactory receptor is triggered, it causes its cell not simply to fire but to fire in specific patterns. Neurons that speak the same code end up connected at the same glomerulus. Science , this issue p. eaaw5030 The temporal pattern of neuronal firing rather than its synchronicity refines olfactory codes in the brain. Neural circuits emerge through the interplay of genetic programming and activity-dependent processes. During the development of the mouse olfactory map, axons segregate into distinct glomeruli in an olfactory receptor (OR)–dependent manner. ORs generate a combinatorial code of axon-sorting molecules whose expression is regulated by neural activity. However, it remains unclear how neural activity induces OR-specific expression patterns of axon-sorting molecules. We found that the temporal patterns of spontaneous neuronal spikes were not spatially organized but were correlated with the OR types. Receptor substitution experiments demonstrated that ORs determine spontaneous activity patterns. Moreover, optogenetically differentiated patterns of neuronal activity induced specific expression of the corresponding axon-sorting molecules and regulated axonal segregation. Thus, OR-dependent temporal patterns of spontaneous activity play instructive roles in generating the combinatorial code of axon-sorting molecules during olfactory map formation.

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 direct access of olfactory afferents to memory-related cortical systems has inspired theories about the role of the olfactory pathways in the development of cortical neurodegeneration in Alzheimer’s disease (AD). In this study, we used baseline olfactory identification measures with longitudinal flortaucipir and PiB PET, diffusion MRI of 89 cognitively normal older adults (73.82 ± 8.44 years; 56% females), and a transcriptomic data atlas to investigate the spatiotemporal spreading and genetic vulnerabilities of AD-related pathology aggregates in the olfactory system. We find that odor identification deficits are predominantly associated with tau accumulation in key areas of the olfactory pathway, with a particularly strong predictive power for longitudinal tau progression. We observe that tau spreads from the medial temporal lobe structures toward the olfactory system, not the reverse. Moreover, we observed a genetic background of odor perception-related genes that might confer vulnerability to tau accumulation along the olfactory system. The role of olfactory pathways in the development of neurodegeneration in Alzheimer’s disease is not well understood. Here, the authors show odor identification deficits are predictive of tau accumulation and progression in olfactory pathways, and that tau spreads from medial temporal lobe structures towards the olfactory system.

Odors evoke complex spatiotemporal patterns of activity in the olfactory bulb. The authors show that the spike rates of downstream piriform cortex neurons (PCNs) reflect the relative timing of activation. Posterior PCNs are more sensitive to input timing than anterior PCNs. Odor stimulation evokes complex spatiotemporal activity in the olfactory bulb, suggesting that both the identity of activated neurons and the timing of their activity convey information about odors. However, whether and how downstream neurons decipher these temporal patterns remains unknown. We addressed this question by measuring the spiking activity of downstream neurons while optogenetically stimulating two foci in the olfactory bulb with varying relative timing in mice. We found that the overall spike rates of piriform cortex neurons (PCNs) were sensitive to the relative timing of activation. Posterior PCNs showed higher sensitivity to relative input times than neurons in the anterior piriform cortex. In contrast, olfactory bulb neurons rarely showed such sensitivity. Thus, the brain can transform a relative time code in the periphery into a firing rate–based representation in central brain areas, providing evidence for the relevance of a relative time–based code in the olfactory bulb.