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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.

Petzold and colleagues show that serotonergic innervation of the olfactory bulb functions to attenuate odor-evoked transmitter release from olfactory sensory neurons (ORNs). This effect is indirect, as serotonin stimulates 5-HT2C receptors on juxtaglomerular interneurons, whose release of GABA inhibits glutamate release from ORN terminals via GABAB receptors. Centrifugal serotonergic fibers innervate the olfactory bulb, but the importance of these projections for olfactory processing is unclear. We examined serotonergic modulation of sensory input to olfactory glomeruli using mice that express synaptopHluorin in olfactory receptor neurons (ORN). Odor-evoked synaptic input to glomeruli was attenuated by increased serotonin signaling through serotonin 2C (5-HT2C) receptors and amplified by decreased serotonergic activity. Intravital multiphoton calcium imaging revealed that 5-HT2C receptor activation amplified odor-evoked activity in a subset of juxtaglomerular cells and attenuated glutamate release from ORN terminals via GABA B receptors. Endogenous serotonin released by electrical stimulation of the dorsal raphe nucleus attenuated odor-evoked responses without detectable bias in glomerular position or odor identity. Weaker glomerular responses, however, were less sensitive to raphe stimulation than strong responses. Our data indicate that the serotonergic system regulates odor inputs in the olfactory bulb and suggest that behavioral states may alter odor processing at the earliest stages.

Across species, neural circuits show remarkable regularity, suggesting that their structure has been driven by underlying optimality principles. Here we ask whether we can predict the neural circuitry of diverse species by optimizing the neural architecture to make learning as efficient as possible. We focus on the olfactory system, primarily because it has a relatively simple evolutionarily conserved structure and because its input- and intermediate-layer sizes exhibit a tight allometric scaling. In mammals, it has been shown that the number of neurons in layer 2 of piriform cortex scales as the number of glomeruli (the input units) to the 3/2 power; in invertebrates, we show that the number of mushroom body Kenyon cells scales as the number of glomeruli to the 7/2 power. To understand these scaling laws, we model the olfactory system as a three-layer nonlinear neural network and analytically optimize the intermediate-layer size for efficient learning from limited samples. We find, as observed, a power-law scaling, with the exponent depending strongly on the number of samples and thus on longevity. The 3/2 scaling seen in mammals is consistent with observed longevity, but the 7/2 scaling in invertebrates is not. However, when a fraction of the olfactory circuit is genetically specified, not learned, scaling becomes steeper for species with a small number of glomeruli and recovers consistency with the invertebrate scaling. This study provides analytic insight into the principles underlying both allometric scaling across species and optimal architectures in artificial networks.

Drosophila olfactory local interneurons (LNs) in the antennal lobe are highly diverse and variable. How and when distinct types of LNs emerge, differentiate, and integrate into the olfactory circuit is unknown. Through systematic developmental analyses, we found that LNs are recruited to the adult olfactory circuit in three groups. Group 1 LNs are residual larval LNs. Group 2 are adult-specific LNs that emerge before cognate sensory and projection neurons establish synaptic specificity, and Group 3 LNs emerge after synaptic specificity is established. Group 1 larval LNs are selectively reintegrated into the adult circuit through pruning and re-extension of processes to distinct regions of the antennal lobe, while others die during metamorphosis. Precise temporal control of this pruning and cell death shapes the global organization of the adult antennal lobe. Our findings provide a road map to understand how LNs develop and contribute to constructing the olfactory circuit. Local interneurons (LNs) in the Drosophila olfactory system are highly diverse. Here, the authors labeled different LN types and described how different LN subtypes are integrated into the developing circuit.

Mammalian sensory systems develop through both activity-dependent and activity-independent processes. While the foundational neural circuits are encoded by genetics, their refinement depends on activity-driven mechanisms. During the neonatal critical period - a specific developmental phase - sensory circuits adapt and mature in response to environmental stimuli. Initially, this plasticity is reversible, but over time, it becomes permanent. Lack of adequate stimulation during this phase can lead to impaired neural function, highlighting the importance of sensory input for optimal system development. In mice, olfactory neural circuits are first established largely through genetic programming. However, early exposure to environmental odors is crucial in shaping these circuits, affecting both odor perception and social behaviors. This review explores recent findings on the development of olfactory circuits in mice and their impact on behavior.

Fetal Alcohol Spectrum Disorders (FASD), resulting from maternal alcohol consumption during pregnancy, are a prominent non-genetic cause of physical disabilities and brain damage in children. Alongside common symptoms like distinct facial features and neurocognitive deficits, sensory anomalies, including olfactory dysfunction, are frequently noted in FASD-afflicted children. However, the precise mechanisms underpinning the olfactory abnormalities induced by prenatal alcohol exposure (PAE) remain elusive. Utilizing rodents as a model organism with varying timing, duration, dosage, and administration routes of alcohol exposure, prior studies have documented impairments in olfactory system development caused by PAE. Many reported a reduction in the olfactory bulb (OB) volume accompanied by reduced OB neuron counts, suggesting the OB is a brain region vulnerable to PAE. In contrast, no significant olfactory system defects were observed in some studies, though subtle alterations might exist. These findings suggest that the timing, duration, and extent of fetal alcohol exposure can yield diverse effects on olfactory system development. To enhance comprehension of PAE-induced olfactory dysfunctions, this review summarizes key findings from previous research on the olfactory systems of offspring prenatally exposed to alcohol.

Neural circuitry formation depends on the molecular control of axonal projection during development. By screening with fluorophore-assisted light inactivation in the developing mouse brain, we identified cartilage acidic protein—1B as a key molecule for lateral olfactory tract (LOT) formation and named it LOT usher substance (LOTUS). We further identified Nogo receptor—1 (NgR1) as a LOTUS-binding protein. NgR1 is a receptor of myelin-derived axon growth inhibitors, such as Nogo, which prevent neural regeneration in the adult. LOTUS suppressed Nogo-NgR1 binding and Nogo-induced growth cone collapse. A defasciculated LOT was present in lotus-deficient mice but not in mice lacking both lotus- and ngr1. These findings suggest that endogenous antagonism of NgR1 by LOTUS is crucial for normal LOT formation.

This study shows a new molecular mechanism governing olfactory receptor neuron (ORN) subtype diversification from a shared precursor cell. Selection of ORNs in Drosophila is mediated by Notch signaling. Chromatin modifications directed to specific genes targeted by Notch modify the responses to this signal and diversify ORN identity and circuitry. Neuronal-class diversification is central during neurogenesis. This requirement is exemplified in the olfactory system, which utilizes a large array of olfactory receptor neuron (ORN) classes. We discovered an epigenetic mechanism in which neuron diversity is maximized via locus-specific chromatin modifications that generate context-dependent responses from a single, generally used intracellular signal. Each ORN in Drosophila acquires one of three basic identities defined by the compound outcome of three iterated Notch signaling events during neurogenesis. Hamlet, the Drosophila Evi1 and Prdm16 proto-oncogene homolog, modifies cellular responses to these iteratively used Notch signals in a context-dependent manner, and controls odorant receptor gene choice and ORN axon targeting specificity. In nascent ORNs, Hamlet erases the Notch state inherited from the parental cell, enabling a modified response in a subsequent round of Notch signaling. Hamlet directs locus-specific modifications of histone methylation and histone density and controls accessibility of the DNA-binding protein Suppressor of Hairless at the Notch target promoter.

The olfactory system represents an excellent model for studying different aspects of the development of the nervous system ranging from neurogenesis to mechanisms of axon growth and guidance. Important findings in this field come from comparative studies. We have analyzed key events in the development of the olfactory system of the shark Scyliorhinus canicula by combining immunohistochemical and tract-tracing methods. We describe for the first time in a cartilaginous fish an early population of pioneer HuC/D-immunoreactive (ir) neurons that seemed to delaminate from the olfactory pit epithelium and migrate toward the telencephalon before the olfactory nerve was identifiable. A distinct, transient cell population, namely the migratory mass, courses later on in apposition to the developing olfactory nerve. It contains olfactory ensheathing glial (GFAP-ir) cells and HuC/D-ir neurons, some of which course toward an extrabulbar region. We also demonstrate that Pax6-ir cells coursing along the developing olfactory pathways in S. canicula are young migrating (HuC/D and DCX-ir) neurons of the migratory mass that do not form part of the terminal nerve pathway. Evidences that these Pax6 neurons originate in the olfactory epithelium are also reported. As Pax6 neurons in the olfactory epithelium show characteristics of olfactory receptor neurons, and migrating Pax6-ir neurons formed transient corridors along the course of olfactory axons at the entrance of the olfactory bulb, we propose that these neurons could play a role as guideposts for axons of olfactory receptor neurons growing toward the olfactory bulb.

An essential feature of the organization and function of the vertebrate and insect olfactory systems is the generation of a variety of olfactory receptor neurons (ORNs) that have different specificities in regard to both odorant receptor expression and axonal targeting. Yet the underlying mechanisms that generate this neuronal diversity remain elusive. Here we demonstrate that the Notch signal is involved in the diversification of ORNs in Drosophila melanogaster . A systematic clonal analysis showed that a cluster of ORNs housed in each sensillum were differentiated into two classes, depending on the level of Notch activity in their sibling precursors. Notably, ORNs of different classes segregated their axonal projections into distinct domains in the antennal lobes. In addition, both the odorant receptor expression and the axonal targeting of ORNs were specified according to their Notch-mediated identities. Thus, Notch signaling contributes to the diversification of ORNs, thereby regulating multiple developmental events that establish the olfactory map in Drosophila .