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Transmitter receptors constitute a key component of the molecular machinery for intercellular communication in the brain. Recent efforts have mapped the density of diverse transmitter receptors across the human cerebral cortex with an unprecedented level of detail. Here, we distill these observations into key organizational principles. We demonstrate that receptor densities form a natural axis in the human cerebral cortex, reflecting decreases in differentiation at the level of laminar organization and a sensory-to-association axis at the functional level. Along this natural axis, key organizational principles are discerned: progressive molecular diversity (increase of the diversity of receptor density); excitation/inhibition (increase of the ratio of excitatory-to-inhibitory receptor density); and mirrored, orderly changes of the density of ionotropic and metabotropic receptors. The uncovered natural axis formed by the distribution of receptors aligns with the axis that is formed by other dimensions of cortical organization, such as the myelo- and cytoarchitectonic levels. Therefore, the uncovered natural axis constitutes a unifying organizational feature linking multiple dimensions of the cerebral cortex, thus bringing order to the heterogeneity of cortical organization.

Type 2 innate lymphoid cells (ILC2s) both contribute to mucosal homeostasis and initiate pathologic inflammation in allergic asthma. However, the signals that direct ILC2s to promote homeostasis versus inflammation are unclear. To identify such molecular cues, we profiled mouse lung-resident ILCs using single-cell RNA sequencing at steady state and after in vivo stimulation with the alarmin cytokines IL-25 and IL-33. ILC2s were transcriptionally heterogeneous after activation, with subpopulations distinguished by expression of proliferative, homeostatic and effector genes. The neuropeptide receptor Nmur1 was preferentially expressed by ILC2s at steady state and after IL-25 stimulation. Neuromedin U (NMU), the ligand of NMUR1, activated ILC2s in vitro , and in vivo co-administration of NMU with IL-25 strongly amplified allergic inflammation. Loss of NMU–NMUR1 signalling reduced ILC2 frequency and effector function, and altered transcriptional programs following allergen challenge in vivo . Thus, NMUR1 signalling promotes inflammatory ILC2 responses, highlighting the importance of neuro-immune crosstalk in allergic inflammation at mucosal surfaces. Neuromedin receptor NMUR1 is specifically expressed by a subpopulation of type 2 innate lymphoid cells and promotes the inflammatory response of these cells in response to allergens, indicating the importance of neuro-immune crosstalk in allergic responses. Neuron regulation of immune cells Vijay Kuchroo and colleagues use single-cell RNA sequencing techniques to analyse the responses of lung innate lymphoid cells in mice to the epithelial-cell-derived cytokines IL-15 and IL-33. They identify the neuromedin U receptor NMUR1 as a receptor specifically expressed by a subpopulation of type 2 innate lymphoid cells (ILC2s), and show that it is activated by IL-25 plus the neuropeptide ligand neuromedin U (NMU), generating a lung inflammatory response. Loss of NMU–NMUR1 signalling results in allergic lung inflammation.

•We correlate gene expression and protein density for 27 receptors and transporters•Only 5HT1a, CB1, D2, and MOR show consistent expression-density correspondence•Expression-density associations are related to population variance•We replicate results using PET, autoradiography, microarray, and RNAseq data•We recommend being cautious when substituting gene expression for receptor density Neurotransmitter receptors modulate signaling between neurons. Thus, neurotransmitter receptors and transporters play a key role in shaping brain function. Due to the lack of comprehensive neurotransmitter receptor/transporter density datasets, microarray gene expression measuring mRNA transcripts is often used as a proxy for receptor densities. In the present report, we comprehensively test the spatial correlation between gene expression and protein density for a total of 27 neurotransmitter receptors, receptor binding-sites, and transporters across 9 different neurotransmitter systems, using both PET and autoradiography radioligand-based imaging modalities. We find poor spatial correspondences between gene expression and density for all neurotransmitter receptors and transporters except four single-protein metabotropic receptors (5-HT1A, CB1, D2, and MOR). These expression-density associations are related to gene differential stability and can vary between cortical and subcortical structures. Altogether, we recommend using direct measures of receptor and transporter density when relating neurotransmitter systems to brain structure and function.

Intestinal type 2 innate lymphoid cells express the neuropeptide receptor NMUR1, which makes them responsive to neuronal neuromedin U, thereby promoting a type 2 cytokine response and accelerated expulsion of the gastro-intestinal nematode Nippostrongylus brasiliensis . Neuron regulation of immune cells Group 2 innate lymphoid cells (ILC2s) are entangled with cholinergic SNAP-25-expressing neurons. David Artis and colleagues report that ILC2s express the neuropeptide receptor NMUR1, making them responsive to neuronal neuromedin. In mice, this promoted a tissue-protective type 2 response and accelerated expulsion of the gastrointestinal nematode Nippostrongylus brasiliensis . Elsewhere in this issue, Henrique Veiga-Fernandes and colleagues also provide evidence that ILC2s express Nmur1 and respond to neuromedin expressed by adjacent enteric neurons. In mice, the interaction results in an enhanced and immediate response of ILC2s to infection by the parasite N. brasiliensis . The type 2 cytokines interleukin (IL)-4, IL-5, IL-9 and IL-13 have important roles in stimulating innate and adaptive immune responses that are required for resistance to helminth infection, promotion of allergic inflammation, metabolic homeostasis and tissue repair 1 , 2 , 3 . Group 2 innate lymphoid cells (ILC2s) produce type 2 cytokines, and although advances have been made in understanding the cytokine milieu that promotes ILC2 responses 4 , 5 , 6 , 7 , 8 , 9 , how ILC2 responses are regulated by other stimuli remains poorly understood. Here we demonstrate that ILC2s in the mouse gastrointestinal tract co-localize with cholinergic neurons that express the neuropeptide neuromedin U (NMU) 10 , 11 . In contrast to other haematopoietic cells, ILC2s selectively express the NMU receptor 1 (NMUR1). In vitro stimulation of ILC2s with NMU induced rapid cell activation, proliferation, and secretion of the type 2 cytokines IL-5, IL-9 and IL-13 that was dependent on cell-intrinsic expression of NMUR1 and G αq protein. In vivo administration of NMU triggered potent type 2 cytokine responses characterized by ILC2 activation, proliferation and eosinophil recruitment that was associated with accelerated expulsion of the gastrointestinal nematode Nippostrongylus brasiliensis or induction of lung inflammation. Conversely, worm burden was higher in Nmur1 −/− mice than in control mice. Furthermore, use of gene-deficient mice and adoptive cell transfer experiments revealed that ILC2s were necessary and sufficient to mount NMU-elicited type 2 cytokine responses. Together, these data indicate that the NMU–NMUR1 neuronal signalling circuit provides a selective mechanism through which the enteric nervous system and innate immune system integrate to promote rapid type 2 cytokine responses that can induce anti-microbial, inflammatory and tissue-protective type 2 responses at mucosal sites.

Dynamics and functions of neural circuits depend on interactions mediated by receptors. Therefore, a comprehensive map of receptor organization across cortical regions is needed. In this study, we used in vitro receptor autoradiography to measure the density of 14 neurotransmitter receptor types in 109 areas of macaque cortex. We integrated the receptor data with anatomical, genetic and functional connectivity data into a common cortical space. We uncovered a principal gradient of receptor expression per neuron. This aligns with the cortical hierarchy from sensory cortex to higher cognitive areas. A second gradient, driven by serotonin 5-HT 1A receptors, peaks in the anterior cingulate, default mode and salience networks. We found a similar pattern of 5-HT 1A expression in the human brain. Thus, the macaque may be a promising translational model of serotonergic processing and disorders. The receptor gradients may enable rapid, reliable information processing in sensory cortical areas and slow, flexible integration in higher cognitive areas. Froudist-Walsh et al. reveal organizational principles of receptor densities in macaque cortex. Densities of multiple receptor types align with changes in dendritic properties, myelin and functional networks. Data are openly released to the community.

Neurotransmitters are conventionally viewed as nerve-secreted substances that mediate the stimulatory or inhibitory neuronal functions through binding to their respective receptors. In the past decades, many novel discoveries come to light elucidating the regulatory roles of neurotransmitters in the physiological and pathological functions of tissues and organs. Notably, emerging data suggest that cancer cells take advantage of the neurotransmitters-initiated signaling pathway to activate uncontrolled proliferation and dissemination. In addition, neurotransmitters can affect immune cells and endothelial cells in the tumor microenvironment to promote tumor progression. Therefore, a better understanding of the mechanisms underlying neurotransmitter function in tumorigenesis, angiogenesis, and inflammation is expected to enable the development of the next generation of antitumor therapies. Here, we summarize the recent important studies on the different neurotransmitters, their respective receptors, target cells, as well as pro/antitumor activity of specific neurotransmitter/receptor axis in cancers and provide perspectives and insights regarding the rationales and strategies of targeting neurotransmitter system to cancer treatment.

Dopamine is synonymous with reward in mammals but associated with aversive reinforcement in insects, where reward seems to be signalled by octopamine; here it is shown that flies have discrete populations of dopamine neurons representing positive or negative values that are coordinately regulated by octopamine. Shared neuronal reward signals The neurotransmitter dopamine has been synonymous with reward in mammals, but is associated with aversive reinforcement in insects. In insects, it was thought, reward was signalled by octopamine. Now Scott Waddell and colleagues show that flies have discrete 'negative' and 'positive' populations of dopamine neurons, which are coordinately regulated by octopamine. This work reconciles previous findings with octopamine and dopamine, and suggests that reinforcement systems in flies are more like those in mammals than previously thought. Dopamine is synonymous with reward and motivation in mammals 1 , 2 . However, only recently has dopamine been linked to motivated behaviour and rewarding reinforcement in fruitflies 3 , 4 . Instead, octopamine has historically been considered to be the signal for reward in insects 5 , 6 , 7 . Here we show, using temporal control of neural function in Drosophila , that only short-term appetitive memory is reinforced by octopamine. Moreover, octopamine-dependent memory formation requires signalling through dopamine neurons. Part of the octopamine signal requires the α-adrenergic-like OAMB receptor in an identified subset of mushroom-body-targeted dopamine neurons. Octopamine triggers an increase in intracellular calcium in these dopamine neurons, and their direct activation can substitute for sugar to form appetitive memory, even in flies lacking octopamine. Analysis of the β-adrenergic-like OCTβ2R receptor reveals that octopamine-dependent reinforcement also requires an interaction with dopamine neurons that control appetitive motivation. These data indicate that sweet taste engages a distributed octopamine signal that reinforces memory through discrete subsets of mushroom-body-targeted dopamine neurons. In addition, they reconcile previous findings with octopamine and dopamine and suggest that reinforcement systems in flies are more similar to mammals than previously thought.

Systematic spatial variation in micro-architecture is observed across the cortex. These micro-architectural gradients are reflected in neural activity, which can be captured by neurophysiological time-series. How spontaneous neurophysiological dynamics are organized across the cortex and how they arise from heterogeneous cortical micro-architecture remains unknown. Here we extensively profile regional neurophysiological dynamics across the human brain by estimating over 6800 time-series features from the resting state magnetoencephalography (MEG) signal. We then map regional time-series profiles to a comprehensive multi-modal, multi-scale atlas of cortical micro-architecture, including microstructure, metabolism, neurotransmitter receptors, cell types and laminar differentiation. We find that the dominant axis of neurophysiological dynamics reflects characteristics of power spectrum density and linear correlation structure of the signal, emphasizing the importance of conventional features of electromagnetic dynamics while identifying additional informative features that have traditionally received less attention. Moreover, spatial variation in neurophysiological dynamics is co-localized with multiple micro-architectural features, including gene expression gradients, intracortical myelin, neurotransmitter receptors and transporters, and oxygen and glucose metabolism. Collectively, this work opens new avenues for studying the anatomical basis of neural activity. How neurophysiological dynamics are organized across the cortex and their relationship with cortical micro-architecture is not well understood. Here, the authors find the dominant axis of neurophysiological dynamics reflects characteristics of the power spectrum and the linear correlation structure of the signal, and that spatial variation in neurophysiological dynamics is colocalized with multiple micro-architectural features.

•Receptor density and gene expression data are from the same human hippocampal tissue.•Significant differences in receptor density only found in metabotropic receptors.•Significant differences in RNA expression mostly pertained ionotropic receptors.•Complex correlation between receptor densities and corresponding gene expressions. Neurotransmitter receptors are key molecules in signal transmission, their alterations are associated with brain dysfunction. Relationships between receptors and their corresponding genes are poorly understood, especially in humans. We combined in vitro receptor autoradiography and RNA sequencing to quantify, in the same tissue samples (7 subjects), the densities of 14 receptors and expression levels of their corresponding 43 genes in the Cornu Ammonis (CA) and dentate gyrus (DG) of human hippocampus. Significant differences in receptor densities between both structures were found only for metabotropic receptors, whereas significant differences in RNA expression levels mostly pertained ionotropic receptors. Receptor fingerprints of CA and DG differ in shapes but have similar sizes; the opposite holds true for their “RNA fingerprints”, which represent the expression levels of multiple genes in a single area. In addition, the correlation coefficients between receptor densities and corresponding gene expression levels vary widely and the mean correlation strength was weak-to-moderate. Our results suggest that receptor densities are not only controlled by corresponding RNA expression levels, but also by multiple regionally specific post-translational factors.

Pentameric ligand-gated ion channels (pLGICs) are ubiquitous neurotransmitter receptors in Bilateria, with a small number of known prokaryotic homologues. Here we describe a new inventory and phylogenetic analysis of pLGIC genes across all kingdoms of life. Our main finding is a set of pLGIC genes in unicellular eukaryotes, some of which are metazoan-like Cys-loop receptors, and others devoid of Cys-loop cysteines, like their prokaryotic relatives. A number of such \"Cys-less\" receptors also appears in invertebrate metazoans. Together, those findings draw a new distribution of pLGICs in eukaryotes. A broader distribution of prokaryotic channels also emerges, including a major new archaeal taxon, Thaumarchaeota. More generally, pLGICs now appear nearly ubiquitous in major taxonomic groups except multicellular plants and fungi. However, pLGICs are sparsely present in unicellular taxa, suggesting a high rate of gene loss and a non-essential character, contrasting with their essential role as synaptic receptors of the bilaterian nervous system. Multiple alignments of these highly divergent sequences reveal a small number of conserved residues clustered at the interface between the extracellular and transmembrane domains. Only the \"Cys-loop\" proline is absolutely conserved, suggesting the more fitting name \"Pro loop\" for that motif, and \"Pro-loop receptors\" for the superfamily. The infered molecular phylogeny shows a Cys-loop and a Cys-less clade in eukaryotes, both containing metazoans and unicellular members. This suggests new hypotheses on the evolutionary history of the superfamily, such as a possible origin of the Cys-loop cysteines in an ancient unicellular eukaryote. Deeper phylogenetic relationships remain uncertain, particularly around the split between bacteria, archaea, and eukaryotes.