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Sneezing and coughing are primary symptoms of many respiratory viral infections and allergies. It is generally assumed that sneezing and coughing involve common sensory receptors and molecular neurotransmission mechanisms. Here, we show that the nasal mucosa is innervated by several discrete populations of sensory neurons, but only one population (MrgprC11+MrgprA3−) mediates sneezing responses to a multitude of nasal irritants, allergens, and viruses. Although this population also innervates the trachea, it does not mediate coughing, as revealed by our newly established cough model. Instead, a distinct sensory population (somatostatin [SST+]) mediates coughing but not sneezing, unraveling an unforeseen sensory difference between sneezing and coughing. At the circuit level, sneeze and cough signals are transmitted and modulated by divergent neuropathways. Together, our study reveals the difference in sensory receptors and neurotransmission/modulation mechanisms between sneezing and coughing, offering neuronal drug targets for symptom management in respiratory viral infections and allergies. [Display omitted] • Sneezing and coughing are mediated by distinct sensory populations • Nasal MrgprC11-expressing sensory neurons serve as a core "sneeze" population • Airway SST-expressing sensory neurons mediate chemically induced cough • Sneezing and coughing are transmitted and modulated by divergent neuropathways Sneezing and coughing are frequently associated with allergies and respiratory viral infections. This study reveals that sneezing and coughing are initiated by discrete sensory receptors and transmitted by divergent neuropathways, offering drug targets for managing pathological sneezing and coughing. [ABSTRACT FROM AUTHOR]

Pacinian corpuscle neurons are specialized low-threshold mechanoreceptors (LTMRs) that are tuned to detect high-frequency vibration (∼50–2,000 Hz); however, it is unclear how Pacinians and other LTMRs encode mechanical forces encountered during naturalistic behavior. Here, we developed methods to record LTMRs in awake, freely moving mice. We find that Pacinians, but not other LTMRs, encode subtle vibrations of surfaces encountered by the animal, including low-amplitude vibrations initiated over 2 m away. Strikingly, Pacinians are also highly active during a wide variety of natural behaviors, including walking, grooming, digging, and climbing. Pacinians in the hindlimb are sensitive enough to be activated by forelimb- or upper-body-dominant behaviors. Finally, we find that Pacinian LTMRs have diverse tuning and sensitivity. Our findings suggest a Pacinian population code for the representation of vibro-tactile features generated by self-initiated movements and low-amplitude environmental vibrations emanating from distant locations. • Recording of Pacinian neurons in awake, freely moving animals • Pacinian neurons are activated by self-generated movement • Pacinian neurons are activated by distant and subtle environmental vibrations • Diverse tuning results in activation by different behaviors and environments Turecek and Ginty record from mechanosensory neurons in awake, freely moving animals. They find that Pacinian neurons tuned to mechanical vibration can detect body movement and subtle environmental vibrations from great distances. Pacinian neurons also span a range of sensitivities, allowing them to encode a wide range of environmental stimuli. [ABSTRACT FROM AUTHOR]

The sensory nervous system possesses the ability to integrate exogenous threats and endogenous signals to mediate downstream effector functions. Sensory neurons have been shown to activate or suppress host defense and immunity against pathogens, depending on the tissue and disease state. Through this lens, pro- and anti-inflammatory neuroimmune effector functions can be interpreted as evolutionary adaptations by host or pathogen. Here, we discuss recent and impactful examples of neuroimmune circuitry that regulate tissue homeostasis, autoinflammation, and host defense. Apparently paradoxical or conflicting reports in the literature also highlight the complexity of neuroimmune interactions that may depend on tissue- and microbe-specific cues. These findings expand our understanding of the nuanced mechanisms and the greater context of sensory neurons in innate immunity. Tissue-innervating neurons communicate with local immune and non-immune cells to balance homeostasis and inflammation. Deng, Gillis, Kaplan, and Chiu review some of the most well-defined and compelling pathways by which peripheral neurons regulate autoinflammation, host defense, and tissue repair. They discuss recent studies in murine models and invertebrates, demonstrating that neurons have served as immune effectors and/or regulators throughout evolution. [ABSTRACT FROM AUTHOR]

Skin-to-skin contact is widespread during social interactions and essential for establishing intimate relationships. To understand the skin-to-brain circuits underlying pleasurable touch, a new study has used mouse genetic tools to specifically target and study sensory neurons that transmit social touch and their role during sexual behavior in mice. [ABSTRACT FROM AUTHOR]

The gut is innervated by sensory neurons that relay mechanical and chemical signals to the brain. Two new studies characterize the spinal sensory neurons that innervate the intestines and reveal a role for Piezo2 in these cells in sensing colonic distension and regulating gastrointestinal motility. [ABSTRACT FROM AUTHOR]

Reproductive behaviors differ across species, but the mechanisms that control variation in mating and parental care systems remain unclear. In many animal species, pheromones guide mating and parental care. However, it is not well understood how vertebrate pheromone signaling evolution can lead to new reproductive behavior strategies. In fishes, prostaglandin F 2α (PGF 2α) drives mating and reproductive pheromone signaling in fertile females, but this pheromonal activity appears restricted to specific lineages, and it remains unknown how a female fertility pheromone is sensed for most fish species. Here, we utilize single-cell transcriptomics and CRISPR gene editing in a cichlid fish model to identify and test the roles of key genes involved in olfactory sensing of reproductive cues. We find that a pheromone receptor, Or113a, detects fertile cichlid females and thereby promotes male attraction and mating behavior, sensing a ligand other than PGF 2α. Furthermore, while cichlid fishes exhibit extensive parental care, for most species, care is provided solely by females. We find that males initiate mouthbrooding parental care if they have disrupted signaling in ciliated sensory neurons due to cnga2b mutation or if or113a is inactivated. Together, these results show that distinct mechanisms of pheromonal signaling drive reproductive behaviors across taxa. Additionally, these findings indicate that a single pheromone receptor has gained a novel role in behavior regulation, driving avoidance of paternal care among haplochromine cichlid fishes. Lastly, a sexually dimorphic, evolutionarily derived parental behavior is controlled by central circuits present in both sexes, while olfactory signals gate this behavior in a sex-specific manner. [Display omitted] • Single-nucleus RNA sequencing reveals cell types in the cichlid olfactory epithelium • Male detection of fertile females uses the ciliated sensory neuron channel Cnga2b • Olfactory receptor Or113a detects fertile females, promoting male mating • Males mutant for cnga2b or or113a initiate mouthbrooding care behavior Li et al. discover that male cichlid fish use the olfactory receptor Or113a to detect fertile female cues. Surprisingly, Or113a also mediates males' avoidance of parental care. In CRISPR-generated mutant cichlids, males retrieve eggs and mouthbrood them, a behavior normally displayed only by females. [ABSTRACT FROM AUTHOR]

Vagal nerve stimulation has emerged as a promising modality for treating a wide range of chronic conditions, including metabolic disorders. However, the cellular and molecular pathways driving these clinical benefits remain largely obscure. Here, we demonstrate that fibroblast growth factor 3 (Fgf3) mRNA is upregulated in the mouse vagal ganglia under acute metabolic stress. Systemic and vagal sensory overexpression of Fgf3 enhanced glucose-stimulated insulin secretion (GSIS), improved glucose excursion, and increased energy expenditure and physical activity. Fgf3-elicited insulinotropic and glucose-lowering responses were recapitulated when overexpression of Fgf3 was restricted to the pancreas-projecting vagal sensory neurons. Genetic ablation of Fgf3 in pancreatic vagal afferents exacerbated high-fat diet-induced glucose intolerance and blunted GSIS. Finally, electrostimulation of the vagal afferents enhanced GSIS and glucose clearance independently of efferent outputs. Collectively, we demonstrate a direct role for the vagal afferent signaling in GSIS and identify Fgf3 as a vagal sensory-derived metabolic factor that controls pancreatic β-cell activity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Electrical excitability—the ability to fire and propagate action potentials—is a signature feature of neurons. How neurons become excitable during development and whether excitability is an intrinsic property of neurons remain unclear. Here, we demonstrate that Schwann cells, the most abundant glia in the peripheral nervous system, promote somatosensory neuron excitability during development. We find that Schwann cells secrete prostaglandin E 2 , which is necessary and sufficient to induce developing somatosensory neurons to express normal levels of genes required for neuronal function, including voltage-gated sodium channels, and to fire action potential trains. Inactivating this signaling pathway in Schwann cells impairs somatosensory neuron maturation, causing multimodal sensory defects that persist into adulthood. Collectively, our studies uncover a neurodevelopmental role for prostaglandin E 2 distinct from its established role in inflammation, revealing a cell non-autonomous mechanism by which glia regulate neuronal excitability to enable the development of normal sensory functions. [Display omitted] • Developing sensory neurons require signaling from glia to become fully excitable • Prostaglandin E 2 (PGE 2) is secreted by Schwann cells and promotes neuronal excitability • Mechanistically, PGE 2 from Schwann cells induces neuronal gene expression, including Na V s • Schwann cell-secreted PGE 2 promotes neuronal maturation and normal sensory function How do neurons become electrically excitable during development? This study reveals that Schwann cells make and secrete the prostaglandin PGE 2 , which is critical for sensory neurons to express voltage-gated sodium channels (Na V s), fire action potential trains, and support normal sensory functions. [ABSTRACT FROM AUTHOR]

The representation of odors in the locust antennal lobe with its >2,000 glomeruli has long remained a perplexing puzzle. We employed the CRISPR-Cas9 system to generate transgenic locusts expressing the genetically encoded calcium indicator GCaMP in olfactory sensory neurons. Using two-photon functional imaging, we mapped the spatial activation patterns representing a wide range of ecologically relevant odors across all six developmental stages. Our findings reveal a functionally ring-shaped organization of the antennal lobe composed of specific glomerular clusters. This configuration establishes an odor-specific chemotopic representation by encoding different chemical classes and ecologically distinct odors in the form of glomerular rings. The ring-shaped glomerular arrangement, which we confirm by selective targeting of OR70a-expressing sensory neurons, occurs throughout development, and the odor-coding pattern within the glomerular population is consistent across developmental stages. Mechanistically, this unconventional spatial olfactory code reflects the locust-specific and multiplexed glomerular innervation pattern of the antennal lobe. [Display omitted] • A transgenic line was established to express GCaMP6s in olfactory sensory neurons • Calcium imaging reveals a functionally ring-shaped odor code of glomerular clusters • Distinct ring regions encode chemical identity and ecological significance • The ring-shaped odor-coding pattern occurs consistently throughout development Migratory locusts, genetically expressing the calcium sensor GCaMP6s in olfactory sensory neurons, have an unconventional, ring-shaped olfactory code of glomerular clusters in the antennal lobe, a pattern that occurs consistently throughout development. [ABSTRACT FROM AUTHOR]

Social memory has been developed in humans and other animals to recognize familiar conspecifics and is essential for their survival and reproduction. Here, we demonstrated that parvalbumin-positive neurons in the sensory thalamic reticular nucleus (sTRN Pvalb ) are necessary and sufficient for mice to memorize conspecifics. sTRN Pvalb neurons receiving glutamatergic projections from the posterior parietal cortex (PPC) transmit individual information by inhibiting the parafascicular thalamic nucleus (PF). Mice in which the PPC CaMKII →sTRN Pvalb →PF circuit was inhibited exhibited a disrupted ability to discriminate familiar conspecifics from novel ones. More strikingly, a subset of sTRN Pvalb neurons with high electrophysiological excitability and complex dendritic arborizations is involved in the above corticothalamic pathway and stores social memory. Single-cell RNA sequencing revealed the biochemical basis of these subset cells as a robust activation of protein synthesis. These findings elucidate that sTRN Pvalb neurons modulate social memory by coordinating a hitherto unknown corticothalamic circuit and inhibitory memory engram. [Display omitted] • Parvalbumin neurons in the sTRN mediate the recognition of familiar conspecifics • The encoding and retrieval of social memory require PPC→sTRN and sTRN→PF circuits • GABA release controlled by the PPC→sTRN→PF circuit is involved in social memory • The inhibitory engram cells in the sTRN may store individual information The establishment and refinement of higher brain functions during evolution require various core brain regions to accurately and efficiently control specific types of memories. Wang et al. demonstrate that the sensory reticular thalamus specifically mediates social memory, making it an ideal target for treating social amnesia. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are submicron membranous structures and key mediators of intercellular communication. 1,2 Recent research has highlighted roles for cilia-derived EVs in signal transduction, underscoring their importance as bioactive extracellular organelles containing conserved ciliary signaling proteins. 3,4 Members of the transient receptor potential (TRP) channel polycystin-2 (PKD-2) family are found in ciliary EVs of the green algae Chlamydomonas and the nematode Caenorhabditis elegans 5,6 and in EVs in the mouse embryonic node and isolated from human urine. 7,8 In C. elegans , PKD-2 is expressed in male-specific EV-releasing sensory neurons, which extend ciliary tips to ciliary pore and directly release EVs into the environment. 6,9 Males release EVs in a mechanically stimulated manner, regulate EV cargo content in response to mating partners, and deposit PKD-2::GFP-labeled EVs on the vulval cuticle of hermaphrodites during mating. 9,10 Combined, our findings suggest that ciliary EV release is a dynamic process. Herein, we identify mechanisms controlling dynamic EV shedding using time-lapse imaging. Cilia can sustain the release of PKD-2-labeled EVs for 2 h. This extended release doesn't require neuronal transmission. Instead, ciliary intrinsic mechanisms regulate PKD-2 ciliary membrane replenishment and dynamic EV release. The kinesin-3 motor kinesin-like protein 6 (KLP-6) is necessary for initial and extended EV release, while the transition zone protein NPHP-4 is required only for sustained EV release. The dynamic replenishment of PKD-2 at the ciliary tip is key to sustained EV release. Our study provides a comprehensive portrait of real-time ciliary EV release and mechanisms supporting cilia as proficient EV release platforms. [Display omitted] • C. elegans neurons dynamically release PKD-2 carrying ciliary EVs for 2 h • Sustained ciliary EV release does not rely on neuronal transmission • Replenishment of PKD-2 at the ciliary tip is key to sustained release of ciliary EVs • Ciliary tip replenishment requires transition zone component NPHP-4 Wang et al. provide a comprehensive and mechanistic portrait of real-time ciliary EV release. C. elegans sensory neurons continuously release EVs from cilia, a process independent of neuronal transmission. Instead, the ciliary kinesin-3 kinesin-like protein 6 (KLP-6) and transition zone protein NPHP-4 maintain a dynamic ciliary tip pool of PKD-2 for sustained EV release. [ABSTRACT FROM AUTHOR]

The vagus nerve is an indispensable body-brain connection that controls vital aspects of autonomic physiology like breathing, heart rate, blood pressure, and gut motility, reflexes like coughing and swallowing, and survival behaviors like feeding, drinking, and sickness responses. Classical physiological studies and recent molecular/genetic approaches have revealed a tremendous diversity of vagal sensory neuron types that innervate different internal organs, with many cell types remaining poorly understood. Here, we review the state of knowledge related to vagal sensory neurons that innervate the respiratory, cardiovascular, and digestive systems. We focus on cell types and their response properties, physiological/behavioral roles, engaged neural circuits and, when possible, sensory receptors. We are only beginning to understand the signal transduction mechanisms used by vagal sensory neurons and upstream sentinel cells, and future studies are needed to advance the field of interoception to the level of mechanistic understanding previously achieved for our external senses. Prescott and Liberles review sensory biology of the vagus nerve, a major arm of the interoceptive nervous system and vital body-brain relay. Vagal sensory neuron functions, anatomical projections, responses, and sensory receptors are discussed across physiological systems. [ABSTRACT FROM AUTHOR]

Many studies have shown that the excitation and inhibition received by cortical neurons remain roughly balanced across many conditions. A key question for understanding the dynamical regime of cortex is the nature of this balancing. Theorists have shown that network dynamics can yield systematic cancellation of most of a neuron's excitatory input by inhibition. We review a wide range of evidence pointing to this cancellation occurring in a regime in which the balance is loose, meaning that the net input remaining after cancellation of excitation and inhibition is comparable in size with the factors that cancel, rather than tight, meaning that the net input is very small relative to the canceling factors. This choice of regime has important implications for cortical functional responses, as we describe: loose balance, but not tight balance, can yield many nonlinear population behaviors seen in sensory cortical neurons, allow the presence of correlated variability, and yield decrease of that variability with increasing external stimulus drive as observed across multiple cortical areas. Excitation and inhibition are balanced or cancel out in cerebral cortex. Ahmadian and Miller distinguish tight versus loose balance, according to the size of the residual after cancellation. They show this critically affects cortical dynamics, and summarize evidence strongly supporting loose balance. [ABSTRACT FROM AUTHOR]

The response of individual neurons to stable sensory input or behavioral output can change over time. A new study provides evidence from the mouse visual system that such drift does not follow the hierarchy of information flow across the brain. [ABSTRACT FROM AUTHOR]

The activity of neurons in sensory areas sometimes covaries with upcoming choices in decision-making tasks. However, the prevalence, causal origin, and functional role of choice-related activity remain controversial. Understanding the circuit-logic of decision signals in sensory areas will require understanding their laminar specificity, but simultaneous recordings of neural activity across the cortical layers in forced-choice discrimination tasks have not yet been performed. Here, we describe neural activity from such recordings in the auditory cortex of mice during a frequency discrimination task with delayed report, which, as we show, requires the auditory cortex. Stimulus-related information was widely distributed across layers but disappeared very quickly after stimulus offset. Choice selectivity emerged toward the end of the delay period—suggesting a top-down origin—but only in the deep layers. Early stimulus-selective and late choice-selective deep neural ensembles were correlated, suggesting that the choice-selective signal fed back to the auditory cortex is not just action specific but develops as a consequence of the sensory-motor contingency imposed by the task. [Display omitted] • Stimulus-related information is widespread across the layers of the auditory cortex • Stimulus-related information is transient and disappears within a few hundred ms • Choice-related information appears later, but only in the deep layers • Choice-related information is learned and reflects task contingencies Using an appropriate task design and laminar recordings in the mouse auditory cortex during a frequency discrimination task, Steinfeld et al. show that stimulus-related information is widespread across the cortical layers but disappears quickly, whereas choice-related information appears later but only in the deep layers. [ABSTRACT FROM AUTHOR]

Phasic (fast) and tonic (sustained) inhibition of γ-aminobutyric acid (GABA) are fundamental for regulating day-to-day activities, neuronal excitability, and plasticity. However, the mechanisms and physiological functions of glial GABA transductions remain poorly understood. Here, we report that the AMsh glia in Caenorhabditis elegans exhibit both phasic and tonic GABAergic signaling, which distinctively regulate olfactory adaptation and neuronal aging. Through genetic screening, we find that GABA permeates through bestrophin-9/-13/-14 anion channels from AMsh glia, which primarily activate the metabolic GABA B receptor GBB-1 in the neighboring ASH sensory neurons. This tonic action of glial GABA regulates the age-associated changes of ASH neurons and olfactory responses via a conserved signaling pathway, inducing neuroprotection. In addition, the calcium-evoked, vesicular glial GABA release acts upon the ionotropic GABA A receptor LGC-38 in ASH neurons to regulate olfactory adaptation. These findings underscore the fundamental significance of glial GABA in maintaining healthy aging and neuronal stability. [Display omitted] • AMsh glia modulate the adaptation and aging rate of ASH sensory neurons • Tonic glial GABA release via bestrophin channels regulates neuronal aging • Phasic glial GABA release regulates sensory adaptation • GABA A and GABA B receptors differentially function in adaptation and aging Cheng et al. report two modes, phasic and tonic, of GABA transductions that alternatively regulate short-term sensory adaptation and long-term neuronal aging in a Caenorhabditis elegans glia-neuron circuit. They propose that targeting glia-neuronal GABAergic transductions could serve as a lifelong strategy for promoting healthy aging and preserving neuronal stability. [ABSTRACT FROM AUTHOR]

A central question for regenerative neuroscience is whether synthetic neural circuits, such as those built from two species, can function in an intact brain. Here, we apply blastocyst complementation to selectively build and test interspecies neural circuits. Despite approximately 10–20 million years of evolution, and prominent species differences in brain size, rat pluripotent stem cells injected into mouse blastocysts develop and persist throughout the mouse brain. Unexpectedly, the mouse niche reprograms the birth dates of rat neurons in the cortex and hippocampus, supporting rat-mouse synaptic activity. When mouse olfactory neurons are genetically silenced or killed, rat neurons restore information flow to odor processing circuits. Moreover, they rescue the primal behavior of food seeking, although less well than mouse neurons. By revealing that a mouse can sense the world using neurons from another species, we establish neural blastocyst complementation as a powerful tool to identify conserved mechanisms of brain development, plasticity, and repair. [Display omitted] • Rat stem cells develop in mouse blastocysts to broadly populate two-species brains • Rat neurons develop synchronously and synapse with cognate mouse neurons • Genetic models of circuit loss or silencing unveil rescue capacity of exogenous neurons • Rat sensory neurons restore the primal behavior of food seeking to anosmic mice Generating brains from two different species via blastocyst complementation enables synchronous development of appropriate interspecies circuits. When host sensory neurons are disabled, donor neurons restore a primal odor-driven food-seeking behavior, showing that one species can sense and respond to the world through the cognate neurons of another. [ABSTRACT FROM AUTHOR]

Infections of the lung cause observable sickness thought to be secondary to inflammation. Signs of sickness are crucial to alert others via behavioral-immune responses to limit contact with contagious individuals. Gram-negative bacteria produce exopolysaccharide (EPS) that provides microbial protection; however, the impact of EPS on sickness remains uncertain. Using genome-engineered Pseudomonas aeruginosa (P. aeruginosa) strains, we compared EPS-producers versus non-producers and a virulent Escherichia coli (E. coli) lung infection model in male and female mice. EPS-negative P. aeruginosa and virulent E. coli infection caused severe sickness, behavioral alterations, inflammation, and hypothermia mediated by TLR4 detection of the exposed lipopolysaccharide (LPS) in lung TRPV1+ sensory neurons. However, inflammation did not account for sickness. Stimulation of lung nociceptors induced acute stress responses in the paraventricular hypothalamic nuclei by activating corticotropin-releasing hormone neurons responsible for sickness behavior and hypothermia. Thus, EPS-producing biofilm pathogens evade initiating a lung-brain sensory neuronal response that results in sickness. [Display omitted] • Non-biofilm P. aeruginosa induce greater sickness than biofilm-producing strains • Lung TRPV1+ nociceptors detect LPS from non-biofilm bacterial pneumonias via TLR4 • Vagal nociceptors in the lung activate acute stress neurocircuits in the hypothalamus • CRH from the PVN of the hypothalamus drives sickness behavior in non-biofilm infections Biofilm production alters sickness during P. aeruginosa pneumonia by masking the ability of TLR4-TRPV1+ lung nociceptors to activate corticotropin-releasing hormone-mediated acute stress pathways in the paraventricular nuclei of the brain. [ABSTRACT FROM AUTHOR]

Proprioception tells the brain the state of the body based on distributed sensory neurons. Yet, the principles that govern proprioceptive processing are poorly understood. Here, we employ a task-driven modeling approach to investigate the neural code of proprioceptive neurons in cuneate nucleus (CN) and somatosensory cortex area 2 (S1). We simulated muscle spindle signals through musculoskeletal modeling and generated a large-scale movement repertoire to train neural networks based on 16 hypotheses, each representing different computational goals. We found that the emerging, task-optimized internal representations generalize from synthetic data to predict neural dynamics in CN and S1 of primates. Computational tasks that aim to predict the limb position and velocity were the best at predicting the neural activity in both areas. Since task optimization develops representations that better predict neural activity during active than passive movements, we postulate that neural activity in the CN and S1 is top-down modulated during goal-directed movements. [Display omitted] • We combine motion capture, biomechanics, and representation learning • Computational task training is used to test hypotheses of proprioceptive coding • Task-driven models predict neural activity better than linear and data-driven models • Computational task performance correlates with neural explained variance Neural networks optimized to perform computational tasks, which were proposed as hypotheses of the proprioceptive system, develop representations that generalize from synthetic data to predict neural dynamics in CN and S1 of primates. [ABSTRACT FROM AUTHOR]

For sexually reproducing animals, selecting optimal mates is important for maximizing reproductive fitness. In the nematode C. elegans , populations reproduce largely by hermaphrodite self-fertilization, but the cross-fertilization of hermaphrodites by males also occurs. Males' ability to recognize hermaphrodites involves several sensory cues, but an integrated view of the ways males use these cues in their native context to assess characteristics of potential mates has been elusive. Here, we examine the mate-preference behavior of C. elegans males evoked by natively produced cues. We find that males use a combination of volatile sex pheromones (VSPs), ascaroside sex pheromones, surface-associated cues, and other signals to assess multiple features of potential mates. Specific aspects of mate preference are communicated by distinct signals: developmental stage and sex are signaled by ascaroside pheromones and surface cues, whereas the presence of a self-sperm-depleted hermaphrodite is likely signaled by VSPs. Furthermore, males prefer to interact with virgin over mated, and well-fed over food-deprived, hermaphrodites; these preferences are likely adaptive and are also mediated by ascarosides and other cues. Sex-typical mate-preference behavior depends on the sexual state of the nervous system, such that pan-neuronal genetic masculinization in hermaphrodites generates male-typical social behavior. We also identify an unexpected role for the sex-shared ASH sensory neurons in male attraction to ascaroside sex pheromones. Our findings lead to an integrated view in which the distinct physical properties of various mate-preference cues guide a flexible, stepwise behavioral program by which males assess multiple features of potential mates to optimize mate preference. • C. elegans males can detect a potential mate's sex, stage, health, and mating history • Diverse chemical and physical signals enable stepwise evaluation of potential mates • Males prefer virgin, well-fed mates, likely by using honest indicators of fitness • Genetic masculinization of hermaphrodite neurons elicits male-like mate preference The selection of optimal mates is central to animal fitness and evolution. Here, Luo et al. find that diverse sensory signals inform C. elegans males about the sex, stage, feeding status, and mating history of potential mates. Sex-specific detection and integration of these signals enables a stepwise program that subserves male mate preference. [ABSTRACT FROM AUTHOR]

Dorsal root ganglia (DRG) somatosensory neurons detect mechanical, thermal, and chemical stimuli acting on the body. Achieving a holistic view of how different DRG neuron subtypes relay neural signals from the periphery to the CNS has been challenging with existing tools. Here, we develop and curate a mouse genetic toolkit that allows for interrogating the properties and functions of distinct cutaneous targeting DRG neuron subtypes. These tools have enabled a broad morphological analysis, which revealed distinct cutaneous axon arborization areas and branching patterns of the transcriptionally distinct DRG neuron subtypes. Moreover, in vivo physiological analysis revealed that each subtype has a distinct threshold and range of responses to mechanical and/or thermal stimuli. These findings support a model in which morphologically and physiologically distinct cutaneous DRG sensory neuron subtypes tile mechanical and thermal stimulus space to collectively encode a wide range of natural stimuli. [Display omitted] • A mouse genetic toolkit for labeling DRG neuron subtypes, including CGRP+ subtypes • DRG neuron subtypes exhibit distinct cutaneous axon branching patterns and areas • DRG neuron subtypes have distinct thresholds to mechanical/thermal stimuli • DRG neuron subtype response profiles tile mechanical and thermal stimulus space A DRG neuron genetic toolkit reveals morphological and physiological heterogeneity across the transcriptionally distinct somatosensory neuron subtypes, and findings suggest population coding schemes for the neuronal representation of mechanical and thermal stimuli acting on the skin. [ABSTRACT FROM AUTHOR]

How genetic loss of the sodium channel Na V 1.7 results in painlessness is puzzling. MacDonald et al. (2021) demonstrate that instead of impairing peripheral excitability, Na V 1.7 channels at central terminals of pain-sensing afferents play a pivotal role in the balance between pain and analgesia. [ABSTRACT FROM AUTHOR]

Proteasomes are critical for peripheral nervous system (PNS) function. Here, we investigate mammalian PNS proteasomes and reveal the presence of the neuronal membrane proteasome (NMP). We show that specific inhibition of the NMP on distal nerve fibers innervating the mouse hind paw leads to reduction in mechanical and pain sensitivity. Through investigating PNS NMPs, we demonstrate their presence on the somata and proximal and distal axons of a subset of dorsal root ganglion (DRG) neurons. Single-cell RNA sequencing experiments reveal that the NMP-expressing DRGs are primarily MrgprA3 + and Cysltr2 + . NMP inhibition in DRG cultures leads to cell-autonomous and non-cell-autonomous changes in Ca 2+ signaling induced by KCl depolarization, αβ-meATP, or the pruritogen histamine. Taken together, these data support a model whereby NMPs are expressed on a subset of somatosensory DRGs to modulate signaling between neurons of distinct sensory modalities and indicate the NMP as a potential target for controlling pain., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Host-associated microbiomes are emerging as important modifiers of brain activity and behavior. Metabolic, immune, and neuronal pathways are proposed to mediate communication across the so-called microbiota-gut-brain axis. However, strong mechanistic evidence, especially for direct signaling between microbes and sensory neurons, is lacking. Here, we discuss microbial regulation of short-chain fatty acids, neurotransmitters, as-yet-uncharacterized biochemicals, and derivatives of neuromodulatory drugs as important areas for assessing microbial interactions with the nervous system. While microbiomes are emerging as important modifiers of neurophysiology and behavior, pathways for microbial modulation of neuronal activity are poorly understood. Jameson et al. discuss microbial interactions with dietary molecules, neurotransmitters, uncharacterized biochemicals, and neuromodulatory drugs as important areas for continued research toward uncovering mechanisms for microbial signaling to neurons. [ABSTRACT FROM AUTHOR]

Behavior relies on activity in structured neural circuits that are distributed across the brain, but most experiments probe neurons in a single area at a time. Using multiple Neuropixels probes, we recorded from multi-regional loops connected to the anterior lateral motor cortex (ALM), a circuit node mediating memory-guided directional licking. Neurons encoding sensory stimuli, choices, and actions were distributed across the brain. However, choice coding was concentrated in the ALM and subcortical areas receiving input from the ALM in an ALM-dependent manner. Diverse orofacial movements were encoded in the hindbrain; midbrain; and, to a lesser extent, forebrain. Choice signals were first detected in the ALM and the midbrain, followed by the thalamus and other brain areas. At movement initiation, choice-selective activity collapsed across the brain, followed by new activity patterns driving specific actions. Our experiments provide the foundation for neural circuit models of decision-making and movement initiation. [Display omitted] • Anatomy-guided activity recordings in multi-regional neural circuits during behavior • Movement encoding is strongest in the medulla, followed by the midbrain and cortex • Choice coding arises in a specific multi-regional circuit distributed across the brain • Coding of choice and action exhibit strong correlations across brain areas A sparse neural network, distributed across major brain compartments, produces tightly orchestrated activity patterns underlying decision-making and movement initiation. [ABSTRACT FROM AUTHOR]

Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with JAK1 gain-of-function (GoF) variants develop atopic dermatitis (AD) and asthma. To explore tissue-specific functions, we inserted a human JAK1 GoF variant (JAK1 GoF) into mice and observed the development of spontaneous AD-like skin disease but unexpected resistance to lung inflammation when JAK1 GoF expression was restricted to the stroma. We identified a previously unrecognized role for JAK1 in vagal sensory neurons in suppressing airway inflammation. Additionally, expression of Calcb /CGRPβ was dependent on JAK1 in the vagus nerve, and CGRPβ suppressed group 2 innate lymphoid cell function and allergic airway inflammation. Our findings reveal evolutionarily conserved but distinct functions of JAK1 in sensory neurons across tissues. This biology raises the possibility that therapeutic JAK inhibitors may be further optimized for tissue-specific efficacy to enhance precision medicine in the future. [Display omitted] • A human germline JAK1 GoF variant promotes spontaneous skin inflammation in mice • Vagal sensory neuron expression of JAK1 GoF promotes immune homeostasis in the lung • A neuronal JAK1-CGRPβ axis suppresses ILC2 responses and allergic lung inflammation Janus kinase 1 signaling exerts distinct effects across cell types and tissues, with JAK1 signaling in vagal sensory neurons promoting anti-inflammatory responses in the lung. [ABSTRACT FROM AUTHOR]

Insects and mammals have independently evolved odorant receptor genes that are arranged in large genomic tandem arrays. In mammals, each olfactory sensory neuron chooses to express a single receptor in a stochastic process that includes substantial chromatin rearrangements. Here, we show that ants, which have the largest odorant receptor repertoires among insects, employ a different mechanism to regulate gene expression from tandem arrays. Using single-nucleus RNA sequencing, we found that ant olfactory sensory neurons choose different transcription start sites along an array but then produce mRNA from many downstream genes. This can result in transcripts from dozens of receptors being present in a single nucleus. Such rampant receptor co-expression at first seems difficult to reconcile with the narrow tuning of the ant olfactory system. However, RNA fluorescence in situ hybridization showed that only mRNA from the most upstream transcribed odorant receptor seems to reach the cytoplasm where it can be translated into protein, whereas mRNA from downstream receptors gets sequestered in the nucleus. This implies that, despite the extensive co-expression of odorant receptor genes, each olfactory sensory neuron ultimately only produces one or very few functional receptors. Evolution has thus found different molecular solutions in insects and mammals to the convergent challenge of selecting small subsets of receptors from large odorant receptor repertoires. [Display omitted] • Ant olfactory sensory neurons co-express many odorant receptor genes • Each neuron chooses a transcription start site and expresses the downstream genes • Only mRNA from the most upstream expressed gene is exported into the cytoplasm • This ensures neurons have narrow receptor profiles despite rampant co-expression Brahma et al. report a new mechanism of transcriptional control at the large genomic tandem arrays of ant odorant receptors. Although sensory neurons often co-express many genes along an array, only mRNA from one gene is exported into the cytoplasm, where it can be translated. This ensures narrow receptor profiles despite rampant co-expression. [ABSTRACT FROM AUTHOR]

Interview with Craig Montell, whose work focuses on identifying receptors, channels and sensory neurons important in vision, taste, and temperature sensation. [ABSTRACT FROM AUTHOR]

In a recent issue of Nature, Hoeffel et al. describe a novel pathway of sterile tissue repair utilizing a mouse model of sunburn. This wound healing pathway is coordinated by sensory neuron-derived TAFA4 that induces IL-10 production from Tim4+ dermal macrophages to prevent sustained inflammation and the emergence of tissue fibrosis. [ABSTRACT FROM AUTHOR]

IL-31 receptor blockade suppresses pruritus of atopic dermatitis. However, cell-type-specific contributions of IL-31 receptor to itch, its expression mechanism, and the downstream signaling pathway to induce itch remain unknown. Here, using conditional knockout mice, we demonstrate that IL-31-induced itch requires sensory neuronal IL-31 receptor and STAT3. We find that IL-31 receptor expression is dependent on STAT3 in sensory neurons. In addition, pharmacological experiments suggest that STAT3 activation is important for the itch-inducing signaling downstream of the IL-31 receptor. A cutaneous IL-31 injection induces the nuclear accumulation of activated STAT3 first in sensory neurons that abundantly express IL-31 receptor and then in other itch-transmitting neurons. IL-31 enhances itch induced by various pruritogens including even chloroquine. Finally, pruritus associated with dermatitis is partially dependent on sensory neuronal IL-31 receptor and strongly on sensory neuronal STAT3. Thus, sensory neuronal STAT3 is essential for IL-31-induced itch and further contributes to IL-31-independent inflammatory itch., Competing Interests: Declaration of interests All authors declare that they have no relevant conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Sensory neurons have surfaced as key instigators of skin inflammation. In this issue of Cell , Zhang et al. define an anti-inflammatory Langerhans cell (LC)-neuron-mast cell (MC) circuit that underlies skin immune homeostasis. They uncover a role for LCs in maintaining innervation of MrgprD+ nonpeptidergic neurons that restrain MC activation via glutamate secretion. [ABSTRACT FROM AUTHOR]

Itch is an unpleasant sensation that evokes a desire to scratch. The skin barrier is constantly exposed to microbes and their products. However, the role of microbes in itch generation is unknown. Here, we show that Staphylococcus aureus , a bacterial pathogen associated with itchy skin diseases, directly activates pruriceptor sensory neurons to drive itch. Epicutaneous S. aureus exposure causes robust itch and scratch-induced damage. By testing multiple isogenic bacterial mutants for virulence factors, we identify the S. aureus serine protease V8 as a critical mediator in evoking spontaneous itch and alloknesis. V8 cleaves proteinase-activated receptor 1 (PAR1) on mouse and human sensory neurons. Targeting PAR1 through genetic deficiency, small interfering RNA (siRNA) knockdown, or pharmacological blockade decreases itch and skin damage caused by V8 and S. aureus exposure. Thus, we identify a mechanism of action for a pruritogenic bacterial factor and demonstrate the potential of inhibiting V8-PAR1 signaling to treat itch. [Display omitted] • S. aureus induces itch and scratch damage with epicutaneous skin exposure • V8 protease (SspA) is necessary and sufficient for itch during S. aureus exposure • S. aureus V8 activates mouse and human sensory neurons through PAR1 • PAR1 deficiency or blockade abrogates S. aureus -induced itch and skin damage Itch evokes a desire to scratch, but the link between microbes and itch was unclear. Staphylococcus aureus , a bacterial pathogen, secretes a protease V8 that activates PAR1 expressed on neurons to drive itch and skin damage. [ABSTRACT FROM AUTHOR]

The olfactory bulb (OB) is a critical component of mammalian olfactory neuroanatomy. Beyond being the first and sole relay station for olfactory information to the rest of the brain, it also contains elaborate stereotypical circuitry that is considered essential for olfaction. Indeed, substantial lesions of the OB in rodents lead to anosmia. Here, we examined the circuitry that underlies olfaction in a mouse model with severe developmental degeneration of the OB. These mice could perform odor-guided tasks and even responded normally to innate olfactory cues. Despite the near total loss of the OB, piriform cortices in these mice responded to odors, and its neural activity sufficed to decode odor identity. We found that sensory neurons express the full repertoire of olfactory receptors, and their axons project primarily to the rudiments of the OB but also, ectopically, to olfactory cortical regions. Within the OB, the number of principal neurons was greatly reduced, and the morphology of their dendrites was abnormal, extending over large regions within the OB. Glomerular organization was totally lost in the severe cases of OB degeneration and altered in the more conserved OBs. This study shows that olfactory functionality can be preserved despite reduced and aberrant circuitry that is missing many of the elements believed to be essential for olfaction, and it may explain reported retention of olfaction in humans with degenerated OBs. • Mice with severely degenerated olfactory bulbs could perform odor-guided tasks • The olfactory cortex displayed intact responsiveness to odors • The circuitry at the level of olfactory epithelium and bulb was highly abnormal • Our study may explain smell retention in humans without olfactory bulbs Mammalian olfaction is thought to rely on stereotyped circuitry. Licht et al. describe a mouse model that retains a functional sense of smell despite severe olfactory bulb degeneration. These mice can perform odor-guided tasks and have functional odor representations in piriform cortex, despite extremely aberrant olfactory bulb circuitry. [ABSTRACT FROM AUTHOR]

Olfaction is a fundamental sense guiding animals to their food. How the olfactory system evolves and influences behavior is still poorly understood. Here, we selected five drosophilid species, including Drosophila melanogaster , inhabiting different ecological niches to compare their olfactory systems at multiple levels. We first identified ecologically relevant natural food odorants from every species and established species-specific odorant preferences. To compare odor coding in sensory neurons, we analyzed the antennal lobe (AL) structure, generated glomerular atlases, and developed GCaMP transgenic lines for all species. Although subsets of glomeruli showed distinct tuning profiles, odorants inducing species-specific preferences were coded generally similarly. Species distantly related or occupying different habitats showed more evident differences in odor coding, and further analysis revealed that changes in olfactory receptor (OR) sequences partially explain these differences. Our results demonstrate that genetic distance in phylogeny and ecological niche occupancy are key determinants in the evolution of ORs, AL structures, odor coding, and behavior. Interestingly, changes in odor coding among species could not be explained by evolutionary changes at a single olfactory processing level but rather are a complex phenomenon based on changes at multiple levels. [Display omitted] • Drosophila flies detect a diverse range of host plant and non-host plant odorants • The same odorants can have different valences in different species • Differences in odor coding and behavior depend on phylogeny and the species' ecology By comparing five Drosophila species that differ in their phylogenetic distance from each other and the similarity of their ecological niche, Depetris et al. show that both phylogeny and the ecological niche are key factors in the evolution of olfactory receptors, antennal lobe structures, odor coding, and behavior in drosophilid flies. [ABSTRACT FROM AUTHOR]

Our ability to sense and move our bodies relies on proprioceptors, sensory neurons that detect mechanical forces within the body. Different subtypes of proprioceptors detect different kinematic features, such as joint position, movement, and vibration, but the mechanisms that underlie proprioceptor feature selectivity remain poorly understood. Using single-nucleus RNA sequencing (RNA-seq), we found that proprioceptor subtypes in the Drosophila leg lack differential expression of mechanosensitive ion channels. However, anatomical reconstruction of the proprioceptors and connected tendons revealed major biomechanical differences between subtypes. We built a model of the proprioceptors and tendons that identified a biomechanical mechanism for joint angle selectivity and predicted the existence of a topographic map of joint angle, which we confirmed using calcium imaging. Our findings suggest that biomechanical specialization is a key determinant of proprioceptor feature selectivity in Drosophila. More broadly, the discovery of proprioceptive maps reveals common organizational principles between proprioception and other topographically organized sensory systems. [Display omitted] • Proprioceptors in the Drosophila leg are organized into three groups • Each group is biomechanically specialized to detect distinct features of leg joint kinematics • A mechanical doohickey in the femur decomposes tibia joint movements into orthogonal components • The cell bodies of position-tuned proprioceptors form a goniotopic map of joint angle The sense of self relies on proprioceptors, sensory neurons that detect mechanical forces within the body. Mamiya and colleagues investigate how proprioceptors detect specific mechanical features, such as joint position and movement. They show how feature selectivity arises from the biomechanics of the proprioceptive organ and discover topographic neural maps of leg joint angle and vibration frequency. [ABSTRACT FROM AUTHOR]

Efficient sensory processing requires the nervous system to adjust to ongoing features of the environment. In primary visual cortex (V1), neuronal activity strongly depends on recent stimulus history. Existing models can explain effects of prolonged stimulus presentation but remain insufficient for explaining effects observed after shorter durations commonly encountered under natural conditions. We investigated the mechanisms driving adaptation in response to brief (100 ms) stimuli in L2/3 V1 neurons by performing in vivo whole-cell recordings to measure membrane potential and synaptic inputs. We find that rapid adaptation is generated by stimulus-specific suppression of excitatory and inhibitory synaptic inputs. Targeted optogenetic experiments reveal that these synaptic effects are due to input-specific short-term depression of transmission between layers 4 and 2/3. Thus, brief stimulus presentation engages a distinct adaptation mechanism from that previously reported in response to prolonged stimuli, enabling flexible control of sensory encoding across a wide range of timescales. [Display omitted] • Brief visual experience induces long-lasting adaptation of L2/3 neurons in mouse V1 • Adaptation decreases both stimulus-evoked synaptic excitation and inhibition • Activation of L4 is necessary and sufficient to induce effects of adaptation • Adaptation reflects short-term depression of L4 excitatory inputs to L2/3 neurons Sensory adaptation filters stimulus information by reducing responses to redundant inputs. Using a combination of in vivo and in vitro electrophysiological approaches, Li and Glickfeld find that short-term depression generates stimulus-specific adaptation in superficial layers of mouse primary visual cortex and shapes temporal integration at a seconds-long timescale. [ABSTRACT FROM AUTHOR]

Pain often persists in patients with an inflammatory disease, even when inflammation has subsided. The molecular mechanisms leading to this failure in pain resolution and the transition to chronic pain are poorly understood. Mitochondrial dysfunction in sensory neurons links to chronic pain, but its role in resolution of inflammatory pain is unclear. Transient inflammation causes neuronal plasticity, called hyperalgesic priming, which impairs resolution of pain induced by a subsequent inflammatory stimulus. We identify that hyperalgesic priming in mice increases the expression of a mitochondrial protein (ATPSc-KMT) and causes mitochondrial and metabolic disturbances in sensory neurons. Inhibition of mitochondrial respiration, knockdown of ATPSCKMT expression, or supplementation of the affected metabolite is sufficient to restore resolution of inflammatory pain and prevents chronic pain development. Thus, inflammation-induced mitochondrial-dependent disturbances in sensory neurons predispose to a failure in resolution of inflammatory pain and development of chronic pain., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The sense of touch is fundamental as it provides vital, moment-to-moment information about the nature of our physical environment. Primary sensory neurons provide the basis for this sensation in the periphery; however, recent work demonstrates that touch transduction mechanisms also occur upstream of the sensory neurons via non-neuronal cells such as Merkel cells and keratinocytes. Within the spinal cord, deep dorsal horn circuits transmit innocuous touch centrally and also transform touch into pain in the setting of injury. Here non-neuronal cells play a key role in the induction and maintenance of persistent mechanical pain. This review highlights recent advances in our understanding of mechanosensation, including a growing appreciation for the role of non-neuronal cells in both touch and pain. Moehring et al. review recent advances in the field of somatosensory mechanotransduction and describe the molecular and cellular circuits underlying our sense of touch in both normal healthy conditions and in pathological conditions. [ABSTRACT FROM AUTHOR]

Sensory neurons detect mechanical forces from both the environment and internal organs to regulate physiology. PIEZO2 is a mechanosensory ion channel critical for touch, proprioception, and bladder stretch sensation, yet its broad expression in sensory neurons suggests it has undiscovered physiological roles. To fully understand mechanosensory physiology, we must know where and when PIEZO2-expressing neurons detect force. The fluorescent styryl dye FM 1-43 was previously shown to label sensory neurons. Surprisingly, we find that the vast majority of FM 1-43 somatosensory neuron labeling in mice in vivo is dependent on PIEZO2 activity within the peripheral nerve endings. We illustrate the potential of FM 1-43 by using it to identify novel PIEZO2-expressing urethral neurons that are engaged by urination. These data reveal that FM 1-43 is a functional probe for mechanosensitivity via PIEZO2 activation in vivo and will facilitate the characterization of known and novel mechanosensory processes in multiple organ systems. • FM 1-43 is a fluorescent dye that labels mouse sensory neurons in vivo • Sensory neuron FM 1-43 labeling requires the activity of the mechanosensor PIEZO2 • FM 1-43 reveals a PIEZO2-dependent urethral neuron that is engaged during urination • This dye is a useful tool for identifying when and where PIEZO2 is active in vivo Mechanosensory processes are critical for the function of many organ systems. Villarino et al. find that the fluorescent dye FM 1-43 specifically labels the activity of the mechanosensitive ion channel PIEZO2 in mouse sensory neurons in vivo. This tool enables characterization of neuronal processes that rely on this important mechanosensor. [ABSTRACT FROM AUTHOR]

Although essential and conserved, sleep is not without its challenges that must be overcome; most notably, it renders animals vulnerable to threats in the environment. Infection and injury increase sleep demand, which dampens sensory responsiveness to stimuli, including those responsible for the initial insult. Stress-induced sleep in Caenorhabditis elegans occurs in response to cellular damage following noxious exposures the animals attempted to avoid. Here, we describe a G-protein-coupled receptor (GPCR) encoded by npr-38 , which is required for stress-related responses including avoidance, sleep, and arousal. Overexpression of npr-38 shortens the avoidance phase and causes animals to initiate movement quiescence and arouse early. npr-38 functions in the ADL sensory neurons, which express neuropeptides encoded by nlp-50 , also required for movement quiescence. npr-38 regulates arousal by acting on the DVA and RIS interneurons. Our work demonstrates that this single GPCR regulates multiple aspects of the stress response by functioning in sensory and sleep interneurons. [Display omitted] • npr-38 is required for sleep, avoidance, and general arousal • npr-38 is required in the ADL sensory neurons for sleep and avoidance • npr-38 is required in the RIS and DVA interneurons for arousal • The ADL neurons express nlp-50 neuropeptides which are required for sleep Sleep promotes recovery from injury or illness; however, it renders animals vulnerable to threats. The mechanisms that regulate transitions between threat avoidance and sleep are not well understood. Le, McCarthy, et al. describe a G-protein-coupled receptor, npr-38 , that is required in the ADL sensory neurons for avoidance and sleep in Caenorhabditis elegans. [ABSTRACT FROM AUTHOR]

The gastrointestinal tract is in a state of constant motion. These movements are tightly regulated by the presence of food and help digestion by mechanically breaking down and propelling gut content. Mechanical sensing in the gut is thought to be essential for regulating motility; however, the identity of the neuronal populations, the molecules involved, and the functional consequences of this sensation are unknown. Here, we show that humans lacking PIEZO2 exhibit impaired bowel sensation and motility. Piezo2 in mouse dorsal root, but not nodose ganglia is required to sense gut content, and this activity slows down food transit rates in the stomach, small intestine, and colon. Indeed, Piezo2 is directly required to detect colon distension in vivo. Our study unveils the mechanosensory mechanisms that regulate the transit of luminal contents throughout the gut, which is a critical process to ensure proper digestion, nutrient absorption, and waste removal. [Display omitted] • Individuals with PIEZO2 syndrome present impaired bowel sensation and GI dysfunction • Piezo2 in DRG neurons plays an important role in regulating gut motility • Lack of Piezo2 from sensory neurons accelerates gastric emptying and intestinal transit • DRG neurons detect colon distension via Piezo2 Piezo2 in dorsal root ganglia neurons is required to sense gut content and slow down food transit rates in the stomach, small intestine, and colon. [ABSTRACT FROM AUTHOR]

Vagal sensory neurons monitor mechanical and chemical stimuli in the gastrointestinal tract. Major efforts are underway to assign physiological functions to the many distinct subtypes of vagal sensory neurons. Here, we use genetically guided anatomical tracing, optogenetics, and electrophysiology to identify and characterize vagal sensory neuron subtypes expressing Prox2 and Runx3 in mice. We show that three of these neuronal subtypes innervate the esophagus and stomach in regionalized patterns, where they form intraganglionic laminar endings. Electrophysiological analysis revealed that they are low-threshold mechanoreceptors but possess different adaptation properties. Lastly, genetic ablation of Prox2 and Runx3 neurons demonstrated their essential roles for esophageal peristalsis in freely behaving mice. Our work defines the identity and function of the vagal neurons that provide mechanosensory feedback from the esophagus to the brain and could lead to better understanding and treatment of esophageal motility disorders. [Display omitted] • Prox2/Runx3 vagal sensory neurons form intraganglionic laminar endings in the esophagus • Prox2/Runx3 vagal sensory neurons function as mechanoreceptors • Prox2/Runx3 vagal sensory neurons are required for swallowing in freely behaving mice The vagal sensory neurons that monitor esophageal stretch and distension belong to the MM2 and MM8 subtypes of Prox2/Runx3 neurons. These two subtypes are key for swallowing in vivo , as their ablation causes severe esophageal dysmotility. Knowledge about their molecular makeup might help treat esophageal disease. [ABSTRACT FROM AUTHOR]

Ants communicate via large arrays of pheromones and possess expanded, highly complex olfactory systems, with antennal lobes in the brain comprising up to ∼500 glomeruli. This expansion implies that odors could activate hundreds of glomeruli, which would pose challenges for higher-order processing. To study this problem, we generated transgenic ants expressing the genetically encoded calcium indicator GCaMP in olfactory sensory neurons. Using two-photon imaging, we mapped complete glomerular responses to four ant alarm pheromones. Alarm pheromones robustly activated ≤6 glomeruli, and activity maps for the three pheromones inducing panic alarm in our study species converged on a single glomerulus. These results demonstrate that, rather than using broadly tuned combinatorial encoding, ants employ precise, narrowly tuned, and stereotyped representations of alarm pheromones. The identification of a central sensory hub glomerulus for alarm behavior suggests that a simple neural architecture is sufficient to translate pheromone perception into behavioral outputs. [Display omitted] • An efficient transgenesis method for the clonal raider ant • Generation of a transgenic line expressing GCaMP6s in olfactory sensory neurons • Calcium imaging reveals highly stereotyped odor encoding in the ant antennal lobe • Alarm pheromones are sparsely encoded and activate a core glomerulus A transgenesis method for the clonal raider ant, yielding expression of the genetically encoded calcium indicator GCaMP6s in all olfactory sensory neurons, has shown how ants use spatially precise encodings for alarm pheromones. [ABSTRACT FROM AUTHOR]

Evolution has generated an enormous variety of morphological, physiological, and behavioral traits in animals. How do behaviors evolve in different directions in species equipped with similar neurons and molecular components? Here we adopted a comparative approach to investigate the similarities and differences of escape behaviors in response to noxious stimuli and their underlying neural circuits between closely related drosophilid species. Drosophilids show a wide range of escape behaviors in response to noxious cues, including escape crawling, stopping, head casting, and rolling. Here we find that D. santomea , compared with its close relative D. melanogaster , shows a higher probability of rolling in response to noxious stimulation. To assess whether this behavioral difference could be attributed to differences in neural circuitry, we generated focused ion beam-scanning electron microscope volumes of the ventral nerve cord of D. santomea to reconstruct the downstream partners of mdIV, a nociceptive sensory neuron in D. melanogaster. Along with partner interneurons of mdVI (including Basin-2, a multisensory integration neuron necessary for rolling) previously identified in D. melanogaster , we identified two additional partners of mdVI in D. santomea. Finally, we showed that joint activation of one of the partners (Basin-1) and a common partner (Basin-2) in D. melanogaster increased rolling probability, suggesting that the high rolling probability in D. santomea is mediated by the additional activation of Basin-1 by mdIV. These results provide a plausible mechanistic explanation for how closely related species exhibit quantitative differences in the likelihood of expressing the same behavior. [Display omitted] • Larvae of 12 drosophilids exhibit diverse escape responses to noxious stimulation • D. santomea larvae roll more than D. melanogaster larvae upon noxious stimulation • Connectomics identify a connection in D. santomea not present in D. melanogaster • The newly identified connection may underlie the species difference in behavior Zhu et al. characterize escape responses in 12 drosophilids and find that compared to D. melanogaster , D. santomea is more likely to roll in response to noxious stimulation. Upon analyzing the nociceptive connectome of D. santomea , they discover a novel connection between sensory neurons and interneurons that explains this species difference. [ABSTRACT FROM AUTHOR]

Light touch sensation begins with activation of low-threshold mechanoreceptor (LTMR) endings in the skin and propagation of their signals to the spinal cord and brainstem. We found that the clustered protocadherin gamma (Pcdhg) gene locus, which encodes 22 cell-surface homophilic binding proteins, is required in somatosensory neurons for normal behavioral reactivity to a range of tactile stimuli. Developmentally, distinct Pcdhg isoforms mediate LTMR synapse formation through neuron-neuron interactions and peripheral axonal branching through neuron-glia interactions. The Pcdhgc3 isoform mediates homophilic interactions between sensory axons and spinal cord neurons to promote synapse formation in vivo and is sufficient to induce postsynaptic specializations in vitro. Moreover, loss of Pcdhgs and somatosensory synaptic inputs to the dorsal horn leads to fewer corticospinal synapses on dorsal horn neurons. These findings reveal essential roles for Pcdhg isoform diversity in somatosensory neuron synapse formation, peripheral axonal branching, and stepwise assembly of central mechanosensory circuitry. [Display omitted] • Pcdhg isoforms have compartmentalized roles in touch sensory neuron development • Pcdhgc3 promotes synapse formation between sensory neurons and spinal cord neurons • Pcdhgs promote peripheral axonal branching through neuron-glia interactions • Sensory inputs to the spinal cord regulate the assembly of spinal cord circuitry Meltzer et al. show that the clustered protocadherin gamma (Pcdhg) gene locus regulates somatosensory neuron synapse formation and peripheral axonal branching. Pcdhgc3 is the only isoform that promotes synapse formation between sensory neurons and spinal cord neurons. Further, they found that somatosensory inputs regulate the assembly of spinal cord circuitry. [ABSTRACT FROM AUTHOR]

In Drosophila , a dedicated olfactory channel senses a male pheromone, cis -vaccenyl acetate (cVA), promoting female courtship while repelling males. Here, we show that separate cVA-processing streams extract qualitative and positional information. cVA sensory neurons respond to concentration differences in a 5-mm range around a male. Second-order projection neurons encode the angular position of a male by detecting inter-antennal differences in cVA concentration, which are amplified through contralateral inhibition. At the third circuit layer, we identify 47 cell types with diverse input-output connectivity. One population responds tonically to male flies, a second is tuned to olfactory looming, while a third integrates cVA and taste to coincidentally promote female mating. The separation of olfactory features resembles the mammalian what and where visual streams; together with multisensory integration, this enables behavioral responses appropriate to specific ethological contexts. [Display omitted] • cVA male pheromone has a 5-mm signaling range, activating 2 parallel central pathways • Pheromone neurons have spatial receptive fields sharpened by contralateral inhibition • Position (where) and identity (what) are separated at the 3rd layer of cVA processing • Integrating taste and cVA in sexually dimorphic aSP-g controls female receptivity An active contrast circuit effectively allows flies to "see" each other using smell. [ABSTRACT FROM AUTHOR]

Summary In senses as diverse as vision, hearing, touch, and the electrosense, sensory neurons receive bottom-up input from the environment, as well as top-down input from feedback loops involving higher brain regions [ 1–4 ]. Through connectivity with local inhibitory interneurons, these feedback loops can exert both positive and negative control over fundamental aspects of neural coding, including bursting [ 5, 6 ] and synchronous population activity [ 7, 8 ]. Here we show that a prominent midbrain feedback loop synthesizes a neural code for motion reversal in the hindbrain electrosensory ON- and OFF-type pyramidal cells. This top-down mechanism generates an accurate bidirectional encoding of object position, despite the inability of the electrosensory afferents to generate a consistent bottom-up representation [ 9, 10 ]. The net positive activity of this midbrain feedback is additionally regulated through a hindbrain feedback loop, which reduces stimulus-induced bursting and also dampens the ON and OFF cell responses to interfering sensory input [ 11 ]. We demonstrate that synthesis of motion representations and cancellation of distracting signals are mediated simultaneously by feedback, satisfying an accepted definition of spatial attention [ 12 ]. The balance of excitatory and inhibitory feedback establishes a “focal” distance for optimized neural coding, whose connection to a classic motion-tracking behavior provides new insight into the computational roles of feedback and active dendrites in spatial localization [ 13, 14 ]. [ABSTRACT FROM AUTHOR]

In a heterogeneous and changing environment, oviposition site selection strongly affects the survival and fitness of the offspring. 1,2 Similarly, competition between larvae affects their prospects. 3 However, little is known about the involvement of pheromones in regulating these processes. 4,5,6,7,8 Here, we show that mated females of Drosophila melanogaster prefer to lay eggs on substrates containing extracts of conspecific larvae. After analyzing these extracts chemically, we test each compound in an oviposition assay and find that mated females display a dose-dependent preference to lay eggs on substrates spiked with (Z)-9-octadecenoic acid ethyl ester (OE). This egg-laying preference relies on gustatory receptor Gr32a and tarsal sensory neurons expressing this receptor. The concentration of OE also regulates larval place choice in a dose-dependent manner. Physiologically, OE activates female tarsal Gr32a+ neurons. In conclusion, our results reveal a cross-generation communication strategy essential for oviposition site selection and regulation of larval density. • Drosophila females prefer laying eggs on substrate containing larval chemicals • Larval chemical (Z)-9-octadecenoic acid ethyl ester (OE) stimulates oviposition • OE-dependent oviposition preference relies on Gr32a and tarsal sensory neurons • OE activates Gr32a-positive tarsal sensory neurons Zhang et al. show that Drosophila larval chemicals influence where females lay eggs. One of the components, (Z)-9-octadecenoic acid ethyl ester (OE), acts as an oviposition cue, and OE detection relies on female tarsal gustatory sensory neurons that express Gr32a. In addition, OE regulates larval social grouping in a dose-dependent manner. [ABSTRACT FROM AUTHOR]

Neurons modify their transcriptomes in response to an animal's experience. How specific experiences are transduced to modulate gene expression and precisely tune neuronal functions are not fully defined. Here, we describe the molecular profile of a thermosensory neuron pair in C. elegans experiencing different temperature stimuli. We find that distinct salient features of the temperature stimulus, including its duration, magnitude of change, and absolute value, are encoded in the gene expression program in this single neuron type, and we identify a novel transmembrane protein and a transcription factor whose specific transcriptional dynamics are essential to drive neuronal, behavioral, and developmental plasticity. Expression changes are driven by broadly expressed activity-dependent transcription factors and corresponding cis -regulatory elements that nevertheless direct neuron- and stimulus-specific gene expression programs. Our results indicate that coupling of defined stimulus characteristics to the gene regulatory logic in individual specialized neuron types can customize neuronal properties to drive precise behavioral adaptation. • The gene expression profile of AFD reflects defined temperature experience features • Altered expression is mediated by classic activity-dependent regulatory pathways • Specific gene expression changes drive developmental and behavioral flexibility • Linking stimulus aspects with transcription enables precise neuronal plasticity Harris et al. describe how distinct features of a sensory experience are encoded in the transcriptional profile of a thermosensory neuron pair. Modification of the gene expression program via classic activity-dependent pathways drives neuronal plasticity in response to defined temperature changes and underlies concomitant behavioral adaptation. [ABSTRACT FROM AUTHOR]

The pathogenic bacterium Streptococcus pneumoniae (S. pneumoniae) can invade the cerebrospinal fluid (CSF) and cause meningitis with devastating consequences. Whether and how sensory cells in the central nervous system (CNS) become activated during bacterial infection, as recently reported for the peripheral nervous system, is not known. We find that CSF infection by S. pneumoniae in larval zebrafish leads to changes in posture and behavior that are reminiscent of pneumococcal meningitis, including dorsal arching and epileptic-like seizures. We show that during infection, invasion of the CSF by S. pneumoniae massively activates in vivo sensory neurons contacting the CSF, referred to as "CSF-cNs" and previously shown to detect spinal curvature and to control posture, locomotion, and spine morphogenesis. We find that CSF-cNs express orphan bitter taste receptors and respond in vitro to bacterial supernatant and metabolites via massive calcium transients, similar to the ones observed in vivo during infection. Upon infection, CSF-cNs also upregulate the expression of numerous cytokines and complement components involved in innate immunity. Accordingly, we demonstrate, using cell-specific ablation and blockade of neurotransmission, that CSF-cN neurosecretion enhances survival of the host during S. pneumoniae infection. Finally, we show that CSF-cNs respond to various pathogenic bacteria causing meningitis in humans, as well as to the supernatant of cells infected by a neurotropic virus. Altogether, our work uncovers that central sensory neurons in the spinal cord, previously involved in postural control and morphogenesis, contribute as well to host survival by responding to the invasion of the CSF by pathogenic bacteria during meningitis. [Display omitted] • Infection of zebrafish with S. pneumoniae elicits pathognomonic signs of meningitis • CSF-cNs show massive activation when S. pneumoniae invade the CSF • Metabolites secreted by S. pneumoniae induce similar activation of CSF-cNs • CSF-cN secretion increases host survival upon S. pneumoniae infection Prendergast et al. discover that cerebrospinal fluid-contacting neurons (CSF-cNs), which are known to detect spinal curvature and control posture, also respond to bacterial metabolites, and during infections of the central nervous system, they secrete compounds that promote host survival. [ABSTRACT FROM AUTHOR]