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Paclitaxel is a chemotherapy drug widely used for the treatment of various cancers based on its ability to potently stabilize cellular microtubules and block division in cancer cells. Paclitaxel-based treatment, however, accumulates in peripheral system sensory neurons and leads to a high incidence rate (over 50%) of chemotherapy induced peripheral neuropathy in patients. Using an established preclinical model of paclitaxel-induced peripheral neuropathy (PIPN), we examined proteomic changes in dorsal root ganglia (DRG) of adult male mice that were treated with paclitaxel (8 mg/kg, at 4 injections every other day) relative to vehicle-treated mice. High throughput proteomics based on liquid chromatography electrospray ionization mass spectrometry identified 165 significantly altered proteins in lumbar DRG. Gene ontology enrichment and bioinformatic analysis revealed an effect of paclitaxel on pathways for mitochondrial regulation, axonal function, and inflammatory purinergic signaling as well as microtubule activity. These findings provide insight into molecular mechanisms that can contribute to PIPN in patients. [ABSTRACT FROM AUTHOR]

Mutations in the presenilin (PS) genes are a predominant cause of familial Alzheimer's disease (fAD). An ortholog of PS in the genetic model organism Caenorhabditis elegans (C. elegans) is sel-12. Mutations in the presenilin genes are commonly thought to lead to fAD by upregulating the expression of amyloid beta (Aβ), however this hypothesis has been challenged by recent evidence. As C. elegans lack amyloid beta (Aβ), the goal of this work was to examine Aβ-independent effects of mutations in sel-12 and PS1/PS2 on behaviour and sensory neuron morphology across the lifespan in a C. elegans model. Olfactory chemotaxis experiments were conducted on sel-12(ok2078) loss-of-function mutant worms. Adult sel-12 mutant worms showed significantly lower levels of chemotaxis to odorants compared to wild-type worms throughout their lifespan, and this deficit increased with age. The chemotaxis phenotype in sel-12 mutant worms is rescued by transgenic over-expression of human wild-type PS1, but not the classic fAD-associated variant PS1C410Y, when expression was driven by either the endogenous sel-12 promoter (Psel-12), a pan-neuronal promoter (Primb-1), or by a promoter whose primary expression was in the sensory neurons responsible for the chemotaxis behavior (Psra-6, Podr-10). The behavioural phenotype was also rescued by over-expressing an atypical fAD-linked mutation in PS1 (PS1ΔS169) that has been reported to leave the Notch pathway intact. An examination of the morphology of polymodal nociceptive (ASH) neurons responsible for the chemotaxis behavior also showed increased neurodegeneration over time in sel-12 mutant worms that could be rescued by the same transgenes that rescued the behaviour, demonstrating a parallel with the observed behavioral deficits. Thus, we report an Aβ-independent neurodegeneration in C. elegans that was rescued by cell specific over-expression of wild-type human presenilin. [ABSTRACT FROM AUTHOR]

Graphosoma rubrolineatum (Hemiptera: Pentatomidae) is an important pest of vegetables and herbs (e.g., Umbelliferae and Cruciferae) in China, Siberia, Korea, and Japan. Insects are highly dependent on their olfactory system to detect odorants. However, no molecular-mediated olfactory genes in G. rubrolineatum have yet been identified. In this study, we first established the antennal transcriptome of G. rubrolineatum and identified 189 candidate olfactory genes, including 31 odorant-binding proteins (OBPs), 15 chemosensory proteins (CSPs), four sensory neuron membrane proteins (SNMPs),94 odorant receptors (ORs), 23 ionotropic receptors (IRs), and 22 gustatory receptors (GRs). Additionally, phylogenetic trees were constructed for olfactory genes between G. rubrolineatum and other hemipteran insects. We also detected the expression profiles of ten OBPs, five CSPs, two SNMPs, five ORs, four IRs, and four GRs by real-time quantitative PCR. The results revealed that most genes (GrubOBP1/11/31, GrubCSP3/8, GrubSNMP1a/1b, GrubOrco/OR9/11/13, GrubGR1/4/22, GrubIR25/75h/76b/GluR1) were highly expressed in the antennae, GrubOBP13/31 and GrubCSP4/11/12 were highly expressed in the legs, while GrubOBP20 and GrubGR19 were highly expressed in the wings. Our results will enrich the gene inventory of G. rubrolineatum and provide further insight into the molecular chemosensory mechanisms of G. rubrolineatum. [ABSTRACT FROM AUTHOR]

Sensory neurons specialize in detecting and signaling the presence of diverse environmental stimuli. Neuronal injury or disease may undermine such signaling, diminishing the availability of crucial information. Can animals distinguish between a stimulus not being present and the inability to sense that stimulus in the first place? To address this question, we studied Caenorhabditis elegans nematode worms that lack gentle body touch sensation due to genetic mechanoreceptor dysfunction. We previously showed that worms can compensate for the loss of touch by enhancing their sense of smell, via an FLP-20 neuropeptide pathway. Here, we find that touch-deficient worms exhibit, in addition to sensory compensation, also cautious-like behavior, as if preemptively avoiding potential undetectable hazards. Intriguingly, these behavioral adjustments are abolished when the touch neurons are removed, suggesting that touch neurons are required for signaling the unavailability of touch information, in addition to their conventional role of signaling touch stimulation. Furthermore, we found that the ASE taste neurons, which similarly to the touch neurons, express the FLP-20 neuropeptide, exhibit altered FLP-20 expression levels in a touch-dependent manner, thus cooperating with the touch circuit. These results imply a novel form of neuronal signaling that enables C. elegans to distinguish between lack of touch stimulation and loss of touch sensation, producing adaptive behavioral adjustments that could overcome the inability to detect potential threats. Sensory loss deprives animals of important information. This study shows that Caenorhabditis elegans worms lacking touch sensation show cautious-like behaviors, indicating that the touch neurons provide not only information about the presence or absence of touch stimuli, but also about the unavailability of touch information. [ABSTRACT FROM AUTHOR]

The efficient coding approach proposes that neural systems represent as much sensory information as biological constraints allow. It aims at formalizing encoding as a constrained optimal process. A different approach, that aims at formalizing decoding, proposes that neural systems instantiate a generative model of the sensory world. Here, we put forth a normative framework that characterizes neural systems as jointly optimizing encoding and decoding. It takes the form of a variational autoencoder: sensory stimuli are encoded in the noisy activity of neurons to be interpreted by a flexible decoder; encoding must allow for an accurate stimulus reconstruction from neural activity. Jointly, neural activity is required to represent the statistics of latent features which are mapped by the decoder into distributions over sensory stimuli; decoding correspondingly optimizes the accuracy of the generative model. This framework yields in a family of encoding-decoding models, which result in equally accurate generative models, indexed by a measure of the stimulus-induced deviation of neural activity from the marginal distribution over neural activity. Each member of this family predicts a specific relation between properties of the sensory neurons—such as the arrangement of the tuning curve means (preferred stimuli) and widths (degrees of selectivity) in the population—as a function of the statistics of the sensory world. Our approach thus generalizes the efficient coding approach. Notably, here, the form of the constraint on the optimization derives from the requirement of an accurate generative model, while it is arbitrary in efficient coding models. Moreover, solutions do not require the knowledge of the stimulus distribution, but are learned on the basis of data samples; the constraint further acts as regularizer, allowing the model to generalize beyond the training data. Finally, we characterize the family of models we obtain through alternate measures of performance, such as the error in stimulus reconstruction. We find that a range of models admits comparable performance; in particular, a population of sensory neurons with broad tuning curves as observed experimentally yields both low reconstruction stimulus error and an accurate generative model that generalizes robustly to unseen data. Author summary: Our brain represents the sensory world in the activity of populations of neurons. Two theories have addressed the nature of these representations. The first theory—efficient coding—posits that neurons encode as much information as possible about sensory stimuli, subject to resource constraints such as limits on energy consumption. The second one—generative modeling—focuses on decoding, and is organized around the idea that neural activity plays the role of a latent variable from which sensory stimuli can be simulated. Our work subsumes the two approaches in a unifying framework based on the mathematics of variational autoencoders. Unlike in efficient coding, which assumes full knowledge of stimulus statistics, here representations are learned from examples, in a joint optimization of encoding and decoding. This new framework yields a range of optimal representations, corresponding to different models of neural selectivity and reconstruction performances, depending on the resource constraint. The form of the constraint is not arbitrary but derives from the optimization framework, and its strength tunes the ability of the model to generalize beyond the training example. Central to the approach, and to the nature of the representations it implies, is the interplay of encoding and decoding, itself central to brain processing. [ABSTRACT FROM AUTHOR]

Sensory neurons reconstruct the world from action potentials (spikes) impinging on them. To effectively transfer information about the stimulus to the next processing level, a neuron needs to be able to adapt its working range to the properties of the stimulus. Here, we focus on the intrinsic neural properties that influence information transfer in cortical neurons and how tightly their properties need to be tuned to the stimulus statistics for them to be effective. We start by measuring the intrinsic information encoding properties of putative excitatory and inhibitory neurons in L2/3 of the mouse barrel cortex. Excitatory neurons show high thresholds and strong adaptation, making them fire sparsely and resulting in a strong compression of information, whereas inhibitory neurons that favour fast spiking transfer more information. Next, we turn to computational modelling and ask how two properties influence information transfer: 1) spike-frequency adaptation and 2) the shape of the IV-curve. We find that a subthreshold (but not threshold) adaptation, the 'h-current', and a properly tuned leak conductance can increase the information transfer of a neuron, whereas threshold adaptation can increase its working range. Finally, we verify the effect of the IV-curve slope in our experimental recordings and show that excitatory neurons form a more heterogeneous population than inhibitory neurons. These relationships between intrinsic neural features and neural coding that had not been quantified before will aid computational, theoretical and systems neuroscientists in understanding how neuronal populations can alter their coding properties, such as through the impact of neuromodulators. Why the variability of intrinsic properties of excitatory neurons is larger than that of inhibitory ones is an exciting question, for which future research is needed. Author summary: Intracellular information transfer from synaptic input to output spike train is necessarily lossy. Here, we explicitly measure the mutual information between a neuron's input and spike output and show that information transfer is more lossy and heterogeneous for excitatory than for inhibitory neurons. By using computational modelling we show that the shape of the input-output curve as well as how fast a neuron adapts to its input collectively determine the rate of information loss. These insights will help both experimentalists and modellers in designing and simulating experiments that investigate how network coding properties can adapt to the environment, for instance through the effects of neuromodulators. [ABSTRACT FROM AUTHOR]

An animal's skin provides a first point of contact with the sensory environment, including noxious cues that elicit protective behavioral responses. Nociceptive somatosensory neurons densely innervate and intimately interact with epidermal cells to receive these cues, however the mechanisms by which epidermal interactions shape processing of noxious inputs is still poorly understood. Here, we identify a role for dendrite intercalation between epidermal cells in tuning sensitivity of Drosophila larvae to noxious mechanical stimuli. In wild-type larvae, dendrites of nociceptive class IV da neurons intercalate between epidermal cells at apodemes, which function as body wall muscle attachment sites, but not at other sites in the epidermis. From a genetic screen we identified miR-14 as a regulator of dendrite positioning in the epidermis: miR-14 is expressed broadly in the epidermis but not in apodemes, and miR-14 inactivation leads to excessive apical dendrite intercalation between epidermal cells. We found that miR-14 regulates expression and distribution of the epidermal Innexins ogre and Inx2 and that these epidermal gap junction proteins restrict epidermal dendrite intercalation. Finally, we found that altering the extent of epidermal dendrite intercalation had corresponding effects on nociception: increasing epidermal intercalation sensitized larvae to noxious mechanical inputs and increased mechanically evoked calcium responses in nociceptive neurons, whereas reducing epidermal dendrite intercalation had the opposite effects. Altogether, these studies identify epidermal dendrite intercalation as a mechanism for mechanical coupling of nociceptive neurons to the epidermis, with nociceptive sensitivity tuned by the extent of intercalation. Author summary: Our skin provides a first point of contact for a variety of sensory inputs, including noxious cues that elicit pain. Although specialized interactions between skin cells and sensory neurons are known to shape responses to a variety of mechanosensory stimuli including gentle touch and vibration, interactions with skin cells that shape responses to painful mechanical inputs are less well defined. Using the fruit fly Drosophila melanogaster as a model system, we demonstrate that the pattern of epidermal innervation, specifically the extent of dendrite intercalation between epidermal cells, tunes the animal's sensitivity to noxious mechanical stimuli. Similar mechanisms may regulate sensitivity to painful mechanical inputs in both pathological and physiological states in vertebrates. [ABSTRACT FROM AUTHOR]

The efficient coding hypothesis posits that early sensory neurons transmit maximal information about sensory stimuli, given internal constraints. A central prediction of this theory is that neurons should preferentially encode stimuli that are most surprising. Previous studies suggest this may be the case in early visual areas, where many neurons respond strongly to rare or surprising stimuli. For example, previous research showed that when presented with a rhythmic sequence of full-field flashes, many retinal ganglion cells (RGCs) respond strongly at the instance the flash sequence stops, and when another flash would be expected. This phenomenon is called the 'omitted stimulus response'. However, it is not known whether the responses of these cells varies in a graded way depending on the level of stimulus surprise. To investigate this, we presented retinal neurons with extended sequences of stochastic flashes. With this stimulus, the surprise associated with a particular flash/silence, could be quantified analytically, and varied in a graded manner depending on the previous sequences of flashes and silences. Interestingly, we found that RGC responses could be well explained by a simple normative model, which described how they optimally combined their prior expectations and recent stimulus history, so as to encode surprise. Further, much of the diversity in RGC responses could be explained by the model, due to the different prior expectations that different neurons had about the stimulus statistics. These results suggest that even as early as the retina many cells encode surprise, relative to their own, internally generated expectations. Author summary: A long-standing theory suggests that sensory neurons work to transmit as much visual information as possible using little energy. According to this idea, sensory neurons should put most energy into encoding stimuli that are unexpected or surprising. Previous research has shown that this may be true for certain neurons in the retina, that respond strongly when they see something unusual, like a sudden change in a sequence of flashes. Here, to test this theory, we presented the retina with random sequences of light flashes, and measured whether retinal neuron responses correlated with how surprising each flash in the sequence was. Consistent with the theory, we found that retinal neuron responses in our experiment could be explained by a model that assumed that they encode surprise. Moreover, differences between each neuron's responses could be predicted due to their different expectations about which stimuli were most likely. [ABSTRACT FROM AUTHOR]

Influenza A virus (IAV) is a common respiratory pathogen and a global cause of significant and often severe morbidity. Although inflammatory immune responses to IAV infections are well described, little is known about how neuroimmune processes contribute to IAV pathogenesis. In the present study, we employed surgical, genetic, and pharmacological approaches to manipulate pulmonary vagal sensory neuron innervation and activity in the lungs to explore potential crosstalk between pulmonary sensory neurons and immune processes. Intranasal inoculation of mice with H1N1 strains of IAV resulted in stereotypical antiviral lung inflammation and tissue pathology, changes in breathing, loss of body weight and other clinical signs of severe IAV disease. Unilateral cervical vagotomy and genetic ablation of pulmonary vagal sensory neurons had a moderate effect on the pulmonary inflammation induced by IAV infection, but significantly worsened clinical disease presentation. Inhibition of pulmonary vagal sensory neuron activity via inhalation of the charged sodium channel blocker, QX-314, resulted in a moderate decrease in lung pathology, but again this was accompanied by a paradoxical worsening of clinical signs. Notably, vagal sensory ganglia neuroinflammation was induced by IAV infection and this was significantly potentiated by QX-314 administration. This vagal ganglia hyperinflammation was characterized by alterations in IAV-induced host defense gene expression, increased neuropeptide gene and protein expression, and an increase in the number of inflammatory cells present within the ganglia. These data suggest that pulmonary vagal sensory neurons play a role in the regulation of the inflammatory process during IAV infection and suggest that vagal neuroinflammation may be an important contributor to IAV pathogenesis and clinical presentation. Targeting these pathways could offer therapeutic opportunities to treat IAV-induced morbidity and mortality. Author summary: Influenza viruses are a common respiratory pathogen that represent a constant and pervasive threat to human health. Although the inflammatory and immune responses to influenza viral infections are well described, little is known about the role the nervous system plays in the formation and progression of disease. The lungs receive a rich supply of sensory nerve fibers from the vagus nerve. These nerves are critical for protecting the lungs against harmful stimuli and play an important defence role against pathogens, including viruses. Here we use several complex animal models to demonstrate the impact lung sensory neurons have on influenza viral infection and disease outcome. We demonstrate that ablation of lung sensory neurons and inhibition of their neural activity significantly worsens the clinical outcome in mice infected with influenza virus, however with only a moderate impact on lung pathology. Interestingly, when the activity of these neurons is inhibited during influenza viral infection, this drives a hyper neuroinflammatory response within the vagal sensory ganglia, where their cell bodies are located. Our work provides new insights into how these lung sensory neurons are involved in influenza viral infections and may offer therapeutic opportunities to treat influenza-induced morbidity and mortality. [ABSTRACT FROM AUTHOR]

In vertebrates, olfactory receptors localize on multiple cilia elaborated on dendritic knobs of olfactory sensory neurons (OSNs). Although olfactory cilia dysfunction can cause anosmia, how their differentiation is programmed at the transcriptional level has remained largely unexplored. We discovered in zebrafish and mice that Foxj1, a forkhead domain-containing transcription factor traditionally linked with motile cilia biogenesis, is expressed in OSNs and required for olfactory epithelium (OE) formation. In keeping with the immotile nature of olfactory cilia, we observed that ciliary motility genes are repressed in zebrafish, mouse, and human OSNs. Strikingly, we also found that besides ciliogenesis, Foxj1 controls the differentiation of the OSNs themselves by regulating their cell type–specific gene expression, such as that of olfactory marker protein (omp) involved in odor-evoked signal transduction. In line with this, response to bile acids, odors detected by OMP-positive OSNs, was significantly diminished in foxj1 mutant zebrafish. Taken together, our findings establish how the canonical Foxj1-mediated motile ciliogenic transcriptional program has been repurposed for the biogenesis of immotile olfactory cilia, as well as for the development of the OSNs. Olfaction is mediated by ciliated sensory neurons, but how olfactory cilia and sensory neuron differentiation is regulated has remained obscure. This study of zebrafish and mice shows that the forkhead domain transcription factor Foxj1 is critical for olfactory cilia and sensory neuron differentiation. [ABSTRACT FROM AUTHOR]

Neurons throughout the brain modulate their firing rate lawfully in response to sensory input. Theories of neural computation posit that these modulations reflect the outcome of a constrained optimization in which neurons aim to robustly and efficiently represent sensory information. Our understanding of how this optimization varies across different areas in the brain, however, is still in its infancy. Here, we show that neural sensory responses transform along the dorsal stream of the visual system in a manner consistent with a transition from optimizing for information preservation towards optimizing for perceptual discrimination. Focusing on the representation of binocular disparities—the slight differences in the retinal images of the two eyes—we re-analyze measurements characterizing neuronal tuning curves in brain areas V1, V2, and MT (middle temporal) in the macaque monkey. We compare these to measurements of the statistics of binocular disparity typically encountered during natural behaviors using a Fisher Information framework. The differences in tuning curve characteristics across areas are consistent with a shift in optimization goals: V1 and V2 population-level responses are more consistent with maximizing the information encoded about naturally occurring binocular disparities, while MT responses shift towards maximizing the ability to support disparity discrimination. We find that a change towards tuning curves preferring larger disparities is a key driver of this shift. These results provide new insight into previously-identified differences between disparity-selective areas of cortex and suggest these differences play an important role in supporting visually-guided behavior. Our findings emphasize the need to consider not just information preservation and neural resources, but also relevance to behavior, when assessing the optimality of neural codes. Author summary: The nervous system needs to transform information from the sensory organs into signals that can be used to guide behavior. Neural activity is noisy and can consume large amount of energy, so sensory neurons must optimize their information processing so as to limit energy consumption while maintaining key behaviorally-relevant information. In this report, we re-examine classically-defined brain areas in the visual processing hierarchy, and ask whether neurons in these areas vary lawfully in how they represent sensory information. Our results suggest that neurons in these brain areas shift from being an optimal conduit for conveying sensory information towards prioritizing information that supports key perceptual discriminations during natural tasks. [ABSTRACT FROM AUTHOR]

Sensory neurons enable an organism to perceive external stimuli, which is essential for survival. The sensory capacity of a neuron depends on the elaboration of its dendritic arbor and the localization of sensory ion channels to the dendritic membrane. However, it is not well understood when and how ion channels localize to growing sensory dendrites and whether their delivery is coordinated with growth of the dendritic arbor. We investigated the localization of the DEG/ENaC/ASIC ion channel Pickpocket (Ppk) in the peripheral sensory neurons of developing fruit flies. We used CRISPR-Cas9 genome engineering approaches to tag endogenous Ppk1 and visualize it live, including monitoring Ppk1 membrane localization via a novel secreted split-GFP approach. Fluorescently tagged endogenous Ppk1 localizes to dendrites, as previously reported, and, unexpectedly, to axons and axon terminals. In dendrites, Ppk1 is present throughout actively growing dendrite branches and is stably integrated into the neuronal cell membrane during the expansive growth of the arbor. Although Ppk channels are dispensable for dendrite growth, we found that an over-active channel mutant severely reduces dendrite growth, likely by acting at an internal membrane and not the dendritic membrane. Our data reveal that the molecular motor dynein and recycling endosome GTPase Rab11 are needed for the proper trafficking of Ppk1 to dendrites. Based on our data, we propose that Ppk channel transport is coordinated with dendrite morphogenesis, which ensures proper ion channel density and distribution in sensory dendrites. Author summary: Peripheral sensory neurons are essential for an organism to interact with its environment. Neurons are composed of signal-receiving dendrites and a signal-sending axon. Ion channels distributed throughout sensory dendrites transduce external stimuli into chemical signals, however the mechanisms that localize ion channels to sensory dendrites are not well understood. Both the composition of ion channels in the dendrites and the structure of a sensory neuron's dendritic arbor are important for how it functions to sense external stimuli. Using live imaging and genomic engineering, we have discovered that the localization of a sensory ion channel, Pickpocket, in fruit fly sensory neurons is coordinated with growth of the dendritic arbor and that Pickpocket levels scale in proportion to dendrite length, even when transport to dendrites is disrupted. We also developed a novel genetically encoded approach to visualize the membrane expression of proteins in a living organism utilizing the split-GFP system. We found that both the secretory and endosomal networks mediate the forward trafficking of Pickpocket during neuronal morphogenesis, thus coordinating membrane growth with ion channel delivery. Our findings reveal that actively growing sensory dendrites are equipped with the ion channels needed for sensing external stimuli. [ABSTRACT FROM AUTHOR]

Heterotrimeric G (αβγ) proteins are canonical transducers of G-protein-coupled receptor (GPCR) signaling and play critical roles in communication between cells and their environment. Many GPCRs and heterotrimeric G proteins localize to primary cilia and modulate cilia morphology via mechanisms that are not well understood. Here, we show that RIC-8, a cytosolic guanine nucleotide exchange factor (GEF) and chaperone for Gα protein subunits, shapes cilia membrane morphology in a subset of Caenorhabditis elegans sensory neurons. Consistent with its role in ciliogenesis, C. elegans RIC-8 localizes to cilia in different sensory neuron types. Using domain mutagenesis, we demonstrate that while the GEF function alone is not sufficient, both the GEF and Gα-interacting chaperone motifs of RIC-8 are required for its role in cilia morphogenesis. We identify ODR-3 as the RIC-8 Gα client and demonstrate that RIC-8 functions in the same genetic pathway with another component of the non-canonical G protein signaling AGS-3 to shape cilia morphology. Notably, despite defects in AWC cilia morphology, ags-3 null mutants exhibit normal chemotaxis toward benzaldehyde unlike odr-3 mutant animals. Collectively, our findings describe a novel function for the evolutionarily conserved protein RIC-8 and non-canonical RIC-8-AGS-3-ODR-3 signaling in cilia morphogenesis and uncouple Gα ODR-3 functions in ciliogenesis and olfaction. Author summary: Primary cilia are specialized cellular compartments that mediate communication between cells and their environment. In humans, deficits in cilia assembly and function manifest in genetic diseases called ciliopathies. While the molecular machinery of all major signaling pathways engaged in cell-cell and cell-environment communication is present inside cilia of different cell types, the mechanisms by which these signaling factors modulate cilia structure or cilia-dependent cellular functions are not well understood. In this study, we identify a new ciliary signaling module comprised of RIC-8 and Gα ODR-3 –key transducer of olfactory signaling–and find that RIC-8-dependent signaling is critically important for formation of specialized ciliary structures in C. elegans neurons. Our findings provide new insight into mechanisms of cilia assembly and highlight distinct functions of Gα ODR-3 in sensory transduction and cilia formation. [ABSTRACT FROM AUTHOR]

mTORC1 (mechanistic target of rapamycin complex 1) is a metabolic sensor that promotes growth when nutrients are abundant. Ubiquitous inhibition of mTORC1 extends lifespan in multiple organisms but also disrupts several anabolic processes resulting in stunted growth, slowed development, reduced fertility, and disrupted metabolism. However, it is unclear if these pleotropic effects of mTORC1 inhibition can be uncoupled from longevity. Here, we utilize the auxin-inducible degradation (AID) system to restrict mTORC1 inhibition to C. elegans neurons. We find that neuron-specific degradation of RAGA-1, an upstream activator of mTORC1, or LET-363, the ortholog of mammalian mTOR, is sufficient to extend lifespan in C. elegans. Unlike raga-1 loss of function genetic mutations or somatic AID of RAGA-1, neuronal AID of RAGA-1 robustly extends lifespan without impairing body size, developmental rate, brood size, or neuronal function. Moreover, while degradation of RAGA-1 in all somatic tissues alters the expression of thousands of genes, demonstrating the widespread effects of mTORC1 inhibition, degradation of RAGA-1 in neurons only results in around 200 differentially expressed genes with a specific enrichment in metabolism and stress response. Notably, our work demonstrates that targeting mTORC1 specifically in the nervous system in C. elegans uncouples longevity from growth and reproductive impairments, and that many canonical effects of low mTORC1 activity are not required to promote healthy aging. These data challenge previously held ideas about the mechanisms of mTORC1 lifespan extension and underscore the potential of promoting longevity by neuron-specific mTORC1 modulation. Author summary: Inhibition of the metabolic pathway mTORC1 has been shown to extend lifespan in many organisms and has gained traction as a possible anti-aging therapeutic. However, in addition to lifespan extension, chronic and body-wide mTORC1 inhibition results in a downregulation of anabolic processes that leads to unwanted side effects such as impaired growth, development, and reproduction in C. elegans, Drosophila melanogaster, and mice. An open question in the field is if mTORC1 inhibition can be restricted to specific tissues to promote longevity while minimizing the anabolic trade-offs. In this study, we test this hypothesis using the model organism C. elegans and the auxin-inducible degradation (AID) system which provides many advantages over previous techniques used to study the tissue-specificity of mTORC1 in aging. We find that degradation of mTORC1 pathway components specifically in the neurons robustly extends lifespan while preserving normal growth, development, and reproduction. Furthermore, we find that animals with neuronal mTORC1 inhibition maintain functional sensory neurons and have changes in the expression of genes related to stress response and metabolism. This work challenges previously held theories that anabolic trade-offs are required for mTORC1 longevity and highlights a critical role for neuronal mTORC1 in the regulation of organismal aging. [ABSTRACT FROM AUTHOR]

Growing evidence indicates that only a sparse subset from a pool of sensory neurons is active for the encoding of visual stimuli at any instant in time. Traditionally, to replicate such biological sparsity, generative models have been using the ℓ1 norm as a penalty due to its convexity, which makes it amenable to fast and simple algorithmic solvers. In this work, we use biological vision as a test-bed and show that the soft thresholding operation associated to the use of the ℓ1 norm is highly suboptimal compared to other functions suited to approximating ℓp with 0 ≤ p < 1 (including recently proposed continuous exact relaxations), in terms of performance. We show that ℓ1 sparsity employs a pool with more neurons, i.e. has a higher degree of overcompleteness, in order to maintain the same reconstruction error as the other methods considered. More specifically, at the same sparsity level, the thresholding algorithm using the ℓ1 norm as a penalty requires a dictionary of ten times more units compared to the proposed approach, where a non-convex continuous relaxation of the ℓ0 pseudo-norm is used, to reconstruct the external stimulus equally well. At a fixed sparsity level, both ℓ0- and ℓ1-based regularization develop units with receptive field (RF) shapes similar to biological neurons in V1 (and a subset of neurons in V2), but ℓ0-based regularization shows approximately five times better reconstruction of the stimulus. Our results in conjunction with recent metabolic findings indicate that for V1 to operate efficiently it should follow a coding regime which uses a regularization that is closer to the ℓ0 pseudo-norm rather than the ℓ1 one, and suggests a similar mode of operation for the sensory cortex in general. Author summary: Recordings in the brain indicate that relatively few sensory neurons are active at any instant. This so called sparse coding is considered a hallmark of efficiency in the encoding of natural stimuli by sensory neurons. Computational works have shown that if we add sparse activity as an optimization term in a generative model encoding natural images then the model will learn units with receptive fields (RFs) similar to the neurons in the primary visual cortex (V1). Traditionally, computational models have used the ℓ1 norm as the sparsity term to be minimized, because of its convexity and claims of optimality. Here we show that by using sparsity inducing regularizers that approximate the ℓ0 pseudo-norm, we get sparser activations for the same quality of encoding. Moreover, for a certain level of sparsity, both ℓ0 and ℓ1 based generative models produce RFs similar to V1 biological neurons, but the ℓ1 model has five times worse encoding performance. Our study thus shows that sparsity-inducing regularizers approaching the ℓ0 pseudo-norm are more appropriate for modelling biological vision from an efficiency point of view. [ABSTRACT FROM AUTHOR]

Animal venom peptides represent valuable compounds for biomedical exploration. The venoms of marine cone snails constitute a particularly rich source of peptide toxins, known as conotoxins. Here, we identify the sequence of an unusually large conotoxin, Mu8.1, which defines a new class of conotoxins evolutionarily related to the well-known con-ikot-ikots and 2 additional conotoxin classes not previously described. The crystal structure of recombinant Mu8.1 displays a saposin-like fold and shows structural similarity with con-ikot-ikot. Functional studies demonstrate that Mu8.1 curtails calcium influx in defined classes of murine somatosensory dorsal root ganglion (DRG) neurons. When tested on a variety of recombinantly expressed voltage-gated ion channels, Mu8.1 displayed the highest potency against the R-type (Cav2.3) calcium channel. Ca2+ signals from Mu8.1-sensitive DRG neurons were also inhibited by SNX-482, a known spider peptide modulator of Cav2.3 and voltage-gated K+ (Kv4) channels. Our findings highlight the potential of Mu8.1 as a molecular tool to identify and study neuronal subclasses expressing Cav2.3. Importantly, this multidisciplinary study showcases the potential of uncovering novel structures and bioactivities within the largely unexplored group of macro-conotoxins. Animal venom peptides represent valuable compounds for biomedical exploration, including conotoxins from marine cone snails. In this study, the identification of a previously unrecognized superfamily of large conotoxins reveals structural and evolutionary insight into a toxin that inhibits neuronal Cav2.3 voltage-gated calcium channels. [ABSTRACT FROM AUTHOR]

Patients with systemic lupus erythematosus (SLE) often suffer from chronic pain. Little is known about the peripheral mechanisms underlying the genesis of chronic pain induced by SLE. The aim of this study was to investigate whether and how membrane properties in nociceptive neurons in the dorsal root ganglions (DRGs) are altered by SLE. We found elevation of resting membrane potentials, smaller capacitances, lower action potential thresholds and rheobases in nociceptive neurons in the DRGs from MRL/lpr mice (an SLE mouse model) with thermal hyperalgesia. DRGs from MRL/lpr mice had increased protein expressions in TNFα, IL-1β, and phosphorylated ERK but suppressed AMPK activity, and no changes in sodium channel 1.7 protein expression. We showed that intraplantar injection of Compound C (an AMPK inhibitor) induced thermal hyperalgesia in normal mice while intraplantar injection of AICAR (an AMPK activator) reduced thermal hyperalgesia in MRL/Lpr mice. Upon inhibition of AMPK membrane properties in nociceptive neurons from normal control mice could be rapidly switched to those found in SLE mice with thermal hyperalgesia. Our study indicates that increased excitability in peripheral nociceptive sensory neurons contributes to the genesis of thermal hyperalgesia in mice with SLE, and AMPK regulates membrane properties in nociceptive sensory neurons as well as thermal hyperalgesia in mice with SLE. Our study provides a basis for targeting signaling pathways regulating membrane properties of peripheral nociceptive neurons as a means for conquering chronic pain caused by SLE. [ABSTRACT FROM AUTHOR]

The mosquito, Aedes aegypti, is highly anthropophilic and transmits debilitating arboviruses within human populations and between humans and non-human primates. Female mosquitoes are attracted to sources of blood by responding to odor plumes that are emitted by their preferred hosts. Acidic volatile compounds, including carboxylic acids, represent particularly salient odors driving this attraction. Importantly, carboxylic acids are major constituents of human sweat and volatiles generated by skin microbes. As such, they are likely to impact human host preference, a dominant factor in disease transmission cycles. A more complete understanding of mosquito host attraction will necessitate the elucidation of molecular mechanisms of volatile odor detection that function in peripheral sensory neurons. Recent studies have shown that members of the variant ionotropic glutamate receptor gene family are necessary for physiological and behavioral responses to acidic volatiles in Aedes. In this study, we have identified a subfamily of variant ionotropic receptors that share sequence homology across several important vector species and are likely to be activated by carboxylic acids. Moreover, we demonstrate that selected members of this subfamily are activated by short-chain carboxylic acids in a heterologous cell expression system. Our results are consistent with the hypothesis that members of this receptor class underlie acidic volatile sensitivity in vector mosquitoes and provide a frame of reference for future development of novel mosquito attractant and repellent technologies. Author summary: Many mosquitoes can transmit viruses that cause debilitating illnesses in human populations during the act of blood-feeding by female mosquitoes. Females locate people and other animals by responding to the odors they emit. Among the most important odors that attract females are carboxylic acids, which are components of human sweat. As such, carboxylic acids impact human host feeding, a dominant factor in disease transmission. In this study, we have identified chemical receptors that are localized in the mosquito antennae and detect carboxylic acids. These receptors are highly similar in important disease-transmitting mosquitoes, including Aedes aegypti, a species that transmits Yellow Fever, Dengue, and Zika. Using a cell expression system, we demonstrate that selected receptors are activated by short-chain carboxylic acids in a manner consistent with their function in mosquito attraction. Our results provide a frame of reference for the future development of new mosquito attractant and repellent technologies that may help reduce the global burden of infectious diseases. [ABSTRACT FROM AUTHOR]

Mas-related G-protein-coupled receptors X1-X4 (MRGPRX1-X4) are 4 primate-specific receptors that are recently reported to be responsible for many biological processes, including itch sensation, pain transmission, and inflammatory reactions. MRGPRX1 is the first identified human MRGPR, and its expression is restricted to primary sensory neurons. Due to its dual roles in itch and pain signaling pathways, MRGPRX1 has been regarded as a promising target for itch remission and pain inhibition. Here, we reported a cryo-electron microscopy (cryo-EM) structure of Gq-coupled MRGPRX1 in complex with a synthetic agonist compound 16 in an active conformation at an overall resolution of 3.0 Å via a NanoBiT tethering strategy. Compound 16 is a new pain-relieving compound with high potency and selectivity to MRGPRX1 over other MRGPRXs and opioid receptor. MRGPRX1 was revealed to share common structural features of the Gq-mediated receptor activation mechanism of MRGPRX family members, but the variable residues in orthosteric pocket of MRGPRX1 exhibit the unique agonist recognition pattern, potentially facilitating to design MRGPRX1-specific modulators. Together with receptor activation and itch behavior evaluation assays, our study provides a structural snapshot to modify therapeutic molecules for itch relieving and analgesia targeting MRGPRX1. [ABSTRACT FROM AUTHOR]

Males have finite resources to spend on reproduction. Thus, males rely on a 'time investment strategy' to maximize their reproductive success. For example, male Drosophila melanogaster extends their mating duration when surrounded by conditions enriched with rivals. Here we report a different form of behavioral plasticity whereby male fruit flies exhibit a shortened duration of mating when they are sexually experienced; we refer to this plasticity as 'shorter-mating-duration (SMD)'. SMD is a plastic behavior and requires sexually dimorphic taste neurons. We identified several neurons in the male foreleg and midleg that express specific sugar and pheromone receptors. Using a cost-benefit model and behavioral experiments, we further show that SMD behavior exhibits adaptive behavioral plasticity in male flies. Thus, our study delineates the molecular and cellular basis of the sensory inputs required for SMD; this represents a plastic interval timing behavior that could serve as a model system to study how multisensory inputs converge to modify interval timing behavior for improved adaptation. Author summary: To maximize their return on investment, male flies utilize a wide variety of sensory inputs, including memories of past sexual encounters. Therefore, when males have sufficient sexual experiences, they shorten their mating duration. The term "Shorter-Mating-Duration" (SMD) was coined to describe this behavior. SMD must be triggered by sugar and pheromone, which is detected by cells and receptors in the male forelegs. We found that these cells include male-specific sensory neurons that are tuned to collect on a male's sexual experiences and relay that information to the brain, where it is used to determine how long to spend mating the next available mate. We hypothesize that SMD can serve as a straightforward genetic model system through which we can investigate "interval timing," the capacity of animals to distinguish between periods ranging from minutes to hours in duration. [ABSTRACT FROM AUTHOR]

In complex natural environments, sensory systems are constantly exposed to a large stream of inputs. Novel or rare stimuli, which are often associated with behaviorally important events, are typically processed differently than the steady sensory background, which has less relevance. Neural signatures of such differential processing, commonly referred to as novelty detection, have been identified on the level of EEG recordings as mismatch negativity (MMN) and on the level of single neurons as stimulus-specific adaptation (SSA). Here, we propose a multi-scale recurrent network with synaptic depression to explain how novelty detection can arise in the whisker-related part of the somatosensory thalamocortical loop. The "minimalistic" architecture and dynamics of the model presume that neurons in cortical layer 6 adapt, via synaptic depression, specifically to a frequently presented stimulus, resulting in reduced population activity in the corresponding cortical column when compared with the population activity evoked by a rare stimulus. This difference in population activity is then projected from the cortex to the thalamus and amplified through the interaction between neurons of the primary and reticular nuclei of the thalamus, resulting in rhythmic oscillations. These differentially activated thalamic oscillations are forwarded to cortical layer 4 as a late secondary response that is specific to rare stimuli that violate a particular stimulus pattern. Model results show a strong analogy between this late single neuron activity and EEG-based mismatch negativity in terms of their common sensitivity to presentation context and timescales of response latency, as observed experimentally. Our results indicate that adaptation in L6 can establish the thalamocortical dynamics that produce signatures of SSA and MMN and suggest a mechanistic model of novelty detection that could generalize to other sensory modalities. Author summary: Cortical sensory neurons have been shown to be capable of novelty detection, that is they respond more vigorously when a novel, unexpected stimulus is presented, and less so when the stimulus is part of a predictable sequence. However, the neural mechanism underlying this capability is not yet fully understood. Here, we developed a minimalistic thalamocortical network model that accounts for novelty detection and reproduces physiologically observed neural response patterns in the anaesthetized somatosensory cortex. Specifically, our results demonstrate that the novelty signal arises from the recurrent interplay between thalamic neurons and cortical neurons in layers 4 and 6, without the need of other components. This work therefore provides a concrete mechanism that can serve as a starting point for further investigating the neural circuit mechanisms underlying novelty detection. [ABSTRACT FROM AUTHOR]

Neurite pruning and regrowth are important mechanisms to adapt neural circuits to distinct developmental stages. Neurite regrowth after pruning often depends on differential regulation of growth signaling pathways, but their precise mechanisms of action during regrowth are unclear. Here, we show that the PI3K/TORC1 pathway is required for dendrite regrowth after pruning in Drosophila peripheral neurons during metamorphosis. TORC1 impinges on translation initiation, and our analysis of 5' untranslated regions (UTRs) of remodeling factor mRNAs linked to actin suggests that TOR selectively stimulates the translation of regrowth over pruning factors. Furthermore, we find that dendrite regrowth also requires the GTPase RalA and the exocyst complex as regulators of polarized secretion, and we provide evidence that this pathway is also regulated by TOR. We propose that TORC1 coordinates dendrite regrowth after pruning by coordinately stimulating the translation of regrowth factors involved in cytoskeletal regulation and secretion. Author summary: During development, neurons grow axons and dendrites that they use to make synaptic connections. Such connections are often fine-tuned through pruning and regrowth of axons and dendrites, but the coordination of the two processes is not well understood. It had previously been shown that hormone signaling suppresses the TORC1 growth pathway during pruning of Drosophila sensory neuron dendrites. We found that TORC1 is required for the subsequent regrowth of these dendrites. TORC1 activates protein biosynthesis, and our analyses suggest that it primarily targets neurite growth pathways, but not pruning pathways. These growth pathways include the actin cytoskeleton and the secretion machinery with the small GTPase RalA. Thus, the TORC1 growth pathway is a major hub coordinating neurite pruning and regrowth. [ABSTRACT FROM AUTHOR]

Recent advances in molecular transduction of odorants in the Olfactory Sensory Neurons (OSNs) of the Drosophila Antenna have shown that the odorant object identity is multiplicatively coupled with the odorant concentration waveform. The resulting combinatorial neural code is a confounding representation of odorant semantic information (identity) and syntactic information (concentration). To distill the functional logic of odor information processing in the Antennal Lobe (AL) a number of challenges need to be addressed including 1) how is the odorant semantic information decoupled from the syntactic information at the level of the AL, 2) how are these two information streams processed by the diverse AL Local Neurons (LNs) and 3) what is the end-to-end functional logic of the AL? By analyzing single-channel physiology recordings at the output of the AL, we found that the Projection Neuron responses can be decomposed into a concentration-invariant component, and two transient components boosting the positive/negative concentration contrast that indicate onset/offset timing information of the odorant object. We hypothesized that the concentration-invariant component, in the multi-channel context, is the recovered odorant identity vector presented between onset/offset timing events. We developed a model of LN pathways in the Antennal Lobe termed the differential Divisive Normalization Processors (DNPs), which robustly extract the semantics (the identity of the odorant object) and the ON/OFF semantic timing events indicating the presence/absence of an odorant object. For real-time processing with spiking PN models, we showed that the phase-space of the biological spike generator of the PN offers an intuit perspective for the representation of recovered odorant semantics and examined the dynamics induced by the odorant semantic timing events. Finally, we provided theoretical and computational evidence for the functional logic of the AL as a robust ON-OFF odorant object identity recovery processor across odorant identities, concentration amplitudes and waveform profiles. Author Summary: A major challenge in the study of the Drosophila early olfactory sensory system is to determine how an odorant object (the smell of a rose) is reliably identified in the face of fluctuations of the concentration amplitude of the molecules within the odorant plume. More fundamentally, the question arises how semantic information, often associated with subjective perception, can be characterized. To address this challenge, we leveraged the unique combinatorial odorant code of Drosophila and presented a formal treatment of the identity of an odorant object as its semantic information (or semantics for short). Grounded in the physiology of the fly brain, we identified the functional roles played by Local Neurons in the fruit fly Antennal Lobe in the recovery of the semantics and the onset/offset timing information (or semantic timing). Our model of the Antennal Lobe circuit is built with a highly versatile canonical model of neural computation—the differential Divisive Normalization Processor. [ABSTRACT FROM AUTHOR]

Understanding how neural populations encode sensory stimuli remains a central problem in neuroscience. Here we performed multi-unit recordings from sensory neural populations in the electrosensory system of the weakly electric fish Apteronotus leptorhynchus in response to stimuli located at different positions along the rostro-caudal axis. Our results reveal that the spatial dependence of correlated activity along receptive fields can help mitigate the deleterious effects that these correlations would otherwise have if they were spatially independent. Moreover, using mathematical modeling, we show that experimentally observed heterogeneities in the receptive fields of neurons help optimize information transmission as to object location. Taken together, our results have important implications for understanding how sensory neurons whose receptive fields display antagonistic center-surround organization encode location. Important similarities between the electrosensory system and other sensory systems suggest that our results will be applicable elsewhere. Author summary: Despite decades of research, the functional roles of neural heterogeneities towards understanding how sensory inputs are encoded by neural populations remains poorly understood. Here we use multi-unit recordings from sensory neural populations using high-density arrays (i.e., Neuropixels probes) and mathematical modeling to understand how a heterogeneous neural population with antagonistic center-surround receptive field organization encodes object location. We recorded the activities of pyramidal cells within the electrosensory lateral line lobe of weakly electric fish in response to a prey-like stimulus. Overall, we found that the receptive fields were highly heterogeneous even when they overlap considerably. We also found that correlated trial-to-trial variabilities of neural responses (i.e., spike-count correlations) varied along the receptive field. Specifically, correlation magnitude was highest towards the receptive field edges and dropped sharply near the midpoint. Using Fisher information analysis, we determined that the spike-count correlations introduced redundancy, but that the deleterious effect was in part mitigated by their spatial dependence. To better understand how heterogeneities within the receptive field, as well as spatially dependent correlations, influence information transmission, we built a mathematical model. Overall, our model reproduced experimental data and predicted that the level of heterogeneity in receptive field position seen experimentally is optimal for information transmission. Given that there are important parallels between the electrosensory system and other senses (e.g., vision), it is likely that our results will be applicable elsewhere. [ABSTRACT FROM AUTHOR]

In mammals, pain is regulated by the combination of an ascending stimulating and descending inhibitory pain pathway. It remains an intriguing question whether such pain pathways are of ancient origin and conserved in invertebrates. Here we report a new Drosophila pain model and use it to elucidate the pain pathways present in flies. The model employs transgenic flies expressing the human capsaicin receptor TRPV1 in sensory nociceptor neurons, which innervate the whole fly body, including the mouth. Upon capsaicin sipping, the flies abruptly displayed pain-related behaviors such as running away, scurrying around, rubbing vigorously, and pulling at their mouth parts, suggesting that capsaicin stimulated nociceptors in the mouth via activating TRPV1. When reared on capsaicin-containing food, the animals died of starvation, demonstrating the degree of pain experienced. This death rate was reduced by treatment both with NSAIDs and gabapentin, analgesics that inhibit the sensitized ascending pain pathway, and with antidepressants, GABAergic agonists, and morphine, analgesics that strengthen the descending inhibitory pathway. Our results suggest Drosophila to possess intricate pain sensitization and modulation mechanisms similar to mammals, and we propose that this simple, non-invasive feeding assay has utility for high-throughput evaluation and screening of analgesic compounds. [ABSTRACT FROM AUTHOR]

Animals alter their behavior in manners that depend on environmental conditions as well as their developmental and metabolic states. For example, C. elegans is quiescent during larval molts or during conditions of satiety. By contrast, worms enter an exploration state when removed from food. Sensory perception influences movement quiescence (defined as a lack of body movement), as well as the expression of additional locomotor states in C. elegans that are associated with increased or reduced locomotion activity, such as roaming (exploration behavior) and dwelling (local search). Here we find that movement quiescence is enhanced, and exploration behavior is reduced in G protein-coupled receptor kinase grk-2 mutant animals. grk-2 was previously shown to act in chemosensation, locomotion, and egg-laying behaviors. Using neuron-specific rescuing experiments, we show that GRK-2 acts in multiple ciliated chemosensory neurons to control exploration behavior. grk-2 acts in opposite ways from the cGMP-dependent protein kinase gene egl-4 to control movement quiescence and exploration behavior. Analysis of mutants with defects in ciliated sensory neurons indicates that grk-2 and the cilium-structure mutants act in the same pathway to control exploration behavior. We find that GRK-2 controls exploration behavior in an opposite manner from the neuropeptide receptor NPR-1 and the neuropeptides FLP-1 and FLP-18. Finally, we show that secretion of the FLP-1 neuropeptide is negatively regulated by GRK-2 and that overexpression of FLP-1 reduces exploration behavior. These results define neurons and molecular pathways that modulate movement quiescence and exploration behavior. Author summary: Many modulatory neurotransmitters affect behavior by binding to G protein-coupled receptors (GPCRs) and initiating signals that modify neuronal activity. GPCRs are regulated by G protein-coupled receptor kinases (GRKs). GRKs phosphorylate and promote the inactivation of GPCRs. Here we identify GRK-2 as a regulator of distinct locomotor states in C. elegans. We find that GRK-2 acts in olfactory sensory neurons to promote exploration and suppress movement quiescence. Additionally, we show that GRK-2 acts in opposition to a neuropeptide signaling pathway that acts in interneurons. Thus, this study demonstrates critical roles for GRK-2 in regulating neuromodulatory signaling and locomotor behavior. [ABSTRACT FROM AUTHOR]

The pathophysiology underlying olfactory dysfunction is still poorly understood, and more efficient biomolecular tools are necessary to explore this aspect. Immunohistochemistry (IHC) on cross sections is one of the major tools to study the olfactory epithelium (OE), but does not allow reliable counting of olfactory sensory neurons (OSNs) or cartography of the OE. In this study, we want to present an easy immunostaining technique to compensate for these defects of IHC. Using the rat model, we first validated and pre-screened the key OSN markers by IHC on cross sections of the OE. Tuj-1, OMP, DCX, PGP9.5, and N-cadherin were selected for immunostaining on flat-mounted OE because of their staining of OSN dendrites. A simple technique for immunostaining on flat-mounted septal OE was developed: fixation of the isolated septum mucosa in 0.5% paraformaldehyde (PFA) preceded by pretreatment of the rat head in 1% PFA for 1 hour. This technique allowed us to correctly reveal the olfactory areas using all the 5 selected markers on septum mucosa. By combining the mature OSN marker (OMP) and an immature OSN marker (Tuj-1), we quantified the mature (OMP+, Tuj-1-), immature (OMP-, Tuj-1+), transitory (OMP+, Tuj-1+) and total OSN density on septal OE. They were respectively 42080 ± 11820, 49384 ± 7134, 14448 ± 5865 and 105912 ± 13899 cells per mm2 (mean ± SD). Finally, the same immunostaining technique described above was performed with Tuj-1 for OE cartography on ethmoid turbinates without flat-mount. [ABSTRACT FROM AUTHOR]

Activity of sensory neurons is driven not only by external stimuli but also by feedback signals from higher brain areas. Attention is one particularly important internal signal whose presumed role is to modulate sensory representations such that they only encode information currently relevant to the organism at minimal cost. This hypothesis has, however, not yet been expressed in a normative computational framework. Here, by building on normative principles of probabilistic inference and efficient coding, we developed a model of dynamic population coding in the visual cortex. By continuously adapting the sensory code to changing demands of the perceptual observer, an attention-like modulation emerges. This modulation can dramatically reduce the amount of neural activity without deteriorating the accuracy of task-specific inferences. Our results suggest that a range of seemingly disparate cortical phenomena such as intrinsic gain modulation, attention-related tuning modulation, and response variability could be manifestations of the same underlying principles, which combine efficient sensory coding with optimal probabilistic inference in dynamic environments. Activity of sensory neurons is driven not only by external stimuli but also by feedback signals from higher brain areas, such as those related to attention. A theory developed in this study links diverse, seemingly distinct cortical phenomena to established principles of efficient sensory coding and perceptual inference. [ABSTRACT FROM AUTHOR]

Neurons in sensory areas encode/represent stimuli. Surprisingly, recent studies have suggested that, even during persistent performance, these representations are not stable and change over the course of days and weeks. We examine stimulus representations from fluorescence recordings across hundreds of neurons in the visual cortex using in vivo two-photon calcium imaging and we corroborate previous studies finding that such representations change as experimental trials are repeated across days. This phenomenon has been termed "representational drift". In this study we geometrically characterize the properties of representational drift in the primary visual cortex of mice in two open datasets from the Allen Institute and propose a potential mechanism behind such drift. We observe representational drift both for passively presented stimuli, as well as for stimuli which are behaviorally relevant. Across experiments, the drift differs from in-session variance and most often occurs along directions that have the most in-class variance, leading to a significant turnover in the neurons used for a given representation. Interestingly, despite this significant change due to drift, linear classifiers trained to distinguish neuronal representations show little to no degradation in performance across days. The features we observe in the neural data are similar to properties of artificial neural networks where representations are updated by continual learning in the presence of dropout, i.e. a random masking of nodes/weights, but not other types of noise. Therefore, we conclude that a potential reason for the representational drift in biological networks is driven by an underlying dropout-like noise while continuously learning and that such a mechanism may be computational advantageous for the brain in the same way it is for artificial neural networks, e.g. preventing overfitting. Author summary: Recently, it has been shown that the neuronal representations of sensory information in the brain can vary, even during seemingly stable performance. Why such "representational drift" occurs in the brain is currently unknown. In this work, using experimental data that images thousands of neurons across many mice, we precisely quantify how certain representations change over time with geometric tools used to understand high-dimensional data. Across two datasets where mice are either passively viewing a movie or actively performing a task, we find the representational changes have strikingly similar geometric properties. We then induce representational changes in an artificial neural network by injecting it with several distinct types of noise while it continues to adjust its components to maintain stable performance. Comparing the properties of its representational drift to what we observed in experiment, only a specific category of noise, known as "dropout", matches the geometry we observed in experiments. This hints at a potential biological mechanism underlying representational drift: a random suppression of certain neuronal components and a subsequent compensating change in other components. Additionally, dropout is well-known for helping artificial neural networks learn better, potentially hinting at a computational advantage to drift in the brain. [ABSTRACT FROM AUTHOR]

We previously reported that knocking out signal peptide peptidase (SPP), a glycoprotein K (gK) binding partner, in mouse peripheral sensory neurons reduced latency-reactivation in infected mice without affecting primary virus replication or eye disease. Since virus replication in the eye plays an essential role in eye disease, we generated a conditional knockout mouse lacking SPP expression in the eye by crossing Pax6 (paired box 6)-Cre mice that have intact Pax6 expression with SPPflox/flox mice. Significantly less SPP protein expression was detected in the eyes of Pax6-SPP-/- mice than in WT control mice. HSV-1 replication in the eyes of Pax6-SPP-/- mice was significantly lower than in WT control mice. Levels of gB, gK, and ICP0 transcripts in corneas, but not trigeminal ganglia (TG), of Pax6-SPP-/- infected mice were also significantly lower than in WT mice. Corneal scarring and angiogenesis were significantly lower in Pax6-SPP-/- mice than in WT control mice, while corneal sensitivity was significantly higher in Pax6-SPP-/- mice compared with WT control mice. During acute viral infection, absence of SPP in the eye did not affect CD4 expression but did affect CD8α and IFNγ expression in the eye. However, in the absence of SPP, latency-reactivation was similar in Pax6-SPP-/- and WT control groups. Overall, our results showed that deleting SPP expression in the eyes reduced primary virus replication in the eyes, reduced CD8α and IFNγ mRNA expression, reduced eye disease and reduced angiogenesis but did not alter corneal sensitivity or latency reactivation to HSV-1 infection. Thus, blocking gK binding to SPP in the eye may have therapeutic potential by reducing both virus replication in the eye and eye disease associated with virus replication. Author summary: Interaction of HSV-1 gK and signal peptide peptidase (SPP) plays an essential role in HSV-1 infectivity. To evaluate the importance of gK binding to SPP in the eye following primary virus replication and latency-reactivation, we evaluated SPP in the eye using Pax6-SPP-/- conditional knockout mice. The absence of SPP in the eye significantly reduced primary virus replication and eye disease but does not affect latency-reactivation. [ABSTRACT FROM AUTHOR]

Brains must represent the outside world so that animals survive and thrive. In early sensory systems, neural populations have diverse receptive fields structured to detect important features in inputs, yet significant variability has been ignored in classical models of sensory neurons. We model neuronal receptive fields as random, variable samples from parameterized distributions and demonstrate this model in two sensory modalities using data from insect mechanosensors and mammalian primary visual cortex. Our approach leads to a significant theoretical connection between the foundational concepts of receptive fields and random features, a leading theory for understanding artificial neural networks. The modeled neurons perform a randomized wavelet transform on inputs, which removes high frequency noise and boosts the signal. Further, these random feature neurons enable learning from fewer training samples and with smaller networks in artificial tasks. This structured random model of receptive fields provides a unifying, mathematically tractable framework to understand sensory encodings across both spatial and temporal domains. Author summary: Evolution has ensured that animal brains are dedicated to extracting useful information from raw sensory stimuli while discarding everything else. Models of sensory neurons are a key part of our theories of how the brain represents the world. In this work, we model the tuning properties of sensory neurons in a way that incorporates randomness and builds a bridge to a leading mathematical theory for understanding how artificial neural networks learn. Our models capture important properties of large populations of real neurons presented with varying stimuli. Moreover, we give a precise mathematical formula for how sensory neurons in two distinct areas, one involving a gyroscopic organ in insects and the other visual processing center in mammals, transform their inputs. We also find that artificial models imbued with properties from real neurons learn more efficiently, with shorter training time and fewer examples, and our mathematical theory explains some of these findings. This work expands our understanding of sensory representation in large networks with benefits for both the neuroscience and machine learning communities. [ABSTRACT FROM AUTHOR]

The decision to engage in courtship depends on external cues from potential mates and internal cues related to maturation, health, and experience. Hormones allow for coordinated conveyance of such information to peripheral tissues. Here, we show Ecdysis-Triggering Hormone (ETH) is critical for courtship inhibition after completion of copulation in Drosophila melanogaster. ETH deficiency relieves post-copulation courtship inhibition (PCCI) and increases male-male courtship. ETH appears to modulate perception and attractiveness of potential mates by direct action on primary chemosensory neurons. Knockdown of ETH receptor (ETHR) expression in GR32A-expressing neurons leads to reduced ligand sensitivity and elevated male-male courtship. We find OR67D also is critical for normal levels of PCCI after mating. ETHR knockdown in OR67D-expressing neurons or GR32A-expressing neurons relieves PCCI. Finally, ETHR silencing in the corpus allatum (CA), the sole source of juvenile hormone, also relieves PCCI; treatment with the juvenile hormone analog methoprene partially restores normal post-mating behavior. We find that ETH, a stress-sensitive reproductive hormone, appears to coordinate multiple sensory modalities to guide Drosophila male courtship behaviors, especially after mating. Author summary: The decision of when to reproduce is paramount for organismal survival. In models like mice and flies, we have a comprehensive understanding of neuronal substrates for perception of mates and courtship drive, but how these substrates adapt to malleable internal and external environments remains unclear. Here, we show that post-mating refractoriness depends upon a peptide hormone, Ecdysis-Triggering Hormone (ETH). We show repression of courtship toward recently-mated females depends upon pheromone cues and that ETH deficiency impairs perception of female matedness. ETH signaling appears to promote the activity and function of pheromone-sensing primary olfactory and gustatory sensory neurons. Additionally, ETH sets internal levels of Juvenile Hormone, a hormone known to inhibit courtship drive in flies. Elimination of ETH or its receptor in primary sensory neurons or the glandular source of Juvenile Hormone reduces male post-copulation courtship inhibition (PCCI), causing continued courtship toward female counterparts after successful mating. Our data suggest ETH and its targets are critical for post-mating refractoriness in males. [ABSTRACT FROM AUTHOR]

Cyclic nucleotide-gated (CNG) ion channels of olfactory sensory neurons contain three types of homologue subunits, two CNGA2 subunits, one CNGA4 subunit and one CNGB1b subunit. Each subunit carries an intracellular cyclic nucleotide binding domain (CNBD) whose occupation by up to four cyclic nucleotides evokes channel activation. Thereby, the subunits interact in a cooperative fashion. Here we studied 16 concatamers with systematically disabled, but still functional, binding sites and quantified channel activation by systems of intimately coupled state models transferred to 4D hypercubes, thereby exploiting a weak voltage dependence of the channels. We provide the complete landscape of free energies for the complex activation process of heterotetrameric channels, including 32 binding steps, in both the closed and open channel, as well as 16 closed-open isomerizations. The binding steps are specific for the subunits and show pronounced positive cooperativity for the binding of the second and the third ligand. The energetics of the closed-open isomerizations were disassembled to elementary subunit promotion energies for channel opening, ΔΔGfpn , adding to the free energy of the closed-open isomerization of the empty channel, E0. The ΔΔGfpn values are specific for the four subunits and presumably invariant for the specific patterns of liganding. In conclusion, subunit cooperativity is confined to the CNBD whereas the subunit promotion energies for channel opening are independent. Author summary: Olfactory sensory neurons (OSNs) in the nose transmit the information of odor molecules to electrical signals that are conducted to central parts of the brain. Olfactory cyclic nucleotide-gated (CNG) ion channels, located in the cell membrane of the OSNs, are relevant proteins in this process. These olfactory CNG channels are formed by three types of homologue subunits and each of these subunits contains a cyclic nucleotide binding domain (CNBD). A channel is activated by the binding of up to four cyclic nucleotides. The process of channel activation is only poorly understood. Herein we analyzed this activation process in great detail by concatenating these four subunits, disabling the CNBDs by mutations and performing extended computational fit analyses providing all 32 constants for the different binding steps at different degrees of liganding and, in addition, elementary subunit promotion energies for channel opening for all subunits. Our data suggest that subunit cooperativity is confined to the action of the CNBD. [ABSTRACT FROM AUTHOR]

The valence and salience of individual odorants are modulated by an animal's innate preferences, learned associations, and internal state, as well as by the context of odorant presentation. The mechanisms underlying context-dependent flexibility in odor valence are not fully understood. Here, we show that the behavioral response of Caenorhabditis elegans to bacterially produced medium-chain alcohols switches from attraction to avoidance when presented in the background of a subset of additional attractive chemicals. This context-dependent reversal of odorant preference is driven by cell-autonomous inversion of the response to these alcohols in the single AWC olfactory neuron pair. We find that while medium-chain alcohols inhibit the AWC olfactory neurons to drive attraction, these alcohols instead activate AWC to promote avoidance when presented in the background of a second AWC-sensed odorant. We show that these opposing responses are driven via engagement of distinct odorant-directed signal transduction pathways within AWC. Our results indicate that context-dependent recruitment of alternative intracellular signaling pathways within a single sensory neuron type conveys opposite hedonic valences, thereby providing a robust mechanism for odorant encoding and discrimination at the periphery. This study examines how context modulates the valence of individual odorants in the nematode Caenorhabditis elegans, revealing that context-dependent engagement of distinct intracellular signaling pathways within a single sensory neuron type is sufficient to switch olfactory preference behavior to an individual odorant from attraction to aversion. [ABSTRACT FROM AUTHOR]

Animals detect changes in both their environment and their internal state and modify their behavior accordingly. Yet, it remains largely to be clarified how information of environment and internal state is integrated and how such integrated information modifies behavior. Well-fed C. elegans migrates to past cultivation temperature on a thermal gradient, which is disrupted when animals are starved. We recently reported that the neuronal activities synchronize between a thermosensory neuron AFD and an interneuron AIY, which is directly downstream of AFD, in well-fed animals, while this synchrony is disrupted in starved animals. However, it remained to be determined whether the disruption of the synchrony is derived from modulation of the transmitter release from AFD or from the modification of reception or signal transduction in AIY. By performing forward genetics on a transition of thermotaxis behavior along starvation, we revealed that OLA-1, an Obg-like ATPase, functions in AFD to promote disruption of AFD-AIY synchrony and behavioral transition. Our results suggest that the information of hunger is delivered to the AFD thermosensory neuron and gates transmitter release from AFD to disrupt thermotaxis, thereby shedding light onto a mechanism for the integration of environmental and internal state to modulate behavior. Author summary: As we humans perceive food smell more attractive when we are hungry, animal's internal state such as satiety affects their sensory stimulus-induced behavior. However, it is not fully understood how multiple external and internal inputs are integrated in the nervous system to modify behavior. In this study, we analyzed the effect of starvation on the thermotaxis behavior of the nematode C. elegans. Animals migrate toward past cultivation temperature on a thermal gradient without food, which is disrupted by starvation. We have found that an ATPase, called OLA-1, which is universally conserved both in prokaryotes and eukaryotes, acts in the thermosensory neuron to modulate its communication with a downstream interneuron, resulting in a modification of the thermotaxis behavior. Our results provided a molecular and neural-circuit mechanism by which animals integrate information of their internal state with that of the external environment to modify their behavior. [ABSTRACT FROM AUTHOR]

Metabolic homeostasis is coordinated through a robust network of signaling pathways acting across all tissues. A key part of this network is insulin-like signaling, which is fundamental for surviving glucose stress. Here, we show that Caenorhabditis elegans fed excess dietary glucose reduce insulin-1 (INS-1) expression specifically in the BAG glutamatergic sensory neurons. We demonstrate that INS-1 expression in the BAG neurons is directly controlled by the transcription factor ETS-5, which is also down-regulated by glucose. We further find that INS-1 acts exclusively from the BAG neurons, and not other INS-1-expressing neurons, to systemically inhibit fat storage via the insulin-like receptor DAF-2. Together, these findings reveal an intertissue regulatory pathway where regulation of insulin expression in a specific neuron controls systemic metabolism in response to excess dietary glucose. Metabolic homeostasis is coordinated through a robust network of signaling pathways acting across all tissues. This study shows that Caenorhabditis elegans nematodes fed excess dietary glucose reduce the expression of insulin-1 specifically in the BAG glutamatergic sensory neurons, and that insulin-1 produced by these neurons systemically inhibits fat storage via the insulin-like receptor DAF-2. [ABSTRACT FROM AUTHOR]

Olfactory integration is important for survival in a natural habitat. However, how the nervous system processes signals of two odorants present simultaneously to generate a coherent behavioral response is poorly understood. Here, we characterize circuit basis for a form of olfactory integration in Caenorhabditis elegans. We find that the presence of a repulsive odorant, 2-nonanone, that signals threat strongly blocks the attraction of other odorants, such as isoamyl alcohol (IAA) or benzaldehyde, that signal food. Using a forward genetic screen, we found that genes known to regulate the structure and function of sensory neurons, osm-5 and osm-1, played a critical role in the integration process. Loss of these genes mildly reduces the response to the repellent 2-nonanone and disrupts the integration effect. Restoring the function of OSM-5 in either AWB or ASH, two sensory neurons known to mediate 2-nonanone-evoked avoidance, is sufficient to rescue. Sensory neurons AWB and downstream interneurons AVA, AIB, RIM that play critical roles in olfactory sensorimotor response are able to process signals generated by 2-nonanone or IAA or the mixture of the two odorants and contribute to the integration. Thus, our results identify redundant neural circuits that regulate the robust effect of a repulsive odorant to block responses to attractive odorants and uncover the neuronal and cellular basis for this complex olfactory task. Author summary: In their natural environment, animals, including humans, encounter complex olfactory stimuli. Thus, how the brain processes multiple sensory cues to generate a coherent behavioral output is critical for the survival of the animal. In the present study, we combined molecular cellular genetics, optical physiology and behavioral analysis to study a common olfactory phenomenon in which the presence of one odorant blocks the response to another. Our results show that the integrated response is regulated by redundant neuronal circuits that engage several interneurons essential for olfactory sensorimotor responses, a mechanism that likely ensures a robust behavioral response to sensory cues representing information critical for survival. [ABSTRACT FROM AUTHOR]

We previously reported that HSV-1 infectivity in vitro and in vivo requires HSV glycoprotein K (gK) binding to the ER signal peptide peptidase (SPP). Anterograde-retrograde transport via peripheral nerves between the site of infection (i.e., eye) and the site of latency (neurons) is a critical process to establish latency and subsequent viral reactivation. Given the essential role of neurons in HSV-1 latency-reactivation, we generated mice lacking SPP specifically in peripheral sensory neurons by crossing Advillin-Cre mice with SPPfl/fl mice. Expression of SPP mRNA and protein were significantly lower in neurons of Avil-SPP-/- mice than in control mice despite similar levels of HSV-1 replication in the eyes of Avil-SPP-/- mice and control mice. Viral transcript levels in isolated neurons of infected mice on days 2 and 5 post infection were lower than in control mice. Significantly less LAT, gB, and PD-1 expression was seen during latency in isolated neurons and total trigeminal ganglia (TG) of Avil-SPP-/- mice than in control mice. Finally, reduced latency and reduced T cell exhaustion in infected Avil-SPP-/- mice correlated with slower and no reactivation. Overall, our results suggest that blocking SPP expression in peripheral sensory neurons does not affect primary virus replication or eye disease but does reduce latency-reactivation. Thus, blocking of gK binding to SPP may be a useful tool to reduce latency-reactivation. Author summary: HSV-1 gK and the ER protein SPP are both essential and highly conserved proteins. Their interaction is important for virus infectivity in vitro and in vivo. To evaluate the importance of gK binding to SPP in the peripheral nervous system, we generated SPP conditional knockout mice in peripheral nervous system using Advillin-Cre mice. The absence of SPP in peripheral nervous system significantly reduced latency-reactivation as well as T cell exhaustion. [ABSTRACT FROM AUTHOR]

The study investigated the cellular and molecular mechanisms in the peripheral nervous system (PNS) underlying the symptoms of urologic chronic pelvic pain syndrome (UCPPS) in mice. This work also aimed to test the feasibility of reversing peripheral sensitization in vivo in alleviating UCPPS symptoms. Intravesical instillation of vascular endothelial growth factor A (VEGFA) was used to induce UCPPS-like symptoms in mice. Spontaneous voiding spot assays and manual Von Frey tests were used to evaluate the severity of lower urinary tract symptoms (LUTS) and visceral hypersensitivity in VEGFA-instilled mice. Bladder smooth muscle strip contractility recordings (BSMSC) were used to identify the potential changes in myogenic and neurogenic detrusor muscle contractility at the tissue-level. Quantitative real-time PCR (qPCR) and fluorescent immunohistochemistry were performed to compare the expression levels of VEGF receptors and nociceptors in lumbosacral dorsal root ganglia (DRG) between VEGFA-instilled mice and saline-instilled controls. To manipulate primary afferent activity, Gi-coupled Designer Receptors Exclusively Activated by Designer Drugs (Gi-DREADD) were expressed in lumbosacral DRG neurons of TRPV1-Cre-ZGreen mice via targeted adeno-associated viral vector (AAVs) injections. A small molecule agonist of Gi-DREADD, clozapine-N-oxide (CNO), was injected into the peritoneum (i. p.) in awake animals to silence TRPV1 expressing sensory neurons in vivo during physiological and behavioral recordings of bladder function. Intravesical instillation of VEGFA in the urinary bladders increased visceral mechanical sensitivity and enhanced RTX-sensitive detrusor contractility. Sex differences were identified in the baseline detrusor contractility responses and VEGF-induced visceral hypersensitivity. VEGFA instillations in the urinary bladder led to significant increases in the mRNA and protein expression of transient receptor potential cation channel subfamily A member 1 (TRPA1) in lumbosacral DRG, whereas the expression levels of transient receptor potential cation channel subfamily V member 1 (TRPV1) and VEGF receptors (VEGFR1 and VEGFR2) remained unchanged when compared to saline-instilled animals. Importantly, the VEGFA-induced visceral hypersensitivity was reversed by Gi-DREADD-mediated neuronal silencing in lumbosacral sensory neurons. Activation of bladder VEGF signaling causes sensory neural plasticity and visceral hypersensitivity in mice, confirming its role of an UCPPS biomarker as identified by the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) research studies. Pharmacogenetic inhibition of lumbosacral sensory neurons in vivo completely reversed VEGFA-induced pelvic hypersensitivity in mice, suggesting the strong therapeutic potential for decreasing primary afferent activity in the treatment of pain severity in UCPPS patients. [ABSTRACT FROM AUTHOR]

The number of neurons in mammalian cortex varies by multiple orders of magnitude across different species. In contrast, the ratio of excitatory to inhibitory neurons (E:I ratio) varies in a much smaller range, from 3:1 to 9:1 and remains roughly constant for different sensory areas within a species. Despite this structure being important for understanding the function of neural circuits, the reason for this consistency is not yet understood. While recent models of vision based on the efficient coding hypothesis show that increasing the number of both excitatory and inhibitory cells improves stimulus representation, the two cannot increase simultaneously due to constraints on brain volume. In this work, we implement an efficient coding model of vision under a constraint on the volume (using number of neurons as a surrogate) while varying the E:I ratio. We show that the performance of the model is optimal at biologically observed E:I ratios under several metrics. We argue that this happens due to trade-offs between the computational accuracy and the representation capacity for natural stimuli. Further, we make experimentally testable predictions that 1) the optimal E:I ratio should be higher for species with a higher sparsity in the neural activity and 2) the character of inhibitory synaptic distributions and firing rates should change depending on E:I ratio. Our findings, which are supported by our new preliminary analyses of publicly available data, provide the first quantitative and testable hypothesis based on optimal coding models for the distribution of excitatory and inhibitory neural types in the mammalian sensory cortices. Author summary: Neurons in the brain come in two main types: excitatory and inhibitory. The interplay between them shapes neural computation. Despite brain sizes varying by several orders of magnitude across species, the ratio of excitatory and inhibitory sub-populations (E:I ratio) remains relatively constant, and we don't know why. Simulations of theoretical models of the brain can help answer such questions, especially when experiments are prohibitive or impossible. Here we placed one such theoretical model of sensory coding ('sparse coding' that minimizes the simultaneously active neurons) under a biophysical 'volume' constraint that fixes the total number of neurons available. We vary the E:I ratio in the model (which cannot be done in experiments), and reveal an optimal E:I ratio where the representation of sensory stimulus and energy consumption within the circuit are concurrently optimal. We also show that varying the population sparsity changes the optimal E:I ratio, spanning the relatively narrow ranges observed in biology. Crucially, this minimally parameterized theoretical model makes predictions about structure (recurrent connectivity) and activity (population sparsity) in neural circuits with different E:I ratios (i.e., different species), of which we verify the latter in a first-of-its-kind inter-species comparison using newly publicly available data. [ABSTRACT FROM AUTHOR]

Taxane-induced peripheral neuropathy (TIPN) is a devastating survivorship issue for many cancer patients. In addition to its impact on quality of life, this toxicity may lead to dose reductions or treatment discontinuation, adversely impacting survival outcomes and leading to health disparities in African Americans (AA). Our lab has previously identified deleterious mutations in SET-Binding Factor 2 (SBF2) that significantly associated with severe TIPN in AA patients. Here, we demonstrate the impact of SBF2 on taxane-induced neuronal damage using an ex vivo model of SBF2 knockdown of induced pluripotent stem cell-derived sensory neurons. Knockdown of SBF2 exacerbated paclitaxel changes to cell viability and neurite outgrowth while attenuating paclitaxel-induced sodium current inhibition. Our studies identified paclitaxel-induced expression changes specific to mature sensory neurons and revealed candidate genes involved in the exacerbation of paclitaxel-induced phenotypes accompanying SBF2 knockdown. Overall, these findings provide ex vivo support for the impact of SBF2 on the development of TIPN and shed light on the potential pathways involved. Author summary: Taxanes, including paclitaxel, are cancer therapy agents that are widely used with curative potential. However, one of the most common side effects of taxanes, taxane-induced peripheral neuropathy (TIPN), is a devastating survivorship issue for many cancer patients. The employment of taxanes in chemotherapeutic regimens is limited by the severity of TIPN, which may cause lifelong debilitating pain and lack of sensation. Traditionally, African American women have reported higher rates of severe neuropathy with paclitaxel treatment, which has impacted their health outcomes negatively and contributed to treatment disparities. We have previously identified the association of developing severe TIPN with gene SBF2, which is a gene known for causing an inherited neuropathy, Charcot-Marie-Tooth disease type 4B2. In this study, we demonstrated that lower expressions of SBF2 impacted the neuronal morphologic and functional changes resultant from paclitaxel treatment. Moreover, we highlighted candidate genes and inflammatory molecular pathways as potential contributors to the progression of TIPN for future therapeutic target developments. [ABSTRACT FROM AUTHOR]

Hydrogen peroxide (H2O2) is the most common chemical threat that organisms face. Here, we show that H2O2 alters the bacterial food preference of Caenorhabditis elegans, enabling the nematodes to find a safe environment with food. H2O2 induces the nematodes to leave food patches of laboratory and microbiome bacteria when those bacterial communities have insufficient H2O2-degrading capacity. The nematode's behavior is directed by H2O2-sensing neurons that promote escape from H2O2 and by bacteria-sensing neurons that promote attraction to bacteria. However, the input for H2O2-sensing neurons is removed by bacterial H2O2-degrading enzymes and the bacteria-sensing neurons' perception of bacteria is prevented by H2O2. The resulting cross-attenuation provides a general mechanism that ensures the nematode's behavior is faithful to the lethal threat of hydrogen peroxide, increasing the nematode's chances of finding a niche that provides both food and protection from hydrogen peroxide. Author summary: One of the most common lethal threats that nematodes encounter is hydrogen peroxide, which is produced by a wide variety of microorganisms. In this microbial battlefield, how do nematodes find a niche that provides the food and safety necessary for growth and reproduction? In the present study, we developed a model ecosystem to study the behavioral mechanisms that enable the nematode C. elegans to find those niches. We found that C. elegans adjust their behavior to find bacterial communities that provide protection from hydrogen peroxide. Hydrogen peroxide and bacteria had opposing effects on the activity of sensory neurons that modulate the nematode's locomotion towards bacteria and away from hydrogen peroxide. The diminished perception of bacteria unable to degrade hydrogen peroxide in the environment represents a general mechanism enabling nematodes to leave environments where the bacterial community does not provide them and their future progeny with sufficient protection from hydrogen peroxide. [ABSTRACT FROM AUTHOR]

When flies explore their environment, they encounter odors in complex, highly intermittent plumes. To navigate a plume and, for example, find food, they must solve several challenges, including reliably identifying mixtures of odorants and their intensities, and discriminating odorant mixtures emanating from a single source from odorants emitted from separate sources and just mixing in the air. Lateral inhibition in the antennal lobe is commonly understood to help solving these challenges. With a computational model of the Drosophila olfactory system, we analyze the utility of an alternative mechanism for solving them: Non-synaptic ("ephaptic") interactions (NSIs) between olfactory receptor neurons that are stereotypically co-housed in the same sensilla. We find that NSIs improve mixture ratio detection and plume structure sensing and do so more efficiently than the traditionally considered mechanism of lateral inhibition in the antennal lobe. The best performance is achieved when both mechanisms work in synergy. However, we also found that NSIs decrease the dynamic range of co-housed ORNs, especially when they have similar sensitivity to an odorant. These results shed light, from a functional perspective, on the role of NSIs, which are normally avoided between neurons, for instance by myelination. Author summary: Myelin is important to isolate neurons and avoid disruptive electrical interference between them; it can be found in almost any neural assembly. However, there are a few exceptions to this rule and it remains unclear why. One particularly interesting case is the electrical interaction between olfactory sensory neurons co-housed in the sensilla of insects. Here, we investigate a computational model of the early stages of the Drosophila olfactory system and observe that the electrical interference between olfactory receptor neurons can be a useful trait that can help flies, and other insects, to navigate the complex odor plumes in their natural environment. Our modelling results shed new light on the trade-off of adopting this mechanism: We find that the non-synaptic interactions (NSIs) improve both the identification of the concentration ratio in mixtures of odorants and the discrimination of odorant mixtures emanating from a single source from odorants emitted from separate sources—both highly advantageous. However, they also tend to decrease the dynamic range of the olfactory sensory neurons—a clear disadvantage. [ABSTRACT FROM AUTHOR]

Emergent response properties of sensory neurons depend on circuit connectivity and somatodendritic processing. Neurons of the barn owl's external nucleus of the inferior colliculus (ICx) display emergence of spatial selectivity. These neurons use interaural time difference (ITD) as a cue for the horizontal direction of sound sources. ITD is detected by upstream brainstem neurons with narrow frequency tuning, resulting in spatially ambiguous responses. This spatial ambiguity is resolved by ICx neurons integrating inputs over frequency, a relevant processing in sound localization across species. Previous models have predicted that ICx neurons function as point neurons that linearly integrate inputs across frequency. However, the complex dendritic trees and spines of ICx neurons raises the question of whether this prediction is accurate. Data from in vivo intracellular recordings of ICx neurons were used to address this question. Results revealed diverse frequency integration properties, where some ICx neurons showed responses consistent with the point neuron hypothesis and others with nonlinear dendritic integration. Modeling showed that varied connectivity patterns and forms of dendritic processing may underlie observed ICx neurons' frequency integration processing. These results corroborate the ability of neurons with complex dendritic trees to implement diverse linear and nonlinear integration of synaptic inputs, of relevance for adaptive coding and learning, and supporting a fundamental mechanism in sound localization. Author summary: Neurons at higher stages of sensory pathways often display selectivity for properties of sensory stimuli that result from computations performed within the nervous system. These emergent response properties can be produced by patterns of neural connectivity and processing that occur within individual cells. Here we investigated whether neural connectivity and single-neuron computation may contribute to the emergence of spatial selectivity in auditory neurons in the barn owl's midbrain. We used data from in vivo intracellular recordings to test the hypothesis from previous modeling work that these cells function as point neurons that perform a linear sum of their inputs in their subthreshold responses. Results indicate that while some neurons show responses consistent with the point neuron hypothesis, others match predictions of nonlinear integration, indicating a diversity of frequency integration properties across neurons. Modeling further showed that varied connectivity patterns and forms of single-neuron computation may underlie observed responses. These results demonstrate that neurons with complex morphologies may implement diverse integration of synaptic inputs, relevant for adaptive coding and learning. [ABSTRACT FROM AUTHOR]

Nervous systems extract and process information from the environment to alter animal behavior and physiology. Despite progress in understanding how different stimuli are represented by changes in neuronal activity, less is known about how they affect broader neural network properties. We developed a framework for using graph-theoretic features of neural network activity to predict ecologically relevant stimulus properties, in particular stimulus identity. We used the transparent nematode, Caenorhabditis elegans, with its small nervous system to define neural network features associated with various chemosensory stimuli. We first immobilized animals using a microfluidic device and exposed their noses to chemical stimuli while monitoring changes in neural activity of more than 50 neurons in the head region. We found that graph-theoretic features, which capture patterns of interactions between neurons, are modulated by stimulus identity. Further, we show that a simple machine learning classifier trained using graph-theoretic features alone, or in combination with neural activity features, can accurately predict salt stimulus. Moreover, by focusing on putative causal interactions between neurons, the graph-theoretic features were almost twice as predictive as the neural activity features. These results reveal that stimulus identity modulates the broad, network-level organization of the nervous system, and that graph theory can be used to characterize these changes. Author summary: Animals use their nervous systems to detect and respond to changes in their external environment. A central challenge in computational neuroscience is to determine how specific properties of these stimuli affect interactions between neurons. While most studies have focused on the neurons in the sensory periphery, recent advances allow us to probe how the rest of the nervous system responds to sensory stimulation. We recorded activity of neurons within the C. elegans head region while the animal was exposed to various chemosensory stimuli. We then used computational methods to identify various stimuli by analyzing neural activity. Specifically, we used a combination of population-level activity statistics (e.g., average, standard deviation, frequency-based measures) and graph-theoretic features of functional network structure (e.g., transitivity, which is the existence of strongly connected triplets of neurons) to accurately predict salt stimulus. Our method is general and can be used across species, particularly in instances where the identities of individual neurons are unknown. These results also suggest that neural activity downstream of the sensory periphery contains a signature of changes in the environment.​ [ABSTRACT FROM AUTHOR]

To survive elevated temperatures, ectotherms adjust the fluidity of membranes by fine-tuning lipid desaturation levels in a process previously described to be cell autonomous. We have discovered that, in Caenorhabditis elegans, neuronal heat shock factor 1 (HSF-1), the conserved master regulator of the heat shock response (HSR), causes extensive fat remodeling in peripheral tissues. These changes include a decrease in fat desaturase and acid lipase expression in the intestine and a global shift in the saturation levels of plasma membrane's phospholipids. The observed remodeling of plasma membrane is in line with ectothermic adaptive responses and gives worms a cumulative advantage to warm temperatures. We have determined that at least 6 TAX-2/TAX-4 cyclic guanosine monophosphate (cGMP) gated channel expressing sensory neurons, and transforming growth factor ß (TGF-β)/bone morphogenetic protein (BMP) are required for signaling across tissues to modulate fat desaturation. We also find neuronal hsf-1 is not only sufficient but also partially necessary to control the fat remodeling response and for survival at warm temperatures. This is the first study to show that a thermostat-based mechanism can cell nonautonomously coordinate membrane saturation and composition across tissues in a multicellular animal. In response to heat, ectotherms exhibit an adaptive response characterized by changes in membrane fluidity. This study in the nematode Caenorhabditis elegans shows that neuronal HSF-1 is critical for this remodeling, suggesting a neuronal thermostat-based mechanism that can non-cell-autonomously coordinate the animal's response to heat. [ABSTRACT FROM AUTHOR]

The assembly of neuronal circuits involves the migrations of neurons from their place of birth to their final location in the nervous system, as well as the coordinated growth and patterning of axons and dendrites. In screens for genes required for patterning of the nervous system, we identified the catp-8/P5A-ATPase as an important regulator of neural patterning. P5A-ATPases are part of the P-type ATPases, a family of proteins known to serve a conserved function as transporters of ions, lipids and polyamines in unicellular eukaryotes, plants, and humans. While the function of many P-type ATPases is relatively well understood, the function of P5A-ATPases in metazoans remained elusive. We show here, that the Caenorhabditis elegans ortholog catp-8/P5A-ATPase is required for defined aspects of nervous system development. Specifically, the catp-8/P5A-ATPase serves functions in shaping the elaborately sculpted dendritic trees of somatosensory PVD neurons. Moreover, catp-8/P5A-ATPase is required for axonal guidance and repulsion at the midline, as well as embryonic and postembryonic neuronal migrations. Interestingly, not all axons at the midline require catp-8/P5A-ATPase, although the axons run in the same fascicles and navigate the same space. Similarly, not all neuronal migrations require catp-8/P5A-ATPase. A CATP-8/P5A-ATPase reporter is localized to the ER in most, if not all, tissues and catp-8/P5A-ATPase can function both cell-autonomously and non-autonomously to regulate neuronal development. Genetic analyses establish that catp-8/P5A-ATPase can function in multiple pathways, including the Menorin pathway, previously shown to control dendritic patterning in PVD, and Wnt signaling, which functions to control neuronal migrations. Lastly, we show that catp-8/P5A-ATPase is required for localizing select transmembrane proteins necessary for dendrite morphogenesis. Collectively, our studies suggest that catp-8/P5A-ATPase serves diverse, yet specific, roles in different genetic pathways and may be involved in the regulation or localization of transmembrane and secreted proteins to specific subcellular compartments. Author summary: P-type ATPases are a large family of transporters that are conserved from unicellular eukaryotes and plants to metazoans. Structurally and functionally, they fall into five subfamilies, P1 to P5, of which the latter is further divided into P5A and P5B-type ATPases. Unlike for other P-type ATPases, no mutant phenotypes for the P5A-type ATPases have been described in metazoans. Here, we show that the catp-8/P5A-ATPase in the nematode Caenorhabditis elegans is involved in multiple aspects of neuronal patterning, including neuronal migrations as well as axon guidance and dendrite patterning. A functional fluorescent reporter fusion shows the CATP-8/P5A-ATPase is expressed in most, if not all, tissues in the endoplasmic reticulum and that catp-8 can function both in neurons and surrounding tissues from where it orchestrates neuronal development. Genetically, catp-8 acts in multiple pathways during these processes, including the Wnt signaling and the Menorin pathway. Imaging studies suggest that the catp-8/P5A-ATPase is necessary for proper localization of cell-surface transmembrane proteins to dendrites of sensory neurons, but likely not for their trafficking. In summary, we propose that CATP-8/P5A-ATPase serves a function in the ER during development of select neurons, by localizing certain transmembrane, and possibly, secreted proteins. [ABSTRACT FROM AUTHOR]

We present a general physicochemical sampling model for olfaction, based on established pharmacological laws, in which arbitrary combinations of odorant ligands and receptors can be generated and their individual and collective effects on odor representations and olfactory performance measured. Individual odor ligands exhibit receptor-specific affinities and efficacies; that is, they may bind strongly or weakly to a given receptor, and can act as strong agonists, weak agonists, partial agonists, or antagonists. Ligands interacting with common receptors compete with one another for dwell time; these competitive interactions appropriately simulate the degeneracy that fundamentally defines the capacities and limitations of odorant sampling. The outcome of these competing ligand-receptor interactions yields a pattern of receptor activation levels, thereafter mapped to glomerular presynaptic activation levels based on the convergence of sensory neuron axons. The metric of greatest interest is the mean discrimination sensitivity, a measure of how effectively the olfactory system at this level is able to recognize a small change in the physicochemical quality of a stimulus. This model presents several significant outcomes, both expected and surprising. First, adding additional receptors reliably improves the system's discrimination sensitivity. Second, in contrast, adding additional ligands to an odor scene initially can improve discrimination sensitivity, but eventually will reduce it as the number of ligands increases. Third, the presence of antagonistic ligand-receptor interactions produced clear benefits for sensory system performance, generating higher absolute discrimination sensitivities and increasing the numbers of competing ligands that could be present before discrimination sensitivity began to be impaired. Finally, the model correctly reflects and explains the modest reduction in odor discrimination sensitivity exhibited by transgenic mice in which the specificity of glomerular targeting by primary olfactory neurons is partially disrupted. Author summary: We understand most sensory systems by comparing the responses of the system against objective external physical measurements. For example, we know that our ability to distinguish small changes in color is greater for some colors than for others, and that we can distinguish sounds more acutely when they are within the range of pitches used for speech. Similar principles presumably apply to the sense of smell, but odorous chemicals are harder to physically quantify than light or sound because they cannot be organized in terms of a straightforward physical variable like wavelength or frequency. That said, the physical properties of interactions between chemicals and cellular receptors (such as those in the olfactory system) are well understood. What we lack is a systematic framework within which these pharmacological principles can be organized to study odor sampling in the way that we have long studied visual and auditory sampling. We here propose and describe such a framework for odor sampling, and show that it successfully replicates some established but unexplained experimental results. [ABSTRACT FROM AUTHOR]

The duration of a stimulus plays an important role in the coding of sensory information. The role of stimulus duration is extensively studied in the tactile, visual, and auditory system. In the olfactory system, temporal properties of the stimulus are key for obtaining information when an odor is released in the environment. However, how the stimulus duration influences the odor perception is not well understood. To test this, we activated the olfactory bulbs with blue light in mice expressing channelrhodopsin in the olfactory sensory neurons (OSNs) and assessed the relevance of stimulus duration on olfactory perception using foot shock associated active avoidance behavioral task on a "two-arms maze". Our behavior data demonstrate that the stimulus duration plays an important role in olfactory perception and the associated behavioral responses. [ABSTRACT FROM AUTHOR]

Trpm8 (transient receptor potential cation channel, subfamily M, member 8) is expressed by sensory neurons and is involved in the detection of environmental cold temperatures. TRPM8 activity triggers an increase in uncoupling protein 1 (Ucp1)-dependent brown adipose tissue (BAT) thermogenesis. Bone density and marrow adipose tissue are both influenced by rodent housing temperature and brown adipose tissue, but it is unknown if TRPM8 is involved in the co-regulation of thermogenesis and bone homeostasis. To address this, we examined the bone phenotypes of one-year-old Trpm8 knockout mice (Trpm8-KO) after a 4-week cold temperature challenge. Male Trpm8-KO mice had lower bone mineral density than WT, with smaller bone size (femur length and cross-sectional area) being the most striking finding, and exhibited a delayed cold acclimation with increased BAT expression of Dio2 and Cidea compared to WT. In contrast to males, female Trpm8-KO mice had low vertebral bone microarchitectural parameters, but no genotype-specific alterations in body temperature. Interestingly, Trpm8 was not required for cold-induced trabecular bone loss in either sex, but bone marrow adipose tissue in females was significantly suppressed by Trpm8 deletion. In summary, we identified sex differences in the role of TRPM8 in maintaining body temperature, bone microarchitecture and marrow adipose tissue. Identifying mechanisms through which cold temperature and BAT influence bone could help to ameliorate potential bone side effects of obesity treatments designed to stimulate thermogenesis. [ABSTRACT FROM AUTHOR]