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1. Differences in olfactory bulb mitral cell spiking with ortho- and retronasal stimulation revealed by data-driven models

   https://doi.org/10.1371/journal.pcbi.1009169  

   Craft, Michelle F. ; Barreiro, Andrea K. ; Gautam, Shree Hari ; Shew, Woodrow L. ; Ly, Cheng ( September 2021 , PLOS Computational Biology)

   Migliore, Michele (Ed.)

   The majority of olfaction studies focus on orthonasal stimulation where odors enter via the front nasal cavity, while retronasal olfaction, where odors enter the rear of the nasal cavity during feeding, is understudied. The coding of retronasal odors via coordinated spiking of neurons in the olfactory bulb ( OB ) is largely unknown despite evidence that higher level processing is different than orthonasal. To this end, we use multi-electrode array in vivo recordings of rat OB mitral cells ( MC ) in response to a food odor with both modes of stimulation, and find significant differences in evoked firing rates and spike count covariances (i.e., noise correlations). Differences in spiking activity often have implications for sensory coding, thus we develop a single-compartment biophysical OB model that is able to reproduce key properties of important OB cell types. Prior experiments in olfactory receptor neurons ( ORN ) showed retro stimulation yields slower and spatially smaller ORN inputs than with ortho, yet whether this is consequential for OB activity remains unknown. Indeed with these specifications for ORN inputs, our OB model captures the salient trends in our OB data. We also analyze how first and second order ORN input statistics dynamically transfer to MC spiking statistics with a phenomenological linear-nonlinear filter model, and find that retro inputs result in larger linear filters than ortho inputs. Finally, our models show that the temporal profile of ORN is crucial for capturing our data and is thus a distinguishing feature between ortho and retro stimulation, even at the OB. Using data-driven modeling, we detail how ORN inputs result in differences in OB dynamics and MC spiking statistics. These differences may ultimately shape how ortho and retro odors are coded. 

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2. Changes in pairwise correlations during running reshape global network state in the main olfactory bulb

   https://doi.org/10.1152/jn.00464.2020  

   Chockanathan, Udaysankar ; Crosier, Emily J. ; Waddle, Spencer ; Lyman, Edward ; Gerkin, Richard C. ; Padmanabhan, Krishnan ( May 2021 , Journal of Neurophysiology)

   null (Ed.)

   Neural codes for sensory inputs have been hypothesized to reside in a broader space defined by ongoing patterns of spontaneous activity. To understand the structure of this spontaneous activity in the olfactory system, we performed high-density recordings of neural populations in the main olfactory bulb of awake mice. We observed changes in pairwise correlations of spontaneous activity between mitral and tufted (M/T) cells when animals were running, which resulted in an increase in the entropy of the population. Surprisingly, pairwise maximum entropy models that described the population activity using only assumptions about the firing rates and correlations of neurons were better at predicting the global structure of activity when animals were stationary as compared to when they were running, implying that higher order (3rd, 4th order) interactions governed population activity during locomotion. Taken together, we found that locomotion alters the functional interactions that shape spontaneous population activity at the earliest stages of olfactory processing, one synapse away from the sensory receptors in the nasal epithelium. These data suggest that the coding space available for sensory representations responds adaptively to the animal’s behavioral state. NEW & NOTEWORTHY The organization and structure of spontaneous population activity in the olfactory system places constraints of how odor information is represented. Using high-density electrophysiological recordings of mitral and tufted cells, we found that running increases the dimensionality of spontaneous activity, implicating higher order interactions among neurons during locomotion. Behavior, thus, flexibly alters neuronal activity at the earliest stages of sensory processing. 

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3. Diverse states and stimuli tune olfactory receptor expression levels to modulate food-seeking behavior

   https://doi.org/10.7554/eLife.79557  

   McLachlan, Ian G ; Kramer, Talya S ; Dua, Malvika ; DiLoreto, Elizabeth M ; Gomes, Matthew A ; Dag, Ugur ; Srinivasan, Jagan ; Flavell, Steven W ( August 2022 , eLife)

   Animals must weigh competing needs and states to generate adaptive behavioral responses to the environment. Sensorimotor circuits are thus tasked with integrating diverse external and internal cues relevant to these needs to generate context-appropriate behaviors. However, the mechanisms that underlie this integration are largely unknown. Here, we show that a wide range of states and stimuli converge upon a single Caenorhabditis elegans olfactory neuron to modulate food-seeking behavior. Using an unbiased ribotagging approach, we find that the expression of olfactory receptor genes in the AWA olfactory neuron is influenced by a wide array of states and stimuli, including feeding state, physiological stress, and recent sensory cues. We identify odorants that activate these state-dependent olfactory receptors and show that altered expression of these receptors influences food-seeking and foraging. Further, we dissect the molecular and neural circuit pathways through which external sensory information and internal nutritional state are integrated by AWA. This reveals a modular organization in which sensory and state-related signals arising from different cell types in the body converge on AWA and independently control chemoreceptor expression. The synthesis of these signals by AWA allows animals to generate sensorimotor responses that reflect the animal’s overall state. Our findings suggest a general model in which sensory- and state-dependent transcriptional changes at the sensory periphery modulate animals’ sensorimotor responses to meet their ongoing needs and states. 

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4. Spleen glia are a transcriptionally unique glial subtype interposed between immune cells and sympathetic axons

   https://doi.org/10.1002/glia.23993  

   Lucas, Tawaun A. ; Zhu, Li ; Buckwalter, Marion S. ( March 2021 , Glia)

   Glia are known to play important roles in the brain, the gut, and around the sciatic nerve. While the gut has its own specialized nervous system, other viscera are innervated solely by autonomic nerves. The functions of glia that accompany autonomic innervation are not well known, even though they are one of the most abundant cell types in the peripheral nervous system. Here, we focused on non‐myelinating Schwann cells in the spleen, spleen glia. The spleen is a major immune organ innervated by the sympathetic nervous system, which modulates immune function. This interaction is known as neuroimmune communication. We establish that spleen glia can be visualized using both immunohistochemistry for S100B and GFAP and with a reporter mouse. Spleen glia ensheath sympathetic axons and are localized to the lymphocyte‐rich white pulp areas of the spleen. We sequenced the spleen glia transcriptome and identified genes that are likely involved in axonal ensheathment and communication with both nerves and immune cells. Spleen glia express receptors for neurotransmitters made by sympathetic axons (adrenergic, purinergic, and Neuropeptide Y), and also cytokines, chemokines, and their receptors that may communicate with immune cells in the spleen. We also established similarities and differences between spleen glia and other glial types. While all glia share many genes in common, spleen glia differentially express genes associated with immune responses, including genes involved in cytokine‐cytokine receptor interactions, phagocytosis, and the complement cascade. Thus, spleen glia are a unique glial type, physically and transcriptionally poised to participate in neuroimmune communication in the spleen.

    

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5. Role of Viral Hemorrhagic Septicemia Virus Matrix (M) Protein in Suppressing Host Transcription

   https://doi.org/10.1128/JVI.00279-17  

   Ke, Qi ; Weaver, Wade ; Pore, Adam ; Gorgoglione, Bartolomeo ; Wildschutte, Julia Halo ; Xiao, Peng ; Shepherd, Brian S. ; Spear, Allyn ; Malathi, Krishnamurthy ; Stepien, Carol A. ; et al ( July 2017 , Journal of Virology)

   Viral Hemorrhagic Septicemia virus (VHSV) is a pathogenic fish rhabdovirus found in discrete locales throughout the northern hemisphere. VHSV infection of fish cells leads to upregulation of the host's virus detection response, but the virus quickly suppresses interferon (IFN) production and antiviral genes expression. By systematically screening each of the six VHSV structural and nonstructural genes, we have identified matrix protein (M) as its most potent anti-host protein. VHSV-IVb M alone suppressed mitochondrial antiviral signaling protein (MAVS) and type I IFN-induced gene expression in a dose-dependent manner. M also suppressed the constitutively active SV40 promoter and globally decreased cellular RNA levels. Chromatin immunoprecipitation (ChIP) studies illustrated that M inhibited RNA polymerase II (RNAP II) recruitment to gene promoters, and decreased RNAP II CTD Ser2 phosphorylation during VHSV infection. However, transcription directed by RNAP I-III was suppressed by M. To identify regions of functional importance, M proteins from a variety of VHSV strains were tested in cell-based transcriptional inhibition assays. M protein of a particular VHSV-Ia strain, F1, was significantly less potent than -IVb M at inhibiting SV40/luc expression, yet differed by just four amino acids. Mutation of D62 to alanine alone, or in combination with an E181 to alanine mutation (D62A/E181A), dramatically reduced the ability of -IVb M to suppress host transcription. Introducing either M D62A or D62A/E181A mutations into VHSV-IVb via reverse genetics resulted in viruses that replicated efficiently but exhibited less cytotoxicity and reduced anti-transcriptional activities, implicating M as a primary regulator of cytopathicity and host transcriptional suppression. Importance: Viruses must suppress host antiviral responses to replicate and spread between hosts. In these studies, we identified the matrix protein of the deadly fish Novirhabdovirus, VHSV, as a critical mediator of host suppression during infection. Our studies indicated that M alone could block cellular gene expression at very low expression levels. We identified several subtle mutations in M that were less potent at suppressing host transcription. When these mutations were engineered back into recombinant viruses, the resulting viruses replicated well but elicited less toxicity in infected cells and activated host innate immune responses more robustly. These data demonstrated that VHSV M plays an important role in mediating both virus-induced cell toxicity and viral replication. Our data suggest that its roles in these two processes can be separated to design effective attenuated viruses for vaccine candidates. 

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