More Like this

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 transfermore »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.« less
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)

   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 constraintsmore »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.« less
3. 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 mutationmore »(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.« less
4. Single-cell RNA transcriptome analysis of CNS immune cells reveals CXCL16/CXCR6 as maintenance factors for tissue-resident T cells that drive synapse elimination

   https://doi.org/10.1186/s13073-022-01111-0  

   Rosen, Sarah F. ; Soung, Allison L. ; Yang, Wei ; Ai, Shenjian ; Kanmogne, Marlene ; Davé, Veronica A. ; Artyomov, Maxim ; Magee, Jeffrey A. ; Klein, Robyn S. ( September 2022 , Genome Medicine)

   Emerging RNA viruses that target the central nervous system (CNS) lead to cognitive sequelae in survivors. Studies in humans and mice infected with West Nile virus (WNV), a re-emerging RNA virus associated with learning and memory deficits, revealed microglial-mediated synapse elimination within the hippocampus. Moreover, CNS-resident memory T (T_RM) cells activate microglia, limiting synapse recovery and inducing spatial learning defects in WNV-recovered mice. The signals involved in T cell-microglia interactions are unknown.

   Here, we examined immune cells within the murine WNV-recovered forebrain using single-cell RNA sequencing to identify putative ligand-receptor pairs involved in intercellular communication between T cells and microglia. Clustering and differential gene analyses were followed by protein validation and genetic and antibody-based approaches utilizing an established murine model of WNV recovery in which microglia and complement promote ongoing hippocampal synaptic loss.

   Profiling of host transcriptome immune cells at 25 days post-infection in mice revealed a shift in forebrain homeostatic microglia to activated subpopulations with transcriptional signatures that have previously been observed in studies of neurodegenerative diseases. Importantly, CXCL16/CXCR6, a chemokine signaling pathway involved in T_RM cell biology, was identified as critically regulating CXCR6 expressing CD8⁺T_RM cell numbers within the WNV-recovered forebrain. We demonstrate that CXCL16 is highlymore »expressed by all myeloid cells, and its unique receptor, CXCR6, is highly expressed on all CD8⁺T cells. Using genetic and pharmacological approaches, we demonstrate that CXCL16/CXCR6 not only is required for the maintenance of WNV-specific CD8 T_RM cells in the post-infectious CNS, but also contributes to their expression of T_RM cell markers. Moreover, CXCR6⁺CD8⁺T cells are required for glial activation and ongoing synapse elimination.

   We provide a comprehensive assessment of the role of CXCL16/CXCR6 as an interaction link between microglia and CD8⁺T cells that maintains forebrain T_RM cells, microglial and astrocyte activation, and ongoing synapse elimination in virally recovered animals. We also show that therapeutic targeting of CXCL16 in mice during recovery may reduce CNS CD8⁺T_RM cells.

   « less
5. An Evolutionary Microcircuit Approach to the Neural Basis of High Dimensional Sensory Processing in Olfaction

   https://doi.org/10.3389/fncel.2021.658480  

   Shepherd, Gordon M. ; Rowe, Timothy B. ; Greer, Charles A. ( April 2021 , Frontiers in Cellular Neuroscience)

   Odor stimuli consist of thousands of possible molecules, each molecule with many different properties, each property a dimension of the stimulus. Processing these high dimensional stimuli would appear to require many stages in the brain to reach odor perception, yet, in mammals, after the sensory receptors this is accomplished through only two regions, the olfactory bulb and olfactory cortex. We take a first step toward a fundamental understanding by identifying the sequence of local operations carried out by microcircuits in the pathway. Parallel research provided strong evidence that processed odor information is spatial representations of odor molecules that constitute odor images in the olfactory bulb and odor objects in olfactory cortex. Paleontology provides a unique advantage with evolutionary insights providing evidence that the basic architecture of the olfactory pathway almost from the start ∼330 million years ago (mya) has included an overwhelming input from olfactory sensory neurons combined with a large olfactory bulb and olfactory cortex to process that input, driven by olfactory receptor gene duplications. We identify a sequence of over 20 microcircuits that are involved, and expand on results of research on several microcircuits that give the best insights thus far into the nature of the high dimensionalmore »processing.« less