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Neuron Jul 2023Although the etiology of major depressive disorder remains poorly understood, reduced gamma oscillations is an emerging biomarker. Olfactory bulbectomy, an established...
Although the etiology of major depressive disorder remains poorly understood, reduced gamma oscillations is an emerging biomarker. Olfactory bulbectomy, an established model of depression that reduces limbic gamma oscillations, suffers from non-specific effects of structural damage. Here, we show that transient functional suppression of olfactory bulb neurons or their piriform cortex efferents decreased gamma oscillation power in limbic areas and induced depression-like behaviors in rodents. Enhancing transmission of gamma oscillations from olfactory bulb to limbic structures by closed-loop electrical neuromodulation alleviated these behaviors. By contrast, silencing gamma transmission by anti-phase closed-loop stimulation strengthened depression-like behaviors in naive animals. These induced behaviors were neutralized by ketamine treatment that restored limbic gamma power. Taken together, our results reveal a causal link between limbic gamma oscillations and depression-like behaviors in rodents. Interfering with these endogenous rhythms can affect behaviors in rodent models of depression, suggesting that restoring gamma oscillations may alleviate depressive symptoms.
Topics: Animals; Olfactory Bulb; Rodentia; Depression; Depressive Disorder, Major; Neurons
PubMed: 37164008
DOI: 10.1016/j.neuron.2023.04.013 -
Immunity Jul 2021COVID-19 can cause severe neurological symptoms, but the underlying pathophysiological mechanisms are unclear. Here, we interrogated the brain stems and olfactory bulbs...
COVID-19 can cause severe neurological symptoms, but the underlying pathophysiological mechanisms are unclear. Here, we interrogated the brain stems and olfactory bulbs in postmortem patients who had COVID-19 using imaging mass cytometry to understand the local immune response at a spatially resolved, high-dimensional, single-cell level and compared their immune map to non-COVID respiratory failure, multiple sclerosis, and control patients. We observed substantial immune activation in the central nervous system with pronounced neuropathology (astrocytosis, axonal damage, and blood-brain-barrier leakage) and detected viral antigen in ACE2-receptor-positive cells enriched in the vascular compartment. Microglial nodules and the perivascular compartment represented COVID-19-specific, microanatomic-immune niches with context-specific cellular interactions enriched for activated CD8 T cells. Altered brain T-cell-microglial interactions were linked to clinical measures of systemic inflammation and disturbed hemostasis. This study identifies profound neuroinflammation with activation of innate and adaptive immune cells as correlates of COVID-19 neuropathology, with implications for potential therapeutic strategies.
Topics: Blood-Brain Barrier; Brain; CD8-Positive T-Lymphocytes; COVID-19; Cell Communication; Central Nervous System; Humans; Immune Checkpoint Proteins; Inflammation; Lymphocyte Activation; Microglia; Multiple Sclerosis; Olfactory Bulb; Respiratory Insufficiency; SARS-CoV-2; Spike Glycoprotein, Coronavirus; T-Lymphocyte Subsets
PubMed: 34174183
DOI: 10.1016/j.immuni.2021.06.002 -
Cell Oct 2022In most sensory modalities, neuronal connectivity reflects behaviorally relevant stimulus features, such as spatial location, orientation, and sound frequency. By...
In most sensory modalities, neuronal connectivity reflects behaviorally relevant stimulus features, such as spatial location, orientation, and sound frequency. By contrast, the prevailing view in the olfactory cortex, based on the reconstruction of dozens of neurons, is that connectivity is random. Here, we used high-throughput sequencing-based neuroanatomical techniques to analyze the projections of 5,309 mouse olfactory bulb and 30,433 piriform cortex output neurons at single-cell resolution. Surprisingly, statistical analysis of this much larger dataset revealed that the olfactory cortex connectivity is spatially structured. Single olfactory bulb neurons targeting a particular location along the anterior-posterior axis of piriform cortex also project to matched, functionally distinct, extra-piriform targets. Moreover, single neurons from the targeted piriform locus also project to the same matched extra-piriform targets, forming triadic circuit motifs. Thus, as in other sensory modalities, olfactory information is routed at early stages of processing to functionally diverse targets in a coordinated manner.
Topics: Mice; Animals; Olfactory Pathways; Olfactory Cortex; Olfactory Bulb; Neurons; High-Throughput Nucleotide Sequencing
PubMed: 36306734
DOI: 10.1016/j.cell.2022.09.038 -
Nature Methods Oct 2019Spatial and molecular characteristics determine tissue function, yet high-resolution methods to capture both concurrently are lacking. Here, we developed high-definition...
Spatial and molecular characteristics determine tissue function, yet high-resolution methods to capture both concurrently are lacking. Here, we developed high-definition spatial transcriptomics, which captures RNA from histological tissue sections on a dense, spatially barcoded bead array. Each experiment recovers several hundred thousand transcript-coupled spatial barcodes at 2-μm resolution, as demonstrated in mouse brain and primary breast cancer. This opens the way to high-resolution spatial analysis of cells and tissues.
Topics: Animals; Breast Neoplasms; Female; Gene Expression Profiling; Humans; Mice; Olfactory Bulb; Sequence Analysis, RNA; Single-Cell Analysis; Tissue Array Analysis; Transcriptome
PubMed: 31501547
DOI: 10.1038/s41592-019-0548-y -
Cell and Tissue Research Jan 2021
Topics: Animals; Humans; Odorants; Olfactory Bulb; Olfactory Cortex; Olfactory Mucosa; Olfactory Pathways; Olfactory Perception; Receptors, Odorant; Smell
PubMed: 33447882
DOI: 10.1007/s00441-020-03389-1 -
PLoS Pathogens Jan 2021Neuropilin-1 (NRP-1), a member of a family of signaling proteins, was shown to serve as an entry factor and potentiate SARS Coronavirus 2 (SARS-CoV-2) infectivity in... (Review)
Review
Neuropilin-1 (NRP-1), a member of a family of signaling proteins, was shown to serve as an entry factor and potentiate SARS Coronavirus 2 (SARS-CoV-2) infectivity in vitro. This cell surface receptor with its disseminated expression is important in angiogenesis, tumor progression, viral entry, axonal guidance, and immune function. NRP-1 is implicated in several aspects of a SARS-CoV-2 infection including possible spread through the olfactory bulb and into the central nervous system and increased NRP-1 RNA expression in lungs of severe Coronavirus Disease 2019 (COVID-19). Up-regulation of NRP-1 protein in diabetic kidney cells hint at its importance in a population at risk of severe COVID-19. Involvement of NRP-1 in immune function is compelling, given the role of an exaggerated immune response in disease severity and deaths due to COVID-19. NRP-1 has been suggested to be an immune checkpoint of T cell memory. It is unknown whether involvement and up-regulation of NRP-1 in COVID-19 may translate into disease outcome and long-term consequences, including possible immune dysfunction. It is prudent to further research NRP-1 and its possibility of serving as a therapeutic target in SARS-CoV-2 infections. We anticipate that widespread expression, abundance in the respiratory and olfactory epithelium, and the functionalities of NRP-1 factor into the multiple systemic effects of COVID-19 and challenges we face in management of disease and potential long-term sequelae.
Topics: COVID-19; Diabetic Nephropathies; Humans; Immunologic Memory; Neuropilin-1; Olfactory Bulb; Respiratory Mucosa; SARS-CoV-2; T-Lymphocytes; Virus Internalization
PubMed: 33395426
DOI: 10.1371/journal.ppat.1009153 -
Cell Reports Dec 2023Co-transmission of multiple neurotransmitters from a single neuron increases the complexity of signaling information within defined neuronal circuits. Superficial...
Co-transmission of multiple neurotransmitters from a single neuron increases the complexity of signaling information within defined neuronal circuits. Superficial short-axon cells in the olfactory bulb release both dopamine and γ-aminobutyric acid (GABA), yet the specific targets of these neurotransmitters and their respective roles in olfaction have remained unknown. Here, we implement intersectional genetics in mice to selectively block GABA or dopamine release from superficial short-axon cells to identify their distinct cellular targets, impact on circuit function, and behavioral contribution of each neurotransmitter toward olfactory behaviors. We provide functional and anatomical evidence for divergent superficial short-axon cell signaling onto downstream neurons to shape patterns of mitral cell firing that contribute to olfactory-related behaviors.
Topics: Mice; Animals; Olfactory Bulb; Smell; Dopamine; Interneurons; gamma-Aminobutyric Acid; Neurotransmitter Agents
PubMed: 37980561
DOI: 10.1016/j.celrep.2023.113471 -
Current Opinion in Neurobiology Oct 2020Olfaction is crucial for animal survival and human well-being. The olfactory bulb is the obligatory input station for olfactory information. In contrast to the... (Review)
Review
Olfaction is crucial for animal survival and human well-being. The olfactory bulb is the obligatory input station for olfactory information. In contrast to the traditional view as a static relay station, recent evidence indicates that the olfactory bulb dynamically processes olfactory information in an experience-dependent and context-dependent manner. Here, we review recent studies on experience-dependent plasticity of the main circuit components within the olfactory bulb of rodents. We argue that the olfactory bulb plasticity allows optimal representations of behaviorally-relevant odors in the continuously changing olfactory environment.
Topics: Animals; Odorants; Olfactory Bulb; Olfactory Pathways; Smell
PubMed: 32062045
DOI: 10.1016/j.conb.2020.01.007 -
Development (Cambridge, England) Feb 2022The mammalian main olfactory bulb is a crucial processing centre for the sense of smell. The olfactory bulb forms early during development and is functional from birth.... (Review)
Review
The mammalian main olfactory bulb is a crucial processing centre for the sense of smell. The olfactory bulb forms early during development and is functional from birth. However, the olfactory system continues to mature and change throughout life as a target of constitutive adult neurogenesis. Our Review synthesises current knowledge of prenatal, postnatal and adult olfactory bulb development, focusing on the maturation, morphology, functions and interactions of its diverse constituent glutamatergic and GABAergic cell types. We highlight not only the great advances in the understanding of olfactory bulb development made in recent years, but also the gaps in our present knowledge that most urgently require addressing.
Topics: Animals; Axons; Bone Morphogenetic Proteins; Neurogenesis; Olfactory Bulb; Olfactory Receptor Neurons; Signal Transduction; Synapses
PubMed: 35147186
DOI: 10.1242/dev.200210 -
The Journal of Comparative Neurology Aug 2022Olfactory epithelium (OE) is capable of lifelong regeneration due to presence of basal progenitor cells that respond to injury or neuronal loss with increased activity....
Olfactory epithelium (OE) is capable of lifelong regeneration due to presence of basal progenitor cells that respond to injury or neuronal loss with increased activity. However, this capability diminishes with advancing age and a decrease in odor perception in older individuals is well established. To characterize changes associated with age in the peripheral olfactory system, an in-depth analysis of the OE and its neuronal projections onto the olfactory bulb (OB) as a function of age was performed. Human olfactory tissue autopsy samples from 36 subjects with an average age of 74.1 years were analyzed. Established cell type-specific antibodies were used to identify OE component cells in whole mucosal sheets and epithelial sections as well as glomeruli and periglomerular structures in OB sections. With age, a reduction in OE area occurs across the mucosa progressing in a posterior-dorsal direction. Deterioration of the olfactory system is accompanied with diminution of neuron-containing OE, mature olfactory sensory neurons (OSNs) and OB innervation. On an individual level, the neuronal density within the epithelium appears to predict synapse density within the OB. The innervation of the OB is uneven with higher density at the ventral half that decreases with age as opposed to stable innervation at the dorsal half. Respiratory metaplasia, submucosal cysts, and neuromata, were commonly identified in aged OE. The finding of respiratory metaplasia and aneuronal epithelium with reduction in global basal cells suggests a progression of stem cell quiescence as an underlying pathophysiology of age-related smell loss in humans. KEY POINTS: A gradual loss of olfactory sensory neurons with age in human olfactory epithelium is also reflected in a reduction in glomeruli within the olfactory bulb. This gradual loss of neurons and synaptic connections with age occurs in a specific, spatially inhomogeneous manner. Decreasing mitotically active olfactory epithelium basal cells may contribute to age-related neuronal decline and smell loss in humans.
Topics: Aged; Anosmia; Humans; Metaplasia; Olfactory Bulb; Olfactory Mucosa; Olfactory Receptor Neurons
PubMed: 35397118
DOI: 10.1002/cne.25325