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  1. Article ; Online: Layer-specific mitochondrial diversity across hippocampal CA2 dendrites.

    Pannoni, Katy E / Gil, Daniela / Cawley, Mikel L / Alsalman, Mayd M / Campbell, Logan A / Farris, Shannon

    Hippocampus

    2023  Volume 33, Issue 3, Page(s) 182–196

    Abstract: CA2 is an understudied subregion of the hippocampus that is critical for social memory. Previous studies identified multiple components of the mitochondrial calcium uniporter (MCU) complex as selectively enriched in CA2. The MCU complex regulates calcium ...

    Abstract CA2 is an understudied subregion of the hippocampus that is critical for social memory. Previous studies identified multiple components of the mitochondrial calcium uniporter (MCU) complex as selectively enriched in CA2. The MCU complex regulates calcium entry into mitochondria, which in turn regulates mitochondrial transport and localization to active synapses. We found that MCU is strikingly enriched in CA2 distal apical dendrites, precisely where CA2 neurons receive entorhinal cortical input carrying social information. Furthermore, MCU-enriched mitochondria in CA2 distal dendrites are larger compared to mitochondria in CA2 proximal apical dendrites and neighboring CA1 apical dendrites, which was confirmed in CA2 with genetically labeled mitochondria and electron microscopy. MCU overexpression in neighboring CA1 led to a preferential localization of MCU in the proximal dendrites of CA1 compared to the distal dendrites, an effect not seen in CA2. Our findings demonstrate that mitochondria are molecularly and structurally diverse across hippocampal cell types and circuits, and suggest that MCU can be differentially localized within dendrites, possibly to meet local energy demands.
    MeSH term(s) Hippocampus/metabolism ; Mitochondria/metabolism ; Neurons/metabolism ; Dendrites/physiology ; Synapses/physiology ; Calcium/metabolism
    Chemical Substances Calcium (SY7Q814VUP)
    Language English
    Publishing date 2023-02-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1074352-2
    ISSN 1098-1063 ; 1050-9631
    ISSN (online) 1098-1063
    ISSN 1050-9631
    DOI 10.1002/hipo.23512
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  2. Article: MCU-enriched dendritic mitochondria regulate plasticity in distinct hippocampal circuits.

    Pannoni, Katy E / Fischer, Quentin S / Tarannum, Renesa / Cawley, Mikel L / Alsalman, Mayd M / Acosta, Nicole / Ezigbo, Chisom / Gil, Daniela V / Campbell, Logan A / Farris, Shannon

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Mitochondria are dynamic organelles that are morphologically and functionally diverse across cell types and subcellular compartments in order to meet unique energy demands. Mitochondrial dysfunction has been implicated in a wide variety of neurological ... ...

    Abstract Mitochondria are dynamic organelles that are morphologically and functionally diverse across cell types and subcellular compartments in order to meet unique energy demands. Mitochondrial dysfunction has been implicated in a wide variety of neurological disorders, including psychiatric disorders like schizophrenia and bipolar disorder. Despite it being well known that mitochondria are essential for synaptic transmission and synaptic plasticity, the mechanisms regulating mitochondria in support of normal synapse function are incompletely understood. The mitochondrial calcium uniporter (MCU) regulates calcium entry into the mitochondria, which in turn regulates the bioenergetics and distribution of mitochondria to active synapses. Evidence suggests that calcium influx via MCU couples neuronal activity to mitochondrial metabolism and ATP production, which would allow neurons to rapidly adapt to changing energy demands. Intriguingly, MCU is uniquely enriched in hippocampal CA2 distal dendrites relative to neighboring hippocampal CA1 or CA3 distal dendrites, however, the functional significance of this enrichment is not clear. Synapses from the entorhinal cortex layer II (ECII) onto CA2 distal dendrites readily express long term potentiation (LTP), unlike the LTP-resistant synapses from CA3 onto CA2 proximal dendrites, but the mechanisms underlying these different plasticity profiles are unknown. We hypothesized that enrichment of MCU near ECII-CA2 synapses promotes LTP in an otherwise plasticity-restricted cell type. Using a CA2-specific MCU knockout (cKO) mouse, we found that MCU is required for LTP at distal dendrite synapses but does not affect the lack of LTP at proximal dendrite synapses. Loss of LTP at ECII-CA2 synapses correlated with a trend for decreased spine density in CA2 distal dendrites of cKO mice compared to control (CTL) mice, which was predominantly seen in immature spines. Moreover, mitochondria were significantly smaller and more numerous across all dendritic layers of CA2 in cKO mice compared to CTL mice, suggesting an overall increase in mitochondrial fragmentation. Fragmented mitochondria might have functional changes, such as altered ATP production, that might explain a deficit in synaptic plasticity. Collectively, our data reveal that MCU regulates layer-specific forms of plasticity in CA2 dendrites, potentially by maintaining proper mitochondria morphology and distribution within dendrites. Differences in MCU expression across different cell types and circuits might be a general mechanism to tune the sensitivity of mitochondria to cytoplasmic calcium levels to power synaptic plasticity.
    Language English
    Publishing date 2024-04-03
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.11.10.566606
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Protein-retention expansion microscopy for visualizing subcellular organelles in fixed brain tissue.

    Campbell, Logan A / Pannoni, Katy E / Savory, Niesha A / Lal, Dinesh / Farris, Shannon

    Journal of neuroscience methods

    2021  Volume 361, Page(s) 109285

    Abstract: Background: Protein expansion microscopy (proExM) is a powerful technique that crosslinks proteins to a swellable hydrogel to physically expand and optically clear biological samples. The resulting increased resolution (~70 nm) and physical separation ... ...

    Abstract Background: Protein expansion microscopy (proExM) is a powerful technique that crosslinks proteins to a swellable hydrogel to physically expand and optically clear biological samples. The resulting increased resolution (~70 nm) and physical separation of labeled proteins make it an attractive tool for studying the localization of subcellular organelles in densely packed tissues, such as the brain. However, the digestion and expansion process greatly reduce fluorescence signals making it necessary to optimize ExM conditions per sample for specific end goals.
    New method: Here we compare the staining and digestion conditions of existing proExM workflows to identify the optimal protocol for visualizing subcellular organelles (mitochondria and the Golgi apparatus) within reporter-labeled neurons in fixed mouse brain tissue.
    Results: We found that immunostaining before proExM and using a proteinase K based digestion for 8 h consistently resulted in robust fluorescence retention for immunolabeled subcellular organelles and genetically-encoded reporters.
    Comparison with existing methods: With these methods, we more accurately quantified mitochondria size and number and better visualized Golgi ultrastructure in individual CA2 neurons in the mouse hippocampus.
    Conclusions: This organelle optimized proExM protocol will be broadly useful for investigators interested in visualizing the spatial distribution of immunolabeled subcellular organelles in various reporter mouse lines, reducing effort, time and resources on the optimization process.
    MeSH term(s) Animals ; Brain ; Mice ; Microscopy, Fluorescence ; Mitochondria ; Organelles/metabolism ; Staining and Labeling
    Language English
    Publishing date 2021-07-07
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 282721-9
    ISSN 1872-678X ; 0165-0270
    ISSN (online) 1872-678X
    ISSN 0165-0270
    DOI 10.1016/j.jneumeth.2021.109285
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    Zs.A 1486: Show issues Location:
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  4. Article ; Online: Model of severe malaria in young mice suggests unique response of CD4 T cells.

    Smith, Margaret R / Gbedande, Komi / Johnson, Corey M / Campbell, Logan A / Onjiko, Robert S / Domingo, Nadia D / Opata, Michael M

    Parasite immunology

    2022  Volume 44, Issue 12, Page(s) e12952

    Abstract: Severe malaria occurs most in young children but is poorly understood due to the absence of a developmentally-equivalent rodent model to study the pathogenesis of the disease. Though functional and quantitative deficiencies in innate response and a ... ...

    Abstract Severe malaria occurs most in young children but is poorly understood due to the absence of a developmentally-equivalent rodent model to study the pathogenesis of the disease. Though functional and quantitative deficiencies in innate response and a biased T helper 1 (Th1) response are reported in newborn pups, there is little information available about this intermediate stage of the adaptive immune system in murine neonates. To fill this gap in knowledge, we have developed a mouse model of severe malaria in young mice using 15-day old mice (pups) infected with Plasmodium chabaudi. We observe similar parasite growth pattern in pups and adults, with a 60% mortality and a decrease in the growth rate of the surviving young mice. Using a battery of behavioral assays, we observed neurological symptoms in pups that do not occur in infected wildtype adults. CD4
    MeSH term(s) Animals ; Mice ; CD4-Positive T-Lymphocytes/immunology ; Malaria/complications ; Malaria/immunology ; Mice, Inbred C57BL ; Plasmodium chabaudi ; Th1 Cells/immunology ; Disease Models, Animal ; Nervous System Diseases/etiology
    Language English
    Publishing date 2022-10-04
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 424444-8
    ISSN 1365-3024 ; 0141-9838
    ISSN (online) 1365-3024
    ISSN 0141-9838
    DOI 10.1111/pim.12952
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: A histone methylation-MAPK signaling axis drives durable epithelial-mesenchymal transition in hypoxic pancreatic cancer.

    Brown, Brooke A / Myers, Paul J / Adair, Sara J / Pitarresi, Jason R / Sah-Teli, Shiv K / Campbell, Logan A / Hart, William S / Barbeau, Michelle C / Leong, Kelsey / Seyler, Nicholas / Kane, William / Lee, Kyoung Eun / Stelow, Edward / Jones, Marieke / Simon, M Celeste / Koivunen, Peppi / Bauer, Todd W / Stanger, Ben Z / Lazzara, Matthew J

    Cancer research

    2024  

    Abstract: The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) plays a key role in tumor progression and response to therapy. The dense PDAC stroma causes hypovascularity, which leads to hypoxia. Here, we showed that hypoxia drives long-lasting ... ...

    Abstract The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) plays a key role in tumor progression and response to therapy. The dense PDAC stroma causes hypovascularity, which leads to hypoxia. Here, we showed that hypoxia drives long-lasting epithelial-mesenchymal transition (EMT) in PDAC primarily through a positive-feedback histone methylation-MAPK signaling axis. Transformed cells preferentially underwent EMT in hypoxic tumor regions in multiple model systems. Hypoxia drove a cell-autonomous EMT in PDAC cells which, unlike EMT in response to growth factors, could last for weeks. Furthermore, hypoxia reduced histone demethylase KDM2A activity, suppressed PP2 family phosphatase expression, and activated MAPKs to post-translationally stabilize histone methyltransferase NSD2, leading to an H3K36me2-dependent EMT in which hypoxia-inducible factors played only a supporting role. Hypoxia-driven EMT could be antagonized in vivo by combinations of MAPK inhibitors. Collectively, these results suggest hypoxia promotes durable EMT in PDAC by inducing a histone methylation-MAPK axis that can be effectively targeted with multi-drug therapies, providing a potential strategy for overcoming chemoresistance.
    Language English
    Publishing date 2024-03-12
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-22-2945
    Database MEDical Literature Analysis and Retrieval System OnLINE

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