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  1. Article: Inputs to the locus coeruleus from the periaqueductal gray and rostroventral medulla shape opioid-mediated descending pain modulation.

    Lubejko, Susan T / Livrizzi, Giulia / Patel, Janki / Yung, Jean C / Yaksh, Tony L / Banghart, Matthew R

    bioRxiv : the preprint server for biology

    2023  

    Abstract: The supraspinal descending pain modulatory system (DPMS) shapes pain perception via monoaminergic modulation of sensory information in the spinal cord. However, the role and synaptic mechanisms of descending noradrenergic signaling remain unclear. Here, ... ...

    Abstract The supraspinal descending pain modulatory system (DPMS) shapes pain perception via monoaminergic modulation of sensory information in the spinal cord. However, the role and synaptic mechanisms of descending noradrenergic signaling remain unclear. Here, we establish that noradrenergic neurons of the locus coeruleus (LC) are essential for supraspinal opioid antinociception. Unexpectedly, given prior emphasis on descending serotonergic pathways, we find that opioid antinociception is primarily driven by excitatory output from the ventrolateral periaqueductal gray (vlPAG) to the LC. Furthermore, we identify a previously unknown opioid-sensitive inhibitory input from the rostroventromedial medulla (RVM), the suppression of which disinhibits LC neurons to drive spinal noradrenergic antinociception. We also report the presence of prominent bifurcating outputs from the vlPAG to the LC and the RVM. Our findings significantly revise current models of the DPMS and establish a novel supraspinal antinociceptive pathway that may contribute to multiple forms of descending pain modulation.
    Language English
    Publishing date 2023-10-10
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.10.10.561768
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Inputs to the locus coeruleus from the periaqueductal gray and rostroventral medulla shape opioid-mediated descending pain modulation.

    Lubejko, Susan T / Livrizzi, Giulia / Buczynski, Stanley A / Patel, Janki / Yung, Jean C / Yaksh, Tony L / Banghart, Matthew R

    Science advances

    2024  Volume 10, Issue 17, Page(s) eadj9581

    Abstract: The supraspinal descending pain modulatory system (DPMS) shapes pain perception via monoaminergic modulation of sensory information in the spinal cord. However, the role and synaptic mechanisms of descending noradrenergic signaling remain unclear. Here, ... ...

    Abstract The supraspinal descending pain modulatory system (DPMS) shapes pain perception via monoaminergic modulation of sensory information in the spinal cord. However, the role and synaptic mechanisms of descending noradrenergic signaling remain unclear. Here, we establish that noradrenergic neurons of the locus coeruleus (LC) are essential for supraspinal opioid antinociception. While much previous work has emphasized the role of descending serotonergic pathways, we find that opioid antinociception is primarily driven by excitatory output from the ventrolateral periaqueductal gray (vlPAG) to the LC. Furthermore, we identify a previously unknown opioid-sensitive inhibitory input from the rostroventromedial medulla (RVM), the suppression of which disinhibits LC neurons to drive spinal noradrenergic antinociception. We describe pain-related activity throughout this circuit and report the presence of prominent bifurcating outputs from the vlPAG to the LC and the RVM. Our findings substantially revise current models of the DPMS and establish a supraspinal antinociceptive pathway that may contribute to multiple forms of descending pain modulation.
    MeSH term(s) Locus Coeruleus/metabolism ; Locus Coeruleus/drug effects ; Periaqueductal Gray/metabolism ; Periaqueductal Gray/drug effects ; Animals ; Medulla Oblongata/metabolism ; Medulla Oblongata/drug effects ; Pain/drug therapy ; Pain/metabolism ; Analgesics, Opioid/pharmacology ; Male ; Adrenergic Neurons/metabolism ; Adrenergic Neurons/drug effects ; Mice ; Neural Pathways/drug effects
    Chemical Substances Analgesics, Opioid
    Language English
    Publishing date 2024-04-26
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.adj9581
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: The role of endogenous opioid neuropeptides in neurostimulation-driven analgesia.

    Lubejko, Susan T / Graham, Robert D / Livrizzi, Giulia / Schaefer, Robert / Banghart, Matthew R / Creed, Meaghan C

    Frontiers in systems neuroscience

    2022  Volume 16, Page(s) 1044686

    Abstract: Due to the prevalence of chronic pain worldwide, there is an urgent need to improve pain management strategies. While opioid drugs have long been used to treat chronic pain, their use is severely limited by adverse effects and abuse liability. ... ...

    Abstract Due to the prevalence of chronic pain worldwide, there is an urgent need to improve pain management strategies. While opioid drugs have long been used to treat chronic pain, their use is severely limited by adverse effects and abuse liability. Neurostimulation techniques have emerged as a promising option for chronic pain that is refractory to other treatments. While different neurostimulation strategies have been applied to many neural structures implicated in pain processing, there is variability in efficacy between patients, underscoring the need to optimize neurostimulation techniques for use in pain management. This optimization requires a deeper understanding of the mechanisms underlying neurostimulation-induced pain relief. Here, we discuss the most commonly used neurostimulation techniques for treating chronic pain. We present evidence that neurostimulation-induced analgesia is in part driven by the release of endogenous opioids and that this endogenous opioid release is a common endpoint between different methods of neurostimulation. Finally, we introduce technological and clinical innovations that are being explored to optimize neurostimulation techniques for the treatment of pain, including multidisciplinary efforts between neuroscience research and clinical treatment that may refine the efficacy of neurostimulation based on its underlying mechanisms.
    Language English
    Publishing date 2022-12-14
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2453005-0
    ISSN 1662-5137
    ISSN 1662-5137
    DOI 10.3389/fnsys.2022.1044686
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: In vivo

    McClain, Shannan P / Ma, Xiang / Johnson, Desiree A / Johnson, Caroline A / Layden, Aryanna E / Yung, Jean C / Lubejko, Susan T / Livrizzi, Giulia / Jenny He, X / Zhou, Jingjing / Ventriglia, Emilya / Rizzo, Arianna / Levinstein, Marjorie / Gomez, Juan L / Bonaventura, Jordi / Michaelides, Michael / Banghart, Matthew R

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Traditional methods for site-specific drug delivery in the brain are slow, invasive, and difficult to interface with recordings of neural activity. Here, we demonstrate the feasibility and experimental advantages of : Highlights: A photoactivatable ... ...

    Abstract Traditional methods for site-specific drug delivery in the brain are slow, invasive, and difficult to interface with recordings of neural activity. Here, we demonstrate the feasibility and experimental advantages of
    Highlights: A photoactivatable opioid agonist (PhOX) and antagonist (PhNX) for
    Language English
    Publishing date 2023-02-03
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.02.02.526901
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: In vivo photopharmacology with light-activated opioid drugs.

    McClain, Shannan P / Ma, Xiang / Johnson, Desiree A / Johnson, Caroline A / Layden, Aryanna E / Yung, Jean C / Lubejko, Susan T / Livrizzi, Giulia / He, X Jenny / Zhou, Jingjing / Chang-Weinberg, Janie / Ventriglia, Emilya / Rizzo, Arianna / Levinstein, Marjorie / Gomez, Juan L / Bonaventura, Jordi / Michaelides, Michael / Banghart, Matthew R

    Neuron

    2023  Volume 111, Issue 24, Page(s) 3926–3940.e10

    Abstract: Traditional methods for site-specific drug delivery in the brain are slow, invasive, and difficult to interface with recordings of neural activity. Here, we demonstrate the feasibility and experimental advantages of in vivo photopharmacology using "caged" ...

    Abstract Traditional methods for site-specific drug delivery in the brain are slow, invasive, and difficult to interface with recordings of neural activity. Here, we demonstrate the feasibility and experimental advantages of in vivo photopharmacology using "caged" opioid drugs that are activated in the brain with light after systemic administration in an inactive form. To enable bidirectional manipulations of endogenous opioid receptors in vivo, we developed photoactivatable oxymorphone (PhOX) and photoactivatable naloxone (PhNX), photoactivatable variants of the mu opioid receptor agonist oxymorphone and the antagonist naloxone. Photoactivation of PhOX in multiple brain areas produced local changes in receptor occupancy, brain metabolic activity, neuronal calcium activity, neurochemical signaling, and multiple pain- and reward-related behaviors. Combining PhOX photoactivation with optical recording of extracellular dopamine revealed adaptations in the opioid sensitivity of mesolimbic dopamine circuitry in response to chronic morphine administration. This work establishes a general experimental framework for using in vivo photopharmacology to study the neural basis of drug action.
    MeSH term(s) Analgesics, Opioid/pharmacology ; Oxymorphone/pharmacology ; Pharmaceutical Preparations ; Dopamine/metabolism ; Naloxone/pharmacology ; Receptors, Opioid, mu/metabolism
    Chemical Substances Analgesics, Opioid ; Oxymorphone (9VXA968E0C) ; Pharmaceutical Preparations ; Dopamine (VTD58H1Z2X) ; Naloxone (36B82AMQ7N) ; Receptors, Opioid, mu
    Language English
    Publishing date 2023-10-16
    Publishing country United States
    Document type Journal Article
    ZDB-ID 808167-0
    ISSN 1097-4199 ; 0896-6273
    ISSN (online) 1097-4199
    ISSN 0896-6273
    DOI 10.1016/j.neuron.2023.09.017
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Maternal insulin resistance multigenerationally impairs synaptic plasticity and memory via gametic mechanisms.

    Fusco, Salvatore / Spinelli, Matteo / Cocco, Sara / Ripoli, Cristian / Mastrodonato, Alessia / Natale, Francesca / Rinaudo, Marco / Livrizzi, Giulia / Grassi, Claudio

    Nature communications

    2019  Volume 10, Issue 1, Page(s) 4799

    Abstract: Metabolic diseases harm brain health and cognitive functions, but whether maternal metabolic unbalance may affect brain plasticity of next generations is still unclear. Here, we demonstrate that maternal high fat diet (HFD)-dependent insulin resistance ... ...

    Abstract Metabolic diseases harm brain health and cognitive functions, but whether maternal metabolic unbalance may affect brain plasticity of next generations is still unclear. Here, we demonstrate that maternal high fat diet (HFD)-dependent insulin resistance multigenerationally impairs synaptic plasticity, learning and memory. HFD downregulates BDNF and insulin signaling in maternal tissues and epigenetically inhibits BDNF expression in both germline and hippocampus of progeny. Notably, exposure of the HFD offspring to novel enriched environment restores Bdnf epigenetic activation in the male germline and counteracts the transmission of cognitive impairment to the next generations. BDNF administration to HFD-fed mothers or preserved insulin sensitivity in HFD-fed p66Shc KO mice also prevents the intergenerational transmission of brain damage to the progeny. Collectively, our data suggest that maternal diet multigenerationally impacts on descendants' brain health via gametic mechanisms susceptible to lifestyle.
    MeSH term(s) Animals ; Brain-Derived Neurotrophic Factor/genetics ; Brain-Derived Neurotrophic Factor/metabolism ; Cyclic AMP Response Element-Binding Protein/genetics ; Cyclic AMP Response Element-Binding Protein/metabolism ; Diet, High-Fat/adverse effects ; Epigenesis, Genetic ; Female ; Forkhead Box Protein O3/metabolism ; Gene Expression Regulation ; Hippocampus/physiopathology ; Histone Deacetylase 2/metabolism ; Insulin Resistance ; Learning/physiology ; Male ; Memory/physiology ; Mice, Inbred C57BL ; Mice, Knockout ; Neuronal Plasticity/physiology ; Ovary/metabolism ; Sirtuin 2/metabolism ; Src Homology 2 Domain-Containing, Transforming Protein 1/genetics
    Chemical Substances Bdnf protein, mouse ; Brain-Derived Neurotrophic Factor ; Creb1 protein, mouse ; Cyclic AMP Response Element-Binding Protein ; Forkhead Box Protein O3 ; FoxO3 protein, mouse ; Shc1 protein, mouse ; Src Homology 2 Domain-Containing, Transforming Protein 1 ; Sirt2 protein, mouse (EC 3.5.1.-) ; Sirtuin 2 (EC 3.5.1.-) ; Hdac2 protein, mouse (EC 3.5.1.98) ; Histone Deacetylase 2 (EC 3.5.1.98)
    Language English
    Publishing date 2019-10-22
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-019-12793-3
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  7. Article ; Online: Multimodal profiling of single-cell morphology, electrophysiology, and gene expression using Patch-seq.

    Cadwell, Cathryn R / Scala, Federico / Li, Shuang / Livrizzi, Giulia / Shen, Shan / Sandberg, Rickard / Jiang, Xiaolong / Tolias, Andreas S

    Nature protocols

    2017  Volume 12, Issue 12, Page(s) 2531–2553

    Abstract: Neurons exhibit a rich diversity of morphological phenotypes, electrophysiological properties, and gene-expression patterns. Understanding how these different characteristics are interrelated at the single-cell level has been difficult because of the ... ...

    Abstract Neurons exhibit a rich diversity of morphological phenotypes, electrophysiological properties, and gene-expression patterns. Understanding how these different characteristics are interrelated at the single-cell level has been difficult because of the lack of techniques for multimodal profiling of individual cells. We recently developed Patch-seq, a technique that combines whole-cell patch-clamp recording, immunohistochemistry, and single-cell RNA-sequencing (scRNA-seq) to comprehensively profile single neurons from mouse brain slices. Here, we present a detailed step-by-step protocol, including modifications to the patching mechanics and recording procedure, reagents and recipes, procedures for immunohistochemistry, and other tips to assist researchers in obtaining high-quality morphological, electrophysiological, and transcriptomic data from single neurons. Successful implementation of Patch-seq allows researchers to explore the multidimensional phenotypic variability among neurons and to correlate gene expression with phenotype at the level of single cells. The entire procedure can be completed in ∼2 weeks through the combined efforts of a skilled electrophysiologist, molecular biologist, and biostatistician.
    MeSH term(s) Animals ; Cells, Cultured ; Electrophysiological Phenomena ; Gene Expression Profiling/methods ; Immunohistochemistry/methods ; Mice ; Neurons/cytology ; Neurons/metabolism ; Patch-Clamp Techniques/methods ; Sequence Analysis, RNA/methods ; Single-Cell Analysis/methods ; Transcriptome
    Language English
    Publishing date 2017-11-16
    Publishing country England
    Document type Journal Article
    ZDB-ID 2244966-8
    ISSN 1750-2799 ; 1754-2189
    ISSN (online) 1750-2799
    ISSN 1754-2189
    DOI 10.1038/nprot.2017.120
    Database MEDical Literature Analysis and Retrieval System OnLINE

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