scholarly journals Intrinsic braking role of descending locus coeruleus noradrenergic neurons in acute and chronic itch in mice

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Keisuke Koga ◽  
Yuto Shiraishi ◽  
Ryo Yamagata ◽  
Hidetoshi Tozaki-Saitoh ◽  
Miho Shiratori-Hayashi ◽  
...  
Keyword(s):  
Locus Coeruleus ◽  
Noradrenergic Neurons ◽  
Cell Type ◽  
Patch Clamp Recording ◽  
Peptide Receptor ◽  
Gastrin Releasing Peptide ◽  
Unpleasant Sensation ◽  
Chronic Itch ◽  
The Brain

Abstract Itch is defined as an unpleasant sensation that provokes a desire to scratch. Our understanding of neuronal circuits for itch information transmission and processing in the spinal dorsal horn (SDH) has progressively advanced following the identification of SDH neuron subsets that are crucial for scratching behavior in models of itch. However, little is known about the control of acute and chronic itch by descending signals from the brain to the SDH. In this study, using genetic approaches that enable cell-type and circuit-specific functional manipulation, we reveal an intrinsic potential of locus coeruleus (LC)-noradrenergic (NAergic) neurons that project to the SDH to control acute and chronic itch. Activation and silencing of SDH-projecting LC-NAergic neurons reduced and enhanced scratching behavior, respectively, in models of histamine-dependent and -independent acute itch. Furthermore, in a model of chronic itch associated with contact dermatitis, repetitive scratching behavior was suppressed by the activation of the descending LC-NAergic pathway and by knocking out NA transporters specific to descending LC-NAergic neurons using a CRISPR-Cas9 system. Moreover, patch-clamp recording using spinal slices showed that noradrenaline facilitated inhibitory synaptic inputs onto gastrin-releasing peptide receptor-expressing SDH neurons, a neuronal subset known to be essential for itch transmission. Our findings suggest that descending LC-NAergic signaling intrinsically controls acute and chronic itch and provide potential therapeutic strategies for the treatment of acute and chronic itch.

scholarly journals The specification of noradrenergic locus coeruleus (LC) neurones depends on bone morphogenetic proteins (BMPs)

Development ◽  
2002 ◽  
Vol 129 (4) ◽  
pp. 983-991 ◽  
Author(s):  
Astrid Vogel-Höpker ◽  
Hermann Rohrer
Keyword(s):  
Transcription Factors ◽  
Locus Coeruleus ◽  
Bone Morphogenetic Proteins ◽  
Chick Embryos ◽  
Dorsal Midline ◽  
Neural Crest Development ◽  
Roof Plate ◽  
Rhombic Lip ◽  
The Brain

The role of BMPs in the development of the major noradrenergic centre of the brain, the locus coeruleus (LC), was investigated. LC generation is reflected by initial expression of the transcription factors Phox2a and Phox2b in dorsal rhombomere1 (r1), followed by expression of dopamine-β-hydroxylase and tyrosine hydroxylase. Bmp5 is expressed in the dorsal neuroepithelium in proximity to Phox2-expressing cells. BMP inhibition in stage 10 chick embryos resulted in the lack of LC neurones or in their generation at the dorsal midline, and loss of roof plate and rhombic lip, but it did not affect neural crest development. These results reveal late essential BMP functions in the specification of dorsal neuronal phenotypes in r1, including LC neurones, and in the development of dorsal midline structures.

AB0100 Role of gastrin-releasing peptide and the rc-3095, an antagonist of gastrin-releasin peptide receptor, in experimental arthritis synovial fibroblast

2013 ◽  
Vol 72 (Suppl 3) ◽  
pp. A816.1-A816
Author(s):  
P. G. Oliveira ◽  
L. I. Filippin ◽  
M. Farinon ◽  
V. O. N. Teixeira ◽  
G. Schwartzmann ◽  
...  
Keyword(s):  
Synovial Fibroblast ◽  
Experimental Arthritis ◽  
Peptide Receptor ◽  
Gastrin Releasing Peptide

scholarly journals Role of the locus coeruleus noradrenergic neurons on the hypercapnic ventilatory response

2007 ◽  
Vol 21 (6) ◽  
Author(s):  
Luciane H. Gargaglioni ◽  
Vivian Biancardi ◽  
Kênia C. Bícego ◽  
Luiz G. S. Branco
Keyword(s):  
Locus Coeruleus ◽  
Ventilatory Response ◽  
Noradrenergic Neurons ◽  
Hypercapnic Ventilatory Response

scholarly journals ErbB4 deletion in noradrenergic neurons in the locus coeruleus induces mania-like behavior via elevated catecholamines

2018 ◽  
Author(s):  
Shu-Xia Cao ◽  
Ying Zhang ◽  
Xing-Yue Hu ◽  
Bin Hong ◽  
Peng Sun ◽  
...  
Keyword(s):  
Locus Coeruleus ◽  
Critical Role ◽  
Anxiety And Depression ◽  
Spontaneous Firing ◽  
Noradrenergic Neurons ◽  
Neuronal Function ◽  
Conditional Deletion ◽  
Manic Depressive ◽  
Deficient Mice

Dysfunction of the noradrenergic (NE) neurons is implicated in the pathogenesis of manic-depressive psychosis (MDP). ErbB4 is highly expressed in NE neurons, and its genetic variation has been linked to MDP; however, how ErbB4 regulates NE neuronal function and contributes to MDP pathogenesis is unclear. Here we find that conditional deletion of ErbB4 in locus coeruleus (LC) NE neurons increases neuronal spontaneous firing through NMDA receptor hyperfunction, and elevates catecholamines in the cerebrospinal fluid (CSF). Furthermore, ErbB4-deficient mice present mania-like behaviors, including hyperactivity, reduced anxiety and depression, and increased sucrose preference. These behaviors are completely rescued by the anti-manic drug lithium or antagonists of catecholaminergic receptors. Our study demonstrates the critical role of ErbB4 signaling in regulating LC-NE neuronal function, reinforcing the view that dysfunction of the NE system may contribute to the pathogenesis of mania-associated disorder.

scholarly journals The Norepinephrine Metabolite DOPEGAL Confers Locus Coeruleus Tau Vulnerability and Propagation via Asparagine Endopeptidase

2019 ◽  
Author(s):  
Seong Su Kang ◽  
Xia Liu ◽  
Eun Hee Ahn ◽  
Jie Xiang ◽  
Fredric P. Manfredsson ◽  
...  
Keyword(s):  
Monoamine Oxidase ◽  
Locus Coeruleus ◽  
Selective Vulnerability ◽  
Monoamine Oxidase A ◽  
Noradrenergic Neurons ◽  
Tau Pathology ◽  
Intact Cells ◽  
Tau Aggregation ◽  
The Brain

AbstractAberrant Tau inclusions in the locus coeruleus (LC) are the earliest detectable Alzheimer’s disease (AD)-like neuropathology in the human brain; however, why LC neurons are selectively vulnerable to developing early Tau pathology and degenerating later in disease and whether the LC might seed the stereotypical spread of Tau pathology to the rest of the brain remain unclear. Here we show that 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), which is produced exclusively in noradrenergic neurons by monoamine oxidase A (MAO-A) metabolism of norepinephrine (NE), activates asparagine endopeptidase (AEP) that cleaves Tau at residue N368 into aggregation- and propagation-prone forms, thereby leading to LC degeneration and the spread of Tau pathology. DOPEGAL triggers AEP-cleaved Tau aggregationin vitroand in intact cells, resulting in LC neurotoxicity and propagation of pathology to the forebrain. Thus, our findings reveal a novel molecular mechanism underlying the selective vulnerability of LC neurons in AD.

scholarly journals Enhanced aversive memory retrieval by chemogenetic activation of locus coeruleus norepinephrine neurons

2019 ◽  
Author(s):  
Ryoji Fukabori ◽  
Yoshio Iguchi ◽  
Shigeki Kato ◽  
Kazumi Takahashi ◽  
Satoshi Eifuku ◽  
...  
Keyword(s):  
Locus Coeruleus ◽  
Memory Retrieval ◽  
Adrenergic Receptors ◽  
Retrieval Process ◽  
Memory Store ◽  
Facilitative Role ◽  
Pharmacological Blockade ◽  
The Brain ◽  
Stimulation Of

AbstractThe ability to retrieve memory store in response to the environment is essential for animal behavioral adaptation. Norepinephrine (NE)-containing neurons in the brain play a key role in the modulation of synaptic plasticity underlying various processes of memory formation. However, the role of the central NE system in memory retrieval remains unclear. In this study, we developed a neural chemogenetic activation strategy using insect olfactory Ionotropic Receptors (IRs), and used it for selective stimulation of NE neurons in the locus coeruleus (LC) in transgenic mice. Ligand-induced activation of LC NE neurons resulted in enhancement of the retrieval process of conditioned taste aversion, which was mediated through at least partly adrenergic receptors in the amygdala. Pharmacological blockade of LC activity confirmed the facilitative role of these neurons in memory retrieval. Our findings indicate that the LC-amygdalar pathway is required and sufficient for enhancing the recall of taste associative memory.

scholarly journals Optogenetic stimulation of long-range inputs and functional characterization of connectivity in patch-clamp recordings in mouse brain slices

2018 ◽  
Author(s):  
Louis Richevaux ◽  
Louise Schenberg ◽  
Mathieu Beraneck ◽  
Desdemona Fricker
Keyword(s):  
Patch Clamp ◽  
Long Range ◽  
Brain Slices ◽  
Cell Type ◽  
Patch Clamp Recording ◽  
Axon Terminals ◽  
Optogenetic Stimulation ◽  
Cell Type Specific ◽  
The Brain ◽  
Stimulation Of

Knowledge of cell type specific synaptic connectivity is a crucial prerequisite for understanding brain wide neuronal circuits. The functional investigation of long-range connections requires targeted recordings of single neurons combined with the specific stimulation of identified distant inputs. This is often difficult to achieve with conventional, electrical stimulation techniques, because axons from converging upstream brain areas may intermingle in the target region. The stereotaxic targeting of a specific brain region for virus-mediated expression of light sensitive ion channels allows to selectively stimulate axons coming from that region with light. Intracerebral stereotaxic injections can be used in well-delimited structures, such as the anterodorsal thalamic nuclei, and also in other subcortical or cortical areas throughout the brain. Here we describe a set of techniques for precise stereotaxic injection of viral vectors expressing channelrhodopsin in the anterodorsal thalamus, followed by photostimulation of their axon terminals in hippocampal slices. In combination with whole-cell patch clamp recording from a postsynaptically connected presubicular neuron, photostimulation of thalamic axons allows the detection of functional synaptic connections, their pharmacological characterization, and the evaluation of their strength in the brain slice preparation. We demonstrate that axons originating in the anterodorsal thalamus ramify densely in presubicular layers 1 and 3. The photostimulation of Chronos expressing thalamic axon terminals in presubiculum initiates short latency postsynaptic responses in a presubicular layer3 neuron, indicating a monosynaptic connection. In addition, biocytin filling of the recorded neuron and posthoc revelation confirms the layer localization and pyramidal morphology of the postsynaptic neuron. Taken together, the optogenetic stimulation of long-range inputs in ex vivo brain slices is a useful method to determine the cell-type specific functional connectivity from distant brain regions.

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