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Physiology (Bethesda, Md.) Nov 2020Opioids depress minute ventilation primarily by reducing respiratory rate. This results from direct effects on the preBötzinger Complex as well as from depression of... (Review)
Review
Opioids depress minute ventilation primarily by reducing respiratory rate. This results from direct effects on the preBötzinger Complex as well as from depression of the Parabrachial/Kölliker-Fuse Complex, which provides excitatory drive to preBötzinger Complex neurons mediating respiratory phase-switch. Opioids also depress awake drive from the forebrain and chemodrive.
Topics: Analgesics, Opioid; Animals; Humans; Neurons; Respiratory Center; Respiratory Insufficiency
PubMed: 33052772
DOI: 10.1152/physiol.00015.2020 -
Acta Dermato-venereologica Jan 2020Basic mechanisms and pathways of itch signaling are reviewed, with an emphasis on the progress to date as well as remaining challenges in translating current knowledge... (Review)
Review
Basic mechanisms and pathways of itch signaling are reviewed, with an emphasis on the progress to date as well as remaining challenges in translating current knowledge to the clinical treatment of chronic itch. Recent studies reveal 3 subsets of pruriceptive sensory neurons highly expressing itch-related genes. Their fibers project into the spinal cord to activate neurons expressing gastrin releasing peptide (GRP) and its receptor (GRPR), which connect to neurons that express the substance P (NK-1) receptor and project to the parabrachial nucleus and thalamus. Spinal inhibitory interneurons release GABA, glycine and dynorphin to modulate segmental itch transmission. However, near-ly all pruriceptive neurons also respond to algogens such as capsaicin. Alternative theories of itch-pain discrimination, such as intensity or spatial contrast, are based on the observation that focal stimulation of nociceptive nerve endings elicits itch while more wide-spread stimulation elicits pain. These findings cloud the issue of a labeled line for itch- a long-debated but currently unresolved challenge. In higher primates there is a dichotomy of histaminergic and non-histaminergic itch-signaling pathways which is less demarcated in rodents, suggesting species differences. A cardinal symptom of chronic itch is alloknesis, i.e., mechanical or touch-evoked itch. Recent evidence indicates that low-threshold mechanosensory afferents can access the spinal itch pathway, but are normally kept in check by inhibitory interneurons expressing neuropeptide Y (NPY). In chronic itch, NPY-mediated inhibition is reduced, allowing touch to excite itch-signaling pathways. These recent advances provide novel targets for development of therapeutic strategies to relieve chronic itch.
Topics: Animals; Antipruritics; Biomedical Research; Humans; Pruritus; Signal Transduction; Skin
PubMed: 31940043
DOI: 10.2340/00015555-3343 -
The Journal of Neuroscience : the... Jul 2023The amygdala plays a key role in the processing of itch and pain signals as well as emotion. A previous study revealed that the central nucleus of the amygdala...
The amygdala plays a key role in the processing of itch and pain signals as well as emotion. A previous study revealed that the central nucleus of the amygdala (CeA)-parabrachial nucleus (PBN) pathway is involved in pain regulation. The same pathway might also control itch. To test this possibility, prodynorphin (Pdyn)-Cre mice were used to optogenetically manipulate Pdyn CeA-to-PBN projections. We found that optogenetic stimulation of Pdyn amygdala neurons or Pdyn CeA-to-PBN projections inhibited histamine-evoked and chloroquine-evoked scratching. The number of Fos-positive neurons in the PBN increased following intradermal injection of chloroquine. Optogenetic stimulation of Pdyn CeA-to-PBN projections suppressed the increase in Fos expression in the PBN. Optogenetic stimulation of Pdyn CeA-to-PBN projections increased thermal and mechanical thresholds without affecting anxiety-like behavior. These results highlight the importance of dynorphinergic projections from the central amygdala to the parabrachial nucleus in the regulation of itch signaling. The central nucleus of the amygdala (CeA)-parabrachial nucleus (PBN) pathway regulates pain signaling. Using prodynorphin (Pdyn)-cre mice, we investigated the role of Pdyn CeA-to-PBN projections in itch. Optogenetic stimulation of Pdyn CeA-to-PBN projections inhibited pruritogen-evoked scratching and neuronal activity (c-Fos expression) in the PBN. Together, dynorphinergic projections from the central amygdala to the parabrachial nucleus are important for regulating itch information.
Topics: Mice; Animals; Parabrachial Nucleus; Central Amygdaloid Nucleus; Pain; Neurons; Pruritus; Chloroquine
PubMed: 37399333
DOI: 10.1523/JNEUROSCI.0726-23.2023 -
The Journal of Comparative Neurology Jul 2022Diverse neurons in the parabrachial nucleus (PB) communicate with widespread brain regions. Despite evidence linking them to a variety of homeostatic functions, it...
Diverse neurons in the parabrachial nucleus (PB) communicate with widespread brain regions. Despite evidence linking them to a variety of homeostatic functions, it remains difficult to determine which PB neurons influence which functions because their subpopulations intermingle extensively. An improved framework for identifying these intermingled subpopulations would help advance our understanding of neural circuit functions linked to this region. Here, we present the foundation of a developmental-genetic ontology that classifies PB neurons based on their intrinsic, molecular features. By combining transcription factor labeling with Cre fate-mapping, we find that the PB is a blend of two, developmentally distinct macropopulations of glutamatergic neurons. Neurons in the first macropopulation express Lmx1b (and, to a lesser extent, Lmx1a) and are mutually exclusive with those in a second macropopulation, which derive from precursors expressing Atoh1. This second, Atoh1-derived macropopulation includes many Foxp2-expressing neurons, but Foxp2 also identifies a subset of Lmx1b-expressing neurons in the Kölliker-Fuse nucleus (KF) and a population of GABAergic neurons ventrolateral to the PB ("caudal KF"). Immediately ventral to the PB, Phox2b-expressing glutamatergic neurons (some coexpressing Lmx1b) occupy the KF, supratrigeminal nucleus, and reticular formation. We show that this molecular framework organizes subsidiary patterns of adult gene expression (including Satb2, Calca, Grp, and Pdyn) and predicts output projections to the amygdala (Lmx1b), hypothalamus (Atoh1), and hindbrain (Phox2b/Lmx1b). Using this molecular ontology to organize, interpret, and communicate PB-related information could accelerate the translation of experimental findings from animal models to human patients.
Topics: Animals; Brain; GABAergic Neurons; Humans; Hypothalamus; Kolliker-Fuse Nucleus; Parabrachial Nucleus; Pons; Transcription Factors
PubMed: 35134251
DOI: 10.1002/cne.25307 -
Frontiers in Neural Circuits 2022
Topics: Humans; Neurons; Pain
PubMed: 36034336
DOI: 10.3389/fncir.2022.977404 -
Frontiers in Physiology 2014The lateral parabrachial nucleus (LPBN) is located in an anatomical position that enables it to perform a critical role in relaying signals related to the regulation of... (Review)
Review
The lateral parabrachial nucleus (LPBN) is located in an anatomical position that enables it to perform a critical role in relaying signals related to the regulation of fluid and electrolyte intake and cardiovascular function from the brainstem to the forebrain. Early neuroanatomical studies have described the topographic organization of blood pressure sensitive neurons and functional studies have demonstrated a major role for the LPBN in regulating cardiovascular function, including blood pressure, in response to hemorrhages, and hypovolemia. In addition, inactivation of the LPBN induces overdrinking of water in response to a range of dipsogenic treatments primarily, but not exclusively, those associated with endogenous centrally acting angiotensin II. Moreover, treatments that typically cause water intake stimulate salt intake under some circumstances particularly when serotonin receptors in the LPBN are blocked. This review explores the expanding body of evidence that underlies the complex neural network within the LPBN influencing salt appetite, thirst and the regulation of blood pressure. Importantly understanding the interactions among neurons in the LPBN that affect fluid balance and cardiovascular control may be critical to unraveling the mechanisms responsible for hypertension.
PubMed: 25477821
DOI: 10.3389/fphys.2014.00436 -
ELife Mar 2023Defensive behaviors are critical for animal's survival. Both the paraventricular nucleus of the hypothalamus (PVN) and the parabrachial nucleus (PBN) have been shown to...
Defensive behaviors are critical for animal's survival. Both the paraventricular nucleus of the hypothalamus (PVN) and the parabrachial nucleus (PBN) have been shown to be involved in defensive behaviors. However, whether there are direct connections between them to mediate defensive behaviors remains unclear. Here, by retrograde and anterograde tracing, we uncover that cholecystokinin (CCK)-expressing neurons in the lateral PBN (LPB) directly project to the PVN. By in vivo fiber photometry recording, we find that LPB neurons actively respond to various threat stimuli. Selective photoactivation of LPB neurons promotes aversion and defensive behaviors. Conversely, photoinhibition of LPB neurons attenuates rat or looming stimuli-induced flight responses. Optogenetic activation of LPB axon terminals within the PVN or PVN glutamatergic neurons promotes defensive behaviors. Whereas chemogenetic and pharmacological inhibition of local PVN neurons prevent LPB-PVN pathway activation-driven flight responses. These data suggest that LPB neurons recruit downstream PVN neurons to actively engage in flight responses. Our study identifies a previously unrecognized role for the LPB-PVN pathway in controlling defensive behaviors.
Topics: Rats; Animals; Hypothalamus; Paraventricular Hypothalamic Nucleus; Cholecystokinin; Neurons; Parabrachial Nucleus
PubMed: 36930206
DOI: 10.7554/eLife.85450 -
Nature Communications Dec 2022The basal ganglia including the subthalamic nucleus (STN) and substantia nigra pars reticulata (SNr) are involved in pain-related responses, but how they regulate pain...
The basal ganglia including the subthalamic nucleus (STN) and substantia nigra pars reticulata (SNr) are involved in pain-related responses, but how they regulate pain processing remains unknown. Here, we identify a pathway, consisting of GABAergic neurons in the SNr (SNr) and glutamatergic neurons in the STN (STN) and the lateral parabrachial nucleus (LPB), that modulates acute and persistent pain states in both male and female mice. The activity of STN neurons was enhanced in acute and persistent pain states. This enhancement was accompanied by hypoactivity in SNr neurons and strengthening of the STN-LPB glutamatergic projection. Reversing the dysfunction in the SNr-STN-LPB pathway attenuated activity of LPB neurons and mitigated pain-like behaviors. Therefore, the SNr-STN-LPB pathway regulates pathological pain and is a potential target for pain management.
Topics: Male; Female; Mice; Animals; Substantia Nigra; Electric Stimulation; GABAergic Neurons; gamma-Aminobutyric Acid; Pain
PubMed: 36522327
DOI: 10.1038/s41467-022-35474-0 -
BioRxiv : the Preprint Server For... Jan 2023In addition to its canonical function in protecting from pathogens, the immune system can also promote behavioural alterations . The scope and mechanisms of behavioural...
In addition to its canonical function in protecting from pathogens, the immune system can also promote behavioural alterations . The scope and mechanisms of behavioural modifications by the immune system are not yet well understood. Using a mouse food allergy model, here we show that allergic sensitization drives antigen-specific behavioural aversion. Allergen ingestion activates brain areas involved in the response to aversive stimuli, including the nucleus of tractus solitarius, parabrachial nucleus, and central amygdala. Food aversion requires IgE antibodies and mast cells but precedes the development of gut allergic inflammation. The ability of allergen-specific IgE and mast cells to promote aversion requires leukotrienes and growth and differentiation factor 15 (GDF15). In addition to allergen-induced aversion, we find that lipopolysaccharide-induced inflammation also resulted in IgE-dependent aversive behaviour. These findings thus point to antigen-specific behavioural modifications that likely evolved to promote niche selection to avoid unfavourable environments.
PubMed: 36712030
DOI: 10.1101/2023.01.19.524823 -
Journal of Neurophysiology Feb 2023The parabrachial nucleus (PB) in the upper brainstem receives interoceptive information and sends a massive output projection directly to the cerebral cortex. Its...
The parabrachial nucleus (PB) in the upper brainstem receives interoceptive information and sends a massive output projection directly to the cerebral cortex. Its glutamatergic axons primarily target the midinsular cortex, and we have proposed that this PB-insular projection promotes arousal. Here, we test whether stimulating this projection causes wakefulness. We combined optogenetics and video-electroencephalography (vEEG) in mice to test this hypothesis by stimulating PB axons in the insular cortex. Stimulating this projection did not alter the cortical EEG or awaken mice. Also, despite a tendency toward aversion, PB-insular stimulation did not significantly alter real-time place preference (RTPP). These results are not consistent with the hypothesis that the direct PB-insular projection is part of the ascending arousal system. A brainstem region critical for wakefulness overlaps the medial parabrachial nucleus (PB) and has functional and direct axonal connectivity with the insular cortex. In this study, we hypothesized that this direct projection from the PB to the insular cortex promotes arousal. However, photostimulating PB axons in the insular cortex did not alter the cortical EEG or awaken mice. This information constrains the possible circuit connections through which brainstem neurons may sustain arousal.
Topics: Mice; Animals; Cerebral Cortex; Brain Stem; Electroencephalography; Arousal; Wakefulness
PubMed: 36542422
DOI: 10.1152/jn.00318.2022