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Regulation of vagally-evoked respiratory responses by the lateral parabrachial nucleus in the mouse.Respiratory Physiology & Neurobiology Oct 2023Vagal sensory inputs to the brainstem can alter breathing through the modulation of pontomedullary respiratory circuits. In this study, we set out to investigate the...
Vagal sensory inputs to the brainstem can alter breathing through the modulation of pontomedullary respiratory circuits. In this study, we set out to investigate the localised effects of modulating lateral parabrachial nucleus (LPB) activity on vagally-evoked changes in breathing pattern. In isoflurane-anaesthetised and instrumented mice, electrical stimulation of the vagus nerve (eVNS) produced stimulation frequency-dependent changes in diaphragm electromyograph (dEMG) activity with an evoked tachypnoea and apnoea at low and high stimulation frequencies, respectively. Muscimol microinjections into the LPB significantly attenuated eVNS-evoked respiratory rate responses. Notably, muscimol injections reaching the caudal LPB, previously unrecognised for respiratory modulation, potently modulated eVNS-evoked apnoea, whilst muscimol injections reaching the intermediate LPB selectively modulated the eVNS-evoked tachypnoea. The effects of muscimol on eVNS-evoked breathing rate changes occurred without altering basal eupneic breathing. These results highlight novel roles for the LPB in regulating vagally-evoked respiratory reflexes.
Topics: Animals; Mice; Respiratory Rate; Apnea; Muscimol; Parabrachial Nucleus; Tachypnea
PubMed: 37597796
DOI: 10.1016/j.resp.2023.104141 -
Biology Feb 2024In humans, speech is a complex process that requires the coordinated involvement of various components of the phonatory system, which are monitored by the central... (Review)
Review
In humans, speech is a complex process that requires the coordinated involvement of various components of the phonatory system, which are monitored by the central nervous system. The larynx in particular plays a crucial role, as it enables the vocal folds to meet and converts the exhaled air from our lungs into audible sounds. Voice production requires precise and sustained exhalation, which generates an air pressure/flow that creates the pressure in the glottis required for voice production. Voluntary vocal production begins in the laryngeal motor cortex (LMC), a structure found in all mammals, although the specific location in the cortex varies in humans. The LMC interfaces with various structures of the central autonomic network associated with cardiorespiratory regulation to allow the perfect coordination between breathing and vocalization. The main subcortical structure involved in this relationship is the mesencephalic periaqueductal grey matter (PAG). The PAG is the perfect link to the autonomic pontomedullary structures such as the parabrachial complex (PBc), the Kölliker-Fuse nucleus (KF), the nucleus tractus solitarius (NTS), and the nucleus retroambiguus (nRA), which modulate cardiovascular autonomic function activity in the vasomotor centers and respiratory activity at the level of the generators of the laryngeal-respiratory motor patterns that are essential for vocalization. These cores of autonomic structures are not only involved in the generation and modulation of cardiorespiratory responses to various stressors but also help to shape the cardiorespiratory motor patterns that are important for vocal production. Clinical studies show increased activity in the central circuits responsible for vocalization in certain speech disorders, such as spasmodic dysphonia because of laryngeal dystonia.
PubMed: 38392336
DOI: 10.3390/biology13020118 -
BioRxiv : the Preprint Server For... Nov 2023Itch is a protective sensation that drives scratching. Although specific cell types have been proposed to underlie itch, the neural circuit basis for itch remains...
Itch is a protective sensation that drives scratching. Although specific cell types have been proposed to underlie itch, the neural circuit basis for itch remains unclear. Here, we used two-photon Ca imaging of the dorsal horn to visualize the neuronal populations that are activated by itch-inducing agents. We identify a convergent population of spinal neurons that is defined by the expression of GRPR. Moreover, we discover that itch is conveyed to the brain via GRPR-expressing spinal output neurons that target the lateral parabrachial nucleus. Further, we show that nalfurafine, a clinically effective kappa opioid receptor agonist, relieves itch by inhibiting GRPR spinoparabrachial neurons. Finally, we demonstrate that a subset of GRPR spinal neurons show persistent, cell-intrinsic Ca oscillations. These experiments provide the first population-level view of the spinal neurons that respond to pruritic stimuli, pinpoint the output neurons that convey itch to the brain, and identify the cellular target of kappa opioid receptor agonists for the inhibition of itch.
PubMed: 37873278
DOI: 10.1101/2023.09.29.560205 -
Cell Reports Apr 2024The motivation to eat is suppressed by satiety and aversive stimuli such as nausea. The neural circuit mechanisms of appetite suppression by nausea are not well...
The motivation to eat is suppressed by satiety and aversive stimuli such as nausea. The neural circuit mechanisms of appetite suppression by nausea are not well understood. Pkcδ neurons in the lateral subdivision of the central amygdala (CeA) suppress feeding in response to satiety signals and nausea. Here, we characterized neurons enriched in the medial subdivision (CeM) of the CeA marked by expression of Dlk1. CeA neurons are activated by nausea, but not satiety, and specifically suppress feeding induced by nausea. Artificial activation of CeA neurons suppresses drinking and social interactions, suggesting a broader function in attenuating motivational behavior. CeA neurons form projections to many brain regions and exert their anorexigenic activity by inhibition of neurons of the parabrachial nucleus. CeA neurons are inhibited by appetitive CeA neurons, but also receive long-range monosynaptic inputs from multiple brain regions. Our results illustrate a CeA circuit that regulates nausea-induced feeding suppression.
Topics: Animals; Neurons; Central Amygdaloid Nucleus; Calcium-Binding Proteins; Mice; Feeding Behavior; Nausea; Male; Mice, Inbred C57BL; Intercellular Signaling Peptides and Proteins
PubMed: 38551964
DOI: 10.1016/j.celrep.2024.113990 -
BioRxiv : the Preprint Server For... Jun 2024Osteoarthritis (OA) represents a significant pain challenge globally, as current treatments are limited and come with substantial and adverse side effects. Voltage-gated...
Osteoarthritis (OA) represents a significant pain challenge globally, as current treatments are limited and come with substantial and adverse side effects. Voltage-gated calcium channels have proved to be pharmacologically effective targets, with multiple FDA-approved Ca2.2 modulators available for the treatment of pain. Although effective, drugs targeting Ca2.2 are complicated by the same obstacles facing other pain therapeutics-invasive routes of administration, narrow therapeutic windows, side effects, and addiction potential. We have identified a key regulator of Ca2.2 channels, collapsing response mediator protein 2 (CRMP2), that allows us to indirectly regulate Ca2.2 expression and function. We developed a peptidomimetic modulator of CRMP2, CBD3063, that effectively reverses neuropathic and inflammatory pain without negative side effects by reducing membrane expression of Ca2.2. Using a rodent model of OA, we demonstrate the intraperitoneal administration of CBD3063 alleviates both evoked and non-evoked behavioral hallmarks of OA pain. Further, we reveal that CBD3063 reduces OA-induced increased neural activity in the parabrachial nucleus, a key supraspinal site modulating the pain experience. Together, these studies suggest CBD3063 is an effective analgesic for OA pain.
PubMed: 38895294
DOI: 10.1101/2024.06.05.596514 -
ENeuro Feb 2024The transition from acute to chronic pain involves maladaptive plasticity in central nociceptive pathways. Growing evidence suggests that changes within the parabrachial...
The transition from acute to chronic pain involves maladaptive plasticity in central nociceptive pathways. Growing evidence suggests that changes within the parabrachial nucleus (PBN), an important component of the spino-parabrachio-amygdaloid pain pathway, are key contributors to the development and maintenance of chronic pain. In animal models of chronic pain, PBN neurons become sensitive to normally innocuous stimuli and responses to noxious stimuli become amplified and more often produce after-discharges that outlast the stimulus. Using slice electrophysiology and two mouse models of neuropathic pain, sciatic cuff and chronic constriction of the infraorbital nerve (CCI-ION), we find that changes in the firing properties of PBN neurons and a shift in inhibitory synaptic transmission may underlie this phenomenon. Compared to PBN neurons from shams, a larger proportion of PBN neurons from mice with a sciatic cuff were spontaneously active at rest, and these same neurons showed increased excitability relative to shams. In contrast, quiescent PBN neurons from cuff mice were less excitable than those from shams. Despite an increase in excitability in a subset of PBN neurons, the presence of after-discharges frequently observed were largely absent in both injury models. However, GABA-mediated presynaptic inhibition of GABAergic terminals is enhanced in PBN neurons after CCI-ION. These data suggest that the amplified activity of PBN neurons observed in rodent models of chronic pain arise through a combination of changes in firing properties and network excitability. Hyperactivity of neurons in the parabrachial nucleus (PBN) is causally linked to exaggerated pain behaviors in rodent models of chronic pain but the underlying mechanisms remain unknown. Using two mouse models of neuropathic pain, we show the intrinsic properties of PBN neurons are largely unaltered following injury. However, subsets of PBN neurons become more excitable and GABA receptor mediated suppression of inhibitory terminals is enhanced after injury. Thus, shifts in network excitability may be a contributing factor in injury induced potentiation of PBN activity.
PubMed: 38331576
DOI: 10.1523/ENEURO.0416-23.2024 -
Cell Reports Jan 2024Thirst and salt appetite are temporarily suppressed after water and salt ingestion, respectively, before absorption; however, the underlying neural mechanisms remain...
Thirst and salt appetite are temporarily suppressed after water and salt ingestion, respectively, before absorption; however, the underlying neural mechanisms remain unclear. The parabrachial nucleus (PBN) is the relay center of ingestion signals from the digestive organs. We herein identify two distinct neuronal populations expressing cholecystokinin (Cck) mRNA in the lateral PBN that are activated in response to water and salt intake, respectively. The two Cck neurons in the dorsal-lateral compartment of the PBN project to the median preoptic nucleus and ventral part of the bed nucleus of the stria terminalis, respectively. The optogenetic stimulation of respective Cck neurons suppresses thirst or salt appetite under water- or salt-depleted conditions. The combination of optogenetics and in vivo Ca imaging during ingestion reveals that both Cck neurons control GABAergic neurons in their target nuclei. These findings provide the feedback mechanisms for the suppression of thirst and salt appetite after ingestion.
Topics: Appetite; Cholecystokinin; Sodium Chloride, Dietary; Feedback; Thirst; Sodium Chloride; GABAergic Neurons; Water
PubMed: 38157299
DOI: 10.1016/j.celrep.2023.113619 -
BioRxiv : the Preprint Server For... Jan 2024The central nucleus (CeN) of the amygdala is an important afferent to the DA system that mediates motivated learning. We previously found that CeN terminals in nonhuman...
UNLABELLED
The central nucleus (CeN) of the amygdala is an important afferent to the DA system that mediates motivated learning. We previously found that CeN terminals in nonhuman primates primarily overlap the elongated lateral VTA (parabrachial pigmented nucleus, PBP, A10), and retrorubral field(A8) subregion. Here, we examined CeN afferent contacts on cell somata and proximal dendrites of DA and GABA neurons, and distal dendrites of each, using confocal and electron microscopy (EM) methods, respectively. At the soma/proximal dendrites, the proportion of TH+ and GAD1+ cells receiving at least one CeN afferent contact was surprisingly similar (TH = 0.55: GAD1=0.55 in PBP; TH = 0.56; GAD1 =0.51 in A8), with the vast majority of contacted TH+ and GAD1+ soma/proximal dendrites received 1-2 contacts. Similar numbers of tracer-labeled terminals also contacted TH-positive and GAD1-positive small dendrites and/or spines (39% of all contacted dendrites were either TH- or GAD1-labeled). Overall, axon terminals had more symmetric (putative inhibitory) axonal contacts with no difference in the relative distribution in the PBP versus A8, or onto TH+ versus GAD1+ dendrites/spines in either region. The striking uniformity in the amygdalonigral projection across the PBP-A8 terminal field suggests that neither neurotransmitter phenotype nor midbrain location dictates likelihood of a terminal contact. We discuss how this afferent uniformity can play out in recently discovered differences in DA:GABA cell densities between the PBP and A8, and affect specific outputs.
SIGNIFICANCE STATEMENT
The amygdala's central nucleus (CeN) channels salient cues to influence both appetitive and aversive responses via DA outputs. In higher species, the broad CeN terminal field overlaps the parabrachial pigmented nucleus ('lateral A10') and the retrorubral field (A8). We quantified terminal contacts in each region on DA and GABAergic soma/proximal dendrites and small distal dendrites. There was striking uniformity in contacts on DA and GABAergic cells, regardless of soma and dendritic compartment, in both regions. Most contacts were symmetric (putative inhibitory) with little change in the ratio of inhibitory to excitatory contacts by region.We conclude that post-synaptic shifts in DA-GABA ratios are key to understanding how these relatively uniform inputs can produce diverse effects on outputs.
PubMed: 38293165
DOI: 10.1101/2024.01.16.575910 -
BioRxiv : the Preprint Server For... May 2024Obese subjects often exhibit hypersomnia accompanied by severe sleep fragmentation, while emerging evidence suggests that poor sleep quality promotes overeating and...
Obese subjects often exhibit hypersomnia accompanied by severe sleep fragmentation, while emerging evidence suggests that poor sleep quality promotes overeating and exacerbates diet-induced obesity (DIO). However, the neural circuit and signaling mechanism underlying the reciprocal control of appetite and sleep is yet not elucidated. Here, we report a neural circuit where prokineticin receptor 2 (PROKR2)-expressing neurons within the parabrachial nucleus (PBN) of the brainstem received direct projections from neuropeptide Y receptor Y2 (NPY2R)-expressing neurons within the lateral preoptic area (LPO) of the hypothalamus. The RNA-Seq results revealed in the PBN is the most regulated GPCR signaling gene that is responsible for comorbidity of obesity and sleep dysfunction. Furthermore, those NPY2R neurons are minimally active during NREM sleep and maximally active during wakefulness and REM sleep. Activation of the NPY2R →PBN circuit or the postsynaptic PROKR2 neurons suppressed feeding of a high-fat diet and abrogated morbid sleep patterns in DIO mice. Further studies showed that genetic ablation of the PROKR2 signaling within PROKR2 neurons alleviated the hyperphagia and weight gain, and restored sleep dysfunction in DIO mice. We further discovered pterostilbene, a plant-derived stilbenoid, is a powerful anti-obesity and sleep-improving agent, robustly suppressed hyperphagia and promoted reconstruction of a healthier sleep architecture, thereby leading to significant weight loss. Collectively, our results unveil a neural mechanism for the reciprocal control of appetite and sleep, through which pterostilbene, along with a class of similarly structured compounds, may be developed as effective therapeutics for tackling obesity and sleep disorders.
PubMed: 38746393
DOI: 10.1101/2024.04.30.591948 -
Journal of Neurochemistry Dec 2023Chemogenetic activation of oxytocin receptor-expressing neurons in the parabrachial nucleus (Oxtr neurons) acts as a satiation signal for water. In this research, we...
Chemogenetic activation of oxytocin receptor-expressing neurons in the parabrachial nucleus (Oxtr neurons) acts as a satiation signal for water. In this research, we investigated the effect of activating Oxtr neurons on satiation for different types of fluids. Chemogenetic activation of Oxtr neurons in male and female transgenic Oxtr mice robustly suppressed the rapid, initial (15-min) intake of several solutions after dehydration: water, sucrose, ethanol and saccharin, but only slightly decreased intake of Ensure®, a highly caloric solution (1 kcal/mL; containing 3.72 g protein, 3.27 g fat, 13.42 g carbohydrates, and 1.01 g dietary fibre per 100 mL). Oxtr neuron activation also suppressed cumulative, longer-term (2-h) intake of lower caloric, less palatable solutions, but not highly caloric, palatable solutions. These results suggest that Oxtr neurons predominantly control initial fluid-satiation responses after rehydration, but not longer-term intake of highly caloric, palatable solutions. The suppression of fluid intake was not because of anxiogenesis, but because Oxtr neuron activation decreased anxiety-like behaviour. To investigate the role of different PBN subdivisions on the intake of different solutions, we examined FOS as a proxy marker of PBN neuron activation. Different PBN subdivisions were activated by different solutions: the dorsolateral PBN similarly by all fluids; the external lateral PBN by caloric but not non-caloric solutions; and the central lateral PBN primarily by highly palatable solutions, suggesting PBN subdivisions regulate different aspects of fluid intake. To explore the possible mechanisms underlying the minimal suppression of Ensure® after Oxtr neuron activation, we demonstrated in in vitro slice recordings that the feeding-associated agouti-related peptide (AgRP) inhibited Oxtr neuron firing in a concentration-related manner, suggesting possible inhibition by feeding-related neurocircuitry of fluid satiation neurocircuitry. Overall, this research suggests that although palatable beverages like sucrose- and ethanol-containing beverages activate fluid satiation signals encoded by Oxtr neurons, these neurons can be inhibited by hunger-related signals (agouti-related peptide, AgRP), which may explain why these fluids are often consumed in excess of what is required for fluid satiation.
Topics: Mice; Male; Female; Animals; Parabrachial Nucleus; Agouti-Related Protein; Satiation; Water; Sucrose; Ethanol
PubMed: 37855271
DOI: 10.1111/jnc.15991