-
Trends in Neurosciences May 2018The parabrachial nucleus (PBN), which is located in the pons and is dissected by one of the major cerebellar output tracks, is known to relay sensory information... (Review)
Review
The parabrachial nucleus (PBN), which is located in the pons and is dissected by one of the major cerebellar output tracks, is known to relay sensory information (visceral malaise, taste, temperature, pain, itch) to forebrain structures including the thalamus, hypothalamus, and extended amygdala. The availability of mouse lines expressing Cre recombinase selectively in subsets of PBN neurons and viruses for Cre-dependent gene expression is beginning to reveal the connectivity and functions of PBN component neurons. This review focuses on PBN neurons expressing calcitonin gene-related peptide (CGRP) that play a major role in regulating appetite and transmitting real or potential threat signals to the extended amygdala. The functions of other specific PBN neuronal populations are also discussed. This review aims to encourage investigation of the numerous unanswered questions that are becoming accessible.
Topics: Animals; Calcitonin Gene-Related Peptide; Humans; Neurons; Parabrachial Nucleus
PubMed: 29703377
DOI: 10.1016/j.tins.2018.03.007 -
Nature Communications Nov 2020The lateral parabrachial nucleus (LPBN) is known to relay noxious information to the amygdala for processing affective responses. However, it is unclear whether the LPBN...
The lateral parabrachial nucleus (LPBN) is known to relay noxious information to the amygdala for processing affective responses. However, it is unclear whether the LPBN actively processes neuropathic pain characterized by persistent hyperalgesia with aversive emotional responses. Here we report that neuropathic pain-like hypersensitivity induced by common peroneal nerve (CPN) ligation increases nociceptive stimulation-induced responses in glutamatergic LPBN neurons. Optogenetic activation of GABAergic LPBN neurons does not affect basal nociception, but alleviates neuropathic pain-like behavior. Optogenetic activation of glutamatergic or inhibition of GABAergic LPBN neurons induces neuropathic pain-like behavior in naïve mice. Inhibition of glutamatergic LPBN neurons alleviates both basal nociception and neuropathic pain-like hypersensitivity. Repetitive pharmacogenetic activation of glutamatergic or GABAergic LPBN neurons respectively mimics or prevents the development of CPN ligation-induced neuropathic pain-like hypersensitivity. These findings indicate that a delicate balance between excitatory and inhibitory LPBN neuronal activity governs the development and maintenance of neuropathic pain.
Topics: Animals; Disease Models, Animal; Excitatory Amino Acid Agonists; Excitatory Postsynaptic Potentials; GABA Agonists; Glutamic Acid; Humans; Hyperalgesia; Inhibitory Postsynaptic Potentials; Male; Mice; Mice, Transgenic; Neural Pathways; Neuralgia; Neurons; Nociception; Optogenetics; Parabrachial Nucleus; Peroneal Nerve; Stereotaxic Techniques; gamma-Aminobutyric Acid
PubMed: 33239627
DOI: 10.1038/s41467-020-19767-w -
Neuron Aug 2023The central nervous system regulates systemic immune responses by integrating the physiological and behavioral constraints faced by an individual. Corticosterone (CS),...
The central nervous system regulates systemic immune responses by integrating the physiological and behavioral constraints faced by an individual. Corticosterone (CS), the release of which is controlled in the hypothalamus by the paraventricular nucleus (PVN), is a potent negative regulator of immune responses. Using the mouse model, we report that the parabrachial nucleus (PB), an important hub linking interoceptive afferent information to autonomic and behavioral responses, also integrates the pro-inflammatory cytokine IL-1β signal to induce the CS response. A subpopulation of PB neurons, directly projecting to the PVN and receiving inputs from the vagal complex (VC), responds to IL-1β to drive the CS response. Pharmacogenetic reactivation of these IL-1β-activated PB neurons is sufficient to induce CS-mediated systemic immunosuppression. Our findings demonstrate an efficient brainstem-encoded modality for the central sensing of cytokines and the regulation of systemic immune responses.
Topics: Animals; Mice; Cytokines; Corticosterone; Feedback; Parabrachial Nucleus; Hypothalamus; Paraventricular Hypothalamic Nucleus
PubMed: 37279750
DOI: 10.1016/j.neuron.2023.05.009 -
Nature Communications Dec 2022Feeding behavior is adaptively regulated by external and internal environment, such that feeding is suppressed when animals experience pain, sickness, or fear. While the...
Feeding behavior is adaptively regulated by external and internal environment, such that feeding is suppressed when animals experience pain, sickness, or fear. While the lateral parabrachial nucleus (lPB) plays key roles in nociception and stress, neuronal pathways involved in feeding suppression induced by fear are not fully explored. Here, we investigate the parasubthalamic nucleus (PSTN), located in the lateral hypothalamus and critically involved in feeding behaviors, as a target of lPB projection neurons. Optogenetic activation of lPB-PSTN terminals in male mice promote avoidance behaviors, aversive learning, and suppressed feeding. Inactivation of the PSTN and lPB-PSTN pathway reduces fear-induced feeding suppression. Activation of PSTN neurons expressing pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide enriched in the PSTN, is sufficient for inducing avoidance behaviors and feeding suppression. Blockade of PACAP receptors impaires aversive learning induced by lPB-PSTN photomanipulation. These findings indicate that lPB-PSTN pathway plays a pivotal role in fear-induced feeding suppression.
Topics: Mice; Male; Animals; Parabrachial Nucleus; Fear; Pain; Hypothalamic Area, Lateral; Pituitary Adenylate Cyclase-Activating Polypeptide
PubMed: 36585411
DOI: 10.1038/s41467-022-35634-2 -
Neuron Jun 2020The lateral parabrachial nucleus (lPBN) is a major target of spinal projection neurons conveying nociceptive input into supraspinal structures. However, the functional...
The lateral parabrachial nucleus (lPBN) is a major target of spinal projection neurons conveying nociceptive input into supraspinal structures. However, the functional role of distinct lPBN efferents in diverse nocifensive responses have remained largely uncharacterized. Here we show that that the lPBN is required for escape behaviors and aversive learning to noxious stimulation. In addition, we find that two populations of efferent neurons from different regions of the lPBN collateralize to distinct targets. Activation of efferent projections to the ventromedial hypothalamus (VMH) or lateral periaqueductal gray (lPAG) drives escape behaviors, whereas activation of lPBN efferents to the bed nucleus stria terminalis (BNST) or central amygdala (CEA) generates an aversive memory. Finally, we provide evidence that dynorphin-expressing neurons, which span cytoarchitecturally distinct domains of the lPBN, are required for aversive learning.
Topics: Animals; Avoidance Learning; Central Amygdaloid Nucleus; Escape Reaction; Mice; Neural Pathways; Neurons, Efferent; Nociception; Optogenetics; Pain; Parabrachial Nucleus; Periaqueductal Gray; Septal Nuclei; Ventromedial Hypothalamic Nucleus
PubMed: 32289251
DOI: 10.1016/j.neuron.2020.03.014 -
Neuron Sep 2020The parabrachial nucleus (PBN) is one of the major targets of spinal projection neurons and plays important roles in pain. However, the architecture of the...
The parabrachial nucleus (PBN) is one of the major targets of spinal projection neurons and plays important roles in pain. However, the architecture of the spinoparabrachial pathway underlying its functional role in nociceptive information processing remains elusive. Here, we report that the PBN directly relays nociceptive signals from the spinal cord to the intralaminar thalamic nuclei (ILN). We demonstrate that the spinal cord connects with the PBN in a bilateral manner and that the ipsilateral spinoparabrachial pathway is critical for nocifensive behavior. We identify Tacr1-expressing neurons as the major neuronal subtype in the PBN that receives direct spinal input and show that these neurons are critical for processing nociceptive information. Furthermore, PBN neurons receiving spinal input form functional monosynaptic excitatory connections with neurons in the ILN, but not the amygdala. Together, our results delineate the neural circuit underlying nocifensive behavior, providing crucial insight into the circuit mechanism underlying nociceptive information processing.
Topics: Afferent Pathways; Amygdala; Animals; Functional Laterality; Intralaminar Thalamic Nuclei; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Nociception; Parabrachial Nucleus; Spinal Cord
PubMed: 32649865
DOI: 10.1016/j.neuron.2020.06.017 -
Cell Reports Nov 2021Depression symptoms are often found in patients suffering from chronic pain, a phenomenon that is yet to be understood mechanistically. Here, we systematically...
Depression symptoms are often found in patients suffering from chronic pain, a phenomenon that is yet to be understood mechanistically. Here, we systematically investigate the cellular mechanisms and circuits underlying the chronic-pain-induced depression behavior. We show that the development of chronic pain is accompanied by depressive-like behaviors in a mouse model of trigeminal neuralgia. In parallel, we observe increased activity of the dopaminergic (DA) neuron in the midbrain ventral tegmental area (VTA), and inhibition of this elevated VTA DA neuron activity reverses the behavioral manifestations of depression. Further studies establish a pathway of glutamatergic projections from the spinal trigeminal subnucleus caudalis (Sp5C) to the lateral parabrachial nucleus (LPBN) and then to the VTA. These glutamatergic projections form a direct circuit that controls the development of the depression-like behavior under the state of the chronic neuropathic pain.
Topics: Action Potentials; Animals; Behavior, Animal; Chronic Pain; Depression; Disease Models, Animal; Dopamine Plasma Membrane Transport Proteins; Dopaminergic Neurons; Female; Glutamic Acid; Male; Mice, Inbred C57BL; Mice, Transgenic; Neural Pathways; Parabrachial Nucleus; Trigeminal Caudal Nucleus; Trigeminal Neuralgia; Ventral Tegmental Area; Vesicular Glutamate Transport Protein 2; Mice
PubMed: 34731609
DOI: 10.1016/j.celrep.2021.109936 -
Cell Nov 2022After ingestion of toxin-contaminated food, the brain initiates a series of defensive responses (e.g., nausea, retching, and vomiting). How the brain detects ingested...
After ingestion of toxin-contaminated food, the brain initiates a series of defensive responses (e.g., nausea, retching, and vomiting). How the brain detects ingested toxin and coordinates diverse defensive responses remains poorly understood. Here, we developed a mouse-based paradigm to study defensive responses induced by bacterial toxins. Using this paradigm, we identified a set of molecularly defined gut-to-brain and brain circuits that jointly mediate toxin-induced defensive responses. The gut-to-brain circuit consists of a subset of Htr3a+ vagal sensory neurons that transmit toxin-related signals from intestinal enterochromaffin cells to Tac1+ neurons in the dorsal vagal complex (DVC). Tac1+ DVC neurons drive retching-like behavior and conditioned flavor avoidance via divergent projections to the rostral ventral respiratory group and lateral parabrachial nucleus, respectively. Manipulating these circuits also interferes with defensive responses induced by the chemotherapeutic drug doxorubicin. These results suggest that food poisoning and chemotherapy recruit similar circuit modules to initiate defensive responses.
Topics: Animals; Mice; Neurons; Neurons, Afferent; Parabrachial Nucleus; Vagus Nerve; Brain-Gut Axis
PubMed: 36323317
DOI: 10.1016/j.cell.2022.10.001 -
The Journal of Neuroscience : the... Aug 2023The parabrachial nuclear complex (PBN) is a nexus for aversion and for the sensory and affective components of pain perception. We have previously shown that during...
The parabrachial nuclear complex (PBN) is a nexus for aversion and for the sensory and affective components of pain perception. We have previously shown that during chronic pain PBN neurons in anesthetized rodents have amplified activity. We report a method to record from PBN neurons of behaving, head-restrained mice while applying reproducible noxious stimuli. We find that both spontaneous and evoked activity are higher in awake animals compared with urethane anesthetized mice. Fiber photometry of calcium responses from calcitonin-gene-related peptide-expressing PBN neurons demonstrates that these neurons respond to noxious stimuli. In both males and females with neuropathic or inflammatory pain, responses of PBN neurons remain amplified for at least 5 weeks, in parallel with increased pain metrics. We also show that PBN neurons can be rapidly conditioned to respond to innocuous stimuli after pairing with noxious stimuli. Finally, we demonstrate that changes in PBN neuronal activity are correlated with changes in arousal, measured as changes in pupil area. The parabrachial complex is a nexus of aversion, including pain. We report a method to record from parabrachial nucleus neurons of behaving mice while applying reproducible noxious stimuli. This allowed us to track parabrachial activity over time in animals with neuropathic or inflammatory pain. It also allowed us to show that the activity of these neurons correlates with arousal states and that these neurons can be conditioned to respond to innocuous stimuli.
Topics: Male; Female; Mice; Animals; Parabrachial Nucleus; Nociception; Wakefulness; Calcitonin Gene-Related Peptide; Chronic Pain
PubMed: 37451980
DOI: 10.1523/JNEUROSCI.0587-23.2023 -
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