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Nature Neuroscience Oct 2021Pain decreases the activity of many ventral tegmental area (VTA) dopamine (DA) neurons, yet the underlying neural circuitry connecting nociception and the DA system is...
Pain decreases the activity of many ventral tegmental area (VTA) dopamine (DA) neurons, yet the underlying neural circuitry connecting nociception and the DA system is not understood. Here we show that a subpopulation of lateral parabrachial (LPB) neurons is critical for relaying nociceptive signals from the spinal cord to the substantia nigra pars reticulata (SNR). SNR-projecting LPB neurons are activated by noxious stimuli and silencing them blocks pain responses in two different models of pain. LPB-targeted and nociception-recipient SNR neurons regulate VTA DA activity directly through feed-forward inhibition and indirectly by inhibiting a distinct subpopulation of VTA-projecting LPB neurons thereby reducing excitatory drive onto VTA DA neurons. Correspondingly, ablation of SNR-projecting LPB neurons is sufficient to reduce pain-mediated inhibition of DA release in vivo. The identification of a neural circuit conveying nociceptive input to DA neurons is critical to our understanding of how pain influences learning and behavior.
Topics: Animals; Behavior, Animal; Brain Mapping; Dopaminergic Neurons; Male; Mesencephalon; Mice; Mice, Inbred C57BL; Neural Pathways; Neurons; Nociception; Optogenetics; Pain; Pain Management; Parabrachial Nucleus; Spinal Cord; Substantia Nigra; Ventral Tegmental Area
PubMed: 34373644
DOI: 10.1038/s41593-021-00903-8 -
Neuron Mar 2022Breathing can be heavily influenced by pain or internal emotional states, but the neural circuitry underlying this tight coordination is unknown. Here we report that...
Breathing can be heavily influenced by pain or internal emotional states, but the neural circuitry underlying this tight coordination is unknown. Here we report that Oprm1 (μ-opioid receptor)-expressing neurons in the lateral parabrachial nucleus (PBL) are crucial for coordinating breathing with affective pain in mice. Individual PBL neuronal activity synchronizes with breathing rhythm and responds to noxious stimuli. Manipulating PBL activity directly changes breathing rate, affective pain perception, and anxiety. Furthermore, PBL neurons constitute two distinct subpopulations in a "core-shell" configuration that divergently projects to the forebrain and hindbrain. Through non-overlapping projections to the central amygdala and pre-Bötzinger complex, these two subpopulations differentially regulate breathing, affective pain, and negative emotions. Moreover, these subsets form recurrent excitatory networks through reciprocal glutamatergic projections. Together, our data define the divergent parabrachial opioidergic circuits as a common neural substrate that coordinates breathing with various sensations and behaviors such as pain and emotional processing.
Topics: Animals; Brain Stem; Central Amygdaloid Nucleus; Emotions; Mice; Neural Pathways; Pain; Parabrachial Nucleus
PubMed: 34921781
DOI: 10.1016/j.neuron.2021.11.029 -
Cell Metabolism Jul 2021Sensory neurons relay gut-derived signals to the brain, yet the molecular and functional organization of distinct populations remains unclear. Here, we employed...
Sensory neurons relay gut-derived signals to the brain, yet the molecular and functional organization of distinct populations remains unclear. Here, we employed intersectional genetic manipulations to probe the feeding and glucoregulatory function of distinct sensory neurons. We reconstruct the gut innervation patterns of numerous molecularly defined vagal and spinal afferents and identify their downstream brain targets. Bidirectional chemogenetic manipulations, coupled with behavioral and circuit mapping analysis, demonstrated that gut-innervating, glucagon-like peptide 1 receptor (GLP1R)-expressing vagal afferents relay anorexigenic signals to parabrachial nucleus neurons that control meal termination. Moreover, GLP1R vagal afferent activation improves glucose tolerance, and their inhibition elevates blood glucose levels independent of food intake. In contrast, gut-innervating, GPR65-expressing vagal afferent stimulation increases hepatic glucose production and activates parabrachial neurons that control normoglycemia, but they are dispensable for feeding regulation. Thus, distinct gut-innervating sensory neurons differentially control feeding and glucoregulatory neurocircuits and may provide specific targets for metabolic control.
Topics: Afferent Pathways; Animals; Appetite; Appetite Regulation; Brain-Gut Axis; Cell Communication; Energy Metabolism; Glucagon-Like Peptide-1 Receptor; Glucose; Homeodomain Proteins; Male; Mice, Transgenic; Nodose Ganglion; Receptors, G-Protein-Coupled; Sensory Receptor Cells; Transcription Factors; Vagus Nerve; Wnt1 Protein
PubMed: 34043943
DOI: 10.1016/j.cmet.2021.05.002 -
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 -
Sleep & Breathing = Schlaf & Atmung Dec 2023The purpose of this study is to examine the pathophysiology underlying sleep apnea (SA). (Review)
Review
OBJECTIVE
The purpose of this study is to examine the pathophysiology underlying sleep apnea (SA).
BACKGROUND
We consider several critical features of SA including the roles played by the ascending reticular activating system (ARAS) that controls vegetative functions and electroencephalographic findings associated with both SA and normal sleep. We evaluate this knowledge together with our current understanding of the anatomy, histology, and physiology of the mesencephalic trigeminal nucleus (MTN) and mechanisms that contribute directly to normal and disordered sleep. MTN neurons express γ-aminobutyric acid (GABA) receptors which activate them (make chlorine come out of the cells) and that can be activated by GABA released from the hypothalamic preoptic area.
METHOD
We reviewed the published literature focused on sleep apnea (SA) reported in Google Scholar, Scopus, and PubMed databases.
RESULTS
The MTN neurons respond to the hypothalamic GABA release by releasing glutamate that activates neurons in the ARAS. Based on these findings, we conclude that a dysfunctional MTN may be incapable of activating neurons in the ARAS, notably those in the parabrachial nucleus, and that this will ultimately lead to SA. Despite its name, obstructive sleep apnea (OSA) is not caused by an airway obstruction that prevents breathing.
CONCLUSIONS
While obstruction may contribute to the overall pathology, the primary factor involved in this scenario is the lack of neurotransmitters.
Topics: Humans; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Respiration; Sleep; gamma-Aminobutyric Acid
PubMed: 36976413
DOI: 10.1007/s11325-023-02783-7 -
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 -
Nature Apr 2024Empirical evidence suggests that heat exposure reduces food intake. However, the neurocircuit architecture and the signalling mechanisms that form an associative...
Empirical evidence suggests that heat exposure reduces food intake. However, the neurocircuit architecture and the signalling mechanisms that form an associative interface between sensory and metabolic modalities remain unknown, despite primary thermoceptive neurons in the pontine parabrachial nucleus becoming well characterized. Tanycytes are a specialized cell type along the wall of the third ventricle that bidirectionally transport hormones and signalling molecules between the brain's parenchyma and ventricular system. Here we show that tanycytes are activated upon acute thermal challenge and are necessary to reduce food intake afterwards. Virus-mediated gene manipulation and circuit mapping showed that thermosensing glutamatergic neurons of the parabrachial nucleus innervate tanycytes either directly or through second-order hypothalamic neurons. Heat-dependent Fos expression in tanycytes suggested their ability to produce signalling molecules, including vascular endothelial growth factor A (VEGFA). Instead of discharging VEGFA into the cerebrospinal fluid for a systemic effect, VEGFA was released along the parenchymal processes of tanycytes in the arcuate nucleus. VEGFA then increased the spike threshold of Flt1-expressing dopamine and agouti-related peptide (Agrp)-containing neurons, thus priming net anorexigenic output. Indeed, both acute heat and the chemogenetic activation of glutamatergic parabrachial neurons at thermoneutrality reduced food intake for hours, in a manner that is sensitive to both Vegfa loss-of-function and blockage of vesicle-associated membrane protein 2 (VAMP2)-dependent exocytosis from tanycytes. Overall, we define a multimodal neurocircuit in which tanycytes link parabrachial sensory relay to the long-term enforcement of a metabolic code.
Topics: Animals; Female; Male; Mice; Agouti-Related Protein; Arcuate Nucleus of Hypothalamus; Brain Stem; Dopamine; Eating; Ependymoglial Cells; Feeding Behavior; Glutamic Acid; Hot Temperature; Hypothalamus; Neural Pathways; Neurons; Parabrachial Nucleus; Thermosensing; Time Factors; Vascular Endothelial Growth Factor A
PubMed: 38538787
DOI: 10.1038/s41586-024-07232-3 -
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 -
Peptides Oct 2020Amylin is a peptide hormone that is mainly known to be produced by pancreatic β-cells in response to a meal but amylin is also produced by brain cells in discrete brain... (Review)
Review
Amylin is a peptide hormone that is mainly known to be produced by pancreatic β-cells in response to a meal but amylin is also produced by brain cells in discrete brain areas albeit in a lesser amount. Amylin receptor (AMY) is composed of the calcitonin core-receptor (CTR) and one of the 3 receptor activity modifying protein (RAMP), thus forming AMY1-3; RAMP enhances amylin binding properties to the CTR. However, amylin receptor agonist such as salmon calcitonin is able to bind CTR alone. Peripheral amylin's main binding site is located in the area postrema (AP) which then propagate the signal to the nucleus of the solitary tract and lateral parabrachial nucleus (LPBN) and it is then transmitted to the forebrain areas such as central amygdala and bed nucleus of the stria terminalis. Amylin's activation of these different brain areas mediates eating and other metabolic pathways controlling energy expenditure and glucose homeostasis. Peripheral amylin can also bind in the arcuate nucleus of the hypothalamus where it acts independently of the AP to activate POMC and NPY neurons. Amylin activation of NPY neurons has been shown to be transmitted to LPBN neurons to act on eating while amylin POMC signaling affects energy expenditure and locomotor activity. While a large amount of experiments have already been conducted, future studies will have to further investigate how amylin is taken up by forebrain areas and deepen our understanding of amylin action on peripheral metabolism.
Topics: Animals; Appetite Depressants; Brain; Eating; Humans; Islet Amyloid Polypeptide; Pancreatic Hormones; Signal Transduction
PubMed: 32634450
DOI: 10.1016/j.peptides.2020.170366 -
Nature Communications May 2023Itch is an annoying sensation consisting of both sensory and emotional components. It is known to involve the parabrachial nucleus (PBN), but the following transmission...
Itch is an annoying sensation consisting of both sensory and emotional components. It is known to involve the parabrachial nucleus (PBN), but the following transmission nodes remain elusive. The present study identified that the PBN-central medial thalamic nucleus (CM)-medial prefrontal cortex (mPFC) pathway is essential for itch signal transmission at the supraspinal level in male mice. Chemogenetic inhibition of the CM-mPFC pathway attenuates scratching behavior or chronic itch-related affective responses. CM input to mPFC pyramidal neurons is enhanced in acute and chronic itch models. Specifically chronic itch stimuli also alter mPFC interneuron involvement, resulting in enhanced feedforward inhibition and a distorted excitatory/inhibitory balance in mPFC pyramidal neurons. The present work underscores CM as a transmit node of the itch signal in the thalamus, which is dynamically engaged in both the sensory and affective dimensions of itch with different stimulus salience.
Topics: Mice; Male; Animals; Intralaminar Thalamic Nuclei; Sensation; Prefrontal Cortex; Interneurons; Anxiety
PubMed: 37137899
DOI: 10.1038/s41467-023-38264-4