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Nature Nov 2020The anterolateral pathway consists of ascending spinal tracts that convey pain, temperature and touch information from the spinal cord to the brain. Projection neurons...
The anterolateral pathway consists of ascending spinal tracts that convey pain, temperature and touch information from the spinal cord to the brain. Projection neurons of the anterolateral pathway are attractive therapeutic targets for pain treatment because nociceptive signals emanating from the periphery are channelled through these spinal projection neurons en route to the brain. However, the organizational logic of the anterolateral pathway remains poorly understood. Here we show that two populations of projection neurons that express the structurally related G-protein-coupled receptors (GPCRs) TACR1 and GPR83 form parallel ascending circuit modules that cooperate to convey thermal, tactile and noxious cutaneous signals from the spinal cord to the lateral parabrachial nucleus of the pons. Within this nucleus, axons of spinoparabrachial (SPB) neurons that express Tacr1 or Gpr83 innervate distinct sets of subnuclei, and strong optogenetic stimulation of the axon terminals induces distinct escape behaviours and autonomic responses. Moreover, SPB neurons that express Gpr83 are highly sensitive to cutaneous mechanical stimuli and receive strong synaptic inputs from both high- and low-threshold primary mechanosensory neurons. Notably, the valence associated with activation of SPB neurons that express Gpr83 can be either positive or negative, depending on stimulus intensity. These findings reveal anatomically, physiologically and functionally distinct subdivisions of the SPB tract that underlie affective aspects of touch and pain.
Topics: Animals; Axons; Female; Male; Mechanotransduction, Cellular; Mice; Neural Pathways; Pain; Philosophy; Receptors, G-Protein-Coupled; Sensory Receptor Cells; Skin; Spinal Cord; Synapses; Touch
PubMed: 33116307
DOI: 10.1038/s41586-020-2860-1 -
Neural Plasticity 2022Chronic pain patients often develop mental disorders, and anxiety disorders are common. We hypothesize that the comorbid anxiety results from an imbalance between the... (Review)
Review
Chronic pain patients often develop mental disorders, and anxiety disorders are common. We hypothesize that the comorbid anxiety results from an imbalance between the reward and antireward system due to persistent pain, which leads to the dysfunction of the pain and anxiety regulatory system. In this review, we will focus on changes in neuroplasticity, especially in neural circuits, during chronic pain and anxiety as observed in animal studies. Several neural circuits within specific regions of the brain, including the nucleus accumbens, lateral habenular, parabrachial nucleus, medial septum, anterior cingulate cortex, amygdala, hippocampus, medial prefrontal cortex, and bed nucleus of the stria terminalis, will be discussed based on novel findings after chemogenetic or optogenetic manipulation. We believe that these animal studies provide novel insights into human conditions and can guide clinical practice.
Topics: Animals; Anxiety; Anxiety Disorders; Brain; Chronic Pain; Comorbidity; Humans
PubMed: 35211169
DOI: 10.1155/2022/4217593 -
Neuron Jun 2023The sensation of itch is a protective response that is elicited by either mechanical or chemical stimuli. The neural pathways for itch transmission in the skin and...
The sensation of itch is a protective response that is elicited by either mechanical or chemical stimuli. The neural pathways for itch transmission in the skin and spinal cord have been characterized previously, but the ascending pathways that transmit sensory information to the brain to evoke itch perception have not been identified. Here, we show that spinoparabrachial neurons co-expressing Calcrl and Lbx1 are essential for generating scratching responses to mechanical itch stimuli. Moreover, we find that mechanical and chemical itch are transmitted by separate ascending pathways to the parabrachial nucleus, where they engage separate populations of FoxP2 neurons to drive scratching behavior. In addition to revealing the architecture of the itch transmission circuitry required for protective scratching in healthy animals, we identify the cellular mechanisms underlying pathological itch by showing the ascending pathways for mechanical and chemical itch function cooperatively with the FoxP2 neurons to drive chronic itch and hyperknesis/alloknesis.
Topics: Mice; Animals; Mice, Inbred C57BL; Pruritus; Skin; Neurons; Sensation
PubMed: 37023756
DOI: 10.1016/j.neuron.2023.03.013 -
Cell Nov 2022Methods for acquiring spatially resolved omics data from complex tissues use barcoded DNA arrays of low- to sub-micrometer features to achieve single-cell resolution....
Methods for acquiring spatially resolved omics data from complex tissues use barcoded DNA arrays of low- to sub-micrometer features to achieve single-cell resolution. However, fabricating such arrays (randomly assembled beads, DNA nanoballs, or clusters) requires sequencing barcodes in each array, limiting cost-effectiveness and throughput. Here, we describe a vastly scalable stamping method to fabricate polony gels, arrays of ∼1-micrometer clonal DNA clusters bearing unique barcodes. By enabling repeatable enzymatic replication of barcode-patterned gels, this method, compared with the sequencing-dependent array fabrication, reduced cost by at least 35-fold and time to approximately 7 h. The gel stamping was implemented with a simple robotic arm and off-the-shelf reagents. We leveraged the resolution and RNA capture efficiency of polony gels to develop Pixel-seq, a single-cell spatial transcriptomic assay, and applied it to map the mouse parabrachial nucleus and analyze changes in neuropathic pain-regulated transcriptomes and cell-cell communication after nerve ligation.
Topics: Mice; Animals; Transcriptome; Chronic Pain; DNA; RNA; Gels
PubMed: 36368323
DOI: 10.1016/j.cell.2022.10.021 -
Nature Communications Feb 2023As a traditional medical therapy, stimulation at the Lianquan (CV23) acupoint, located at the depression superior to the hyoid bone, has been shown to be beneficial in...
Electroacupuncture improves swallowing function in a post-stroke dysphagia mouse model by activating the motor cortex inputs to the nucleus tractus solitarii through the parabrachial nuclei.
As a traditional medical therapy, stimulation at the Lianquan (CV23) acupoint, located at the depression superior to the hyoid bone, has been shown to be beneficial in dysphagia. However, little is known about the neurological mechanism by which this peripheral stimulation approach treats for dysphagia. Here, we first identified a cluster of excitatory neurons in layer 5 (L5) of the primary motor cortex (M1) that can regulate swallowing function in male mice by modulating mylohyoid activity. Moreover, we found that focal ischemia in the M1 mimicked the post-stroke dysphagia (PSD) pathology, as indicated by impaired water consumption and electromyographic responses in the mylohyoid. This dysfunction could be rescued by electroacupuncture (EA) stimulation at the CV23 acupoint (EA-CV23) in a manner dependent on the excitatory neurons in the contralateral M1 L5. Furthermore, neuronal activation in both the parabrachial nuclei (PBN) and nucleus tractus solitarii (NTS), which was modulated by the M1, was required for the ability of EA-CV23 treatment to improve swallowing function in male PSD model mice. Together, these results uncover the importance of the M1-PBN-NTS neural circuit in driving the protective effect of EA-CV23 against swallowing dysfunction and thus reveal a potential strategy for dysphagia intervention.
Topics: Male; Mice; Animals; Solitary Nucleus; Deglutition; Deglutition Disorders; Electroacupuncture; Motor Cortex; Stroke
PubMed: 36781899
DOI: 10.1038/s41467-023-36448-6 -
Cell Reports Oct 2019Pain perception is essential for survival and can be amplified or suppressed by expectations, experiences, and context. The neural mechanisms underlying bidirectional...
Pain perception is essential for survival and can be amplified or suppressed by expectations, experiences, and context. The neural mechanisms underlying bidirectional modulation of pain remain largely unknown. Here, we demonstrate that the central nucleus of the amygdala (CeA) functions as a pain rheostat, decreasing or increasing pain-related behaviors in mice. This dual and opposing function of the CeA is encoded by opposing changes in the excitability of two distinct subpopulations of GABAergic neurons that receive excitatory inputs from the parabrachial nucleus (PB). Thus, cells expressing protein kinase C-delta (CeA-PKCδ) are sensitized by nerve injury and increase pain-related responses. In contrast, cells expressing somatostatin (CeA-Som) are inhibited by nerve injury and their activity drives antinociception. Together, these results demonstrate that the CeA can amplify or suppress pain in a cell-type-specific manner, uncovering a previously unknown mechanism underlying bidirectional control of pain in the brain.
Topics: Animals; Central Amygdaloid Nucleus; Enzyme Activation; Female; Hypersensitivity; MAP Kinase Signaling System; Mice, Inbred C57BL; Models, Neurological; Nerve Tissue; Neuralgia; Neurons; Protein Kinase C-delta; Proto-Oncogene Proteins c-fos; Sciatic Nerve; Temperature; Touch
PubMed: 31597095
DOI: 10.1016/j.celrep.2019.09.011 -
Nature Communications Aug 2023Thermal homeostasis is vital for mammals and is controlled by brain neurocircuits. Yet, the neural pathways responsible for cold defense regulation are still unclear....
Thermal homeostasis is vital for mammals and is controlled by brain neurocircuits. Yet, the neural pathways responsible for cold defense regulation are still unclear. Here, we found that a pathway from the lateral parabrachial nucleus (LPB) to the dorsomedial hypothalamus (DMH), which runs parallel to the canonical LPB to preoptic area (POA) pathway, is also crucial for cold defense. Together, these pathways make an equivalent and cumulative contribution, forming a parallel circuit. Specifically, activation of the LPB → DMH pathway induced strong cold-defense responses, including increases in thermogenesis of brown adipose tissue (BAT), muscle shivering, heart rate, and locomotion. Further, we identified somatostatin neurons in the LPB that target DMH to promote BAT thermogenesis. Therefore, we reveal a parallel circuit governing cold defense in mice, which enables resilience to hypothermia and provides a scalable and robust network in heat production, reshaping our understanding of neural circuit regulation of homeostatic behaviors.
Topics: Mice; Animals; Thermogenesis; Preoptic Area; Neural Pathways; Homeostasis; Hypothermia; Adipose Tissue, Brown; Cold Temperature; Mammals
PubMed: 37582782
DOI: 10.1038/s41467-023-40504-6 -
ELife Nov 2021Hypersomnolence disorder (HD) is characterized by excessive sleep, which is a common sequela following stroke, infection, or tumorigenesis. HD is traditionally thought...
Hypersomnolence disorder (HD) is characterized by excessive sleep, which is a common sequela following stroke, infection, or tumorigenesis. HD is traditionally thought to be associated with lesions of wake-promoting nuclei. However, lesions of a single wake-promoting nucleus, or even two simultaneously, did not exert serious HD. Therefore, the specific nucleus and neural circuitry for HD remain unknown. Here, we observed that the paraventricular nucleus of the hypothalamus (PVH) exhibited higher c-fos expression during the active period (23:00) than during the inactive period (11:00) in mice. Therefore, we speculated that the PVH, in which most neurons are glutamatergic, may represent one of the key arousal-controlling centers. By using vesicular glutamate transporter 2 (vglut2) mice together with fiber photometry, multichannel electrophysiological recordings, and genetic approaches, we found that PVH neurons were most active during wakefulness. Chemogenetic activation of PVH neurons induced wakefulness for 9 hr, and photostimulation of PVH→parabrachial complex/ventral lateral septum circuits immediately drove transitions from sleep to wakefulness. Moreover, lesioning or chemogenetic inhibition of PVH neurons dramatically decreased wakefulness. These results indicate that the PVH is critical for arousal promotion and maintenance.
Topics: Animals; Arousal; Disorders of Excessive Somnolence; Male; Mice; Neurons; Paraventricular Hypothalamic Nucleus; Vesicular Glutamate Transport Protein 2; Wakefulness
PubMed: 34787078
DOI: 10.7554/eLife.69909 -
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