Itch, in particular chronic forms, has been widely recognized as an important clinical problem, but much less is known about the mechanisms of itch in comparison with other sensory modalities such as ...pain. Recently, considerable progress has been made in dissecting the circuit mechanisms of itch at both the spinal and supraspinal levels. Major components of the spinal neural circuit underlying both chemical and mechanical itch have now been identified, along with the circuits relaying ascending transmission and the descending modulation of itch. In this review, we summarize the progress in elucidating the neural circuit mechanism of itch at spinal and supraspinal levels.
Dopamine (DA) neurons in the VTA play essential roles in adaptive motivated behavior, which requires rapid discrimination between positive and negative motivational signature. However, the precise ...functional DA circuitry processing reward and aversive information remain elusive. Here, we report that the encoding of reward and aversion by the DA system in the NAc is tightly associated with its anatomical location. By recording the dynamics of DA release with genetically encoded fluorescent DA sensor using
fiber photometry in freely moving male mice, we found that the DA-sensor signal in the dorsomedial NAc shell and dorsolateral NAc shell were increased during rewarding events and decreased during aversive noxious events. In contrast, the release of DA in the ventromedial NAc shell was increased by both rewarding and aversive stimuli, whereas the DA-sensor signal in the central ventromedial NAc shell and ventrolateral NAc shell showed complex dynamics. Furthermore, the activity of DA fibers in different subregions of NAc measured with calcium sensor largely recapitulated the changes of DA-sensor signal in response to rewarding and aversive stimuli. In addition, correlation analysis showed that the response magnitude of DA-sensor or fibers significantly changed along the DV axis of the NAc. These results revealed the distinct role of the mesolimbic DA system in different subregions of NAc in encoding value and salience.
Adaptive motivated behavior requires rapid discrimination between favorable and harmful events and is dynamically modulated by dopamine (DA) neurons in the VTA. However, the precise relationship between distinct DA circuitry and reward/aversion signal encoding is not well understood. Here, by recording the dynamics of DA release and the activity of DA fibers in each subregion of the NAc using
fiber photometry in freely moving animals, we found that the DA system in the dorsomedial/dorsolateral, ventromedial, and ventrolateral NAc shell plays different roles in encoding value and salience. These results extend our knowledge about how the mesolimbic DA system process motivational information at the circuitry level.
Itching, or pruritus, is defined as an unpleasant cutaneous sensation that serves as a physiological self-protective mechanism to prevent the body from being hurt by harmful external agents. Chronic ...itch represents a significant clinical problem resulting from renal diseases and liver diseases, as well as several serious skin diseases such as atopic dermatitis. The identity of the itch-specific mediator in the central nervous system, however, remains elusive. Here we describe that the gastrin-releasing peptide receptor (GRPR) plays an important part in mediating itch sensation in the dorsal spinal cord. We found that gastrin-releasing peptide is specifically expressed in a small subset of peptidergic dorsal root ganglion neurons, whereas expression of its receptor GRPR is restricted to lamina I of the dorsal spinal cord. GRPR mutant mice showed comparable thermal, mechanical, inflammatory and neuropathic pain responses relative to wild-type mice. In contrast, induction of scratching behaviour was significantly reduced in GRPR mutant mice in response to pruritogenic stimuli, whereas normal responses were evoked by painful stimuli. Moreover, direct spinal cerebrospinal fluid injection of a GRPR antagonist significantly inhibited scratching behaviour in three independent itch models. These data demonstrate that GRPR is required for mediating the itch sensation rather than pain, at the spinal level. Our results thus indicate that GRPR may represent the first molecule that is dedicated to mediating the itch sensation in the dorsal horn of the spinal cord, and thus may provide a central therapeutic target for antipruritic drug development.
Uncontrollable itch-scratching cycles lead to serious skin damage in patients with chronic itch. However, the neural mechanism promoting the itch-scratching cycle remains elusive. Here, we report ...that tachykinin 1 (Tac1)-expressing glutamatergic neurons in the lateral and ventrolateral periaqueductal gray (l/vlPAG) facilitate the itch-scratching cycle. We found that l/vlPAG neurons exhibited scratching-behavior-related neural activity and that itch-evoked scratching behavior was impaired after suppressing the activity of l/vlPAG neurons. Furthermore, we showed that the activity of Tac1-expressing glutamatergic neurons in the l/vlPAG was elevated during itch-induced scratching behavior and that ablating or suppressing the activity of these neurons decreased itch-induced scratching behavior. Importantly, activation of Tac1-expressing neurons induced robust spontaneous scratching and grooming behaviors. The scratching behavior evoked by Tac1-expressing neuron activation was suppressed by ablation of spinal neurons expressing gastrin-releasing peptide receptor (GRPR), the key relay neurons for itch. These results suggest that Tac1-expressing neurons in the l/vlPAG promote itch-scratching cycles.
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•Neurons in l/vlPAG exhibit scratching behavior related to neural activities•Ablation of Tac1+ but not SST+ neurons decreases itch-induced scratching behavior•Activation of Tac1+ neurons induces spontaneous scratching and grooming behaviors•l/vlPAG Tac1+ neurons modulate spinal itch processing via a RVM-dependent pathway
Gao et al. demonstrate that Tac1-expressing neurons in the l/vlPAG modulate spinal itch processing via a descending pathway. These neurons represent a critical component in the neural circuit that drives the itch-scratching cycle.
Although itch sensation is an important protective mechanism for animals, chronic itch remains a challenging clinical problem. Itch processing has been studied extensively at the spinal level. ...However, how itch information is transmitted to the brain and what central circuits underlie the itch-induced scratching behavior remain largely unknown. We found that the spinoparabrachial pathway was activated during itch processing and that optogenetic suppression of this pathway impaired itch-induced scratching behaviors. Itch-mediating spinal neurons, which express the gastrin-releasing peptide receptor, are disynaptically connected to the parabrachial nucleus via glutamatergic spinal projection neurons. Blockade of synaptic output of glutamatergic neurons in the parabrachial nucleus suppressed pruritogen-induced scratching behavior. Thus, our studies reveal a central neural circuit that is critical for itch signal processing.
Mu-opioid receptors (MORs) are crucial for analgesia by both exogenous and endogenous opioids. However, the distinct mechanisms underlying these two types of opioid analgesia remain largely unknown. ...Here, we demonstrate that analgesic effects of exogenous and endogenous opioids on inflammatory pain are mediated by MORs expressed in distinct subpopulations of neurons in mice. We found that the exogenous opioid-induced analgesia of inflammatory pain is mediated by MORs in Vglut2
glutamatergic but not GABAergic neurons. In contrast, analgesia by endogenous opioids is mediated by MORs in GABAergic rather than Vglut2
glutamatergic neurons. Furthermore, MORs expressed at the spinal level is mainly involved in the analgesic effect of morphine in acute pain, but not in endogenous opioid analgesia during chronic inflammatory pain. Thus, our study revealed distinct mechanisms underlying analgesia by exogenous and endogenous opioids, and laid the foundation for further dissecting the circuit mechanism underlying opioid analgesia.
Circuit Mechanisms of Itch in the Brain Mu, Di; Sun, Yan-Gang
Journal of investigative dermatology,
January 2022, 2022-01-00, 20220101, Volume:
142, Issue:
1
Journal Article
Peer reviewed
Open access
Itch is an unpleasant somatic sensation with the desire to scratch, and it consists of sensory, affective, and motivational components. Acute itch serves as a critical protective mechanism because an ...itch-evoked scratching response will help to remove harmful substances invading the skin. Recently, exciting progress has been made in deciphering the mechanisms of itch at both the peripheral nervous system and the CNS levels. Key neuronal subtypes and circuits have been revealed for ascending transmission and the descending modulation of itch. In this review, we mainly summarize the current understanding of the central circuit mechanisms of itch in the brain.
Itch and pain are two distinct sensations. Although our previous study suggested that gastrin-releasing peptide receptor (GRPR) is an itch-specific gene in the spinal cord, a long-standing question ...of whether there are separate neuronal pathways for itch and pain remains unsettled. We selectively ablated lamina I neurons expressing GRPR in the spinal cord of mice. These mice showed profound scratching deficits in response to all of the itching (pruritogenic) stimuli tested, irrespective of their histamine dependence. In contrast, pain behaviors were unaffected. Our data also suggest that GRPR⁺ neurons are different from the spinothalamic tract neurons that have been the focus of the debate. Together, the present study suggests that GRPR⁺ neurons constitute a long-sought labeled line for itch sensation in the spinal cord.
Transparent conductive electrodes, as transmission windows of photons and electrons, play important roles in high‐performance organic optoelectronic devices. The replacement of widely used indium tin ...oxide (ITO) electrodes has been attempted due to the increasing cost and intrinsically brittle characteristics of ITO. Ultrathin metal films, with excellent optoelectrical features, high flexibility, and sufficient mechanical stability, have been considered a potential candidate for the use as transparent conductive electrodes. However, ultrathin metal films follow the Volmer–Weber mechanism, resulting in a rough and discontinuous morphology with poor optoelectrical properties due to the bad adhesion to substrates. This review summarizes the progress in strategies for preparing ultrathin and ultrasmooth metal films with superior transmittance and conductivity by successfully suppressing the Volmer–Weber mechanism. The electrical and optical performances of the ultrathin metal films based on improved nucleation processes, as well as applications in ITO‐free organic optoelectronic devices, are also described and discussed in detail.
The development of ultrathin metal films with improved metal nucleation processes based on various strategies is summarized in this review. The great progress in the properties of ultrathin metal films as well as their application in indium tin oxide (ITO)‐free organic optoelectronic devices as transparent conductive electrodes are described.
Stretchable organic light-emitting devices are becoming increasingly important in the fast-growing fields of wearable displays, biomedical devices and health-monitoring technology. Although highly ...stretchable devices have been demonstrated, their luminous efficiency and mechanical stability remain impractical for the purposes of real-life applications. This is due to significant challenges arising from the high strain-induced limitations on the structure design of the device, the materials used and the difficulty of controlling the stretch-release process. Here we have developed a laser-programmable buckling process to overcome these obstacles and realize a highly stretchable organic light-emitting diode with unprecedented efficiency and mechanical robustness. The strained device luminous efficiency -70 cd A(-1) under 70% strain - is the largest to date and the device can accommodate 100% strain while exhibiting only small fluctuations in performance over 15,000 stretch-release cycles. This work paves the way towards fully stretchable organic light-emitting diodes that can be used in wearable electronic devices.
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