痒觉的中枢环路机制
|
摘要
痒觉是一种诱发抓挠行为的不愉快的感受。近年来,我们对痒觉信息在脊髓水平处理的分子和细胞机制已经有了较为深入的认识。然而,痒觉信息如何从脊髓传递到大脑并不清楚。我们发现,在痒觉诱发抓挠行为的过程中,脊髓中投射到臂旁核的神经元被激活,光遗传学抑制这条环路的活性可以减少痒觉诱发的抓挠行为。脊髓中痒觉特异的胃泌素释放肽受体阳性神经元与投射到臂旁核的脊髓投射神经元形成兴奋性突触连接。我们进一步研究了臂旁核在痒觉诱发的抓挠行为过程中的活性变化和功能。我们发现,臂旁核神经元的兴奋性与痒觉诱发的抓挠过程具有很强的相关性。整体抑制臂旁核神经元的活性或者选择性阻断兴奋性神经元的突触传递可以显著降低急性痒引起的抓挠行为,并减缓慢性痒的形成。我们的工作揭示了痒觉从脊髓传递到大脑的一条重要环路,并且证实臂旁核是参与痒觉信息处理的重要脑区。该研究为深入解析痒觉信息加工的脑内环路机制提供了重要基础。
Itch, or pruritus, is an unpleasant cutaneous sensation that triggers scratching behaviors. Much progress has been made in understanding the molecular and cellular mechanisms of itch 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(GRPR), are di-synaptically connected to parabrachial nucleus(PBN) via glutamatergic spinal projection neurons. In addition, we confirmed the functional role of PBN in itch processing. We found that the activity of PBN neurons was elevated during itch processing. At behavioral level,inhibition of the PBN neurons or blockade of synaptic release of glutamatergic neurons in the PBN suppressed pruritogen-induced scratching behavior and relieved chronic itch, suggesting that PBN is important for itch processing. In summary, we demonstrated that the spinoparabrachial pathway plays a key role in transmitting itch signals from the spinal cord to the brain, and identified the PBN as a first central relay for the itch signal processing. Our study paves the way for further dissection of central circuit mechanisms underlying itch sensation.
Itch, or pruritus, is an unpleasant cutaneous sensation that triggers scratching behaviors. Much progress has been made in understanding the molecular and cellular mechanisms of itch 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(GRPR), are di-synaptically connected to parabrachial nucleus(PBN) via glutamatergic spinal projection neurons. In addition, we confirmed the functional role of PBN in itch processing. We found that the activity of PBN neurons was elevated during itch processing. At behavioral level,inhibition of the PBN neurons or blockade of synaptic release of glutamatergic neurons in the PBN suppressed pruritogen-induced scratching behavior and relieved chronic itch, suggesting that PBN is important for itch processing. In summary, we demonstrated that the spinoparabrachial pathway plays a key role in transmitting itch signals from the spinal cord to the brain, and identified the PBN as a first central relay for the itch signal processing. Our study paves the way for further dissection of central circuit mechanisms underlying itch sensation.
引文
[1]Jutel M,Akdis M,Akdis CA.Histamine,histamine receptors and their role in immune pathology.Clin Exp Allergy 2009;39(12):1786-800.
[2]Shim WS,Tak MH,Lee MH,Kim M,Kim M,Koo JY,et al.TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and12-lipoxygenase.J Neurosci 2007;27(9):2331-7.
[3]Dong X,Han S,Zylka MJ,Simon MI,Anderson DJ.A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons.Cell2001;106(5):619-32.
[4]Han L,Ma C,Liu Q,Weng HJ,Cui Y,Tang Z,et al.A subpopulation of nociceptors specifically linked to itch.Nat Neurosci 2012;16(2):174-82.
[5]Sun YG,Chen ZF.A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord.Nature 2007;448(7154):700-3.
[6]Sun YG,Zhao ZQ,Meng XL,Yin J,Liu XY,Chen ZF.Cellular basis of itch sensation.Science2009;325(5947):1531-4.
[7]Mishra SK,Hoon MA.The cells and circuitry for itch responses in mice.Science 2013;340(6135):968-71.
[8]Foster E,Wildner H,Tudeau L,Haueter S,Ralvenius WT,Jeqen M,et al.Targeted ablation,silencing,and activation establish glycinergic dorsal horn neurons as key components of a spinal gate for pain and itch.Neuron 2015;85(6):1289-304.
[9]Ross SE,Mardinly AR,Mc Cord AE,Zurawski J,Cohen S,Jung C,et al.Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice.Neuron 2010;65(6):886-98.
[10]Bourane S,Duan B,Koch SC,Dalet A,Britz O,Garcia-Campmany L,et al.Gate control of mechanical itch by a subpopulation of spinal cord interneurons.Science 2015;350(6260):550-4.
[11]Bernard JF,Dallel R,Raboisson P,Villanueva L,Bars D Le.Organization of the efferent projections from the spinal cervical enlargement to the parabrachial area and periaqueductal graye.A PHA-L study in the rat.J Comp Neurol 1995;353(4):480-505.
[12]Todd AJ.Neuronal circuitry for pain processing in the dorsal horn.Nat Rev Neurosci 2010;11(12):823-36.
[13]Kaur S,Pedersen NP,Yokota S,Hur EE,Fuller PM,Lazarus M,et al.Glutamatergic signaling from the parabrachial nucleus plays a critical role in hypercapnic arousal.J Neurosci 2013;33(18):7627-40.
[14]Herbert H,Moga MM,Saper CB.Connections of the parabrachial nucleus with the nucleus of the solitary tract and the medullary reticular formation in the rat.J Comp Neurol 1990;293(4):540-80.
[15]Bernard JF,Alden M,Besson JM.The organization of the efferent projections from the pontine parabrachial area to the amygdaloid complex:a Phaseolus vulgaris leucoagglutinin(PHA-L)study in the rat.J Comp Neurol 1993;329(2):201-29.
[16]Jasmin L,Burkey AR,Card JP,Basbaum AI.Transneuronal labeling of a nociceptive pathway,the spino-(trigemino-)parabrachio-amygdaloid,in the rat.J Neurosci 1997;17(10):3751-65.
[17]Hylden JL,Hayashi H,Dubner R,Bennett GJ.Physiology and morphology of the lamina I spinomesencephalic projection.J Comp Neurol1986;247(4):505-15.
[18]Jansen NA,Giesler GJ.Response characteristics of pruriceptive and nociceptive trigeminoparabrachial tract neurons in the rat.J Neurophysiol 2015;113(1):58-70.
[19]Han S,Soleiman MT,Soden ME,Zweifel LS,Palmiter RD.Elucidating an Affective Pain Circuit that Creates a Threat Memory.Cell 2015;162(2):363-74.
[20]Basbaum AI,Bautista DM,Scherrer G,Julius D.Cellular and molecular mechanisms of pain.Cell2009;139(2):267-84.
[21]Carter ME,Soden ME,Zweifel LS,Palmiter RD.Genetic identification of a neural circuit that suppresses appetite.Nature 2013;503(7474):111-4.
[22]Mu D,Deng J,Liu KF,Wu ZY,Shi YF,Guo WM,et al.A central neural circuit for itch sensation.Science 2017;357(6352):695-9.
[23]Imayoshi I,Sakamoto M,Ohtsuka T,Takao K,Miyakawa T,Yamaguchi M,et al.Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain.Nat Neurosci 2008;11(10):1153-61.
[24]Wang X,Zhang J,Eberhart D,Urban R,Meda K,Solorzano C,et al.Excitatory superficial dorsal horn interneurons are functionally heterogeneous and required for the full behavioral expression of pain and itch.Neuron 2013;78(2):312-24.
[25]Armbruster BN,Li X,Pausch MH,Herlitze S,Roth BL.Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand.Proc Natl Acad Sci U S A 2007;104(12):5163-8.
[26]Inagaki N,Shiraishi N,Igeta K,Itoh T,Chikumoto T,Nagao M,et al.Inhibition of scratching behavior associated with allergic dermatitis in mice by tacrolimus,but not by dexamethasone.Eur J Pharmacol 2006;546(1-3):189-96.
[27]Schneider G,St?nder S,Burgmer M,Driesch G,Heuft G,Weckesser M.Significant differences in central imaging of histamine-induced itch between atopic dermatitis and healthy subjects.Eur J Pain2008;12(7):834-41.
[2]Shim WS,Tak MH,Lee MH,Kim M,Kim M,Koo JY,et al.TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and12-lipoxygenase.J Neurosci 2007;27(9):2331-7.
[3]Dong X,Han S,Zylka MJ,Simon MI,Anderson DJ.A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons.Cell2001;106(5):619-32.
[4]Han L,Ma C,Liu Q,Weng HJ,Cui Y,Tang Z,et al.A subpopulation of nociceptors specifically linked to itch.Nat Neurosci 2012;16(2):174-82.
[5]Sun YG,Chen ZF.A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord.Nature 2007;448(7154):700-3.
[6]Sun YG,Zhao ZQ,Meng XL,Yin J,Liu XY,Chen ZF.Cellular basis of itch sensation.Science2009;325(5947):1531-4.
[7]Mishra SK,Hoon MA.The cells and circuitry for itch responses in mice.Science 2013;340(6135):968-71.
[8]Foster E,Wildner H,Tudeau L,Haueter S,Ralvenius WT,Jeqen M,et al.Targeted ablation,silencing,and activation establish glycinergic dorsal horn neurons as key components of a spinal gate for pain and itch.Neuron 2015;85(6):1289-304.
[9]Ross SE,Mardinly AR,Mc Cord AE,Zurawski J,Cohen S,Jung C,et al.Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice.Neuron 2010;65(6):886-98.
[10]Bourane S,Duan B,Koch SC,Dalet A,Britz O,Garcia-Campmany L,et al.Gate control of mechanical itch by a subpopulation of spinal cord interneurons.Science 2015;350(6260):550-4.
[11]Bernard JF,Dallel R,Raboisson P,Villanueva L,Bars D Le.Organization of the efferent projections from the spinal cervical enlargement to the parabrachial area and periaqueductal graye.A PHA-L study in the rat.J Comp Neurol 1995;353(4):480-505.
[12]Todd AJ.Neuronal circuitry for pain processing in the dorsal horn.Nat Rev Neurosci 2010;11(12):823-36.
[13]Kaur S,Pedersen NP,Yokota S,Hur EE,Fuller PM,Lazarus M,et al.Glutamatergic signaling from the parabrachial nucleus plays a critical role in hypercapnic arousal.J Neurosci 2013;33(18):7627-40.
[14]Herbert H,Moga MM,Saper CB.Connections of the parabrachial nucleus with the nucleus of the solitary tract and the medullary reticular formation in the rat.J Comp Neurol 1990;293(4):540-80.
[15]Bernard JF,Alden M,Besson JM.The organization of the efferent projections from the pontine parabrachial area to the amygdaloid complex:a Phaseolus vulgaris leucoagglutinin(PHA-L)study in the rat.J Comp Neurol 1993;329(2):201-29.
[16]Jasmin L,Burkey AR,Card JP,Basbaum AI.Transneuronal labeling of a nociceptive pathway,the spino-(trigemino-)parabrachio-amygdaloid,in the rat.J Neurosci 1997;17(10):3751-65.
[17]Hylden JL,Hayashi H,Dubner R,Bennett GJ.Physiology and morphology of the lamina I spinomesencephalic projection.J Comp Neurol1986;247(4):505-15.
[18]Jansen NA,Giesler GJ.Response characteristics of pruriceptive and nociceptive trigeminoparabrachial tract neurons in the rat.J Neurophysiol 2015;113(1):58-70.
[19]Han S,Soleiman MT,Soden ME,Zweifel LS,Palmiter RD.Elucidating an Affective Pain Circuit that Creates a Threat Memory.Cell 2015;162(2):363-74.
[20]Basbaum AI,Bautista DM,Scherrer G,Julius D.Cellular and molecular mechanisms of pain.Cell2009;139(2):267-84.
[21]Carter ME,Soden ME,Zweifel LS,Palmiter RD.Genetic identification of a neural circuit that suppresses appetite.Nature 2013;503(7474):111-4.
[22]Mu D,Deng J,Liu KF,Wu ZY,Shi YF,Guo WM,et al.A central neural circuit for itch sensation.Science 2017;357(6352):695-9.
[23]Imayoshi I,Sakamoto M,Ohtsuka T,Takao K,Miyakawa T,Yamaguchi M,et al.Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain.Nat Neurosci 2008;11(10):1153-61.
[24]Wang X,Zhang J,Eberhart D,Urban R,Meda K,Solorzano C,et al.Excitatory superficial dorsal horn interneurons are functionally heterogeneous and required for the full behavioral expression of pain and itch.Neuron 2013;78(2):312-24.
[25]Armbruster BN,Li X,Pausch MH,Herlitze S,Roth BL.Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand.Proc Natl Acad Sci U S A 2007;104(12):5163-8.
[26]Inagaki N,Shiraishi N,Igeta K,Itoh T,Chikumoto T,Nagao M,et al.Inhibition of scratching behavior associated with allergic dermatitis in mice by tacrolimus,but not by dexamethasone.Eur J Pharmacol 2006;546(1-3):189-96.
[27]Schneider G,St?nder S,Burgmer M,Driesch G,Heuft G,Weckesser M.Significant differences in central imaging of histamine-induced itch between atopic dermatitis and healthy subjects.Eur J Pain2008;12(7):834-41.