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Chronic sleep fragmentation enhances habenula cholinergic neural activity

Molecular Psychiatry (2019) | Download Citation

Abstract

Sleep is essential to emotional health. Sleep disturbance, particularly REM sleep disturbance, profoundly impacts emotion regulation, but the underlying neural mechanisms remain elusive. Here we show that chronic REM sleep disturbance, achieved in mice by chronic sleep fragmentation (SF), enhanced neural activity in the medial habenula (mHb), a brain region increasingly implicated in negative affect. Specifically, after a 5-day SF procedure that selectively fragmented REM sleep, cholinergic output neurons (ChNs) in the mHb exhibited increased spontaneous firing rate and enhanced firing regularity in brain slices. The SF-induced firing changes remained intact upon inhibition of glutamate, GABA, acetylcholine, and histamine receptors, suggesting cell-autonomous mechanisms independent of synaptic transmissions. Moreover, the SF-induced hyperactivity was not because of enhanced intrinsic membrane excitability, but was accompanied by depolarized resting membrane potential in mHb ChNs. Furthermore, inhibition of TASK-3 (KCNK9) channels, a subtype of two-pore domain K+ channels, mimicked the SF effects by increasing the firing rate and regularity, as well as depolarizing the resting membrane potential in mHb ChNs in control-sleep mice. These effects of TASK-3 inhibition were absent in SF mice, suggesting reduced TASK-3 activity following SF. By contrast, inhibition of small-conductance Ca2+-activated K+ (SK) channels did not produce similar effects. Thus, SF compromised TASK-3 function in mHb ChNs, which likely led to depolarized resting membrane potential and increased spontaneous firing. These results not only demonstrate that selective REM sleep disturbance leads to hyperactivity of mHb ChNs, but also identify a key molecular substrate through which REM sleep disturbance may alter affect regulation.

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References

  1. 1.

    Medic G, Wille M, Hemels ME. Short- and long-term health consequences of sleep disruption. Nat Sci Sleep. 2017;9:151–61.

  2. 2.

    Finan PH, Quartana PJ, Smith MT. The effects of sleep continuity disruption on positive mood and sleep architecture in healthy adults. Sleep. 2015;38:1735–42.

  3. 3.

    Logan RW, Hasler BP, Forbes EE, Franzen PL, Torregrossa MM, Huang YH, et al. Impact of sleep and circadian rhythms on addiction vulnerability in adolescents. Biol Psychiatry. 2018;83:987–96.

  4. 4.

    Meerlo P, Havekes R, Steiger A. Chronically restricted or disrupted sleep as a causal factor in the development of depression. Curr Top Behav Neurosci. 2015;25:459–81.

  5. 5.

    Krystal AD. Psychiatric disorders and sleep. Neurol Clin. 2012;30:1389–413.

  6. 6.

    Anderson KN, Bradley AJ. Sleep disturbance in mental health problems and neurodegenerative disease. Nat Sci Sleep. 2013;5:61–75.

  7. 7.

    Palmer CA, Alfano CA. Sleep and emotion regulation: an organizing, integrative review. Sleep Med Rev. 2017;31:6–16.

  8. 8.

    Goldstein AN, Walker MP. The role of sleep in emotional brain function. Annu Rev Clin Psychol. 2014;10:679–708.

  9. 9.

    Krause AJ, Simon EB, Mander BA, Greer SM, Saletin JM, Goldstein-Piekarski AN, et al. The sleep-deprived human brain. Nat Rev Neurosci. 2017;18:404–18.

  10. 10.

    Hall M, Levenson J, Hasler B. Sleep and Emotion. In: Morin CM, Espie CA, editors. The Oxford handbook of sleep and sleep disorders. Oxford University Press, New York, NY, 2012.

  11. 11.

    Gruber R, Cassoff J. The interplay between sleep and emotion regulation: conceptual framework empirical evidence and future directions. Curr Psychiatry Rep. 2014;16:500.

  12. 12.

    Minkel JD, McNealy K, Gianaros PJ, Drabant EM, Gross JJ, Manuck SB, et al. Sleep quality and neural circuit function supporting emotion regulation. Biol Mood Anxiety Disord. 2012;2:22.

  13. 13.

    Simon EB, Oren N, Sharon H, Kirschner A, Goldway N, Okon-Singer H, et al. Losing Neutrality: The Neural Basis of Impaired Emotional Control without Sleep. J Neurosci. 2015;35:13194–205.

  14. 14.

    Viswanath H, Carter AQ, Baldwin PR, Molfese DL, Salas R. The medial habenula: still neglected. Front Hum Neurosci. 2013;7:931.

  15. 15.

    Zhang J, Tan L, Ren Y, Liang J, Lin R, Feng Q, et al. Presynaptic excitation via gabab receptors in habenula cholinergic neurons regulates fear memory expression. Cell. 2016;166:716–28.

  16. 16.

    Kobayashi Y, Sano Y, Vannoni E, Goto H, Suzuki H, Oba A, et al. Genetic dissection of medial habenula-interpeduncular nucleus pathway function in mice. Front Behav Neurosci. 2013;7:17.

  17. 17.

    Lopez AJ, Jia Y, White AO, Kwapis JL, Espinoza M, Hwang P, et al. Medial habenula cholinergic signaling regulates cocaine-associated relapse-like behavior. Addict Biol. 2018. [Epub ahead of print]

  18. 18.

    Fowler CD, Lu Q, Johnson PM, Marks MJ, Kenny PJ. Habenular alpha5 nicotinic receptor subunit signalling controls nicotine intake. Nature. 2011;471:597–601.

  19. 19.

    Frahm S, Slimak MA, Ferrarese L, Santos-Torres J, Antolin-Fontes B, Auer S, et al. Aversion to nicotine is regulated by the balanced activity of beta4 and alpha5 nicotinic receptor subunits in the medial habenula. Neuron. 2011;70:522–35.

  20. 20.

    Han S, Yang SH, Kim JY, Mo S, Yang E, Song KM, et al. Down-regulation of cholinergic signaling in the habenula induces anhedonia-like behavior. Sci Rep. 2017;7:900.

  21. 21.

    Yamaguchi T, Danjo T, Pastan I, Hikida T, Nakanishi S. Distinct roles of segregated transmission of the septo-habenular pathway in anxiety and fear. Neuron. 2013;78:537–44.

  22. 22.

    Tallini YN, Shui B, Greene KS, Deng KY, Doran R, Fisher PJ, et al. BAC transgenic mice express enhanced green fluorescent protein in central and peripheral cholinergic neurons. Physiol Genomics. 2006;27:391–7.

  23. 23.

    Chen B, Wang Y, Liu X, Liu Z, Dong Y, Huang YH. Sleep Regulates Incubation of Cocaine Craving. J Neurosci. 2015;35:13300–10.

  24. 24.

    Liu Z, Wang Y, Cai L, Li Y, Chen B, Dong Y, et al. Prefrontal cortex to accumbens projections in sleep regulation of reward. J Neurosci. 2016;36:7897–910.

  25. 25.

    Winters BD, Huang YH, Dong Y, Krueger JM. Sleep loss alters synaptic and intrinsic neuronal properties in mouse prefrontal cortex. Brain Res. 2011;1420:1–7.

  26. 26.

    Ting JT, Daigle TL, Chen Q, Feng G. Acute brain slice methods for adult and aging animals: application of targeted patch clamp analysis and optogenetics. Methods Mol Biol. 2014;1183:221–42.

  27. 27.

    Colavito V, Fabene PF, Grassi-Zucconi G, Pifferi F, Lamberty Y, Bentivoglio M, et al. Experimental sleep deprivation as a tool to test memory deficits in rodents. Front Syst Neurosci. 2013;7:106.

  28. 28.

    Malisch JL, Breuner CW, Gomes FR, Chappell MA, Garland T Jr. Circadian pattern of total and free corticosterone concentrations, corticosteroid-binding globulin, and physical activity in mice selectively bred for high voluntary wheel-running behavior. Gen Comp Endocrinol. 2008;156:210–7.

  29. 29.

    Aizawa H, Kobayashi M, Tanaka S, Fukai T, Okamoto H. Molecular characterization of the subnuclei in rat habenula. J Comp Neurol. 2012;520:4051–66.

  30. 30.

    Cuello AC, Emson PC, Paxinos G, Jessell T. Substance P containing and cholinergic projections from the habenula. Brain Res. 1978;149:413–29.

  31. 31.

    Choi K, Lee Y, Lee C, Hong S, Lee S, Kang SJ, et al. Optogenetic activation of septal GABAergic afferents entrains neuronal firing in the medial habenula. Sci Rep. 2016;6:34800.

  32. 32.

    Shih PY, Engle SE, Oh G, Deshpande P, Puskar NL, Lester HA, et al. Differential expression and function of nicotinic acetylcholine receptors in subdivisions of medial habenula. J Neurosci. 2014;34:9789–802.

  33. 33.

    Dao DQ, Perez EE, Teng Y, Dani JA, De Biasi M. Nicotine enhances excitability of medial habenular neurons via facilitation of neurokinin signaling. J Neurosci. 2014;34:4273–84.

  34. 34.

    Bell MI, Richardson PJ, Lee K. Histamine depolarizes cholinergic interneurones in the rat striatum via a H(1)-receptor mediated action. Br J Pharmacol. 2000;131:1135–42.

  35. 35.

    Gorelova N, Reiner PB. Histamine depolarizes cholinergic septal neurons. J Neurophysiol. 1996;75:707–14.

  36. 36.

    Palacios JM, Wamsley JK, Kuhar MJ. The distribution of histamine H1-receptors in the rat brain: an autoradiographic study. Neuroscience. 1981;6:15–37.

  37. 37.

    Pillot C, Heron A, Cochois V, Tardivel-Lacombe J, Ligneau X, Schwartz JC, et al. A detailed mapping of the histamine H(3) receptor and its gene transcripts in rat brain. Neuroscience. 2002;114:173–93.

  38. 38.

    Vizuete ML, Traiffort E, Bouthenet ML, Ruat M, Souil E, Tardivel-Lacombe J, et al. Detailed mapping of the histamine H2 receptor and its gene transcripts in guinea-pig brain. Neuroscience. 1997;80:321–43.

  39. 39.

    Sheffield EB, Quick MW, Lester RA. Nicotinic acetylcholine receptor subunit mRNA expression and channel function in medial habenula neurons. Neuropharmacology. 2000;39:2591–603.

  40. 40.

    Bischoff S, Leonhard S, Reymann N, Schuler V, Shigemoto R, Kaupmann K, et al. Spatial distribution of GABA(B)R1 receptor mRNA and binding sites in the rat brain. J Comp Neurol. 1999;412:1–16.

  41. 41.

    Stocker M, Pedarzani P. Differential distribution of three Ca(2 + )-activated K( + ) channel subunits, SK1, SK2, and SK3, in the adult rat central nervous system. Mol Cell Neurosci. 2000;15:476–93.

  42. 42.

    Sakhi K, Belle MD, Gossan N, Delagrange P, Piggins HD. Daily variation in the electrophysiological activity of mouse medial habenula neurones. J Physiol. 2014;592:587–603.

  43. 43.

    O’Connell AD, Morton MJ, Hunter M. Two-pore domain K + channels-molecular sensors. Biochim Biophys Acta. 2002;1566:152–61.

  44. 44.

    Braun AP. Two-pore domain potassium channels: variation on a structural theme. Channels (Austin). 2012;6:139–40.

  45. 45.

    Talley EM, Solorzano G, Lei Q, Kim D, Bayliss DA. Cns distribution of members of the two-pore-domain (KCNK) potassium channel family. J Neurosci. 2001;21:7491–505.

  46. 46.

    Lesage F, Barhanin J. Molecular physiology of pH-sensitive background K(2P) channels. Physiology. 2011;26:424–37.

  47. 47.

    Bayliss DA, Barhanin J, Gestreau C, Guyenet PG. The role of pH-sensitive TASK channels in central respiratory chemoreception. Pflugers Arch. 2015;467:917–29.

  48. 48.

    Meadows HJ, Randall AD. Functional characterisation of human TASK-3, an acid-sensitive two-pore domain potassium channel. Neuropharmacology. 2001;40:551–9.

  49. 49.

    Chatelain FC, Bichet D, Douguet D, Feliciangeli S, Bendahhou S, Reichold M, et al. TWIK1, a unique background channel with variable ion selectivity. Proc Natl Acad Sci USA. 2012;109:5499–504.

  50. 50.

    Baglioni C, Regen W, Teghen A, Spiegelhalder K, Feige B, Nissen C, et al. Sleep changes in the disorder of insomnia: a meta-analysis of polysomnographic studies. Sleep Med Rev. 2014;18:195–213.

  51. 51.

    Ermis U, Krakow K, Voss U. Arousal thresholds during human tonic and phasic REM sleep. J Sleep Res. 2010;19:400–6.

  52. 52.

    Gulyani S, Majumdar S, B.N. M. Rapid eye movement sleep and significance of its deprivation studies - a review. Sleep and Hypnosis. 2000;2:49–68.

  53. 53.

    Tuesta LM, Chen Z, Duncan A, Fowler CD, Ishikawa M, Lee BR, et al. GLP-1 acts on habenular avoidance circuits to control nicotine intake. Nat Neurosci. 2017;20:708–16.

  54. 54.

    Kim Y, Bang H, Kim D. TASK-3, a new member of the tandem pore K( + ) channel family. J Biol Chem. 2000;275:9340–7.

  55. 55.

    Talley EM, Bayliss DA. Modulation of TASK-1 (Kcnk3) and TASK-3 (Kcnk9) potassium channels: volatile anesthetics and neurotransmitters share a molecular site of action. J Biol Chem. 2002;277:17733–42.

  56. 56.

    Vu MT, Du G, Bayliss DA, Horner RL. TASK Channels on Basal Forebrain Cholinergic Neurons Modulate Electrocortical Signatures of Arousal by Histamine. J Neurosci. 2015;35:13555–67.

  57. 57.

    Berg AP, Bayliss DA. Striatal cholinergic interneurons express a receptor-insensitive homomeric TASK-3-like background K + current. J Neurophysiol. 2007;97:1546–52.

  58. 58.

    Cho CH, Hwang EM, Park JY. Emerging Roles of TWIK-1 Heterodimerization in the Brain. Int J Mol Sci. 2017;19:1.

  59. 59.

    Plant LD, Zuniga L, Araki D, Marks JD, Goldstein SA. SUMOylation silences heterodimeric TASK potassium channels containing K2P1 subunits in cerebellar granule neurons. Sci Signal. 2012;5:ra84.

  60. 60.

    Brickley SG, Aller MI, Sandu C, Veale EL, Alder FG, Sambi H, et al. TASK-3 two-pore domain potassium channels enable sustained high-frequency firing in cerebellar granule neurons. J Neurosci. 2007;27:9329–40.

  61. 61.

    Goldstein SA, Bockenhauer D, O’Kelly I, Zilberberg N. Potassium leak channels and the KCNK family of two-P-domain subunits. Nat Rev Neurosci. 2001;2:175–84.

  62. 62.

    Bennett BD, Callaway JC, Wilson CJ. Intrinsic membrane properties underlying spontaneous tonic firing in neostriatal cholinergic interneurons. J Neurosci. 2000;20:8493–503.

  63. 63.

    Murkar ALA, De Koninck J. Consolidative mechanisms of emotional processing in REM sleep and PTSD. Sleep Med Rev. 2018;41:173–84.

  64. 64.

    Groch S, Wilhelm I, Diekelmann S, Born J. The role of REM sleep in the processing of emotional memories: evidence from behavior and event-related potentials. Neurobiol Learn Mem. 2013;99:1–9.

  65. 65.

    Mathis V, Kenny PJ. From controlled to compulsive drug-taking: The role of the habenula in addiction. Neurosci Biobehav Rev. 2018. [Epub ahead of print]

  66. 66.

    Zhao-Shea R, DeGroot SR, Liu L, Vallaster M, Pang X, Su Q, et al. Increased CRF signalling in a ventral tegmental area-interpeduncular nucleus-medial habenula circuit induces anxiety during nicotine withdrawal. Nat Commun. 2015;6:6770.

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Acknowledgements

We thank Rachel L. Hines and Fei Wang for assistance with sleep scoring. Research reported in this publication was supported by the National Institute on Drug Abuse of the National Institutes of Health under Award Numbers DA035805 (YH), MH101147 (YH), DA047108 (YH), DA043826 (YH), DA023206 (YD), DA040620 (YD), DA044538 (YD).

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Author notes

    • Feifei Ge

    Present address: Department of Human Anatomy and Histoembryology, School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, 210023, Nanjing, China

    • Ping Mu

    Present address: College of Life Sciences, Ludong University, 186 Hongqi Middle Road, Yantai, 264025, Shandong, China

Affiliations

  1. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

    • Feifei Ge
    • , Ping Mu
    • , Rong Guo
    • , Li Cai
    • , Zheng Liu
    • , Yan Dong
    •  & Yanhua H. Huang
  2. Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA

    • Yan Dong

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The authors declare that they have no conflict of interest.

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The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Correspondence to Yanhua H. Huang.

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https://doi.org/10.1038/s41380-019-0419-z