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題名 干擾素引起小鼠憂鬱行為之細胞分子機制研究
Investigating the cellular and molecular mechanisms underlying interferon-alpha (IFN-α) induced depressive-like behavior in the mouse作者 張凱傑
Chang, Kai-Chieh貢獻者 陳紹寬<br>廖瑞銘
Chen, Shau-Kwaun<br>Liao, Ruey-Ming
張凱傑
Chang, Kai-Chieh關鍵詞 憂鬱症
干擾素-α
發炎
下視丘
海馬迴
前額葉皮質
依核
杏仁核
Depression
Interferon-alpha
Inflammation
Hypothalamus
Hippocampus
Prefrontal cortex
Nucleus accumbens
Amygdala日期 2021 上傳時間 1-七月-2021 19:57:45 (UTC+8) 摘要 臨床研究中發現，長期的發炎與憂鬱症有緊密的關聯。然而，發炎與重度憂鬱症(Major Depression Disorder, MDD)之間的因果關係與病理機制尚未釐清。干擾素-α (IFN-α)屬於第一類型的干擾素。常被用於治療自體免疫性疾病，病毒性疾病和癌症。然而長期使用IFN-α也會導致憂鬱。長期接受IFN-α治療的患者中大約有15％至40％被診斷患有憂鬱症，由於使用IFN-α也會誘導發炎，因此長期使用IFN-α導致憂鬱的分子機制可能與發炎引起憂鬱的機制相似。長期注射IFN-α的小鼠也會引起類似憂鬱的行為表現，因此可用做IFN-α導致憂鬱的動物模式。前人研究發現，大腦中發炎及微膠質細胞的活化，及神經細胞的IFN-α受體的訊息傳導被活化，均與此異常行為的發生有密切的關聯。本研究旨在了解第一類型干擾素誘導憂鬱症的細胞分子機制，透過為期四周的腹腔注射IFN-α來誘導小鼠出現憂鬱行為，包括懸尾實驗以及強迫游泳中的僵直時間會更長，糖水偏好測試中糖水的飲用量減少，相比之下透過施打IFN-α處理的小鼠在高腳十字迷宮和開放場域的行為測試中並未出現焦慮行為。我們透過文獻回顧挑選在憂鬱症的致病中幾個關鍵的大腦核區，包括前額葉皮質、依核、海馬迴、杏仁核以及下視丘，並檢驗在各腦區干擾素是否可直接作用，及是否造成發炎。我們檢驗在這些腦區中干擾素訊息傳遞的下游基因IFNRA、IRF1和STAT1，以及發炎因子TNF-α和iNOS等的基因表現。我們發現干擾素可直接作用在下視丘中，並引起發炎。另在海馬迴中干擾素訊息傳遞的下游基因表現也顯著上升，但並未有發炎的現象。因此干擾素引起憂鬱可能是先作用在下視丘或海馬迴，再進一步影響血清素及多巴胺等系統。我們進一步對施打了IFN-α的下視丘中數種神經胜肽的表現進行分析，發現許多神經胜肽的mRNA表現量有所抑制。另外在海馬迴以及杏仁核中我們發現PKA活性受到抑制。總而言之我們的實驗結果顯示，IFN-α在腹腔施打在大腦中的初級作用點應為下視丘或海馬迴，可能經由造成神經胜肽的功能低下後進一步造成憂鬱的症狀，我們的發現將會提供有關IFN-α與憂鬱症之間的致病機制的重要資訊及新的研究方向。
Clinical studies revealed that inflammation is highly associated with the pathogenesis of major depression disorder (MDD). However, the causative relationship and the cellular and molecular mechanisms of inflammation induced MDD have not been established. Type I interferons, such as Interferon-alpha (IFN-α), function as an inflammatory regulator that displays a unique pharmacological profile, including induce pro-inflammatory cytokines and prevent the virus producing and replicating the RNA and DNA. Based on these pharmacological characteristics, IFN-α is often used for treating the autoimmune disease, viral disease, and various cancers. Chronic treatment of IFN-α leads to one notable adverse side effect: depression. About 15% to 40% of patients were diagnosed with depression after receiving IFN-α treatment for several months. The mechanisms of IFN-α induced depression might be similar to the mechanisms underlying inflammation induced depression. Therefore, the IFN-α can be used as an animal model of depression. Previous studies suggested that the activation of myeloid cells, including microglia and perivascular macrophages, contributes to IFN-α induced depression. Additionally, the phenotypes of conditional mutants indicated that IFN-α Signaling in neurons is essential for the onset of the pathological behavior. This study aimed to understand the cellular and molecular mechanism of type-I interferon induced depression. Daily injected with IFN-α through intraperitoneal route for four weeks induced depressive like behavior, including longer immobility time in tail suspension and forced swim test, as well as reduced sugar intake in sucrose preference test. In comparison, these IFN-α treated mice did not exhibit anxiety-like behavior in elevated plus maze and open field test. We first identify the primary target brain regions of IFN-α. Five brain regions that are involved in depression, including hypothalamus, amygdala, nucleus accumbens, hippocampus and prefrontal cortex, were examined. The expression of inflammatory genes, TNF-α and iNOS, as well as the downstream genes of interferon signaling, IFNRA, IRF1 and STAT1, were determined. As we expected, our preliminary data suggested that inflammatory genes and interferon signaling were only upregulated in hypothalamus, possibly due to the higher permeability to blood brain barrier as a circumventricular organ. Based on the above observations, we hypothesized that chronic treatment of IFN-α induces hypothalamic inflammation, disrupts the normal functions of neuropeptide system and trigger depressive like behavior or indirectly affect mesolimbic pathways to generate anhedonia. The expressions of various neuropeptide genes in the IFN-α treated hypothalamus were further evaluated. Numbers of neuropeptide mRNA level are decrease. In addition, IFN-α treatment downregulated the activation of protein kinase A, which is a major downstream target of monoaminergic receptors, in the hippocampus and amygdala. In conclusion, our results suggested IFN-α can directly suppress the functions of neuroendocrine system, and possibly in turn affect serotonergic or dopaminergic system. Our finding will provide important information about the pathological mechanisms of IFN-α induced depression.參考文獻 Arion D, Unger T, Lewis DA, Levitt P, Mirnics K (2007) Molecular evidence for increased expression of genes related to immune and chaperone function in the prefrontal cortex in schizophrenia. Biol Psychiatry 62:711-721.Bhatti Z, Berenson CS (2007) Adult systemic cat scratch disease associated with therapy for hepatitis C. BMC Infect Dis 7:1-4.Boutrel B, Kenny PJ, Specio SE, Martin-Fardon R, Markou A, Koob GF, de Lecea L (2005) Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior. Proceedings of the National Academy of Sciences 102:19168-19173.Boyle MP, Brewer JA, Funatsu M, Wozniak DF, Tsien JZ, Izumi Y, Muglia LJ (2005) Acquired deficit of forebrain glucocorticoid receptor produces depression-like changes in adrenal axis regulation and behavior. Proceedings of the National Academy of Sciences 102:473-478.Brown AS, Derkits EJ (2010) Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry 167:261-280.Burguillos MA, Deierborg T, Kavanagh E, Persson A, Hajji N, Garcia-Quintanilla A, Cano J, Brundin P, Englund E, Venero JL (2011) Caspase signalling controls microglia activation and neurotoxicity. Nature 472:319-324.Burke HM, Davis MC, Otte C, Mohr DC (2005) Depression and cortisol responses to psychological stress: a meta-analysis. Psychoneuroendocrinology 30:846-856.Carson DS, Guastella AJ, Taylor ER, McGregor IS (2013) A brief history of oxytocin and its role in modulating psychostimulant effects. Journal of psychopharmacology 27:231-247.Carswell E, Old LJ, Kassel R, Green S, Fiore N, Williamson B (1975) An endotoxin-induced serum factor that causes necrosis of tumors. Proceedings of the National Academy of Sciences 72:3666-3670.Chan SW, Harmer CJ, Norbury R, O’Sullivan U, Goodwin GM, Portella MJ (2016) Hippocampal volume in vulnerability and resilience to depression. J Affect Disord 189:199-202.Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98:437-451.Cryan JF, Mombereau C (2004) In search of a depressed mouse: utility of models for studying depression-related behavior in genetically modified mice. Mol Psychiatry 9:326-357.D`haenen HA, Bossuyt A (1994) Dopamine D2 receptors in depression measured with single photon emission computed tomography. Biol Psychiatry 35:128-132.Dai D, Li Q-C, Zhu Q-B, Hu S-H, Balesar R, Swaab D, Bao A-M (2017) Direct involvement of androgen receptor in oxytocin gene expression: possible relevance for mood disorders. Neuropsychopharmacology 42:2064-2071.Dantzer R, O`Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nature reviews neuroscience 9:46-56.Decourt B, K Lahiri D, N Sabbagh M (2017) Targeting tumor necrosis factor alpha for Alzheimer’s disease. Current Alzheimer Research 14:412-425.Deuschle M, Schweiger U, Weber B, Gotthardt U, Körner A, Schmider J, Standhardt H, Lammers C-H, Heuser I (1997) Diurnal activity and pulsatility of the hypothalamus-pituitary-adrenal system in male depressed patients and healthy controls. The Journal of Clinical Endocrinology & Metabolism 82:234-238.Diorio D, Viau V, Meaney MJ (1993) The role of the medial prefrontal cortex (cingulate gyrus) in the regulation of hypothalamic-pituitary-adrenal responses to stress. Journal of Neuroscience 13:3839-3847.Eaton WW, Byrne M, Ewald H, Mors O, Chen C-Y, Agerbo E, Mortensen PB (2006) Association of schizophrenia and autoimmune diseases: linkage of Danish national registers. Am J Psychiatry 163:521-528.Ehrlich I, Humeau Y, Grenier F, Ciocchi S, Herry C, Lüthi A (2009) Amygdala inhibitory circuits and the control of fear memory. Neuron 62:757-771.Engelmann M, Landgraf R, Wotjak CT (2004) The hypothalamic–neurohypophysial system regulates the hypothalamic–pituitary–adrenal axis under stress: an old concept revisited. Front Neuroendocrinol 25:132-149.Everitt BJ, Parkinson JA, Olmstead MC, Arroyo M, Robledo P, Robbins TW (1999) Associative processes in addiction and reward the role of amygdala‐ventral striatal subsystems. Ann N Y Acad Sci 877:412-438.Eyding D, Lelgemann M, Grouven U, Härter M, Kromp M, Kaiser T, Kerekes MF, Gerken M, Wieseler B (2010) Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials. BMJ 341:c4737.Fahey B, Hickey B, Kelleher D, O’Dwyer A-M, O’Mara SM (2007) The widely-used anti-viral drug interferon-alpha induces depressive-and anxiogenic-like effects in healthy rats. Behav Brain Res 182:80-87.Fang FC (2004) Antimicrobial reactive oxygen and nitrogen species: concepts and controversies. Nature Reviews Microbiology 2:820-832.Felger JC, Alagbe O, Hu F, Mook D, Freeman AA, Sanchez MM, Kalin NH, Ratti E, Nemeroff CB, Miller AH (2007) Effects of interferon-alpha on rhesus monkeys: a nonhuman primate model of cytokine-induced depression. Biol Psychiatry 62:1324-1333.Felger JC, Mun J, Kimmel HL, Nye JA, Drake DF, Hernandez CR, Freeman AA, Rye DB, Goodman MM, Howell LL (2013) Chronic interferon-α decreases dopamine 2 receptor binding and striatal dopamine release in association with anhedonia-like behavior in nonhuman primates. Neuropsychopharmacology 38:2179-2187.Fienberg AA, Greengard P (2000) The DARPP-32 knockout mouse. Brain Res Brain Res Rev 31:313-319.Fioravanti J, Medina-Echeverz J, Ardaiz N, Gomar C, Parra-Guillén ZP, Prieto J, Berraondo P (2012) The fusion protein of IFN-α and apolipoprotein AI crosses the blood–brain barrier by a saturable transport mechanism. The Journal of Immunology 188:3988-3992.Frank MG, Baratta MV, Sprunger DB, Watkins LR, Maier SF (2007) Microglia serve as a neuroimmune substrate for stress-induced potentiation of CNS pro-inflammatory cytokine responses. Brain Behav Immun 21:47-59.Freeman MR, Rowitch DH (2013) Evolving concepts of gliogenesis: a look way back and ahead to the next 25 years. Neuron 80:613-623.Fry M, Ferguson AV (2007) The sensory circumventricular organs: brain targets for circulating signals controlling ingestive behavior. Physiol Behav 91:413-423.Fu X-Y, Kessler DS, Veals SA, Levy DE, Darnell J (1990) ISGF3, the transcriptional activator induced by interferon alpha, consists of multiple interacting polypeptide chains. Proceedings of the National Academy of Sciences 87:8555-8559.Gauzzi MC, Barbieri G, Richter MF, Uzé G, Ling L, Fellous M, Pellegrini S (1997) The amino-terminal region of Tyk2 sustains the level of interferon α receptor 1, a component of the interferon α/β receptor. Proceedings of the National Academy of Sciences 94:11839-11844.Gawin FH, Kleber HD (1986) Abstinence symptomatology and psychiatric diagnosis in cocaine abusers: clinical observations. Arch Gen Psychiatry 43:107-113.Gold P, Chrousos G (2002) Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Mol Psychiatry 7:254-275.Greig NH, Fredericks WR, Holloway HW, Soncrant TT, Rapoport SI (1988) Delivery of human interferon-alpha to brain by transient osmotic blood-brain barrier modification in the rat. J Pharmacol Exp Ther 245:581-586.Guo J, Zhang W, Zhang L, Ding H, Zhang J, Song C, Zhang Y, Xia N, Li M, Liang Y (2016) Probable involvement of p11 with interferon alpha induced depression. Sci Rep 6:1-15.Haenisch B, Bilkei‐Gorzo A, Caron MG, Bönisch H (2009) Knockout of the norepinephrine transporter and pharmacologically diverse antidepressants prevent behavioral and brain neurotrophin alterations in two chronic stress models of depression. J Neurochem 111:403-416.Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM, Sinton CM, Sugiyama F, Yagami K-i, Goto K, Yanagisawa M (2001) Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30:345-354.Harris GC, Wimmer M, Aston-Jones G (2005) A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437:556-559.Hastings RS, Parsey RV, Oquendo MA, Arango V, Mann JJ (2004) Volumetric analysis of the prefrontal cortex, amygdala, and hippocampus in major depression. Neuropsychopharmacology 29:952-959.Hauser P, Khosla J, Aurora H, Laurin J, Kling M, Hill J, Gulati M, Thornton A, Schultz R, Valentine AD (2002) A prospective study of the incidence and open-label treatment of interferon-induced major depressive disorder in patients with hepatitis C. Mol Psychiatry 7:942-947.Heaton RK, Nelson LM, Thompson DS, Burks JS, Franklin GM (1985) Neuropsychological findings in relapsing-remitting and chronic-progressive multiple sclerosis. J Consult Clin Psychol 53:103.Hedlund PB, Huitron-Resendiz S, Henriksen SJ, Sutcliffe JG (2005) 5-HT7 receptor inhibition and inactivation induce antidepressantlike behavior and sleep pattern. Biol Psychiatry 58:831-837.Heinrichs M, Domes G (2008) Neuropeptides and social behaviour: effects of oxytocin and vasopressin in humans. Prog Brain Res 170:337-350.Horvath TL, Naftolin F, Kalra SP, Leranth C (1992) Neuropeptide-Y innervation of beta-endorphin-containing cells in the rat mediobasal hypothalamus: a light and electron microscopic double immunostaining analysis. Endocrinology 131:2461-2467.Inutsuka A, Yamanaka A (2013) The physiological role of orexin/hypocretin neurons in the regulation of sleep/wakefulness and neuroendocrine functions. Front Endocrinol (Lausanne) 4:18.Iqbal S, Hayman EG, Hong C, Stokum JA, Kurland DB, Gerzanich V, Simard JM (2016) Inducible nitric oxide synthase (NOS-2) in subarachnoid hemorrhage: Regulatory mechanisms and therapeutic implications. Brain circulation 2:8.Isella V, Iurlaro S, Piolti R, Ferrarese C, Frattola L, Appollonio I, Melzi P, Grimaldi M (2003) Physical anhedonia in Parkinson’s disease. J Neurol Neurosurg Psychiatry 74:1308-1311.Jarrard LE (1993) On the role of the hippocampus in learning and memory in the rat. Behav Neural Biol 60:9-26.Kajihara M, Montagnese S, Khanna P, Amodio P, Schapira AH, Dusheiko GM, Morgan MY (2010) Parkinsonism in patients with chronic hepatitis C treated with interferon-α2b: a report of two cases. Eur J Gastroenterol Hepatol 22:628-631.Kang HJ, Voleti B, Hajszan T, Rajkowska G, Stockmeier CA, Licznerski P, Lepack A, Majik MS, Jeong LS, Banasr M (2012) Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat Med 18:1413-1417.Kim JJ, Diamond DM (2002) The stressed hippocampus, synaptic plasticity and lost memories. Nature Reviews Neuroscience 3:453.Kim JJ, Rison RA, Fanselow MS (1993) Effects of amygdala, hippocampus, and periaqueductal gray lesions on short-and long-term contextual fear. Behav Neurosci 107:1093.Kirkwood JM, Ernstoff MS (1990) Role of Interferons in the Thearpy of Melanoma. J Invest Dermatol 95.Klawonn AM, Fritz M, Nilsson A, Bonaventura J, Shionoya K, Mirrasekhian E, Karlsson U, Jaarola M, Granseth B, Blomqvist A (2018) Motivational valence is determined by striatal melanocortin 4 receptors. The Journal of Clinical Investigation 128:3160-3170.Koob GF, Le Moal M (2001) Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24:97-129.Krystal AD, Benca RM, Kilduff TS (2013) Understanding the sleep-wake cycle: sleep, insomnia, and the orexin system. The Journal of clinical psychiatry 74:3-20.Kuteeva E, Hökfelt T, Wardi T, Ogren S (2008) Galanin, galanin receptor subtypes and depression-like behaviour. Cellular and molecular life sciences: CMLS 65:1854-1863.Lammel S, Lim BK, Malenka RC (2014) Reward and aversion in a heterogeneous midbrain dopamine system. Neuropharmacology 76:351-359.Legros J-J (2001) Inhibitory effect of oxytocin on corticotrope function in humans: are vasopressin and oxytocin ying–yang neurohormones? Psychoneuroendocrinology 26:649-655.Levenson JL, Fallon HJ (1993) Fluoxetine Treatment of Depression Caused by Interferon-α. American Journal of Gastroenterology (Springer Nature) 88.Levy DE, Kessler D, Pine R, Darnell J (1989) Cytoplasmic activation of ISGF3, the positive regulator of interferon-alpha-stimulated transcription, reconstituted in vitro. Genes Dev 3:1362-1371.Li N, Liu R-J, Dwyer JM, Banasr M, Lee B, Son H, Li X-Y, Aghajanian G, Duman RS (2011) Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 69:754-761.Lim BK, Huang KW, Grueter BA, Rothwell PE, Malenka RC (2012) Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens. Nature 487:183-189.Lin S, Storlien LH, Huang X-F (2000) Leptin receptor, NPY, POMC mRNA expression in the diet-induced obese mouse brain. Brain Res 875:89-95.Loomer HP, Saunders JC, Kline NS (1957) A clinical and pharmacodynamic evaluation of iproniazid as a psychic energizer. Psychiatr Res Rep Am Psychiatr Assoc.Lotrich FE (2009) Major depression during interferon-α treatment: vulnerability and prevention. Dialogues Clin Neurosci 11:417.M Schmidt F, C Kirkby K, Lichtblau N (2016) Inflammation and immune regulation as potential drug targets in antidepressant treatment. Curr Neuropharmacol 14:674-687.Mayer-Barber KD, Barber DL, Shenderov K, White SD, Wilson MS, Cheever A, Kugler D, Hieny S, Caspar P, Núñez G (2010) Cutting edge: caspase-1 independent IL-1β production is critical for host resistance to Mycobacterium tuberculosis and does not require TLR signaling in vivo. The Journal of Immunology 184:3326-3330.Melén K, Kinnunen L, Julkunen I (2001) Arginine/lysine-rich structural element is involved in interferon-induced nuclear import of STATs. J Biol Chem 276:16447-16455.Menard C, Pfau ML, Hodes GE, Kana V, Wang VX, Bouchard S, Takahashi A, Flanigan ME, Aleyasin H, LeClair KB (2017) Social stress induces neurovascular pathology promoting depression. Nat Neurosci 20:1752-1760.Mervaala E, Föhr J, Könönen M, Valkonen-Korhonen M, Vainio P, Partanen K, Partanen J, Tiihonen J, Viinamäki H, Karjalainen A-K (2000) Quantitative MRI of the hippocampus and amygdala in severe depression. Psychol Med 30:117-125.Meyer JH, Krüger S, Wilson AA, Christensen BK, Goulding VS, Schaffer A, Minifie C, Houle S, Hussey D, Kennedy SH (2001) Lower dopamine transporter binding potential in striatum during depression. Neuroreport 12:4121-4125.Meynen G, Unmehopa UA, van Heerikhuize JJ, Hofman MA, Swaab DF, Hoogendijk WJ (2006) Increased arginine vasopressin mRNA expression in the human hypothalamus in depression: a preliminary report. Biol Psychiatry 60:892-895.Miller AH, Raison CL (2016) The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nature reviews immunology 16:22.Montgomery SA (1997) Reboxetine: additional benefits to the depressed patient. Journal of psychopharmacology (Oxford, England) 11:S9.Murakami Y, Ishibashi T, Tomita E, Imamura Y, Tashiro T, Watcharanurak K, Nishikawa M, Takahashi Y, Takakura Y, Mitani S (2016) Depressive symptoms as a side effect of Interferon-α therapy induced by induction of indoleamine 2, 3-dioxygenase 1. Sci Rep 6:1-12.Nazimek K, Strobel S, Bryniarski P, Kozlowski M, Filipczak-Bryniarska I, Bryniarski K (2017) The role of macrophages in anti-inflammatory activity of antidepressant drugs. Immunobiology 222:823-830.Nestler EJ, Carlezon Jr WA (2006) The mesolimbic dopamine reward circuit in depression. Biol Psychiatry 59:1151-1159.Nie X, Kitaoka S, Tanaka K, Segi-Nishida E, Imoto Y, Ogawa A, Nakano F, Tomohiro A, Nakayama K, Taniguchi M (2018) The innate immune receptors TLR2/4 mediate repeated social defeat stress-induced social avoidance through prefrontal microglial activation. Neuron 99:464-479. e467.Nishi A, Kuroiwa M, Shuto T (2011) Mechanisms for the modulation of dopamine D1 receptor signaling in striatal neurons. Front Neuroanat 5:43.Novikov A, Cardone M, Thompson R, Shenderov K, Kirschman KD, Mayer-Barber KD, Myers TG, Rabin RL, Trinchieri G, Sher A (2011) Mycobacterium tuberculosis triggers host type I IFN signaling to regulate IL-1β production in human macrophages. The journal of immunology 187:2540-2547.Ogawa Y, Kanbayashi T, Yano T, Sawaishi Y, Saito Y, Shimizu T (2003) Cerebrospinal fluid‐orexin decreases during intraventricular α‐interferon therapy of the patients with subacute sclerosing panencephalitis. Sleep Biol Rhythms 1:143-145.Ozsoy S, Esel E, Kula M (2009) Serum oxytocin levels in patients with depression and the effects of gender and antidepressant treatment. Psychiatry Res 169:249-252.Pariante CM, Lightman SL (2008) The HPA axis in major depression: classical theories and new developments. Trends Neurosci 31:464-468.Perry VH, Holmes C (2014) Microglial priming in neurodegenerative disease. Nature Reviews Neurology 10:217-224.Ragimbeau J, Dondi E, Alcover A, Eid P, Uzé G, Pellegrini S (2003) The tyrosine kinase Tyk2 controls IFNAR1 cell surface expression. The EMBO journal 22:537-547.Raison CL, Rye DB, Woolwine BJ, Vogt GJ, Bautista BM, Spivey JR, Miller AH (2010) Chronic interferon-alpha administration disrupts sleep continuity and depth in patients with hepatitis C: association with fatigue, motor slowing, and increased evening cortisol. Biol Psychiatry 68:942-949.Raison CL, Borisov AS, Broadwell SD, Capuron L, Woolwine BJ, Jacobson IM, Nemeroff CB, Miller AH (2005) Depression during pegylated interferon-alpha plus ribavirin therapy: prevalence and prediction. The Journal of clinical psychiatry 66:41.Ramboz S, Oosting R, Amara DA, Kung HF, Blier P, Mendelsohn M, Mann JJ, Brunner D, Hen R (1998) Serotonin receptor 1A knockout: an animal model of anxiety-related disorder. Proceedings of the National Academy of Sciences 95:14476-14481.Reich N, Evans B, Levy D, Fahey D, Knight E, Darnell J (1987) Interferon-induced transcription of a gene encoding a 15-kDa protein depends on an upstream enhancer element. Proceedings of the National Academy of Sciences 84:6394-6398.Reyes-Vázquez C, Prieto-Gómez B, Dafny N (2012) Interferon modulates central nervous system function. Brain Res 1442:76-89.Rose-John S (2018) Interleukin-6 family cytokines. Cold Spring Harb Perspect Biol 10:a028415.Ross S, Renyi A (1969) Inhibition of the uptake of tritiated 5-hydroxytryptamine in brain tissue. Eur J Pharmacol 7:270-277.Saal D, Dong Y, Bonci A, Malenka RC (2003) Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron 37:577-582.Saracco G, Olivero A, Ciancio A, Carenzi S, Rizzetto M (2003) Therapy of chronic hepatitis C: a critical review. Current Drug Targets-Infectious Disorders 3:25-32.Schindler C, Fu X-Y, Improta T, Aebersold R, Darnell JE (1992) Proteins of transcription factor ISGF-3: one gene encodes the 91-and 84-kDa ISGF-3 proteins that are activated by interferon alpha. Proceedings of the National Academy of Sciences 89:7836-7839.Schneider WM, Chevillotte MD, Rice CM (2014) Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol 32:513-545.Schultz W (1998) Predictive reward signal of dopamine neurons. J Neurophysiol 80:1-27.Sheline YI (2011) Depression and the hippocampus: cause or effect? Biol Psychiatry 70:308.Shi L, Fatemi SH, Sidwell RW, Patterson PH (2003) Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. Journal of Neuroscience 23:297-302.Smith AS, Ågmo A, Birnie AK, French JA (2010) Manipulation of the oxytocin system alters social behavior and attraction in pair-bonding primates, Callithrix penicillata. Horm Behav 57:255-262.Smith RA, Norris F, Palmer D, Bernhardt L, Wills RJ (1985) Distribution of alpha interferon in serum and cerebrospinal fluid after systemic administration. Clin Pharmacol Ther 37:85-88.Sofroniew MV (2015a) Astrocyte barriers to neurotoxic inflammation. Nature Reviews Neuroscience 16:249-263.Sofroniew MV (2015b) Astrogliosis. Cold Spring Harb Perspect Biol 7:a020420.Stevenson CW, Gratton A (2004) Basolateral amygdala dopamine receptor antagonism modulates initial reactivity to but not habituation of the acoustic startle response. Behav Brain Res 153:383-387.Strauss GP, Gold JM (2012) A new perspective on anhedonia in schizophrenia. Am J Psychiatry 169:364-373.Sullivan RM, Dufresne MM (2006) Mesocortical dopamine and HPA axis regulation: role of laterality and early environment. Brain Res 1076:49-59.Tatsumi M, Groshan K, Blakely RD, Richelson E (1997) Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol 340:249-258.Thurzó B, Jászberényi M, Bagosi Z, Pataki I, Kádár E, Szabó G, Telegdy G (2016) Evidence of the dopamine-2 receptor mediated inhibition of the hypothalamic-pituitary-adrenal system; a rodent model of hypercortisolism in chronic neuropsychiatric disorders.Träskman L, Åsberg M, Bertilsson L, Sjüstrand L (1981) Monoamine metabolites in CSF and suicidal behavior. Arch Gen Psychiatry 38:631-636.Tsai H-C, Zhang F, Adamantidis A, Stuber GD, Bonci A, De Lecea L, Deisseroth K (2009) Phasic firing in dopaminergic neurons is sufficient for behavioral conditioning. Science 324:1080-1084.Turan T, Uysal C, Asdemir A, Kılıç E (2013) May oxytocin be a trait marker for bipolar disorder? Psychoneuroendocrinology 38:2890-2896.Tye KM, Mirzabekov JJ, Warden MR, Ferenczi EA, Tsai H-C, Finkelstein J, Kim S-Y, Adhikari A, Thompson KR, Andalman AS (2013) Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature 493:537-541.Verkhratsky A, Sofroniew MV, Messing A, deLanerolle NC, Rempe D, Rodríguez JJ, Nedergaard M (2012) Neurological diseases as primary gliopathies: a reassessment of neurocentrism. ASN Neuro 4:AN20120010.Wachholz S, Eßlinger M, Plümper J, Manitz M-P, Juckel G, Friebe A (2016) Microglia activation is associated with IFN-α induced depressive-like behavior. Brain Behav Immun 55:105-113.Wang J, Campbell I, Zhang H (2008) Systemic interferon-α regulates interferon-stimulated genes in the central nervous system. Mol Psychiatry 13:293-301.Willner P, Lappas S, Cheeta S, Muscat R (1994) Reversal of stress-induced anhedonia by the dopamine receptor agonist, pramipexole. Psychopharmacology (Berl) 115:454-462.Willner P, Towell A, Sampson D, Sophokleous S, Muscat R (1987) Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacology (Berl) 93:358-364.Wise RA (1996) Addictive drugs and brain stimulation reward. Annu Rev Neurosci 19:319-340.Yohn CN, Gergues MM, Samuels BA (2017) The role of 5-HT receptors in depression. Mol Brain 10:1-12.Zhang H, Wang W, Jiang Z, Shang J, Zhang L (2010) Differential involvement of 5-HT1A and 5-HT1B/1D receptors in human interferon-alpha-induced immobility in the mouse forced swimming test. Arzneimittelforschung 60:109-115.Zheng L-S, Kaneko N, Sawamoto K (2015) Minocycline treatment ameliorates interferon-alpha-induced neurogenic defects and depression-like behaviors in mice. Front Cell Neurosci 9:5.Zheng L-S, Hitoshi S, Kaneko N, Takao K, Miyakawa T, Tanaka Y, Xia H, Kalinke U, Kudo K, Kanba S (2014) Mechanisms for interferon-α-induced depression and neural stem cell dysfunction. Stem cell reports 3:73-84. 描述 碩士
國立政治大學
神經科學研究所
107754001資料來源 http://thesis.lib.nccu.edu.tw/record/#G0107754001 資料類型 thesis dc.contributor.advisor 陳紹寬<br>廖瑞銘 zh_TW dc.contributor.advisor Chen, Shau-Kwaun<br>Liao, Ruey-Ming en_US dc.contributor.author (Authors) 張凱傑 zh_TW dc.contributor.author (Authors) Chang, Kai-Chieh en_US dc.creator (作者) 張凱傑 zh_TW dc.creator (作者) Chang, Kai-Chieh en_US dc.date (日期) 2021 en_US dc.date.accessioned 1-七月-2021 19:57:45 (UTC+8) - dc.date.available 1-七月-2021 19:57:45 (UTC+8) - dc.date.issued (上傳時間) 1-七月-2021 19:57:45 (UTC+8) - dc.identifier (Other Identifiers) G0107754001 en_US dc.identifier.uri (URI) http://nccur.lib.nccu.edu.tw/handle/140.119/135983 - dc.description (描述) 碩士 zh_TW dc.description (描述) 國立政治大學 zh_TW dc.description (描述) 神經科學研究所 zh_TW dc.description (描述) 107754001 zh_TW dc.description.abstract (摘要) 臨床研究中發現，長期的發炎與憂鬱症有緊密的關聯。然而，發炎與重度憂鬱症(Major Depression Disorder, MDD)之間的因果關係與病理機制尚未釐清。干擾素-α (IFN-α)屬於第一類型的干擾素。常被用於治療自體免疫性疾病，病毒性疾病和癌症。然而長期使用IFN-α也會導致憂鬱。長期接受IFN-α治療的患者中大約有15％至40％被診斷患有憂鬱症，由於使用IFN-α也會誘導發炎，因此長期使用IFN-α導致憂鬱的分子機制可能與發炎引起憂鬱的機制相似。長期注射IFN-α的小鼠也會引起類似憂鬱的行為表現，因此可用做IFN-α導致憂鬱的動物模式。前人研究發現，大腦中發炎及微膠質細胞的活化，及神經細胞的IFN-α受體的訊息傳導被活化，均與此異常行為的發生有密切的關聯。本研究旨在了解第一類型干擾素誘導憂鬱症的細胞分子機制，透過為期四周的腹腔注射IFN-α來誘導小鼠出現憂鬱行為，包括懸尾實驗以及強迫游泳中的僵直時間會更長，糖水偏好測試中糖水的飲用量減少，相比之下透過施打IFN-α處理的小鼠在高腳十字迷宮和開放場域的行為測試中並未出現焦慮行為。我們透過文獻回顧挑選在憂鬱症的致病中幾個關鍵的大腦核區，包括前額葉皮質、依核、海馬迴、杏仁核以及下視丘，並檢驗在各腦區干擾素是否可直接作用，及是否造成發炎。我們檢驗在這些腦區中干擾素訊息傳遞的下游基因IFNRA、IRF1和STAT1，以及發炎因子TNF-α和iNOS等的基因表現。我們發現干擾素可直接作用在下視丘中，並引起發炎。另在海馬迴中干擾素訊息傳遞的下游基因表現也顯著上升，但並未有發炎的現象。因此干擾素引起憂鬱可能是先作用在下視丘或海馬迴，再進一步影響血清素及多巴胺等系統。我們進一步對施打了IFN-α的下視丘中數種神經胜肽的表現進行分析，發現許多神經胜肽的mRNA表現量有所抑制。另外在海馬迴以及杏仁核中我們發現PKA活性受到抑制。總而言之我們的實驗結果顯示，IFN-α在腹腔施打在大腦中的初級作用點應為下視丘或海馬迴，可能經由造成神經胜肽的功能低下後進一步造成憂鬱的症狀，我們的發現將會提供有關IFN-α與憂鬱症之間的致病機制的重要資訊及新的研究方向。 zh_TW dc.description.abstract (摘要) Clinical studies revealed that inflammation is highly associated with the pathogenesis of major depression disorder (MDD). However, the causative relationship and the cellular and molecular mechanisms of inflammation induced MDD have not been established. Type I interferons, such as Interferon-alpha (IFN-α), function as an inflammatory regulator that displays a unique pharmacological profile, including induce pro-inflammatory cytokines and prevent the virus producing and replicating the RNA and DNA. Based on these pharmacological characteristics, IFN-α is often used for treating the autoimmune disease, viral disease, and various cancers. Chronic treatment of IFN-α leads to one notable adverse side effect: depression. About 15% to 40% of patients were diagnosed with depression after receiving IFN-α treatment for several months. The mechanisms of IFN-α induced depression might be similar to the mechanisms underlying inflammation induced depression. Therefore, the IFN-α can be used as an animal model of depression. Previous studies suggested that the activation of myeloid cells, including microglia and perivascular macrophages, contributes to IFN-α induced depression. Additionally, the phenotypes of conditional mutants indicated that IFN-α Signaling in neurons is essential for the onset of the pathological behavior. This study aimed to understand the cellular and molecular mechanism of type-I interferon induced depression. Daily injected with IFN-α through intraperitoneal route for four weeks induced depressive like behavior, including longer immobility time in tail suspension and forced swim test, as well as reduced sugar intake in sucrose preference test. In comparison, these IFN-α treated mice did not exhibit anxiety-like behavior in elevated plus maze and open field test. We first identify the primary target brain regions of IFN-α. Five brain regions that are involved in depression, including hypothalamus, amygdala, nucleus accumbens, hippocampus and prefrontal cortex, were examined. The expression of inflammatory genes, TNF-α and iNOS, as well as the downstream genes of interferon signaling, IFNRA, IRF1 and STAT1, were determined. As we expected, our preliminary data suggested that inflammatory genes and interferon signaling were only upregulated in hypothalamus, possibly due to the higher permeability to blood brain barrier as a circumventricular organ. Based on the above observations, we hypothesized that chronic treatment of IFN-α induces hypothalamic inflammation, disrupts the normal functions of neuropeptide system and trigger depressive like behavior or indirectly affect mesolimbic pathways to generate anhedonia. The expressions of various neuropeptide genes in the IFN-α treated hypothalamus were further evaluated. Numbers of neuropeptide mRNA level are decrease. In addition, IFN-α treatment downregulated the activation of protein kinase A, which is a major downstream target of monoaminergic receptors, in the hippocampus and amygdala. In conclusion, our results suggested IFN-α can directly suppress the functions of neuroendocrine system, and possibly in turn affect serotonergic or dopaminergic system. Our finding will provide important information about the pathological mechanisms of IFN-α induced depression. en_US dc.description.tableofcontents 謝致 I摘要 IIAbstract IV目錄 VI縮寫對照表 IX緒論 1文獻回顧 11. 憂鬱症 12. 干擾素α(Interferon alpha, IFN-α) 73. 憂鬱症相關大腦核區 10研究目的及策略 141. 研究目的及動機 142. 實驗設計 15材料與方法 171. 實驗設計及受試動物 172. 行為測試 173. 免疫組織染色(Immunohistochemistry, IHC) 184. 西方墨點(Western blot) 195. quantitative Polymerase Chain Reaction (qPCR) 206. Enzyme linked immunosorbent assay (ELISA) 207. 統計分析 21實驗結果 221. 長期施打IFN-α影響小鼠出現憂鬱行為 222. 腹腔施打IFN-α會在下視丘以及海馬迴活化IFN-α的訊息傳遞因子 233. IFN-α調節周邊免疫以及中樞神經系統的發炎反應 244. 施打IFN-α會導致下視丘的功能失調 275. 海馬迴以及杏仁核的蛋白酶A會因為IFN-α而發生改變 29討論 31實驗結果 36圖一 小鼠的在接受IFN-α後的基本生理體徵。 36圖二 在接受IFN-α後並不會誘發焦慮行為但會發生憂鬱行為。 38圖三 IFN-α調節下視丘中的IFN-α訊息傳遞路徑上的因子。 40圖四 IFN-α部分涉及調節前額葉皮質中的IFN-α訊息傳遞路徑上的因子。 41圖五 IFN-α不涉及調節依核中的IFN-α訊息傳遞路徑上的因子。 42圖六 IFN-α活化部分海馬迴中的IFN-α訊息傳遞路徑上的因子。 43圖七 IFN-α不涉及調節杏仁核中的IFN-α訊息傳遞路徑上的因子。 44圖八 長期施打干擾素會調節周邊免疫的發炎。 45圖九 小鼠下視丘的免疫細胞及免疫反應受到IFN-α而活化。 47圖十 IFN-α不參與調節前額葉皮質部分發炎因子的RNA表現量。 48圖十一 IFN-α不參與調節依核部分發炎因子的RNA表現量。 49圖十二 IFN-α不參與調節海馬迴中發炎因子的RNA表現量。 50圖十三 IFN-α不參與調節杏仁核中部分發炎因子的RNA表現量。 51圖十四 長期施打IFN-α的小鼠其行為及其大腦中的分子表現的相關值。 52圖十五HPA系統與IFN-α之間的相互作用。 53圖十六 下視丘分泌神經胜肽的功能異常。 54圖十七 大腦中蛋白酶A迴路的異常在接受IFN-α後的變化。 57圖十八: IFN-α引發憂鬱行為的假設。 58參考文獻 59附錄: 74附錄一:裂解緩衝液(Lysis Buffer)配方 74附錄二:loading dye配方 74附錄三:Running Gel 配方 74附錄四:Stacking Gel 配方 75附錄五:Tank Buffer 配方 75附錄六:Transfer Buffer 配方 75附錄七:RT混合液體 76附錄八:cDNA混合液體 76 zh_TW dc.format.extent 2458589 bytes - dc.format.mimetype application/pdf - dc.source.uri (資料來源) http://thesis.lib.nccu.edu.tw/record/#G0107754001 en_US dc.subject (關鍵詞) 憂鬱症 zh_TW dc.subject (關鍵詞) 干擾素-α zh_TW dc.subject (關鍵詞) 發炎 zh_TW dc.subject (關鍵詞) 下視丘 zh_TW dc.subject (關鍵詞) 海馬迴 zh_TW dc.subject (關鍵詞) 前額葉皮質 zh_TW dc.subject (關鍵詞) 依核 zh_TW dc.subject (關鍵詞) 杏仁核 zh_TW dc.subject (關鍵詞) Depression en_US dc.subject (關鍵詞) Interferon-alpha en_US dc.subject (關鍵詞) Inflammation en_US dc.subject (關鍵詞) Hypothalamus en_US dc.subject (關鍵詞) Hippocampus en_US dc.subject (關鍵詞) Prefrontal cortex en_US dc.subject (關鍵詞) Nucleus accumbens en_US dc.subject (關鍵詞) Amygdala en_US dc.title (題名) 干擾素引起小鼠憂鬱行為之細胞分子機制研究 zh_TW dc.title (題名) Investigating the cellular and molecular mechanisms underlying interferon-alpha (IFN-α) induced depressive-like behavior in the mouse en_US dc.type (資料類型) thesis en_US dc.relation.reference (參考文獻) Arion D, Unger T, Lewis DA, Levitt P, Mirnics K (2007) Molecular evidence for increased expression of genes related to immune and chaperone function in the prefrontal cortex in schizophrenia. Biol Psychiatry 62:711-721.Bhatti Z, Berenson CS (2007) Adult systemic cat scratch disease associated with therapy for hepatitis C. BMC Infect Dis 7:1-4.Boutrel B, Kenny PJ, Specio SE, Martin-Fardon R, Markou A, Koob GF, de Lecea L (2005) Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior. Proceedings of the National Academy of Sciences 102:19168-19173.Boyle MP, Brewer JA, Funatsu M, Wozniak DF, Tsien JZ, Izumi Y, Muglia LJ (2005) Acquired deficit of forebrain glucocorticoid receptor produces depression-like changes in adrenal axis regulation and behavior. Proceedings of the National Academy of Sciences 102:473-478.Brown AS, Derkits EJ (2010) Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry 167:261-280.Burguillos MA, Deierborg T, Kavanagh E, Persson A, Hajji N, Garcia-Quintanilla A, Cano J, Brundin P, Englund E, Venero JL (2011) Caspase signalling controls microglia activation and neurotoxicity. Nature 472:319-324.Burke HM, Davis MC, Otte C, Mohr DC (2005) Depression and cortisol responses to psychological stress: a meta-analysis. Psychoneuroendocrinology 30:846-856.Carson DS, Guastella AJ, Taylor ER, McGregor IS (2013) A brief history of oxytocin and its role in modulating psychostimulant effects. Journal of psychopharmacology 27:231-247.Carswell E, Old LJ, Kassel R, Green S, Fiore N, Williamson B (1975) An endotoxin-induced serum factor that causes necrosis of tumors. Proceedings of the National Academy of Sciences 72:3666-3670.Chan SW, Harmer CJ, Norbury R, O’Sullivan U, Goodwin GM, Portella MJ (2016) Hippocampal volume in vulnerability and resilience to depression. J Affect Disord 189:199-202.Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98:437-451.Cryan JF, Mombereau C (2004) In search of a depressed mouse: utility of models for studying depression-related behavior in genetically modified mice. Mol Psychiatry 9:326-357.D`haenen HA, Bossuyt A (1994) Dopamine D2 receptors in depression measured with single photon emission computed tomography. Biol Psychiatry 35:128-132.Dai D, Li Q-C, Zhu Q-B, Hu S-H, Balesar R, Swaab D, Bao A-M (2017) Direct involvement of androgen receptor in oxytocin gene expression: possible relevance for mood disorders. Neuropsychopharmacology 42:2064-2071.Dantzer R, O`Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nature reviews neuroscience 9:46-56.Decourt B, K Lahiri D, N Sabbagh M (2017) Targeting tumor necrosis factor alpha for Alzheimer’s disease. Current Alzheimer Research 14:412-425.Deuschle M, Schweiger U, Weber B, Gotthardt U, Körner A, Schmider J, Standhardt H, Lammers C-H, Heuser I (1997) Diurnal activity and pulsatility of the hypothalamus-pituitary-adrenal system in male depressed patients and healthy controls. The Journal of Clinical Endocrinology & Metabolism 82:234-238.Diorio D, Viau V, Meaney MJ (1993) The role of the medial prefrontal cortex (cingulate gyrus) in the regulation of hypothalamic-pituitary-adrenal responses to stress. Journal of Neuroscience 13:3839-3847.Eaton WW, Byrne M, Ewald H, Mors O, Chen C-Y, Agerbo E, Mortensen PB (2006) Association of schizophrenia and autoimmune diseases: linkage of Danish national registers. Am J Psychiatry 163:521-528.Ehrlich I, Humeau Y, Grenier F, Ciocchi S, Herry C, Lüthi A (2009) Amygdala inhibitory circuits and the control of fear memory. Neuron 62:757-771.Engelmann M, Landgraf R, Wotjak CT (2004) The hypothalamic–neurohypophysial system regulates the hypothalamic–pituitary–adrenal axis under stress: an old concept revisited. Front Neuroendocrinol 25:132-149.Everitt BJ, Parkinson JA, Olmstead MC, Arroyo M, Robledo P, Robbins TW (1999) Associative processes in addiction and reward the role of amygdala‐ventral striatal subsystems. Ann N Y Acad Sci 877:412-438.Eyding D, Lelgemann M, Grouven U, Härter M, Kromp M, Kaiser T, Kerekes MF, Gerken M, Wieseler B (2010) Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials. BMJ 341:c4737.Fahey B, Hickey B, Kelleher D, O’Dwyer A-M, O’Mara SM (2007) The widely-used anti-viral drug interferon-alpha induces depressive-and anxiogenic-like effects in healthy rats. Behav Brain Res 182:80-87.Fang FC (2004) Antimicrobial reactive oxygen and nitrogen species: concepts and controversies. Nature Reviews Microbiology 2:820-832.Felger JC, Alagbe O, Hu F, Mook D, Freeman AA, Sanchez MM, Kalin NH, Ratti E, Nemeroff CB, Miller AH (2007) Effects of interferon-alpha on rhesus monkeys: a nonhuman primate model of cytokine-induced depression. Biol Psychiatry 62:1324-1333.Felger JC, Mun J, Kimmel HL, Nye JA, Drake DF, Hernandez CR, Freeman AA, Rye DB, Goodman MM, Howell LL (2013) Chronic interferon-α decreases dopamine 2 receptor binding and striatal dopamine release in association with anhedonia-like behavior in nonhuman primates. Neuropsychopharmacology 38:2179-2187.Fienberg AA, Greengard P (2000) The DARPP-32 knockout mouse. Brain Res Brain Res Rev 31:313-319.Fioravanti J, Medina-Echeverz J, Ardaiz N, Gomar C, Parra-Guillén ZP, Prieto J, Berraondo P (2012) The fusion protein of IFN-α and apolipoprotein AI crosses the blood–brain barrier by a saturable transport mechanism. The Journal of Immunology 188:3988-3992.Frank MG, Baratta MV, Sprunger DB, Watkins LR, Maier SF (2007) Microglia serve as a neuroimmune substrate for stress-induced potentiation of CNS pro-inflammatory cytokine responses. Brain Behav Immun 21:47-59.Freeman MR, Rowitch DH (2013) Evolving concepts of gliogenesis: a look way back and ahead to the next 25 years. Neuron 80:613-623.Fry M, Ferguson AV (2007) The sensory circumventricular organs: brain targets for circulating signals controlling ingestive behavior. Physiol Behav 91:413-423.Fu X-Y, Kessler DS, Veals SA, Levy DE, Darnell J (1990) ISGF3, the transcriptional activator induced by interferon alpha, consists of multiple interacting polypeptide chains. Proceedings of the National Academy of Sciences 87:8555-8559.Gauzzi MC, Barbieri G, Richter MF, Uzé G, Ling L, Fellous M, Pellegrini S (1997) The amino-terminal region of Tyk2 sustains the level of interferon α receptor 1, a component of the interferon α/β receptor. Proceedings of the National Academy of Sciences 94:11839-11844.Gawin FH, Kleber HD (1986) Abstinence symptomatology and psychiatric diagnosis in cocaine abusers: clinical observations. Arch Gen Psychiatry 43:107-113.Gold P, Chrousos G (2002) Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Mol Psychiatry 7:254-275.Greig NH, Fredericks WR, Holloway HW, Soncrant TT, Rapoport SI (1988) Delivery of human interferon-alpha to brain by transient osmotic blood-brain barrier modification in the rat. J Pharmacol Exp Ther 245:581-586.Guo J, Zhang W, Zhang L, Ding H, Zhang J, Song C, Zhang Y, Xia N, Li M, Liang Y (2016) Probable involvement of p11 with interferon alpha induced depression. Sci Rep 6:1-15.Haenisch B, Bilkei‐Gorzo A, Caron MG, Bönisch H (2009) Knockout of the norepinephrine transporter and pharmacologically diverse antidepressants prevent behavioral and brain neurotrophin alterations in two chronic stress models of depression. J Neurochem 111:403-416.Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM, Sinton CM, Sugiyama F, Yagami K-i, Goto K, Yanagisawa M (2001) Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30:345-354.Harris GC, Wimmer M, Aston-Jones G (2005) A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437:556-559.Hastings RS, Parsey RV, Oquendo MA, Arango V, Mann JJ (2004) Volumetric analysis of the prefrontal cortex, amygdala, and hippocampus in major depression. Neuropsychopharmacology 29:952-959.Hauser P, Khosla J, Aurora H, Laurin J, Kling M, Hill J, Gulati M, Thornton A, Schultz R, Valentine AD (2002) A prospective study of the incidence and open-label treatment of interferon-induced major depressive disorder in patients with hepatitis C. Mol Psychiatry 7:942-947.Heaton RK, Nelson LM, Thompson DS, Burks JS, Franklin GM (1985) Neuropsychological findings in relapsing-remitting and chronic-progressive multiple sclerosis. J Consult Clin Psychol 53:103.Hedlund PB, Huitron-Resendiz S, Henriksen SJ, Sutcliffe JG (2005) 5-HT7 receptor inhibition and inactivation induce antidepressantlike behavior and sleep pattern. Biol Psychiatry 58:831-837.Heinrichs M, Domes G (2008) Neuropeptides and social behaviour: effects of oxytocin and vasopressin in humans. Prog Brain Res 170:337-350.Horvath TL, Naftolin F, Kalra SP, Leranth C (1992) Neuropeptide-Y innervation of beta-endorphin-containing cells in the rat mediobasal hypothalamus: a light and electron microscopic double immunostaining analysis. Endocrinology 131:2461-2467.Inutsuka A, Yamanaka A (2013) The physiological role of orexin/hypocretin neurons in the regulation of sleep/wakefulness and neuroendocrine functions. Front Endocrinol (Lausanne) 4:18.Iqbal S, Hayman EG, Hong C, Stokum JA, Kurland DB, Gerzanich V, Simard JM (2016) Inducible nitric oxide synthase (NOS-2) in subarachnoid hemorrhage: Regulatory mechanisms and therapeutic implications. Brain circulation 2:8.Isella V, Iurlaro S, Piolti R, Ferrarese C, Frattola L, Appollonio I, Melzi P, Grimaldi M (2003) Physical anhedonia in Parkinson’s disease. J Neurol Neurosurg Psychiatry 74:1308-1311.Jarrard LE (1993) On the role of the hippocampus in learning and memory in the rat. Behav Neural Biol 60:9-26.Kajihara M, Montagnese S, Khanna P, Amodio P, Schapira AH, Dusheiko GM, Morgan MY (2010) Parkinsonism in patients with chronic hepatitis C treated with interferon-α2b: a report of two cases. Eur J Gastroenterol Hepatol 22:628-631.Kang HJ, Voleti B, Hajszan T, Rajkowska G, Stockmeier CA, Licznerski P, Lepack A, Majik MS, Jeong LS, Banasr M (2012) Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat Med 18:1413-1417.Kim JJ, Diamond DM (2002) The stressed hippocampus, synaptic plasticity and lost memories. Nature Reviews Neuroscience 3:453.Kim JJ, Rison RA, Fanselow MS (1993) Effects of amygdala, hippocampus, and periaqueductal gray lesions on short-and long-term contextual fear. Behav Neurosci 107:1093.Kirkwood JM, Ernstoff MS (1990) Role of Interferons in the Thearpy of Melanoma. J Invest Dermatol 95.Klawonn AM, Fritz M, Nilsson A, Bonaventura J, Shionoya K, Mirrasekhian E, Karlsson U, Jaarola M, Granseth B, Blomqvist A (2018) Motivational valence is determined by striatal melanocortin 4 receptors. The Journal of Clinical Investigation 128:3160-3170.Koob GF, Le Moal M (2001) Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24:97-129.Krystal AD, Benca RM, Kilduff TS (2013) Understanding the sleep-wake cycle: sleep, insomnia, and the orexin system. The Journal of clinical psychiatry 74:3-20.Kuteeva E, Hökfelt T, Wardi T, Ogren S (2008) Galanin, galanin receptor subtypes and depression-like behaviour. Cellular and molecular life sciences: CMLS 65:1854-1863.Lammel S, Lim BK, Malenka RC (2014) Reward and aversion in a heterogeneous midbrain dopamine system. Neuropharmacology 76:351-359.Legros J-J (2001) Inhibitory effect of oxytocin on corticotrope function in humans: are vasopressin and oxytocin ying–yang neurohormones? Psychoneuroendocrinology 26:649-655.Levenson JL, Fallon HJ (1993) Fluoxetine Treatment of Depression Caused by Interferon-α. American Journal of Gastroenterology (Springer Nature) 88.Levy DE, Kessler D, Pine R, Darnell J (1989) Cytoplasmic activation of ISGF3, the positive regulator of interferon-alpha-stimulated transcription, reconstituted in vitro. Genes Dev 3:1362-1371.Li N, Liu R-J, Dwyer JM, Banasr M, Lee B, Son H, Li X-Y, Aghajanian G, Duman RS (2011) Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 69:754-761.Lim BK, Huang KW, Grueter BA, Rothwell PE, Malenka RC (2012) Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens. Nature 487:183-189.Lin S, Storlien LH, Huang X-F (2000) Leptin receptor, NPY, POMC mRNA expression in the diet-induced obese mouse brain. Brain Res 875:89-95.Loomer HP, Saunders JC, Kline NS (1957) A clinical and pharmacodynamic evaluation of iproniazid as a psychic energizer. Psychiatr Res Rep Am Psychiatr Assoc.Lotrich FE (2009) Major depression during interferon-α treatment: vulnerability and prevention. Dialogues Clin Neurosci 11:417.M Schmidt F, C Kirkby K, Lichtblau N (2016) Inflammation and immune regulation as potential drug targets in antidepressant treatment. Curr Neuropharmacol 14:674-687.Mayer-Barber KD, Barber DL, Shenderov K, White SD, Wilson MS, Cheever A, Kugler D, Hieny S, Caspar P, Núñez G (2010) Cutting edge: caspase-1 independent IL-1β production is critical for host resistance to Mycobacterium tuberculosis and does not require TLR signaling in vivo. The Journal of Immunology 184:3326-3330.Melén K, Kinnunen L, Julkunen I (2001) Arginine/lysine-rich structural element is involved in interferon-induced nuclear import of STATs. J Biol Chem 276:16447-16455.Menard C, Pfau ML, Hodes GE, Kana V, Wang VX, Bouchard S, Takahashi A, Flanigan ME, Aleyasin H, LeClair KB (2017) Social stress induces neurovascular pathology promoting depression. Nat Neurosci 20:1752-1760.Mervaala E, Föhr J, Könönen M, Valkonen-Korhonen M, Vainio P, Partanen K, Partanen J, Tiihonen J, Viinamäki H, Karjalainen A-K (2000) Quantitative MRI of the hippocampus and amygdala in severe depression. Psychol Med 30:117-125.Meyer JH, Krüger S, Wilson AA, Christensen BK, Goulding VS, Schaffer A, Minifie C, Houle S, Hussey D, Kennedy SH (2001) Lower dopamine transporter binding potential in striatum during depression. Neuroreport 12:4121-4125.Meynen G, Unmehopa UA, van Heerikhuize JJ, Hofman MA, Swaab DF, Hoogendijk WJ (2006) Increased arginine vasopressin mRNA expression in the human hypothalamus in depression: a preliminary report. Biol Psychiatry 60:892-895.Miller AH, Raison CL (2016) The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nature reviews immunology 16:22.Montgomery SA (1997) Reboxetine: additional benefits to the depressed patient. Journal of psychopharmacology (Oxford, England) 11:S9.Murakami Y, Ishibashi T, Tomita E, Imamura Y, Tashiro T, Watcharanurak K, Nishikawa M, Takahashi Y, Takakura Y, Mitani S (2016) Depressive symptoms as a side effect of Interferon-α therapy induced by induction of indoleamine 2, 3-dioxygenase 1. Sci Rep 6:1-12.Nazimek K, Strobel S, Bryniarski P, Kozlowski M, Filipczak-Bryniarska I, Bryniarski K (2017) The role of macrophages in anti-inflammatory activity of antidepressant drugs. Immunobiology 222:823-830.Nestler EJ, Carlezon Jr WA (2006) The mesolimbic dopamine reward circuit in depression. Biol Psychiatry 59:1151-1159.Nie X, Kitaoka S, Tanaka K, Segi-Nishida E, Imoto Y, Ogawa A, Nakano F, Tomohiro A, Nakayama K, Taniguchi M (2018) The innate immune receptors TLR2/4 mediate repeated social defeat stress-induced social avoidance through prefrontal microglial activation. Neuron 99:464-479. e467.Nishi A, Kuroiwa M, Shuto T (2011) Mechanisms for the modulation of dopamine D1 receptor signaling in striatal neurons. Front Neuroanat 5:43.Novikov A, Cardone M, Thompson R, Shenderov K, Kirschman KD, Mayer-Barber KD, Myers TG, Rabin RL, Trinchieri G, Sher A (2011) Mycobacterium tuberculosis triggers host type I IFN signaling to regulate IL-1β production in human macrophages. The journal of immunology 187:2540-2547.Ogawa Y, Kanbayashi T, Yano T, Sawaishi Y, Saito Y, Shimizu T (2003) Cerebrospinal fluid‐orexin decreases during intraventricular α‐interferon therapy of the patients with subacute sclerosing panencephalitis. Sleep Biol Rhythms 1:143-145.Ozsoy S, Esel E, Kula M (2009) Serum oxytocin levels in patients with depression and the effects of gender and antidepressant treatment. Psychiatry Res 169:249-252.Pariante CM, Lightman SL (2008) The HPA axis in major depression: classical theories and new developments. Trends Neurosci 31:464-468.Perry VH, Holmes C (2014) Microglial priming in neurodegenerative disease. Nature Reviews Neurology 10:217-224.Ragimbeau J, Dondi E, Alcover A, Eid P, Uzé G, Pellegrini S (2003) The tyrosine kinase Tyk2 controls IFNAR1 cell surface expression. The EMBO journal 22:537-547.Raison CL, Rye DB, Woolwine BJ, Vogt GJ, Bautista BM, Spivey JR, Miller AH (2010) Chronic interferon-alpha administration disrupts sleep continuity and depth in patients with hepatitis C: association with fatigue, motor slowing, and increased evening cortisol. Biol Psychiatry 68:942-949.Raison CL, Borisov AS, Broadwell SD, Capuron L, Woolwine BJ, Jacobson IM, Nemeroff CB, Miller AH (2005) Depression during pegylated interferon-alpha plus ribavirin therapy: prevalence and prediction. The Journal of clinical psychiatry 66:41.Ramboz S, Oosting R, Amara DA, Kung HF, Blier P, Mendelsohn M, Mann JJ, Brunner D, Hen R (1998) Serotonin receptor 1A knockout: an animal model of anxiety-related disorder. Proceedings of the National Academy of Sciences 95:14476-14481.Reich N, Evans B, Levy D, Fahey D, Knight E, Darnell J (1987) Interferon-induced transcription of a gene encoding a 15-kDa protein depends on an upstream enhancer element. Proceedings of the National Academy of Sciences 84:6394-6398.Reyes-Vázquez C, Prieto-Gómez B, Dafny N (2012) Interferon modulates central nervous system function. Brain Res 1442:76-89.Rose-John S (2018) Interleukin-6 family cytokines. Cold Spring Harb Perspect Biol 10:a028415.Ross S, Renyi A (1969) Inhibition of the uptake of tritiated 5-hydroxytryptamine in brain tissue. Eur J Pharmacol 7:270-277.Saal D, Dong Y, Bonci A, Malenka RC (2003) Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron 37:577-582.Saracco G, Olivero A, Ciancio A, Carenzi S, Rizzetto M (2003) Therapy of chronic hepatitis C: a critical review. Current Drug Targets-Infectious Disorders 3:25-32.Schindler C, Fu X-Y, Improta T, Aebersold R, Darnell JE (1992) Proteins of transcription factor ISGF-3: one gene encodes the 91-and 84-kDa ISGF-3 proteins that are activated by interferon alpha. Proceedings of the National Academy of Sciences 89:7836-7839.Schneider WM, Chevillotte MD, Rice CM (2014) Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol 32:513-545.Schultz W (1998) Predictive reward signal of dopamine neurons. J Neurophysiol 80:1-27.Sheline YI (2011) Depression and the hippocampus: cause or effect? Biol Psychiatry 70:308.Shi L, Fatemi SH, Sidwell RW, Patterson PH (2003) Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. Journal of Neuroscience 23:297-302.Smith AS, Ågmo A, Birnie AK, French JA (2010) Manipulation of the oxytocin system alters social behavior and attraction in pair-bonding primates, Callithrix penicillata. Horm Behav 57:255-262.Smith RA, Norris F, Palmer D, Bernhardt L, Wills RJ (1985) Distribution of alpha interferon in serum and cerebrospinal fluid after systemic administration. Clin Pharmacol Ther 37:85-88.Sofroniew MV (2015a) Astrocyte barriers to neurotoxic inflammation. Nature Reviews Neuroscience 16:249-263.Sofroniew MV (2015b) Astrogliosis. Cold Spring Harb Perspect Biol 7:a020420.Stevenson CW, Gratton A (2004) Basolateral amygdala dopamine receptor antagonism modulates initial reactivity to but not habituation of the acoustic startle response. Behav Brain Res 153:383-387.Strauss GP, Gold JM (2012) A new perspective on anhedonia in schizophrenia. Am J Psychiatry 169:364-373.Sullivan RM, Dufresne MM (2006) Mesocortical dopamine and HPA axis regulation: role of laterality and early environment. Brain Res 1076:49-59.Tatsumi M, Groshan K, Blakely RD, Richelson E (1997) Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol 340:249-258.Thurzó B, Jászberényi M, Bagosi Z, Pataki I, Kádár E, Szabó G, Telegdy G (2016) Evidence of the dopamine-2 receptor mediated inhibition of the hypothalamic-pituitary-adrenal system; a rodent model of hypercortisolism in chronic neuropsychiatric disorders.Träskman L, Åsberg M, Bertilsson L, Sjüstrand L (1981) Monoamine metabolites in CSF and suicidal behavior. Arch Gen Psychiatry 38:631-636.Tsai H-C, Zhang F, Adamantidis A, Stuber GD, Bonci A, De Lecea L, Deisseroth K (2009) Phasic firing in dopaminergic neurons is sufficient for behavioral conditioning. Science 324:1080-1084.Turan T, Uysal C, Asdemir A, Kılıç E (2013) May oxytocin be a trait marker for bipolar disorder? Psychoneuroendocrinology 38:2890-2896.Tye KM, Mirzabekov JJ, Warden MR, Ferenczi EA, Tsai H-C, Finkelstein J, Kim S-Y, Adhikari A, Thompson KR, Andalman AS (2013) Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature 493:537-541.Verkhratsky A, Sofroniew MV, Messing A, deLanerolle NC, Rempe D, Rodríguez JJ, Nedergaard M (2012) Neurological diseases as primary gliopathies: a reassessment of neurocentrism. ASN Neuro 4:AN20120010.Wachholz S, Eßlinger M, Plümper J, Manitz M-P, Juckel G, Friebe A (2016) Microglia activation is associated with IFN-α induced depressive-like behavior. Brain Behav Immun 55:105-113.Wang J, Campbell I, Zhang H (2008) Systemic interferon-α regulates interferon-stimulated genes in the central nervous system. Mol Psychiatry 13:293-301.Willner P, Lappas S, Cheeta S, Muscat R (1994) Reversal of stress-induced anhedonia by the dopamine receptor agonist, pramipexole. Psychopharmacology (Berl) 115:454-462.Willner P, Towell A, Sampson D, Sophokleous S, Muscat R (1987) Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacology (Berl) 93:358-364.Wise RA (1996) Addictive drugs and brain stimulation reward. Annu Rev Neurosci 19:319-340.Yohn CN, Gergues MM, Samuels BA (2017) The role of 5-HT receptors in depression. Mol Brain 10:1-12.Zhang H, Wang W, Jiang Z, Shang J, Zhang L (2010) Differential involvement of 5-HT1A and 5-HT1B/1D receptors in human interferon-alpha-induced immobility in the mouse forced swimming test. Arzneimittelforschung 60:109-115.Zheng L-S, Kaneko N, Sawamoto K (2015) Minocycline treatment ameliorates interferon-alpha-induced neurogenic defects and depression-like behaviors in mice. Front Cell Neurosci 9:5.Zheng L-S, Hitoshi S, Kaneko N, Takao K, Miyakawa T, Tanaka Y, Xia H, Kalinke U, Kudo K, Kanba S (2014) Mechanisms for interferon-α-induced depression and neural stem cell dysfunction. Stem cell reports 3:73-84. zh_TW dc.identifier.doi (DOI) 10.6814/NCCU202100467 en_US
