臺灣博碩士論文加值系統

食慾素 (orexin; OX)為下視丘產生的神經肽 (neuropeptide)，負責調控能量代謝與睡眠平衡，近年來也有許多研究指出食慾素系統失調是造成憂鬱症的原因之一，而懷孕時期受到細菌或病毒感染可能會造成胎兒大腦發育受損並造成胎兒罹患精神疾病如憂鬱症的風險上升，過去的實驗已經證實大鼠懷孕前期受到細菌內毒素脂多醣 (lipopolysaccharide; LPS)感染會造成子代成熟後表現類憂鬱行為，本實驗在母鼠 (Sprague Dawley; SD)懷孕10.5天 (E10.5)時利用腹腔注射低劑量 (20000U/kg)的LPS使母鼠產下具有憂鬱傾向的子代，再進一步探討具有憂鬱傾向的大鼠大腦內食慾素系統與一般大鼠之間的差異，實驗結果發現胚胎期受到LPS影響不會影響大鼠的體重與出生隻數，但是LPS大鼠下視丘內的OX-A和OX-B細胞數目會變少，並且降低LPS大鼠在受到強制游泳實驗 (forced swimming test; FST)或空間限制實驗 (restraint stress; RST)壓力時的OX-A細胞活化程度，並從線性關係分析中發現OX-A細胞活化程度與大鼠在FST中類憂鬱行為表現呈現負相關，而LPS的影響也使得LPS大鼠在受到FST或RST壓力時血液中皮脂酮 (corticosterone)異常升高與OX-A濃度異常降低，但是從蛋白質分析中觀察到，未受到壓力刺激時LPS大鼠多個與憂鬱情緒調控相關的腦區內前體蛋白 (prepro-OX)、OX-B和食慾素受體OXR-1、OXR-2並不會改變，我們推論胚胎期受到LPS的作用會改變身體內的食慾素系統，此改變可能參與大鼠類憂鬱行為的表現。

Orexins (OX) are neuropeptides produced by hypothalamus, which are responsible for energy metabolism and sleep-wake balance. In recent years, many studies have shown that the imbalance of orexin system might be one of the causes of depression. The infection of bacteria or viruses during pregnancy may result in fetal brain damage and increase the risk of psychiatric disorders such as depression in the offspring. Previous studies have shown that exposure to the bacterial endotoxin lipopolysaccharide (LPS) in early stage of pregnancy will produce offspring that exhibit depression-like behaviors in adulthood. In the present study, we injected low dose lipopolysaccharide (20000 U/kg, ip) to the pregnant rat (Sprague Dawley; SD) on early stage of pregnancy (E10.5) to produce offsping with depression-like behaviors. Then we investigated the differences in orexin system between the control rat and the rat with depression tendencies. The results indicate that embryonic exposure to LPS does not affect the body weight and birth number of the rat offspring. However, the numbers of orexin A (OX-A) and orexin (OX-B) neurons in the hypothalamus of LPS rats are significantly decreased. LPS treatment also reduces the activation of OX-A neurons when the rat is under the stress produced by forced swimming test (FST) or restraint stress test (RST). Furthermore, the linear regression analysis shows that the OX-A neuron activation has tendency to be negatively correlated with the immobile time of FST. In addition, prenatal LPS exposure makes the offspring exhibit unusually high corticosterone in the blood when they are stressd by FST or RST, while their serum OX-A level is significantly decreased. However, the protein experiments indicate that LPS treatment did not change the concentration of the prepro-OX, OX-B, and the orexin receptor 1 (OXR-1) and orexin receptor 2 (OXR-2) in several brain regions associated with depression during baseline period. In conclusion, our results provide evidences that prenatal LPS exposure will change orexin system and these change might participate on the expression of depression-like behaviors.

中文摘要 ⅰ
ABSTRACT ⅱ
目錄 ⅲ
圖目錄 ⅳ
縮寫表 ⅴ
第一章 緒論 1
1-1 憂鬱症 1
1-2 憂鬱症病因假說 2
1-3 大腦內食慾素系統 5
1-4 食慾素系統與憂鬱症相關研究 7
1-5 胚胎期感染 8
1-6 酯多糖 9
1-7 胚胎期暴露於酯多糖的憂鬱症動物模式 9
研究動機 11
研究目的 12
第二章 實驗材料 13
第三章 實驗結果 27
實驗一、利用胚胎期遭受LPS的憂鬱症動物模式比較憂鬱症大鼠與正常大鼠下視丘食慾素系統差異 27
實驗二、藉由胚胎期遭受LPS的憂鬱症動物模式探討大鼠類憂鬱行為的表現程度與OX-A、OX-B活化程度之間的關聯性 29
實驗三、比較憂鬱傾向大鼠與正常大鼠大腦中，和憂鬱行為相關的多個腦區內PREPRO OX和OX-B以及OXR-1, 2表現量差異 34
第四章 討論 38
第五章 結論 46
第六章 參考文獻 47
第七章 附錄 81

圖目錄
圖一、實驗設計與時間流程 58
圖二、施打LPS後並不會對懷孕的子代隻數與子代體重造成影響 59
圖三、不同年齡的LPS大鼠與CON大鼠下視丘內OX-A、OX-B神經細胞數目 的差異 62
圖四、LPS大鼠在強迫游泳實驗 (Forced swimming test, FST)的類憂鬱行為表現 63
圖五、大鼠經過FST後，下視丘OX-A、OX-B神經細胞活化情形 66
圖六、大鼠下視丘OX-A、OX-B神經細胞活化程度與FST中類憂鬱行為表現程度之相關性 67
圖七、大鼠經過空間限制壓力 (Restraint stress, RST)後下視丘OX-A、OX-B神經細胞活化情形 70
圖八、大鼠受到壓力時，血液中皮脂酮 (Corticosterone)濃度的變化 71
圖九、大鼠受到壓力時，血液中OX-A濃度的變化 72
圖十、大鼠內側前額葉皮質 (Medial prefrontal cortex)中Prepro OX、OX-B、OXR-1、OXR-2蛋白質表現 73
圖十一、大鼠伏隔核 (Nucleus accumbens)中Prepro OX、OX-B、OXR-1、OXR-2蛋白質表現 74
圖十二、大鼠丘腦室旁核 (Paraventricular nucleus of the thalamus)中Prepro OX、OX-B、OXR-1、OXR-2蛋白質表現 75
圖十三、大鼠下視丘 (Hypothalamus)中Prepro OX、OX-B、OXR-1、OXR-2蛋白質表現 76
圖十四、大鼠海馬迴齒狀部 (Dentate gyrus of hippocampus)中Prepro OX、OX-B、OXR-1、OXR-2蛋白質表現 77
圖十五、大鼠中央杏仁核 (Amygdala)中Prepro OX、OX-B、OXR-1、OXR-2蛋白質表現 78
圖十六、大鼠腹側背蓋區 (Ventral tegamental area)中Prepro OX、OX-B、OXR-1、OXR-2蛋白質表現 79
圖十七、大鼠中縫背核 (Dorsal raphe nucleus)中Prepro OX、OX-B、OXR-1蛋白質表現 80

Akbari, E., Naghdi, N., & Motamedi, F. (2007). The selective orexin 1 receptor antagonist SB-334867-A impairs acquisition and consolidation but not retrieval of spatial memory in Morris water maze. Peptides, 28(3), 650-656.
Allard, J. S., Tizabi, Y., Shaffery, J. P., Ovid Trouth, C., & Manaye, K. (2004). Stereological analysis of the hypothalamic hypocretin/orexin neurons in an animal model of depression. Neuropeptides, 38(5), 311-315.
Amiot, C., Brischoux, F., Colard, C., La Roche, A., Fellmann, D., & Risold, P. Y. (2005). Hypocretin/orexin-containing neurons are produced in one sharp peak in the developing ventral diencephalon. Eur J Neurosci, 22(2), 531-534.
Arendt, D. H., Ronan, P. J., Oliver, K. D., Callahan, L. B., Summers, T. R., & Summers, C. H. (2013). Depressive behavior and activation of the orexin/hypocretin system. Behav Neurosci, 127(1), 86-94.
Åsberg, M., Bertilsson, L., Mårtensson, B., Scalia-Tomba, G. P., Thorén, P., & Träskman-Bendz, L. (1984). CSF monoamine metabolites in melancholia. Acta Psychiatrica Scandinavica, 69(3), 201-219.
Baumann, C. R., Clark, E. L., Pedersen, N. P., Hecht, J. L., & Scammell, T. E. (2008). Do enteric neurons make hypocretin? Regul Pept, 147(1-3), 1-3.
Bransfield, R. C., Wulfman, J. S., Harvey, W. T., & Usman, A. I. (2008). The association between tick-borne infections, Lyme borreliosis and autism spectrum disorders. Medical Hypotheses, 70(5), 967-974.
Bremner, J. D., Narayan, M., Anderson, E. R., Staib, L. H., Miller, H. L., & Charney, D. S. (2000). Hippocampal Volume Reduction in Major Depression. American Journal of Psychiatry, 157(1), 115-118.
Coppen, A. (1967). The Biochemistry of Affective Disorders. The British Journal of Psychiatry, 113(504), 1237.
Cutter, W., Norbury, R., & Murphy, D. (2003). Oestrogen, brain function, and neuropsychiatric disorders. Journal of Neurology, Neurosurgery, and Psychiatry, 74(7), 837-840.
Dammann, O., & Leviton, A. (1998). Infection remote from the brain, neonatal white matter damage, and cerebral palsy in the preterm infant. Seminars in Pediatric Neurology, 5(3), 190-201.
Date, Y., Ueta, Y., Yamashita, H., Yamaguchi, H., Matsukura, S., Kangawa, K., Nakazato, M. (1999). Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proceedings of the National Academy of Sciences of the United States of America, 96(2), 748-753.
Deadwyler, S. A., Porrino, L., Siegel, J. M., & Hampson, R. E. (Eds.). (2007) The Journal of Neuroscience (Vols. 27).
Duman, R. S., Malberg, J., Nakagawa, S., & D’Sa, C. (2000). Neuronal plasticity and survival in mood disorders. Biological Psychiatry, 48(8), 732-739.
Eriksson, P. S., Perfilieva, E., Bjork-Eriksson, T., Alborn, A.-M., Nordborg, C., Peterson, D. A., & Gage, F. H. (1998). Neurogenesis in the adult human hippocampus. Nat Med, 4(11), 1313-1317.
España, R., & Calipari, E. (2012). Hypocretin/orexin regulation of dopamine signaling: implications for reward and reinforcement mechanisms. Frontiers in Behavioral Neuroscience, 6(54).
Fakhoury, M. (2014). Affective Disorders and Antidepressant Drugs. Open Access Library Journal, 1(05), 1.
Faro, S., & Fenner, D. E. (1998). Urinary tract infections. Clin Obstet Gynecol, 41(3), 744-754.
Ferrari, A. J., Charlson, F. J., Norman, R. E., Patten, S. B., Freedman, G., Murray, C. J. L., Whiteford, H. A. (2013). Burden of Depressive Disorders by Country, Sex, Age, and Year: Findings from the Global Burden of Disease Study 2010. PLOS Medicine, 10(11), e1001547.
Gayle, D. A., Beloosesky, R., Desai, M., Amidi, F., Nuñez, S. E., & Ross, M. G. (2004). Maternal LPS induces cytokines in the amniotic fluid and corticotropin releasing hormone in the fetal rat brain. American Journal of Physiology - Regulatory, Integrative and Comparative Physiology, 286(6), R1024.
Gould, E., Tanapat, P., McEwen, B. S., Flugge, G., & Fuchs, E. (1998). Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc Natl Acad Sci U S A, 95(6), 3168-3171.
Grafe, L. A., Cornfeld, A., Luz, S., Valentino, R., & Bhatnagar, S. (2017). Orexins Mediate Sex Differences in the Stress Response and in Cognitive Flexibility. Biological Psychiatry, 81(8), 683-692.
Haefner, H. K. (1999). Current evaluation and management of vulvovaginitis. Clin Obstet Gynecol, 42(2), 184-195.
Hanson, N. D., Owens, M. J., & Nemeroff, C. B. (2011). Depression, Antidepressants, and Neurogenesis: A Critical Reappraisal. Neuropsychopharmacology, 36(13), 2589-2602.
Hava, G., Vered, L., Yael, M., Mordechai, H., & Mahoud, H. (2006). Alterations in behavior in adult offspring mice following maternal inflammation during pregnancy. Dev Psychobiol, 48(2), 162-168.
Haynes, A. C., Jackson, B., Overend, P., Buckingham, R. E., Wilson, S., Tadayyon, M., & Arch, J. R. S. (1999). Effects of single and chronic intracerebroventricular administration of the orexins on feeding in the rat. Peptides, 20(9), 1099-1105.
Herbert, J., Goodyer, I. M., Grossman, A. B., Hastings, M. H., de Kloet, E. R., Lightman, S. L., Seckl, J. R. (2006). Do corticosteroids damage the brain? Neuroendocrinol, 18(6), 393-411.
Hoffman, G. E., Smith, M. S., & Verbalis, J. G. (1993). c-Fos and Related Immediate Early Gene Products as Markers of Activity in Neuroendocrine Systems. Frontiers in Neuroendocrinology, 14(3), 173-213.
Hunt, N. J., Rodriguez, M. L., Waters, K. A., & Machaalani, R. (2015). Changes in orexin (hypocretin) neuronal expression with normal aging in the human hypothalamus. Neurobiology of Aging, 36(1), 292-300.
IASP. (2012). World Health Organization, World suicide prevention day 2012.
Ito, N., Yabe, T., Gamo, Y., Nagai, T., Oikawa, T., Yamada, H., & Hanawa, T. (2008). I.c.v. administration of orexin-A induces an antidepressive-like effect through hippocampal cell proliferation. Neuroscience, 157(4), 720-732.
Ito, N., Yabe, T., Nagai, T., Oikawa, T., Yamada, H., & Hanawa, T. (2009). A possible mechanism underlying an antidepressive-like effect of Kososan, a Kampo medicine, via the hypothalamic orexinergic system in the stress-induced depression-like model mice. Biol Pharm Bull, 32(10), 1716-1722.
Jarskog, L. F., Xiao, H., Wilkie, M. B., Lauder, J. M., & Gilmore, J. H. (1997). Cytokine regulation of embryonic rat dopamine and serotonin neuronal survival in vitro. Int J Dev Neurosci, 15(6), 711-716.
Johren, O., Neidert, S. J., Kummer, M., Dendorfer, A., & Dominiak, P. (2001). Prepro-orexin and orexin receptor mRNAs are differentially expressed in peripheral tissues of male and female rats. Endocrinology, 142(8), 3324-3331.
Kalil, B., Leite, C. M., Carvalho-Lima, M., & Anselmo-Franci, J. A. (2013). Role of sex steroids in progesterone and corticosterone response to acute restraint stress in rats: sex differences. Stress, 16(4), 452-460.
Kastin, A. J., & Akerstrom, V. (1999). Orexin A but not orexin B rapidly enters brain from blood by simple diffusion. J Pharmacol Exp Ther, 289(1), 219-223.
Katsuki, H., & Akaike, A. (2004). Excitotoxic degeneration of hypothalamic orexin neurons in slice culture. Neurobiology of Disease, 15(1), 61-69.
Kendler, K. S., Gatz, M., Gardner, C. O., & Pedersen, N. L. (2006). A Swedish national twin study of lifetime major depression. Am J Psychiatry, 163(1), 109-114.
Kessler, B. A., Stanley, E. M., Frederick-Duus, D., & Fadel, J. (2011). Age-related loss of orexin/hypocretin neurons. Neuroscience, 178, 82-88.
Kirchgessner, A. L., & Liu, M. (1999). Orexin synthesis and response in the gut. Neuron, 24(4), 941-951.
Kokras, N., Antoniou, K., Mikail, H. G., Kafetzopoulos, V., Papadopoulou-Daifoti, Z., & Dalla, C. (2015). Forced swim test: What about females? Neuropharmacology, 99, 408-421.
Lauder, J. M. (1990). Ontogeny of the serotonergic system in the rat: serotonin as a developmental signal. Ann N Y Acad Sci, 600, 297-313; discussion 314.
Levinson, D. F. (2006). The genetics of depression: a review. Biol Psychiatry, 60(2), 84-92.
Lin, Y. L., Lin, S. Y., & Wang, S. (2012). Prenatal lipopolysaccharide exposure increases anxiety-like behaviors and enhances stress-induced corticosterone responses in adult rats. Brain Behav Immun, 26(3), 459-468.
Lin, Y. L., & Wang, S. (2014). Prenatal lipopolysaccharide exposure increases depression-like behaviors and reduces hippocampal neurogenesis in adult rats. Behav Brain Res, 259, 24-34.
Lohoff, F. W. (2010). Overview of the Genetics of Major Depressive Disorder. Current psychiatry reports, 12(6), 539-546.
Lutter, M., Krishnan, V., Russo, S. J., Jung, S., McClung, C. A., & Nestler, E. J. (2008). Orexin Signaling Mediates the Antidepressant-Like Effect of Calorie Restriction. The Journal of neuroscience : the official journal of the Society for Neuroscience, 28(12), 3071-3075.
Malberg, J. E., Eisch, A. J., Nestler, E. J., & Duman, R. S. (2000). Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci, 20(24), 9104-9110.
McCormick, C. M., Smith, C., & Mathews, I. Z. (2008). Effects of chronic social stress in adolescence on anxiety and neuroendocrine response to mild stress in male and female rats. Behavioural brain research, 187(2), 228-238.
McEwen, B. S. (1999). Stress and hippocampal plasticity. Annu Rev Neurosci, 22, 105-122.
Meyer, U., Feldon, J., Schedlowski, M., & Yee, B. K. (2005). Towards an immuno-precipitated neurodevelopmental animal model of schizophrenia. Neuroscience & Biobehavioral Reviews, 29(6), 913-947.
Meyer, U., Nyffeler, M., Engler, A., Urwyler, A., Schedlowski, M., Knuesel, I., Feldon, J. (2006). The Time of Prenatal Immune Challenge Determines the Specificity of Inflammation-Mediated Brain and Behavioral Pathology. The Journal of Neuroscience, 26(18), 4752.
Mileykovskiy, B. Y., Kiyashchenko, L. I., & Siegel, J. M. (2005). Behavioral Correlates of Activity in Identified Hypocretin/Orexin Neurons. Neuron, 46(5), 787-798.
Muraki, Y., Yamanaka, A., Tsujino, N., Kilduff, T. S., Goto, K., & Sakurai, T. (2004). Serotonergic Regulation of the Orexin/Hypocretin Neurons through the 5-HT Receptor. The Journal of Neuroscience, 24(32), 7159.
Nemeroff, C. B., & Vale, W. W. (2005). The neurobiology of depression: inroads to treatment and new drug discovery. J Clin Psychiatry, 66 Suppl 7, 5-13.
Nutt, D. J. (2008). Relationship of neurotransmitters to the symptoms of major depressive disorder. J Clin Psychiatry, 69 Suppl E1, 4-7.
Palhagen, S., Qi, H., Martensson, B., Walinder, J., Granerus, A. K., & Svenningsson, P. (2010). Monoamines, BDNF, IL-6 and corticosterone in CSF in patients with Parkinson's disease and major depression. J Neurol, 257(4), 524-532.
Pariante, C. M., & Lightman, S. L. (2008). The HPA axis in major depression: classical theories and new developments. Trends in Neurosciences, 31(9), 464-468.
Peyron, C., Faraco, J., Rogers, W., Ripley, B., Overeem, S., Charnay, Y., Mignot, E. (2000). A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med, 6(9), 991-997.
Peyron, C., Tighe, D. K., van den Pol, A. N., de Lecea, L., Heller, H. C., Sutcliffe, J. G., & Kilduff, T. S. (1998). Neurons Containing Hypocretin (Orexin) Project to Multiple Neuronal Systems. The Journal of Neuroscience, 18(23), 9996.
PICCINELLI, M., & WILKINSON, G. (2000). Gender differences in depression. Critical review, 177(6), 486-492.
Porkka-Heiskanen, T., Alanko, L., Kalinchuk, A., Heiskanen, S., & Stenberg, D. (2004). The effect of age on prepro-orexin gene expression and contents of orexin A and B in the rat brain. Neurobiology of Aging, 25(2), 231-238.
Porkka-Heiskanen, T., Alanko, L., Kalinchuk, A., Heiskanen, S., & Stenberg, D. (2004). The effect of age on prepro-orexin gene expression and contents of orexin A and B in the rat brain. Neurobiol Aging, 25(2), 231-238.
Porsolt, R. D., Le Pichon, M., & Jalfre, M. (1977). Depression: a new animal model sensitive to antidepressant treatments. Nature, 266(5604), 730-732.
Randeva, H. S., Karteris, E., Grammatopoulos, D., & Hillhouse, E. W. (2001). Expression of orexin-A and functional orexin type 2 receptors in the human adult adrenals: implications for adrenal function and energy homeostasis. J Clin Endocrinol Metab, 86(10), 4808-4813.
Rotter, A., Asemann, R., Decker, A., Kornhuber, J., & Biermann, T. (2011). Orexin expression and promoter-methylation in peripheral blood of patients suffering from major depressive disorder. Journal of Affective Disorders, 131(1–3), 186-192.
Sakamoto, F., Yamada, S., & Ueta, Y. (2004). Centrally administered orexin-A activates corticotropin-releasing factor-containing neurons in the hypothalamic paraventricular nucleus and central amygdaloid nucleus of rats: possible involvement of central orexins on stress-activated central CRF neurons. Regul Pept, 118(3), 183-191.
Sakurai, T. (2014). The role of orexin in motivated behaviours. Nat Rev Neurosci, 15(11), 719-731.
Sakurai, T., Amemiya, A., Ishii, M., Matsuzaki, I., Chemelli, R. M., Tanaka, H., Yanagisawa, M. (1998). Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell, 92(4), 573-585.
Salomon, R. M., Ripley, B., Kennedy, J. S., Johnson, B., Schmidt, D., Zeitzer, J. M., Mignot, E. (2003). Diurnal variation of cerebrospinal fluid hypocretin-1 (Orexin-A) levels in control and depressed subjects. Biological Psychiatry, 54(2), 96-104.
Sapolsky, R. M. (1996). Stress, Glucocorticoids, and Damage to the Nervous System: The Current State of Confusion. Stress, 1(1), 1-19.
Schmidt, F. M., Arendt, E., Steinmetzer, A., Bruegel, M., Kratzsch, J., Strauß, M., Schönknecht, P. (2011). CSF-hypocretin-1 levels in patients with major depressive disorder compared to healthy controls. Psychiatry Research, 190(2), 240-243.
Scott, M. M., Marcus, J. N., Pettersen, A., Birnbaum, S. G., Mochizuki, T., Scammell, T. E., . . . Lutter, M. (2011). Hcrtr1 and 2 signaling differentially regulates depression-like behaviors. Behavioural brain research, 222(2), 289-294.
Siuciak, J. A., Lewis, D. R., Wiegand, S. J., & Lindsay, R. M. (1997). Antidepressant-Like Effect of Brain-derived Neurotrophic Factor (BDNF). Pharmacology Biochemistry and Behavior, 56(1), 131-137.
Smart, D., & Jerman, J. C. (2002). The physiology and pharmacology of the orexins. Pharmacology & Therapeutics, 94(1–2), 51-61.
Smith, M. A., Makino, S., Kim, S. Y., & Kvetnansky, R. (1995). Stress increases brain-derived neurotropic factor messenger ribonucleic acid in the hypothalamus and pituitary. Endocrinology, 136(9), 3743-3750.
Smith, M. A., Makino, S., Kvetnansky, R., & Post, R. M. (1995). Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. The Journal of Neuroscience, 15(3), 1768.
Specht, L. A., Pickel, V. M., Joh, T. H., & Reis, D. J. (1981). Light-microscopic immunocytochemical localization of tyrosine hydroxylase in prenatal rat brain. I. Early ontogeny. J Comp Neurol, 199(2), 233-253.
Spinazzi, R., Andreis, P. G., Rossi, G. P., & Nussdorfer, G. G. (2006). Orexins in the Regulation of the Hypothalamic-Pituitary-Adrenal Axis. Pharmacological Reviews, 58(1), 46.
Taheri, S., Gardiner, J., Hafizi, S., Murphy, K., Dakin, C., Seal, L., Bloom, S. (2001). Orexin A immunoreactivity and preproorexin mRNA in the brain of Zucker and WKY rats. Neuroreport, 12(3), 459-464.
Thoenen, H. (1995). Neurotrophins and Neuronal Plasticity. Science, 270(5236), 593.
Tsujino, N., & Sakurai, T. (2009). Orexin/Hypocretin: A Neuropeptide at the Interface of Sleep, Energy Homeostasis, and Reward System. Pharmacological Reviews, 61(2), 162.
Vreeburg, S. A., Hoogendijk, W. G., van Pelt, J., & et al. (2009). Major depressive disorder and hypothalamic-pituitary-adrenal axis activity: Results from a large cohort study. Arch Gen Psychiatry, 66(6), 617-626.
Wang, J. W., David, D. J., Monckton, J. E., Battaglia, F., & Hen, R. (2008). Chronic fluoxetine stimulates maturation and synaptic plasticity of adult-born hippocampal granule cells. J Neurosci, 28(6), 1374-1384.
Wang, S., Yan, J. Y., Lo, Y. K., Carvey, P. M., & Ling, Z. (2009). Dopaminergic and serotoninergic deficiencies in young adult rats prenatally exposed to the bacterial lipopolysaccharide. Brain Res, 1265, 196-204.
Weiser, M. J., & Handa, R. J. (2009). Estrogen impairs glucocorticoid dependent negative feedback on the hypothalamic-pituitary-adrenal axis via estrogen receptor alpha within the hypothalamus. Neuroscience, 159(2), 883-895.
Wharton, W., Gleason, C. E., Olson, S. R. M. S., Carlsson, C. M., & Asthana, S. (2012). Neurobiological Underpinnings of the Estrogen – Mood Relationship. Current psychiatry reviews, 8(3), 247-256.
WHO. (2001). Burden of Mental and Behavioural Disorders.
WHO. (2012). Depression - World Health Organization.
Winsky-Sommerer, R., Yamanaka, A., Diano, S., Borok, E., Roberts, A. J., Sakurai, T., de Lecea, L. (2004). Interaction between the Corticotropin-Releasing Factor System and Hypocretins (Orexins): A Novel Circuit Mediating Stress Response. The Journal of Neuroscience, 24(50), 11439.
Winsky-Sommerer, R., Yamanaka, A., Diano, S., Borok, E., Roberts, A. J., Sakurai, T., de Lecea, L. (2004). Interaction between the corticotropin-releasing factor system and hypocretins (orexins): a novel circuit mediating stress response. J Neurosci, 24(50), 11439-11448.