甲狀腺素為調節生理代謝作用的重要激素，先前動物研究也顯示，成年大鼠甲狀腺機能減退，可能會誘發憂鬱行為的表現，臨床也觀察到許多憂鬱症併發甲狀腺功能缺失的病例，而且甲狀腺素與抗憂鬱劑共同使用還能增強抗憂鬱劑的治療效果。另外，甲狀腺素的缺乏也被認為會減少海馬迴齒狀迴的成體神經新生，而海馬迴的神經新生又被認為與憂鬱症的產生及相關治療有密切關連。然而，過去多數文獻指出，血清素的神經傳導作用失衡是引發憂鬱症的主因，而常用的抗憂鬱劑－百憂解，即是以增加腦中血清素濃度，改善憂鬱行為的表現。而近年則有研究指出，長期使用百憂解治療的大鼠海馬迴內神經新生較正常大鼠多。由於甲狀腺素的調控與憂鬱症之間可能有密切的因果關連，且在憂鬱症相關研究中一直是個重要但尚未解決的難題，因此，本研究欲藉由甲狀腺摘除引發類憂鬱行為之動物模式及百憂解的投予，來釐清甲狀腺功能缺失所引發之類憂鬱行為與海馬迴成體神經新生現象及血清素神經傳導系統的可能作用路徑。初步實驗結果發現，在8週齡摘除甲狀腺的大鼠，在11週齡的強迫游泳行為測試中表現顯著的類憂鬱行為，但海馬迴齒狀迴的成體神經新生現象未減低。因此，進一步對甲狀腺摘除個體投予百憂解並觀察其行為及海馬迴內神經新生的變化，結果顯示，長期投予百憂解，可改善甲狀腺摘除後引發的類憂鬱行為，但海馬迴神經新生現象未有顯著變化。因此，以RT-PCR方法測定血清素相關受器5-HT1A、5-HT2A、5-HT2C及5-HT3A在海馬迴及縫核的表現量。研究結果發現，甲狀腺摘除大鼠縫核的5-HT1A受器表現量顯著上升，而在投予百憂解之甲狀腺摘除大鼠海馬迴中則是觀察到5-HT1A受器表現量顯著下降，推測甲狀腺摘除引發之憂鬱行為表現及投藥後的行為改善，可能與5-HT1A受器表現量的改變有關。由本研究一系列實驗結果推知，甲狀腺功能異常所造成的類憂鬱行為表現可能與血清素系統中5-HT1A受器的調控有較大的關聯，此項成果除幫助探究憂鬱症成因，也有助於相關治療藥物的開發。

Thyroid hormones (THs) are important on the regulation of physiological functions, especially metabolism. It also modulates the rate of neuronal proliferation in the central nervous system. In hippocampus, THs are essential for the adult neurogenesis. Recent studies suggest that it also involves in the pathogenesis of atypical depression in human. It is widely accepted that major depression is resulted from the imbalance and dysfunction of serotonin (5-HT) in brain. Accumulated clinical results showed the co-treatment of antidepressants with THs have better therapeutic effect on depression patients. Fluoxetine, a serotonin selected reuptake inhibitor (SSRI), can enhance the adult neurogenesis in hippocampus. These evidences suggest that the defect of adult neurogenesis caused by the imbalances of the level of THs and 5-HT may responsible for formation of depression disorder. However, the detail mechanism remains unclear.
In the present study, we investigate the possible linkage between adult neurogenesis and the depression-like behavior induced by thyroidectomies. Rats which were thyroidectomized at 8 weeks old showed increase of depression-like behavior on force-swimming test at the age of 11 weeks. It can be rescue by fluoxetine treatment. However, the level of adult neurogenesis in hippocampus did not show significant changes in the fluoxetine treated rats comparing with vehicle control animal.
The expression of different serotonin receptor subtypes including 5-HT1A ,5-HT2A ,5-HT2C and 5-HT3A in the hippocampus and raphe nuclei were measured by SQ-RT-PCR paradigm. Results showed revealed that the expression of 5-HT1A receptors in Raphe nuclei and hippocampus of thyroidectomized rats were up-regulated and down-regulated respectively. In addition, systemic administration of Prozac restored the expression of 5-HT1A receptor into normal level. We concluded that the increase of depression-like behavior in thyroidectomized rats is resulted from the imbalance of 5-HT function rather than impairment of adult neurogenesis in hippocampus. Further experiments are required to obtain a complete and clear picture regard to the mechanism of hypothyroidism and atypical depression.

Abrous DN, Koehl M, Le Moal M. 2005. Adult neurogenesis: from precursors to network and physiology. Physiol Rev 85: 523-69
Airan RD, Meltzer LA, Roy M, Gong Y, Chen H, Deisseroth K. 2007. High-speed imaging reveals neurophysiological links to behavior in an animal model of depression. Science 317: 819-23
Altamura AC, Moro AR, Percudani M. 1994. Clinical pharmacokinetics of fluoxetine. Clin Pharmacokinet 26: 201-14
Altshuler LL, Bauer M, Frye MA, Gitlin MJ, Mintz J, Szuba MP, Leight KL, Whybrow PC. 2001. Does thyroid supplementation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature. Am J Psychiatry 158: 1617-22
Ambrogini P, Cuppini R, Ferri P, Mancini C, Ciaroni S, Voci A, Gerdoni E, Gallo G. 2005. Thyroid hormones affect neurogenesis in the dentate gyrus of adult rat. Neuroendocrinology 81: 244-53
Andó S, Panno ML, Beraldi E, Tarantino G, Salerno M, Palmero S, Prati M, Fugassa E. 1990. Influence of hypothyroidism on in-vitro testicular steroidogenesis in adult rats. Exp Clin Endocrinol 96: 149-56
Andrade TG, Macedo CE, Zangrossi H, Jr., Graeff FG. 2004. Anxiolytic-like effects of median raphe nucleus lesion in the elevated T-maze. Behav Brain Res 153: 55-60
Araya AV, Massardo T, Fiedler J, Risco L, Quintana JC and Liberman C. 2012. Depressive disorders and thyroid function. Ward LS (ed). Thyroid and Parathyroid Diseases - New Insights into Some Old and Some New Issues, pp. 259-78
Aronson R, Offman HJ, Joffe RT, Naylor CD. 1996. Triiodothyronine augmentation in the treatment of refractory depression. A meta-analysis. Arch Gen Psychiatry 53: 842-8
Asberg M, Thoren P, Traskman L, Bertilsson L, Ringberger V. 1976. "Serotonin depression": A biochemical subgroup within the affective disorders? Science 191: 478-80
Barnes NM and Sharp T. 1999. A review of central 5-HT receptors and their function. Neuropharmacology 38: 1083-152
Bauer M, Heinz A, Whybrow PC. 2002. Thyroid hormones, serotonin and mood: of synergy and significance in the adult brain. Mol Psychiatry 7: 140-56
Baumgartner A. 2000. Thyroxine and the treatment of affective disorders: an overview of the results of basic and clinical research. Int J Neuropsychopharmacol 3: 149-65
Becker S and Wojtowicz JM. 2007. A model of hippocampal neurogenesis in memory and mood disorders. Trends Cogn Sci 11: 70-6
Berton O and Nestler EJ. 2006. New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci 7: 137-51
Blier P and de Montigny C. 1994. Current advances and trends in the treatment of depression. Trends Pharmacol Sci 15: 220-6
Blier P, de Montigny C, Chaput Y. 1987. Modifications of the serotonin system by antidepressant treatments: implications for the therapeutic response in major depression. J Clin Psychopharmacol 7: 24S-35S
Boldrini M, Hen R, Underwood MD, Rosoklija GB, Dwork AJ, Mann JJ, Arango V. 2012. Hippocampal angiogenesis and progenitor cell proliferation are increased with antidepressant use in major depression. Biol Psychiatry 72: 562-71
Campbell S, Marriott M, Nahmias C, MacQueen GM. 2004. Lower hippocampal volume in patients suffering from depression: a meta-analysis. Am J Psychiatry 161: 598-607
Carroll BJ, Martin FI, Davies B. 1968. Resistance to suppression by dexamethasone of plasma 11-O.H.C.S. levels in severe depressive illness. Br Med J 3: 285-7
Celada P, Puig M, Amargos-Bosch M, Adell A, Artigas F. 2004. The therapeutic role of 5-HT1A and 5-HT2A receptors in depression. J Psychiatry Neurosci 29: 252-65
Chalmers DT and Watson SJ. 1991. Comparative anatomical distribution of 5-HT1A receptor mRNA and 5-HT1A binding in rat brain--a combined in situ hybridization/ in vitro receptor autoradiographic study. Brain Res 561: 51-60
Chan S and Kilby MD. 2000. Thyroid hormone and central nervous system development. J Endocrinol 165: 1-8
Christie BR and Cameron HA. 2006. Neurogenesis in the adult hippocampus. Hippocampus 16: 199-207
Courtin F, Chantoux F, Francon J. 1988. Thyroid hormone metabolism in neuron-enriched primary cultures of fetal rat brain cells. Mol Cell Endocrinol 58: 73-84
de Escobar GM, Obregon MJ, del Rey FE. 2004. Maternal thyroid hormones early in pregnancy and fetal brain development. Best Pract Res Clin Endocrinol Metab 18: 225-48
Delgado PL, Price LH, Miller HL, Salomon RM, Aghajanian GK, Heninger GR, Charney DS. 1994. Serotonin and the neurobiology of depression. Effects of tryptophan depletion in drug-free depressed patients. Arch Gen Psychiatry 51: 865-74
Demartini B, Masu A, Scarone S, Pontiroli AE, Gambini O. 2010. Prevalence of depression in patients affected by subclinical hypothyroidism. Panminerva Med 52: 277-82
Desouza LA, Ladiwala U, Daniel SM, Agashe S, Vaidya RA, Vaidya VA. 2005. Thyroid hormone regulates hippocampal neurogenesis in the adult rat brain. Mol Cell Neurosci 29: 414-26
Dietrich JW, Landgrafe G, and Fotiadou EH. 2012. TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis. J Thyroid Res 2012: 351864
Eisch AJ and Petrik D. 2012. Depression and hippocampal neurogenesis: a road to remission? Science 338: 72-5
Eravci M, Pinna G, Meinhold H, Baumgartner A. 2000. Effects of pharmacological and nonpharmacological treatments on thyroid hormone metabolism and concentrations in rat brain. Endocrinology 141: 1027-40
Ernst C, Olson AK, Pinel JP, Lam RW, Christie BR. 2006. Antidepressant effects of exercise: evidence for an adult-neurogenesis hypothesis? J Psychiatry Neurosci 31: 84-92
Escobar-Morreale HF, Escobar del Rey F, Morreale de Escobar G. 1997. Thyroid hormones influence serum leptin concentrations in the rat. Endocrinology 138: 4485-8
Gibbons RD, Hur K, Brown CH, Davis JM, Mann JJ. 2012. Benefits from antidepressants: synthesis of 6-week patient-level outcomes from double-blind placebo-controlled randomized trials of fluoxetine and venlafaxine. Arch Gen Psychiatry 69: 572-9
Goodwin FK and Post RM. 1983. 5-hydroxytryptamine and depression: a model for the interaction of normal variance with pathology. Br J Clin Pharmacol 15 Suppl 3: 393S-405S
Gould NF, Holmes MK, Fantie BD, Luckenbaugh DA, Pine DS, Gould TD, Burgess N, Manji HK, Zarate CA, Jr. 2007. Performance on a virtual reality spatial memory navigation task in depressed patients. Am J Psychiatry 164: 516-9
Gross CG. 2000. Neurogenesis in the adult brain: death of a dogma. Nat Rev Neurosci 1: 67-73
Heinz A, Ragan P, Jones DW, Hommer D, Williams W, Knable MB, Gorey JG, Doty L, Geyer C, Lee KS, Coppola R, Weinberger DR, Linnoila M. 1998. Reduced central serotonin transporters in alcoholism. Am J Psychiatry 155: 1544-9
Heisler LK, Chu HM, Brennan TJ, Danao JA, Bajwa P, Parsons LH, Tecott LH. 1998. Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice. Proc Natl Acad Sci U S A 95: 15049-54
Holick KA, Lee DC, Hen R, Dulawa SC. 2008. Behavioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor. Neuropsychopharmacol 33: 406-17
Jayatissa MN, Henningsen K, Nikolajsen G, West MJ, Wiborg O. 2010. A reduced number of hippocampal granule cells does not associate with an anhedonia-like phenotype in a rat chronic mild stress model of depression. Stress 13: 95-105
Jha S, Dong B, Sakata K. 2011. Enriched environment treatment reverses depression-like behavior and restores reduced hippocampal neurogenesis and protein levels of brain-derived neurotrophic factor in mice lacking its expression through promoter IV. Transl Psychiatry 1: e40
Jobe PC, Dailey JW, Wernicke JF. 1999. A noradrenergic and serotonergic hypothesis of the linkage between epilepsy and affective disorders. Crit Rev Neurobiol 13: 317-56
Kansagra SM, McCudden CR, Willis MS. 2010. The challenges and complexities of thyroid hormone replacement. Lab Med 41: 338-48
Knoth R, Singec I, Ditter M, Pantazis G, Capetian P, Meyer RP, Horvat V, Volk B, Kempermann G. 2010. Murine features of neurogenesis in the human hippocampus across the lifespan from 0 to 100 years. PLoS One 5: e8809
Kulikov A, Torresani J, Jeanningros R. 1997. Experimental hypothyroidism increases immobility in rats in the forced swim paradigm. Neurosci Lett 234: 111-4
Lagace DC, Donovan MH, DeCarolis NA, Farnbauch LA, Malhotra S, Berton O, Nestler EJ, Krishnan V, Eisch AJ. 2010. Adult hippocampal neurogenesis is functionally important for stress-induced social avoidance. Proc Natl Acad Sci U S A 107: 4436-41
Lanfumey L, Mongeau R, Cohen-Salmon C, Hamon M. 2008. Corticosteroid-serotonin interactions in the neurobiological mechanisms of stress-related disorders. Neurosci Biobehav Rev 32: 1174-84
Lledo PM, Alonso M, Grubb MS. 2006. Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci 7: 179-93
MacQueen GM, Campbell S, McEwen BS, Macdonald K, Amano S, Joffe RT, Nahmias C, Young LT. 2003. Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci U S A 100: 1387-92
Madeira MD, Cadete-Leite A, Andrade JP, Paula-Barbosa MM. 1991. Effects of hypothyroidism upon the granular layer of the dentate gyrus in male and female adult rats: a morphometric study. J Comp Neurol 314: 171-86
Maes M and Meltzer HY. 1995. The serotonin hypotheses of major depression. In: Bloom FE, Kupfer DJ (eds). Psychopharmacology: The Fourth Generation of Progess. New York: Raven Press, pp. 933-44
Malberg JE, Eisch AJ, Nestler EJ, Duman RS. 2000. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 20: 9104-10
Malison RT, Price LH, Berman R, van Dyck CH, Pelton GH, Carpenter L, Sanacora G, Owens MJ, Nemeroff CB, Rajeevan N, Baldwin RM, Seibyl JP, Innis RB, Charney DS. 1998. Reduced brain serotonin transporter availability in major depression as measured by [123I]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane and single photon emission computed tomography. Biol Psychiatry 44: 1090-8
Markou K, Georgopoulos N, Kyriazopoulou V, Vagenakis AG. 2001. Iodine-Induced hypothyroidism. Thyroid 11: 501-10
Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis S, Jerabek PA. 2000. Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry 48: 830-43
McEwen BS. 2003. Mood disorders and allostatic load. Biol Psychiatry 54: 200-7
Miller KJ, Parsons TD, Whybrow PC, Van Herle K, Rasgon N, Van Herle A, Martinez D, Silverman DH, Bauer M. 2007. Verbal memory retrieval deficits associated with untreated hypothyroidism. J Neuropsychiatry Clin Neurosci 19: 132-6
Mirescu C and Gould E. 2006. Stress and adult neurogenesis. Hippocampus 16: 233-8
Montero-Pedrazuela A, Venero C, Lavado-Autric R, Fernandez-Lamo I, Garcia-Verdugo JM, Bernal J, Guadano-Ferraz A. 2006. Modulation of adult hippocampal neurogenesis by thyroid hormones: implications in depressive-like behavior. Mol Psychiatry 11: 361-71
Morreale de Escobar G, Obregon MJ, Ruiz de Ona C, Escobar del Rey F. 1988. Transfer of thyroxine from the mother to the rat fetus near term: effects on brain 3,5,3'-triiodothyronine deficiency. Endocrinology 122: 1521-31
Moser MB and Moser EI. 1998. Functional differentiation in the hippocampus. Hippocampus 8: 608-19
Nease DE, Jr. and Maloin JM. 2003. Depression screening: a practical strategy. J Fam Pract 52: 118-24
Nilsson M, Perfilieva E, Johansson U, Orwar O, Eriksson PS. 1999. Enriched environment increases neurogenesis in the adult rat dentate gyrus and improves spatial memory. J Neurobiol 39: 569-78
Obregon MJ, Mallol J, Pastor R, Escobar GMD, Rey FED. 1984. L-thyroxine and 3,5,3’-triiodo-L-thyronine in rat embryos before onset of fetal thyroid function. Endocrinology 114: 305-07
Olivares EL, Silva-Almeida C, Pestana FM, Sonoda-Cortes R, Araujo IG, Rodrigues NC, Mecawi AS, Cortes WS, Marassi MP, Reis LC, Rocha FF. 2012. Social stress-induced hypothyroidism is attenuated by antidepressant treatment in rats. Neuropharmacology 62: 446-56
Rajkumar R and Mahesh R. 2010. The auspicious role of the 5-HT3 receptor in depression: a probable neuronal target? J Psychopharmacol 24: 455-69
Papakostas GI, Cooper-Kazaz R, Appelhof BC, Posternak MA, Johnson DP, Klibanski A, Lerer B, Fava M. 2009. Simultaneous initiation (coinitiation) of pharmacotherapy with triiodothyronine and a selective serotonin reuptake inhibitor for major depressive disorder: a quantitative synthesis of double-blind studies. Int Clin Psychopharmacol 24: 19-25
Paxinos G and Watson C. 1997. The rat brain in stereotaxic coordinates. New York: Academic Press
Pellow S, Chopin P, File SE, Briley M. 1985. Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14: 149-67
Pineyro G and Blier P. 1999. Autoregulation of serotonin neurons: role in antidepressant drug action. Pharmacol Rev 51: 533-91
Pompeiano M, Palacios JM, Mengod G. 1992. Distribution and cellular localization of mRNA coding for 5-HT1A receptor in the rat brain: correlation with receptor binding. J Neurosci 12: 440-53
Porsolt RD, Le Pichon M, Jalfre M. 1977. Depression: a new animal model sensitive to antidepressant treatments. Nature 266: 730-2
Prange AJ, Jr., Wilson IC, Rabon AM, Lipton MA. 1969. Enhancement of imipramine antidepressant activity by thyroid hormone. Am J Psychiatry 126: 457-69
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. Proc Natl Acad Sci U S A 95: 14476-81
Redei EE, Solberg LC, Kluczynski JM, Pare WP. 2001. Paradoxical hormonal and behavioral responses to hypothyroid and hyperthyroid states in the Wistar-Kyoto rat. Neuropsychopharmacol 24: 632-9
Samuels MH, Schuff KG, Carlson NE, Carello P, Janowsky JS. 2007. Health status, mood, and cognition in experimentally induced subclinical hypothyroidism. J Clin Endocrinol Metab 92: 2545-51
Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. 2003. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301: 805-9
Sapolsky RM. 2000. Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry 57: 925-35
Scott BW, Wojtowicz JM, Burnham WM. 2000. Neurogenesis in the dentate gyrus of the rat following electroconvulsive shock seizures. Exp Neurol 165: 231-6
Seminowicz DA, Mayberg HS, McIntosh AR, Goldapple K, Kennedy S, Segal Z, Rafi-Tari S. 2004. Limbic-frontal circuitry in major depression: a path modeling meta-analysis. Neuroimage 22: 409-18
Siever LJ and Davis KL. 1985. Overview: toward a dysregulation hypothesis of depression. Am J Psychiatry 142: 1017-31
Singhal RL, Rastogi RB, Hrdina PD. 1975. Brain biogenic amines and altered thyroid function. Life Sci 17: 1617-26
Stockmeier CA, Shapiro LA, Dilley GE, Kolli TN, Friedman L, Rajkowska G. 1998. Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression-postmortem evidence for decreased serotonin activity. J Neurosci 18: 7394-401
Strawn JR, Ekhator NN, D'Souza BB, Geracioti TD, Jr. 2004. Pituitary-thyroid state correlates with central dopaminergic and serotonergic activity in healthy humans. Neuropsychobiology 49: 84-7
Tanaka K, Inada M, Ishii H, Naito K, Nishikawa M, Mashio Y, Imura H. 1981. Inner ring monodeiodination of thyroxine and 3,5,3'-L-triiodothyronine in rat brain. Endocrinology 109: 1619-24
Uchida K, Yonezawa M, Nakamura S, Kobayashi T, Machida T. 2005. Impaired neurogenesis in the growth-retarded mouse is reversed by T3 treatment. Neuroreport 16: 103-6
Videbech P and Ravnkilde B. 2004. Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry 161: 1957-66
Vulsma T, Gons MH, de Vijlder JJ. 1989. Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis. N Engl J Med 321: 13-6
Weiss JM, Goodman PA, Losito BG, Corrigan S, Charry JM, Bailey WH. 1981. Behavioral depression produced by an uncontrollable stressor: Relationship to norepinephrine, dopamine, and serotonin levels in various regions of rat brain. Brain Res Brain Res Rev 3: 167-205
Wheatley D. 1972. Potentiation of amitriptyline by thyroid hormone. Arch Gen Psychiatry 26: 229-33
Whybrow PC, Prange AJ, Jr., Treadway CR. 1969. Mental changes accompanying thyroid gland dysfunction. A reappraisal using objective psychological measurement. Arch Gen Psychiatry 20: 48-63
Wilcoxon JS, Nadolski GJ, Samarut J, Chassande O, Redei EE. 2007. Behavioral inhibition and impaired spatial learning and memory in hypothyroid mice lacking thyroid hormone receptor alpha. Behav Brain Res 177: 109-16
Wilson IC, Prange AJ, Jr., McClane TK, Rabon AM, Lipton MA. 1970. Thyroid-hormone enhancement of imipramine in nonretarded depressions. N Engl J Med 282: 1063-7
Wiskott L, Rasch MJ, Kempermann G. 2006. A functional hypothesis for adult hippocampal neurogenesis: avoidance of catastrophic interference in the dentate gyrus. Hippocampus 16: 329-43