Depresyon Patofizyolojisinde Hipokampusun Rolü

Eş seçiminden belleğe, çok önemli işlevleri olan hippokampusun, aynı zamanda limbik korteksin bir parçası olarak emosyonların düzenlenmesinde de önemli görevleri vardır. Major depresif bozukluk (MDB) patofizyolojisinde rol oynayan pek çok beyin bölgesiyle olan karşılıklı etkileşimi yanı sıra hippokampusun antidepresanlara yanıt olarak gözlenen nörogeneze de sahne olması beyin görüntüleme çalışmalarında ön plana çıkmasını sağlamıştır. Nörogenezden sorumlu olan beyin kökenli nörotrofik faktörün (BDNF) antidepresan yanıt ile ilişkili olduğu ve nörogenez engellendiği takdirde antidepresan ilaçların etkisiz kaldığı hayvan çalışmalarında gösterilmiştir. Depresyonda BDNF düzeyinin düşmesi sonucu nörogenezin azalması ile birlikte glukokortikoidlerin de olumsuz etkileri ile hippokampusta atrofi gelişmesi beklenmektedir. Bununla birlikte yineleyici ve ağır seyreden depresyonların hippokampal hacimde (HKH) küçülmeye yol açması daha olasıdır, çünkü ilk atak depresyon hastalarının manyetik rezonans görüntüleme yöntemleri ile ölçülen HKH'leri sağlıklı kişilerden çoğunlukla farklı bulunmamıştır. Bu bulgular, hippokampustaki atrofinin ancak uzun dönemde gözlenebileceği ve BDNF düşüklüğünün bu duruma zemin hazırladığını düşündürmektedir. Buna karşılık hastalık öncesinde genetik ya da çevresel nedenlerle HKH'nin küçük olmasının da MDB'a yatkınlığa neden olabileceği öne sürülmüşse de bu tür bir yatkınlık için yeterli kanıt bulunmamaktadır ve depresyon seyrinde hippokampusta küçülmenin olduğuna yönelik görüş daha ön plana çıkmaktadır. İlk atak MDB hastalarında saptanan serum BDNF (sBDNF) düzeyindeki düşüklüğe karşın hastaların HKH'lerinin sağlıklı bireylerden farklı bulunmaması ve sBDNF düzeyi ile HKH arasında sadece hastalarda pozitif korelasyon gözlenmesi bu görüşü desteklemektedir. Bu bulgu, depresif hastaların hippokampuslarının BDNF düzeylerindeki dalgalanmalara hassas olduğunu düşündürmüştür. BDNF'nin MDB patogenezinde oynadığı rolün daha iyi aydınlatılabilmesi için hipotalamo-pituiter-adrenal eksendeki dengesizlikler ve monoaminlerin etkilerinin de göz önünde tutulduğu izlem çalışmalarına gereksinim vardır. Elde edilecek sonuçlar dirençli veya yineleyici depresif bozukluğu olan hastaların tedavisinde yol gösterici olabilir.

The Role of Hippocampus in the Pathophysiology of Depression

Hippocampus, as a part of the limbic cortex, has a variety of functions ranging from mating behavior to memory besides its role in the regulation of emotions. The hippocampus has reciprocal interactions of with other brain regions which act in the pathophysiology of major depressive disorder (MDD). Moreover, since the hippocampus is a scene for the neurogenesis, which can be seen as a response to antidepressant treatment, the hippocampus became a focus of attention in neuroimaging studies of MDD. It has been shown that brain derived neurotrophic factor (BDNF), that is responsible from the neurogenesis, is associated with the response to the antidepressants and antidepressant drugs are ineffective if neurogenesis is hindered.Hippocampal atrophy is expected with the decrease of neurogenesis as a result of the lower BDNF levels with the deleterious effects of glucocorticoids in depression. Recurrent and severe depression seems to cause such a volume reduction though first episode MDD subjects do not differ from healthy individuals in respect to their hippocampal volumes (HCVs) measured by magnetic resonance imaging methods. One may argue regarding these findings that the atrophy in the hippocampus may be observed in the long term and the decrease in BDNF levels may predispose the volume reduction. Although it has been postulated that smaller HCV as a result of genetic and environmental factors and prior to the illness, may cause a vulnerability to MDD, sufficient evidence has not been accumulated yet and the view that HCV loss develops as depression progresses is widely accepted. Findings that serum BDNF (sBDNF) is lower in MDD patients though HCVs of patients do not differ from healthy individuals and the positive correlation of sBDNF with HCV seen only in the patient group support this view. It can be assumed that depressed patients have sensitivity for the fluctuations in BDNF levels. Follow-up studies which consider effects of hipotalamo-pituiter-adrenal axis dysregulation and monoamine systems are needed to further elucidate the role of BDNF in the pathogenesis of MDD. Results of these studies may lead the way for the treatment of resistant or recurrent depressive disorder.

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  • Wong ML, Licino J. Research and treatment approaches to depression. Nat Rev Neuroscience 2001, 2:343-351
  • Rihmer Z, Angst J. Mood Disorders: Epidemiology. Kaplan & Saddock’s com- prehensive textbook of psychiatry. (Ed.ler: Saddock B, Saddock VA): 1575- 1581. Lippincott Williams &Williams, 2005.
  • Sapolsky RM. The influence of social hierarchy on primate health. Science 2005, 308:648-652.
  • Balu DT, Lucki I. Adult hippocampal neurogenesis: Regulation, functional implications, and contribution to disease pathology. Neurosci Biobehav Rev 2009, 33:232-252.
  • Altman, J. Autoradiographic investigation of cell proliferation in the brains of rats and rats. Anat Rec 1963, 145: 573–591.
  • Altman, J, Das GD. Post-natal origin of microneurones in the rat brain. Nature 1965, 207:953–956.
  • Altman, J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 1965, 124: 319–335.
  • Kaplan MS, Hinds JW. Neurogenesis in the adult rat: electron microscopic analysis of light radioautographs. Science 1977, 197:1092–1094.
  • Kaplan MS, Bell DH. Mitotic neuroblasts in the 9-day-old and 11-monthold rodent hippocampus. J Neurosci 1984, 4:1429–1441.
  • Kaplan MS, McNelly NA, Hinds JW. Population dynamics of adult-formed granule neurons of the rat olfactory bulb. J Comp Neurol 1985, 239:117–125.
  • Goldman SA, Nottebohm F. Neuronal production, migration, and differentiation in a vocal control nucleus of the adult female canary brain. Proc Natl Acad Sci U S A 1983, 80:2390–2394.
  • Gould E, Cameron HA, Daniels DC, Woolley CS, McEwen BS. Adrenal hormones suppress cell division in the adult rat dentate gyrus. J Neurosci 1992, 12:3642– 3650.
  • Gould E, McEwen BS, Tanapat P, Galea LA, Fuchs E. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J Neurosci 1997, 17:2492–2498
  • Gould E, Tanapat P, McEwen BS, Flugge G, Fuchs E. Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc Natl Acad Sci U S A 1998, 95:3168–3171.
  • Gould E, Reeves AJ, Graziano MS, Gross CG. Neurogenesis in the neocortex of adult primates. Science 1999, 286:548–552.
  • Gould E, Reeves AJ, Fallah M, Tanapat P, Gross CG, Fuchs E. Hippocampal neurogenesis in adult Old World primates. Proc Natl Acad Sci U S A 1999, 96:5263–5267.
  • Gould E, Vail N, Wagers M, Gross CG. Adult-generated hippocampal andneocortical neurons in macaques have a transient existence. Proc Natl Acad Sci U S A 2001, 98: 10910–10917.
  • Manganas LN, Zhang X, Li Y, Hazel RD, Smith SD, Wagshul ME ve ark. Magnetic resonance spectroscopy identifies neural progenitor cells in the live human brain. Science 2007, 318:980-985.
  • Kim JJ, Diamond DM. The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci 2002,3:453-462
  • Sapolsky RM, Krey LC, McEwen BS. Prolonged glucocorticoid exposure reduces hippocampal neuron number: implications for aging. J Neurosci 1985, 5:1222-1227.
  • Sapolsky RM, Krey LC, McEwen BS. The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. Endocr Rev 1986, 7:284-301.
  • Sapolsky RM. Stress, glucocorticods, and damage to the nervous system. The current state of confusion. Stress 1996, 1:1-16
  • Jöels M. Functional actions of corticosteroids in the hippocampus. European Journal of Pharmacology 2008, 583:312-321
  • Mesulam MM. Behavioral neuroanatomy. In Principles of behavioral and cognitive neurology. (ed. MM Mesulam) Oxford University Press, 2000.pp: 1- 120.
  • Maguire EA, Gadian DG, Johnsrude IS, Good CD, Ashburner J, Frackowiak RS ve ark. Navigation-related structural change in the hippocampi of taxi drivers. Proc Natl Acad Sci U S A 2000, 97:4398-4403.
  • Lepage M, Habib R, Tulving E. Hippocampal PET activations of memory encoding and retrieval: the HIPER model. Hippocampus 1998; 8(4):313-322.
  • Strange BA, Dolan RJ. Adaptive anterior hippocampal responses to oddball stimuli. Hippocampus 2001; 11(6):690-698.
  • Gönül AS, Demirel O, Kitis Ö, Eker C, Donat-Eker Ö, Ozan E. The effects of formal education on adult brain: a voxel based morphometry – dartel study. Klinik Psikofarmakoloji Bülteni 2009 (baskıda)
  • DiRocco DP, Xia Z. Alpha males win again. Nat Neurosci 2007, 10:938-40.
  • Pierri JN, Lewis DA. Functional neuroanatomy. In Kaplan & Saddock’s comprehensive textbook of psychiatry. (ed.ler Saddock BJ, Saddock VA): 3-32 Lippincott, Williams and Wilkins, 2005.
  • Duman RS and Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry 2006, 59:1116-1127
  • Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S ve ark. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 2003, 301:805-809.
  • Krishnan V, Nestler E. The molecular neurobiology of depression. Nature 2008, 455:894-902
  • Karege F, Perret G, Bondolfi G, Schwald M, Bertschy G, Aubry JM. Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res 2002, 109:143-148
  • Gonul AS, Akdeniz F, Taneli F, Donat O, Eker C, Vahip S. Effect of treatment on serum brain-derived neurotrophic factor levels in depressed patients. Eur Arch Psychiatry Clin Neurosci 2005, 255:381-386.
  • Eker MC ve Gönül AS. Volumetric MRI studies of the hippocampus in major depressive disorder: meanings of inconsistency and directions for future re- search. World J Biol Psychiatry. 2009 Apr 17:1-17. [Epub ahead of print]
  • Posener JA, Wang L, Price JL, Gado MH, Province MA, Miller MI ve ark. High- dimensional mapping of the hippocampus in depression. Am J Psychiatry 2003, 160:83-89.
  • MacQueen GM, Campbell S, McEwen BS, Macdonald K, Amano S, Joffe RT, ve ark. Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci U S A 2003, 100:1387-1392.
  • Sheline YI. Neuroimaging studies of mood disorder effects on the brain. Biol Psychiatry 2003, 54:338-352.
  • Eker C, Ovali GY, Ozan E, Eker OD, Kitis O, Coburn K ve ark. No pituitary gland volume change in medication-free depressed patients. Prog Neuropsycho- pharmacol Biol Psychiatry 2008, 32:1628-1632.
  • Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A 1996,93:3908- 3913.
  • Colla M, Kronenberg G, Deuschle M, Meichel K, Hagen T, Bohrer M ve ark. Hippocampal volume reduction and HPA-system activity in major depression. J Psychiatr Res. 2007, 41:553-560
  • Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiolo- gy of depression. Neuron 2002, 34:13-25
  • Gilbertson MW, Shenton ME, Ciszewski A, Kasai K, Lasko NB, Orr SP ve ark. Smaller hippocampal volume predicts pathologic vulnerability to psychologi- cal trauma. Nat Neurosci 2002, 5:1242-1247
  • Weaver ICG, Szyf M, Meaney MJ. From maternal care to gene expression: DNA methylation and the maternal programming of stress responses. Endocrine Research 2002, 28:699.
  • Weaver ICG, Diorio J, Seckl JR, Szyf M, Meaney M. Early environmental regula- tion of hippocampal glucocorticoid receptor gene expression. Characteriza- tion of intracelluar mediators and genomic target sites. Ann NY Acad Sci 2004, 1024:182-212.
  • Weaver ICG, Cervoni N, Champagne FA, Alessio A, Sharma S, Secki JR ve ark. Epigenetic programming by maternal behaviour. Nat Neurosci 2004, 7:847- 854.
  • Lyons DM, Yang C, Sawyer-Glover AM, Moseley ME, Schatzberg AF. Early life stress and inherited variation in monkey hippocampal volumes. Arch Gen Psy- chiatry 2001, 58:1145-1151.
  • Kronmüller KT, Pantel J, Köhler S, Victor D, Giesel F, Magnotta VA ve ark. Hip- pocampal volume and 2-year outcome in depression. Br J Psychiatry 2008, 192:472-473.
  • Frodl T, Jager M, Smajstrlova I, Born C, Bottlender R, Palladino T ve ark. Effect of hippocampal and amydala volumes on clinical outcomes in major depres- sion: a 3-year prospective magnetic resonance imaging study. J Psychiatry Neurosci 2008, 33:423-430.
  • Frodl TS, Koutsouleris N, Bottlender R, Born C, Jäger M, Scupin I ve ark. Depression-related variation in brain morphology over 3 years: effects of stress? Arch Gen Psychiatry 2008, 65:1156-1165.
  • Eker MÇ, Kitiș Ö, Donat-Eker Ö, Ozan E, Gönül AS. İlaç kullanmayan ilk atak major depresif bozukluk hastalarında serum BDNF düzeylerinin hippokampus hacimleri ile ilișkisi. 13. Bahar Sempozyumunda poster bildiri olarak sunulmuș- tur.
  • Psikiyatride Güncel Yaklașımlar – Current Approaches in Psychiatry
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