The Role of Hippocampus in the Pathophysiology of Depression

Abstract

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.

Keywords

• hippocampus, depression, neurogenesis, brain derived neurotrophic factor (BDNF), magnetic resonance imaging (MRI)

Depresyon Patofizyolojisinde Hipokampusun Rolü

Öz

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.

Anahtar Kelimeler

• hippokampus. depresyon, beyin kökenli nörotrofik faktör (BDNF), nörogenez, manyetik rezonans görüntüleme (MRG)

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