Neurogenesis hypothesis of depression

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In humans, adult neurogenesis occurs in the subgranular zone of the dentate gyrus in the hippocampus (marked by 'DG' in the image)

Adult neurogenesis is the process by which functional, mature neurons are produced from neural stem cells (NSCs) in the adult brain. In most mammals, including humans, it only occurs in the subgranular zone of the hippocampus, and in the olfactory bulb.[1] The neurogenesis hypothesis of depression proposes that major depressive disorder is caused, at least partly, by impaired neurogenesis in the subgranular zone of the hippocampus.[2]

Overview[edit]

Hippocampal neurogenesis

In the subgranular zone in the dentate gyrus of the hippocampus, NSCs differentiate into granule cells. These new granule cells are implicated in memory formation and learning.[3] The number of granule cells generated in the dentate gyrus each month is approximately 6% of the total population of dentate gyrus neurons.[3] The magnitude of this continuous production of new neurons indicates that they have an important role in hippocampal function.

Inadequacy of the monoamine hypothesis of depression

While depression is a complex condition with many factors involved, it is commonly attributed to an imbalance of several key monoamine neurotransmitters, including serotonin, dopamine and norepinephrine. This monoamine hypothesis of depression is popular because of the simplicity of the explanation.[4] However, the hypothesis is incomplete, as several lines of evidence suggests that depression is more than just a monoamine imbalance. For example, antidepressants usually take several weeks to reduce a patient's depressive symptoms, which is inconsistent with the finding that monoamine levels are affected within hours of using antidepressants.[5] This suggests that antidepressants need to affect other biological systems, apart from monoamines, in order to reduce depressive symptoms.

Relationship between neurogenesis and depression

Stress has been reported to impair many aspects of hippocampal neurogenesis, including:[3]

The neurogenesis hypothesis of depression posits that:[3]

  • Stressful experiences have a negative effect on the process of neurogenesis in the subgranular zone of the dentate gyrus.
  • Alternations in the rate of neurogenesis play a fundamental role in the pathology and treatment of major depression.

Experimental evidence[edit]

The neurogenesis hypothesis of depression gained popularity due to the large number of correlative studies which indicate a relationship between impaired hippocampal neurogenesis and depression. For example, reduced hippocampal volume is associated with depression, which impaired neurogenesis may contribute to.[6]

Conflicting evidence

Studies with rats demonstrated that the administration of antidepressants increases hippocampal neurogenesis.[7] Furthermore, studies with non-human primates found that stress, which is a predisposing factor to depression in humans, impairs hippocampal neurogenesis.[8]

However, other studies have demonstrated that neuronal ablation does not always impair neurogenesis in laboratory animals.[9] Furthermore, it was found that stress does not necessarily impair neurogenesis in laboratory animals.[10] Furthermore, some of the effects of antidepressants are neurogenesis-independent.[11]

Regarding these conflicting findings, Hanson et al., (2011) has suggested that neurogenesis in the adult dentate gyrus “can be regulated by stress and antidepressants under certain as-yet-undefined conditions”.

Lack of human studies

As it is not currently possible to track neurogenesis in humans in real-time, most studies have relied on animal models of depressive behaviours resulting from impaired neurogenesis.[2]

See also[edit]

References[edit]

  1. ^ Ming, Guo-li; Song, Hongjun (2011-05-26). "Adult Neurogenesis in the Mammalian Brain: Significant Answers and Significant Questions". Neuron. 70 (4): 687–702. doi:10.1016/j.neuron.2011.05.001. ISSN 0896-6273. PMC 3106107. PMID 21609825.
  2. ^ a b Schoenfeld, Timothy J.; Cameron, Heather A. (2015). "Adult Neurogenesis and Mental Illness". Neuropsychopharmacology. 40 (1): 113–128. doi:10.1038/npp.2014.230. ISSN 1740-634X. PMC 4262910. PMID 25178407.
  3. ^ a b c d Hanson, Nicola D; Owens, Michael J; Nemeroff, Charles B (2011). "Depression, Antidepressants, and Neurogenesis: A Critical Reappraisal". Neuropsychopharmacology. 36 (13): 2589–2602. doi:10.1038/npp.2011.220. ISSN 0893-133X. PMC 3230505. PMID 21937982.
  4. ^ Boku, Shuken; Nakagawa, Shin; Toda, Hiroyuki; Hishimoto, Akitoyo (2018). "Neural basis of major depressive disorder: Beyond monoamine hypothesis: Neural basis of major depressive disorder". Psychiatry and Clinical Neurosciences. 72 (1): 3–12. doi:10.1111/pcn.12604. PMID 28926161. S2CID 12091197.
  5. ^ Yu, Hui; Chen, Zhe-yu (2011). "The role of BDNF in depression on the basis of its location in the neural circuitry". Acta Pharmacologica Sinica. 32 (1): 3–11. doi:10.1038/aps.2010.184. ISSN 1671-4083. PMC 4003317. PMID 21131999.
  6. ^ Eisch, Amelia J.; Petrik, David (2012-10-05). "Depression and Hippocampal Neurogenesis: A Road to Remission?". Science. 338 (6103): 72–75. Bibcode:2012Sci...338...72E. doi:10.1126/science.1222941. ISSN 0036-8075. PMC 3756889. PMID 23042885.
  7. ^ Malberg, Jessica E.; Eisch, Amelia J.; Nestler, Eric J.; Duman, Ronald S. (2000-12-15). "Chronic Antidepressant Treatment Increases Neurogenesis in Adult Rat Hippocampus". The Journal of Neuroscience. 20 (24): 9104–9110. doi:10.1523/jneurosci.20-24-09104.2000. ISSN 0270-6474. PMC 6773038. PMID 11124987.
  8. ^ Eberhard, Czéh, Boldizsár Michaelis, Thomas Watanabe, Takashi Frahm, Jens de Biurrun, Gabriel van Kampen, Marja Bartolomucci, Alessandro Fuchs. Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. The National Academy of Sciences. OCLC 678732674.{{cite book}}: CS1 maint: multiple names: authors list (link)
  9. ^ Jayatissa, Magdalena Niepsuj; Henningsen, Kim; Nikolajsen, Gitte; West, Mark J.; Wiborg, Ove (2009-11-23). "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 (2): 95–105. doi:10.3109/10253890902951786. ISSN 1025-3890. PMID 19929309. S2CID 40313114.
  10. ^ Lagace, Diane C.; Donovan, Michael H.; DeCarolis, Nathan A.; Farnbauch, Laure A.; Malhotra, Shveta; Berton, Olivier; Nestler, Eric J.; Krishnan, Vaishnav; Eisch, Amelia J. (2010-02-22). "Adult hippocampal neurogenesis is functionally important for stress-induced social avoidance". Proceedings of the National Academy of Sciences. 107 (9): 4436–4441. Bibcode:2010PNAS..107.4436L. doi:10.1073/pnas.0910072107. ISSN 0027-8424. PMC 2840117. PMID 20176946.
  11. ^ Holmes, Megan; Bombail, Vincent (2009-09-23). "Faculty Opinions recommendation of Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression". doi:10.3410/f.1164974.625838. {{cite journal}}: Cite journal requires |journal= (help)
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