Corticosterone-Mediated BDNF Changes and Their Effects on Adult Neurogenesis in Depression
DOI:
https://doi.org/10.61173/5p3enw85Keywords:
Corticosterone, BDNF, Adult neurogenesis, DepressionAbstract
Adult neurogenesis, the process of generating functional neurons from neural precursor cells in the adult brain, is essential for cognitive function and emotional regulation. Major Depressive Disorder (MDD), characterized by persistent sadness and decreased psychosocial function, is associated with impaired adult hippocampal neurogenesis (AHN). Elevated levels of corticosterone (CORT), a glucocorticoid released in response to stress, have been shown to downregulate brain-derived neurotrophic factor (BDNF), a crucial regulator of neurogenesis, thereby inhibiting AHN. Despite significant advances in understanding the impact of CORT and BDNF on neurogenesis, the precise molecular and cellular pathways involved remain unclear. This review highlights key gaps in the research, particularly the need for a deeper understanding of how glucocorticoid and mineralocorticoid receptors regulate BDNF transcription, the role of autophagic pathways in BDNF degradation, and the influence of glutamatergic signaling on these processes. Future research should focus on elucidating these mechanisms to develop targeted therapeutic strategies, including pharmacological interventions that modulate BDNF and CORT levels and lifestyle modifications like exercise and adequate sleep to enhance neurogenesis. Understanding these complex interactions will be crucial for advancing treatments for depression and improving mental health outcomes.References
[1] Altman J. Are new neurons formed in the brains of adult mammals? Science. 1962;135(3509):1127-8.
[2] Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. Journal of Comparative Neurology. 1965;124(3):319-35.
[3] Goldman SA, Nottebohm F. Neuronal production, migration, and differentiation in a vocal control nucleus of the adult female canary brain. Proceedings of the National Academy of Sciences. 1983;80(8):2390-4.
[4] Jurkowski MP, Bettio L, K. Woo E, Patten A, Yau S-Y, Gil- Mohapel J. Beyond the hippocampus and the SVZ: adult neurogenesis throughout the brain. Frontiers in cellular neuroscience. 2020;14:576444.
[5] Ming G-l, Song H. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron. 2011;70(4):687-702.
[6] Lee B. National, state-level, and county-level prevalence estimates of adults aged≥ 18 years self-reporting a lifetime diagnosis of depression—United States, 2020. MMWR Morbidity and Mortality Weekly Report. 2023;72.
[7] Mikulska J, Juszczyk G, Gawrońska-Grzywacz M, Herbet M. HPA axis in the pathomechanism of depression and schizophrenia: new therapeutic strategies based on its participation. Brain sciences. 2021;11(10):1298.
[8] Brummelte S, Galea LA. Chronic high corticosterone reduces neurogenesis in the dentate gyrus of adult male and female rats. Neuroscience. 2010;168(3):680-90.
[9] Shin HS, Lee SH, Moon HJ, So YH, Jang HJ, Lee K-H, et al. Prolonged stress response induced by chronic stress and corticosterone exposure causes adult neurogenesis inhibition and astrocyte loss in mouse hippocampus. Brain Research Bulletin. 2024;208:110903.
[10] Lu B, Nagappan G, Lu Y. BDNF and synaptic plasticity, cognitive function, and dysfunction. Neurotrophic factors. 2014:223-50.
[11] Zhang K, Wang F, Zhai M, He M, Hu Y, Feng L, et al. Hyperactive neuronal autophagy depletes BDNF and impairs adult hippocampal neurogenesis in a corticosterone-induced mouse model of depression. Theranostics. 2023;13(3):1059.
[12] Wang CS, Kavalali ET, Monteggia LM. BDNF signaling in context: From synaptic regulation to psychiatric disorders. Cell. 2022;185(1):62-76.
[13] Colucci-D’Amato L, Speranza L, Volpicelli F. Neurotrophic factor BDNF, physiological functions and therapeutic potential in depression, neurodegeneration and brain cancer. International journal of molecular sciences. 2020;21(20):7777.
[14] Cheng S-M, Lee S-D. Exercise training enhances BDNF/ TrkB signaling pathway and inhibits apoptosis in diabetic cerebral cortex. International Journal of Molecular Sciences. 2022;23(12):6740.
[15] Dokter M, Busch R, Poser R, Vogt M, von Bohlen Und Halbach V, Gass P, et al. Implications of p75NTR for dentate gyrus morphology and hippocampus-related behavior revisited. Brain Structure and Function. 2015;220:1449-62.
[16] Chao MV. Neurotrophins and their receptors: a convergence point for many signalling pathways. Nature Reviews Neuroscience. 2003;4(4):299-309.
[17] Rossi C, Angelucci A, Costantin L, Braschi C, Mazzantini M, Babbini F, et al. Brain‐derived neurotrophic factor (BDNF) is required for the enhancement of hippocampal neurogenesis following environmental enrichment. European Journal of Neuroscience. 2006;24(7):1850-6.
[18] Prowse N, Dwyer Z, Thompson A, Fortin T, Elson K, Robeson H, et al. Early life selective knockdown of the TrkB receptor and maternal separation modulates adult stress phenotype. Behavioural Brain Research. 2020;378:112260.
[19] Groves N, O’Keeffe I, Lee W, Toft A, Blackmore D, Bandhavkar S, et al. Blockade of TrkB but not p75NTR activates a subpopulation of quiescent neural precursor cells and enhances neurogenesis in the adult mouse hippocampus. Developmental Neurobiology. 2019;79(9-10):868-79.
[20] Sun Y-X, Su Y-A, Wang Q, Zheng J-Y, Zhang C-C, Wang T, et al. The causal involvement of the BDNF-TrkB pathway in dentate gyrus in early-life stress-induced cognitive deficits in male mice. Translational Psychiatry. 2023;13(1):173.
[21] Schaaf MJ, de Jong J, de Kloet ER, Vreugdenhil E. Downregulation of BDNF mRNA and protein in the rat hippocampus by corticosterone. Brain research. 1998;813(1):112-20.
[22] Schaaf M, De Kloet E, Vreugdenhil E. Corticosterone effects on BDNF expression in the hippocampus implications for memory formation. Stress. 2000;3(3):201-8.
[23] Pereira GC, Roversi K, Trevisan G, Burger ME, Bochi GV. Glucocorticoid and brain-derived neurotrophic factor relationship: A brief investigation into the model of depression by chronic administration of corticosterone. Behavioural Pharmacology. 2020;31(4):407-12.
[24] Jeong S-H, An H-K, Ha S, Yu S-W. Distinct signaling pathways for autophagy-driven cell death and survival in adult hippocampal neural stem cells. International Journal of Molecular Sciences. 2023;24(9):8289.
[25] Tornese P, Sala N, Bonini D, Bonifacino T, La Via L, Milanese M, et al. Chronic mild stress induces anhedonic behavior and changes in glutamate release, BDNF trafficking and dendrite morphology only in stress vulnerable rats. The Dean&Francis rapid restorative action of ketamine. Neurobiology of stress. 2019;10:100160.
[26] Agasse F, Mendez-David I, Christaller W, Carpentier R, Braz BY, David DJ, et al. Chronic Corticosterone Elevation Suppresses Adult Hippocampal Neurogenesis by Hyperphosphorylating Huntingtin. Cell Reports. 2020;32(1):107865.
[27] Numakawa T, Kumamaru E, Adachi N, Yagasaki Y, Izumi A, Kunugi H. Glucocorticoid receptor interaction with TrkB promotes BDNF-triggered PLC-γ signaling for glutamate release via a glutamate transporter. Proceedings of the National Academy of Sciences. 2009;106(2):647-52.
[28] Zhao C, Deng W, Gage FH. Mechanisms and Functional Implications of Adult Neurogenesis. Cell. 2008;132(4):645-60.
[29] Åmellem I, Yovianto G, Chong HT, Nair RR, Cnops V, Thanawalla A, et al. Role of NMDA Receptors in Adult Neurogenesis and Normal Development of the Dentate Gyrus. eneuro. 2021;8(4):ENEURO.0566-20.
[30] Schloesser RJ, Jimenez DV, Hardy NF, Paredes D, Catlow BJ, Manji HK, et al. Atrophy of pyramidal neurons and increased stress-induced glutamate levels in CA3 following chronic suppression of adult neurogenesis. Brain Structure and Function. 2014;219:1139-48.
[31] Kinlein SA, Wallace NK, Savenkova MI, Karatsoreos IN. Chronic hypothalamic-pituitary-adrenal axis disruption alters glutamate homeostasis and neural responses to stress in male C57Bl6/N mice. Neurobiology of Stress. 2022;19:100466.
[32] Pierone BC, Pereira CA, Garcez ML, Kaster MP. Stress and signaling pathways regulating autophagy: from behavioral models to psychiatric disorders. Experimental Neurology. 2020;334:113485.
[33] Hill AS, Sahay A, Hen R. Increasing adult hippocampal neurogenesis is sufficient to reduce anxiety and depression-like behaviors. Neuropsychopharmacology. 2015;40(10):2368-78.
[34] Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Journal of Neuroscience. 2000;20(24):9104-10.
[35] Malberg JE, Hen R, Madsen TM. Adult neurogenesis and antidepressant treatment: The surprise finding by Ron Duman and the field 20 years later. Biological psychiatry. 2021;90(2):96- 101.
[36] Choi SH, Bylykbashi E, Chatila ZK, Lee SW, Pulli B, Clemenson GD, et al. Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model. Science. 2018;361(6406):eaan8821.
[37] Mirescu C, Peters JD, Noiman L, Gould E. Sleep deprivation inhibits adult neurogenesis in the hippocampus by elevating glucocorticoids. Proceedings of the National Academy of Sciences. 2006;103(50):19170-5.
[38] Tunc-Ozcan E, Peng C-Y, Zhu Y, Dunlop SR, Contractor A, Kessler JA. Activating newborn neurons suppresses depression and anxiety-like behaviors. Nature communications. 2019;10(1):3768.
Downloads
Published
Issue
Section
License
Copyright (c) 2024 by the authors.

This work is licensed under a Creative Commons Attribution 4.0 International License.
