Davinder Mand

Introduction: Major Depressive Disorder (MDD) is a mood disorder with a global burden¹. Depression is due to many factors including neurotransmitter irregularities, genetics, environmental and social factors². Chronic stress and genetic susceptibility play a causative role in MDD; chronic stress increases the risk of acquiring MDD in mouse models³. Brain Derived Neurotrophic Factor (BDNF) is a neurotrophin released by dopaminergic neurons projecting from the VTA^3,4. BDNF is specific for the Tropomyosin-receptor-kinase B (TrkB) receptor. BDNF levels in the VTA-NAc and VTA-mPFC pathways are increased and decreased, respectively, in response to chronic social defeat stress³. Increased BDNF in the VTA-NAc acts as a pro-depressant³. Proper application and use of TrkB agonists and inhibitors can prevent or address the increased and decreased levels of BDNF in response to chronic social stress. Methods: Using a chronic stress paradigm, social avoidance behaviors were observed in response to the model and exogenous BDNF injection⁵. Mice in a learned helplessness paradigm were used along with exogenous BDNF, TrkB agonist and TrkB antagonist to measure changes in the hippocampus, another location often observed with decreased BDNF following chronic social stress⁶. TrkB agonist and antagonist were injected in various parts of the mouse brain, including the NAc shell and core, and the effects of agonists and antagonists were measured⁶.  Following optogenetic stimulation of the VTA-NAc pathway, other mice were observed for changes in social avoidance behavior following a chronic social defeat stress model⁷. Results: There was a significant increase in social avoidance behavior following in the control “stressed” mice and the “stressed” mice with exogenous BDNF injection. Following a learned helplessness (LH) model, infusion of BDNF agonist led to anti-depressant effects in the hippocampus⁶. Mice underwent the same LH models and had increased levels of phosphorylated of the TrkB receptor⁶. 11 days following social defeat stress, optogenetic stimulation of the VTA-NAc, increased social avoidance behavior, however, TrkB inhibitor blocked optogenetically induced social avoidance behaviors⁷. Conclusion: Increased levels of BDNF in the VTA-NAc pathway and decreased levels in the VTA-mPFC pathways are implicated in a pro-depressant state. TrkB receptor antagonists blocked social avoidance behavior following chronic social defeat and TrkB agonists in the mPFC and hippocampus promoted anti-depressant effects. The effects of TrkB agonists and antagonists are significant in the treatment of depression if either is able to localize to the correct area of the brain (NAc vs mPFC) to carry out the respective anti-depressive effects.

1. Ferrari, A.J., Somerville, A.J., Baxter, A.J., Norman, R, Patten, S.B., Vos, T. and Whiteford H.A. Global variation in the prevalence and incidence of major depressive disorder: a systematic review of the epidemiological literature. Psychol Med 2013;43:471-481.
2. Moylan, S, Maes, M, N.R. Wray and M Berk. The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications. Mol Psychiatry. 2013;18(5):595-606.
3. Russo, S.J., and Nestler, E.J. The brain reward circuitry in mood disorders. Nat Rev Neurosci. 2013;14(9):609-25.
4. Ihara K, Yoshida H, Jones PB, et al. Serum BDNF levels before and after the development of mood disorders: a case-control study in a population cohort. Transl Psychiatry. 2016;6:e782.
5. Liu D, Tang QQ, Yin C, et al. BDNF-mediated projection-specific regulation of depressive-like and nociceptive behaviors in mesolimbic reward circuitry. Pain. 2018;159(1):175-188.
6. Shirayama Y, Yang C, Zhang JC, Ren Q, Yao W, Hashimoto K. Alterations in brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in the brain regions of a learned helplessness rat model and the antidepressant effects of a TrkB agonist and antagonist. Eur Neuropsychopharmacol. 2015;25(12):2449-2458.
7. Wook Koo J, Labonte B, Engmann O, et al. Essential Role of Mesolimbic Brain-Derived Neurotrophic Factor in Chronic Social Stress-Induced Depressive Behaviors. Biol Psychiatry. 2016;80(6):469-478.