Medial Forebrain Bundle Deep Brain Stimulation Reverses Anhedonic-Like Behavior in a Chronic Model of Depression: Importance of BDNF and Inflammatory Cytokines Manoj P. Dandekar 1 & Ashwini Saxena 1 & Giselli Scaini 1 & Joo Hyun Shin 2 & Agata Migut 2 & Vijayasree Vayalanellore Giridharan 1 & Yuzhi Zhou 1,3 & Tatiana Barichello 1,4,5 & Jair C. Soares 5,6 & Joao Quevedo 1,4,5,6 & Albert J. Fenoy 2 Received: 8 May 2018 /Accepted: 4 October 2018 # Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract Deep brain stimulation (DBS) of the medial forebrain bundle (MFB) displays a promising antidepressant effects in patients with treatment-refractory depression; however, a clear consensus on underlying mechanisms is still enigmatic. Herein, we investigated the effects of MFB-DBS on anhedonic-like behavior using the Froot Loops® consumption in a chronic unpredictable mild stress (CUS) model of depression, biochemical estimation of peripheral and central inflam- matory cytokines, stress hormone, and brain-derived neurotrophic factor (BDNF). Seven days of MFB-DBS significantly reversed the 42-day CUS-generated anhedonic-like phenotype (p < 0.02) indicated by an increase in Froot Loops® consumption. Gross locomotor activity and body weight remained unaffected across the different groups. A dramatic augmentation of adrenocorticotropic hormone levels was seen in the plasma and cerebrospinal fluid (CSF) samples of CUS rats, which significantly reduced following MFB-DBS treatment. However, C-reactive protein levels were found to be unaffected. Interestingly, decreased levels of BDNF in the CUS animals were augmented in the plasma, CSF, and hippocampus following MFB-DBS, but remained unaltered in the nucleus accumbens (NAc). While multiplex assay revealed no change in the neuronal levels of inflammatory cytokines including IL-1α, IL-4, IL-10, IL-12, IL-13, and IL- 17 in the neuroanatomical framework of the hippocampus and NAc, increased levels of IL-1β, IL-2, IL-5, IL-6, IL-7, IL- 18, TNF-α, and INF-γ were seen in these brain structures after CUS and were differentially modulated in the presence of MFB stimulation. Here, we show that there is dysregulation of BDNF and neuroimmune mediators in a stress-driven chronic depression model, and that chronic MFB-DBS has the potential to undo these aberrations. Keywords Deep brain stimulation . MFB . Anhedonia . Chronic unpredictable mild stress . BDNF . Cytokines * Albert J. Fenoy Albert.J.Fenoy@uth.tmc.edu 1 Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA 2 Department of Neurosurgery, McGovern Medical School, Mischer Neurosurgical Associates, The University of Texas Health Science Center at Houston (UTHealth), 6400 Fannin, Suite 2800, Houston, TX 77030, USA 3 Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, People’ s Republic of China 4 Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA 5 Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil 6 Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA Molecular Neurobiology https://doi.org/10.1007/s12035-018-1381-5