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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
  • Ashwini Saxena
  • Giselli Scaini
  • Joo Hyun Shin
  • Agata Migut
  • Vijayasree Vayalanellore Giridharan
  • Yuzhi Zhou
  • Tatiana Barichello
  • Jair C. Soares
  • Joao Quevedo
  • Albert J. Fenoy
Article

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 inflammatory 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 

Notes

Funding

The Translational Psychiatry Program (USA) is funded by the Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth).

Laboratory of Neurosciences (Brazil) is one of the centers of the National Institute for Molecular Medicine (INCT-MM) and one of the members of the Center of Excellence in Applied Neurosciences of Santa Catarina (NENASC). Its research is supported by grants from CNPq (JQ), FAPESC (JQ), Instituto Cérebro e Mente (JQ), and UNESC (JQ). JQ is a 1A CNPq Research Fellow.

This work was partly supported by R01MH068766 and K24 RR020571, the Dunn Foundation, and Pat Rutherford, Jr. Chair in Psychiatry at UTHealth.

Dr. Fenoy used Mischer Neurological Institute funds for this project.

Compliance with Ethical Standards

All protocols were approved by the Institutional Animal Welfare Committee of the University of Texas Health Science Center at Houston, Texas, USA.

Conflict of Interest

Drs. Albert J. Fenoy and Joao Quevedo reported no biomedical financial interests.

Dr. Jair C. Soares has received grants/research supports from Bristol-Meyers Squibb, Forest Laboratories, Merck, Elan Pharmaceuticals, J&J, Stanley Medical Research Institute, and NIH, and serves as a consultant for Pfizer, Abbot, and Astellas Pharma, Inc.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • 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
  1. 1.Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical SchoolThe University of Texas Health Science Center at Houston (UTHealth)HoustonUSA
  2. 2.Department of Neurosurgery, McGovern Medical School, Mischer Neurosurgical AssociatesThe University of Texas Health Science Center at Houston (UTHealth)HoustonUSA
  3. 3.Modern Research Center for Traditional Chinese MedicineShanxi UniversityTaiyuanPeople’s Republic of China
  4. 4.Neuroscience Graduate ProgramThe University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical SciencesHoustonUSA
  5. 5.Translational Psychiatry Laboratory, Graduate Program in Health SciencesUniversity of Southern Santa Catarina (UNESC)CriciúmaBrazil
  6. 6.Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical SchoolThe University of Texas Health Science Center at Houston (UTHealth)HoustonUSA

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