Skip to main content

Advertisement

SpringerLink
Log in

Medial Forebrain Bundle Deep Brain Stimulation Reverses Anhedonic-Like Behavior in a Chronic Model of Depression: Importance of BDNF and Inflammatory Cytokines

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Fava M (2003) Diagnosis and definition of treatment-resistant depression. Biol Psychiatry 53(8):649–659

    Article  PubMed  Google Scholar 

  2. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME et al (2006) Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 163(11):1905–1917. https://doi.org/10.1176/ajp.2006.163.11.1905

    Article  PubMed  Google Scholar 

  3. Mrazek DA, Hornberger JC, Altar CA, Degtiar I (2014) A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996-2013. Psychiatr Serv 65(8):977–987. https://doi.org/10.1176/appi.ps.201300059

    Article  PubMed  Google Scholar 

  4. Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63(8):856–864. https://doi.org/10.1001/archpsyc.63.8.856

    Article  CAS  PubMed  Google Scholar 

  5. Akhtar H, Bukhari F, Nazir M, Anwar MN, Shahzad A (2016) Therapeutic efficacy of neurostimulation for depression: techniques, current modalities, and future challenges. Neurosci Bull 32(1):115–126. https://doi.org/10.1007/s12264-015-0009-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhou C, Zhang H, Qin Y, Tian T, Xu B, Chen J, Zhou X, Zeng L et al (2018) A systematic review and meta-analysis of deep brain stimulation in treatment-resistant depression. Prog Neuro-Psychopharmacol Biol Psychiatry 82:224–232. https://doi.org/10.1016/j.pnpbp.2017.11.012

    Article  Google Scholar 

  7. Dandekar MP, Fenoy AJ, Carvalho AF, Soares JC, Quevedo J (2018) Deep brain stimulation for treatment-resistant depression: an integrative review of preclinical and clinical findings and translational implications. Mol Psychiatry 23:1094–1112. https://doi.org/10.1038/mp.2018.2

    Article  CAS  PubMed  Google Scholar 

  8. Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, Kennedy SH (2005) Deep brain stimulation for treatment-resistant depression. Neuron 45(5):651–660. https://doi.org/10.1016/j.neuron.2005.02.014

    Article  CAS  PubMed  Google Scholar 

  9. Delaloye S, Holtzheimer PE (2014) Deep brain stimulation in the treatment of depression. Dialogues Clin Neurosci 16(1):83–91

    PubMed  PubMed Central  Google Scholar 

  10. Coenen VA, Amtage F, Volkmann J, Schlapfer TE (2015) Deep brain stimulation in neurological and psychiatric disorders. Dtsch Arztebl Int 112(31–32):519–526. https://doi.org/10.3238/arztebl.2015.0519

    Article  PubMed  PubMed Central  Google Scholar 

  11. Bewernick BH, Kayser S, Gippert SM, Switala C, Coenen VA, Schlaepfer TE (2017) Deep brain stimulation to the medial forebrain bundle for depression- long-term outcomes and a novel data analysis strategy. Brain Stimul 10(3):664–671. https://doi.org/10.1016/j.brs.2017.01.581

    Article  PubMed  Google Scholar 

  12. Jimenez F, Velasco F, Salin-Pascual R, Hernandez JA, Velasco M, Criales JL, Nicolini H (2005) A patient with a resistant major depression disorder treated with deep brain stimulation in the inferior thalamic peduncle. Neurosurgery 57(3):585–593 discussion 585-593

    Article  PubMed  Google Scholar 

  13. Jimenez F, Nicolini H, Lozano AM, Piedimonte F, Salin R, Velasco F (2013) Electrical stimulation of the inferior thalamic peduncle in the treatment of major depression and obsessive compulsive disorders. World Neurosurg 80(3–4):S30.e17–S30.e25. https://doi.org/10.1016/j.wneu.2012.07.010

    Article  Google Scholar 

  14. Sartorius A, Kiening KL, Kirsch P, von Gall CC, Haberkorn U, Unterberg AW, Henn FA, Meyer-Lindenberg A (2010) Remission of major depression under deep brain stimulation of the lateral habenula in a therapy-refractory patient. Biol Psychiatry 67(2):e9–e11. https://doi.org/10.1016/j.biopsych.2009.08.027

    Article  PubMed  Google Scholar 

  15. Schneider TM, Beynon C, Sartorius A, Unterberg AW, Kiening KL (2013) Deep brain stimulation of the lateral habenular complex in treatment-resistant depression: traps and pitfalls of trajectory choice. Neurosurgery 72(2 Suppl Operative):ons184–ons193; discussion ons193. https://doi.org/10.1227/NEU.0b013e318277a5aa

    Article  PubMed  Google Scholar 

  16. Morishita T, Fayad SM, Higuchi MA, Nestor KA, Foote KD (2014) Deep brain stimulation for treatment-resistant depression: systematic review of clinical outcomes. Neurotherapeutics 11(3):475–484. https://doi.org/10.1007/s13311-014-0282-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Dougherty DD, Rezai AR, Carpenter LL, Howland RH, Bhati MT, O’Reardon JP, Eskandar EN, Baltuch GH et al (2015) A randomized sham-controlled trial of deep brain stimulation of the ventral capsule/ventral striatum for chronic treatment-resistant depression. Biol Psychiatry 78(4):240–248. https://doi.org/10.1016/j.biopsych.2014.11.023

    Article  PubMed  Google Scholar 

  18. Bergfeld IO, Mantione M, Hoogendoorn ML, Ruhe HG, Notten P, van Laarhoven J, Visser I, Figee M et al (2016) Deep brain stimulation of the ventral anterior limb of the internal capsule for treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry 73(5):456–464. https://doi.org/10.1001/jamapsychiatry.2016.0152

    Article  PubMed  Google Scholar 

  19. Gersner R, Toth E, Isserles M, Zangen A (2010) Site-specific antidepressant effects of repeated subconvulsive electrical stimulation: potential role of brain-derived neurotrophic factor. Biol Psychiatry 67(2):125–132. https://doi.org/10.1016/j.biopsych.2009.09.015

    Article  CAS  PubMed  Google Scholar 

  20. Hamani C, Machado DC, Hipolide DC, Dubiela FP, Suchecki D, Macedo CE, Tescarollo F, Martins U et al (2012) Deep brain stimulation reverses anhedonic-like behavior in a chronic model of depression: role of serotonin and brain derived neurotrophic factor. Biol Psychiatry 71(1):30–35. https://doi.org/10.1016/j.biopsych.2011.08.025

    Article  CAS  PubMed  Google Scholar 

  21. Dandekar MP, Luse D, Hoffmann C, Cotton P, Peery T, Ruiz C, Hussey C, Giridharan VV et al (2017) Increased dopamine receptor expression and anti-depressant response following deep brain stimulation of the medial forebrain bundle. J Affect Disord 217:80–88. https://doi.org/10.1016/j.jad.2017.03.074

    Article  CAS  PubMed  Google Scholar 

  22. Li P, Huang R, Song W, Ji J, Burgunder JM, Wang X, Zhong Q, Kaelin-Lang A et al (2012) Deep brain stimulation of the globus pallidus internal improves symptoms of chorea-acanthocytosis. Neurol Sci 33(2):269–274. https://doi.org/10.1007/s10072-011-0741-y

    Article  CAS  PubMed  Google Scholar 

  23. Meng H, Wang Y, Huang M, Lin W, Wang S, Zhang B (2011) Chronic deep brain stimulation of the lateral habenula nucleus in a rat model of depression. Brain Res 1422:32–38. https://doi.org/10.1016/j.brainres.2011.08.041

    Article  CAS  PubMed  Google Scholar 

  24. Schmuckermair C, Gaburro S, Sah A, Landgraf R, Sartori SB, Singewald N (2013) Behavioral and neurobiological effects of deep brain stimulation in a mouse model of high anxiety- and depression-like behavior. Neuropsychopharmacology 38(7):1234–1244. https://doi.org/10.1038/npp.2013.21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Veerakumar A, Challis C, Gupta P, Da J, Upadhyay A, Beck SG, Berton O (2014) Antidepressant-like effects of cortical deep brain stimulation coincide with pro-neuroplastic adaptations of serotonin systems. Biol Psychiatry 76(3):203–212. https://doi.org/10.1016/j.biopsych.2013.12.009

    Article  CAS  PubMed  Google Scholar 

  26. Edemann-Callesen H, Voget M, Empl L, Vogel M, Wieske F, Rummel J, Heinz A, Mathe AA et al (2015) Medial forebrain bundle deep brain stimulation has symptom-specific anti-depressant effects in rats and as opposed to ventromedial prefrontal cortex stimulation interacts with the reward system. Brain Stimul 8(4):714–723. https://doi.org/10.1016/j.brs.2015.02.009

    Article  PubMed  Google Scholar 

  27. Lim LW, Prickaerts J, Huguet G, Kadar E, Hartung H, Sharp T, Temel Y (2015) Electrical stimulation alleviates depressive-like behaviors of rats: investigation of brain targets and potential mechanisms. Transl Psychiatry 5:e535. https://doi.org/10.1038/tp.2015.24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lim LW, Janssen ML, Kocabicak E, Temel Y (2015) The antidepressant effects of ventromedial prefrontal cortex stimulation is associated with neural activation in the medial part of the subthalamic nucleus. Behav Brain Res 279:17–21. https://doi.org/10.1016/j.bbr.2014.11.008

    Article  PubMed  Google Scholar 

  29. Puigdemont D, Portella M, Perez-Egea R, Molet J, Gironell A, de Diego-Adelino J, Martin A, Rodriguez R et al (2015) A randomized double-blind crossover trial of deep brain stimulation of the subcallosal cingulate gyrus in patients with treatment-resistant depression: a pilot study of relapse prevention. J Psychiatry Neurosci 40(4):224–231

    Article  PubMed  PubMed Central  Google Scholar 

  30. Holtzheimer PE, Husain MM, Lisanby SH, Taylor SF, Whitworth LA, McClintock S, Slavin KV, Berman J et al (2017) Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial. Lancet Psychiatry 4(11):839–849. https://doi.org/10.1016/S2215-0366(17)30371-1

    Article  PubMed  Google Scholar 

  31. Eitan R, Fontaine D, Benoit M, Giordana C, Darmon N, Israel Z, Linesky E, Arkadir D et al (2018) One year double blind study of high vs low frequency subcallosal cingulate stimulation for depression. J Psychiatr Res 96:124–134. https://doi.org/10.1016/j.jpsychires.2017.09.026

    Article  PubMed  Google Scholar 

  32. Schlaepfer TE, Bewernick BH, Kayser S, Madler B, Coenen VA (2013) Rapid effects of deep brain stimulation for treatment-resistant major depression. Biol Psychiatry 73(12):1204–1212. https://doi.org/10.1016/j.biopsych.2013.01.034

    Article  PubMed  Google Scholar 

  33. Fenoy AJ, Schulz P, Selvaraj S, Burrows C, Spiker D, Cao B, Zunta-Soares G, Gajwani P et al (2016) Deep brain stimulation of the medial forebrain bundle: distinctive responses in resistant depression. J Affect Disord 203:143–151. https://doi.org/10.1016/j.jad.2016.05.064

    Article  PubMed  Google Scholar 

  34. Coenen VA, Madler B, Schlaepfer TE (2013) Reply to: medial forebrain bundle stimulation-speed access to an old or entry into a new depression neurocircuit? Biol Psychiatry 74(12):e45–e46. https://doi.org/10.1016/j.biopsych.2013.06.017

    Article  PubMed  Google Scholar 

  35. Coenen VA, Schlaepfer TE, Maedler B, Panksepp J (2011) Cross-species affective functions of the medial forebrain bundle-implications for the treatment of affective pain and depression in humans. Neurosci Biobehav Rev 35(9):1971–1981. https://doi.org/10.1016/j.neubiorev.2010.12.009

    Article  PubMed  Google Scholar 

  36. Schlaepfer TE, Bewernick BH, Kayser S, Hurlemann R, Coenen VA (2014) Deep brain stimulation of the human reward system for major depression--rationale, outcomes and outlook. Neuropsychopharmacology 39(6):1303–1314. https://doi.org/10.1038/npp.2014.28

    Article  PubMed  PubMed Central  Google Scholar 

  37. Forbes NF, Stewart CA, Matthews K, Reid IC (1996) Chronic mild stress and sucrose consumption: validity as a model of depression. Physiol Behav 60(6):1481–1484

    Article  CAS  PubMed  Google Scholar 

  38. Willner P (2005) Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology 52(2):90–110. https://doi.org/10.1159/000087097

    Article  CAS  PubMed  Google Scholar 

  39. Gamaro GD, Prediger ME, Lopes JB, Dalmaz C (2003) Interaction between estradiol replacement and chronic stress on feeding behavior and on serum leptin. Pharmacol Biochem Behav 76(2):327–333

    Article  CAS  PubMed  Google Scholar 

  40. Rezin GT, Cardoso MR, Goncalves CL, Scaini G, Fraga DB, Riegel RE, Comim CM, Quevedo J et al (2008) Inhibition of mitochondrial respiratory chain in brain of rats subjected to an experimental model of depression. Neurochem Int 53(6–8):395–400. https://doi.org/10.1016/j.neuint.2008.09.012

    Article  CAS  PubMed  Google Scholar 

  41. Reus GZ, Abelaira HM, Stringari RB, Fries GR, Kapczinski F, Quevedo J (2012) Memantine treatment reverses anhedonia, normalizes corticosterone levels and increases BDNF levels in the prefrontal cortex induced by chronic mild stress in rats. Metab Brain Dis 27(2):175–182. https://doi.org/10.1007/s11011-012-9281-2

    Article  CAS  PubMed  Google Scholar 

  42. Della FP, Abelaira HM, Reus GZ, Antunes AR, Dos Santos MA, Zappelinni G, Steckert AV, Vuolo F et al (2012) Tianeptine exerts neuroprotective effects in the brain tissue of rats exposed to the chronic stress model. Pharmacol Biochem Behav 103(2):395–402. https://doi.org/10.1016/j.pbb.2012.09.018

    Article  CAS  PubMed  Google Scholar 

  43. Hamani C, Nobrega JN (2010) Deep brain stimulation in clinical trials and animal models of depression. Eur J Neurosci 32(7):1109–1117. https://doi.org/10.1111/j.1460-9568.2010.07414.x

    Article  PubMed  Google Scholar 

  44. Hamani C, Diwan M, Macedo CE, Brandao ML, Shumake J, Gonzalez-Lima F, Raymond R, Lozano AM et al (2010) Antidepressant-like effects of medial prefrontal cortex deep brain stimulation in rats. Biol Psychiatry 67(2):117–124. https://doi.org/10.1016/j.biopsych.2009.08.025

    Article  PubMed  Google Scholar 

  45. Hamani C, Diwan M, Isabella S, Lozano AM, Nobrega JN (2010) Effects of different stimulation parameters on the antidepressant-like response of medial prefrontal cortex deep brain stimulation in rats. J Psychiatr Res 44(11):683–687. https://doi.org/10.1016/j.jpsychires.2009.12.010

    Article  PubMed  Google Scholar 

  46. Insel N, Pilkiw M, Nobrega JN, Hutchison WD, Takehara-Nishiuchi K, Hamani C (2015) Chronic deep brain stimulation of the rat ventral medial prefrontal cortex disrupts hippocampal-prefrontal coherence. Exp Neurol 269:1–7. https://doi.org/10.1016/j.expneurol.2015.03.023

    Article  PubMed  PubMed Central  Google Scholar 

  47. Kohler CA, Freitas TH, Stubbs B, Maes M, Solmi M, Veronese N, de Andrade NQ, Morris G et al (2017) Peripheral alterations in cytokine and chemokine levels after antidepressant drug treatment for major depressive disorder: systematic review and meta-analysis. Mol Neurobiol. https://doi.org/10.1007/s12035-017-0632-1

  48. Maes M, Yirmyia R, Noraberg J, Brene S, Hibbeln J, Perini G, Kubera M, Bob P et al (2009) The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab Brain Dis 24(1):27–53. https://doi.org/10.1007/s11011-008-9118-1

    Article  CAS  PubMed  Google Scholar 

  49. Rosenblat JD, McIntyre RS, Alves GS, Fountoulakis KN, Carvalho AF (2015) Beyond monoamines-novel targets for treatment-resistant depression: a comprehensive review. Curr Neuropharmacol 13(5):636–655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Calleja-Castillo JM, De La Cruz-Aguilera DL, Manjarrez J, Velasco-Velazquez MA, Morales-Espinoza G, Moreno-Aguilar J, Hernandez ME, Aguirre-Cruz L et al (2013) Chronic deep brain stimulation of the hypothalamic nucleus in wistar rats alters circulatory levels of corticosterone and proinflammatory cytokines. Clin Dev Immunol 2013:698634–698639. https://doi.org/10.1155/2013/698634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Perez-Caballero L, Perez-Egea R, Romero-Grimaldi C, Puigdemont D, Molet J, Caso JR, Mico JA, Perez V et al (2014) Early responses to deep brain stimulation in depression are modulated by anti-inflammatory drugs. Mol Psychiatry 19(5):607–614. https://doi.org/10.1038/mp.2013.63

    Article  CAS  PubMed  Google Scholar 

  52. Valkanova V, Ebmeier KP, Allan CL (2013) CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies. J Affect Disord 150(3):736–744. https://doi.org/10.1016/j.jad.2013.06.004

    Article  CAS  PubMed  Google Scholar 

  53. Duman RS, Monteggia LM (2006) A neurotrophic model for stress-related mood disorders. Biol Psychiatry 59(12):1116–1127. https://doi.org/10.1016/j.biopsych.2006.02.013

    Article  CAS  PubMed  Google Scholar 

  54. Bambico FR, Bregman T, Diwan M, Li J, Darvish-Ghane S, Li Z, Laver B, Amorim BO et al (2015) Neuroplasticity-dependent and -independent mechanisms of chronic deep brain stimulation in stressed rats. Transl Psychiatry 5:e674. https://doi.org/10.1038/tp.2015.166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bruchim-Samuel M, Lax E, Gazit T, Friedman A, Ahdoot H, Bairachnaya M, Pinhasov A, Yadid G (2016) Electrical stimulation of the vmPFC serves as a remote control to affect VTA activity and improve depressive-like behavior. Exp Neurol 283(Pt A):255–263. https://doi.org/10.1016/j.expneurol.2016.05.016

    Article  PubMed  Google Scholar 

  56. Jimenez-Sanchez L, Linge R, Campa L, Valdizan EM, Pazos A, Diaz A, Adell A (2016) Behavioral, neurochemical and molecular changes after acute deep brain stimulation of the infralimbic prefrontal cortex. Neuropharmacology 108:91–102. https://doi.org/10.1016/j.neuropharm.2016.04.020

    Article  CAS  PubMed  Google Scholar 

  57. Moshe H, Gal R, Barnea-Ygael N, Gulevsky T, Alyagon U, Zangen A (2016) Prelimbic stimulation ameliorates depressive-like behaviors and increases regional BDNF expression in a novel drug-resistant animal model of depression. Brain Stimul 9(2):243–250. https://doi.org/10.1016/j.brs.2015.10.009

    Article  PubMed  Google Scholar 

  58. Willner P, Towell A, Sampson D, Sophokleous S, Muscat R (1987) Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacology 93(3):358–364

    Article  CAS  PubMed  Google Scholar 

  59. Furlanetti LL, Coenen VA, Aranda IA, Dobrossy MD (2015) Chronic deep brain stimulation of the medial forebrain bundle reverses depressive-like behavior in a hemiparkinsonian rodent model. Exp Brain Res 233(11):3073–3085. https://doi.org/10.1007/s00221-015-4375-9

    Article  PubMed  PubMed Central  Google Scholar 

  60. Willner P (2017) The chronic mild stress (CMS) model of depression: history, evaluation and usage. Neurobiol Stress 6:78–93. https://doi.org/10.1016/j.ynstr.2016.08.002

    Article  PubMed  Google Scholar 

  61. Hamani C, Amorim BO, Wheeler AL, Diwan M, Driesslein K, Covolan L, Butson CR, Nobrega JN (2014) Deep brain stimulation in rats: different targets induce similar antidepressant-like effects but influence different circuits. Neurobiol Dis 71:205–214. https://doi.org/10.1016/j.nbd.2014.08.007

    Article  PubMed  PubMed Central  Google Scholar 

  62. Kim Y, Morath B, Hu C, Byrne LK, Sutor SL, Frye MA, Tye SJ (2016) Antidepressant actions of lateral habenula deep brain stimulation differentially correlate with CaMKII/GSK3/AMPK signaling locally and in the infralimbic cortex. Behav Brain Res 306:170–177. https://doi.org/10.1016/j.bbr.2016.02.039

    Article  CAS  PubMed  Google Scholar 

  63. Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates. Academic Press, San Diego

    Google Scholar 

  64. Friedman A, Frankel M, Flaumenhaft Y, Merenlender A, Pinhasov A, Feder Y, Taler M, Gil-Ad I et al (2009) Programmed acute electrical stimulation of ventral tegmental area alleviates depressive-like behavior. Neuropsychopharmacology 34(4):1057–1066. https://doi.org/10.1038/npp.2008.177

    Article  CAS  PubMed  Google Scholar 

  65. Germano IM, Gracies JM, Weisz DJ, Tse W, Koller WC, Olanow CW (2004) Unilateral stimulation of the subthalamic nucleus in Parkinson disease: a double-blind 12-month evaluation study. J Neurosurg 101(1):36–42. https://doi.org/10.3171/jns.2004.101.1.0036

    Article  PubMed  Google Scholar 

  66. Schlaepfer TE, Cohen MX, Frick C, Kosel M, Brodesser D, Axmacher N, Joe AY, Kreft M et al (2008) Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. Neuropsychopharmacology 33(2):368–377. https://doi.org/10.1038/sj.npp.1301408

    Article  PubMed  Google Scholar 

  67. Gazit T, Friedman A, Lax E, Samuel M, Zahut R, Katz M, Abraham L, Tischler H et al (2015) Programmed deep brain stimulation synchronizes VTA gamma band field potential and alleviates depressive-like behavior in rats. Neuropharmacology 91:135–141. https://doi.org/10.1016/j.neuropharm.2014.12.003

    Article  CAS  PubMed  Google Scholar 

  68. Furlanetti LL, Coenen VA, Dobrossy MD (2016) Ventral tegmental area dopaminergic lesion-induced depressive phenotype in the rat is reversed by deep brain stimulation of the medial forebrain bundle. Behav Brain Res 299:132–140. https://doi.org/10.1016/j.bbr.2015.11.036

    Article  CAS  PubMed  Google Scholar 

  69. Russo SJ, Nestler EJ (2013) The brain reward circuitry in mood disorders. Nat Rev Neurosci 14(9):609–625. https://doi.org/10.1038/nrn3381

    Article  CAS  PubMed  Google Scholar 

  70. Garcia LS, Comim CM, Valvassori SS, Reus GZ, Stertz L, Kapczinski F, Gavioli EC, Quevedo J (2009) Ketamine treatment reverses behavioral and physiological alterations induced by chronic mild stress in rats. Prog Neuro-Psychopharmacol Biol Psychiatry 33(3):450–455. https://doi.org/10.1016/j.pnpbp.2009.01.004

    Article  CAS  Google Scholar 

  71. Lucca G, Comim CM, Valvassori SS, Reus GZ, Vuolo F, Petronilho F, Dal-Pizzol F, Gavioli EC et al (2009) Effects of chronic mild stress on the oxidative parameters in the rat brain. Neurochem Int 54(5–6):358–362. https://doi.org/10.1016/j.neuint.2009.01.001

    Article  CAS  PubMed  Google Scholar 

  72. Lucca G, Comim CM, Valvassori SS, Reus GZ, Vuolo F, Petronilho F, Gavioli EC, Dal-Pizzol F et al (2009) Increased oxidative stress in submitochondrial particles into the brain of rats submitted to the chronic mild stress paradigm. J Psychiatr Res 43(9):864–869. https://doi.org/10.1016/j.jpsychires.2008.11.002

    Article  PubMed  Google Scholar 

  73. Ely DR, Dapper V, Marasca J, Correa JB, Gamaro GD, Xavier MH, Michalowski MB, Catelli D et al (1997) Effect of restraint stress on feeding behavior of rats. Physiol Behav 61(3):395–398

    Article  CAS  PubMed  Google Scholar 

  74. Bregman T, Reznikov R, Diwan M, Raymond R, Butson CR, Nobrega JN, Hamani C (2015) Antidepressant-like effects of medial forebrain bundle deep brain stimulation in rats are not associated with accumbens dopamine release. Brain Stimul 8(4):708–713. https://doi.org/10.1016/j.brs.2015.02.007

    Article  PubMed  Google Scholar 

  75. Furlanetti LL, Dobrossy MD, Aranda IA, Coenen VA (2015) Feasibility and safety of continuous and chronic bilateral deep brain stimulation of the medial forebrain bundle in the naive Sprague-Dawley rat. Behav Neurol 2015:256196–256113. https://doi.org/10.1155/2015/256196

    Article  PubMed  PubMed Central  Google Scholar 

  76. Dwivedi Y (2009) Brain-derived neurotrophic factor: role in depression and suicide. Neuropsychiatr Dis Treat 5:433–449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hamani C, Pilitsis J, Rughani AI, Rosenow JM, Patil PG, Slavin KS, Abosch A, Eskandar E et al (2014) Deep brain stimulation for obsessive-compulsive disorder: systematic review and evidence-based guideline sponsored by the American Society for Stereotactic and Functional Neurosurgery and the Congress of Neurological Surgeons (CNS) and endorsed by the CNS and American Association of Neurological Surgeons. Neurosurgery 75(4):327–333; quiz 333. https://doi.org/10.1227/NEU.0000000000000499

    Article  PubMed  Google Scholar 

  78. Autry AE, Monteggia LM (2012) Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 64(2):238–258. https://doi.org/10.1124/pr.111.005108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Nibuya M, Morinobu S, Duman RS (1995) Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 15(11):7539–7547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Smith MA, Makino S, Kvetnansky R, Post RM (1995) Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci 15(3 Pt 1):1768–1777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, Nakazato M, Watanabe H et al (2003) Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry 54(1):70–75

    Article  CAS  PubMed  Google Scholar 

  82. Karege F, Perret G, Bondolfi G, Schwald M, Bertschy G, Aubry JM (2002) Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res 109(2):143–148

    Article  CAS  PubMed  Google Scholar 

  83. Hong Z, Li W, Qu B, Zou X, Chen J, Sander JW, Zhou D (2014) Serum brain-derived neurotrophic factor levels in epilepsy. Eur J Neurol 21(1):57–64. https://doi.org/10.1111/ene.12232

    Article  CAS  PubMed  Google Scholar 

  84. Hoshaw BA, Malberg JE, Lucki I (2005) Central administration of IGF-I and BDNF leads to long-lasting antidepressant-like effects. Brain Res 1037(1–2):204–208. https://doi.org/10.1016/j.brainres.2005.01.007

    Article  CAS  PubMed  Google Scholar 

  85. Chen B, Dowlatshahi D, MacQueen GM, Wang JF, Young LT (2001) Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry 50(4):260–265

    Article  CAS  PubMed  Google Scholar 

  86. Markham A, Bains R, Franklin P, Spedding M (2014) Changes in mitochondrial function are pivotal in neurodegenerative and psychiatric disorders: how important is BDNF? Br J Pharmacol 171(8):2206–2229. https://doi.org/10.1111/bph.12531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kim Y, McGee S, Czeczor JK, Walker AJ, Kale RP, Kouzani AZ, Walder K, Berk M et al (2016) Nucleus accumbens deep-brain stimulation efficacy in ACTH-pretreated rats: alterations in mitochondrial function relate to antidepressant-like effects. Transl Psychiatry 6(6):e842. https://doi.org/10.1038/tp.2016.84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Krishnan V, Nestler EJ (2010) Linking molecules to mood: new insight into the biology of depression. Am J Psychiatry 167(11):1305–1320. https://doi.org/10.1176/appi.ajp.2009.10030434

    Article  PubMed  PubMed Central  Google Scholar 

  89. Larsen MH, Mikkelsen JD, Hay-Schmidt A, Sandi C (2010) Regulation of brain-derived neurotrophic factor (BDNF) in the chronic unpredictable stress rat model and the effects of chronic antidepressant treatment. J Psychiatr Res 44(13):808–816. https://doi.org/10.1016/j.jpsychires.2010.01.005

    Article  PubMed  Google Scholar 

  90. Tanti A, Belzung C (2013) Neurogenesis along the septo-temporal axis of the hippocampus: are depression and the action of antidepressants region-specific? Neuroscience 252:234–252. https://doi.org/10.1016/j.neuroscience.2013.08.017

    Article  CAS  PubMed  Google Scholar 

  91. Bessa JM, Morais M, Marques F, Pinto L, Palha JA, Almeida OF, Sousa N (2013) Stress-induced anhedonia is associated with hypertrophy of medium spiny neurons of the nucleus accumbens. Transl Psychiatry 3:e266. https://doi.org/10.1038/tp.2013.39

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Dinan TG, Lavelle E, Cooney J, Burnett F, Scott L, Dash A, Thakore J, Berti C (1997) Dexamethasone augmentation in treatment-resistant depression. Acta Psychiatr Scand 95(1):58–61

    Article  CAS  PubMed  Google Scholar 

  93. Tapia-Arancibia L, Rage F, Givalois L, Arancibia S (2004) Physiology of BDNF: focus on hypothalamic function. Front Neuroendocrinol 25(2):77–107. https://doi.org/10.1016/j.yfrne.2004.04.001

    Article  CAS  PubMed  Google Scholar 

  94. McEwen BS (2005) Glucocorticoids, depression, and mood disorders: structural remodeling in the brain. Metab Clin Exp 54(5 Suppl 1):20–23. https://doi.org/10.1016/j.metabol.2005.01.008

    Article  CAS  PubMed  Google Scholar 

  95. Krishnan V, Nestler EJ (2008) The molecular neurobiology of depression. Nature 455(7215):894–902. https://doi.org/10.1038/nature07455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Jehn CF, Becker B, Flath B, Nogai H, Vuong L, Schmid P, Luftner D (2015) Neurocognitive function, brain-derived neurotrophic factor (BDNF) and IL-6 levels in cancer patients with depression. J Neuroimmunol 287:88–92. https://doi.org/10.1016/j.jneuroim.2015.08.012

    Article  CAS  PubMed  Google Scholar 

  97. Zincir S, Ozturk P, Bilgen AE, Izci F, Yukselir C (2016) Levels of serum immunomodulators and alterations with electroconvulsive therapy in treatment-resistant major depression. Neuropsychiatr Dis Treat 12:1389–1396. https://doi.org/10.2147/NDT.S106652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kulmatycki KM, Jamali F (2001) Therapeutic relevance of altered cytokine expression. Cytokine 14(1):1–10. https://doi.org/10.1006/cyto.2000.0827

    Article  CAS  PubMed  Google Scholar 

  99. Raison CL, Capuron L, Miller AH (2006) Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 27(1):24–31. https://doi.org/10.1016/j.it.2005.11.006

    Article  CAS  PubMed  Google Scholar 

  100. Goldsmith DR, Rapaport MH, Miller BJ (2016) A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry 21(12):1696–1709. https://doi.org/10.1038/mp.2016.3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Lanquillon S, Krieg JC, Bening-Abu-Shach U, Vedder H (2000) Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology 22(4):370–379. https://doi.org/10.1016/S0893-133X(99)00134-7

    Article  CAS  PubMed  Google Scholar 

  102. Eller T, Aluoja A, Maron E, Vasar V (2009) Soluble interleukin-2 receptor and tumor necrosis factor levels in depressed patients in Estonia. Medicina 45(12):971–977

    Article  PubMed  Google Scholar 

  103. Yoshimura R, Hori H, Ikenouchi-Sugita A, Umene-Nakano W, Ueda N, Nakamura J (2009) Higher plasma interleukin-6 (IL-6) level is associated with SSRI- or SNRI-refractory depression. Prog Neuro-Psychopharmacol Biol Psychiatry 33(4):722–726. https://doi.org/10.1016/j.pnpbp.2009.03.020

    Article  CAS  Google Scholar 

  104. Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctot KL (2010) A meta-analysis of cytokines in major depression. Biol Psychiatry 67(5):446–457. https://doi.org/10.1016/j.biopsych.2009.09.033

    Article  CAS  PubMed  Google Scholar 

  105. Strawbridge R, Arnone D, Danese A, Papadopoulos A, Herane Vives A, Cleare AJ (2015) Inflammation and clinical response to treatment in depression: a meta-analysis. Eur Neuropsychopharmacol 25(10):1532–1543. https://doi.org/10.1016/j.euroneuro.2015.06.007

    Article  CAS  PubMed  Google Scholar 

  106. Karson A, Demirtas T, Bayramgurler D, Balci F, Utkan T (2013) Chronic administration of infliximab (TNF-alpha inhibitor) decreases depression and anxiety-like behaviour in rat model of chronic mild stress. Basic Clin Pharmacol Toxicol 112(5):335–340. https://doi.org/10.1111/bcpt.12037

    Article  CAS  PubMed  Google Scholar 

  107. Krugel U, Fischer J, Radicke S, Sack U, Himmerich H (2013) Antidepressant effects of TNF-alpha blockade in an animal model of depression. J Psychiatr Res 47(5):611–616. https://doi.org/10.1016/j.jpsychires.2013.01.007

    Article  PubMed  Google Scholar 

  108. Tyring S, Gottlieb A, Papp K, Gordon K, Leonardi C, Wang A, Lalla D, Woolley M et al (2006) Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet 367(9504):29–35. https://doi.org/10.1016/S0140-6736(05)67763-X

    Article  CAS  PubMed  Google Scholar 

  109. Schmidt FM, Kirkby KC, Himmerich H (2014) The TNF-alpha inhibitor etanercept as monotherapy in treatment-resistant depression - report of two cases. Psychiatr Danub 26(3):288–290

    PubMed  Google Scholar 

  110. Black C, Miller BJ (2015) Meta-analysis of cytokines and chemokines in suicidality: distinguishing suicidal versus nonsuicidal patients. Biol Psychiatry 78(1):28–37. https://doi.org/10.1016/j.biopsych.2014.10.014

    Article  CAS  PubMed  Google Scholar 

  111. Huang ZB, Sheng GQ (2010) Interleukin-1beta with learning and memory. Neurosci Bull 26(6):455–468. https://doi.org/10.1007/s12264-010-6023-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Wang N, Yu HY, Shen XF, Gao ZQ, Yang C, Yang JJ, Zhang GF (2015) The rapid antidepressant effect of ketamine in rats is associated with down-regulation of pro-inflammatory cytokines in the hippocampus. Ups J Med Sci 120(4):241–248. https://doi.org/10.3109/03009734.2015.1060281

    Article  PubMed  PubMed Central  Google Scholar 

  113. Maes M, Song C, Lin AH, Bonaccorso S, Kenis G, De Jongh R, Bosmans E, Scharpe S (1999) Negative immunoregulatory effects of antidepressants: inhibition of interferon-gamma and stimulation of interleukin-10 secretion. Neuropsychopharmacology 20(4):370–379. https://doi.org/10.1016/S0893-133X(98)00088-8

    Article  CAS  PubMed  Google Scholar 

  114. Kubera M, Lin AH, Kenis G, Bosmans E, van Bockstaele D, Maes M (2001) Anti-inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio. J Clin Psychopharmacol 21(2):199–206

    Article  CAS  PubMed  Google Scholar 

  115. Haapakoski R, Mathieu J, Ebmeier KP, Alenius H, Kivimaki M (2015) Cumulative meta-analysis of interleukins 6 and 1beta, tumour necrosis factor alpha and C-reactive protein in patients with major depressive disorder. Brain Behav Immun 49:206–215. https://doi.org/10.1016/j.bbi.2015.06.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Simon NM, McNamara K, Chow CW, Maser RS, Papakostas GI, Pollack MH, Nierenberg AA, Fava M et al (2008) A detailed examination of cytokine abnormalities in Major Depressive Disorder. Eur Neuropsychopharmacol 18(3):230–233. https://doi.org/10.1016/j.euroneuro.2007.06.004

    Article  CAS  PubMed  Google Scholar 

  117. Dahl J, Ormstad H, Aass HC, Malt UF, Bendz LT, Sandvik L, Brundin L, Andreassen OA (2014) The plasma levels of various cytokines are increased during ongoing depression and are reduced to normal levels after recovery. Psychoneuroendocrinology 45:77–86. https://doi.org/10.1016/j.psyneuen.2014.03.019

    Article  CAS  PubMed  Google Scholar 

  118. Schmidt FM, Lichtblau N, Minkwitz J, Chittka T, Thormann J, Kirkby KC, Sander C, Mergl R et al (2014) Cytokine levels in depressed and non-depressed subjects, and masking effects of obesity. J Psychiatr Res 55:29–34. https://doi.org/10.1016/j.jpsychires.2014.04.021

    Article  PubMed  Google Scholar 

  119. Maes M, Bosmans E, De Jongh R, Kenis G, Vandoolaeghe E, Neels H (1997) Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine 9(11):853–858. https://doi.org/10.1006/cyto.1997.0238

    Article  CAS  PubMed  Google Scholar 

  120. Yang JJ, Wang N, Yang C, Shi JY, Yu HY, Hashimoto K (2015) Serum interleukin-6 is a predictive biomarker for ketamine’s antidepressant effect in treatment-resistant patients with major depression. Biol Psychiatry 77(3):e19–e20. https://doi.org/10.1016/j.biopsych.2014.06.021

    Article  CAS  PubMed  Google Scholar 

  121. Manikowska K, Mikolajczyk M, Mikolajczak PL, Bobkiewicz-Kozlowska T (2014) The influence of mianserin on TNF-alpha, IL-6 and IL-10 serum levels in rats under chronic mild stress. Pharmacol Rep 66(1):22–27. https://doi.org/10.1016/j.pharep.2013.06.003

    Article  CAS  PubMed  Google Scholar 

  122. Schmidt FM, Schroder T, Kirkby KC, Sander C, Suslow T, Holdt LM, Teupser D, Hegerl U et al (2016) Pro- and anti-inflammatory cytokines, but not CRP, are inversely correlated with severity and symptoms of major depression. Psychiatry Res 239:85–91. https://doi.org/10.1016/j.psychres.2016.02.052

    Article  CAS  PubMed  Google Scholar 

  123. Ricken R, Busche M, Schlattmann P, Himmerich H, Bopp S, Bschor T, Richter C, Stamm TJ et al (2018) Cytokine serum levels remain unchanged during lithium augmentation of antidepressants in major depression. J Psychiatr Res 96:203–208. https://doi.org/10.1016/j.jpsychires.2017.10.002

    Article  PubMed  Google Scholar 

  124. Thomas AJ, Davis S, Morris C, Jackson E, Harrison R, O’Brien JT (2005) Increase in interleukin-1beta in late-life depression. Am J Psychiatry 162(1):175–177. https://doi.org/10.1176/appi.ajp.162.1.175

    Article  PubMed  Google Scholar 

  125. Steptoe A, Kunz-Ebrecht SR, Owen N (2003) Lack of association between depressive symptoms and markers of immune and vascular inflammation in middle-aged men and women. Psychol Med 33(4):667–674

    Article  CAS  PubMed  Google Scholar 

  126. Hocaoglu C, Kural B, Aliyazicioglu R, Deger O, Cengiz S (2012) IL-1beta, IL-6, IL-8, IL-10, IFN-gamma, TNF-alpha and its relationship with lipid parameters in patients with major depression. Metab Brain Dis 27(4):425–430. https://doi.org/10.1007/s11011-012-9323-9

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  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

    Manoj P. Dandekar, Ashwini Saxena, Giselli Scaini, Vijayasree Vayalanellore Giridharan, Yuzhi Zhou, Tatiana Barichello & Joao Quevedo

  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

    Joo Hyun Shin, Agata Migut & Albert J. Fenoy

  3. Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, 030006, People’s Republic of China

    Yuzhi Zhou

  4. Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA

    Tatiana Barichello & Joao Quevedo

  5. Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil

    Tatiana Barichello, Jair C. Soares & Joao Quevedo

  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

    Jair C. Soares & Joao Quevedo

Authors
  1. Manoj P. Dandekar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ashwini Saxena
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Giselli Scaini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joo Hyun Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Agata Migut
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vijayasree Vayalanellore Giridharan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuzhi Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tatiana Barichello
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jair C. Soares
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Joao Quevedo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Albert J. Fenoy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Albert J. Fenoy.

Ethics declarations

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dandekar, M.P., Saxena, A., Scaini, G. et al. Medial Forebrain Bundle Deep Brain Stimulation Reverses Anhedonic-Like Behavior in a Chronic Model of Depression: Importance of BDNF and Inflammatory Cytokines. Mol Neurobiol 56, 4364–4380 (2019). https://doi.org/10.1007/s12035-018-1381-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-018-1381-5

Keywords

Search

Navigation