title: Electrical stimulation of the vmPFC serves as a remote control to affect VTA activity and improve depressive-like behavior.
abstract: Despite progress in elucidating mechanisms of depression, the efficacy of different treatments remains inadequate. Recent small-scale clinical studies suggested anti-depressant treatment using deep brain stimulation (DBS) of the ventral capsule/ventral striatum or subgenual cingulate cortex (SCC), yet controlled, multi-center trials were unsuccessful. We recently suggested the ventral tegmental area (VTA) as an important intersection for treating depression. We also found that stimulation of the VTA of a genetic rat model of depression (Flinders Sensitive Line (FSL) rats) with a programmed pattern designed to mimic the burst firing of normal rats decreases depressive-like behavior. Herein, we examined the possibility of reaching the VTA - located deep in the brain stem - through its direct connection to the ventro-medial prefrontal cortex (vmPFC), which parallels the human SCC. Thus, we compared treatment of FSLs with modified versions of DBS - either chronic-intermittent low-frequency electrical stimulation of the vmPFC, or patterned acute electrical stimulation (pAES), which integrates transcranial magnetic stimulation properties, namely, bursts of pulse trains and low frequency stimulation, applied to the VTA. We found that stimulation of the vmPFC (20Hz, 15min/day, 10days) improved depressive-like behavior and VTA local field potential (LFP) activity of FSLs, yet it had only a partial long-term effect on behavior. In particular, vmPFC stimulation decreased theta band activity, which correlated with the improvement in depressive-like behavior of all treated FSLs at day 1, and in ~50% of treated FSLs at day 28 post treatment. pAES of the VTA (10Hz, 20min) caused significant, long-term improvement of depressive-like behavior of FSLs, concurrently with normalizing intra-VTA LFP activity, and increasing VTA LFP synchronicity and hippocampal BDNF mRNA levels. Thus, although low-frequency electrical stimulation of the PFC alters VTA activity, leading to attenuation of depressive-like manifestations, a specific stimulation pattern affecting VTA cell programming is important for long-term efficacy.
authors.affiliation: Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
authors.forename: Merav
authors.initials: M
authors.lastname: Bruchim-Samuel
authors.affiliation: Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
authors.forename: Elad
authors.initials: E
authors.lastname: Lax
authors.affiliation: Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel.
authors.forename: Tomer
authors.initials: T
authors.lastname: Gazit
authors.affiliation: Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
authors.forename: Alexander
authors.initials: A
authors.lastname: Friedman
authors.affiliation: Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
authors.forename: Hadas
authors.initials: H
authors.lastname: Ahdoot
authors.affiliation: Department of Molecular Biology, Ariel University, Israel.
authors.forename: Maryia
authors.initials: M
authors.lastname: Bairachnaya
authors.affiliation: Department of Molecular Biology, Ariel University, Israel.
authors.forename: Albert
authors.initials: A
authors.lastname: Pinhasov
authors.affiliation: Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel; Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel. Electronic address: yadidg@mail.biu.ac.il.
authors.forename: Gal
authors.initials: G
authors.lastname: Yadid
mesh_terms: D000704:Analysis of Variance; D059445:Anhedonia / Q000502:physiology; D000818:Animals; D058256:Brain Waves / Q000502:physiology*; D046690:Deep Brain Stimulation; D003863:Depression / Q000235:genetics / Q000628:therapy*; D004195:Disease Models, Animal; D004567:Electrodes, Implanted; D005106:Exploratory Behavior; D005583:Fourier Analysis; D008297:Male; D017397:Prefrontal Cortex / Q000502:physiology*; D051381:Rats; D013550:Swimming / Q000523:psychology; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000503:physiopathology*
keywords: Deep brain stimulation; Depression; Local field potential; Ventral tegmental area; Ventro-medial prefrontal cortex