title: High-frequency stimulation of the medial prefrontal cortex decreases cellular firing in the dorsal raphe.
abstract: High-frequency deep brain stimulation (HFS-DBS) of the subcallosal cingulate (SCC) region has been investigated as a treatment for refractory forms of depression with a ~50% remission rate in open label studies. However, the therapeutic mechanisms of DBS are still largely unknown. Using anaesthetized Sprague Dawley rats, we recorded neuronal spiking activity in 102 neurons of the dorsal raphe (DR) before, during and after the induction of a 5-min HFS train in the infralimbic region (IL) of the medial prefrontal cortex (mPFC), the rodent homologue of the human SCC. The majority of DR cells (82%) significantly decreased firing rate during HFS (P < 0.01, 55.7 ± 4.5% of baseline, 35 rats). To assess whether mPFC-HFS mediates inhibition of DR cellular firing by stimulating local GABAergic interneurons, the GABAA antagonist bicuculline (Bic, 100 μm) was injected directly into the DR during HFS. Neurons inhibited by HFS recovered their firing rate during Bic+HFS (P < 0.01, n = 15, seven rats) to levels not different from baseline. Cells that were not affected by HFS did not change firing rate during Bic+HFS (P = 0.968, n = 7, three rats). These results indicate that blocking GABAA reverses HFS-mediated inhibition of DR neurons. As the cells that were not inhibited by HFS were also unaffected by HFS+Bic, they are probably not innervated by local GABA. Taken together, our results suggest that mPFC-HFS may exert a preferential effect on DR neurons with GABAA receptors.
authors.affiliation: Institute of Medical Science, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada.
authors.forename: Luka R
authors.initials: LR
authors.lastname: Srejic
authors.forename: Clement
authors.initials: C
authors.lastname: Hamani
authors.forename: William D
authors.initials: WD
authors.lastname: Hutchison
mesh_terms: D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D046690:Deep Brain Stimulation; D065847:Dorsal Raphe Nucleus / Q000502:physiology*; D005071:Evoked Potentials; D018756:GABA Antagonists / Q000494:pharmacology; D059330:GABAergic Neurons / Q000187:drug effects / Q000502:physiology; D007395:Interneurons / Q000187:drug effects / Q000502:physiology; D008297:Male; D017397:Prefrontal Cortex / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018756:GABA Antagonists; D001640:Bicuculline
keywords: cellular firing; depression; dorsal raphe; high-frequency stimulation; medial prefrontal cortex; rat