Modulation of serotonin dynamics in the dorsal raphe nucleus via high frequency medial prefrontal cortex stimulation.
The subcallosal cingulate (SCC) region, or its rodent homologue the medial prefrontal cortex (mPFC), and midbrain dorsal raphe (DR) are crucial nodes of the widespread network implicated in emotional regulation. Stimulation of the SCC is being explored as a potential treatment for depression. Because modulation of the 5-HT system is the most common pharmacological means of treating depression, we sought to establish 5-HT's role in the mPFC-DR projection. Using anaesthetized mice, we recorded neuronal activity in 49 neurons of the DR before, during, and after high frequency stimulation (HFS) of the mPFC. The majority of DR cells (74%) significantly decreased firing rate during HFS (p<0.001, 65.7±9.4% of baseline, 14 mice). To see the effect of mPFC-HFS on 5-HT neurons, we used transgenic mice with expression of the channelrhodopsin fusion protein directed to the 5-HT neuronal population. Neurons were categorized as 5-HT based on their excitatory response to blue light stimulation (p<0.05, n=11). Our main finding was that identified 5-HT neurons in the DR were clearly inhibited by HFS, albeit non-selectively. Lastly, we used fast scan cyclic voltammetry (FSCV) to investigate the effects of mPFC-HFS on the release and reuptake of electrically stimulated 5-HT in the DR of C57BL/6J mice. Serotonin clearance was significantly faster following 5min HFS (2.3±1.0s, n=5, p<0.05) when compared to control levels (3.7±1.0s, n=5), indicating less release or more efficient 5-HT reuptake. Taken together, these findings imply that mPFC stimulation alters 5-HT activity dynamics in the DR. Such altered 5-HT dynamics may modulate the potential therapeutic mechanisms of SCC/mPFC stimulation.
Institute of Medical Science, Faculty of Medicine, University of Toronto, Medical Sciences Bldg, 1 King's College Circle, Rm 2374, Toronto ON M5S 1A8.
Luka R
LR
Srejic
Department of Chemistry and Biochemistry, University of South Carolina, 300 Sumter St. 301c, Columbia, SC 29208 USA.
Kevin M
KM
Wood
Department of Chemistry and Biochemistry, University of South Carolina, 300 Sumter St. 301c, Columbia, SC 29208 USA.
Anisa
A
Zeqja
Department of Chemistry and Biochemistry, University of South Carolina, 300 Sumter St. 301c, Columbia, SC 29208 USA.
Parastoo
P
Hashemi
Department of Physiology, Faculty of Medicine, University of Toronto, Medical Sciences Bldg, 1 King's College Circle, Rm 3209, Toronto ON M5S 1A8; Department of Surgery, Division of Neurosurgery, University of Toronto & Toronto Western Hospital, 399 Bathurst Street, Toronto, Ontario, Canada. Electronic address: whutch@uhnres.utoronto.ca.
William D
WD
Hutchison
D000818:Animals; D065847:Dorsal Raphe Nucleus / Q000378:metabolism*; D004558:Electric Stimulation / Q000379:methods; D008297:Male; D008810:Mice, Inbred C57BL; D009434:Neural Pathways / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*
D012701:Serotonin
Cellular firing; Dorsal raphe; Fast scan cyclic voltammetry; High frequency stimulation; Medial prefrontal cortex; Optogenetics