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Astroglial Control of the Antidepressant-Like Effects of Prefrontal Cortex Deep Brain Stimulation.

Etiévant A, Oosterhof C, Bétry C, Abrial E, Novo-Perez M, Rovera R, Scarna H, Devader C, Mazella J, Wegener G, Sánchez C, Dkhissi-Benyahya O, Gronfier C, Coizet V, Beaulieu JM, Blier P, Lucas G, Haddjeri N - EBioMedicine (2015)

Bottom Line: We found that DBS induced an antidepressant-like response that was prevented by IL-PFC neuronal lesion and by adenosine A1 receptor antagonists including caffeine.Unambiguously, a local glial lesion counteracted all these neurobiological effects of DBS.Further in vivo electrophysiological results revealed that this astrocytic modulation of DBS involved adenosine A1 receptors and K(+) buffering system.

View Article: PubMed Central - PubMed

Affiliation: Stem Cell and Brain Research Institute, INSERM U846, 69500 Bron, France ; Université de Lyon, Université Lyon 1, 69373 Lyon, France ; Department of Psychiatry and Neurosciences, Faculty of Medicine, Laval University-IUSMQ, Québec City, Québec, Canada.

ABSTRACT
Although deep brain stimulation (DBS) shows promising efficacy as a therapy for intractable depression, the neurobiological bases underlying its therapeutic action remain largely unknown. The present study was aimed at characterizing the effects of infralimbic prefrontal cortex (IL-PFC) DBS on several pre-clinical markers of the antidepressant-like response and at investigating putative non-neuronal mechanism underlying DBS action. We found that DBS induced an antidepressant-like response that was prevented by IL-PFC neuronal lesion and by adenosine A1 receptor antagonists including caffeine. Moreover, high frequency DBS induced a rapid increase of hippocampal mitosis and reversed the effects of stress on hippocampal synaptic metaplasticity. In addition, DBS increased spontaneous IL-PFC low-frequency oscillations and both raphe 5-HT firing activity and synaptogenesis. Unambiguously, a local glial lesion counteracted all these neurobiological effects of DBS. Further in vivo electrophysiological results revealed that this astrocytic modulation of DBS involved adenosine A1 receptors and K(+) buffering system. Finally, a glial lesion within the site of stimulation failed to counteract the beneficial effects of low frequency (30 Hz) DBS. It is proposed that an unaltered neuronal-glial system constitutes a major prerequisite to optimize antidepressant DBS efficacy. It is also suggested that decreasing frequency could heighten antidepressant response of partial responders.

No MeSH data available.


Related in: MedlinePlus

Modulation of the IL-PFC DBS-induced antidepressant-like response in the FST. (A) IL-DBS induced a decrease in immobility in FST. Ibotenic acid infusion had no effect on immobility time in the FST but prevented the antidepressant-like effect of IL-DBS. (B) Representative photomicrograph of a coronal NeuN-immunostained section containing the IL-PFC from ibotenic-treated rats. Black arrows represent the outline of the area where a complete disappearance of NeuN-immunoreactivity was observed after an ibotenic acid infusion in IL-PFC. (C) IL-PFC glial lesion counteracted the decrease in immobility in FST induced by high frequency IL-DBS (130 Hz) but did not prevented the antidepressant-like effect induced by low frequency IL-DBS (30 Hz) (**p < 0.01 and ***p < 0.001 vs sham, ##p < 0.01 vs IL-DBS). (D) Schematic representation of coronal brain sections showing the location of implanted electrodes in DBS- (130 Hz) (black squares) or l-AAA + DBS- (130 Hz) (gray dots) treated animals for the Fig. 1C (left) groups. (E) Caffeine (Caf.) abolished the decrease of immobility induced by IL-DBS in FST. SCH442416 induced a reduction of immobility on its own in the FST, but failed to prevent the IL-DBS-induced antidepressant-like effect. DPCPX abolished the decrease of immobility induced by IL-DBS in FST (**p < 0.01 and ***p < 0.001 vs vehicle and #p < 0.05). Results are expressed as mean ± SEM of immobility duration. Numbers at the bottom of the columns represent the number of rats tested per group.
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f0005: Modulation of the IL-PFC DBS-induced antidepressant-like response in the FST. (A) IL-DBS induced a decrease in immobility in FST. Ibotenic acid infusion had no effect on immobility time in the FST but prevented the antidepressant-like effect of IL-DBS. (B) Representative photomicrograph of a coronal NeuN-immunostained section containing the IL-PFC from ibotenic-treated rats. Black arrows represent the outline of the area where a complete disappearance of NeuN-immunoreactivity was observed after an ibotenic acid infusion in IL-PFC. (C) IL-PFC glial lesion counteracted the decrease in immobility in FST induced by high frequency IL-DBS (130 Hz) but did not prevented the antidepressant-like effect induced by low frequency IL-DBS (30 Hz) (**p < 0.01 and ***p < 0.001 vs sham, ##p < 0.01 vs IL-DBS). (D) Schematic representation of coronal brain sections showing the location of implanted electrodes in DBS- (130 Hz) (black squares) or l-AAA + DBS- (130 Hz) (gray dots) treated animals for the Fig. 1C (left) groups. (E) Caffeine (Caf.) abolished the decrease of immobility induced by IL-DBS in FST. SCH442416 induced a reduction of immobility on its own in the FST, but failed to prevent the IL-DBS-induced antidepressant-like effect. DPCPX abolished the decrease of immobility induced by IL-DBS in FST (**p < 0.01 and ***p < 0.001 vs vehicle and #p < 0.05). Results are expressed as mean ± SEM of immobility duration. Numbers at the bottom of the columns represent the number of rats tested per group.

Mentions: Forced-swim test is a frequently used model to screen potential antidepressants (Porsolt et al., 1977). In the present study, it was used to highlight antidepressant-like behavior induced by IL-DBS and its putative glial modulation in rats infused with vehicle or l-AAA gliotoxin in the IL-PFC. As illustrated in Fig. 1D, stimulation electrodes were implanted unilaterally in the infralimbic part of the vmPFC. Two sessions of IL-DBS (Fig. S3) significantly decreased immobility duration in rats with intact IL-PFC demonstrating an antidepressant-like effect of DBS (Fig. 1A). To determine whether IL-DBS involved the local neuronal population, its antidepressant-like effect was assessed in rats infused with ibotenic acid 7 days before the FST (Fig. 1A and B). Our results revealed that neuronal lesion had no effect by itself in the FST, as previously shown (Banasr and Duman, 2008), but robustly prevented the antidepressant-like effect of IL-DBS. Interestingly, the antidepressant-like effect of DBS was prevented by a loss of astrocytes within the stimulated area after l-AAA infusion in rat's IL-PFC (Fig. 1C). Glial lesion had no effect by itself on immobility duration and did not alter locomotor activity of rats (Fig. S4).


Astroglial Control of the Antidepressant-Like Effects of Prefrontal Cortex Deep Brain Stimulation.

Etiévant A, Oosterhof C, Bétry C, Abrial E, Novo-Perez M, Rovera R, Scarna H, Devader C, Mazella J, Wegener G, Sánchez C, Dkhissi-Benyahya O, Gronfier C, Coizet V, Beaulieu JM, Blier P, Lucas G, Haddjeri N - EBioMedicine (2015)

Modulation of the IL-PFC DBS-induced antidepressant-like response in the FST. (A) IL-DBS induced a decrease in immobility in FST. Ibotenic acid infusion had no effect on immobility time in the FST but prevented the antidepressant-like effect of IL-DBS. (B) Representative photomicrograph of a coronal NeuN-immunostained section containing the IL-PFC from ibotenic-treated rats. Black arrows represent the outline of the area where a complete disappearance of NeuN-immunoreactivity was observed after an ibotenic acid infusion in IL-PFC. (C) IL-PFC glial lesion counteracted the decrease in immobility in FST induced by high frequency IL-DBS (130 Hz) but did not prevented the antidepressant-like effect induced by low frequency IL-DBS (30 Hz) (**p < 0.01 and ***p < 0.001 vs sham, ##p < 0.01 vs IL-DBS). (D) Schematic representation of coronal brain sections showing the location of implanted electrodes in DBS- (130 Hz) (black squares) or l-AAA + DBS- (130 Hz) (gray dots) treated animals for the Fig. 1C (left) groups. (E) Caffeine (Caf.) abolished the decrease of immobility induced by IL-DBS in FST. SCH442416 induced a reduction of immobility on its own in the FST, but failed to prevent the IL-DBS-induced antidepressant-like effect. DPCPX abolished the decrease of immobility induced by IL-DBS in FST (**p < 0.01 and ***p < 0.001 vs vehicle and #p < 0.05). Results are expressed as mean ± SEM of immobility duration. Numbers at the bottom of the columns represent the number of rats tested per group.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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f0005: Modulation of the IL-PFC DBS-induced antidepressant-like response in the FST. (A) IL-DBS induced a decrease in immobility in FST. Ibotenic acid infusion had no effect on immobility time in the FST but prevented the antidepressant-like effect of IL-DBS. (B) Representative photomicrograph of a coronal NeuN-immunostained section containing the IL-PFC from ibotenic-treated rats. Black arrows represent the outline of the area where a complete disappearance of NeuN-immunoreactivity was observed after an ibotenic acid infusion in IL-PFC. (C) IL-PFC glial lesion counteracted the decrease in immobility in FST induced by high frequency IL-DBS (130 Hz) but did not prevented the antidepressant-like effect induced by low frequency IL-DBS (30 Hz) (**p < 0.01 and ***p < 0.001 vs sham, ##p < 0.01 vs IL-DBS). (D) Schematic representation of coronal brain sections showing the location of implanted electrodes in DBS- (130 Hz) (black squares) or l-AAA + DBS- (130 Hz) (gray dots) treated animals for the Fig. 1C (left) groups. (E) Caffeine (Caf.) abolished the decrease of immobility induced by IL-DBS in FST. SCH442416 induced a reduction of immobility on its own in the FST, but failed to prevent the IL-DBS-induced antidepressant-like effect. DPCPX abolished the decrease of immobility induced by IL-DBS in FST (**p < 0.01 and ***p < 0.001 vs vehicle and #p < 0.05). Results are expressed as mean ± SEM of immobility duration. Numbers at the bottom of the columns represent the number of rats tested per group.
Mentions: Forced-swim test is a frequently used model to screen potential antidepressants (Porsolt et al., 1977). In the present study, it was used to highlight antidepressant-like behavior induced by IL-DBS and its putative glial modulation in rats infused with vehicle or l-AAA gliotoxin in the IL-PFC. As illustrated in Fig. 1D, stimulation electrodes were implanted unilaterally in the infralimbic part of the vmPFC. Two sessions of IL-DBS (Fig. S3) significantly decreased immobility duration in rats with intact IL-PFC demonstrating an antidepressant-like effect of DBS (Fig. 1A). To determine whether IL-DBS involved the local neuronal population, its antidepressant-like effect was assessed in rats infused with ibotenic acid 7 days before the FST (Fig. 1A and B). Our results revealed that neuronal lesion had no effect by itself in the FST, as previously shown (Banasr and Duman, 2008), but robustly prevented the antidepressant-like effect of IL-DBS. Interestingly, the antidepressant-like effect of DBS was prevented by a loss of astrocytes within the stimulated area after l-AAA infusion in rat's IL-PFC (Fig. 1C). Glial lesion had no effect by itself on immobility duration and did not alter locomotor activity of rats (Fig. S4).

Bottom Line: We found that DBS induced an antidepressant-like response that was prevented by IL-PFC neuronal lesion and by adenosine A1 receptor antagonists including caffeine.Unambiguously, a local glial lesion counteracted all these neurobiological effects of DBS.Further in vivo electrophysiological results revealed that this astrocytic modulation of DBS involved adenosine A1 receptors and K(+) buffering system.

View Article: PubMed Central - PubMed

Affiliation: Stem Cell and Brain Research Institute, INSERM U846, 69500 Bron, France ; Université de Lyon, Université Lyon 1, 69373 Lyon, France ; Department of Psychiatry and Neurosciences, Faculty of Medicine, Laval University-IUSMQ, Québec City, Québec, Canada.

ABSTRACT
Although deep brain stimulation (DBS) shows promising efficacy as a therapy for intractable depression, the neurobiological bases underlying its therapeutic action remain largely unknown. The present study was aimed at characterizing the effects of infralimbic prefrontal cortex (IL-PFC) DBS on several pre-clinical markers of the antidepressant-like response and at investigating putative non-neuronal mechanism underlying DBS action. We found that DBS induced an antidepressant-like response that was prevented by IL-PFC neuronal lesion and by adenosine A1 receptor antagonists including caffeine. Moreover, high frequency DBS induced a rapid increase of hippocampal mitosis and reversed the effects of stress on hippocampal synaptic metaplasticity. In addition, DBS increased spontaneous IL-PFC low-frequency oscillations and both raphe 5-HT firing activity and synaptogenesis. Unambiguously, a local glial lesion counteracted all these neurobiological effects of DBS. Further in vivo electrophysiological results revealed that this astrocytic modulation of DBS involved adenosine A1 receptors and K(+) buffering system. Finally, a glial lesion within the site of stimulation failed to counteract the beneficial effects of low frequency (30 Hz) DBS. It is proposed that an unaltered neuronal-glial system constitutes a major prerequisite to optimize antidepressant DBS efficacy. It is also suggested that decreasing frequency could heighten antidepressant response of partial responders.

No MeSH data available.


Related in: MedlinePlus