Deep brain stimulation in rats: Different targets induce similar antidepressant-like effects but influence different circuits

Abstract

Recent studies in patients with treatment-resistant depression have shown similar results with the use of deep brain stimulation (DBS) in the subcallosal cingulate gyrus (SCG), ventral capsule/ventral striatum (VC/VS) and nucleus accumbens (Acb). As these brain regions are interconnected, one hypothesis is that by stimulating these targets one would just be influencing different relays in the same circuitry. We investigate behavioral, immediate early gene expression, and functional connectivity changes in rats given DBS in homologous regions, namely the ventromedial prefrontal cortex (vmPFC), white matter fibers of the frontal region (WMF) and nucleus accumbens. We found that DBS delivered to the vmPFC, Acb but not WMF induced significant antidepressant-like effects in the FST (31%, 44%, and 17% reduction in immobility compared to controls). Despite these findings, stimulation applied to these three targets induced distinct patterns of regional activity and functional connectivity. While animals given vmPFC DBS had increased cortical zif268 expression, changes after Acb stimulation were primarily observed in subcortical structures. In animals receiving WMF DBS, both cortical and subcortical structures at a distance from the target were influenced by stimulation. In regard to functional connectivity, DBS in all targets decreased intercorrelations among cortical areas. This is in contrast to the clear differences observed in subcortical connectivity, which was reduced after vmPFC DBS but increased in rats receiving Acb or WMF stimulation. In conclusion, results from our study suggest that, despite similar antidepressant-like effects, stimulation of the vmPFC, WMF and Acb induces distinct changes in regional brain activity and functional connectivity.

Acute high frequency stimulation of the prefrontal cortex or nucleus accumbens does not increase hippocampal neurogenesis in rats

“…Male Sprague Dawley rats (200 g) had stainless steel electrodes (cathodes; 250 μm in diameter) bilaterally implanted into the vmPFC or Acb, as previously described (Hamani et al, 2014;Rea et al, 2014). Similar electrodes connected to a bone screw implanted over the somatosensory cortex were used as anodes.…”

“…Controls had electrodes implanted in either the vmPFC or Acb but did not receive stimulation. DBS was conducted for 1 h at 100 μA or 300 μA, 130 Hz, and 90 μs (Hamani et al, 2014).…”

“…Similar to humans, DBS applied to homologous regions in rodents (i.e. the ventromedial prefrontal cortex, vmPFC, and Acb) has been shown to induce antidepressant-like responses in different behavioural tests (Gersner et al, 2010;Hamani et al, 2014Hamani et al, , 2010bHamani and Temel, 2012;Rea et al, 2014).…”

Chronic deep brain stimulation of the rat ventral medial prefrontal cortex disrupts hippocampal–prefrontal coherence

“…Previous experiments from our lab have found that DBS applied to the rodent ventral medial prefrontal cortex (vmPFC) can also induce antidepressant-like effects (Hamani et al, 2010(Hamani et al, , 2012(Hamani et al, , 2014). This treatment model has provided a tool to directly probe how the nervous system is affected by stimulation and how physiological consequences are linked to depression.…”

“…This treatment model has provided a tool to directly probe how the nervous system is affected by stimulation and how physiological consequences are linked to depression. For example, recent work found that patterns of immediate early gene (IEG) expression across regions become less correlated between animals who have received vmPFC stimulation compared with correlations between non-stimulated animals (Hamani et al, 2014;Wheeler et al, 2013). This observation can be considered alongside demonstrations that brains of depressed patients exhibit abnormally high activity correlations ("functional connectivity") between the SCG and connected regions (Greicius et al, 2007;Berman et al, 2011;Zeng et al, 2012;Sambataro et al, 2013;Davey et al, 2012), raising the question of whether DBS may disrupt communication between brain networks that become pathologically hyperactive in depression.…”