Alteration of challenge-induced neuronal activation patterns
The NAcb receives projections from the main monoaminergic nuclei including the raphe nuclei and the locus coeruleus and from regions associated with locomotion, emotion, and memory, including the globus pallidus, the amygdala, the cortex, and the HPC (Nauto and Domesick, 1984). In turn, NAcb projects to pallidal and nigral complexes, to cortical areas such as the medial prefrontal cortex, and to the thalamic and hypothalamic regions. Several of these brain areas have been implicated in the pathophysiology of depression and/or in the processing of antidepressant effects (Krishnan and Nestler, 2008). Furthermore, many of these areas are positioned along the superolateral arm of the medial forebrain bundle, a structure related to the reward circuitry, likely to be stimulated by most of, if not all, the different electrode placements (eg the anterior limb of the internal capsule, the subgenual cingulate gyrus, the NAcb) used in the treatment of TRD patients (Coenen et al, 2011). Regarding potential mechanisms of action identified so far, DBS preferentially modulates network fibers passing the electrode, while local effects of DBS on somatodendritc structures are minor (McIntyre and Grill, 1999; McIntyre et al, 2004; Nowak and Bullier, 1998a, 1998b). Specifically, direct inhibition of the electrode target area by muscimol injections or radiofrequency lesions does not seem to resemble effects of DBS on anxiety/depression networks (Hamani et al, 2010; Rodriguez-Romaguera et al, 2012). To identify distant parts of circuitries affected by NAcb-DBS at the present stimulation conditions, which may underlie the antidepressant effect observed in HAB mice, we used c-Fos mapping in specific brain areas (Singewald, 2007). The focus was laid upon those brain areas that have been previously shown to be associated with therapeutic modulation of enhanced depression-like behavior (Muigg et al, 2007; Sah et al, 2012; Winter et al, 2011).
One candidate area is the HPC, a highly stress-sensitive key brain structure dysregulated in depression (Floresco et al, 2001; Kingwell, 2010) in terms of reduced volume and dysfunctional activation under emotional challenge (Kempton et al, 2011; Lee et al, 2007; Milne et al, 2012; Tan et al, 2012; also see Disner et al (2011)). Interestingly, HAB rats (Muigg et al, 2007; Salomé et al, 2004), and more recently HAB mice (Muigg et al, 2009; Sah et al, 2012), display hypoactivation of the dentate gyrus (DG) by stress challenge. Here, we observed that NAcb-DBS enhanced the c-Fos induction in response to FST stress, suggesting that (i) neuronal DG activity is restored in HAB mice, and (ii) DG activity is strongly correlated with depression-like behavior. To our knowledge, so far changes in DG/HPC activity have not been reported in TRD patients undergoing DBS, while activity of the HPC is enhanced in addicted patients undergoing NAcb-DBS (Heldmann et al, 2012).
In addition, the c-Fos response was enhanced in the OFC and the lateral habenula, but attenuated in the prelimbic cortex following FST. In line with our results, pERK expression is enhanced in prefrontal regions, including the OFC, following ventral striatum/NAcb-DBS, suggesting functional connectivity between these spatially distinct structures (Rodriguez-Romaguera et al, 2012). In further support of our findings, McCracken and Grace (2007, 2009) propose an antidromic activation of NAcb-input fibers descending from the OFC by NAcb-DBS, resulting in the modulation of activity within the OFC and, thus, potentially affecting disturbed communication between prefrontal areas, limbic areas, and the OFC in an ultimately beneficial way.