INTRODUCTION
Major depression is a highly debilitating and life-threatening disorder with a lifetime prevalence of 16.5% (Kessler et al, 2005) affecting 6.9% of the population every year (Wittchen et al, 2011). Available treatments include pharmacological approaches targeting mainly monoaminergic systems and non-pharmacological treatments, including psychotherapy, vagus nerve stimulation, transcranial magnetic stimulation, and electroconvulsive treatment (Moreines et al, 2011). Nevertheless, a significant number of patients remains inadequately treated displaying non-response or partial response after all treatment options have been explored (for a review see Al-Harbi, 2012; Vieta and Colom, 2011). This treatment-resistant depression (TRD) is particularly associated with great economic burden (Fostick et al, 2010), high social and familial impact (for a review see Luciano et al, 2012), and personal suffering. New hope is now given to these individuals by clinical studies demonstrating long-term effects of high-frequency deep brain stimulation (DBS) in terms of improving depressive symptoms of helplessness, anhedonia and anxiety, and, thus, enhancing quality of life (Bewernick et al, 2012; Lozano et al, 2012). Interestingly, physical and psychiatric side effects elicited by DBS can be minimized or abolished by adjustment of the stimulation settings (Bewernick et al, 2012) or, if unacceptable, DBS can be stopped at any time according to the basic principles of medical ethics and, in particular, those issues pertinent to DBS treatment (Schermer, 2011).
Although the ideal targets of DBS for eliciting therapeutic effects in TRD are a matter of debate (Lim et al, 2011), it has been suggested that any brain region of the proposed dysfunctional depression neurocircuitry (Krishnan and Nestler, 2008) may be interesting as affected network components are overlapping (Gutman et al, 2009). Accordingly, DBS has been applied to the subgenual cingulate cortex (Lozano et al, 2012), the ventral striatum (Malone et al, 2009), the nucleus accumbens (NAcb) (Bewernick et al, 2012), and the lateral habenula (Hoyer et al, 2012) of small TRD patient populations. Specifically, promising results have been obtained by DBS to the NAcb (NAcb-DBS), which has induced solid antidepressant, anxiolytic, and antianhedonic effects in patients with TRD (Bewernick et al, 2012). The unique position of the NAcb in the brain enables it to act as a gateway for information being transmitted from emotional centers to motor control regions (Haber and Knutson, 2010). Functionally, the NAcb processes reward and pleasure information and is dysfunctional in patients suffering from depression (Tremblay et al, 2005). This is relevant, as anhedonia is one of the core symptoms of depression and reflects a lack of reward and reward-motivated behavior (Gorwood, 2008). The NAcb receives inputs from midbrain areas, such as the ventral tegmental area, the medial substantia nigra, the dorsal and medial raphe nuclei, the locus coeruleus, as well as from limbic structures, including the amygdala, the hippocampus (HPC), and the prefrontal cortex (Nauta and Domesick, 1984). In turn, it projects to cortical areas (including the infralimibic cortex and the orbitofrontal cortex (OFC)), and to the ventral pallidum, the thalamus, the amygdala, and the hypothalamus (Kelley and Stinus, 1984). Interestingly, as projections of the NAcb are glutamatergic as well as GABAergic, stimulation of the NAcb can modulate neuronal activity of emotion and motivation centers implicated in the pathophysiology of depression in a dual way (also see Schlaepfer et al, 2008).
The mechanisms through which DBS act are poorly understood (Kringelbach et al, 2010). While early observations in Parkinson patients led to the proposal of a functional block of the target region by DBS (Benabid et al, 2002), it is thought nowadays that DBS causes axonal activation and neuronal inhibition (Dostrovsky and Lozano, 2002; Vitek, 2002; see also McIntyre and Grill, 1999; Nowak and Bullier, 1998a, 1998b). Therefore, clinically relevant animal models are pivotal to further study the neurobiological mechanisms underlying the beneficial effects of NAcb-DBS.
This study was aimed at providing the first comprehensive behavioral evaluation of NAcb-DBS in the HAB mouse line selectively bred for high trait anxiety (Landgraf et al, 2007; Sartori et al, 2011a). A characteristic comorbidity in HAB mice is the preference of immobility/passive stress-coping strategies, indicative of enhanced depression-related behavior reflecting depressive patients with comorbid anxiety. To gain insights into neurobiological mechanisms of action of successful NAcb-DBS treatment, we additionally studied stress-induced expression of the immediate-early gene c-Fos as the marker for neuronal activation, as well as a possible alteration of the amount of newly born cells and immature neurons in HAB mice. These sets of experiments were stimulated by studies showing that clinically established antidepressant drugs affect deranged bran activity patterns and adult hippocampal neurogenesis in humans and/or rodents (for a review see Samuels and Hen, 2011).