Research reportAntidepressant actions of lateral habenula deep brain stimulation differentially correlate with CaMKII/GSK3/AMPK signaling locally and in the infralimbic cortex
Introduction
The lateral habenula (LHb) plays a critical role in mood, reward, incentive motivation and stress responses [1], [2], [3], [4], [5]. Patients suffering from severe depression [6] and animal depression models of alpha-methyl-para-tyrosine administration, amphetamine withdrawal, stress exposures, genetic manipulation or selective breeding [5], [7], [8], [9], [10], show elevated activity in this region. Local deactivation of the LHb via lesioning elicits antidepressant responses, promoting escape behavior in the congenital learned helplessness (cLH) rats during inescapable paradigm [11]. These behavioral changes were mediated, in part, by the regulation of dorsal raphe serotonin levels and ventral tegmentum dopamine transmission [11], [12], [13], [14]. Recently, deep brain stimulation (DBS) of the LHb has been trialed for treatment resistant depression (TRD), with therapeutic effects reported to coincide with periods of active stimulation [15]. Similarly, LHb DBS effectively achieved an antidepressant response in the cLH model of depression [16], [17]. Nevertheless, the mechanisms through which LHb activity is up- or downregulated and whether it yields pro- or antidepressant actions, respectively, are not well understood.
Stress-induced molecular adaptations in the LHb region have important implications for modulating associative networks and depression-like behaviors [17], [18], [19], [20]. In particular, recent attention has been given to the role calcium/calmodulin-dependent protein kinase type II (CaMKII) in learning and synaptic plasticity. Both exposure to stress and administration of the antidepressant escitalopram altered the expression of CaMKII in the LHb [19]. In cLH model, CaMKIIα and CaMKIIβ levels were shown to be significantly up-regulated in this region, prior to receiving effective antidepressant treatment [17]. Conversely, the down-regulation or blockade of CaMKIIβ activity reversed the depressive phenotype in these animals in standardized behavioral paradigms [17]. CaMKII is involved in many signaling cascades critical to cellular homeostasis, growth and plasticity, and functions together with glycogen synthase kinase 3 (GSK3) to regulate synaptic vesicle recycling in mature synapses [21], [22]. This activity-dependent interaction poses a possible mechanistic link between high frequency DBS and local CaMKII/GSK3 modulation. GSK3 also serves as a mediator in cellular metabolism and plasticity. Upstream of this, AMP-activated protein kinase (AMPK), a cellular energy sensor, is activated when cellular energy reserves are low and coordinates intracellular functions mediating plasticity [23]. Stress-induced changes in energy metabolism and substrate utilization via this cell signaling system is implicated in the pathophysiology of depression [24], [25]. Plasticity within this intracellular pathway may be an important contributor to the pathophysiological underpinnings of TRD.
Like the LHb, hypermetabolism of the subgenual cingulate gyrus (SCG) is well documented in the TRD population, and down regulation of this activity follows a successful antidepressant response, regardless of treatment method [26], [27], [28], [29], [30]. The LHb and SCG regulate affective and cognitive aspects of depressive symptoms [31], [32], [33], [34]. The link between their hyperactivity and depressive states has been well-documented in patients [27], [35], [36]. Based on the existing literature, LHb function is important for alleviating depression symptomatology. Therefore, the present study further aims to validate this using LHb DBS in an animal model of antidepressant resistance, induced via chronic adrenocorticotropic hormone (ACTH) treatment [37], [38], [39], [40], [41], [42], [43]. In addition, we aimed to quantify antidepressant-like behavioral effects and its associated metabolic signaling in LHb and IL. DBS effects on CaMKIIα/β, GSK3α/β, and AMPK expressions locally as well as in the infralimbic cortex (IL; rodent homologue of SCG), will be examined in terms of the correlative relationship between behavior × protein signal.
Section snippets
Materials and methods
All experiments were approved by Mayo Clinic Institutional Animal Care and Use Committee and conducted in accordance with The Code of Ethics of the EU Directive 2010/63/EU for animal experiments. All animals were housed individually, with food and water available ad libitum.
Electrode localization
Electrode location was confirmed during tissue dissections and representative traces recorded diagrammatically [60]. Bipolar stimulating electrode tips were localized to the LHb (in the range of −3.7 mm posterior to bregma, ±3.7 mm lateral to midline, and −5.7 mm ventral from dura; Fig. 1). No histological damage was observed for animals receiving DBS treatment.
OFT & FST behavioral outcomes following LHb DBS
No statistically significant differences were found for distance nor ambulation across treatment groups (p > 0.05); and in the number of
Discussion
This study demonstrated antidepressant-like effects of LHb DBS in animals pretreated with ACTH and further presents data to suggest these behavioral responses relate to local as well as IL CaMKIIα/β, GSK3α/β and/or AMPK activity. The active DBS group showed significantly reduced immobility behavior during the FST following active stimulation, compared to all other conditions. These results corroborate data obtained using other animal models of antidepressant-resistant depression wherein LHb DBS
Conflicts of interest
Authors report no conflicts of interest.
Acknowledgements
YK supported by Deakin University Awards. SJT supported by a NARSAD YI award, State of Minnesota Mayo-MN partnership and Zarrow Foundation.
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