Role of Extracellular Regulated Kinase 2 Within Lateral Habenula in Mediating Antidepressant Response and Resilience During Adolescence

Abstract

Approximately 13% of children aged 12-17 are diagnosed with major depressive disorder (MDD). This is particularly troubling since according to the World Health Organization, suicide is the second leading cause of death in individuals aged 15-29, suggesting that there is much left to be understood about the underlying neurocircuitry regulating symptoms of MDD. Previous work has shown that extracellular regulated kinase 2 (ERK2) activity in mesolimbic reward structures such as the ventral tegmental area (VTA), is important in mediating stress- and antidepressantresponding. The VTA receives regulatory input from the lateral habenula (LHb) however little is known about how ERK2 is expressed in the LHb after stress. To better understand this mechanism, rt-PCR, used to assess changes in mRNA, and western blot, used for protein analysis, was done for ERK2 and showed that both mRNA and protein levels of ERK2 in the LHB were modulated after stress or antidepressant exposure. To assess if ERK2 modulation could buffer stress-induced deficits, adolescent rats were given micro infusions of wtERK2 to increase ERK2 expression in the LHb, and then exposed to the stress and anxiety-eliciting tasks. Increasing ERK2 in the LHb, through a viral-mediated approach, promoted antidepressant-like responses as seen through increased time spent in the open arms of the elevated plus maze and less time immobile in the forced swim test. A separate group of rats was placed through chronic unpredictable stress and then received site-specific infusions of wtERK2 prior to behavioral testing, in an attempt to reverse stress-induced deficits. Similar to infusions in naïve animals, increasing ERK2 in the LHb was sufficient to promote antidepressant-like responses, when compared to GFP-exposed rats. This data suggests that increasing ERK2 in the LHb promotes resilience to stress and can reverse stress-induced deficits. Overall this data highlights the importance of LHb second-messenger signaling in mediating resilience to stress-eliciting stimuli.