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.
Citation
Alcantara, Lyonna Francesca (2018). Role of Extracellular Regulated Kinase 2 Within Lateral Habenula in Mediating Antidepressant Response and Resilience During Adolescence. Doctoral dissertation, Texas A & M University. Available electronically from https : / /hdl .handle .net /1969 .1 /174037.