Deconstructing Depressogenic Susceptibility and Emotional Resilience in Rats - ABSTRACT
With approximately 350 million people across the world suffering from Major Depression
Disorder (MDD), effective treatment strategies targeted to unmet medical needs of these
individuals need to be identified. Although behavioral therapies have offered encouraging
outcomes, without the adverse effects of long-term use of pharmaceuticals, the lack of appropriate
animal models has served as a barrier to understanding relevant biobehavioral mechanisms
accompanying behavioral therapeutic approaches. The current R15 proposal focuses on a rodent
model of a broad-based behavioral approach, Effort-Based Rewards (EBR), that was
developed in the PI's laboratory. Building on findings of a recent R15 confirming neurobiological
markers of resilience in EBR contingency-trained animals and flexible coping rats, the current
proposal focuses solely on EBR behavioral training. The time course of relevant neurobehavioral
transitions during EBR training (i.e., 5-6 weeks) will be established. Specifically, three aims are
designed to deconstruct the multifaced nature of the depressive phenotype by (1) identifying
behavioral shifts toward emotional resilience by mapping neuroplasticity modifications to two
time-points of EBR training, (2) observing recalibrations in stress responsivity influenced by
hippocampal mineralocorticoid and glucocorticoid receptors, as well as peripheral
dehydroepiandrosterone (DHEA) and corticosterone levels, and (3) using chemogenetic
techniques to manipulate a targeted brain area, the lateral habenula, and associated
compensatory neural responses. Following training, animals will be assessed in various
behavioral tasks designed to generate anxiety in uncertain conditions (i.e., prediction errors). It
is hypothesized that, following EBR training, neuroplasticity measures will be enhanced through
the time course of training; further, shifts from heightened stress responsiveness to emotional
resilience will be driven by stress-related neuroendocrine modifications. Finally, chemogenetic
activation of the lateral habenula is hypothesized to enhance understanding of the constellation
of brain areas accompanying anxiogenic arousal. Thus, the proposed research will utilize an
innovative preclinical model for behavioral therapeutic approaches and will facilitate the
deconstruction of the MDD phenotype specifically related to the acquisition of behavior,
recalibration of stress responsivity, and compensatory responsivity in relevant neural
mechanisms. Undergraduate students and two collaborators will work with the PI to compete
the proposed work.
