As one of the leading causes of disease burden and disability in the world, Major Depressive Disorder (MDD) is a persistent and ever expanding financial and public health concern. Sadly, MDD is quite prevalent in children and adolescents with life-long negative consequences including increased risk for conduct and substance abuse disorders, self-harm as well as suicide, and up to 75% risk of recurrent depressive episodes in adulthood. Although there are treatments available for MDD, they lack in effectiveness, and have a potential for enduing negative side effects. These observations, combined with the realization that decisions involving antidepressant treatment in children and adolescents are primarily based on data from adults, it is critically important to develop more effective treatments to be characterized in ?age-appropriate? models. Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, has recently shown great promise as a rapid-acting and long-lasting treatment for MDD. Therefore, it is conceivable that ketamine could serve as an ideal therapeutic for pediatric MDD. Unfortunately, the efficacy, functionality, and biochemical consequences of ketamine exposure during periods prior to adulthood are not known. Preliminary data presented here suggests that ketamine is an effective antidepressant in adolescents, however the neurobiological underpinning(s) mediating these effects are unknown. To complicate matters, the neural circuits involved in MDD are poorly understood, although studies indicate that the mesolimbic brain pathway plays an essential role in MDD. This neural circuit includes the ventral tegmental area (VTA), prefrontal cortex (PFC), and hippocampus, all of which are known to be sensitive to the effects of stress. Recent evidence has shown that ketamine reverses the deficits associated with stress in the PFC and hippocampus, however its effects in the VTA as well as the neural circuitry involved are unknown. Therefore, to start addressing gaps in our basic understanding, the experiments outlined in this proposal are designed to examine the neurobiological underpinnings of ketamine?s antidepressant effects in adolescent males. This will be accomplished within the framework of the following specific aims: 1) assess the specific contribution(s) of the VTA to the antidepressant-like effects observed after ketamine exposure during adolescence, and 2) determine the neuronal circuitry underlying ketamine?s effects, specifically the neural projection from the VTA to the PFC. I hypothesize that infusing ketamine directly into the VTA will elicit antidepressant-like responses similar to those observed with systemic administration of the drug; and that optical stimulation of VTA-to-PFC pathway will produce antidepressant-like responses in the absence of ketamine. Data derived from this work will reveal novel insight(s) into ketamine?s functional effects in the immature brain, and neural substrates and circuitry underlying its effects on mood-and motivation-related brain areas in a grossly understudied period prior to adulthood, while providing advanced training in behavioral and molecular methods in an exceptional environment.
Considering the fact that nearly 50% of adolescents who suffer from MDD are non-responsive to current treatments, it is critical that more effective treatments be evaluated. The experiments described in this proposal will examine the role of the Ventral Tegmental Area as well as its functional connection to the Prefrontal Cortex in mediating ketamine's antidepressant effects. The results obtained here will help delineate ketamine's neurobiological mechanism(s) of action and further our understanding and treatment of adolescent depression.
| Sial, Omar K; Warren, Brandon L; Alcantara, Lyonna F et al. (2016) Vicarious social defeat stress: Bridging the gap between physical and emotional stress. J Neurosci Methods 258:94-103 |
