Depression takes an enormous toll on individual and economic health. Although current antidepressant therapies provide relief for some individuals, many patients are inadequately treated which can lead to suicide. Thus, there is desperate need to identify new targets for depression treatment. A growing body of preclinical and clinical work implicates maladaptive signaling in the nucleus accumbens in the etiology of depression. Here I aim to identify how dendritic remodeling of nucleus accumbens projection neurons contributes to depression development and symptomology in a preclinical model of depression. Using this model, I have collected preliminary data showing increased dendritic atrophy and upregulation of a dendritic complexity molecule RhoA in specific nucleus accumbens neurons. Further, pharmacological manipulation of RhoA in the nucleus accumbens can promote or prevent depressive outcomes to stress. In this study, we intend to utilize cutting- edge molecular and in vivo imaging techniques to investigate how RhoA mediates dendritic atrophy and depression-like behavior in specific nucleus accumbens neurons.
Specific aim 1 utilizes novel genetic tools to express active and inactive RhoA in select cell types. We will characterize how active and inactive RhoA contribute to depression-like behavior and assess their roles in promoting or preventing depressive outcomes to social stress.
Specific aim 2 utilizes in vivo imaging to test whether blocking active RhoA in select cell types can prevent decreases in neural activity found in mice displaying depressive behaviors. Together, these experiments will provide new information on the molecular mechanisms of dendritic remodeling in depression, which has the potential to inform about future depression therapeutics.
Over 300 million people suffer from depression, exacting a global annual economic cost of $1 trillion. There is desperate need for new antidepressants, but rational treatment development requires a detailed understanding of the neural mechanisms that cause depression. The current proposal will provide evidence for guiding novel treatments by investigating precise molecular mechanisms in depression.
|Fox, Megan E; Chandra, Ramesh; Menken, Miriam S et al. (2018) Dendritic remodeling of D1 neurons by RhoA/Rho-kinase mediates depression-like behavior. Mol Psychiatry :|
|Engeln, Michel; Fox, Megan E; Lobo, Mary Kay (2018) Dopamine Is Differentially Encoded by D2 Receptors in Striatal Subregions. Neuron 98:459-461|