Major depression is a mood disorder affecting 121 million people worldwide and is among the leading causes of disability making it a main contributor to the global burden of disease. Antidepressant (AD) drugs were introduced in the 1950s and have since been refined to have fewer side effects, but little advancement has been made in improving efficacy with only ~50% of patients achieving full remission. In addition, relief from symptoms requires several weeks of chronic AD treatment and the changes occurring during this time that underlie the therapeutic effects are still unknown. Recently, neurogenesis has been shown to be necessary for some of the positive behavioral responses to ADs seen in rodents, and maturation of newborn neurons coincide with the delayed onset of AD action. The primary goal of the research component of this proposal is to understand the on-line contribution of adult-generated dentate gyrus granule cells (GCs) in anxiety-related behavioral tasks after chronic antidepressant treatment. While adult neurogenesis has been implicated in the delayed efficacy of AD treatment, it remains unknown if young neurons drive the behavioral response, or if it is their long-term modification of existing circuitry that contributes to alterations in mood Thus, in this proposal, I provide a strategy for inhibition of adult GCs in a temporally restricted fashion, allowing for either long-term or short-term silencing of adult-generated GCs. To achieve this, I have expressed an evolved G-protein coupled receptor (hM4Di), which is exclusively activated by the pharmacologically inert drug clozapine-N-oxide (CNO), selectively in adult-generated GCs. Upon activation by CNO, hM4Di can induce rapid membrane hyperpolarization and neuronal silencing. This tool will allow me to investigate the consequence of acute or long-term silencing of the population of newborn adult-generated GCs on behavior. These studies will be the first to examine the acute contribution of adult-generated GCs in behavior, as well as determine the mechanism underlying the neurogenesis-dependent behavioral effects of chronic AD treatment.
Identifying how young neurons contribute to the antidepressant-like responses in mice will advance our knowledge of the mechanism of action of antidepressant drugs. Learning how these drugs works will provide potential new targets for the rational design of faster acting, safer, and more effective AD therapies. In addition, studying the contribution of adult-born granule cells to antidepressant action could expand our mechanistic understanding of the overall role of neurogenesis in the hippocampus.
|Tannenholz, Lindsay; Jimenez, Jessica C; Kheirbek, Mazen A (2014) Local and regional heterogeneity underlying hippocampal modulation of cognition and mood. Front Behav Neurosci 8:147|