Major Depressive Disorder (MDD) is one of the top three causes of disability worldwide, but only 60-70% of patients with MDD respond to first-line therapies, and responders have lasting impairments and recurrences. Thus, further research into the molecular basis of depression and antidepressant action is needed. Using chemogenetic techniques, our lab has established a causal relationship between changes in adult hippocampal neurogenesis and anxiety/depression-like behavior in mice. Further, we have shown that acutely increasing new neuron activity without an increase in neurogenesis is sufficient to rapidly induce antidepressant effects. The behavioral consequences of increasing new neuron activity occur within hours, whereas the effects of increasing the number of new neurons and their integration into the hippocampal Dentate Gyrus (DG) takes weeks. Most antidepressants have a therapeutic lag of weeks in patients, but earlier onset of antidepressant effects correlates with decreased suicidal behavior and increased likelihood of remission, making rapid-acting antidepressants desirable. At subanesthetic doses, the NMDA receptor antagonist ketamine exerts antidepressant effects within hours and has sustained therapeutic effects lasting weeks. Understanding its mechanism may inform new antidepressants with minimal therapeutic lag and fewer significant adverse effects. The neurogenic niche is necessary for ketamine's sustained effects and a single dose of ketamine accelerates neurogenesis. I have found that ketamine increases both neurogenesis in the DG and the activity of DG neurons. Here, I propose that effects of ketamine on newborn neuron activity mediate ketamine?s rapid behavioral effect, whereas effects on neurogenesis underlie its longer-term behavioral effect.
In Aim 1, I will determine the contribution of newborn neuron activity to ketamine?s acute behavioral effects. I will define how silencing new neurons alters ketamine?s acute effects in nave mice and mice exposed to unpredictable chronic mild stress (UCMS). To inducibly and specifically silence new neurons, I will use Cre-inducible expression of an inhibitory Designer Receptor Exclusively Activated by Designer Drugs (DREADD) in neural stem/progenitor cells and their progeny. I will administer ketamine and determine how new neuron silencing alters ketamine?s effect on mouse anxiety/depression-like behavior.
In Aim 2, I will examine mechanisms of ketamine?s sustained effects on neurogenesis and behavior and determine if they depend on a reduction in BMP signaling. Neurogenesis in the DG is inhibited by BMP signaling, and inhibition of BMP signaling increases neurogenesis and exerts an antidepressant effect. The behavioral effects of the Selective Serotonin Receptor Inhibitor (SSRI) fluoxetine are mediated by decreased BMP signaling, and I have found that ketamine treatment similarly reduces BMP signaling. I will maintain high BMP signaling in nave mice and mice exposed to UCMS, administer ketamine, and measure behavioral effects. While ketamine use poses its own risks, understanding the mechanisms of its antidepressant effects may inform a new generation of rapid-acting antidepressant medications.
Major Depressive Disorder (MDD) is one of the top three causes of disability worldwide, only 60-70% of patients with MDD respond to first-line therapies, and responders continue to have recurrences and associated morbidity. The goal of this proposal is to investigate the ability of ketamine to increase newborn hippocampal neuron activity and neurogenesis to induce rapid and sustained antidepressant effects in mice. Successful completion of this work will inform us of the poorly understood mechanisms of ketamine?s antidepressant effects and potentially provide exciting new lines of research for clinical antidepressants with rapid and sustained action.
