Depression is a highly prevalent disorder, yet reliable treatments are currently lacking for many people. Because the basic etiology of depression is not yet known, it is currently impossible to create therapeutics that target its underlying neurobiological causes. Evidence from previous research suggests that dysregulated hyperactivity of the noradrenergic locus coeruleus (LC), a brainstem nucleus that has been implicated in neuropsychiatric disorders, may be causally involved in depression. Because norepinephrine transmission itself can have antidepressant properties, it is likely that a different LC-derived neuromodulator is responsible. Galanin is a neuropeptide that is enriched in LC neurons and has pro-depressant effects. Therefore, the overarching hypothesis for this project is that LC hyperactivity and resulting galanin transmission can cause depression-like behavior. The proposed project will combine optogenetic and in vivo electrophysiology techniques to modulate and measure neuron activity with genetic approaches to manipulate galanin in behavioral assays of depression-like behavior in mice.
In Aim 1, I will use optogenetics to determine whether driving LC firing frequencies that cause galanin release can induce depressive-like behavior in wild-type or genetically altered mice with overexpression or depletion of LC-derived galanin.
In Aim 2, I will assess the ability of optogenetically-induced LC hyperactivity to alter the activity of ventral tegmental area (VTA) dopaminergic neurons, which are thought to be compromised in depression-related behaviors, and determine the contribution of galanin using the genetically altered mice described above. These experiments will be the first to precisely test the causal relationship between LC hyperactivity and depression and determine the contribution of LC-derived galanin and suppression of VTA dopamine neurons, which will help pave the way for the development of effective, targeted therapeutics to treat people with depression.
According to the World Health Organization, depression is the leading cause of disability worldwide with a lifetime risk of about 20%, making it one of the largest public health issues we face today. Available antidepressant treatments lack efficacy for many people, indicating an urgent need for targeted therapeutics that address the underlying causes of depression. The goal of this proposal is to test a promising causal mechanism of depression, locus coeruleus hyperactivity-induced galanin transmission, providing important preclinical evidence that could potentially lead to novel LC/galanin therapeutics to treat depression.