Monoamines play a major role in depression. The present proposal will[unreadable] examine this idea by evaluating neural responses in the various mouse models of depression and it will[unreadable] complement the human imagining studies by providing a functional approach for identifying brain areas and[unreadable] neural circuits that may participate in depressive-like behaviors. It will also complement the human[unreadable] morphology experiments by targeting multi-electrodes in mice to cortical layers in frontal cortex that have[unreadable] been shown to change in depressed patients. To better understand the role of monoamines in depression,[unreadable] we will use multi-electrode arrays to investigate changes in cortical and subcortical neuronal activity in[unreadable] genetically-modified mice that have norepinephrine (NE) and/or serotonin (5-HT) dysfunction. Recently, we[unreadable] have developed a method to record activity simultaneously from multiple single neurons in various brain[unreadable] areas of freely-behaving mice. With this approach, cortical and subcortical neuronal activity will be monitored[unreadable] in several mouse models of depression and under different behavioral and treatment conditions. Briefly, we will study vesicular monoamine transporter 2 (VMAT2) heterozygotes, glycogen[unreadable] synthase kinase 3b (GSK) heterozygotes, and mice carrying a polymorphism in the Tph2 gene that has been[unreadable] identified in depressed patients. Wild type (WT) and mutant mice will be implanted with multi-electrode[unreadable] arrays targeted to the dorsomediofrontal and orbitofrontal cortices, nucleus accumbens (NAc), and central[unreadable] and basolateral amygdala (AMY) - the same sites that imagining studies have shown to be affected in[unreadable] human depressed patients. Multiple electrodes will be targeted to each of these areas simultaneously and[unreadable] neural activity will be assessed in freely-behaving mice under baseline conditions, after exposure to chronic[unreadable] stress, and following treatment with anti-depressants. In addition, as many depressed patients show[unreadable] disturbances in wake-sleep cycles, we will also analyze brain state dynamics throughout the cycle in mice[unreadable] under baseline, stress, and treatment conditions. The experiments we propose will allow for the first time the[unreadable] integration of molecular, cellular, systems, and behavioral data within the same animal and this approach[unreadable] should lead to a more complete understanding of the mechanisms underlying depression.