Depression is a psychiatric disorder where a disturbance of mood is the prominent feature. Although the etiology of depression is unknown, alterations in serotonergic and noradrenergic function have been clearly implicated in the disorder. The present Center Grant proposes to examine depression from the perspectives of functional imaging, morphometrics, and pharmacological interventions in humans, as well as through the use of a variety of animal models of depression. The overall objective of the mouse studies is to show how the serotonin (5-HT) and norepinephrine (NE) systems are interdependent in the development and amelioration of symptoms of depression and to reveal the neural mechanisms that contribute to this reaction.
In Aim I, the role of the monoamines will be investigated in the heterozygous vesicular monoamine transporter 2 (VMAT2) animals. Studies will be performed to determine whether antidepressants influence monoamine levels in selected brain regions and whether these alterations are related to responses in several different behavioral models of depression. An inducible VMAT2 knockout (KO) mouse will be developed so that the role of this gene and subsequent alterations in neurochemical and behavioral responses can be readily assessed.
In Aim II, the role of the norepinephrine transporter (NET) in depression will be evaluated. Experiments will be conducted in NET-KO mice to examine the effects of antidepressants on brain monoamines and behavior. An inducible NET-KO mouse line will be developed such that the role of this gene in the prevention of depression can be evaluated at any time.
In Aim III, effects of 5-HT dysfunction will be studied in mice by selectively restoring VMAT-2 function to catecholaminergic neurons in the VMAT2-KO line. In this case, 5-HT and histamine function should be defective. We have generated these mice and plan to create an inducible mouse line for additional studies where disruption of VMAT2 function in 5-HT neurons can occur at the discretion of the investigator. The results from the studies in Project 4 will complement the aims of the other Center projects and they will be coordinated with the clinical Projects to better understand the mechanisms that may underlie depression. Additionally, results from the clinical Projects will be integrated into the mouse Project such that, an attempt will be made to examine some of these same phenomena in mice. From these perspectives, the findings from the mouse studies should be helpful revealing some of the molecular, cellular, and biochemical changes that accompany depressive-like behaviors.
Showing the most recent 10 out of 250 publications
