Negative factors

that decrease synaptogenesis in a circuit-specific manner (eg, stress, excess glucocorticoids, reduced trophic support, and increased inflammatory cytokines) increase vulnerability and/or cause depression, while treatments or conditions that enhance synaptogenesis and increase connectivity (eg, neurotrophic factors, NMDA antagonists) have antidepressant actions and reduce vulnerability. The current review will focus on the signaling pathways and targets that underlie neuronal atrophy, and conversely those that contribute to the reversal of synaptic deficits caused Inhibitors,research,lifescience,medical by stress and depression, notably the role of neurotrophic factors. However, there are also other dysregulated systems of interest that will not be covered in this review, including proinflammatory cytokines, sex steroids Inhibitors,research,lifescience,medical (notably estrogen), and metabolic/feeding factors (ie, insulin/diabetes, leptin, and grehlin) to name a few that play an important role in the pathophysiology of depression and that could provide new therapeutic targets.

Disrupted connectivity of cortical and limbic depression circuitry Brain imaging and postmortem studies have identified key structures involved in the regulation of mood and depression, including the prefrontal cortex (PFC), hippocampus, cingulate cortex, amygdala, and basal ganglia.5,10 Blood flow and functional Inhibitors,research,lifescience,medical imaging studies have identified regions with reduced (PFC and hippocampus) or increased (subcallosal cingulate cortex Inhibitors,research,lifescience,medical and amygdala) activity. Together these studies have contributed to the emergence of a functional depression circuit. Altered activity and functional connections between the regions within this circuit correlate with unbalanced behavior that characterizes depression (see refs 4,5,10 for a complete description and discussion of these models). One model is based on extensive

evidence of decreased Inhibitors,research,lifescience,medical function and activity of the PFC and connections to and from other limbic and subcortical structures implicated in depression.5 Decreased function of the PFC in depressed patients underlies certain abnormal responses (eg, decreased reaction time and cognitive function), as well as a corresponding gain of function of the amygdala (loss of control of emotion and mood, and increased fear anxiety and IIPA axis reactivity), which is negatively www.selleckchem.com/products/XL184.html controlled by PFC. Anacetrapib Disruption of connections between the PFC and amygdala, as well as the ventral striatum, could also contribute to decreased motivation and reward in depression, which could underlie disrupted eating, sleeping, and libido. While this circuit model may be oversimplified, there is sufficient evidence from human, as well as animal studies (see below) to support the hypothesis that there is loss of function, in part from decreased connections between PFC and other brain regions.