A Role for Microglia in Repeated Stress-Induced Functional Changes in the Medial Prefrontal Cortex in Rodents

Excessive or prolonged exposure to stress leads to emotional and cognitive changes, and is a common risk factor for psychiatric disorders, such as major depression. To understand the mechanism underlying neural changes associated with repeated stress, many studies using rodent models of repeated stress have been performed and found structural alterations induced by repeated stress in various brain areas, especially dendritic atrophy, a decrease in the volume of dendritic spines and synaptic loss in pyramidal neurons in the medial prefrontal cortex (mPFC) [1-4]. Previous findings have shown the functional importance of such structural remodeling of mPFC neurons. For example, dendritic atrophy in mPFC neurons correlates to stress-induced decline in mPFC function as measured by attentional set shifting [2], and rapid antidepressant actions of NMDA receptor antagonists in chronic mild stress are associated with the recovery from deficits in spine density and synaptic functions in the mPFC [5]. Further, GATA1, a transcription factor that induces the loss of spines and dendrites in primary neurons, functions in mPFC neurons to cause repeated stress-induced anhedonia, as measured by a reduction in sucrose consumption [6]. Stress-induced structural remodeling in the mPFC also appears to be clinically relevant. Thus, brain imaging and post-mortem brain studies have shown a reduction in the mPFC volume in depressive patients [7], and the deep brain stimulation targeting the white matter adjacent to this region ameliorates depressive symptoms in half of treatment-resistant patients [8]. However, the mechanism underlying structural and functional alterations in the mPFC in stress and depression remains elusive.