PROJECT SUMMARY/ ABSTRACT:
Clinical and preclinical studies have linked synapse loss and impaired prefrontal cortex (PFC) function to
behavioral and cognitive symptoms of psychiatric diseases, such as major depressive disorder (MDD).
Preclinical models, such as chronic unpredictable stress (CUS), are important tools to study these
pathophysiological mechanisms as they recapitulate key neurobiological (i.e., synapse loss in PFC) and
behavioral (i.e., anhedonia, working memory impairment) aspects of MDD. This is significant because exposure
to psychosocial or environmental stressors increases risk of development and recurrence of psychiatric disease.
Accumulating evidence shows that the brain-resident macrophages, microglia, have an active role in regulating
neuroplasticity in physiological and pathological conditions. In support of this work, research in our lab indicates
that dynamic neuron-microglia interactions contribute to neurobiological and behavioral consequences following
chronic stress. In particular, CUS increases neuronal colony stimulating factor-1 (CSF1) signaling in the medial
PFC, which provokes microglia-mediated neuronal remodeling that contributes to synaptic deficits and
behavioral and cognitive consequences.
Stress-induced release of glucocorticoids are implicated in the pathophysiology of psychiatric diseases. The
actions of glucocorticoids are mediated by glucocorticoid receptors (GR), which regulate gene transcription.
Indeed prior work shows that GR signaling alters gene networks that drive structural remodeling and synapse
loss on pyramidal neurons in the PFC. Our recent studies indicate that GR signaling induces neuronal CSF1
signaling in the PFC and provokes microglia-mediated neuronal remodeling in the PFC, which contributes to
development of depressive behaviors after CUS. This work also revealed that GR signaling regulates specific
molecular pathways in neurons (REDD1; regulated in development and DNA damage response 1) and microglia
(TNFa; tumor necrosis factor-a). These findings are relevant because both neuronal REDD1 and microglial TNFa
have critical roles in regulating synaptic plasticity. Studies in this application will determine the contributions of
neuronal or microglial GR signaling and respective downstream mediators in the pathophysiology underlying
behavioral consequences of chronic stress. Here we will use brain region- and cell type-specific genetic and
pharmacological manipulations to test two specific aims: 1) Define the role of neuronal GR signaling and
downstream REDD1 in stress-induced CSF1 signaling, microglia-mediated neuronal remodeling, and associated
behavioral consequences; and 2) Examine the role of microglial GR signaling and downstream TNFa in stress-
induced microglia-mediated neuronal remodeling, synaptic deficits, and associated behavioral consequences.
These studies are significant because they will identify molecular and cellular adaptations that initiate stress-
induced synapse loss in the PFC. We expect to generate novel insight into cell type-specific pathways that drive
the neurobiology of stress, which may guide treatment strategies for psychiatric disease.