Saturday, April 20, 2024
4/20/2024
Project Summary / Abstract Stress-linked disorders such as depression are poorly understood and often difficult to treat. For instance, modern pharmaceuticals relieve depressive symptoms in only 55% of patients treated. This suggests that important aspects of the pathophysiology underlying depression remain untreated. An essential step toward novel therapeutics is understanding the neurobiology of stress and depression. Clinical and preclinical studies suggest that the behavioral and cognitive deficits seen in depression are driven by changes in neurovascular function in corticolimbic brain regions, including the medial prefrontal cortex (mPFC). In particular, chronic stress in rodents promotes astrocyte dystrophy, vascular remodeling, and synapse loss in the mPFC; and these neurobiological responses contribute to the development of working memory impairment and depressive-like behaviors. Despite these findings it remains unclear how dysfunction in astrocytes and neurovascular cells lead to synaptic deficits and associated behavioral consequences in stress. Astrocytes and endothelial cells are main components of the neurovascular unit. Cerebral endothelial cells form the most important component of the blood-brain interface. These cells are ensheathed by astrocytic end-feet high in aquaporin-4 (Aqp4) expression. Aqp4 facilitates interaction between the brain's vascular endothelium, astrocytes, and neurons, and helps stabilize vascular morphology. Patients with depression show diminished perivascular Aqp4 in frontal cortex, alongside reduced expression of factors associated with vascular integrity. Preclinical models show a similar pattern: chronic stress diminishes the number of intact astrocytic endfeet in frontal cortex, and compromises vascular integrity. Together, these data indicate that stress-induced reductions in Aqp4 disrupt astrocyte- endothelial cell interactions, and contribute to behavioral and cognitive impairments. Studies have yet to examine chronic unpredictable stress (CUS) effects on neurovascular unit integrity, or the mechanisms underlying CUS-induced deficits in neurovascular function and behavior. Thus, proposed experiments aim to 1) elucidate molecular mechanisms underlying stress effects on astrocytes and endothelial cells, and 2) assess neurovascular contributions to synapse loss and consequent deficits in cognition and behavior. Aim 1 will use cell type-specific RNA-Seq and immunohistological approaches to examine the extent to which CUS disrupts astrocyte-endothelial cell interactions in the mPFC. Aim 2 will use viral-mediated knockdown or over-expression of astrocytic Aqp4 to determine its role in stress effects on vascular morphology, synaptic remodeling, and associated cognitive-behavioral consequences. Results from this study will elucidate novel, neurovascular pathways through which stress alters neuronal function and behavior. Mechanisms identified may guide the development of innovative treatments for depression, amongst other stress-linked disorders. These studies will also extend my training to include expertise in neurovascular biology, the use of bioinformatics-based approaches, and the application of viral-mediated gene manipulations in model systems.
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