Glucocorticoid Receptor (GR) and Neuropathology in the Amygdala: Linking the Potential Roles of GR in Chronic Outcomes Post-Traumatic Brain Injury

Abstract

Chronic stress and traumatic brain injury (TBI)-related pathophysiology have been associated with the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis – the primary mechanism for responding to stressors through synthesis and release of glucocorticoids (GC). The glucocorticoid receptor (GR)-beta isoform exerts a dominant-negative effect on GR-alpha, the predominant and primarily anti-inflammatory GR, whereby a decreased GR-alpha:GR-beta ratio has been implicated in various inflammatory states, GC resistance, and chronic stress. Given its abundance in the central nervous system (CNS) and its roles beyond inflammation, e.g., neuroplasticity, we propose that GR dysfunction may play a pathophysiologic role in the mediation of glial-driven neuroinflammation, disruption of neurotransmission, and resultant chronic behavioral and affective disabilities following chronic stress, clinical, and experimental TBI. Through a translational model of mild-moderate TBI caused by midline fluid percussion injury (mFPI), we used immunohistochemistry to histologically examine the functional states of microglia and astrocytes, as well as amino-cupric-silver staining to examine neuropathologic changes up to 168-days post injury (DPI) within amygdala nuclei of male and female rats. Additionally, we measured GR protein levels up to 56-DPI to provide molecular context to previously observed findings of changes in neurotransmission within the amygdala and anxiety-like behavior chronically post-mFPI. Our findings suggest that microglia and astrocyte activation within the amygdala are not mediating the aforementioned changes post-mFPI, however, acute decreases in GR protein found at 7-DPI in males may play a role. This is the first chronic histological examination of its kind in the amygdala post-mFPI. Lastly, its inclusion of both male and female animals addresses the underrepresentation of females within experimental TBI research.