Diffuse traumatic brain injury affects chronic corticosterone function in the rat

Abstract

As many as 20–55% of patients with a history of traumatic brain injury (TBI) experience chronic endocrine dysfunction, leading to impaired quality of life, impaired rehabilitation efforts and lowered life expectancy. Endocrine dysfunction after TBI is thought to result from acceleration–deceleration forces to the brain within the skull, creating enduring hypothalamic and pituitary neuropathology, and subsequent hypothalamic–pituitary endocrine (HPE) dysfunction. These experiments were designed to test the hypothesis that a single diffuse TBI results in chronic dysfunction of corticosterone (CORT), a glucocorticoid released in response to stress and testosterone. We used a rodent model of diffuse TBI induced by midline fluid percussion injury (mFPI). At 2months postinjury compared with uninjured control animals, circulating levels of CORT were evaluated at rest, under restraint stress and in response to dexamethasone, a synthetic glucocorticoid commonly used to test HPE axis regulation. Testosterone was evaluated at rest. Further, we assessed changes in injury-induced neuron morphology (Golgi stain), neuropathology (silver stain) and activated astrocytes (GFAP) in the paraventricular nucleus (PVN) of the hypothalamus. Resting plasma CORT levels were decreased at 2months postinjury and there was a blunted CORT increase in response to restraint induced stress. No changes in testosterone were measured. These changes in CORT were observed concomitantly with altered complexity of neuron processes in the PVN over time, devoid of neuropathology or astrocytosis. Results provide evidence that a single moderate diffuse TBI leads to changes in CORT function, which can contribute to the persistence of symptoms related to endocrine dysfunction. Future experiments aim to evaluate additional HP-related hormones and endocrine circuit pathology following diffuse TBI.

Approaches to Monitor Circuit Disruption after Traumatic Brain Injury: Frontiers in Preclinical Research

“…Yet, few studies address the impact of neuroendocrine dysregulation on neurochemical signaling related to TBI-induced PCSs exists. For example, after experimental TBI, chronic dysregulation of the HPA-axis has been implicated by changes in baseline circulating glucocorticoid levels and in response to stress in a sex-specific manner [214][215][216]. Glucocorticoid receptors are located on every cell type and modulate neurotransmission and neuroinflammatory response [217].…”

Diffuse TBI-induced expression of anxiety-like behavior coincides with altered glutamatergic function, TrkB protein levels and region-dependent pathophysiology in amygdala circuitry

“…We have previously reported a significant decrease in basal plasma corticosterone levels and a blunted stress response at 56DPI, indicating chronic dysregulation of the HPA-axis in this TBI model 43 . Chronic dysregulation of corticosterone in response to stress has also been supported in other TBI models at both earlier and later time points 72,73 .…”

“…Burlingame, CA, USA; Catalog#Ba-1100) then incubated with DAB20,43 . The sections were dehydrated with ethanol and cleared in citrisolv before being cover-slipped with DPX.Mosaic images encompassing both hemispheres were taken using a Zeiss microscope (Imager A2; Carl Zeiss, Jena, Germany) in bright-field mode with a digital camera.…”

Experimental Traumatic Brain Injury Induces Chronic Glutamatergic Dysfunction in Amygdala Circuitry Known to Regulate Anxiety-Like Behavior

“…Forty-micron thick sections were taken in the coronal plane and wet-mounted on 2%-gelatin-subbed slides before being stained with ionized calcium binding adaptor molecule (Iba1) primary antibody and 3,3 -Diaminobenzidine (DAB) visualization (NeuroScience Associates, Knoxville, TN, United States) to identify all microglia. Images and analysis of alternate regions of the same histology (for all NSA tissue) has been previously described (Cao et al, 2012;Lifshitz and Lisembee, 2012;Miremami et al, 2014;Rowe et al, 2016;Hoffman et al, 2017;Morrison et al, 2017;Thomas et al, 2018).…”

“…The brains were then cryoprotected in graded sucrose solutions (15% and 30%) and cryosectioned (20 µm). Sections were prepared exactly as previously described using rabbit anti-GFAP primary antibody (1:1000; Dako, catalog# Z0334) and biotinylated horse anti-rabbit secondary antibody (1:250; Vector Laboratories, Burlingame, CA, United States; Catalog#Ba-1100) then incubated with DAB (Rowe et al, 2016;Hoffman et al, 2017). The sections were dehydrated with ethanol and cleared in citriSolv before being cover-slipped with DPX.…”