Aging with TBI vs. Aging: 6-month temporal profiles for neuropathology and astrocyte activation converge in behaviorally relevant thalamocortical circuitry of male and female rats

Abstract

Traumatic brain injury (TBI) manifests late-onset and persisting clinical symptoms with implications for sex differences and increased risk for the development of age-related neurodegenerative diseases. Few studies have evaluated chronic temporal profiles of neuronal and glial pathology that include sex as a biological variable. After experimental diffuse TBI, late-onset and persisting somatosensory hypersensitivity to whisker stimulation develops at one-month post-injury and persists to at least two months post-injury in male rats, providing an in vivo model to evaluate the temporal profile of pathology responsible for morbidity. Whisker somatosensation is dependent on signaling through the thalamocortical relays of the whisker barrel circuit made up of glutamatergic projections between the ventral posteromedial nucleus of the thalamus (VPM) and primary somatosensory barrel cortex (S1BF) with inhibitory (GABA) innervation from the thalamic reticular nucleus (TRN) to the VPM. To evaluate the temporal profiles of pathology, male and female Sprague Dawley rats (n = 5-6/group) were subjected to sham surgery or midline fluid percussion injury (FPI). At 7-, 56-, and 168-days post-injury (DPI), brains were processed for amino-cupric silver stain and glial fibrillary acidic protein (GFAP) immunoreactivity, where pixel density of staining was quantified to determine the temporal profile of neuropathology and astrocyte activation in the VPM, S1BF, and TRN. FPI induced significant neuropathology in all brain regions at 7 DPI. At 168 DPI, neuropathology remained significantly elevated in the VPM and TRN, but returned to sham levels in the S1BF. GFAP immunoreactivity was increased as a function of FPI and DPI, with an FPI × DPI interaction in all regions and an FPI × Sex interaction in the S1BF. The interactions were driven by increased GFAP immunoreactivity in shams over time in the VPM and TRN. In the S1BF, GFAP immunoreactivity increased at 7 DPI and declined to age-matched sham levels by 168 DPI, while GFAP immunoreactivity in shams significantly increased between 7 and 168 days. The FPI × Sex interaction was driven by an overall greater level of GFAP immunoreactivity in FPI males compared to FPI females. Increased GFAP immunoreactivity was associated with an increased number of GFAP-positive soma, predominantly at 7 DPI. Overall, these findings indicate that FPI, time post-injury, sex, region, and aging with injury differentially contribute to chronic changes in neuronal pathology and astrocyte activation after diffuse brain injury. Thus, our results highlight distinct patterns of pathological alterations associated with the development and persistence of morbidity that supports chronic neuropathology, especially within the thalamus. Further, data indicate a convergence between TBI-induced and age-related pathology where further investigation may reveal a role for divergent astrocytic phenotypes associated with increased risk for neurodegenerative diseases.

In VivoPhenotypic Vascular Dysfunction Extends Beyond the Aorta in a Mouse Model for Fibrillin-1 (FBN1) Mutation

“…[49][50][51] Decreased cerebral blood flow velocity correlated with the function of age, increases risks for severity after neurological insult, neuropathology, and cognitive impairment. [52][53][54][55][56] Due to recent findings and the overlapping characteristics displayed with aging, it is plausible that the cerebral vasculature and brain could be affected in MFS patients. Together with the increased risk for cerebral aneurysms and stroke (hemorrhagic and ischemic) in MFS patients, further research is needed to understand the magnitude of risk, the potential discovery of novel targets for prevention and treatment, and the impact of current treatments on neurological concerns.…”

Carvacrol decreases blood–brain barrier permeability post-diffuse traumatic brain injury in rats

“…(2) The experiments only used male rats, despite growing evidence indicating there are sex differences in the acute glial response, including astrocytes, microglia, and infiltrating macrophages that can lower the amount of MMP activation and subsequent degradation of the BBB at the 24 h and 7 days time points. However, there is support that this may be due to a delayed response after TBI, where more chronic time points reveal similar long-term pathology 56 , 57 . Based on these publications, it is likely that a sex-dependent response would be present that requires females to be included in future experiments and in the evaluation of long-term outcomes.…”

Astrocyte‐mediated mechanisms contribute to traumatic brain injury pathology

“…The subset of astrocytes that responds classically with upregulation of intermediate filaments approximately double or triple GFAP levels (Sabetta et al, 2023; Shandra et al, 2019; Singh et al, 2016), which is comparatively mild when compared with focal TBI where GFAP levels are higher (Vijayan et al, 1990). These astrocytes become lightly hypertrophic but proteins important for homeostatic functions including Kir4.1 and Glt1 appear unchanged.…”

“…Astrocytes more distant from a focal lesion also respond by upregulating intermediate filaments, yet proliferate less and their morphology and presumably their molecular makeup do not change as drastically. After mild/diffuse TBI, astrocytes become mildly reactive with upregulation of intermediate filaments in areas where the blood–brain barrier (BBB) is not damaged (Sabetta et al, 2023; Shandra et al, 2019; Singh et al, 2016). In areas with BBB breakdown, astrocytes respond surprisingly differently than they do after focal TBI: they neither upregulate GFAP/vimentin nor proliferate, and instead rapidly lose expression of most astrocyte‐typical proteins (Shandra et al, 2019).…”