Endogenous Sex Steroids Dampen Neuroinflammation and Improve Outcome of Traumatic Brain Injury in Mice

Abstract

The role of biological sex in short-term and long-term outcome after traumatic brain injury (TBI) remains controversial. The observation that exogenous female sex steroids (progesterone and estrogen) reduce brain injury coupled with a small number of clinical studies showing smaller injury in women suggest that sex steroids may play a role in outcome from TBI. We used the controlled cortical impact (CCI) model of TBI in mice to test the hypothesis that after CCI, female mice would demonstrate less injury than male mice, related to the protective role of endogenous steroids. Indeed, adult females exhibit histological protection (3.7 ± 0.5 mm) compared to adult male mice (6.8 ± 0.6 mm), and females that lacked sex steroids (ovex) showed increased injury compared to intact females. Consistent with histology, sensorimotor deficits measured as reduced contralateral limb use were most pronounced in male mice (31.9 ± 6.9% reduced limb use) compared to a 12.7 ± 3.8% reduction in female mice. Ovex mice exhibited behavioral deficits similar to males (31.5 ± 3.9% reduced limb use). Ovex females demonstrated increased microglial activation relative to intact females in both the peri-injury cortex and the reticular thalamic nucleus. Ovex females also demonstrated increased astrogliosis in comparison to both females and males in the peri-injury cortex. These data indicate that female sex steroids reduce brain sensitivity to TBI and that reduced acute neuroinflammation may contribute to the relative protection observed in females.

Direct activation of tachykinin receptors within baroreflex afferent pathway and neurocontrol of blood pressure regulation

“…Taking functional and molecular findings together, the protective effect of estrogen‐specific expression of NKRs in baroreflex afferent pathway could be pinpointed. Consistently, recent animal study showing that intact female mice have a significant lesser damage after traumatic brain injury compared with male and OVX mice and the outcomes of OVX mice recover dramatically with estrogen treatment, suggesting a potential key role of estrogen‐dependent NKRs expression in the protection against neuroinflammation by down‐regulation of SP‐mediated cardiovascular responses, which further explains why the sensitivity to traumatic brain injury and caused brain damage are far less in females.…”

Biological sex does not predict glymphatic influx in healthy young, middle aged or old mice

“…In healthy animals we find no effects of biological sex on glymphatic influx across anesthesia, the day, and in aging. This was unexpected because we know sex affects common disorders, such as cardiovascular disease prevalence 10 , Alzheimer’s disease 11 , 13 , 36 , and recovery from traumatic brain injury 15 – 17 , which generally correlate to glymphatic dysfunction. The observations reported here suggest it is not underlying male/female differences in glymphatic function that drive disease, but rather differences in homeostatic responses to disease that lead to male/female differences in pathology, prevalence, and long-term recovery.…”

“…These differences may be caused by underlying differences in genetic susceptibility, and lifestyle resilience between men and women 13 . Additionally, there is some evidence in humans 14 and from rodent models that male and female animals recover differently after traumatic brain injury, with female mice having reduced neuroinflammation 15 , 16 and male mice having increased angiogenesis a week after injury 17 . How sex may affect the glymphatic system, which is impaired in aging 18 , neurodegenerative disease models 19 – 22 and traumatic brain injury 21 , 23 , remains unknown.…”

Sex Differences in Acute Neuroinflammation after Experimental Traumatic Brain Injury Are Mediated by Infiltrating Myeloid Cells

“…26 In contrast, more recent studies have demonstrated significant sex differences in microglial and astrocyte activation during acute phase responses after moderate-severe TBI. 25,28,29 Nevertheless, all studies to date have used immunohistochemical assessments that provide excellent spatial and morphological resolution of post-traumatic neuroinflammation, but are limited in their ability to provide phenotypic and functional assessments of immune cell function in either resident (microglia) or infiltrating (myeloid, lymphocytes) cells in the central nervous system (CNS). Flow cytometry approaches can distinguish microglia from infiltrating myeloid cells in the brain based on the relative expression of the CD45 antigen, and provide the added advantage of assessing functional responses ex vivo.…”