CNRM Research Highlight: Sex-Dependent Effects of Blast TBI on the Stress Axis
Common psychological symptoms of blast-related traumatic brain injury (TBI), such as depression, anxiety, and post-traumatic stress disorder, have been correlated with a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is a dynamic circuit, which integrates the body’s central nervous system and endocrine system. It is comprised of three components:
- Paraventricular nucleus of the hypothalamus (PVN)
- Anterior pituitary gland
- Adrenal glands
The HPA axis is heavily involved in our body’s hormonal response to physical and/or psychological stressors. In the presence of stress, the PVN produces corticotropin-releasing factor (CRF) and arginine vasopressin (AVP). This production stimulates the pituitary gland to secrete adrenocorticotropin hormone (ACTH), which induces the adrenal glands to synthesize and release glucocorticoids. Glucocorticoids, in turn, produce feedback to reset the activation of the HPA axis. The body becomes vulnerable to developing disorders if the stress axis does not reset properly and is dysregulated. The HPA axis behaves differently in males and females. For example, females exhibit higher basal and stress-induced corticosterone secretions than males and have higher activations of the stress response. In humans, women are also more susceptible than men to develop certain neuropsychiatric disorders and exhibit more symptoms of post-concussive syndrome after TBI.
Over 30% of patients with TBI exhibit neuroendocrine dysfunctions, particularly disruptions in the HPA axis. While it is clear that TBI can cause alterations in the HPA axis, it is unclear how these changes occur. T John Wu, PhD and his team examined how the HPA axis is affected by mild blast TBI (mbTBI) in the CNRM-funded study entitled “Blast TBI's Effect on the Stress Axis.”This study used an Advanced Blast Stimulator (ABS) as a model to replicate mbTBI in adult male and female mice. The ABS accurately simulates shock waves generated by explosive blasts commonly experienced by Service Members. The mice were divided by sex and assigned to either a sham or treatment group. To best mimic mbTBI’s experienced by Service Members, selected groups of male and female mice were also exposed to psychological stressors (e.g., restraint) after their injury. The mice were assessed 7-10 days post-injury.
Ashley Russell, PhD, a former member of Dr. Wu’s lab and recent Neuroscience graduate from the Uniformed Services University, stated “Our study suggests that mild blast traumatic brain injuries dysregulate the neuroendocrine stress axis differently in women and men.” Findings for their study showed that following restraint stress, mbTBI increased corticosterone response but lowered levels of CRF neuronal activation in the PVN of male mice. Conversely, mbTBI female mice had a decreased restraint stress-induced corticosterone response and an increased restraint -induced CRF neuronal activation in the PVN. Dr. Wu’s team further reported that mbTBI did not affect stress-related gene expression in the pituitary gland or the adrenal gland. These findings suggest that HPA axis dysregulation is dependent on central alterations.
CRF has two types of receptors, CRFR1 and CRFR2. The study’s team was surprised to find no changes in CRFR1, but changes in CRFR2 levels in male and female mbTBI groups. Additionally, changes in levels of CRFR2 expression induced by mbTBI differed in brain region and between male and female mice. In male mice, mbTBI increased basal CRFR2 in the ventral hippocampus and decreased restraint stress-induced CRFR2 in the anterior bed nucleus of the stria terminalis and amygdala. In female mice, mbTBI only decreased restraint stress-induced CRFR2 expression in the dorsal hippocampus. Furthermore, both male and female mice demonstrated increased anxiety-like behaviors after mbTBI. However, different anatomical patterns of altered CRFR2 gene expression suggests that region specific alterations after mbTBI might contribute to sex-dependent sensitivities for anxiety disorders.
Ultimately, Dr. Wu and his team found that mbTBI causes a dysregulation in the HPA axis and that males and females utilize different neural pathways to adapt to the injury. While more research is needed, this study also suggests that CRFR2 may provide a potential target to treat anxiety symptoms after injury.
Results from this laboratory were featured in the Huffington Post, the Endocrine Society, and Science Daily. Dr. Mario G. Oyola, a member of the team, won 1st prize in the 2019 National Capital Area TBI Research Symposium’s poster competition for his poster “Chronic Stress Precipitates Detrimental Effects of Mild Traumatic Brain Injury.” Dr. Oyola’s poster presented findings from this study and separate CNRM-funded study by Dr. Wu entitled “Blast TBI’s Effect on the Limbic-HPA Axis.” Dr. Wu thanks this study’s team for their exemplary work and dedication towards this project.
Russell, A. L., Handa, R. J., & Wu, T. J. (2018). Sex-Dependent Effects of Mild Blast-induced Traumatic Brain Injury on Corticotropin-releasing Factor Receptor Gene Expression: Potential Link to Anxiety-like Behaviors. Neuroscience, 392, 1-12. doi:10.1016/j.neuroscience.2018.09.014
Russell, A. L., Richardson, M. R., Bauman, B. M., Hernandez, I. M., Saperstein, S., Handa, R. J., & Wu, T. J. (2018). Differential Responses of the HPA Axis to Mild Blast Traumatic Brain Injury in Male and Female Mice. Endocrinology, 159 (6), 2363-2375. doi:10.1210/en.2018-00203
60 Minutes' Segment on "How IEDs May be Physically Causing PTSD" is a recipient of the Radio Television Digital News Association's National Edward R. Murrow Awards
This 60 Minutes segment shared SFC Brian Mancini's personal story of traumatic brain injury (TBI) and combat blast exposures. It features interviews with Dr. Daniel Perl, USU professor of pathology and director of CNRM's Brain Tissue Repository, as well as work performed by CNRM's Brain Tissue Repository. The Murrow Awards are among the most respected and prestigious journalism awards in the world. Awards recipients embody the values, principles, and standards set forth by Edward R. Murrow, a journalism pioneer who set the standards for the highest quality of broadcast journalism. CNRM thanks 60 Minutes, the Mancini family, Dr. Perl, and the Brain Tissue Repository for their dedication to supporting Service Members and their families.
Funding Opportunity Announcement: CCCRP/JPC-6, "Secondary Analysis of Data in FITBIR"
On May 31st, 2019, the Congressionally Directed Medical Research Programs' (CDMRP) Joint Program Committee-6/Combat Casualty Care Research Program (CCCRP) released a funding opportunity announcement for the secondary analysis of data housed within the Federal Interagency Traumatic Brain Injury Research (FITBIR) Informatics System. More information about this funding opportunity announcement can be found on CDMRP's website and on the Grants.gov website. Letters of intent are due by July 10, 2019 and completed applications are due by August 1, 2019.