RESUMEN
OBJECTIVE: The purpose of this study was to examine the effect of exposure of a low-intensity blast wave on androgen receptor (AR) density in the hippocampus and the potential influence on behavioral and cognitive responses. METHODS: Sprague-Dawley rats were randomly assigned to either a blast exposed group (nâ=â27) or an unexposed (control) group (nâ=â10). Animals were treated identically, except that rats within the control group were not exposed to any of the characteristics of the blast wave. Behavior measures were conducted on day seven post-exposure. The rats were initially assessed in the elevated plus maze followed by the acoustic startle response paradigm. Spatial memory performance using the Morris water-maze test was assessed at 8-days post-exposure, for seven consecutive days. Following all behavioral tests AR immunofluorescence staining was performed in different hippocampal subregions. RESULTS: A significant elevation in anxiety index (pâ<â0.001) and impaired learning (pâ<â0.015) and spatial memory (pâ<â0.0015) were noted in exposed rats. In addition, a significant attenuation of the AR was noted in the CA1 (pâ=â0.006) and dentate gyrus (pâ=â0.031) subregions of the hippocampus in blast exposed animals. Correlational analyses revealed significant associations between AR and both anxiety index (râ=â-.36, pâ=â0.031) and memory (râ=â-0.38, pâ=â0.019). CONCLUSIONS: The results of this study demonstrate that exposure to a low-pressure blast wave resulted in a decrease in AR density, which was associated with significant behavioral and cognitive changes.
RESUMEN
The complex interactions and overlapping symptoms of comorbid post-traumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) induced by an explosive blast wave have become a focus of attention in recent years, making clinical distinction and effective intervention difficult. Because dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is thought to underlie trauma-related (psycho)pathology, we evaluated both the endogenous corticosterone response and the efficacy of exogenous hydrocortisone treatment provided shortly after blast exposure. We employed a controlled experimental blast-wave paradigm in which unanesthetized animals were exposed to visual, auditory, olfactory, and tactile effects of an explosive blast wave produced by exploding a thin copper wire. Endogenous corticosterone concentrations were evaluated at different time points (before, and 3 h, 5 h and 17 days) after blast exposure. Subsequently, the efficacy of exogenous hydrocortisone (25 mg/kg-1 or 125 mg/kg-1) injected intraperitoneally 1 h after exposure was compared with that of a similarly timed saline injection. Validated cognitive and behavioral tests were used to assess both PTSD and mTBI phenotypes on days 7-14 following the blast. Retrospective analysis revealed that animals demonstrating the PTSD phenotype exhibited a significantly blunted endogenous corticosterone response to the blast compared with all other groups. Moreover, a single 125 mg/kg-1 dose of hydrocortisone administered 1 h after exposure significantly reduced the occurrence of the PTSD phenotype. Hydrocortisone treatment did not have a similar effect on the mTBI phenotype. Results of this study indicate that an inadequate corticosteroid response following blast exposure increases risk for PTSD phenotype, and corticosteroid treatment is a potential clinical intervention for attenuating PTSD. The differences in patterns of physiological and therapeutic response between PTSD and mTBI phenotypes lend credence to the retrospective behavioral and cognitive classification criteria we designed, and is in keeping with the assumption that mTBI and PTSD phenotypes may reflect distinct underlying biological and clinical profiles.
Asunto(s)
Antiinflamatorios , Traumatismos por Explosión , Conmoción Encefálica , Corticosterona , Trastornos por Estrés Postraumático , Animales , Antiinflamatorios/sangre , Antiinflamatorios/farmacología , Traumatismos por Explosión/sangre , Traumatismos por Explosión/psicología , Conmoción Encefálica/sangre , Conmoción Encefálica/etiología , Conmoción Encefálica/psicología , Corticosterona/sangre , Corticosterona/farmacología , Masculino , Ratas , Ratas Sprague-Dawley , Trastornos por Estrés Postraumático/sangre , Trastornos por Estrés Postraumático/etiologíaRESUMEN
This study investigated the benefit of ß-alanine (BA) supplementation on behavioral and cognitive responses relating to mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) in rats exposed to a low-pressure blast wave. Animals were fed a normal diet with or without (PL) BA supplementation (100 mg kg-1) for 30-day, prior to being exposed to a low-pressure blast wave. A third group of animals served as a control (CTL). These animals were fed a normal diet, but were not exposed to the blast. Validated cognitive-behavioral paradigms were used to assess both mTBI and PTSD-like behavior on days 7-14 following the blast. Brain-derived neurotrophic factor (BDNF), neuropeptide Y, glial fibrillary acidic protein (GFAP) and tau protein expressions were analyzed a day later. In addition, brain carnosine and histidine content was assessed as well. The prevalence of animals exhibiting mTBI-like behavior was significantly lower (p = 0.044) in BA than PL (26.5 and 46%, respectively), but no difference (p = 0.930) was noted in PTSD-like behavior between the groups (10.2 and 12.0%, respectively). Carnosine content in the cerebral cortex was higher (p = 0.048) for BA compared to PL, while a trend towards a difference was seen in the hippocampus (p = 0.058) and amygdala (p = 0.061). BDNF expression in the CA1 subregion of PL was lower than BA (p = 0.009) and CTL (p < 0.001), while GFAP expression in CA1 (p = 0.003) and CA3 (p = 0.040) subregions were higher in PL than other groups. Results indicated that BA supplementation for 30-day increased resiliency to mTBI in animals exposed to a low-pressure blast wave.
Asunto(s)
Traumatismos por Explosión/metabolismo , Lesiones Encefálicas/metabolismo , Suplementos Dietéticos , Trastornos por Estrés Postraumático/metabolismo , Trastornos por Estrés Postraumático/prevención & control , beta-Alanina/administración & dosificación , Animales , Traumatismos por Explosión/genética , Traumatismos por Explosión/fisiopatología , Química Encefálica , Lesiones Encefálicas/genética , Lesiones Encefálicas/fisiopatología , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Carnosina/metabolismo , Expresión Génica , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Histidina/metabolismo , Masculino , Neuropéptido Y/genética , Neuropéptido Y/metabolismo , Ratas , Ratas Sprague-Dawley , Trastornos por Estrés Postraumático/genética , Trastornos por Estrés Postraumático/fisiopatología , Proteínas tau/genética , Proteínas tau/metabolismoRESUMEN
The intense focus in the clinical literature on the mental and neurocognitive sequelae of explosive blast-wave exposure, especially when comorbid with post-traumatic stress-related disorders (PTSD) is justified, and warrants the design of translationally valid animal studies to provide valid complementary basic data. We employed a controlled experimental blast-wave paradigm in which unanesthetized animals were exposed to visual, auditory, olfactory, and tactile effects of an explosive blast-wave produced by exploding a thin copper wire. By combining cognitive-behavioral paradigms and ex vivo brain MRI to assess mild traumatic brain injury (mTBI) phenotype with a validated behavioral model for PTSD, complemented by morphological assessments, this study sought to examine our ability to evaluate the biobehavioral effects of low-intensity blast overpressure on rats, in a translationally valid manner. There were no significant differences between blast- and sham-exposed rats on motor coordination and strength, or sensory function. Whereas most male rats exposed to the blast-wave displayed normal behavioral and cognitive responses, 23.6% of the rats displayed a significant retardation of spatial learning acquisition, fulfilling criteria for mTBI-like responses. In addition, 5.4% of the blast-exposed animals displayed an extreme response in the behavioral tasks used to define PTSD-like criteria, whereas 10.9% of the rats developed both long-lasting and progressively worsening behavioral and cognitive "symptoms," suggesting comorbid PTSD-mTBI-like behavioral and cognitive response patterns. Neither group displayed changes on MRI. Exposure to experimental blast-wave elicited distinct behavioral and morphological responses modelling mTBI-like, PTSD-like, and comorbid mTBI-PTSD-like responses. This experimental animal model can be a useful tool for elucidating neurobiological mechanisms underlying the effects of blast-wave-induced mTBI and PTSD and comorbid mTBI-PTSD.