ABSTRACT
Traumatic brain injury (TBI) involves diffuse axonal injury and induces subtle but persistent changes in brain tissue and function and poses challenges for early detection of neurological injury. The present study uses an automated behavioral analysis system to assess alterations in rodent behavior in the subacute phase in a preclinical mouse model of TBI, controlled cortical impact (CCI) injury. In the first few weeks following CCI, mice demonstrated normal exploratory behaviors and other typical home-cage behaviors. However, beginning 4 weeks post-injury, CCI mice developed disruptions in sleep-wake patterns, including an increased number of awakenings from sleep. Such impaired sleep maintenance was accompanied by an increased latency to reach peak sleep in CCI mice. These sleep disruptions implicate involvement of the thalamocortical network, the activity of which must be tightly regulated to control sleep maintenance. After injury, there was an increase in reactive microglia in thalamic regions as well as delayed reactive astrocytosis that was evident in the thalamic reticular nucleus, which preceded the development of sleep disruptions. These data suggest that cortical injury may trigger inflammatory responses in deeper neuroanatomical structures, including the thalamic reticular nucleus. Such engagement of the thalamus may perturb the thalamocortical network that regulates sleep/awake patterns and contribute to sleep disruptions observed in this model as well as those documented in patients with TBI.
Subject(s)
Brain Injuries/complications , Brain Injuries/pathology , Gliosis/etiology , Sleep-Wake Transition Disorders/etiology , Thalamus/pathology , Animals , Calcium-Binding Proteins/metabolism , Disease Models, Animal , Exploratory Behavior/physiology , Feeding Behavior , Gene Expression Regulation , Glial Fibrillary Acidic Protein/metabolism , Grooming , Mice , Mice, Inbred C57BL , Microfilament Proteins/metabolismABSTRACT
BACKGROUND: This study identifies the relationship between a test for post-traumatic headache and a marker for acute stress in rodent models of traumatic brain injury. NEW METHOD: C57BL/6 mice and Sprague Dawley rats were divided into Controlled Cortical Impact (CCI) injury, craniotomy (CR), and incision groups. Periorbital and paw allodynia were evaluated using the von Frey test prior to injury and up to four weeks post-operatively. Serum corticosterone was evaluated in groups with and without mild restraint. RESULTS: Periorbital and forepaw thresholds, but not hindpaw thresholds, were reduced in CCI and CR mice compared to incision (p<0.0001 and p<0.01). In contrast to mice, reduced periorbital and forepaw periorbital thresholds were found in CCI rats but not CR rats compared to incision (p<0.0001). Right periorbital thresholds were reduced compared to left thresholds for both rat and mouse at one week (p<0.01), but there were no side differences for forepaw thresholds. Hindpaw thresholds did not change from baseline values for any groups of mice or rats. In mice serum corticosterone levels were increased at one, two and four weeks post-CCI and CR, while the levels for rats were not different from incision (p<0.0001). Corticosterone levels were not different in mice subjected to restraint compared to no restraint. COMPARISON WITH EXISTING METHODS: This study presents novel data for allodynia in a rat model of TBI, and differences among mouse and rat species. CONCLUSIONS: Mechanical allodynia occurs independent of evoked restraint stress, while hypothalamic pituitary adrenal axis activity is dependent on head trauma and species.
Subject(s)
Brain Injuries/complications , Hyperalgesia/etiology , Post-Traumatic Headache/etiology , Stress, Psychological/complications , Touch , Animals , Brain Injuries/physiopathology , Corticosterone/blood , Disease Models, Animal , Face/physiopathology , Forelimb/physiopathology , Functional Laterality , Hindlimb/physiopathology , Hyperalgesia/physiopathology , Male , Mice , Mice, Inbred C57BL , Pain Measurement , Pain Threshold , Post-Traumatic Headache/physiopathology , Rats , Rats, Sprague-Dawley , Restraint, Physical , Stress, Psychological/physiopathology , Time FactorsABSTRACT
Heterotopic ossification consists of ectopic bone formation within soft tissues after surgery or trauma. It can have debilitating consequences, but there is no definitive cure. Here we show that heterotopic ossification was essentially prevented in mice receiving a nuclear retinoic acid receptor-γ (RAR-γ) agonist. Side effects were minimal, and there was no significant rebound effect. To uncover the mechanisms of these responses, we treated mouse mesenchymal stem cells with an RAR-γ agonist and transplanted them into nude mice. Whereas control cells formed ectopic bone masses, cells that had been pretreated with the RAR-γ agonist did not, suggesting that they had lost their skeletogenic potential. The cells became unresponsive to rBMP-2 treatment in vitro and showed decreases in phosphorylation of Smad1, Smad5 and Smad8 and in overall levels of Smad proteins. In addition, an RAR-γ agonist blocked heterotopic ossification in transgenic mice expressing activin receptor-like kinase-2 (ALK2) Q207D, a constitutively active form of the receptor that is related to ALK2 R206H found in individuals with fibrodysplasia ossificans progressiva. The data indicate that RAR-γ agonists are potent inhibitors of heterotopic ossification in mouse models and, thus, may also be effective against injury-induced and congenital heterotopic ossification in humans.
