The present study describes the characterization of an experimental model of closed head injury (CHI) in the mouse. This model is a modification of a setup described and used previously in the rat. The weight-drop device was modified and adapted to the size and weight of the mouse and the typical parameters that define the severity of the injury and its outcome were evaluated. The posttraumatic accumulation of water, i.e., cerebral edema, the disruption of the blood-brain barrier (BBB), histopathology, motor and cognitive functions were studied up to 30 days following CHI. Increases in cerebral water content and of BBB permeability were observed in the injured hemisphere at 4 h (p < 0.05) and 24 h (p < 0.01) postinjury, respectively. By 7 days, edema disappeared, while the BBB remained open for up to 30 days. The motor function was evaluated by a set of criteria termed neurological severity score (NSS). NSS was severely impaired immediately after CHI and later showed a spontaneous progressive recovery, although some residual deficits, mainly of beam-walk and balance, were still present at 30 days. Mice trained in the Morris water maze before the injury demonstrated highly significant deficits in memory retention up to at least 11 days postinjury (p < 0.01). Histopathological analysis revealed significant neuronal cell death in CA1, CA2, and CA3 regions of the left hippocampus following CHI. However, in the right hippocampus, overt neuronal cell death was observed only in area CA3 at 7 days after CHI. These results suggest that the modified model of CHI in mice can reproduce the posttraumatic sequelae observed in rats and show that some of the data obtained in this model are essentially similar to those observed in human head injury. The experimental model of CHI in mice may be a useful tool for studies in animals that carry specific genetic alterations, aimed at manipulating neurochemical pathways involved in the pathophysiology of brain damage.

We have recently reported that in bone the cannabinoid CB1 receptor is present in sympathetic terminals. Here we show that traumatic brain injury (TBI), which in humans enhances peripheral osteogenesis and fracture healing, acutely stimulates bone formation in a distant skeletal site. At this site we demonstrate i) a high level of the main endocannabinoid, 2-arachidonoylglycerol (2-AG), and expression of diacylglycerol lipases, enzymes essential for 2-AG synthesis; ii) that the TBI-induced increase in bone formation is preceded by elevation of the 2-AG and a decrease in norepinephrine (NE) levels. The TBI stimulation of bone formation was absent in CB1-null mice. In wild-type animals it could be mimicked, including the suppression of NE levels, by 2-AG administration. The TBI- and 2-AG-induced stimulation of osteogenesis was restrained by the beta-adrenergic receptor agonist isoproterenol. NE from sympathetic terminals is known to tonically inhibit bone formation by activating osteoblastic beta2-adrenergic receptors. The present findings further demonstrate that the sympathetic control of bone formation is regulated through 2-AG activation of prejunctional CB1. Elevation of bone 2-AG apparently suppresses NE release from bone sympathetic terminals, thus alleviating the inhibition of bone formation. The involvement of osteoblastic CB2 signaling in this process is minimal, if any.

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Major depression is associated with low bone mass and increased incidence of osteoporotic fractures. However, causality between depression and bone loss has not been established. Here, we show that mice subjected to chronic mild stress (CMS), an established model of depression in rodents, display behavioral depression accompanied by impaired bone mass and structure, as portrayed by decreases in trabecular bone volume density, trabecular number, and trabecular connectivity density assessed in the distal femoral metaphysis and L3 vertebral body. Bone remodeling analysis revealed that the CMS-induced skeletal deficiency is accompanied by restrained bone formation resulting from reduced osteoblast number. Antidepressant therapy, which prevents the behavioral responses to CMS, completely inhibits the decrease in bone formation and markedly attenuates the CMS-induced bone loss. The depression-triggered bone loss is associated with a substantial increase in bone norepinephrine levels and can be blocked by the ␤-adrenergic antagonist propranolol, suggesting that the sympathetic nervous system mediates the skeletal effects of stress-induced depression. These results define a linkage among depression, excessive adrenergic activity, and reduced bone formation, thus demonstrating an interaction among behavioral responses, the brain, and the skeleton, which leads to impaired bone structure. Together with the common occurrence of depression and bone loss in the aging population, the present data implicate depression as a potential major risk factor for osteoporosis and the associated increase in fracture incidence.antidepressant ͉ chronic depression ͉ osteoporosis ͉ bone formation ͉ adrenergic signaling

Low-level laser therapy (LLLT) has been evaluated in this study as a potential therapy for traumatic brain injury (TBI). LLLT has been found to modulate various biological processes. Following TBI in mice, we assessed the hypothesis that LLLT might have a beneficial effect on their neurobehavioral and histological outcome. TBI was induced by a weight-drop device, and motor function was assessed 1 h post-trauma using a neurological severity score (NSS). Mice were then divided into three groups of eight mice each: one control group that received a sham LLLT procedure and was not irradiated; and two groups that received LLLT at two different doses (10 and 20 mW/cm(2) ) transcranially. An 808-nm Ga-As diode laser was employed transcranially 4 h post-trauma to illuminate the entire cortex of the brain. Motor function was assessed up to 4 weeks, and lesion volume was measured. There were no significant changes in NSS at 24 and 48 h between the laser-treated and non-treated mice. Yet, from 5 days and up to 28 days, the NSS of the laser-treated mice were significantly lower (p < 0.05) than the traumatized control mice that were not treated with the laser. The lesion volume of the laser treated mice was significantly lower (1.4%) than the non-treated group (12.1%). Our data suggest that a non-invasive transcranial application of LLLT given 4 h following TBI provides a significant long-term functional neurological benefit. Further confirmatory trials are warranted.