Motor Effects of Minimal Traumatic Brain Injury in Mice.

Traumatic brain injury (TBI) is considered to be the leading cause of disability and death among young people. Up to 30% of mTBI patients report motor impairments, such as altered coordination and impaired balance and gait. The objective of the present study was to characterize motor performance and motor learning changes, in order to achieve a more thorough understanding of the possible motor consequences of mTBI in humans. Mice were exposed to traumatic brain injury using the weight-drop model and subsequently subjected to a battery of behavioral motor tests. Immunohistochemistry was conducted in order to evaluate neuronal survival and synaptic connectivity. TBI mice showed a different walking pattern on the Erasmus ladder task, without any significant impairment in motor performance and motor learning. In the running wheels, mTBI mice showed reduced activity during the second dark phase and increased activity during the second light phase compared to the control mice. There was no difference in the sum of wheel revolutions throughout the experiment. On the Cat-Walk paradigm, the mice showed a wider frontal base of support post mTBI. The same mice spent a significantly greater percent of time standing on three paws post mTBI compared with controls. mTBI mice also showed a decrease in the number of neurons in the temporal cortex compared with the control group. In summary, mTBI mice suffered from mild motor impairments, minor changes in the circadian clock, and neuronal damage. A more in-depth examination of the mechanisms by which mTBI compensate for motor deficits is necessary.

Dietary Energy Restriction Ameliorates Cognitive Impairment in a Mouse Model of Traumatic Brain Injury.

Traumatic brain injury (TBI) is one of the most common causes of neurological damage in young people. It was previously reported that dietary restriction, by either intermittent fasting (IF) or daily caloric restriction (CR), could protect neurons against dysfunction and degeneration in animal models of stroke and Parkinson's disease. Recently, several studies have shown that the protein Sirtuin 1 (SIRT1) plays a significant role in the induced neuroprotection following dietary restriction. In the present study, we found a significant reduction of SIRT1 levels in the cortex and hippocampus in a mouse model of mild weight-drop closed head TBI. This reduction was prevented in mice maintained on IF (alternate day fasting) and CR initiated after the head trauma. Hippocampus-dependent learning and memory (measured using a novel object recognition test) was impaired 30 days post-injury in mice fed ad libitum, but not in mice in the IF and CR groups. These results suggest a clinical potential for IF and/or CR as an intervention to reduce brain damage and improve functional outcome in TBI patients.

A study on the mechanism by which MDMA protects against dopaminergic dysfunction after minimal traumatic brain injury (mTBI) in mice.

Driving under methylenedioxymethamphetamine (MDMA) influence increases the risk of being involved in a car accident, which in turn can lead to traumatic brain injury. The behavioral deficits after traumatic brain injury (TBI) are closely connected to dopamine pathway dysregulation. We have previously demonstrated in mice that low MDMA doses prior to mTBI can lead to better performances in cognitive tests. The purpose of this study was to assess in mice the changes in the dopamine system that occurs after both MDMA and minimal traumatic brain injury (mTBI). Experimental mTBI was induced using a concussive head trauma device. One hour before injury, animals were subjected to MDMA. Administration of MDMA before injury normalized the alterations in tyrosine hydroxylase (TH) levels that were observed in mTBI mice. This normalization was also able to lower the elevated dopamine receptor type 2 (D2) levels observed after mTBI. Brain-derived neurotrophic factor (BDNF) levels did not change following injury alone, but in mice subjected to MDMA and mTBI, significant elevations were observed. In the behavioral tests, haloperidol reversed the neuroprotection seen when MDMA was administered prior to injury. Altered catecholamine synthesis and high D2 receptor levels contribute to cognitive dysfunction, and strategies to normalize TH signaling and D2 levels may provide relief for the deficits observed after injury. Pretreatment with MDMA kept TH and D2 receptor at normal levels, allowing regular dopamine system activity. While the beneficial effect we observe was due to a dangerous recreational drug, understanding the alterations in dopamine and the mechanism of dysfunction at a cellular level can lead to legal therapies and potential candidates for clinical use.

Enriched environment improves the cognitive effects from traumatic brain injury in mice.

To date, there is yet no established effective treatment (medication or cognitive intervention) for post-traumatic brain injury (TBI) patients with chronic sequelae. Enriched environment (EE) has been recognized of importance in brain regulation, behaviour and physiology. Rodents reared in, or pre-exposed to EE, recovered better from brain insults. Using the concussive head trauma model of minimal TBI in mice, we evaluated the effect of transition to EE following a weight-drop (30g or 50g) induced mTBI on behavioural and cognitive parameters in mice in the Novel Object Recognition task, the Y- and the Elevated Plus mazes. In all assays, both mTBI groups (30g, 50g) housed in normal conditions were equally and significantly impaired 6 weeks post injury in comparison with the no-mTBI (p<0.001 and p<0.03, respectively) and the mTBI+EE groups (p<0.001 for the 30g, and p<0.017 for the 50g). No differences were found between the control and the EE mice. Two separate finding emerge: (1) the significantly positive effects of the placement in EE following mTBI, on the rehabilitative process of the tested behaviours in the affected mice; (2) the lack of difference between the groups of mice affected by 30g or by 50g. Further studies are needed in order to characterize the exact pathways involved in the positive effects of the EE on mice recovery from mTBI. Possible clinical implications indicate the importance of adapting correlates of EE to humans, i.e., prolonged and intensive physical activity - possibly combined with juggling training and intensive cognitive stimulation.

Hyperbaric oxygen-induced seizures cause a transient decrement in cognitive function.

Hyperbaric oxygen-induced seizures are classified as brief, generalized tonic-clonic seizures. They are believed to cause no residual cognitive damage, although this has not been investigated in depth. In the present study, we examined whether hyperbaric oxygen-induced seizures cause impairment of behavioral and cognitive abilities. Cognitive status was assessed using four behavioral tests: Y-maze, novel object recognition, the elevated plus maze, and a passive avoidance task. Three time intervals were examined: 24h, and 7 and 30 days after the seizures. We found transient impairment of performance in the compressed group on three tests (the novel object recognition paradigm, the Y-maze paradigm, and the passive avoidance task). On the elevated plus maze test, the impairment persisted. The time interval to the appearance of deficits and to eventual recovery was not the same for the different tests. We conclude that hyperbaric oxygen-induced seizures result in transient impairment of performance on behavioral tests in a mouse model. Further investigation is required to establish the mechanism and location of injury, and to determine whether the performance decrement on the elevated plus maze test represents permanent damage or transient damage with slow resolution. These new findings should be taken into account when planning hyperbaric oxygen treatments, to ensure that the chosen protocol is therapeutic yet minimizes the risk of CNS oxygen toxicity.

The nuclear factor erythroid 2-like 2 activator, tert-butylhydroquinone, improves cognitive performance in mice after mild traumatic brain injury.

Traumatic Brain injury affects at least 1.7 million people in the United States alone each year. The majority of injuries are categorized as mild but these still produce lasting symptoms that plague the patient and the medical field. Currently treatments are aimed at reducing a patient's symptoms, but there is no effective method to combat the source of the problem, neuronal loss. We tested a mild, closed head traumatic brain injury model for the effects of modulation of the antioxidant transcription factor Nrf2 by the chemical activator, tert-butylhydroquinone (tBHQ). We found that post-injury visual memory was improved by a 7 day course of treatment and that the level of activated caspase-3 in the hippocampus was reduced. The injury-induced memory loss was also reversed by a single injection at 30 min after injury. Since the protective stress response molecule, HSP70, can be upregulated by Nrf2, we examined protein levels in the hippocampus, and found that HSP70 was elevated by the injury and then further increased by the treatment. To test the possible role of HSP70, model neurons in culture exposed to a mild injury and treated with the Nrf2 activator displayed improved survival that was blocked by the HSP70 inhibitor, VER155008. Following mild traumatic brain injury, there may be a partial protective response and patients could benefit from directed enhancement of regulatory pathways such as Nrf2 for neuroprotection.

Dissociation between the inhibitory and stimulatory effects of opioid peptides on cAMP formation in SK-N-SH neuroblastoma cells.

Opioid agonists either potentiate or suppress basal cAMP production in SK-N-SH cells. The inhibitory effect is mediated by PTX-sensitive GTP-binding proteins, while the stimulatory effect involves Ca++ entry and calmodulin activation. Both pathways can be activated simultaneously by opioid agonists. Low (nM) concentrations of either mu (DAMGO) or delta (DPDPE) selective opioids potentiate cAMP formation. At higher (100 nM) concentrations, however, a net suppression takes over; this suppression can be eliminated by PTX, and the underlying stimulatory effect is disclosed. Micromolar concentrations of either mu or delta selective agonists cross-activate the other (delta or mu) receptors, and augment the stimulatory pathway. The overall outcome (either stimulation or inhibition of cAMP production) is dependent on the balance between the two overlapping pathways, and can be modified by blocking either of the two opposing mechanisms.