Modified Mouse Model of Repetitive Mild Traumatic Brain Injury Incorporating Thinned-Skull Window and Fluid Percussion

Mild traumatic brain injury is a clinically highly heterogeneous neurological disorder. Highly reproducible traumatic brain injury (TBI) animal models ...

Zhejiang Normal University

Fluid percussion (FP) injury model is a popular animal model of traumatic brain injury (TBI), but still there are some issues need to be addressed. To increase the validity and reliability of this technique, we adapted the FP device using electromagnetic protractor, stainless-steel cylinder, changing pressure transducer position, and foam pads to adjust the parameters of FP pulse. Besides, the adjusted FP device is more automatic. The FP pulse is promptly measured and displayed in a graphic user interface software. The modified device resulted in reliable FP pulse. The accuracy of the pendulum leveling was improved with using the electromagnetic protractor with slots. We then collected behavioral, cognition, electrophysiological, and immunohistochemical data to verify the percussion effects in TBI mice. Lateral fluid percussion injury (FPI) or sham treatment was administered at the right frontal motorsensory region of male C57BL/6J mice. TBI mice showed evident motor, cognitive, and functional impairments, characterized by evaluation of neurological, righting, geotaxis and cliff aversion reflexes, limb asymmetrical use, rotarod running, and Morris water maze testing. The neurobehavioral damages were scaled with histopathological findings. Further, the overall firing rates and theta powers in hippocampal CA1 were significantly reduced in TBI mice compared to sham mice at Days 2 and 3 after electrode implanting. The adapted device induced effects on behavior and biology in mice that agree with existing models. These findings confirmed the validity of adjustments, and the modified device may boost the interest in TBI studies.

Modified device for fluid percussion injury in rodents.

Under unfavorable environmental conditions, eukaryotic cells may form stress granules (SGs) in the cytosol to protect against injury and promote cell survival. The initiation, mRNA and protein composition, distribution and degradation of SGs are subject to multiple intracellular post‑translational modifications and signaling pathways to cope with stress damage. Despite accumulated comprehensive knowledge of their composition and dynamics, the function of SGs remains poorly understood. When the stress persists, aberrant and/or persistent intracellular SGs and aggregation of SGs‑related proteins may lead to various diseases. In the present article, the research progress regarding the generation, modification and function of SGs was reviewed. The regulatory effects and influencing factors of SGs in the development of tumors, cardiovascular diseases, viral infections and neurodegenerative diseases were also summarized, which may provide novel insight for preventing and treating SG‑related diseases.

Pathophysiology of stress granules: An emerging link to diseases (Review).

The mechanisms underlying exercise-induced neuroprotective effects after traumatic brain injury (TBI) remained elusive, and there is a lack of effective treatments for TBI. In this study, we investigated the effects of an integrative approach of exercise and Yisaipu (TNFR-IgG fusion protein, TNF inhibitor) in a mouse TBI model. Male C57BL/6J mice were randomly assigned to a sedentary group or a group that followed a voluntary exercise regimen. The effects of 6-week prophylactic preconditioning exercise (PE) alone or in combination with post-TBI Yisaipu treatment on moderate TBI associated deficits were examined. The results showed that combined treatments of PE and post-TBI Yisaipu were superior to single treatments on reducing sensorimotor and gait dysfunctions in mice. These functional improvements were accompanied by reduced systemic inflammation largely via decreased serum TNF-α, boosted autophagic flux, and mitigated lesion volume after TBI. Given these neuroprotective effects, composite approaches such as a combination of exercise and TNF inhibitor may be a promising strategy for facilitating functional recovery from TBI and are worth further investigation.

Neuroprotective effects of voluntary exercise and Yisaipu after traumatic brain injury in mice.

Mild traumatic brain injury (mTBI) is a clinically highly heterogeneous neurological disorder, none of the existing animal models can replicate the entire sequelae. This study aimed to develop a modified closed head injury (CHI) model of repeated mTBI (rmTBI) for investigating Ca fluctuations of the affected neural network, the alternations of electrophysiology, and behavioral dysfunctions. The transcranial Ca study protocol includes AAV-GCaMP6s infection in the right motor cortex, thinned-skull preparation, and two-photon laser scanning microscopy (TPLSM) imaging. The CHI rmTBI model is fabricated using the thinned-skull site and applying 2.0 atm fluid percussion with 48-h interval. The neurological dysfunction, minor motor performance, evident mood, spatial working, and reference deficits we found in this study mimic the clinically relevant syndromes after mTBI. Besides, our study revealed that there was a trend of transition from Ca singlepeak to multipeak and plateau, and the total Ca activities of multipeaks and plateaus (p < .001 vs. pre-rmTBI value) were significantly increased in ipsilateral layer 2/3 motor neurons after rm TBI. In parallel, there is a low-frequency power shift from delta to theta band (p < .01 vs. control) in the ipsilateral layer 2/3 of motor cortex of the rmTBI mice, and the overall firing rates significantly increased (p < .01 vs. control). Moreover, rmTBI causes slight cortical and hippocampal neuron damage and possibly induces neurogenesis in the dentate gyrus (DG). The alternations of Ca and electrophysiological characteristics in layer 2/3 neuronal network, histopathological changes, and possible neurogenesis may play concertedly and partially contribute to the functional outcome post-rmTBI.

Modified mouse model of repeated mild traumatic brain injury through a thinned-skull window and fluid percussion.

The present study aimed to investigate the alterations in functional interaction between hippocampal CA1 and medial entorhinal cortex (MEC) after moderate traumatic brain injury (TBI) in C57BL/6J mice, and the possible beneficial effects of comprehensive exercise (CE). Following TBI, two microelectrodes were implanted into CA1 and MEC for extracellular recording. We found a clear synchronization of neuronal firing in CA1 and MEC, particularly within 100 Hz and peaked at 20-30 Hz range. TBI induced a significant reduction (P < 0.001) of the coherences of firing between 20-40 Hz frequency band. The mean power spectral densities (PSD) of all group mice in MEC were steadily larger than the values in CA1 in both 20-40 Hz and 56-100 Hz ranges. TBI induced significant and consistent increases of averaged 20-40 Hz or 56-100 Hz PSD (P < 0.001 or P < 0.01) in both CA1 and MEC. Injured mice displayed more varied firing patterns, and showed increased burst frequency (BF), burst duration (BD), inter-spike intervals (ISI) and inter-burst interval (IBI). Injured mice also showed worsened neurological function, sleep, gait performance, and working memory. CE facilitated the restoration of aforementioned electrophysiological characteristics and functional deficits in TBI mice. These results suggest that the beneficial effects of CE on TBI functional deficits may be partly attributed to improved neuronal network interaction between CA1 and MEC.

Comprehensive exercise reduces traumatic brain injury deficits via improving the neural network function of hippocampal CA1 and medial entorhinal cortex.

Jihui Wang

College of Physical Education and Health Sciences

Zhejiang Normal University

Modified Mouse Model of Repetitive Mild Traumatic Brain Injury Incorporating Thinned-Skull Window and Fluid Percussion

Jihui Wang

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Zhejiang Normal University

Modified Mouse Model of Repetitive Mild Traumatic Brain Injury Incorporating Thinned-Skull Window and Fluid Percussion

College of Physical Education and Health Sciences