Concussion Induces Hippocampal Circuitry Disruption in Swine

Abstract

Hippocampal-dependent deficits in learning and memory formation are a prominent feature of traumatic brain injury (TBI); however, the role of the hippocampus in cognitive dysfunction after concussion (mild TBI) is unknown. We therefore investigated functional and structural changes in the swine hippocampus following TBI using a model of head rotational acceleration that closely replicates the biomechanics and neuropathology of closed-head TBI in humans. We examined neurophysiological changes using a novel ex vivo hippocampal slice paradigm with extracellular stimulation and recording in the dentate gyrus and CA1 occurring at 7 days following non-impact inertial TBI in swine. Hippocampal neurophysiology post-injury revealed reduced axonal function, synaptic dysfunction, and regional hyperexcitability at one week following even "mild" injury levels. Moreover, these neurophysiological changes occurred in the apparent absence of intra-hippocampal neuronal or axonal degeneration. Input-output curves demonstrated an elevated excitatory post-synaptic potential (EPSP) output for a given fiber volley input in injured versus sham animals, suggesting a form of homeostatic plasticity that manifested as a compensatory response to decreased axonal function in post-synaptic regions. These data indicate that closed-head rotational acceleration-induced TBI, the common cause of concussion in humans, may induce significant alterations in hippocampal circuitry function that have not resolved at 7 days post-injury. This circuitry dysfunction may underlie some of the post-concussion symptomatology associated with the hippocampus, such as post-traumatic amnesia and ongoing cognitive deficits.

A Porcine Model of Traumatic Brain Injury via Head Rotational Acceleration

“…This porcine model of non-impact closed-head rotational-acceleration induced TBI results in different neurological outcomes which are dependent on the plane of head rotation and the level of rotational acceleration/velocity [67, 98, 114, 126, 134]. In general, adult swine undergoing rotational injury in the coronal plane at the levels tested (typically 120–300 rad/s) experience brief or no apnea and do not present a measurable loss-of- consciousness.…”

“…Thus the full spectrum of acute neurological outcomes may be attained based on rotational levels, including no overt changes, transient loss-of-consciousness, prolonged coma, and even death. Overall, based on loss-of-consciousness and neurological recovery, head rotation in the coronal plane at levels generated by the HYGE are considered to induce a “mild” TBI phenotype, whereas sagittal or axial plane rotation is considered to induce a “mild,” “moderate,” or “severe” TBI phenotype depending on the head rotational levels employed [98, 114, 126, 134]. Of note, these observations have been consistent across sexes and strains, and are specifically based on the ranges of angular velocities/acceleration tested to date.…”

“…13). In particular, hippocampal neuronal degeneration has been shown only following relatively high head rotational levels (often complicated by hematoma) but not lower levels associated with concussion [79, 95, 114, 134]. …”

“…Ongoing studies are expanding the use of this model to include novel measurements as well as to translate outcomes utilized in pediatric swine, including behavioral assessment [100, 109, 146], neurophysiological changes [134, 146, 147], and multi-model neuromonitoring [101 – 103, 137]. These lines of study will further advance the capabilities, clinical relevance, and impact of this important model for improving our understanding of TBI sequelae and enhancing our ability to restore neurological function following TBI across a range of severities.…”

A Porcine Model of Peripheral Nerve Injury Enabling Ultra-Long Regenerative Distances: Surgical Approach, Recovery Kinetics, and Clinical Relevance

“…Unlike other widely used models, porcine subjects are particularly well suited as a pre-clinical model because the nerves are remarkably similar to humans. 33 Moreover, the similar physiology between humans and porcine have resulted in its increasing popularity as a preclinical translational research model in various areas, such as traumatic brain injury, [34][35][36][37][38][39][40] spinal cord injury, 41 wound healing, 42 cartilage repair, [43][44][45][46][47] intervertebral disc herniation, 48 coronary artery injury, 49 and gastrointestinal, 50 and hepatic surgery. 51 Indeed, the objective in the development of the porcine model presented in this study was to replicate critical features of extremely challenging repair and regeneration scenarios following major PNI in human.…”