Traumatic Brain Injury – Modeling Neuropsychiatric Symptoms in Rodents

Abstract

Each year in the US, ∼1.5 million people sustain a traumatic brain injury (TBI). Victims of TBI can suffer from chronic post-TBI symptoms, such as sensory and motor deficits, cognitive impairments including problems with memory, learning, and attention, and neuropsychiatric symptoms such as depression, anxiety, irritability, aggression, and suicidal rumination. Although partially associated with the site and severity of injury, the biological mechanisms associated with many of these symptoms – and why some patients experience differing assortments of persistent maladies – are largely unknown. The use of animal models is a promising strategy for elucidation of the mechanisms of impairment and treatment, and learning, memory, sensory, and motor tests have widespread utility in rodent models of TBI and psychopharmacology. Comparatively, behavioral tests for the evaluation of neuropsychiatric symptomatology are rarely employed in animal models of TBI and, as determined in this review, the results have been inconsistent. Animal behavioral studies contribute to the understanding of the biological mechanisms by which TBI is associated with neurobehavioral symptoms and offer a powerful means for pre-clinical treatment validation. Therefore, further exploration of the utility of animal behavioral tests for the study of injury mechanisms and therapeutic strategies for the alleviation of emotional symptoms are relevant and essential.

A Novel Closed-Head Model of Mild Traumatic Brain Injury Using Focal Primary Overpressure Blast to the Cranium in Mice

“…19,20,[22][23][24][25][26]28,[30][31][32][33][128][129][130][131][132][133] These approaches avoid the severe focal contusive brain injury associated with open-skull TBI models, while a single exposure, depending on the blast pressure, can yield axonal injury, microglial activation, edema, and cognitive, emotional, and visual deficits, 20,23,24,26,28,30,31,33,[128][129][130][131]133,134 similar to those observed with our focal blast model. For example, significant rotarod motor deficits and axonal swellings have been reported for 2 weeks after a whole body 15-psi blast in mice, 19,24 and hippocampal neuron loss has been reported in rats 2 weeks after whole body 18-psi blast.…”

“…Our model recapitulates the sensory, motor, and emotional deficits seen after mild TBI in humans 134,[154][155][156] and in other animal models, 8,122 in conjunction with the initial injury being largely limited to axon tracts. 6,8 The device we use is relatively inexpensive to fabricate and thus potentially available to many researchers.…”

“…35,[37][38][39][133][134][135][136]138,139,[141][142][143][144][145][146][147][148] For example, rotarod deficits and axon injury have been reported after weightdrop TBI. 141,149 A more detailed review of functional deficits and brain pathology after TBI created by impact or weight drop on a closed skull has been provided by others.…”

Progression of histopathological and behavioral abnormalities following mild traumatic brain injury in the male ferret

“…Also, we used a rodent-sized apparatus, which may not be large enough to test for dislike of the center zone in ferrets. In addition, anxiety measurements in mice/rats after TBI using the open field test are to date inconclusive (Malkesman et al, 2013). Mice decrease their traverse of the center distance traveled in severe, but not mild, injury (Tucker et al, 2017); our animals more likely fall into the mild injury category.…”

Performance of Male and Female C57BL/6J Mice on Motor and Cognitive Tasks Commonly Used in Pre-Clinical Traumatic Brain Injury Research

“…73 It has been noted that data and conclusions regarding the effects of TBI on anxiety in rodents are inconsistent and that additional research is warranted. 74 In particular, further studies are needed to determine whether there is a time course postinjury for expression of anxiety-like behavior, whether different testing paradigms yield different conclusions, or whether reduced time in the center of the OF (increased thigmotaxis) is related to hyperlocomotion postinjury and possibly not indicative of increased anxiety at all.…”