Repeated Mild Lateral Fluid Percussion Brain Injury in the Rat Causes Cumulative Long-Term Behavioral Impairments, Neuroinflammation, and Cortical Loss in an Animal Model of Repeated Concussion

Abstract

There is growing evidence that repeated brain concussion can result in cumulative and long-term behavioral symptoms, neuropathological changes, and neurodegeneration. Little is known about the factors and mechanisms that contribute to these effects. The current study addresses the need to investigate and better understand the effects of repeated concussion through the development of an animal model. Male Long-Evans rats received 1, 3, or 5 mild lateral fluid percussion injuries or sham injuries spaced 5 days apart. After the final injury, rats received either a short (24 h) or long (8 weeks) post-injury recovery period, followed by a detailed behavioral analysis consisting of tests for rodent anxiety-like behavior, cognition, social behavior, sensorimotor function, and depression-like behavior. Brains were examined immunohistochemically to assess neuroinflammation and cortical damage. Rats given 1, 3, or 5 mild percussion injuries displayed significant short-term cognitive impairments. Rats given repeated mild percussion injuries displayed significantly worse short- and long-term cognitive impairments. Rats given 5 mild percussion injuries also displayed increased anxiety- and depression-like behaviors. Neuropathological analysis revealed short-term neuroinflammation in 3-injury rats, and both short- and long-term neuroinflammation in 5-injury rats. There was also evidence that repeated injuries induced short- and long-term cortical damage. These cumulative and long-term changes are consistent with findings in human patients suffering repeated brain concussion, provide support for the use of repeated mild lateral fluid percussion injuries to study repeated concussion in the rat, and suggest that neuroinflammation may be important for understanding the cumulative and chronic effects of repeated concussion.

Sex matters: repetitive mild traumatic brain injury in adolescent rats

“…Although there is some preliminary human evidence that adolescents may experience worse mTBI outcomes than young adults (see Semple et al, 2015),44 many of the changes in the current study are similar to those observed in adult rats given repeated mTBI. For example, adult male rats administered repeated mild fluid percussion injuries had cumulative and persisting cognitive deficits, motor abnormalities, anxiety‐like behavior, and depression 45, 46. Although we are unaware of any studies that have directly compared the effects of repeated mTBIs at different ages in rats, it should be noted that age‐specific changes do occur after more severe TBI.…”

Transcranial Magnetic Stimulation-Electroencephalography Responses in Recovered and Symptomatic Mild Traumatic Brain Injury

“…The view that recovery might be at least partly achieved by such compensatory mechanisms, rather than full return to baseline condition 48 is supported by several reports suggesting cumulative effects of repeated concussions. [49][50][51][52] …”

Repeated Mild Traumatic Brain Injury Causes Chronic Neuroinflammation, Changes in Hippocampal Synaptic Plasticity, and Associated Cognitive Deficits

“…2,3 It is hypothesized that the first mTBI places the brain in a vulnerable state that is more susceptible to damage from subsequent injuries. [4][5][6] However, the nature of the changes produced by a single mTBI remains insufficiently characterized.…”