Repeated Closed Head Injury in Mice Results in Sustained Motor and Memory Deficits and Chronic Cellular Changes

Abstract

Millions of mild traumatic brain injuries (TBIs) occur every year in the United States, with many people subject to multiple head injuries that can lead to chronic behavioral dysfunction. We previously reported that mild TBI induced using closed head injuries (CHI) repeated at 24h intervals produced more acute neuron death and glial reactivity than a single CHI, and increasing the length of time between injuries to 48h reduced the cumulative acute effects of repeated CHI. To determine whether repeated CHI is associated with behavioral dysfunction or persistent cellular damage, mice receiving either five CHI at 24h intervals, five CHI at 48h intervals, or five sham injuries at 24h intervals were evaluated across a 10 week period after injury. Animals with repeated CHI exhibited motor coordination and memory deficits, but not gait abnormalities when compared to sham animals. At 10wks post-injury, no notable neuron loss or glial reactivity was observed in the cortex, hippocampus, or corpus callosum. Argyrophilic axons were found in the pyramidal tract of some injured animals, but neither silver stain accumulation nor inflammatory responses in the injury groups were statistically different from the sham group in this region. However, argyrophilic axons, microgliosis and astrogliosis were significantly increased within the optic tract of injured animals. Repeated mild CHI also resulted in microgliosis and a loss of neurofilament protein 200 in the optic nerve. Lengthening the inter-injury interval from 24h to 48h did not effectively reduce these behavioral or cellular responses. These results suggest that repeated mild CHI results in persistent behavioral dysfunction and chronic pathological changes within the visual system, neither of which was significantly attenuated by lengthening the inter-injury interval from 24h to 48h.

Age and Diet Affect Genetically Separable Secondary Injuries that Cause Acute Mortality Following Traumatic Brain Injury in Drosophila

“…In general, increasing the interinjury interval reduces physical, cognitive, and behavioral sequelae, as well as mortality (Kanayama et al 1996; Meehan et al 2012; Huang et al 2013; Weil et al 2014; Bolton Hall et al 2016). For example, the mortality percentage is significantly lower for piglets subjected to primary injuries 1 wk apart compared with 1 d apart (Friess et al 2009).…”

“…In humans and flies, the probability of mortality following TBI is associated with age and blood/hemolymph glucose level, which is influenced by diet (Susman et al 2002; Hukkelhoven et al 2003; Griesdale et al 2009; Dhandapani et al 2012; Katzenberger et al 2013, 2015a; Wang et al 2013; Borsage et al 2015; Chong et al 2015). Furthermore, studies of repetitive primary injuries in mammals and flies indicate that the time between primary injuries can affect the probability of mortality (Kanayama et al 1996; Friess et al 2009; Meehan et al 2012; Huang et al 2013; Weil et al 2014; Bolton Hall et al 2016) (Figure 1 and Figure 3). Thus, evolutionarily conserved age-, diet-, and interinjury interval-regulated mechanisms appear to promote secondary injuries that cause mortality.…”

“…Studies of TBI in mammals have shown that repetitive primary injuries produce worse outcomes than single injuries, and that increasing recovery time between repetitive injuries improves outcomes (Kanayama et al 1996; Friess et al 2009; Meehan et al 2012; Huang et al 2013; Weil et al 2014; Bolton Hall et al 2016). Our studies in flies support and extend these findings.…”

An insight into the vision impairment following traumatic brain injury

“…Moreover, the link between ONSD enlargement on an initial CT scan and raised intracranial pressure also needs to be confirmed by further studies (Masquere et al, 2013). Previously, it was shown that repeated mild TBI produced more acute neuron death and glial reactivity than a single TBI along with persistent behavioral dysfunction and chronic pathological changes within the visual system but the symptoms are not associated with lengthening the inter-injury interval (Bolton Hall et al, 2016). More studies are needed to understand in depth how repeated TBI affects the structural and functional integrity of visual systems.…”

Chronic traumatic encephalopathy-integration of canonical traumatic brain injury secondary injury mechanisms with tau pathology

“…For example, in a mouse model of repetitive mild closed head injury, five impacts spaced 24h or 48h apart results in motor and cognitive deficits, axonal degeneration and astrogliosis, particularly in the visual system, ten weeks following injury; however, increases in hyperphosphorylated tau were not seen (Bolton Hall et al , 2016). Similarly, although exposing mice to five injuries spaced 24h apart results in increased hemorrhagic lesions, diffuse axonal injury, neurodegeneration, and astrogliosis 24h post-injury compared to intervals spaced 48h apart, neither injury paradigm results in increased tau phosphorylation (Bolton and Saatman, 2014).…”