Seite - 132 - in Advances in Neuroimmunology

BrainSci. 2017,7, 11 wewillhighlight the twomosthighly-citedanimalmodels,FPIandCCI, it is important tonote that manysimilaritieswithregardto thegeneralneuroinflammatoryresponsesareobservedacross rodent modelsofTBI,despite thedifferentmethodsandmodalitiesof the injuries. 2.1. Percussion InjuryAnimalModels In percussive injury models, there are two devices that are most commonly incorporated into experiments. In the FPImodel, the insult is inflicted by a pendulum striking the piston of a reservoir of fluid, and this generates a fluid pressure pulse that is delivered to the intact dura, viaasyringesecuredoveranopenedmidlineor lateral craniotomy[30,31]. In thesecondpercussive TBI, an injury isdeliveredbyapiston that is controlledeitherpneumaticallyorviaapiezoelectric mechanism [32–34]. Thepercussionproduces brief displacement anddeformationof brain tissue, andtheseverityof injurydependsonthestrengthof thepressurepulse [31],aswellas the location of thecraniotomy/injury. FPImodels replicate clinicalTBIwithout skull fracture [35] and,despite thecraniotomy,areconsideredaclosedhead injurymodel [36]. TheFPImodel isoftenconsidered tobeofmild tomoderateseverity, rather thansevere [30].AnumberofstudieshaveshownthatFPI canreliablyreproduce intracranialhemorrhage[30,31], swelling[31,37],neuroinflammation[37–39] andgraymatter damage [19,30], all ofwhich arepathophysiological changes observed inhuman TBIs [40]. Basedonthepositionof thecraniotomy,FPImodelscanbedividedintomidline (centered onthesagittal suture),parasagittal (<3.5mmlateral tomidline)andlateralmodels (>3.5mmlateral tomidline; LFPI) [31,41–43]. ThemidlineFPImodelofTBIwasfirstdeveloped foruse incats and rabbits [37,44], secondlyadaptedforrats [30]andsubsequentlymodifiedforuse inmice [19,31]. FPI hasalsobeenusedforstudyingTBIpathophysiologyandpharmacologyinotherspecies [37,45,46], althoughthevolumeof literaturepales incomparisonto that for rodents. Inrodents,FPIproducesarapidcombinationof focal cortical contusionanddiffusesubcortical (suchashippocampusandthalamus)neuronal injury. Thesecanoccurwithinminutesof the impact, progress toa lossofneuronsby12handareaccompaniedbyarapidneuroinflammatoryresponsethat is initially focused in theperi-injuryregion[38,39].Neuronaldeathandneuroinflammatorysignaling seemtopeakataroundthreedaysafterFPIandinmanyothermodels [38]. This inflammationpersists, albeitat levels lower thanthepeak,well intochronic timepoints (≥1month). In thedaysandmonths followingthe injury,progressivedegenerativecascades that includechronic inflammationcontinue to beobservedinavarietyofbrainregions implicated inhighercognitive functions. These includethe hippocampus, thalamus,medial septum,striatumandamygdala [35,47,48]. It isoftendeducedthat theneuropathologyintheseregionsunderlies theobservedneurobehavioralandcognitivedeficits that arecommonlyseen intheFPImodel [36,49,50].Ofsignificance is the fact thatanalogoussymptoms areoftenseen inpatientswithTBI-related injuries tocorrespondingbrainregions [36,49]. 2.2. ControlledCortical Impact InjuryAnimalModel TheCCImodel uses apneumatic or electromagnetic impact device todrive a rigid impactor onto the exposed intact dura andmimics cortical tissue loss, acute subdural hematoma, axonal injury, concussion, blood-brain barrier (BBB) dysfunction and even coma [23–25]. It has been appliedtoanumberofanimals, suchas ferrets [24], swineandmonkeys [51]and,mostprominently, rodents [23,25].CCI isdeliveredto the intactdura throughacraniotomyandresults indeformation of theunderlyingcortex [23]. Thedamagecreated ishighly reproducibleand includesarapidand sometimeswidespreadneuropathologicaldamage. Thisdamage ismostprominent in theperi-injury area, includesneurodegenerativeandneuroinflammatory responses [52], andcanalso encompass cortical, hippocampal and thalamicdegeneration [53]. Thehistopathological severity ofCCI rises with increasing corticaldeformation, asdoes the cognitive impairment that is likely related to the extent of damage [54–59]. Similar to theFPImodel, theneuropathologyandassociated cognitive andbehavioraldeficits afterCCIpersist chronically, anddiffuseneuropathology is evident [60,61]. 132