Loss of olfactory function is an early indicator of traumatic brain injury (TBI). The regenerative capacity and well-defined neural maps of the mammalian olfactory system enable investigations into the degeneration and recovery of neural circuits after injury. Here, we introduce a unique olfactory-based model of TBI that reproduces many hallmarks associated with human brain trauma. We performed a unilateral penetrating impact to the mouse olfactory bulb and observed a significant loss of olfactory sensory neurons (OSNs) in the olfactory epithelium (OE) ipsilateral to the injury, but not contralateral. By comparison, we detected the injury markers p75NTR, β-APP, and activated caspase-3 in both the ipsi- and contralateral OE. In the olfactory bulb (OB), we observed a graded cell loss, with ipsilateral showing a greater reduction than contralateral and both significantly less than sham. Similar to OE, injury markers in the OB were primarily detected on the ipsilateral side, but also observed contralaterally. Behavioral experiments measured 4 days after impact also demonstrated loss of olfactory function, yet following a 30-day recovery period, we observed a significant improvement in olfactory function and partial recovery of olfactory circuitry, despite the persistence of TBI markers. Interestingly, by using the M71-IRES-tauLacZ reporter line to track OSN organization, we further determined that inducing neural activity during the recovery period with intense odor conditioning did not enhance the recovery process. Together, these data establish the mouse olfactory system as a new model to study TBI, serving as a platform to understand neural disruption and the potential for circuit restoration.
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References
1.
FaulM., XuL., WaldM.M., CoronadoV., and DellingerA.M. (2010). Traumatic brain injury in the United States: national estimates of prevalence and incidence, 2002–2006. Inj. Prev., 16, A268–A268.
2.
FinkelsteinE., CorsoP.S., and MillerT.R. (2006). The incidence and economic burden of injuries in the United States. Oxford University Press: Oxford, UK.
3.
BramlettH.M., and DietrichW.D. (2004). Pathophysiology of cerebral ischemia and brain trauma: similarities and differences. J. Cereb. Blood Flow Metab., 24, 133–150.
4.
EnriquezP., and BullockR. (2004). Molecular and cellular mechanisms in the pathophysiology of severe head injury. Curr. Pharm. Des., 10, 2131–2143.
CallahanC.D., and HinkebeinJ.H. (2002). Assessment of anosmia after traumatic brain injury: performance characteristics of the University of Pennsylvania Smell Identification Test. J. Head Trauma Rehabil., 17, 251–256.
7.
DotyR.L., YousemD.M., PhamL.T., KreshakA.A., GeckleR., and LeeW.W. (1997). Olfactory dysfunction in patients with head trauma. Arch. Neurol., 54, 1131–1140.
8.
ReiterE.R., DiNardoL.J., and CostanzoR.M. (2004). Effects of head injury on olfaction and taste. Otolaryngol. Clin. North Am., 37, 1167–1184.
9.
SchofieldP.W., MooreT.M., and GardnerA. (2014). Traumatic brain injury and olfaction: a systematic review. Front. Neurol., 5, 5.
10.
HaxelB.R., GrantL., and Mackay-SimA. (2008). Olfactory dysfunction after head injury. J. Head Trauma Rehabil., 23, 407–413.
11.
CreedJ.A., DiLeonardiA.M., FoxD.P., TesslerA.R., and RaghupathiR. (2011). Concussive brain trauma in the mouse results in acute cognitive deficits and sustained impairment of axonal function. J. Neurotrauma, 28, 547–563.
12.
GaoX., and ChenJ. (2013). Moderate traumatic brain injury promotes neural precursor proliferation without increasing neurogenesis in the adult hippocampus. Exp. Neurol., 239, 38–48.
13.
GaoX., Deng-BryantY., ChoW., CarricoK.M., HallE.D., and ChenJ. (2008). Selective death of newborn neurons in hippocampal dentate gyrus following moderate experimental traumatic brain injury. J. Neurosci. Res., 86, 2258–2270.
14.
BelluscioL., and KatzL.C. (2001). Symmetry, stereotypy, and topography of odorant representations in mouse olfactory bulbs. J. Neurosci., 21, 2113–2122.
15.
BozzaT., McGannJ.P., MombaertsP., and WachowiakM. (2004). In vivo imaging of neuronal activity by targeted expression of a genetically encoded probe in the mouse. Neuron, 42, 9–21.
16.
MombaertsP., WangF., DulacC., ChaoS.K., NemesA., MendelsohnM., EdmondsonJ., and AxelR. (1996). Visualizing an olfactory sensory map. Cell, 87, 675–686.
17.
BrennanP.A., and KeverneE.B. (1997). Neural mechanisms of mammalian olfactory learning. Prog. Neurobiol., 51, 457–481.
18.
CummingsD.M., and BelluscioL. (2008). Charting plasticity in the regenerating maps of the mammalian olfactory bulb. Neuroscientist, 14, 251–263.
19.
PotterS.M., ZhengC., KoosD.S., FeinsteinP., FraserS.E., and MombaertsP. (2001). Structure and emergence of specific olfactory glomeruli in the mouse. J. Neurosci., 21, 9713–9723.
20.
TreloarH.B., FeinsteinP., MombaertsP., and GreerC.A. (2002). Specificity of glomerular targeting by olfactory sensory axons. J. Neurosci., 22, 2469–2477.
21.
BozzaT., FeinsteinP., ZhengC., and MombaertsP. (2002). Odorant receptor expression defines functional units in the mouse olfactory system. J. Neurosci., 22, 3033–3043.
22.
GreggB., and ThiessenD.D. (1981). A simple method of olfactory discrimination of urines for the Mongolian gerbil, Meriones unguiculatus. Physiol. Behav., 26, 1133–1136.
23.
AlbertsJ.R., and GalefB.G.Jr. (1971). Acute anosmia in the rat: a behavioral test of a peripherally-induced olfactory deficit. Physiol. Behav., 6, 619–621.
24.
EdwardsD.A., ThompsonM.L., and BurgeK.G. (1972). Olfactory bulb removal vs peripherally induced anosmia: differential effects on the aggressive behavior of male mice. Behav. Biol., 7, 823–828.
25.
ZhaoH., OtakiJ.M., and FiresteinS. (1996). Adenovirus-mediated gene transfer in olfactory neurons in vivo. J. Neurobiol., 30, 521–530.
26.
ChuG.K., YuW., and FehlingsM.G. (2007). The p75 neurotrophin receptor is essential for neuronal cell survival and improvement of functional recovery after spinal cord injury. Neuroscience, 148, 668–682.
27.
HenslerT., SauerlandS., BouillonB., RaumM., RixenD., HellingH.J., AndermahrJ., and NeugebauerE.A. (2002). Association between injury pattern of patients with multiple injuries and circulating levels of soluble tumor necrosis factor receptors, interleukin-6 and interleukin-10, and polymorphonuclear neutrophil elastase. J. Trauma, 52, 962–970.
28.
WangY.X., YouQ., SuW.L., LiQ., HuZ.Q., WangZ.G., SunY.P., ZhuW.X., and RuanC.P. (2013). A study on inhibition of inflammation via p75TNFR signaling pathway activation in mice with traumatic brain injury. J. Surg. Res., 182, 127–133.
29.
ItohT., SatouT., NishidaS., TsubakiM., HashimotoS., and ItoH. (2009). Expression of amyloid precursor protein after rat traumatic brain injury. Neurol. Res., 31, 103–109.
30.
BramlettH.M., KraydiehS., GreenE.J., and DietrichW.D. (1997). Temporal and regional patterns of axonal damage following traumatic brain injury: a beta-amyloid precursor protein immunocytochemical study in rats. J. Neuropathol. Exp. Neurol., 56, 1132–1141.
31.
VeneroJ.L., BurguillosM.A., and JosephB. (2013). Caspases playing in the field of neuroinflammation: old and new players. Dev. Neurosci., 35, 88–101.
32.
YakovlevA.G., KnoblachS.M., FanL., FoxG.B., GoodnightR., and FadenA.I. (1997). Activation of CPP32-like caspases contributes to neuronal apoptosis and neurological dysfunction after traumatic brain injury. J. Neurosci., 17, 7415–7424.
33.
TangC.H., FuX.J., XuX.L., WeiX.J., and PanH.S. (2012). The anti-inflammatory and anti-apoptotic effects of nesfatin-1 in the traumatic rat brain. Peptides, 36, 39–45.
34.
VerhaagenJ., OestreicherA.B., GispenW.H., and MargolisF.L. (1989). The expression of the growth associated protein B50/GAP43 in the olfactory system of neonatal and adult rats. J. Neurosci., 9, 683–691.
35.
StrittmatterS.M., VartanianT., and FishmanM.C. (1992). GAP-43 as a plasticity protein in neuronal form and repair. J. Neurobiol., 23, 507–520.
36.
PelinkaL.E., KroepflA., SchmidhammerR., KrennM., BuchingerW., RedlH., and RaabeA. (2004). Glial fibrillary acidic protein in serum after traumatic brain injury and multiple trauma. J. Trauma, 57, 1006–1012.
37.
MaxwellW.L., PovlishockJ.T., and GrahamD.L. (1997). A mechanistic analysis of nondisruptive axonal injury: a review. J. Neurotrauma, 14, 419–440.
38.
TayaK., MarmarouC.R., OkunoK., PrietoR., and MarmarouA. (2010). Effect of secondary insults upon aquaporin-4 water channels following experimental cortical contusion in rats. J. Neurotrauma, 27, 229–239.
RochefortC., GheusiG., VincentJ.D., and LledoP.M. (2002). Enriched odor exposure increases the number of newborn neurons in the adult olfactory bulb and improves odor memory. J. Neurosci., 22, 2679–2689.
42.
KobayashiM., and CostanzoR.M. (2009). Olfactory nerve recovery following mild and severe injury and the efficacy of dexamethasone treatment. Chem. Senses, 34, 573–580.
43.
DavisA.E. (2000). Mechanisms of traumatic brain injury: biomechanical, structural and cellular considerations. Crit. Care Nurs. Q., 23, 1–13.
44.
RothP., and FarlsK. (2000). Pathophysiology of traumatic brain injury. Crit. Care Nurs. Q., 23, 14–25; quiz, 65.
45.
LaPlacaM.C., PradoG.R., CullenD., and SimonC.M. (2009). Plasma membrane damage as a marker of neuronal injury. Conf. Proc. IEEE Eng. Med. Biol. Soc., 2009, 1113–1116.
46.
GoldingE.M. (2002). Sequelae following traumatic brain injury. The cerebrovascular perspective. Brain Res. Brain Res. Rev., 38, 377–388.
47.
GhirnikarR.S., LeeY.L., and EngL.F. (1998). Inflammation in traumatic brain injury: role of cytokines and chemokines. Neurochem. Res., 23, 329–340.
48.
LenT.K., and NearyJ.P. (2011). Cerebrovascular pathophysiology following mild traumatic brain injury. Clin. Physiol. Funct. Imaging, 31, 85–93.
49.
RzigalinskiB.A., WeberJ.T., WilloughbyK.A., and EllisE.F. (1998). Intracellular free calcium dynamics in stretch-injured astrocytes. J. Neurochem., 70, 2377–2385.
50.
ShaoL., CiallellaJ.R., YanH.Q., MaX., WolfsonB.M., MarionD.W., DekoskyS.T., and DixonC.E. (1999). Differential effects of traumatic brain injury on vesicular acetylcholine transporter and M2 muscarinic receptor mRNA and protein in rat. J. Neurotrauma, 16, 555–566.
51.
YuI., InajiM., MaedaJ., OkauchiT., NariaiT., OhnoK., HiguchiM., and SuharaT. (2010). Glial cell-mediated deterioration and repair of the nervous system after traumatic brain injury in a rat model as assessed by positron emission tomography. J. Neurotrauma, 27, 1463–1475.
52.
HabgoodM.D., ByeN., DziegielewskaK.M., EkC.J., LaneM.A., PotterA., Morganti-KossmannC., and SaundersN.R. (2007). Changes in blood-brain barrier permeability to large and small molecules following traumatic brain injury in mice. Eur. J. Neurosci., 25, 231–238.
53.
UnterbergA.W., StoverJ., KressB., and KieningK.L. (2004). Edema and brain trauma. Neuroscience, 129, 1021–1029.
54.
JimenezD.F., SundraniS., and BaroneC.M. (1997). Posttraumatic anosmia in craniofacial trauma. J. Craniomaxillofac. Trauma, 3, 8–15.
55.
MuellerC.A., and HummelT. (2009). Recovery of olfactory function after nine years of post-traumatic anosmia: a case report. J. Med. Case Reports, 3, 9283.
56.
BuriticaE., VillamilL., GuzmanF., EscobarM.I., Garcia-CairascoN., and PimientaH.J. (2009). Changes in calcium-binding protein expression in human cortical contusion tissue. J. Neurotrauma, 26, 2145–2155.
57.
GiraudJ.C., LebonP., and ZenouM. (1957). [Two cases of traumatic anosmia without fracture of the cranial base]. Rev. Otoneuroophtalmol., 29, 306–307.
58.
van GeelW.J., de ReusH.P., NijzingH., VerbeekM.M., VosP.E., and LamersK.J. (2002). Measurement of glial fibrillary acidic protein in blood: an analytical method. Clin. Chim. Acta, 326, 151–,154.
59.
VosP.E., LamersK.J., HendriksJ.C., van HaarenM., BeemsT., ZimmermanC., van GeelW., de ReusH., BiertJ. and VerbeekM.M. (2004). Glial and neuronal proteins in serum predict outcome after severe traumatic brain injury. Neurology, 62, 1303–1310.
60.
KnoblachS.M., NikolaevaM., HuangX., FanL., KrajewskiS., ReedJ.C., and FadenA.I. (2002). Multiple caspases are activated after traumatic brain injury: evidence for involvement in functional outcome. J. Neurotrauma, 19, 1155–1170.
61.
GentlemanS.M., GrahamD.I., and RobertsG.W. (1993). Molecular pathology of head trauma: altered beta APP metabolism and the aetiology of Alzheimer's disease. Prog. Brain Res., 96, 237–246.
62.
AbrahamsonE.E., IkonomovicM.D., CiallellaJ.R., HopeC.E., PaljugW.R., IsanskiB.A., FloodD.G., ClarkR.S., and DeKoskyS.T. (2006). Caspase inhibition therapy abolishes brain trauma-induced increases in Abeta peptide: implications for clinical outcome. Exp. Neurol., 197, 437–450.
63.
ShiJ., LongoF.M., and MassaS.M. (2013). A small molecule p75(NTR) ligand protects neurogenesis after traumatic brain injury. Stem Cells, 31, 2561–2574.
64.
BlochO., PapadopoulosM.C., ManleyG.T., and VerkmanA.S. (2005). Aquaporin-4 gene deletion in mice increases focal edema associated with staphylococcal brain abscess. J. Neurochem., 95, 254–262.
65.
PapadopoulosM.C., and VerkmanA.S. (2008). Potential utility of aquaporin modulators for therapy of brain disorders. Prog. Brain Res., 170, 589–601.
LvQ., FanX., XuG., LiuQ., TianL., CaiX., SunW., WangX., CaiQ., BaoY., ZhouL., ZhangY., GeL., GuoR., and LiuX. (2013). Intranasal delivery of nerve growth factor attenuates aquaporins-4-induced edema following traumatic brain injury in rats. Brain Res., 1493, 80–89.
68.
IliffJ.J., WangM., LiaoY., PloggB.A., PengW., GundersenG.A., BenvenisteH., VatesG.E., DeaneR., GoldmanS.A., NagelhusE.A., and NedergaardM. (2012). A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci. Transl. Med., 4, 147ra111.
69.
BenowitzL.I., and RouttenbergA. (1997). GAP-43: an intrinsic determinant of neuronal development and plasticity. Trends Neurosci., 20, 84–91.
70.
ThompsonS.N., GibsonT.R., ThompsonB.M., DengY., and HallE.D. (2006). Relationship of calpain-mediated proteolysis to the expression of axonal and synaptic plasticity markers following traumatic brain injury in mice. Exp. Neurol., 201, 253–265.
71.
MarksC.A., ChengK., CummingsD.M., and BelluscioL. (2006). Activity-dependent plasticity in the olfactory intrabulbar map. J. Neurosci., 26, 11257–11266.
72.
CummingsD.M., and BelluscioL. (2010). Continuous neural plasticity in the olfactory intrabulbar circuitry. J. Neurosci., 30, 9172–9180.
73.
HoaneM.R., PierceJ.L., HollandM.A., and AndersonG.D. (2008). Nicotinamide treatment induces behavioral recovery when administered up to 4 hours following cortical contusion injury in the rat. Neuroscience, 154, 861–868.
74.
HoaneM.R., AkstulewiczS.L., and ToppenJ. (2003). Treatment with vitamin B3 improves functional recovery and reduces GFAP expression following traumatic brain injury in rats. J. Neurotrauma, 20, 1189–1199.
75.
KhanM., SakakimaH., DhammuT.S., ShunmugavelA., ImY.B., GilgA.G., SinghA.K., and SinghI. (2011). S-nitrosoglutathione reduces oxidative injury and promotes mechanisms of neurorepair following traumatic brain injury in rats. J. Neuroinflammation, 8, 78.
76.
KhanM., ImY.B., ShunmugavelA., GilgA.G., DhindsaR.K., SinghA.K., and SinghI. (2009). Administration of S-nitrosoglutathione after traumatic brain injury protects the neurovascular unit and reduces secondary injury in a rat model of controlled cortical impact. J. Neuroinflammation, 6, 32.
77.
Alvarez-BuyllaA., and Garcia-VerdugoJ.M. (2002). Neurogenesis in adult subventricular zone. J. Neurosci., 22, 629–634.
78.
Mackay-SimA., and KittelP.W. (1991). On the life span of olfactory receptor neurons. Eur. J. Neurosci., 3, 209–215.
79.
ArdilesY., de laPuente, R., ToledoR., IsgorC., and GuthrieK. (2007). Response of olfactory axons to loss of synaptic targets in the adult mouse. Exp. Neurol., 207, 275–288.
80.
LiuJ., SolwayK., MessingR.O., and SharpF.R. (1998). Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J. Neurosci., 18, 7768–7778.
81.
JinK., MinamiM., LanJ.Q., MaoX.O., BatteurS., SimonR.P., and GreenbergD.A. (2001). Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat. Proc. Natl. Acad. Sci. U. S. A., 98, 4710–4715.
82.
YagitaY., KitagawaK., OhtsukiT., TakasawaK., MiyataT., OkanoH., HoriM., and MatsumotoM. (2001). Neurogenesis by progenitor cells in the ischemic adult rat hippocampus. Stroke, 32, 1890–1896.
83.
UrreaC., CastellanosD.A., SagenJ., TsoulfasP., BramlettH.M., and DietrichW.D. (2007). Widespread cellular proliferation and focal neurogenesis after traumatic brain injury in the rat. Restor. Neurol. Neurosci., 25, 65–76.
84.
GriesbachG.S., Gomez-PinillaF., and HovdaD.A. (2004). The upregulation of plasticity-related proteins following TBI is disrupted with acute voluntary exercise. Brain Res., 1016, 154–162.
85.
SharmaS., ZhuangY., YingZ., WuA., and Gomez-PinillaF. (2009). Dietary curcumin supplementation counteracts reduction in levels of molecules involved in energy homeostasis after brain trauma. Neuroscience, 161, 1037–1044.
86.
WuA., YingZ., and Gomez-PinillaF. (2006). Dietary curcumin counteracts the outcome of traumatic brain injury on oxidative stress, synaptic plasticity, and cognition. Exp. Neurol., 197, 309–317.
87.
GriesbachG.S., Gomez-PinillaF., and HovdaD.A. (2007). Time window for voluntary exercise-induced increases in hippocampal neuroplasticity molecules after traumatic brain injury is severity dependent. J. Neurotrauma, 24, 1161–1171.
88.
GriesbachG.S., HovdaD.A., and Gomez-PinillaF. (2009). Exercise-induced improvement in cognitive performance after traumatic brain injury in rats is dependent on BDNF activation. Brain Res., 1288, 105–115.
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