Hippocampal-dependent deficits in learning and memory formation are a prominent feature of traumatic brain injury (TBI); however, the role of the hippocampus in cognitive dysfunction after concussion (mild TBI) is unknown. We therefore investigated functional and structural changes in the swine hippocampus following TBI using a model of head rotational acceleration that closely replicates the biomechanics and neuropathology of closed-head TBI in humans. We examined neurophysiological changes using a novel ex vivo hippocampal slice paradigm with extracellular stimulation and recording in the dentate gyrus and CA1 occurring at 7 days following non-impact inertial TBI in swine. Hippocampal neurophysiology post-injury revealed reduced axonal function, synaptic dysfunction, and regional hyperexcitability at one week following even “mild” injury levels. Moreover, these neurophysiological changes occurred in the apparent absence of intra-hippocampal neuronal or axonal degeneration. Input–output curves demonstrated an elevated excitatory post-synaptic potential (EPSP) output for a given fiber volley input in injured versus sham animals, suggesting a form of homeostatic plasticity that manifested as a compensatory response to decreased axonal function in post-synaptic regions. These data indicate that closed-head rotational acceleration–induced TBI, the common cause of concussion in humans, may induce significant alterations in hippocampal circuitry function that have not resolved at 7 days post-injury. This circuitry dysfunction may underlie some of the post-concussion symptomatology associated with the hippocampus, such as post-traumatic amnesia and ongoing cognitive deficits.
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References
1.
CoronadoV.G., McGuireL.C., SarmientoK., BellJ., LionbargerM.R., JonesC.D., GellerA.I., KhouryN., and XuL. (2012). Trends in traumatic brain injury in the U.S. and the public health response: 1995–2009. J. Safety Res., 43, 299–307.
2.
GrahamR., RivaraF.P., FordM.A., and SpicerC.M. (2014). Sports-Related Concussions in Youth: Improving the Science, Changing the Culture. The National Academies Press: Washington, D.C.
3.
JordanB.D. (2013). The clinical spectrum of sport-related traumatic brain injury. Nature reviews. Neurology, 9, 222–230.
4.
HogeC.W., McGurkD., ThomasJ.L., CoxA.L., EngelC.C., and CastroC.A. (2008). Mild traumatic brain injury in U.S. soldiers returning from Iraq. N. Engl. J. Med., 358, 453–463.
5.
CaprusoD.X. and LevinH.S. (1992). Cognitive impairment following closed head injury. Neurol. Clin., 10, 879–893.
6.
RyanL.M. and WardenD.L. (2003). Post concussion syndrome. Int. Rev. Psychiatry, 15, 310–316.
7.
MontiJ.M., VossM.W., PenceA., McAuleyE., KramerA.F., and CohenN.J. (2013). History of mild traumatic brain injury is associated with deficits in relational memory, reduced hippocampal volume, and less neural activity later in life. Front. Aging Neurosci., 5, 41.
8.
BrowneK.D., ChenX.H., MeaneyD.F., and SmithD.H. (2011). Mild traumatic brain injury and diffuse axonal injury in swine. J. Neurotrauma, 28, 1747–1755.
9.
BlumbergsP.C., ScottG., ManavisJ., WainwrightH., SimpsonD.A., and McLeanA.J. (1994). Staining of amyloid precursor protein to study axonal damage in mild head injury. Lancet, 344, 1055–1056.
10.
KotapkaM.J., GrahamD.I., AdamsJ.H., and GennarelliT.A. (1992). Hippocampal pathology in fatal non-missile human head injury. Acta Neuropathol. 83, 530–534.
11.
MaxwellW.L., DhillonK., HarperL., EspinJ., MacIntoshT.K., SmithD.H., and GrahamD.I. (2003). There is differential loss of pyramidal cells from the human hippocampus with survival after blunt head injury. J. Neuropathol. Exp. Neurol., 62, 272–279.
12.
GibsonK.L., RemsonL., SmithA., SatterleeN., StrainG.M., and DaniloffJ.K. (1991). Comparison of nerve regeneration through different types of neural prostheses. Microsurgery, 12, 80–85.
13.
HicksR.R., SmithD.H., LowensteinD.H., Saint MarieR., and McIntoshT.K. (1993). Mild experimental brain injury in the rat induces cognitive deficits associated with regional neuronal loss in the hippocampus. J. Neurotrauma, 10, 405–414.
14.
ChristidiF., BiglerE.D., McCauleyS.R., SchnelleK.P., MerkleyT.L., MorsM.B., LiX., MacleodM., ChuZ., HunterJ.V., LevinH.S., CliftonG.L., and WildeE.A. (2011). Diffusion tensor imaging of the perforant pathway zone and its relation to memory function in patients with severe traumatic brain injury. J. Neurotrauma, 28, 711–725.
15.
BiglerE.D., BlatterD.D., AndersonC.V., JohnsonS.C., GaleS.D., HopkinsR.O., and BurnettB. (1997). Hippocampal volume in normal aging and traumatic brain injury. A.J.N.R. Am. J. Neuroradiol., 18, 11–23.
16.
LowensteinD.H., ThomasM.J., SmithD.H., and McIntoshT.K. (1992). Selective vulnerability of dentate hilar neurons following traumatic brain injury: a potential mechanistic link between head trauma and disorders of the hippocampus. J. Neurosci., 12, 4846–4853.
17.
MeaneyD.F., SmithD.H., ShreiberD.I., BainA.C., MillerR.T., RossD.T., and GennarelliT.A. (1995). Biomechanical analysis of experimental diffuse axonal injury. J. Neurotrauma, 12, 689–694.
18.
SmithD.H., ChenX.H., XuB.N., McIntoshT.K., GennarelliT.A., and MeaneyD.F. (1997). Characterization of diffuse axonal pathology and selective hippocampal damage following inertial brain trauma in the pig. J. Neuropathol. Exp. Neurol., 56, 822–834.
19.
CullenD.K., HarrisJ.P., BrowneK.D., WolfJ.A., DudaJ.E., MeaneyD.F., MarguliesS.S., and SmithD.H. (2016). A porcine model of traumatic brain injury via head rotational acceleration, in: Injury Models of Central Nervous System: Traumatic Brain Injury, Methods in Molecular Biology. Humana Press: New York.
20.
MorrisM.D. (2011). Design of Experiments: An Introduction Based on Linear Models. CRC Press, Chapman & Hall, Boca Raton, FL.
21.
R Core Team (2015). R: A language and environment for statistical computing. Available at: https://cran.r-project.org/doc/manuals/fullrefman.pdf. Accessed March31, 2017.
22.
JohnsonV.E., StewartJ.E., BegbieF.D., TrojanowskiJ.Q., SmithD.H., and StewartW. (2013). Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain, 136, 28–42.
23.
SherriffF.E., BridgesL.R., and SivaloganathanS. (1994). Early detection of axonal injury after human head trauma using immunocytochemistry for beta-amyloid precursor protein. Acta Neuropathol. (Berl.), 87, 55–62.
24.
GentlemanS.M., NashM.J., SweetingC.J., GrahamD.I., and RobertsG.W. (1993). Beta-amyloid precursor protein (beta APP) as a marker for axonal injury after head injury. Neurosci. Lett., 160, 139–144.
25.
GentlemanS.M., RobertsG.W., GennarelliT.A., MaxwellW.L., AdamsJ.H., KerrS., and GrahamD.I. (1995). Axonal injury: a universal consequence of fatal closed head injury?. Acta Neuropathol. 89, 537–543.
26.
TrojanowskiJ.Q., WalkensteinN., and LeeV.M. (1986). Expression of neurofilament subunits in neurons of the central and peripheral nervous system: an immunohistochemical study with monoclonal antibodies. J. Neurosci., 6, 650–660.
27.
SmithD.H., NonakaM., MillerR., LeoniM., ChenX.H., AlsopD., and MeaneyD.F. (2000). Immediate coma following inertial brain injury dependent on axonal damage in the brainstem. J. Neurosurg., 93, 315–322.
28.
BrowneK.D., ChenX.H., MeaneyD.F., and SmithD.H. (2011). Mild traumatic brain injury and diffuse axonal injury in swine. J. Neurotrauma, 28, 1747–1755.
29.
EuckerS.A., SmithC., RalstonJ., FriessS.H., and MarguliesS.S. (2011). Physiological and histopathological responses following closed rotational head injury depend on direction of head motion. Exp. Neurol., 227, 79–88.
30.
CreagerR., DunwiddieT., and LynchG. (1980). Paired-pulse and frequency facilitation in the CA1 region of the in vitro rat hippocampus. J. Physiol., 299, 409–424.
31.
McNaughtonB.L. (1980). Evidence for two physiologically distinct perforant pathways to the fascia dentata. Brain Res. 199, 1–19.
32.
ReevesT.M., KaoC.Q., PhillipsL.L., BullockM.R., and PovlishockJ.T. (2000). Presynaptic excitability changes following traumatic brain injury in the rat. J. Neurosci. Res., 60, 370–379.
33.
NorrisC.M. and ScheffS.W. (2009). Recovery of afferent function and synaptic strength in hippocampal CA1 following traumatic brain injury. J. Neurotrauma, 26, 2269–2278.
34.
SmithC.J., XiongG., ElkindJ.A., PutnamB., and CohenA.S. (2015). Brain injury impairs working memory and prefrontal circuit function. Front. Neurol., 6, 240.
35.
JohnsonV.E., StewartW., and SmithD.H. (2012). Axonal pathology in traumatic brain injury. Exp Neurol. 246, 35–43.
36.
SmithD.H. and MeaneyD.F. (2000). Axonal damage in traumatic brain injury. Neuroscientist, 6, 483–495.
37.
OmmayaA.K. and GennarelliT.A. (1974). Cerebral concussion and traumatic unconsciousness. Correlation of experimental and clinical observations of blunt head injuries. Brain, 97, 633–654.
38.
AdamsJ.H., DoyleD., FordI., GennarelliT.A., GrahamD.I., and McClellanD.R. (1989). Diffuse axonal injury in head injury: definition, diagnosis, and grading. Histopathology, 15, 49–59.
LangloisJ.A., Rutland-BrownW., and WaldM.M. (2006). The epidemiology and impact of traumatic brain injury: a brief overview. J. Head Trauma Rehabil., 21, 375–378.
41.
VanderploegR.D., CrowellT.A., and CurtissG. (2001). Verbal learning and memory deficits in traumatic brain injury: encoding, consolidation, and retrieval. J. Clin. Exp. Neuropsychol., 23, 185–195.
42.
De KruijkJ.R., TwijnstraA., and LeffersP. (2001). Diagnostic criteria and differential diagnosis of mild traumatic brain injury. Brain Inj. 15, 99–106.
43.
De MonteV.E., GeffenG.M., and MassavelliB.M. (2006). The effects of post-traumatic amnesia on information processing following mild traumatic brain injury. Brain Inj. 20, 1345–1354.
44.
LeiningerB.E., GramlingS.E., FarrellA.D., KreutzerJ.S., and PeckE.A. (1990). Neuropsychological deficits in symptomatic minor head injury patients after concussion and mild concussion. J. Neurol. Neurosurg. Psychiatry, 53, 293–296.
45.
SanthakumarV., RatzliffA.D., JengJ., TothZ., and SolteszI. (2001). Long-term hyperexcitability in the hippocampus after experimental head trauma. Ann. Neurol., 50, 708–717.
46.
GolaraiG., GreenwoodA.C., FeeneyD.M., and ConnorJ.A. (2001). Physiological and structural evidence for hippocampal involvement in persistent seizure susceptibility after traumatic brain injury. J. Neurosci., 21, 8523–8537.
47.
HanellA., GreerJ., and JacobsK. (2015). Increased network excitability due to altered synaptic inputs to neocortical layer V intact and axotomized pyramidal neurons after mild traumatic brain injury. J. Neurotrauma, 32, 1590–1598.
48.
TurrigianoG.G. (1999). Homeostatic plasticity in neuronal networks: the more things change, the more they stay the same. Trends Neurosci. 22, 221–227.
49.
DinocourtC., AungstS., YangK., and ThompsonS.M. (2011). Homeostatic increase in excitability in area CA1 after Schaffer collateral transection in vivo. Epilepsia, 52, 1656–1665.
50.
SchwarzbachE., BonislawskiD.P., XiongG., and CohenA.S. (2006). Mechanisms underlying the inability to induce area CA1 LTP in the mouse after traumatic brain injury. Hippocampus, 16, 541–550.
51.
WitgenB.M., LifshitzJ., SmithM.L., SchwarzbachE., LiangS.L., GradyM.S., and CohenA.S. (2005). Regional hippocampal alteration associated with cognitive deficit following experimental brain injury: a systems, network and cellular evaluation. Neuroscience, 133, 1–15.
52.
GriesemerD. and MautesA.M. (2007). Closed head injury causes hyperexcitability in rat hippocampal CA1 but not in CA3 pyramidal cells. J. Neurotrauma, 24, 1823–1832.
53.
GennarelliT.A., ThibaultL.E., AdamsJ.H., GrahamD.I., ThompsonC.J., and MarcincinR.P. (1982). Diffuse axonal injury and traumatic coma in the primate. Ann. Neurol., 12, 564–574.
54.
BlumbergsP.C., JonesN.R., and NorthJ.B. (1989). Diffuse axonal injury in head trauma. J. Neurol. Neurosurg. Psychiatry, 52, 838–841.
55.
StoneJ.R., SingletonR.H., and PovlishockJ.T. (2001). Intra-axonal neurofilament compaction does not evoke local axonal swelling in all traumatically injured axons. Exp. Neurol., 172, 320–331.
WolfJ.A., StysP.K., LusardiT., MeaneyD., and SmithD.H. (2001). Traumatic axonal injury induces calcium influx modulated by tetrodotoxin-sensitive sodium channels. J. Neurosci., 21, 1923–1930.
58.
IwataA., StysP.K., WolfJ.A., ChenX.H., TaylorA.G., MeaneyD.F., and SmithD.H. (2004). Traumatic axonal injury induces proteolytic cleavage of the voltage-gated sodium channels modulated by tetrodotoxin and protease inhibitors. J. Neurosci., 24, 4605–4613.
59.
YuenT.J., BrowneK.D., IwataA., and SmithD.H. (2009). Sodium channelopathy induced by mild axonal trauma worsens outcome after a repeat injury. J. Neurosci. Res., 87, 3620–3625.
60.
WolfJ.A. and KochP.F. (2016). Disruption of network synchrony and cognitive dysfunction after traumatic brain injury. Front. Syst. Neurosci., 10, 43.
61.
PajevicS., BasserP.J., and Douglas FieldsR. (2013). Role of myelin plasticity in oscillations and synchrony of neuronal activity. Neuroscience, 276, 135–147.
62.
RutishauserU., RossI.B., MamelakA.N., and SchumanE.M. (2010). Human memory strength is predicted by theta-frequency phase-locking of single neurons. Nature, 464, 903–907.
63.
MaurerA.P. and McNaughtonB.L. (2007). Network and intrinsic cellular mechanisms underlying theta phase precession of hippocampal neurons. Trends Neurosci. 30, 325–333.
64.
LeeD., GurkoffG., IzadiA., BermanR., EkstromA., MuizelaarJ., LyethB., and ShahlaieK. (2013). Medial septal nucleus theta frequency deep brain stimulation improves spatial working memory after traumatic brain injury. J. Neurotrauma, 30, 131–139.
65.
AkamT. and KullmannD.M. (2014). Oscillatory multiplexing of population codes for selective communication in the mammalian brain. Nat. Rev. Neurosci., 15, 111–122.
66.
BraakH. and BraakE. (1992). The human entorhinal cortex: normal morphology and lamina-specific pathology in various diseases. Neurosci. Res., 15, 6–31.
67.
HymanB.T., Van HoesenG.W., KromerL.J., and DamasioA.R. (1986). Perforant pathway changes and the memory impairment of Alzheimer's disease. Ann Neurol, 20, 472–481.
68.
KirkbyD.L. and HigginsG.A. (1998). Characterization of perforant path lesions in rodent models of memory and attention. Eur. J. Neurosci., 10, 823–838.
69.
FisherD.C., LedbetterM.F., CohenN.J., MarmorD., and TulskyD.S. (2000). WAIS-III and WMS-III profiles of mildly to severely brain-injured patients. Appl. Neuropsychol., 7, 126–132.
70.
MathiasJ.L., BeallJ.A., and BiglerE.D. (2004). Neuropsychological and information processing deficits following mild traumatic brain injury. J. Int. Neuropsychol. Soc., 10, 286–297.
71.
YallampalliR., WildeE.A., BiglerE.D., McCauleyS.R., HantenG., TroyanskayaM., HunterJ.V., ChuZ., LiX., and LevinH.S. (2013). Acute white matter differences in the fornix following mild traumatic brain injury using diffusion tensor imaging. J. Neuroimaging, 23, 224–227.
LomoT. (1971). Potentiation of monosynaptic EPSPs in the perforant path-dentate granule cell synapse. Exp. Brain. Res., 12, 46–63.
74.
ZuckerR.S. (1989). Short-term synaptic plasticity. Ann. Rev. Neurosci., 12, 13–31.
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