Skip to main content

Alpha-Linolenic Acid Treatment Reduces the Contusion and Prevents the Development of Anxiety-Like Behavior Induced by a Mild Traumatic Brain Injury in Rats

Abstract

Approximately, 1.7 million Americans suffer a TBI annually and TBI is a major cause of death and disability. The majority of the TBI cases are of the mild type and while most patients recover completely from mild TBI (mTBI) about 10% result in persistent symptoms and some result in lifelong disability. Anxiety disorders are the second most common diagnosis post-TBI. Of note, TBI-induced anxiety disorders are difficult to treat and remain a chronic condition suggesting that new therapies are needed. Previous work from our laboratory demonstrated that a mild TBI induced an anxiety-like phenotype, a key feature of the human condition, associated with loss of GABAergic interneurons and hyperexcitability in the basolateral amygdala (BLA) in rodents 7 and 30 days after a controlled cortical impact (CCI) injury. We now confirm that animals display significantly increased anxiety-like behavior 30 days after CCI. The anxiety-like behavior was associated with a significant loss of GABAergic interneurons and significant reductions in the frequency and amplitude of spontaneous and miniature GABAA-receptor-mediated inhibitory postsynaptic currents (IPSCs) in the BLA. Significantly, subchronic treatment with alpha-linolenic acid (ALA) after CCI prevents the development of anxiety-like behavior, the loss of GABAergic interneurons, hyperexcitability in the BLA and reduces the impact injury. Taken together, administration of ALA after CCI is a potent therapy against the neuropathology and pathophysiological effects of mTBI in the BLA.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. 1.

    Faul M, Xu L, Wald MM, Coronado V, Dellinger AM (2010) Traumatic brain injury in the United States: national estimates of prevalence and incidence, 2002-2006. Injury Prev 16:A268. doi:https://doi.org/10.1136/ip.2010.029215.951

  2. 2.

    Ma VY, Chan L, Carruthers KJ (2014) The incidence, prevalence, costs and impact on disability of common conditions requiring rehabilitation in the US: stroke, spinal cord injury, traumatic brain injury, multiple sclerosis, osteoarthritis, rheumatoid arthritis, limb loss and back pain. Arch Phys Med Rehabil 95:986–995

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Bigler ED, Maxwell WL (2012) Neuropathology of mild traumatic brain injury: relationship to neuroimaging findings. Brain Imaging Behav 6:108–136

    Article  PubMed  Google Scholar 

  4. 4.

    Wagner AK, Postal BA, Darrah SD, Chen X, Ljam AS (2007) Deficits in novelty exploration after controlled cortical impact. J Neurotrauma 24:1308–1320

    Article  PubMed  Google Scholar 

  5. 5.

    Sosin DM, Sniezek JE, Thurman DJ (1996) Incidence of mild and moderate brain injury in the United States, 1991. Brain Inj 10:47–54

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Kelly JP, Rosenberg JH (1997) Diagnosis and management of concussion in sports. Neurology 48:575–580

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    McAllister TW, Flashman LA, McDonald BC, Saykin AJ (2006) Mechanisms of working memory dysfunction after mild and moderate TBI: Evidence from functional MRI and neurogenetics. J Neurotrauma 23:1450–1467

    Article  PubMed  Google Scholar 

  8. 8.

    Bay EH, Liberzon I (2009) Early stress response: a vulnerability framework for functional impairment following mild traumatic brain injury. Res Theory Nurs Pract 23:42–61

    Article  PubMed  Google Scholar 

  9. 9.

    Kennedy JE, Jaffee MS, Leskin GA, Stokes JW, Leal FO, Fitzpatrick PJ (2007) Posttraumatic stress disorder and posttraumatic stress disorder-like symptoms and mild traumatic brain injury. J Rehabil Res Dev 44:895–920

    Article  PubMed  Google Scholar 

  10. 10.

    Lewine JD, Davis JT, Bigler ED, Thoma R, Hill D, Funke M, Sloan JH, Hall S et al (2007) Objective documentation of traumatic brain injury subsequent to mild head trauma: multimodal brain imaging with MEG, SPECT, and MRI. J Head Trauma Rehabil 22:141–155

    Article  PubMed  Google Scholar 

  11. 11.

    Koponen S, Taiminen T, Portin R, Himanen L, Isoniemi H, Heinonen H, Hinkka S, Tenovuo O (2002) Axis I and II psychiatric disorders after traumatic brain injury: a 30-year follow-up study. Am J Psychiatry 159:1315–1321

    Article  PubMed  Google Scholar 

  12. 12.

    Hibbard HR, Uysal S, Kelpler K, Bogdany J, Silver J (1998) Axis I psychopathology in individuals with traumatic brain injury. J Head Trauma Rehabil 13:24–39

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Fann JR, Katon WJ, Uomoto JM, Esselman PC (1995) Psychiatric disorders and functional disability in outpatients with traumatic brain injuries. Am J Psychiatry 152:1493–1499

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Zaninotto AL, Vicentini JE, Fregni F, Rodrigues PA, Botelho C, de Lucia MCS, Paiva WS (2016) Updates and current perspectives of psychiatric assessments after traumatic brain injury: a systematic review. Front Psychiatry 7:95. doi:https://doi.org/10.3389/fpsyt.2016.00095

  15. 15.

    Hoge CW, McGurk D, Thomas JL, Cox AL, Engel CC, Castro CA (2008) Mild traumatic brain injury in U.S. soldiers returning from Iraq. N Engl J Med 358:453–463

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Epstein RS, Ursano RJ (1994) Anxiety disorders. In: Silver JM, Yudofsky SC, Hales RE (eds) Neuropsychiatry of traumatic brain injury. American Psychiatric Press, Washington, D.C., pp. 285–311

    Google Scholar 

  17. 17.

    Hiott DW, Labbate L (2002) Anxiety disorders associated with traumatic brain injuries. NeuroRehabilitation 17:345–355

    PubMed  Google Scholar 

  18. 18.

    Whelan-Goodison R, Ponsford J, Johnston L, Grant F (2009) Psychiatric disorders following traumatic brain injury: Their nature and frequency. J Head Trauma Rehabil 24:324–332

    Article  Google Scholar 

  19. 19.

    Bryant RA (2008) Disentangling mild traumatic brain injury and stress reactions. N Engl J Med 358:525–527

    Article  PubMed  Google Scholar 

  20. 20.

    Holzschneider K, Mulert C (2011) Neurimaging in anxiety disorders. Dialogues Clin Neurosci 13:453–461

    PubMed  PubMed Central  Google Scholar 

  21. 21.

    Matthews SC, Strigo IA, Simmons AN, O’Connell RM, Reinhardt LE, Moseley SA (2011) A multimodal imaging study in U.S. veterans of operations Iraqi and enduring freedom with and without major depression after blast-related concussion. Neuroimage 54(Suppl 1):S69–S75. doi:https://doi.org/10.1016/j.neuroimage.2010.04.269

  22. 22.

    Kris-Etherton PM, Taylor DS, Yu-Poth S, Huth P, Moriarty K, Fishell V, Hargrove RL, Zhao G et al (2000) Polyunsaturated fatty acids in the food chain in the United States. Am J Clin Nutr 71(1 Suppl):179S–188S

    CAS  PubMed  Google Scholar 

  23. 23.

    Simopoulos AP, Leaf A, Salem N Jr (1999) Essentiality of and recommended dietary intakes for omega-6 and omega-3 fatty acids. Ann Nutr Metab 43:127–130

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Owren PA, Hellem AJ, Odegaard A (1964) Linolenic acid for the prevention of thrombosis and myocardial infarction. Lancet 2(7367):975–978

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Holman RG, Johnson SB, Hatch TF (1982) A case of human linolenic acid deficiency involving neurological abnormalities. Am J Clin Nutr 35:617–623

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Sanders TAB, Roshanai F (1983) The influence of different types of omega-3 polyunsaturated fatty acids on blood lipids and platelet function in healthy volunteers. Clin Sci 64:91–99

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Singer P, Berger I, Wirth M (1986) Slow desaturation and elongation of linoleic and alpha-linolenic acid as a rationale of eicosapentaenoic acid-rich diet to lower blood pressure and serum lipids in normal hypertensive patients and hyperlipidemic subjects. Prostaglandins Leukot Med 24:173–193

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Singer P, Jaeger W, Voigt S (1984) Defective desaturation and elongation on n-6 and n-3 fatty acids in hypertensive patients. Prostaglandins Leukot Med 15:159–165

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Adam O, Wolfram G, Zollner N (1986) Effect of alpha-linolenic acid in the human diet on linoleic acid metabolism and prostaglandin metabolism. J Lipid Res 27:421–426

    CAS  PubMed  Google Scholar 

  30. 30.

    Cunnane SC, Ganguli S, Menard C, Liede A, Hamadeh MJ, Chen Z-Y, Wolever TMS, Jenkins DJA (1993) High α-linolenic acid flaxseed (Linum usitatissimum): some nutritional properties in humans. Br J Nutr 69:443–453

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Pawlosky RJ, Hibbeln JR, Novotny JA, Salem N Jr (2001) Physiological compartmental analysis of α-linolenic acid metabolism in adult humans. J Lipid Res 42:1257–1265

    CAS  PubMed  Google Scholar 

  32. 32.

    Anding RH, Hwang DH (1986) Effects of dietary linolenate on the fatty acid composition of brain lipids in rats. Lipids 21(11):697–701

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Lin YH, Salem N Jr (2007) Whole body distribution of deuterated linoleic and α-linolenic acids and their metabolites in the rat. J Lipid Res 48:2709–2724

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Lauritzen I, Blondeau N, Heurteaux C, Widmann C, Romey G, Lazdunski M (2000) Polyunsaturated fatty acids are potent neuroprotectors. EMBO J 19:1784–1793

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Blondeau N, Widmann C, Lazdunski M, Heurteaux C (2001) Activation of the nuclear factor-kappaB is a key event in brain tolerance. J Neurosci 21:4668–4677

    CAS  PubMed  Google Scholar 

  36. 36.

    Marini AM, Jiang X, Wu X, Pan H, Guo Z, Mattson MP, Blondeau N, Novelli A et al (2007) Preconditioning and neurotrophins: a model for brain adaptation to seizures, ischemia and other stressful stimuli. Amino Acids 32:299–304

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Pan H, Hu XZ, Jacobowitz DM, Chen C, McDonough J, Van Shura K, Lyman M, Marini AM (2012) Alpha-linolenic acid is a potent neuroprotective agent against soman-induced neuropathology. Neurotoxicology 33:1219–1229

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Schmitz ML, Baeuerle PA (1991) The p65 subunit is responsible for the strong transcription activating potential of NF-kappa B. EMBO J 10:3805–3817

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Lipsky RH, Xu K, Zhu D, Kelly C, Terhakopian A, Novelli A, Marini AM (2001) Nuclear factor kappaB is a critical determinant in N-methyl-D-aspartate receptor-mediated neuroprotection. J Neurochem 78:254–264

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Jiang X, Tian F, Du Y, Copeland NG, Jenkins NA, Tessarollo L, Wu X, Pan H et al (2008) BHLHB2 controls Bdnf promoter 4 activity and neuronal excitability. J Neurosci 28:1118–1130

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Blondeau N (2016) The nutraceutical potential of omega-3 alpha-linolenic acid in reducing the consequences of stroke. Biochimie 120:49–55

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Sala-Vila A, Guasch-Ferré M, Hu FB, Sánchez-Tainta A et al (2016) Dietary α-linolenic acid, marine ω-3 fatty acids, and mortality in a population with high fish consumption: findings from the PREvención con DIeta MEDiterránea (PREDIMED) study. J Am Heart Assoc 5(1):e002543. doi:https://doi.org/10.1161/JAHA.115.002543

  43. 43.

    Blondeau N, Lipsky RH, Bourourou M, Duncan MW, Gorelick PB, Marini AM (2015) Alpha-linolenic acid: an omega-3 fatty acid with neuroprotective properties-ready for use in the stroke clinic? Biomed Res Int 2015:519830. doi:https://doi.org/10.1155/2015/519830

  44. 44.

    Virtanen JK, Siscovick DS, Lemaitre RN, Longstreth WT, Spiegelman D, Rimm EB, King IB, Mozaffarian D (2013) Circulating omega-3 polyunsaturated fatty acids and subclinical brain abnormalities on MRI in older adults: the cardiovascular health study. J Am Heart Assoc 2(5):e000305. doi:https://doi.org/10.1161/JAHA.113.000305

  45. 45.

    de Goede J, Verschuren WM, Boer JM, Kromhout D, Geleijnse JM (2011) Alpha-linolenic acid intake and 10-year incidence of coronary heart disease and stroke in 20,000 middle-aged men and women in the Netherlands. PLoS One 6(3):e17967. doi:https://doi.org/10.1371/journal.pone.0017967

  46. 46.

    Lang-Lazdunski L, Blondeau N, Jarretou G, Lazdunski M, Heurteaux C (2003) Linolenic acid prevents neuronal cell death and paraplegia after transient spinal cord ischemia in rats. J Vasc Surg 38:564–575

    Article  PubMed  Google Scholar 

  47. 47.

    Heurteaux C, Laigle C, Blondeau N, Jarretou G, Lazdunski M (2006) Alpha-linolenic acid and riluzole treatment confer cerebral protection and improve survival after focal brain ischemia. Neuroscience 137:241–251

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Blondeau N, Nguemeni C, Debruyne DN, Piens M, Wu X, Pan H, Hu X, Gandin C et al (2009) Subchronic alpha-linolenic acid treatment enhances brain plasticity and exerts an antidepressant effect: a versatile potential therapy for stroke. Neuropsychopharmacology 34:2548–2559

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Nguemeni C, Delplanque B, Rovère C, Simon-Rousseau N, Gandin C, Agnani G, Nahon JL, Heurteaux C et al (2010) Dietary supplementation of alpha-linolenic acid in an enriched rapeseed oil diet protects from stroke. Pharmacol Res 61:226–233

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Bourourou M, Heurteaux C, Blondeau N (2016) Alpha-linolenic acid given as enteral or parenteral nutritional intervention against sensorimotor and cognitive deficits in a mouse model of ischemic stroke. Neuropharmacology 108:60–72

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Piermartiri TC, Pan H, Chen J, McDonough J, Grunberg N, Apland JP, Marini AM (2015) Alpha-linolenic acid-induced increase in neurogenesis is a key factor in the improvement in the passive avoidance task after Soman exposure. NeuroMolecular Med 17:251–269

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Pan H, Piermartiri TC, Chen J, McDonough J, Oppel C, Driwech W, Winter K, McFarland E et al (2015) Repeated systemic administration of the nutraceutical alpha-linolenic acid exerts neuroprotective efficacy, an antidepressant effect and improves cognitive performance when given after soman exposure. Neurotoxicology 51:38–50

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Piermartiri T, Pan H, Figueiredo TH, Marini AM (2015) α-Linolenic acid, a nutraceutical with pleiotropic properties that targets endogenous neuroprotective pathways to protect against organophosphate nerve agent-induced neuropathology. Molecules 20(11):20355–20380. doi:https://doi.org/10.3390/molecules201119698

  54. 54.

    Desai A, Park T, Barnes J, Kevala K, Chen H, Kim HY (2016) Reduced acute neuroinflammation and improved functional recovery after traumatic brain injury by α-linolenic acid supplementation in mice. J Neuroinflammation 13:253

    Article  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Almeida-Suhett CP, Prager EM, Pidoplichko V, Figueiredo TH, Marini AM, Li Z, Eiden LE, Braga MF (2014) Reduced GABAergic inhibition in the basolateral amygdala and the development of anxiety-like behaviors after mild traumatic brain injury. PLoS One. doi:https://doi.org/10.1371/journal.pone.0102627

  56. 56.

    Prager EM, Bergstrom HC, Grunberg NE, Johnson LR (2011) The importance of reporting housing and husbandry in rat research. Front Behav Neurosci 5:38

    Article  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Lighthall JW (1988) Controlled cortical impact: A new experimental brain injury model. J Neurotrauma 5:1–15

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Almeida-Suhett CP, Li Z, Marini AM, Braga MF, Eiden LE (2014) Temporal course of changes in gene expression suggests a cytokine-related mechanism for long-term hippocampal alteration after controlled cortical impact. J Neurotrauma 31:683–690

    Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Faraday MM, Elliott BM, Grunberg NE (2001) Adult vs. adolescent rats differ in biobehavioral responses to chronic nicotine administration. Pharmacol Biochem Behav 70:475–489

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Aroniadou-Anderjaska V, Pidoplichko VI, Figueiredo TH, Almeida-Suhett CP, Prager EM, Braga MF (2012) Presynaptic facilitation of glutamate release in the basolateral amygdala: a mechanism for the anxiogenic and seizurogenic function of GluK1 receptors. Neuroscience 221:157–169

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Figueiredo TH, Aroniadou-Anderjaska V, Qashu F, Apland JP, Pidoplichko V, Stevens D, Ferrara TM, Braga MF (2011) Neuroprotective efficacy of caramiphen against soman and mechanisms of its action. Br J Pharmacol 164:1495–1505

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Figueiredo TH, Qashu F, Apland JP, Aroniadou-Anderjaska V, Souza AP, Braga MF (2011) The GluK1 (GluR5) Kainate/{alpha}-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist LY293558 reduces soman-induced seizures and neuropathology. J Pharmacol Exp Ther 336:303–312

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Gundersen HJ, Bendtsen TF, Korbo L, Marcussen N, Moller A, Nielsen K, Nyengaard JR, Pakkenberg B et al (1988) Some new, simple and efficient stereological methods and their use in pathological research and diagnosis. APMIS 96:379–394

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Paxinos G, Watson C (2005) The rat brain in sterotaxic coordinates. Academic Press

  65. 65.

    Gundersen HJ, Jensen EB, Kieu K, Nielsen J (1999) The efficiency of systematic sampling in stereology—reconsidered. J Microsc 193:199–211

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Park K, Lee S, Kang SJ, Choi S, Shin KS (2007) Hyperpolarization-activated currents control the excitability of principal neurons in the basolateral amygdala. Biochem Biophys Res Commun 361:718–724

    CAS  Article  PubMed  Google Scholar 

  67. 67.

    Sah P, Faber ES, Lopez De Armentia M, Power J (2003) The amygdaloid complex: anatomy and physiology. Physiol Rev 83:803–834

    CAS  Article  PubMed  Google Scholar 

  68. 68.

    Andriessen TMJC, Horn J, Franschman G, van der Naalt J, Haitsma I, Jacobs B, Steyerberg EW, Vos PE (2011) Epidemiology, severity classification, and outcome of moderate and severe traumatic brain injury: a prospective multicenter study. J Neurotrauma 28:2019–2013

    Article  PubMed  Google Scholar 

  69. 69.

    Loane DJ, Stoica BA, Faden AI (2015) Neuroprotection for traumatic brain injury. Handb Clin Neurol 127:343–366

    Article  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Loane DJ, Kumar A (2016) Microglia in the TBI brain: the good, the bad and the dysregulated. Exp Neurol 275:316–327

    CAS  Article  PubMed  Google Scholar 

  71. 71.

    Pidoplichko VI, Prager EM, Aroniadou-Anderjaska V, Braga MF (2013) α-7-containing nicotinic acetylcholine receptors on interneurons of the basolateral amygdala and their role in the regulation of network excitability. J Neurophysiol 110:2358–2369

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Basiouni S, Stockel K, Fuhrmann H, Schumann J (2012) Polyunsaturated fatty acids and supplements modulate mast cell membrane microdomain composition. Cell Immunol 275:42–46

    CAS  Article  PubMed  Google Scholar 

  73. 73.

    Simons K, Toomre D (2000) Lipid rafts and signal transduction. Nat Rev Mol Cell Biol 1:31–39

    CAS  Article  PubMed  Google Scholar 

  74. 74.

    Egawa J, Pearn ML, Lemkuil BP, Patel PM, Head BP (2016) Membrane lipid rafts and neurobiology: age-related changes in membrane lipids and loss of neuronal function. J Physiol 594:4565–4579

    CAS  Article  PubMed  Google Scholar 

  75. 75.

    Mutoh T, Hamano T, Tokuda A, Kuriyama M (2000) Unglycosylated Trk protein does not co-localize with ganglioside GM1 in stable clone of PC12 cells overexpressing Trk (PCtrk cells). Glycoconj J 17:233–237

    CAS  Article  PubMed  Google Scholar 

  76. 76.

    Golub T, Wacha S, Caroni P (2004) Spatial and temporal control of signaling through lipid rafts. Curr Opin Neurobiol 14:542–550

    CAS  Article  PubMed  Google Scholar 

  77. 77.

    Besshoh S, Chen S, Brown IR, Gurd JW (2007) Developmental changes in the association of NMDA receptors with lipid rafts. J Neurosci Res 85:1876–1883

    CAS  Article  PubMed  Google Scholar 

  78. 78.

    Marini AM, Rabin SJ, Lipsky RH, Mocchetti I (1998) Activity-dependent release of brain-derived neurotrophic factor underlies the neuroprotective effect of N-methyl-D-aspartate. J Biol Chem 273:29394–29399

    CAS  Article  PubMed  Google Scholar 

  79. 79.

    Tao X, Finkbeiner S, Arnold DB, Shaywitz AJ, Greenberg ME (1998) Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron 20:709–726

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Prince DA, Gu F, Parada I (2016) Antiepileptogenic repair of excitatory and inhibitory synaptic connectivity after neocortical trauma. Prog Brain Res 226:209–227

    CAS  Article  PubMed  Google Scholar 

  81. 81.

    Ikonomidou C, Turski L (2002) Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury? Lancet Neurol 1:383–386

    CAS  Article  PubMed  Google Scholar 

  82. 82.

    Hung HC, Hsiao YH, Gean PW (2015) Sonic hedgehog signaling regulates amygdalar neurogenesis and extinction of fear memory. Eur Neuropsychopharmacol 25:1723–1732

    CAS  Article  PubMed  Google Scholar 

  83. 83.

    Jennett B (1996) Epidemiology of head injury. J Neurol Neurosurg Psychiatry 60:362–369

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Deb S, Lyons I, Koutzoukis C, Ali I, McCarthy G (1999) Rate of psychiatric illness 1 year after traumatic brain injury. Am J Psychiatry 156:374–378

    CAS  PubMed  Google Scholar 

  85. 85.

    MacMillan PJ, Hart RP, Martelli MF, Zasler ND (2002) Pre-injury status and adaptation following traumatic brain injury. Brain Inj 16:41–49

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

Research was sponsored by the US Army Research Office and the Defense Advanced Research Projects Agency (DARPA) and was accomplished under Cooperative Agreement Number W911NF-14-2-0100.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Ann M. Marini.

Ethics declarations

Disclaimer

The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the Army Research Office, DARPA, or the US Government.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Figueiredo, T.H., Harbert, C.L., Pidoplichko, V. et al. Alpha-Linolenic Acid Treatment Reduces the Contusion and Prevents the Development of Anxiety-Like Behavior Induced by a Mild Traumatic Brain Injury in Rats. Mol Neurobiol 55, 187–200 (2018). https://doi.org/10.1007/s12035-017-0732-y

Download citation

Keywords

  • Traumatic brain injury
  • Anxiety disorders
  • Controlled cortical impact
  • Rat
  • Alpha-linolenic acid