Reversal of neuromotor and cognitive dysfunction in an enriched environment combined with multimodal early onset stimulation after traumatic brain injury in rats

Journal of Neurotrauma

Volumn 22, Issue 7, 2005, Pages 772-782

  Maegele, Marc ^a,b   Lippert Gruener, Marcela ^c   Ester Bode, Thorsten ^a,d   Sauerland, Stefan ^a   Schäfer, Ute ^a   Molcany, Marek ^a   Lefering, Rolf ^a   Bouillon, Bertil ^b   Neiss, Wolfram F ^e   Angelov, Doychin N ^e   Klug, Norfried ^c   McIntosh, Tracy K ^f   Neugebauer, Edmund A M ^a  

^a UNIVERSITY OF COLOGNE   (Germany)

^b UNIVERSITY OF WITTEN HERDECKE   (Germany)

^c UNIVERSITY HOSPITAL OF COLOGNE   (Germany)

^d Klinikum Koln Merheim   (Germany)

^e UNIVERSITY OF COLOGNE   (Germany)

^f UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

Cognitive; Enriched environment; Neuromotor; Rat; Recovery; Stimulation; Traumatic brain injury

Indexed keywords

ANIMAL EXPERIMENT; ANIMAL HOUSING; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; AUDITORY STIMULATION; BARNES CIRCULAR MAZE; BRAIN INJURY; COGNITION; COGNITIVE DEFECT; CONTROLLED STUDY; CONVALESCENCE; ENVIRONMENTAL ENRICHMENT; MALE; MAZE TEST; MOTOR DYSFUNCTION; MOTOR SYSTEM; MULTIMODAL EARLY ONSET STIMULATION; NEUROLOGIC EXAMINATION; NONHUMAN; OLFACTORY SYSTEM; RAT; STIMULATION; VISUAL STIMULATION;

ACOUSTIC STIMULATION; ANIMALS; BRAIN INJURIES; COGNITION DISORDERS; DISEASE MODELS, ANIMAL; ENVIRONMENT DESIGN; MALE; MAZE LEARNING; MOVEMENT DISORDERS; ODORS; PHOTIC STIMULATION; PHYSICAL CONDITIONING, ANIMAL; PHYSICAL STIMULATION; PHYSICAL THERAPY MODALITIES; RATS; RATS, SPRAGUE-DAWLEY; RECOVERY OF FUNCTION; TIME FACTORS; TREATMENT OUTCOME;

EID: 22244465511     PISSN: 08977151     EISSN: None     Source Type: Journal    
DOI: 10.1089/neu.2005.22.772     Document Type: Article

References (91)

1. ADEKOYA, N., THURMAN, D.J., WHITE, D.D., and WEBB, K.W. (2002). Surveillance for traumatic brain injury deaths-United States, 1989-1998. MMWR Surveill. Summ. 51, 1-14.
2. ALESSANDRI, B., RICE, A.C., LEVASSEUR, J., DEFORD, M., HAMM, R.J., and BULLOCK, M.R. (2002). Cyclosporin A improves brain tissue oxygen consumption and learning/memory performance after lateral fluid percussion injury in rats. J. Neurotrauma 19, 829-841.
3. BARNES, C.A. (1979). Memory deficits associated with senescence: a neurophysio-logical and behavioral study in the rat. J. Comp. Physiol. Psychol. 93, 74-104.
4. BELAYEV, L., ALONSO, O.F., LIU, Y., et al. (2001). Talampanel, a novel noncompetitive AMPA antagonist, is neuroprotective after traumatic brain injury in rats. J. Neurotrauma 18, 1031-1038.
5. BELAYEV, A., SAUL, I., LIU, Y., et al. (2003). Enriched environment delays the onset of hippocampal damage after global cerebral ischemia in rats. Brain Res. 964, 121-127.
6. BENTZER, P., MATTIASSON, G., McINTOSH, T.K., WIELOCH, T., and GRANDE, P.O. (2001). Infusion of prosta-cyclin following experimental brain injury in the rat reduces cortical lesion volume. J. Neurotrauma 18, 275-285.
7. BOYESON, M.G., and FEENEY, D.M. (1990). Intraventricular norepinephrine facilitates motor recovery following sensorimotor cortex injury. Pharmacol. Biochem. Behav. 35, 497-501.
8. BRAMLETT, H.M., DIETRICH, W.D., GREEN, E.J., and BUSTO, R. (1997). Chronic histopathological consequences of fluid-percussion brain injury in rats: effects of post-traumatic hypothermia. Acta Neuropathol. (Berl.) 93, 190-199.
9. BRENNER, E., MIRMIRAN, M., UYLINGS, H.B., and VAN DER GUGTEN, J. (1983). Impaired growth of the cerebral cortex of rats treated neonatally with 6-hydroxy-dopamine under different environmental conditions. Neurosci. Lett. 42, 13-17.
10. BRUNS, J., JR., and HAUSER, W.A. (2003). The epidemiology of traumatic brain injury: a review. Epilepsia 44, 2-10.
11. CONTI, A.C., RAGHUPATHI, R., TROJANOWSKI, J.Q., and McINTOSH, T.K. (1998). Experimental brain injury induces regionally distinct apoptosis during the acute and delayed post-traumatic period. J. Neurosci. 18, 5663-5672.
12. CORTEZ, S.C., McINTOSH, T.K., and NOBLE, L.J. (1989). Experimental fluid percussion brain injury: vascular disruption and neuronal and glial alterations. Brain Res. 482, 271-282.
13. CZEH, B., SERESS, L., NADEL, L., and BURES, J. (1998). Lateralized fascia dentata lesion and blockade of one hippocampus: effect on spatial memory in rats. Hippocampus 8, 647-650.
14. DIAMOND, M.C. (1967). Extensive cortical depth and neuron size increases in the cortex of environmentally enriched rats. J. Comp. Neurol. 131, 357-364.
15. DIAMOND, M.C., KRECH, D., and ROSENZWEIG, M.R. (1964). The effects of an enriched environment on the histology of the rat cerebral cortex. J. Comp. Neurol. 123, 111-120.
16. DIETRICH, W.D., ALONSO, O., BUSTO, R., and GINSBERG, M.D. (1994a). Widespread metabolic depression and reduced somatosensory circuit activation following traumatic brain injury in rats. J. Neurotrauma 11, 629-640.
17. DIETRICH, W.D., ALONSO, O., BUSTO, R., GLOBUS, M.Y., and GINSBERG, M.D. (1994b). Post-traumatic brain hypothermia reduces histopathological damage following concussive brain injury in the rat. Acta Neuropathol. (Berl.) 87, 250-258.
18. DIETRICH, W.D., ALONSO, O., and HALLEY, M. (1994c). Early microvascular and neuronal consequences of traumatic brain injury: a light and electron microscopic study in rats. J. Neurotrauma 11, 289-301.
19. DIETRICH, W.D., ALONSO, O., HALLEY, M., and BUSTO, R. (1996). Delayed post-traumatic brain hyperthermia worsens outcome after fluid percussion brain injury: a light and electron microscopic study in rats. Neurosurgery 38, 533-541.
20. DIXON, C.E., LYETH, B.G., POVLISHOCK, J.T., et al. (1987). A fluid percussion model of experimental brain injury in the rat. J. Neurosurg. 67, 110-119.
21. EINON, D.F., MORGAN, M.J., and WILL, B.E. (1980). Effects of post-operative environment on recovery from dorsal hippocampal lesions in young rats: tests of spatial memory and motor transfer. Q. J. Exp. Psychol. 32, 137-148.
22. FADEN, A.I., DEMEDIUK, P., PANTER, S.S., and VINK, R. (1989). The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 244, 798-800.
23. FADEN, A.I., KNOBLACH, S.M., CERNAK, I., et al. (2003). Novel diketopiperazine enhances motor and cognitive recovery after traumatic brain injury in rats and shows neuroprotection in vitro and in vivo. J. Cereb. Blood Flow Metab. 23, 342-354.
24. FALKENBERG, T., MOHAMMED, A.K., HENRIKSSON, B., PERSSON, H., WINBLAD, B., and LINDEFORS, N. (1992). Increased expression of brain-derived neurotrophic factor mRNA in rat hippocampus is associated with improved spatial memory and enriched environment. Neurosci. Lett. 138, 153-156.
25. FERCHMIN, P.A., and ETEROVIC, V.A. (1986). Forty minutes of experience increase the weight and RNA content of cerebral cortex in periadolescent rats. Dev. Psychobiol. 19, 511-519.
26. FERCHMIN, P.A., ETEROVIC, V.A., and CAPUTTO, R. (1970). Studies of brain weight and RNA content after short periods of exposure to environmental complexity. Brain Res. 20, 49-57.
27. FINEMAN, I., GIZA, C.C., NAHED, B.V., LEE, S.M., and HOVDA, D.A. (2000). Inhibition of neocortical plasticity during development by a moderate concussive brain injury. J. Neurotrauma 17, 739-749.
28. FOX, G.B., FAN, L., LEVASSEUR, R.A., and FADEN, A.I. (1998). Effect of traumatic brain injury on mouse spatial and nonspatial learning in the Barnes circular maze. J. Neurotrauma 15, 1037-1046.
29. FUKUDA, K., TANNO, H., OKIMURA, Y., NAKAMURA, M., and YAMAURA, A. (1995). The blood-brain barrier disruption to circulating proteins in the early period after fluid percussion brain injury in rats. J. Neurotrauma 12, 315-324.
30. GALANI, R., JARRARD, L.E., WILL, B.E., and KELCHE, C. (1997). Effects of postoperative housing conditions on functional recovery in rats with lesions of the hippocampus, subiculum, or entorhinal cortex. Neurobiol. Learn. Mem. 67, 43-56.
31. GINSBERG, M.D., ZHAO, W., ALONSO, O.F., LOOR-ESTADES, J.Y., DIETRICH, W.D., and BUSTO, R. (1997). Uncoupling of local cerebral glucose metabolism and blood flow after acute fluid-percussion injury in rats. Am. J. Physiol. 272, H2859-2868.
32. GONZALEZ-LIMA, F., FERCHMIN, P.A., ETEROVIC, V.A., and GONZALEZ-LIMA, E.M. (1994). Metabolic activation of the brain of young rats after exposure to environmental complexity. Dev. Psychobiol. 27, 343-351.
33. GREENOUGH, W.T., ALCANTARA, A., HAWRYLAK, N., et al. (1992). Determinates of brain readiness for action: experience shapes memory more than neuronal form. Brain Dys. 5, 129-149.
34. HAMM, R.J., O'DELL, D.M., PIKE, B.R., and LYETH, B.G. (1993). Cognitive impairment following traumatic brain injury: the effect of pre- and post-injury administration of scopolamine and MK-801. Brain Res. Cogn. Brain Res. 1, 223-226.
35. HAMM, R.J., TEMPLE, M.D., O'DELL, D.M., PIKE, B.R., and LYETH, B.G. (1996). Exposure to environmental complexity promotes recovery of cognitive function after traumatic brain injury. J. Neurotrauma 13, 41-47.
36. HAYES, R.L., JENKINS, L.W., LYETH, B.G., et al. (1988). Pretreatment with phencyclidine, an N-methyl-D-aspartate antagonist, attenuates long-term behavioral deficits in the rat produced by traumatic brain injury. J. Neurotrauma 5, 259-274.
37. HELD, J.M., GORDON, J., and GENTILE, A.M. (1985). Environmental influences on locomotor recovery following cortical lesions in rats. Behav. Neurosci. 99, 678-690.
38. HICKS, R., SOARES, H., SMITH, D., and McINTOSH, T. (1996). Temporal and spatial characterization of neuronal injury following lateral fluid-percussion brain injury in the rat. Acta Neuropathol. (Berl.) 91, 236-246.
39. HICKS, R.R., ZHANG, L., ATKINSON, A., STEVENON, M., VENERACION, M., and SEROOGY, K.B. (2002a). Environmental enrichment attenuates cognitive deficits, but does not alter neurotrophin gene expression in the hippocampus following lateral fluid percussion brain injury. Neuroscience 112, 631-637.
40. HICKS, R.R., KEELING, K.L., YANG, M.Y., SMITH, S.A., SIMONS, A.M., and KOTWAL, G.J. (2002b). Vaccinia virus complement control protein enhances functional recovery after traumatic brain injury. J. Neurotrauma 19, 705-714.
41. HILL, S.J., BARBARESE, E., and McINTOSH, T.K. (1996). Regional heterogeneity in the response of astrocytes following traumatic brain injury in the adult rat. J. Neuropathol. Exp. Neurol. 55, 1221-1229.
42. HOVDA, D.A., YOSHINO, A., KAWAMATA, T., KATAYAMA, Y., and BECKER, D.P. (1991). Diffuse prolonged depression of cerebral oxidative metabolism following concussive brain injury in the rat: a cytochrome oxidase histochemistry study. Brain Res. 567, 1-10.
43. ICKES, B.R., PHAM, T.M., SANDERS, L.A., ALBECK, D.S., MOHAMMED, A.H., and GRANHOLM, A.C. (2000). Long-term environmental enrichment leads to regional increases in neurotrophin levels in rat brain. Exp. Neurol. 164, 45-52.
44. INGLIS, F.M., and FIBIGER, H.C. (1995). Increases in hippocampal and frontal cortical acetylcholine release associated with presentation of sensory stimuli. Neuroscience 66, 81-86.
45. IP, E.Y., GIZA, C.C., GRIESBACH, G.S., and HOVDA, D.A. (2002). Effects of enriched environment and fluid percussion injury on dendritic arborization within the cerebral cortex of the developing rat. J. Neurotrauma 19, 573-585.
46. KEMPERMANN, G., KUHN, H.G., and GAGE, F.H. (1997). More hippocampal neurons in adult mice living in an enriched environment. Nature 386, 493-495.
47. KNOBLACH, S.M., and FADEN, A.I. (2002). Administration of either anti-intercellular adhesion molecule-1 or a nonspecific control antibody improves recovery after traumatic brain injury in the rat. J. Neurotrauma 19, 1039-1050.
48. KRECH, D., ROSENZWEIG, M.R., and BENNETT, E.L. (1960). Effects of environmental complexity and training on brain chemistry. J. Comp. Physiol. Psychol. 53, 509-519.
49. LAPLACA, M.C., ZHANG, J., RAGHUPATHI, R., et al. (2001). Pharmacologic inhibition of poly(ADP-ribose) polymerase is neuroprotective following traumatic brain injury in rats. J. Neurotrauma 18, 369-376.
50. LAURER, H.L., LENZLINGER, P.M., and McINTOSH, T.K. (2000). Models of traumatic brain injury. Eur. J. Trauma 26, 95-100.
51. LEVIN, H.S., GOLDSTEIN, F.C., HIGH, W.M., JR., and EISENBERG, H.M. (1988). Disproportionately severe memory deficit in relation to normal intellectual functioning after closed head injury. J. Neurol. Neurosurg. Psychiatry 51, 1294-1301.
52. LILJEQUIST, R., HENRIKSSON, B.G., LATIF, N., PHAM, T., WINBLAD, B., and MOHAMMED, A.H. (1993). Subchronic MK-801 treatment to juvenile rats attenuates environmental effects on adult spatial learning. Behav. Brain Res. 56, 107-114.
53. LIPPERT-GRÜNER, M., and TERHAAG, D. (2000). Multimodal early onset stimulation (MEOS) in rehabilitation after brain injury. Brain Inj. 14, 585-594.
54. LIPPERT-GRÜNER, M., WEDEKIND, C., ERNESTUS, R.I., and KLUG, N. (2002). Early rehabilitative concepts in therapy of the comatose brain injured patients. Acta Neurochir. (Wien) Suppl. 79, 21-23.
55. LIPPERT-GRÜNER, M., WEDEKIND, C., and KLUG, N. (2003). Outcome of prolonged coma following severe traumatic brain injury. Brain Inj. 17, 49-54.
56. LYETH, B.G., JENKINS, L.W., HAMM, R.J., et al. (1990). Prolonged memory impairment in the absence of hippocampal cell death following traumatic brain injury in the rat. Brain Res. 526, 249-258.
57. LYETH, B.G., JIANG, J.Y., DELAHUNTY, T.M., PHILLIPS, L.L., and HAMM, R.J. (1994). Muscarinic cholinergic receptor binding in rat brain following traumatic brain injury. Brain Res. 640, 240-245.
58. MAEGELE, M., ESTER-BODE, T., RIESS, P., et al. (2002). Exposure to complex enriched environment combined with multi-modal stimulation promotes recovery of cognitive function after traumatic brain injury in rats. Langenbecks Arch. Surg. 387, 266 (abst).
59. MARKLUND, N., CLAUSEN, F., McINTOSH, T.K., and HILLERED, L. (2001). Free radical scavenger posttreatment improves functional and morphological outcome after fluid percussion injury in the rat. J. Neurotrauma 18, 821-832.
60. MATTSSON, B., SORENSEN, J.C., ZIMMER, J., and JOHANSSON, B.B. (1997). Neural grafting to experimental neocortical infarcts improves behavioral outcome and reduces thalamic atrophy in rats housed in enriched but not in standard environments. Stroke 28, 1225-1232.
61. MCINTOSH, T.K., VINK, R., NOBLE, L., et al. (1989a). Traumatic brain injury in the rat: characterization of a lateral fluid- percussion model. Neuroscience 28, 233-244.
62. McINTOSH, T.K., VINK, R., SOARES, H., HAYES, R., and SIMON, R. (1989b). Effects of the N-methyl-D-aspartate receptor blocker MK-801 on neurologic function after experimental brain injury. J. Neurotrauma 6, 247-259.
63. MOHAMMED, A.K., JONSSON, G., and ARCHER, T. (1986). Selective lesioning of forebrain noradrenaline neurons at birth abolishes the improved maze learning performance induced by rearing in complex environment. Brain Res. 398, 6-10.
64. NILSSON, M., PERFILIEVA, E., JOHANSSON, U., ORWAR, O., and ERIKSSON, P.S. (1999). Enriched environment increases neurogenesis in the adult rat dentate gyrus and improves spatial memory. J. Neurobiol. 39, 569-578.
65. ODDY, M., COUGHLAN, T., TYERMAN, A., and JENKINS, D. (1985). Social adjustment after closed head injury: a further follow-up seven years after injury. J. Neurol. Neurosurg. Psychiatry 48, 564-568.
66. OKIYAMA, K., SMITH, D.H., THOMAS, M.J., and McINTOSH, T.K. (1992). Evaluation of a novel calcium channel blocker, (S)-emopamil, on regional cerebral edema and neurobehavioral function after experimental brain injury. J. Neurosurg. 77, 607-615.
67. PASSINEAU, M.J., GREEN, E.J., and DIETRICH, W.D. (2001). Therapeutic effects of environmental enrichment on cognitive function and tissue integrity following severe traumatic brain injury in rats. Exp. Neurol. 168, 373-384.
68. PAYLOR, R., MORRISON, S.K., RUDY, J.W., WALTRIP, L.T., and WEHNER, J.M. (1992). Brief exposure to an enriched environment improves performance on the Morris water task and increases hippocampal cytosolic protein kinase C activity in young rats. Behav. Brain Res. 52, 49-59.
69. PHILIPS, M.F., MATTIASSON, G., WIELOCH, T., et al. (2001). Neuroprotective and behavioral efficacy of nerve growth factor-transfected hippocampal progenitor cell transplants after experimental traumatic brain injury. J. Neurosurg. 94, 765-774.
70. PIERCE, J.E., TROJANOWSKI, J.Q., GRAHAM, D.I., SMITH, D.H., and McINTOSH, T.K. (1996). Immunohistochemical characterization of alterations in the distribution of amyloid precursor proteins and beta-amyloid peptide after experimental brain injury in the rat. J. Neurosci. 16, 1083-1090.
71. RICE, A.C., ZSOLDOS, R., CHEN, T., et al. (2002). Lactate administration attenuates cognitive deficits following traumatic brain injury. Brain Res. 928, 156-159.
72. ROSENZWEIG, M.R. (1966). Environmental complexity, cerebral change, and behavior. Am. Psychol. 21, 321-332.
73. ROSENZWEIG, M.R., and BENNETT, E.L. (1969). Effects of differential environments on brain weights and enzyme activities in gerbils, rats, and mice. Dev. Psychobiol. 2, 87-95.
74. ROSENZWEIG, M.R., KRECH, D., BENNETT, E.L., and DIAMOND, M.C. (1962). Effects of environmental complexity and training on brain chemistry and anatomy: a replication and extension. J. Comp. Physiol. Psychol. 55, 429-437.
75. SAATMAN, K.E., BAREYRE, F.M., GRADY, M.S., and McINTOSH, T.K. (2001). Acute cytoskeletal alterations and cell death induced by experimental brain injury are attenuated by magnesium treatment and exacerbated by magnesium deficiency. J. Neuropathol. Exp. Neurol. 60, 183-194.
76. SCHMIDT, R.H., and GRADY, M.S. (1993). Regional patterns of blood-brain barrier breakdown following central and lateral fluid percussion injury in rodents. J. Neurotrauma 10, 415-430.
77. SINSON, G., VODDI, M., and McINTOSH, T.K. (1995). Nerve growth factor administration attenuates cognitive but not neurobehavioral motor dysfunction or hippocampal cell loss following fluid-percussion brain injury in rats. J. Neurochem. 65, 2209-2216.
78. SMITH, D.H., OKIYAMA, K., THOMAS, M.J., CLAUSSEN, B., and McINTOSH, T.K. (1991). Evaluation of memory dysfunction following experimental brain injury using the Morris water maze. J. Neurotrauma 8, 259-269.
79. SOARES, H.D., HICKS, R.R., SMITH, D., and McINTOSH, T.K. (1995). Inflammatory leukocytic recruitment and diffuse neuronal degeneration are separate pathological processes resulting from traumatic brain injury. J. Neurosci. 15, 8223-8233.
80. SOARES, H.D., THOMAS, M., CLOHERTY, K., and McINTOSH, T.K. (1992). Development of prolonged focal cerebral edema and regional cation changes following experimental brain injury in the rat. J. Neurochem. 58, 1845-1852.
81. SOSIN, D.M., SNIEZEK, J.E., and THURMAN, D.J. (1996). Incidence of mild and moderate brain injury in the United States, 1991. Brain Inj. 10, 47-54.
82. SULLIVAN, H.G., MARTINEZ, J., BECKER, D.P., MILLER, J.D., GRIFFITH, R., and WIST, A.O. (1976). Fluid-percussion model of mechanical brain injury in the cat. J. Neurosurg. 45, 521-534.
83. TEES, R.C., BUHRMANN, K., and HANLEY, J. (1990). The effect of early experience on water maze spatial learning and memory in rats. Dev. Psychobiol. 23, 427-439.
84. THURMAN, D.J., ALVERSON, C., DUNN, K.A., GUER-RERO, J., and SNIEZEK, J.E. (1999). Traumatic brain injury in the United States: a public health perspective. J. Head Trauma Rehabil. 14, 602-615.
85. TORASDOTTER, M., METSIS, M., HENRIKSSON, B.G., WINBLAD, B., and MOHAMMED, A.H. (1998). Environmental enrichment results in higher levels of nerve growth factor mRNA in the rat visual cortex and hippocampus. Behav. Brain Res. 93, 83-90.
86. VAN PRAAG, H., KEMPERMANN, G., and GAGE, F.H. (2000). Neural consequences of environmental enrichment. Nat. Rev. Neurosci. 1, 191-198.
87. WAHL, F., GROSJEAN-PIOT, O., BAREYRE, F., UZAN, A., and STUTZMANN, J.M. (2000). Enoxaparin reduces brain edema, cerebral lesions, and improves motor and cognitive impairments induced by a traumatic brain injury in rats. J. Neurotrauma 17, 1055-1065.
88. WHISHAW, I.Q., ZABOROWSKI, J.A., and KOLB, B. (1984). Postsurgical enrichment aids adult hemidecorticate rats on a spatial navigation task. Behav. Neural. Biol. 42, 183-190.
89. WILL, B.E., ROSENZWEIG, M.R., BENNETT, E.L., HEBERT, M., and MORIMOTO, H. (1977). Relatively brief environmental enrichment aids recovery of learning capacity and alters brain measures after postweaning brain lesions in rats. J. Comp. Physiol. Psychol. 91, 33-50.
90. YOSHINO, A., HOVDA, D.A., KAWAMATA, T., KATAYAMA, Y., and BECKER, D.P. (1991). Dynamic changes in local cerebral glucose utilization following cerebral conclusion in rats: evidence of a hyper- and subsequent hypometabolic state. Brain Res. 561, 106-119.
91. YOUNG, D., LAWLOR, P.A., LEONE, P., DRAGUNOW, M., and DURING, M.J. (1999). Environmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective. Nat. Med. 5, 448-453.