Cerebrolysin Improves Motor Abilities and Reverses the Long-Term Memory Acquisition Deficit in Rats with Hypoxic-Ischemic Encephalopathy
Main Article Content
Abstract
Background: Hypoxic-ischemic encephalopathy (HIE) is a neurological condition that leads to motor disabilities and even death in neonates. Unfortunately, few therapeutic alternatives can contribute to brain recovery after HIE damage. Cerebrolysin is a neuropeptide mixture that exerts neuroprotective and neurotrophic effects on injured brain tissue after systemic administration.
Aims: This study evaluated the short- and long-term beneficial effects of Cerebrolysin administration in a rat model of HIE.
Methods: Neonatal 7-day-old rats were subjected to hypoxia-ischemia injury and then intraperitoneally administered Cerebrolysin (10 mL/kg of body weight) once a day for 7 days, from postnatal days 8 to 14. Growth development, blood-brain barrier permeability, and neurobehavioral tests were performed.
Results: Cerebrolysin administration after hypoxic-ischemic insult minimized brain damage, edema and increased cellular viability. Furthermore, this neuroprotective effect improves some motor abnormalities and, during adulthood, reverses the long-term memory acquisition deficit caused by HIE.
Conclusion: Repeated Cerebrolysin administration can safely and effectively reduce HIE motor disabilities and reverse long-term memory acquisition deficits in neonatal rats.
Keywords:
Neuroprotection, novel object recognition, learning and memory, neonatal brain injury, Cerebrolysin
Article Details
How to Cite
BARRIENTOS-ZAVALZA, Ericka et al.
Cerebrolysin Improves Motor Abilities and Reverses the Long-Term Memory Acquisition Deficit in Rats with Hypoxic-Ischemic Encephalopathy.
Medical Research Archives, [S.l.], v. 11, n. 8, aug. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/4345>. Date accessed: 04 dec. 2024.
doi: https://doi.org/10.18103/mra.v11i8.4345.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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4. Simiyu IN, Mchaile DN, Katsongeri K, Philemon RN, Msuya SE. Prevalence, severity and early outcomes of hypoxic ischemic encephalopathy among newborns at a tertiary hospital, in northern Tanzania. doi:10.1186/s12887-017-0876-y.
5. Miguel PM, Schuch CP, Rojas JJ, et al. Neonatal Hypoxia-Ischemia Induces Attention-Deficit Hyperactivity Disorder-Like Behavior in Rats. Behav Neurosci. 2015;129(3):309-320. doi:10.1037/bne0000063.
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7. Kurinczuk JJ, White-Koning M, Badawi N. Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy. Early Hum Dev. 2010;86(6):329-338. doi:10.1016/j.earlhumdev.2010.05.010.
8. Allen KA, Brandon DH. Hypoxic Ischemic Encephalopathy: Pathophysiology and Experimental Treatments. Newborn Infant Nurs Rev. 2011;11(3):125-133. doi:10.1053/j.nainr.2011.07.004.
9. Zhang Y, Chopp M, Zhang ZG, et al. Cerebrolysin Reduces Astrogliosis and Axonal Injury and Enhances Neurogenesis in Rats After Closed Head Injury. Neurorehabil Neural Repair. 2019;33(1):15-26. doi:10.1177/1545968318809916.
10. Stepanichev M, Onufriev M, Aniol V, et al. Effects of cerebrolysin on nerve growth factor system in the aging rat brain. Restor Neurol Neurosci. 2017;35(6):571-581. doi:10.3233/RNN-170724.
11. Young KM, Bartlett PF, Coulson EJ. Neural progenitor number is regulated by nuclear factor-κB p65 and p50 subunit-dependent proliferation rather than cell survival. J Neurosci Res. 2006;83(1):39-49. doi:10.1002/jnr.20702.
12. Muresanu DF, Heiss WD, Hoemberg V, et al. Cerebrolysin and Recovery After Stroke (CARS): A randomized, placebo-controlled, double-blind, multicenter trial. Stroke. 2016;47(1):151-159. doi:10.1161/STROKEAHA.115.009416.
13. Hassanein SMA, Deifalla SM, El-Houssinie M, Mokbel SA. Safety and efficacy of cerebrolysin in infants with communication defects due to severe perinatal brain insult: A randomized controlled clinical trial. J Clin Neurol. 2016;12(1):79-84. doi:10.3988/jcn.2016.12.1.79.
14. Rice JE, Vannucci RC, Brierley JB. The influence of immaturity on hypoxic‐ischemic brain damage in the rat. Ann Neurol. 1981;9(2):131-141. doi:10.1002/ana.410090206.
15. Feather-Schussler DN, Ferguson TS. A Battery of Motor Tests in a Neonatal Mouse Model of Cerebral Palsy. J Vis Exp. 2016;(117):53569. doi:10.3791/53569.
16. Reger ML, Hovda DA, Giza CC. Ontogeny of rat recognition memory measured by the novel object recognition task. Dev Psychobiol. 2009;51(8):672-678. doi:10.1002/dev.20402.
17. Wang Y, Cheung PT, Shen GX, et al. Hypoxic-ischemic brain injury in the neonatal rat model: Relationship between lesion size at early MR imaging and irreversible infarction. Am J Neuroradiol. 2006;27(1):51-54.
18. Tai WC, Burke KA, Dominguez JF, Gundamraj L, Turman JE. Growth deficits in a postnatal day 3 rat model of hypoxic-ischemic brain injury. Behav Brain Res. 2009;202(1):40-49. doi:10.1016/j.bbr.2009.03.043.
19. Luptakova D, Baciak L, Pluhacek T, et al. Membrane depolarization and aberrant lipid distributions in the neonatal rat brain following hypoxic-ischaemic insult. Sci Rep. 2018;8(1):1-11. doi:10.1038/s41598-018-25088-2.
20. Dai C, Liu Y, Dong Z. Tanshinone i alleviates motor and cognitive impairments via suppressing oxidative stress in the neonatal rats after hypoxic-ischemic brain damage. Mol Brain. 2017;10(1):1-11. doi:10.1186/s13041-017-0332-9.
21. Chung AG, Frye JB, Zbesko JC, et al. Liquefaction of the brain following stroke shares a similar molecular and morphological profile with atherosclerosis and mediates secondary neurodegeneration in an osteopontin-dependent mechanism. eNeuro. 2018;5(5). doi:10.1523/ENEURO.0076-18.2018.
22. Zhang Y, Chopp M, Meng Y, et al. Improvement in functional recovery with administration of Cerebrolysin after experimental closed head injury: Laboratory investigation. J Neurosurg. 2013;118(6):1343-1355. doi:10.3171/2013.3.JNS122061.
23. Stokum JA, Kurland DB, Gerzanich V, Simard JM. Mechanisms of Astrocyte-Mediated Cerebral Edema. 2015:317-328. doi:10.1007/s11064-014-1374-3.
24. Dalby T, Wohl E, Dinsmore M, Unger Z, Chowdhury T. Pathophysiology of Cerebral Edema — A Comprehensive Review. 2021.
25. Taniguchi M, Yamashita T, Kumura E, et al. Induction of aquaporin-4 water channel mRNA after focal cerebral ischemia in rat. Mol Brain Res. 2000;78(1-2):131-137. doi:10.1016/S0169-328X(00)00084-X.
26. Yang C, Liu Z, Li H, Zhai F, Liu J, Bian J. Aquaporin-4 knockdown ameliorates hypoxic-ischemic cerebral edema in newborn piglets. IUBMB Life. 2015;67(3):182-190. doi:10.1002/iub.1356.
27. Yano Y, Yano H, Takahashi H, et al. Goreisan Inhibits Upregulation of Aquaporin 4 and Formation of Cerebral Edema in the Rat Model of Juvenile Hypoxic-Ischemic Encephalopathy. 2017. doi:10.1155/2017/3209219.
28. Yang Y, Zhang Y, Wang Z, et al. Attenuation of Acute Phase Injury in Rat Intracranial Hemorrhage by Cerebrolysin that Inhibits Brain Edema and Inflammatory Response. Neurochem Res. 2016;41(4):748-757. doi:10.1007/s11064-015-1745-4.
29. Neurosciences I, Collins F. Direct immunogold labeling of aquaporin-4 in square arrays of astrocyte and ependymocyte plasma membranes in rat brain and spinal cord. 1998;95(September):11981-11986.
30. Li M, Hu H, Pan S, Han M. The effect and mechanism of UCH-L1 inhibitor LDN-57444 on hypoxic / ischemic injury in neonatal rats. 2016;9(8):15561-15567.
31. Ren, JingMei; Sietsma, Dana; Qiu, Shumei; Moessler, Herbert; Finklestein SP. Cerebrolysin enhances functional recovery following focal cerebral infarction in rats. IOS Press. 2007;(1 Jan):25-31.
32. Zhang L, Chopp M, Lu M, et al. Cerebrolysin dose-dependently improves neurological outcome in rats after acute stroke: A prospective, randomized, blinded, and placebo-controlled study. Int J Stroke. 2016;11(3):347-355. doi:10.1177/1747493015625645.
33. Huerta E, De Jesús M, De La Cruz L, Ortiz-Butron F, Flores R, De Jesús Gómez-Villalobos G. Cerebrolysin Effects on Cardiac Neuropathy in Diabetic Rats. Cerebrolysin Eff Card Neuropathy Diabet Rats Pharmacolo-gy Pharm. 2017;8:215-230. doi:10.4236/pp.2017.87015.
34. Durán-Carabali LE, Sanches EF, Odorcyk FK, et al. Tissue Injury and Astrocytic Reaction, But Not Cognitive Deficits, Are Dependent on Hypoxia Duration in Very Immature Rats Undergoing Neonatal Hypoxia–Ischemia. Neurochem Res. 2019;44(11):2631-2642. doi:10.1007/s11064-019-02884-4.
35. Zhang C, Chopp M, Cui Y, et al. Cerebrolysin enhances neurogenesis in the ischemic brain and improves functional outcome after stroke. J Neurosci Res. 2010;88(15):3275-3281. doi:10.1002/jnr.22495.
36. Sakai T, Sasaki M, Kataoka-Sasaki Y, et al. Functional recovery after the systemic administration of mesenchymal stem cells in a rat model of neonatal hypoxia-ischemia. J Neurosurg Pediatr. 2018;22(5):513-522. doi:10.3171/2018.5.PEDS1845.
37. Nasiri J, Safavifar F. Effect of cerebrolysin on gross motor function of children with cerebral palsy: a clinical trial. Acta Neurol Belg. 2017;117(2):501-505. doi:10.1007/s13760-016-0743-x.
38. Hartbauer M, Hutter-Paier B, Skofitsch G, Windisch M. Antiapoptotic effects of the peptidergic drug Cerebrolysin on primary cultures of embryonic chick cortical neurons. J Neural Transm. 2001;108(4):459-473. doi:10.1007/s007020170067.
39. Sharma HS, Muresanu D, Sharma A, Zimmermann-Meinzingen S. Cerebrolysin treatment attenuates heat shock protein overexpression in the brain following heat stress. Ann N Y Acad Sci. 2010;1199(1):138-148.
doi:10.1111/j.1749-6632.2009.05330.x.
40. Rockenstein E, Desplats P, Ubhi K, et al. Neuro-peptide treatment with Cerebrolysin improves the survival of neural stem cell grafts in an APP transgenic model of Alzheimer disease. Stem Cell Res. 2015;15(1):54-67. doi:10.1016/j.scr.2015.04.008.
41. Ennaceur A, Delacour J. A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behav Brain Res. 1988. doi:10.1016/0166-4328(88)90157-X.
42. Darcet F, Mendez-David I, Tritschler L, Gardier AM, Guilloux JP, David DJ. Learning and memory impairments in a neuroendocrine mouse model of anxiety/depression. Front Behav Neurosci. 2014;8(MAY):1-13. doi:10.3389/fnbeh.2014.00136.
43. Hammond RS, Tull LE, Stackman RW. On the delay-dependent involvement of the hippocampus in object recognition memory. Neurobiol Learn Mem. 2004;82(1):26-34. doi:10.1016/j.nlm.2004.03.005.
44. Albasser MM, Davies M, Futter JE, Aggleton JP. Magnitude of the Object Recognition Deficit Associated With Perirhinal Cortex Damage in Rats: Effects of Varying the Lesion Extent and the Duration of the Sample Period. Behav Neurosci. 2009;123(1):115-124. doi:10.1037/a0013829.
45. Baxter MG. “I’ve seen it all before” Explaining age-related impairments in object recognition. Theoretical comment on Burke et al. (2010). Behav Neurosci. 2010;124(5):706-709. doi:10.1037/a0021029.
46. Ennaceur A. One-trial object recognition in rats and mice: Methodological and theoretical issues. Behav Brain Res. 2010. doi:10.1016/j.bbr.2009.12.036.
2. Zhang J, Tucker LD, Yan D, et al. Tert-butylhydroquinone Post-treatment Attenuates Neonatal Hypoxic-ischemic Brain Damage in Rats HHS Public Access. Neurochem Int. 2018;116:1-12. doi:10.1016/j.neuint.2018.03.004.
3. Domínguez-Dieppa F, Cardetti M, Rodríguez S, García-Alix A, Sola A. Hypoxic Ischemic Encephalopathy in Units Reporting to the Ibero-American Society of Neonatology Network: Prevalence and Mortality. Vol 23.; 2021.
4. Simiyu IN, Mchaile DN, Katsongeri K, Philemon RN, Msuya SE. Prevalence, severity and early outcomes of hypoxic ischemic encephalopathy among newborns at a tertiary hospital, in northern Tanzania. doi:10.1186/s12887-017-0876-y.
5. Miguel PM, Schuch CP, Rojas JJ, et al. Neonatal Hypoxia-Ischemia Induces Attention-Deficit Hyperactivity Disorder-Like Behavior in Rats. Behav Neurosci. 2015;129(3):309-320. doi:10.1037/bne0000063.
6. Schwab M, Schaller R, Bauer R, Zwiener U. Morphofunctional effects of moderate forebrain ischemia combined with short-term hypoxia in rats - Protective effects of Cerebrolysin. Exp Toxicol Pathol. 1997;49(1-2):29-37. doi:10.1016/S0940-2993(97)80053-X.
7. Kurinczuk JJ, White-Koning M, Badawi N. Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy. Early Hum Dev. 2010;86(6):329-338. doi:10.1016/j.earlhumdev.2010.05.010.
8. Allen KA, Brandon DH. Hypoxic Ischemic Encephalopathy: Pathophysiology and Experimental Treatments. Newborn Infant Nurs Rev. 2011;11(3):125-133. doi:10.1053/j.nainr.2011.07.004.
9. Zhang Y, Chopp M, Zhang ZG, et al. Cerebrolysin Reduces Astrogliosis and Axonal Injury and Enhances Neurogenesis in Rats After Closed Head Injury. Neurorehabil Neural Repair. 2019;33(1):15-26. doi:10.1177/1545968318809916.
10. Stepanichev M, Onufriev M, Aniol V, et al. Effects of cerebrolysin on nerve growth factor system in the aging rat brain. Restor Neurol Neurosci. 2017;35(6):571-581. doi:10.3233/RNN-170724.
11. Young KM, Bartlett PF, Coulson EJ. Neural progenitor number is regulated by nuclear factor-κB p65 and p50 subunit-dependent proliferation rather than cell survival. J Neurosci Res. 2006;83(1):39-49. doi:10.1002/jnr.20702.
12. Muresanu DF, Heiss WD, Hoemberg V, et al. Cerebrolysin and Recovery After Stroke (CARS): A randomized, placebo-controlled, double-blind, multicenter trial. Stroke. 2016;47(1):151-159. doi:10.1161/STROKEAHA.115.009416.
13. Hassanein SMA, Deifalla SM, El-Houssinie M, Mokbel SA. Safety and efficacy of cerebrolysin in infants with communication defects due to severe perinatal brain insult: A randomized controlled clinical trial. J Clin Neurol. 2016;12(1):79-84. doi:10.3988/jcn.2016.12.1.79.
14. Rice JE, Vannucci RC, Brierley JB. The influence of immaturity on hypoxic‐ischemic brain damage in the rat. Ann Neurol. 1981;9(2):131-141. doi:10.1002/ana.410090206.
15. Feather-Schussler DN, Ferguson TS. A Battery of Motor Tests in a Neonatal Mouse Model of Cerebral Palsy. J Vis Exp. 2016;(117):53569. doi:10.3791/53569.
16. Reger ML, Hovda DA, Giza CC. Ontogeny of rat recognition memory measured by the novel object recognition task. Dev Psychobiol. 2009;51(8):672-678. doi:10.1002/dev.20402.
17. Wang Y, Cheung PT, Shen GX, et al. Hypoxic-ischemic brain injury in the neonatal rat model: Relationship between lesion size at early MR imaging and irreversible infarction. Am J Neuroradiol. 2006;27(1):51-54.
18. Tai WC, Burke KA, Dominguez JF, Gundamraj L, Turman JE. Growth deficits in a postnatal day 3 rat model of hypoxic-ischemic brain injury. Behav Brain Res. 2009;202(1):40-49. doi:10.1016/j.bbr.2009.03.043.
19. Luptakova D, Baciak L, Pluhacek T, et al. Membrane depolarization and aberrant lipid distributions in the neonatal rat brain following hypoxic-ischaemic insult. Sci Rep. 2018;8(1):1-11. doi:10.1038/s41598-018-25088-2.
20. Dai C, Liu Y, Dong Z. Tanshinone i alleviates motor and cognitive impairments via suppressing oxidative stress in the neonatal rats after hypoxic-ischemic brain damage. Mol Brain. 2017;10(1):1-11. doi:10.1186/s13041-017-0332-9.
21. Chung AG, Frye JB, Zbesko JC, et al. Liquefaction of the brain following stroke shares a similar molecular and morphological profile with atherosclerosis and mediates secondary neurodegeneration in an osteopontin-dependent mechanism. eNeuro. 2018;5(5). doi:10.1523/ENEURO.0076-18.2018.
22. Zhang Y, Chopp M, Meng Y, et al. Improvement in functional recovery with administration of Cerebrolysin after experimental closed head injury: Laboratory investigation. J Neurosurg. 2013;118(6):1343-1355. doi:10.3171/2013.3.JNS122061.
23. Stokum JA, Kurland DB, Gerzanich V, Simard JM. Mechanisms of Astrocyte-Mediated Cerebral Edema. 2015:317-328. doi:10.1007/s11064-014-1374-3.
24. Dalby T, Wohl E, Dinsmore M, Unger Z, Chowdhury T. Pathophysiology of Cerebral Edema — A Comprehensive Review. 2021.
25. Taniguchi M, Yamashita T, Kumura E, et al. Induction of aquaporin-4 water channel mRNA after focal cerebral ischemia in rat. Mol Brain Res. 2000;78(1-2):131-137. doi:10.1016/S0169-328X(00)00084-X.
26. Yang C, Liu Z, Li H, Zhai F, Liu J, Bian J. Aquaporin-4 knockdown ameliorates hypoxic-ischemic cerebral edema in newborn piglets. IUBMB Life. 2015;67(3):182-190. doi:10.1002/iub.1356.
27. Yano Y, Yano H, Takahashi H, et al. Goreisan Inhibits Upregulation of Aquaporin 4 and Formation of Cerebral Edema in the Rat Model of Juvenile Hypoxic-Ischemic Encephalopathy. 2017. doi:10.1155/2017/3209219.
28. Yang Y, Zhang Y, Wang Z, et al. Attenuation of Acute Phase Injury in Rat Intracranial Hemorrhage by Cerebrolysin that Inhibits Brain Edema and Inflammatory Response. Neurochem Res. 2016;41(4):748-757. doi:10.1007/s11064-015-1745-4.
29. Neurosciences I, Collins F. Direct immunogold labeling of aquaporin-4 in square arrays of astrocyte and ependymocyte plasma membranes in rat brain and spinal cord. 1998;95(September):11981-11986.
30. Li M, Hu H, Pan S, Han M. The effect and mechanism of UCH-L1 inhibitor LDN-57444 on hypoxic / ischemic injury in neonatal rats. 2016;9(8):15561-15567.
31. Ren, JingMei; Sietsma, Dana; Qiu, Shumei; Moessler, Herbert; Finklestein SP. Cerebrolysin enhances functional recovery following focal cerebral infarction in rats. IOS Press. 2007;(1 Jan):25-31.
32. Zhang L, Chopp M, Lu M, et al. Cerebrolysin dose-dependently improves neurological outcome in rats after acute stroke: A prospective, randomized, blinded, and placebo-controlled study. Int J Stroke. 2016;11(3):347-355. doi:10.1177/1747493015625645.
33. Huerta E, De Jesús M, De La Cruz L, Ortiz-Butron F, Flores R, De Jesús Gómez-Villalobos G. Cerebrolysin Effects on Cardiac Neuropathy in Diabetic Rats. Cerebrolysin Eff Card Neuropathy Diabet Rats Pharmacolo-gy Pharm. 2017;8:215-230. doi:10.4236/pp.2017.87015.
34. Durán-Carabali LE, Sanches EF, Odorcyk FK, et al. Tissue Injury and Astrocytic Reaction, But Not Cognitive Deficits, Are Dependent on Hypoxia Duration in Very Immature Rats Undergoing Neonatal Hypoxia–Ischemia. Neurochem Res. 2019;44(11):2631-2642. doi:10.1007/s11064-019-02884-4.
35. Zhang C, Chopp M, Cui Y, et al. Cerebrolysin enhances neurogenesis in the ischemic brain and improves functional outcome after stroke. J Neurosci Res. 2010;88(15):3275-3281. doi:10.1002/jnr.22495.
36. Sakai T, Sasaki M, Kataoka-Sasaki Y, et al. Functional recovery after the systemic administration of mesenchymal stem cells in a rat model of neonatal hypoxia-ischemia. J Neurosurg Pediatr. 2018;22(5):513-522. doi:10.3171/2018.5.PEDS1845.
37. Nasiri J, Safavifar F. Effect of cerebrolysin on gross motor function of children with cerebral palsy: a clinical trial. Acta Neurol Belg. 2017;117(2):501-505. doi:10.1007/s13760-016-0743-x.
38. Hartbauer M, Hutter-Paier B, Skofitsch G, Windisch M. Antiapoptotic effects of the peptidergic drug Cerebrolysin on primary cultures of embryonic chick cortical neurons. J Neural Transm. 2001;108(4):459-473. doi:10.1007/s007020170067.
39. Sharma HS, Muresanu D, Sharma A, Zimmermann-Meinzingen S. Cerebrolysin treatment attenuates heat shock protein overexpression in the brain following heat stress. Ann N Y Acad Sci. 2010;1199(1):138-148.
doi:10.1111/j.1749-6632.2009.05330.x.
40. Rockenstein E, Desplats P, Ubhi K, et al. Neuro-peptide treatment with Cerebrolysin improves the survival of neural stem cell grafts in an APP transgenic model of Alzheimer disease. Stem Cell Res. 2015;15(1):54-67. doi:10.1016/j.scr.2015.04.008.
41. Ennaceur A, Delacour J. A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behav Brain Res. 1988. doi:10.1016/0166-4328(88)90157-X.
42. Darcet F, Mendez-David I, Tritschler L, Gardier AM, Guilloux JP, David DJ. Learning and memory impairments in a neuroendocrine mouse model of anxiety/depression. Front Behav Neurosci. 2014;8(MAY):1-13. doi:10.3389/fnbeh.2014.00136.
43. Hammond RS, Tull LE, Stackman RW. On the delay-dependent involvement of the hippocampus in object recognition memory. Neurobiol Learn Mem. 2004;82(1):26-34. doi:10.1016/j.nlm.2004.03.005.
44. Albasser MM, Davies M, Futter JE, Aggleton JP. Magnitude of the Object Recognition Deficit Associated With Perirhinal Cortex Damage in Rats: Effects of Varying the Lesion Extent and the Duration of the Sample Period. Behav Neurosci. 2009;123(1):115-124. doi:10.1037/a0013829.
45. Baxter MG. “I’ve seen it all before” Explaining age-related impairments in object recognition. Theoretical comment on Burke et al. (2010). Behav Neurosci. 2010;124(5):706-709. doi:10.1037/a0021029.
46. Ennaceur A. One-trial object recognition in rats and mice: Methodological and theoretical issues. Behav Brain Res. 2010. doi:10.1016/j.bbr.2009.12.036.