BDNF and learning: Evidence that instrumental training promotes learning within the spinal cord by up-regulating BDNF expression.
We have previously shown that the spinal cord is capable of learning a sensorimotor task in the absence of supraspinal input. Given the action of brain-derived neurotrophic factor (BDNF) on hippocampal learning, the current studies examined the role of BDNF in spinal learning. BDNF is a strong synaptic facilitator and, in association with other molecular signals (e.g. cAMP-response element binding protein (CREB), calcium/calmodulin activated protein kinase II (CaMKII) and synapsin I), important for learning. Spinally transected rats given shock to one hind leg when the leg extended beyond a selected threshold exhibited a progressive increase in flexion duration that minimized shock exposure, a simple form of instrumental learning. Instrumental learning resulted in elevated mRNA levels of BDNF, CaMKII, CREB, and synapsin I in the lumbar spinal cord region. The increases in BDNF, CREB, and CaMKII were proportional to the learning performance. Prior work has shown that instrumental training facilitates learning when subjects are tested on the contralateral leg with a higher response criterion. Pretreatment with the BDNF inhibitor TrkB-IgG blocked this facilitatory effect, as did the CaMKII inhibitor AIP. Intrathecal administration of BDNF facilitated learning when subjects were tested with a high response criterion. The findings indicate that instrumental training enables learning and elevates BDNF mRNA levels within the lumbar spinal cord. BDNF is both necessary, and sufficient, to produce the enabling effect.
Gómez-Pinilla
F
F
Division of Neurosurgery, UCLA Brain Injury Research Center, USA. fgomezpi@ucla.edu
Huie
J R
JR
Ying
Z
Z
Ferguson
A R
AR
Crown
E D
ED
Baumbauer
K M
KM
Edgerton
V R
VR
Grau
J W
JW
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology / Q000502:physiology*; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007266:Inhibition, Psychological; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000378:metabolism / Q000473:pathology / Q000534:rehabilitation; D016704:Synapsins / Q000235:genetics / Q000378:metabolism; D013663:Teaching; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D016704:Synapsins; D050882:CREB-Binding Protein; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
Neuron. 2000 Jan;25(1):11-4
10707967
Behav Cogn Neurosci Rev. 2006 Dec;5(4):191-239
17099112
Annu Rev Biochem. 1999;68:821-61
10872467
Eur J Biochem. 2000 Sep;267(17):5280-3
10951185
J Physiol. 2001 May 15;533(Pt 1):91-7
11351017
J Neurophysiol. 2001 Aug;86(2):845-55
11495955
Nat Rev Neurosci. 2002 Mar;3(3):175-90
11994750
J Neurosci. 1999 Nov 15;19(22):9928-38
10559401
Physiol Behav. 2002 Nov;77(2-3):259-67
12419402
Behav Neurosci. 2002 Dec;116(6):1032-51
12492302
Brain Res Brain Res Rev. 2002 Oct;40(1-3):230-9
12589921
J Neurotrauma. 2004 Jan;21(1):109-18
14987470
Annu Rev Neurosci. 2004;27:145-67
15217329
Behav Brain Res. 2004 Oct 5;154(2):431-8
15313031
J Spinal Cord Med. 2004;27(4):365-75
15484667
Exp Brain Res. 1990;79(1):65-74
2311704
Exp Brain Res. 1990;79(1):75-82
2311705
Science. 1992 Jul 10;257(5067):201-6
1378648
Science. 1992 Jul 10;257(5067):206-11
1321493
Neuron. 1992 Dec;9(6):1081-8
1463608
Neuroscience. 1994 Feb;58(4):683-703
7514766
Eur J Neurosci. 1994 May 1;6(5):754-65
8075819
J Neurosci. 1995 Jan;15(1 Pt 2):477-91
7823156
Cell. 1995 Apr 7;81(1):107-15
7720066
J Neurosci. 1995 Jul;15(7 Pt 1):4796-805
7623111
J Neurophysiol. 1995 Sep;74(3):1001-9
7500126
J Cell Biol. 1995 Dec;131(6 Pt 2):1789-800
8557745
J Neurosci. 1996 Apr 1;16(7):2365-72
8601816
Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3679-83
8622996
Neuron. 1996 Jun;16(6):1137-45
8663990
Curr Opin Neurobiol. 1996 Apr;6(2):264-8
8725970
Histochem Cell Biol. 1996 May;105(5):365-73
8781990
Curr Biol. 1997 Jan 1;7(1):1-11
8999994
Neuron. 1997 Feb;18(2):257-67
9052796
Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4239-41
9113972
J Biol Chem. 1997 Sep 26;272(39):24133-6
9305859
Biotechniques. 1997 Nov;23(5):928-34, 936-7
9383561
Neuron. 1997 Nov;19(5):1031-47
9390517
Science. 1998 Feb 6;279(5352):867-9
9452387
Science. 1998 Feb 6;279(5352):870-3
9452388
Eur J Neurosci. 1997 Dec;9(12):2581-7
9517463
Annu Rev Neurosci. 1998;21:127-48
9530494
Exp Neurol. 1998 Nov;154(1):170-84
9875278
Behav Neurosci. 1998 Dec;112(6):1366-86
9926819
J Neurotrauma. 2004 Dec;21(12):1795-817
15684770
Behav Neurosci. 2005 Apr;119(2):538-47
15839800
Curr Neurol Neurosci Rep. 2006 May;6(3):177-80
16635424
Neuroscience. 2006 Aug 11;141(1):421-31
16678969
Nat Neurosci. 2000 Apr;3(4):323-9
10725920