Department of Psychology, Mail Stop 4235, Texas A&M University, College Station, TX 77843, USA.
Neuroscience. 2012 Jan 3;200:74-90. doi: 10.1016/j.neuroscience.2011.10.028. Epub 2011 Oct 25.
Brain-derived neurotrophic factor (BDNF) has been characterized as a potent modulator of neural plasticity in both the brain and spinal cord. The present experiments use an in vivo model system to demonstrate that training with controllable stimulation increases spinal BDNF expression and engages a BDNF-dependent process that promotes adaptive plasticity. Spinally transected rats administered legshock whenever one hind limb is extended (controllable stimulation) exhibit a progressive increase in flexion duration. This simple form of response-outcome (instrumental) learning is not observed when shock is given independent of leg position (uncontrollable stimulation). Uncontrollable electrical stimulation also induces a lasting effect that impairs learning for up to 48 h. Training with controllable shock can counter the adverse consequences of uncontrollable stimulation, to both prevent and reverse the learning deficit. Here it is shown that the protective and restorative effect of instrumental training depends on BDNF. Cellular assays showed that controllable stimulation increased BDNF mRNA expression and protein within the lumbar spinal cord. These changes were associated with an increase in the BDNF receptor TrkB protein within the dorsal horn. Evidence is then presented that these changes play a functional role in vivo. Application of a BDNF inhibitor (TrkB-IgG) blocked the protective effect of instrumental training. Direct (intrathecal) application of BDNF substituted for instrumental training to block both the induction and expression of the learning deficit. Uncontrollable stimulation also induced an increase in mechanical reactivity (allodynia), and this too was prevented by BDNF. TrkB-IgG blocked the restorative effect of instrumental training and intrathecal BDNF substituted for training to reverse the deficit. Taken together, these findings outline a critical role for BDNF in mediating the beneficial effects of controllable stimulation on spinal plasticity.
脑源性神经营养因子 (BDNF) 已被证实为大脑和脊髓中神经可塑性的强效调节剂。本实验采用体内模型系统，证明可控刺激训练可增加脊髓 BDNF 表达，并激活 BDNF 依赖的过程，从而促进适应性可塑性。对接受腿部电击的横断脊髓大鼠进行控制刺激（当一只后肢伸展时给予电击），其伸展持续时间逐渐增加。当电击与腿部位置无关（不可控刺激）时，不会观察到这种简单的反应-结果（工具性）学习形式。不可控电刺激也会产生持久的影响，导致长达 48 小时的学习障碍。与不可控刺激相比，可控电击训练可以预防和逆转学习缺陷，具有保护和恢复作用。研究表明，工具性训练的保护和恢复作用取决于 BDNF。细胞检测表明，可控刺激可增加腰段脊髓内的 BDNF mRNA 表达和蛋白水平。这些变化与背角中 BDNF 受体 TrkB 蛋白的增加有关。随后的证据表明，这些变化在体内具有功能作用。BDNF 抑制剂（TrkB-IgG）的应用阻断了工具性训练的保护作用。BDNF 的直接（鞘内）应用替代了工具性训练，阻断了学习缺陷的诱导和表达。不可控刺激还会引起机械反应性（痛觉过敏）增加，BDNF 也能预防这种情况。TrkB-IgG 阻断了工具性训练的恢复作用，鞘内 BDNF 替代训练可逆转缺陷。综上所述，这些发现概述了 BDNF 在介导可控刺激对脊髓可塑性的有益影响中的关键作用。
