MECHANISM UNDERLYING NGF-INDUCED CORTICAL PLASTICITY

我们的长期研究兴趣是了解成人感觉皮层的可塑性。 为此，我们发现，应用神经营养因子的成人体感皮层导致快速（分钟）和戏剧性的变化，在振幅和面积范围内诱发的触觉刺激的感觉反应。这些结果表明，一个令人惊讶的新的作用，神经营养因子介导快速成人皮质可塑性。 拟议的实验将检查神经营养因子神经生长因子（NGF）诱导这种快速的皮质可塑性的作用和机制。我们将测试的假设，神经生长因子是一个皮质基底前脑胆碱能系统（BFCS）的反馈机制，可以诱导非常快速的皮质可塑性的一部分。 具体而言，NGF可以由激活的皮质神经元释放，这反过来又增强了位于皮质中BFCS投射上的终末的胆碱能释放。 如果得到支持，这一假说将提供一种机制，解释大脑皮层如何自我调节自身的可塑性。 例如，这种可塑性的自我调节可以为皮质提供一种快速增强具有重要行为价值的感觉输入效果的方法。事实上，BFCS通过诱导皮层可塑性而参与增强感觉刺激的行为重要性。本实验旨在证明皮层-BFCS反馈系统通过NGF对皮层BFCS投射的作用，是引起皮层快速可塑性的必要和充分条件。 我们的研究策略是确定NGF/ACh投射到躯体感觉皮层，刺激该系统，然后消除其功能。 拟议的实验的结果将通过使用在体内高分辨率成像的皮层活动进行量化。如果我们的假设得到验证，它将为成人大脑皮层调节自身可塑性的细胞和分子机制以及大脑皮层可塑性的本质提供一个基本的认识。 由于皮质可塑性涉及大脑的许多基本过程，特别是皮质，从损伤和感觉剥夺后的恢复到学习和记忆，因此越来越需要更好地理解这种可塑性的机制。

Our long-range research interest is to understand adult sensory cortical plasticity. To this end, we found that application of neurotrophins to the adult somatosensory sensory cortex resulted in rapid (minutes) and dramatic changes in both amplitude and areal extent of evoked sensory response to tactile stimulation. These results suggest a surprising new role for neurotrophins in mediating rapid adult cortical plasticity. The proposed experiments will examine the role and mechanism by which the neurotrophin nerve growth factor (NGF) induces such rapid cortical plasticity. We will test the hypothesis that NGF is part of a cortex-to-basal forebrain cholinergic system (BFCS) feedback mechanism that can induce very rapid cortical plasticity. Specifically, NGF may be released by activated cortical neurons that, in turn, enhance the cholinergic release from terminals located on BFCS projections in the cortex. If supported, such a hypothesis would provide a mechanism that would explain how the cortex could self-regulate its own plasticity. For example, such self-regulation of plasticity may provide a means for the cortex to enhance rapidly the effects of sensory input that has important behavioral value. Indeed, the BFCS has been implicated in enhancing the behavioral importance of a sensory stimulus by inducing cortical plasticity. Experiments are designed to prove that cortex-to-BFCS feedback system, via the action of NGF on the BF CS projections in the cortex, is both necessary and sufficient to elicit rapid cortical plasticity. Our research strategy is to identify the NGF/ACh projections to the somatosensory cortex, to stimulate that system and then to eliminate its function. The results of the proposed experiments will be quantified by using in vivo high-resolution imaging of cortical activity. If our hypothesis is verified, it will add a fundamental insight to the cellular and molecular mechanisms by which the adult cortex can regulate its own plasticity and to the nature of cortical plasticity in general. As cortical plasticity is implicated in many fundamental processes of the brain in general and the cortex in particular, ranging from recovery after injury and sensory deprivation to learning and memory, there is a growing need to better understand the mechanisms underlying such plasticity.