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，我们发现将神经营养物质应用于成人体感觉皮层会导致对触觉刺激引起的感觉反应的幅度和面积范围发生快速（几分钟）和戏剧性的变化。这些结果表明神经营养因子在调节成人皮层快速可塑性方面具有令人惊讶的新作用。本实验将探讨神经营养因子神经生长因子（NGF）诱导这种快速皮层可塑性的作用和机制。我们将测试NGF是皮层到基底前脑胆碱能系统（BFCS）反馈机制的一部分的假设，该机制可以诱导非常快速的皮层可塑性。具体来说，NGF可能通过激活的皮质神经元释放，进而增强位于皮层BFCS投影末端的胆碱能释放。如果得到支持，这一假设将提供一种机制，解释大脑皮层如何自我调节其自身的可塑性。例如，这种可塑性的自我调节可能为皮层提供了一种手段，可以快速增强具有重要行为价值的感觉输入的效果。事实上，BFCS通过诱导皮质可塑性来增强感觉刺激的行为重要性。实验旨在证明皮层- bfcs反馈系统，通过NGF对皮层BF - CS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在体感觉皮层的投射，刺激该系统，然后消除其功能。所提出的实验结果将通过体内皮层活动的高分辨率成像来量化。如果我们的假设得到证实，它将为成人皮层调节自身可塑性的细胞和分子机制以及皮层可塑性的本质提供一个基本的见解。由于皮层可塑性涉及大脑的许多基本过程，特别是皮层，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了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.