Synaptic basis of perceptual learning in primary auditory cortex

描述（由申请人提供）：大脑具有响应经验而改变的非凡能力。虽然整个神经系统在发育过程中是高度不稳定的，但大脑皮层在整个生命过程中保持可塑性。这种可塑性对于学习和记忆是必不可少的，也是听觉皮层的重要特征，特别是对于学习感觉信号（如语音）的重要性，使用耳蜗植入等设备以及短期耳聋后的恢复。这些变化被认为主要发生在突触，信息处理和可塑性的基本单位。长期突触可塑性需要感觉经验和神经调节系统的激活，这些神经调节系统将行为背景传递到局部皮层回路。然而，人们对突触输入和体内神经调质释放之间的相互作用知之甚少，这使得将感知学习与听觉皮层或其他大脑区域的可塑性联系起来具有挑战性。最近，我们已经开发出一种方法来测量突触修饰的动态数小时，更密切地检查听觉皮层可塑性和听觉感知学习之间的联系。这些实验现在允许构建一个新的框架，用于理解行为背景下的调制和可塑性的一般机制。具体来说，我们将研究皮质和丘脑可塑性的生理作用，以增强听觉感知时，声音与强大的神经调质去甲肾上腺素配对。去甲肾上腺素对于选择性注意、一般唤醒和学习是重要的，是压力的主要因素，并且由蓝斑释放，蓝斑是一个小的且相对均匀的脑干核，适合于直接电生理记录。该建议描述了一系列的电生理和行为实验，将检查蓝斑刺激和去甲肾上腺素释放对成年大鼠听觉皮层的影响。首先，蓝斑刺激将与麻醉动物的听觉刺激配对，用于详细的细胞内记录和机制研究。接下来，将在清醒的动物中进行蓝斑配对，以记录神经调节和皮质可塑性对两种形式的听觉行为（涉及基于积极奖励或消极压力强化）的影响。最后，初步数据表明，这种形式的可塑性是不寻常的长寿和抗灭绝，记录将从蓝斑神经元询问，如果这个神经调节中心变得敏感的听觉刺激，通过更连续的调制“锁定”的皮层电路的变化。总之，在这里，我们将使用在体内的电生理方法来询问去甲肾上腺素能调制，与声输入配对，导致短期和长期的修改听觉丘脑皮层电路和神经调节释放本身，持续改善行为动物的感知能力。

DESCRIPTION (provided by applicant): The brain has the remarkable capability to change in response to experience. While the entire nervous system is highly labile during development, the cerebral cortex remains plastic throughout life. This plasticity is essential for learning and memory, and is an important feature of the auditory cortex, especially for learning the significance of sensory signals such as speech, for the use of devices such as cochlear implants, and for recovery after short-term deafness. These changes are thought to occur primarily at synapses, basic units of information processing and plasticity. Long-term synaptic plasticity requires sensory experience and activation of neuromodulatory systems which convey behavioral context to local cortical circuits. However, little is known about the interactions between synaptic inputs and release of neuromodulators in vivo, making it challenging to relate perceptual learning to plasticity in the auditory cortex or other brain areas. Recently we have developed an approach to measuring the dynamics of synaptic modifications for hours, to more closely examine the links between auditory cortical plasticity and auditory perceptual learning. These experiments now allow the construction of a new framework for understanding general mechanisms of modulation and plasticity in a behavioral context. Specifically, we will study the physiological role of cortical and thalamic plasticity for enhancing auditory perception when sounds are paired with the powerful neuromodulator norepinephrine. Norepinephrine is important for selective attention, general arousal, and learning, is a major factor in stress, and s released by the locus coeruleus, a small and relatively homogeneous brainstem nucleus amenable to direct electrophysiological recordings. This proposal describes a series of electrophysiological and behavioral experiments that will examine the effects of locus coeruleus stimulation and norepinephrine release on the auditory cortex of adult rats. First, locus coeruleus stimulation will be paired with auditory stimuli in anesthetized animals for detailed intracellular recordings and mechanistic studies. Next, locus coeruleus pairing will be performed in awake animals to document the effects of neuromodulation and cortical plasticity on two forms of auditory behavior involving positive reward-based or negative stressful reinforcement. Finally, as preliminary data suggest that this form of plasticity is unusually long-lived and resistant to extinction, recordings will be made from locus coeruleus neurons to ask if this neuromodulatory center becomes sensitized to auditory stimulation to 'lock-in' changes of cortical circuitry via more continuous modulation. In summary, here we will use in vivo electrophysiological methods to ask how noradrenergic modulation, paired with acoustic input, leads to short- and long-term modifications of auditory thalamocortical circuitry and neuromodulatory release itself, to persistently improve perceptual abilities in behaving animals.