Synaptic basis of perceptual learning in primary auditory cortex

描述(由申请人提供)：大脑具有非凡的能力，能够根据经验做出改变。虽然整个神经系统在发育过程中高度不稳定，但大脑皮层在整个生命过程中保持可塑性。这种可塑性对学习和记忆是必不可少的，也是听觉皮质的一个重要特征，特别是对于学习语言等感觉信号的重要性，对于使用人工耳蜗等设备，以及对短期耳聋后的恢复来说。这些变化被认为主要发生在突触，即信息处理和可塑性的基本单位。长期的突触可塑性需要感觉体验和神经调节系统的激活，神经调节系统将行为背景传递到局部皮质回路。然而，对体内突触输入和神经调节剂释放之间的相互作用知之甚少，这使得将知觉学习与听觉皮质或其他大脑区域的可塑性联系起来具有挑战性。最近，我们开发了一种方法来测量几个小时的突触修改的动力学，以更密切地检查听觉皮质可塑性和听觉知觉学习之间的联系。这些实验现在允许构建一个新的框架，用于在行为环境中理解调制和可塑性的一般机制。具体地说，我们将研究当声音与强大的神经调节剂去甲肾上腺素配对时，大脑皮层和丘脑的可塑性在增强听觉感知方面的生理作用。去甲肾上腺素对选择性注意、一般觉醒和学习很重要，是应激的一个主要因素，而S是由蓝斑释放的，蓝斑是一种相对均匀的小脑干核团，可以直接进行电生理记录。这项建议描述了一系列电生理和行为学实验，以考察刺激蓝斑和去甲肾上腺素对成年大鼠听皮层的影响。首先，在麻醉动物中，蓝斑刺激将与听觉刺激配对，以进行详细的细胞内记录和机制研究。接下来，将在清醒的动物身上进行蓝斑配对，以证明神经调节和皮质可塑性对两种形式的听觉行为的影响，包括基于积极奖励的或消极的应激强化。最后，由于初步数据表明这种形式的可塑性是异常长寿和抵抗灭绝的，将从蓝斑神经元进行录音，以询问这个神经调制中心是否通过更连续的调制对听觉刺激变得敏感，从而锁定皮质电路的变化。综上所述，在此，我们将使用体内电生理学方法来研究去甲肾上腺素能调制与声输入相结合，如何导致听觉丘脑皮质回路和神经调制释放本身的短期和长期改变，以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.