Synaptic basis of perceptual learning in primary auditory cortex

描述（由申请人提供）：大脑具有对经验做出反应的非凡能力。虽然整个神经系统在发育过程中高度不稳定，但大脑皮层在一生中都保持着可塑性。这种可塑性对学习和记忆至关重要，是听觉皮层的一个重要特征，特别是对于学习语音等感觉信号的意义，使用人工耳蜗等设备，以及短期耳聋后的恢复。这些变化被认为主要发生在突触，这是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，神经调节系统将行为背景传递给局部皮层回路。然而，关于突触输入和体内神经调节剂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，我们开发了一种方法来测量突触修饰的动态数小时，以更仔细地检查听觉皮质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来理解行为背景下的调节和可塑性的一般机制。具体来说，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，皮层和丘脑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、一般唤醒和学习很重要，是应激的主要因素，由蓝斑核释放，蓝斑核是一个小而相对均匀的脑干核，可以直接进行电生理记录。本文描述了一系列电生理和行为实验，以研究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，在麻醉的动物中，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，蓝斑配对将在清醒的动物中进行，以记录神经调节和皮层可塑性对两种听觉行为的影响，包括积极的基于奖励的或消极的压力强化。最后，由于初步数据表明这种形式的可塑性异常持久且不易消失，因此将对蓝斑神经元进行记录，以询问该神经调节中心是否对听觉刺激变得敏感，从而通过更连续的调制“锁定”皮层回路的变化。总之，在这里，我们将使用体内电生理方法来研究去甲肾上腺素能调节如何与声音输入相结合，导致听觉丘脑皮质回路和神经调节释放本身的短期和长期改变，从而持续提高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.