Neural circuitry for flexible control of auditory perception and behavior

 描述(申请人提供)：哺乳动物的听觉系统可以根据经验和行为背景进行修改。这是初级听觉皮质(A1)的一个重要特征，特别是在形成诸如语音、音乐和其他形式的声学交流等感觉信号的表征方面。随着时间的推移和经验的积累，动物可以学会发出特定的声音，而不是其他声音来表示奖励。此外，动物还可以了解到，相同的声音在不同的环境中需要不同的行为反应。例如，在人类中，在街上听到的枪声与在电影中听到的枪声可能会导致不同的行为反应。相反，创伤后应激障碍患者会听到一声巨响，可能无法做出同样的区分。这种缺陷还与包括自闭症在内的发育和语言障碍有关。因此，了解知觉灵活性的机制对于研究正常或病理性的听觉加工是至关重要的。传统上，感觉信息被认为是以线性方式处理的，其中每个连续的大脑区域提取更复杂的特征，然后将其传输到赋予意义的更高阶区域(前馈处理)。然而，在听觉皮质，这一模型越来越多地受到行为动物的神经记录的挑战，这些动物的背景或行为状态在调节神经元活动方面发挥着重要作用。当相同的声音在一个语境(主动语境)中引起注意，而在另一个语境(被动语境)中不需要注意时，在行为条件下会发生什么？这项建议中的初步数据显示，听觉皮质神经元在这两种情况下具有明显不同的活动模式。控制听觉皮质这种上下文相关活动的确切机制仍不清楚。涉及注意力的神经调节中心可能在语境转换中发挥关键作用，因为它们在长期可塑性和学习中发挥着重要作用。这一提议将检验这样一种假设，即听觉皮质中的上下文依赖是因为远程注意信号直接作用于局部电路而产生的。首先，将进行实验，以测试突触输入，神经元活动的构建块，在两种情况下在听觉皮质中是否不同(目标1)。其次，实验将测试大脑中与注意力有关的脑区--基底核的乙酰胆碱释放投射是否在主动任务中自然活跃，并直接改变听觉皮质的突触重量(目标2)。第三，实验将通过观察来自基底核和听觉皮质局部神经元群体的注意信号来测试学习过程中上下文相关活动的出现(目标3)。经验丰富的导师和合作者团队将提供对候选人的短期和长期成功至关重要的培训，包括：活体全细胞记录、神经元亚型的遗传靶向、神经回路的光遗传调制、突触元素的活体成像。拟议的培训计划结合了实践培训、正式指导、与经验丰富的独立研究人员的咨询、课程作业、独立研究、研讨会出席和专业科学会议。从长远来看，这种支持将使候选人有能力领导一个融合了细胞和系统方法的实验室，以探索灵活听觉感知的神经基础。

 DESCRIPTION (provided by applicant): The mammalian auditory system can be modified by experience and by behavioral context. This is an important feature of the primary auditory cortex (A1), especially in forming representations of sensory signals such as speech, music and other forms of acoustic communication. With time and experience, animals can learn that specific sounds and not others can signal rewards. Moreover, animals can also learn that the same sound in different contexts requires distinct behavioral responses. In humans, for example, the sound of a gunshot heard on the street versus during a movie will likely lead to divergent behavioral responses. Conversely, PTSD patients hear a loud bang and may be unable to make the same differentiation. Such deficits are also implicated in developmental and language disorders including autism. Understanding the mechanisms of perceptual flexibility is thus essential for studies of normal or pathological auditory processing. Classically, sensory information was thought to be processed in a linear manner where each successive brain area extracts more complex features and then transmits this to higher-order areas that confer meaning (feed-forward processing). However, in the auditory cortex, this model is increasingly challenged by neural recordings in behaving animals in which context or behavioral state plays an important role in modulating neuronal activity. What happens during behavioral conditions where the same sound draws attention in one context (active context) but does not require attention in another (passive context)? The preliminary data in this proposal shows that auditory cortical neurons have distinctly different activity patterns in those two contexts. The precise mechanisms that govern this context-dependent activity in auditory cortex remain unknown. Neuromodulatory centers involved in attention may play a critical role in context-switching, given their importance in long-term plasticity and learning. This proposal will test the hypothesis that context- dependence in auditory cortex arises because long-range attentional signals directly act on local circuits. First, experiments will be conducted to test whether synaptic inputs, the building blocks of neuronal activity, are different in auditory cortex in both contexts (Aim 1). Second, experiments will test whether acetylcholine- releasing projections from the nucleus basalis, a brain region involved in attention, are naturally active during the active task and directly alter the synaptic weights in auditory cortex (Aim 2). Third, experiments will test how context-dependent activity emerges over the course of learning by looking at both the attentional signal from the nucleus basalis and the local neuronal population in auditory cortex (Aim 3). An experienced team of mentors and collaborators will provide training critical for the candidate's short- and long-term success, including: in vivo whole-cell recordings, genetic targeting of neuronal subtypes, optogenetic modulation of neural circuits, in vivo imaging of synaptic elements. The proposed training program combines hands-on training, formal mentorship, and consultation with experienced independent researchers, coursework, independent study, seminar attendance, and professional scientific meetings. In the long-term, this support will equip the candidate to lead a laboratory that merges cellular and systems approaches to explore the neural basis of flexible auditory perception.