Synaptic mechanisms of auditory memory

描述（由申请人提供）：初级感觉皮质不仅分析感官信息，而且存储已学习的感官经验信息。听觉皮层（ACx）获得并保留了有关选定声音的行为意义的特定记忆痕迹。在学习过程中，ACx神经元的调谐特性发生了活动依赖性的变化。这种皮层地图的可塑性被认为是听觉记忆的基础，其特点是对行为上重要的音调的反应以牺牲其他频率为代价。在成熟的动物中，它可以通过将选定的音调与基底核的胆碱能投射激活配对来诱导。在幼龄动物中，ACx皮层地图的可塑性可以通过某种声音的被动富集环境来诱导。皮层地图可塑性的细胞机制尚不清楚。在这个项目中，我们将验证我们的假设，即学习过程中皮层反应的双向变化可以通过丘脑皮质兴奋性突触的长期增强（LTP）和长期抑制（LTD）等突触机制进行编码。TC投射为新皮层提供了主要的上行感觉输入，并有助于在感觉皮层中形成皮层图。因此，TC突触的突触可塑性对ACx皮质图谱的可塑性影响很大。然而，假设TC突触的LTP和LTD仅限于出生后早期，在啮齿动物中对应于出生后的前几天。这表明，在成熟动物中，TC突触可塑性不可能是皮层图可塑性和知觉记忆的基础。最近，我们发现在成熟的ACx中，TC突触可塑性并没有丧失；相反，它在出生后的发育过程中获得门控机制，可以通过激活TC投射的突触前末端的胆碱能受体来释放。一旦门控释放，LTP和LTD可以发生在远超过早期临界期的老龄动物的TC突触。利用突触功能的双光子成像、双光子谷氨酸释放和成熟动物TC切片的全细胞记录，我们最近发现了TC突触中LTD和LTP的新的细胞和分子机制。我们也开始描述门控机制。在这里，我们提出验证我们的假设，即TC突触可塑性是成熟动物皮层图谱可塑性的基础。通过体内电生理作图，我们将确定影响TC突触LTP和LTD的机制是否也影响ACx皮层图的可塑性。利用成像和光遗传学，分子和电生理工具，我们将进一步表征TC突触可塑性的机制。确定这些机制将扩大我们对皮层地图可塑性的理解。从这些研究中获得的知识将为进一步阐明听觉记忆的细胞和分子机制提供基础。

DESCRIPTION (provided by applicant): Primary sensory cortices not only analyze sensory information but also store information about learned sensory experiences. The auditory cortex (ACx) acquires and retains specific memory traces about the behavioral significance of selected sounds. During learning, the tuning properties of ACx neurons undergo activity-dependent changes. This cortical map plasticity, which is believed to be a substrate of auditory memory, is characterized by the facilitation of responses to behaviorally important tones at the expense of other frequencies. In mature animals, it can be induced by pairing selected tones with activation of cholinergic projections from the nucleus basalis. In young animals, cortical map plasticity in the ACx can be induced by passive enrichment of the environment with a certain sound. Cellular mechanisms of cortical map plasticity are unknown. In this project, we will test our hypothesis that bidirectional changes in cortical responses during learning can be encoded by synaptic mechanisms such as long-term potentiation (LTP) and long-term depression (LTD) at thalamocortical (TC) excitatory synapses.TC projections provide the major ascending sensory input to the neocortex and contribute to the formation of cortical maps in sensory cortices. Thus, synaptic plasticity at TC synapses should greatly influence cortical map plasticity in the ACx. However, it has been postulated that LTP and LTD at TC synapses are limited to the early postnatal period that in rodents corresponds to the first several postnatal days. This suggests that TC synaptic plasticity cannot be a substrate of cortical map plasticity and perceptual memory in mature animals. Recently, we showed that TC synaptic plasticity is not lost in the mature ACx; instead, it acquires gating mechanisms during postnatal development that can be released by activating cholinergic receptors on presynaptic terminals of TC projections. Once gating is released, LTP and LTD can occur at TC synapses of animals aged far beyond the early critical period. Using 2-photon imaging of synaptic function, 2-photon glutamate uncaging, and whole-cell recordings in TC slices from mature animals, we recently identified novel cellular and molecular mechanisms of LTD and LTP at TC synapses. We also began characterizing the gating mechanisms. Here, we propose to test our hypothesis that TC synaptic plasticity underlies cortical map plasticity in mature animals. Using electrophysiologic mapping in vivo, we will determine whether mechanisms that affect LTP and LTD at TC synapses also affect cortical map plasticity in the ACx. Using imaging and optogenetic, molecular, and electrophysiological tools, we will further characterize the mechanisms of TC synaptic plasticity. Identifying these mechanisms will expand our understanding of cortical map plasticity in the ACx. Knowledge gained from these studies will provide the basis for future elucidation of the cellular and molecular mechanisms of auditory memory.