Synaptic mechanisms of auditory memory

描述(申请人提供)：初级感觉皮质不仅分析感觉信息，还存储有关学习的感觉经验的信息。听觉皮质(ACX)获取并保留关于所选声音的行为意义的特定记忆痕迹。在学习过程中，ACX神经元的调谐特性经历了依赖于活动的变化。这种大脑皮层的可塑性被认为是听觉记忆的底物，其特征是以牺牲其他频率为代价，促进对行为重要音调的反应。在成熟动物中，可以通过将选定的音调与激活基底核的胆碱能投射配对来诱导。在幼年动物中，ACX中皮层MAP的可塑性可以通过被动丰富具有一定声音的环境来诱导。大脑皮层MAP可塑性的细胞机制尚不清楚。在这个项目中，我们将检验我们的假设，即学习过程中皮质反应的双向变化可以由丘脑皮质兴奋性突触的长时程增强(LTP)和长时抑制(LTD)等突触机制编码。丘脑皮质兴奋性突触的长时程增强(LTP)和长时程抑制(LTD)等突触机制为新皮质提供了主要的上行感觉输入，并有助于感觉皮质中皮层地图的形成。因此，TC突触的可塑性应极大地影响ACX内皮质MAP的可塑性。然而，据推测，TC突触上的LTP和LTD仅限于啮齿动物出生后的早期，而啮齿动物的LTP和LTD则对应于出生后的最初几天。提示TC突触可塑性不能作为成熟动物皮层MAP可塑性和知觉记忆的底物。最近，我们发现在成熟的ACX中，TC突触的可塑性并没有丧失；相反，它在出生后的发育过程中获得了门控机制，这种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。一旦门控被释放，LTP和LTD可以发生在年龄远远超过早期临界期的动物的TC突触。通过对成熟动物TC脑片突触功能的双光子成像、双光子谷氨酸去化和全细胞记录，我们最近发现了LTD和LTP在TC突触中的新的细胞和分子机制。我们也开始描述门控机制的特征。在这里，我们建议验证我们的假设，即TC突触可塑性是成熟动物皮质地图可塑性的基础。利用体内电生理标测，我们将确定影响TC突触LTP和LTD的机制是否也影响ACX中皮质MAP的可塑性。利用成像和光遗传学、分子和电生理学等手段，我们将进一步研究TC突触可塑性的机制。弄清这些机制将扩大我们对大脑皮质MAP在ACX可塑性的理解。从这些研究中获得的知识将为未来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.