Synaptic mechanisms of auditory memory

翻译后摘要：初级感觉皮层分析感觉信息和存储有关学习的感觉信息 经验听觉皮层（ACx）获得并保留有关行为意义的记忆痕迹 选择的声音。在学习过程中，ACx神经元的调谐特性经历活动依赖性 变化这种被认为是听觉记忆基底的皮层地图可塑性的特征在于， 通过促进对行为上重要的音调的反应。在幼年动物中， ACx可由被动环境富集与一定的声音诱导。在啮齿类动物中， 地图可塑性限于出生后的几天（即，早期的关键时期）。在成熟的动物中， 只有当音调在行为上是重要的或与调节性的激活配对时，才能诱导可塑性。 (e.g.,胆碱能、多巴胺能、去甲肾上腺素能）投射。在上一个融资期，我们确定 皮层地图可塑性是由与长时程增强（LTP）和长时程增强（LTP）相同的机制编码的。 抑郁症（LTD）在丘脑皮质（TC）兴奋性突触。TC投射是主要的感觉输入， 新皮层，并有助于形成皮层地图。在大脑切片中，我们发现TC突触 在早期的临界期之后，塑性并没有丧失，而是获得了一种可以释放的浇口机制 通过激活突触前末梢上的胆碱能受体。一旦门控被释放，TC突触的LTP/LTD 和皮质地图可塑性在体内发生在年龄超过早期关键期的动物。腺苷机械， 由产生腺苷的外-5'-核苷酸酶（Nt5e）和A1腺苷受体（A1Rs）组成， 门控幼年可塑性可以在成年人中重新建立，如果声音刺激与破坏相结合， Nt5e或A1R信号在听觉丘脑。这种可塑性发生在皮层地图和个人ACx 清醒的成年小鼠的神经元，并与长期改善音调辨别能力。在 这种竞争性的更新，我们建议测试我们的假设，即丘脑中的腺苷机制是 在ACx标测过程中将信息从调节性投射传递到丘脑的主介质 成人的可塑性在目标1中，我们将通过将声音与激活 在激活或去激活门控机构时，调节突起。在目标2中，我们将探讨 通过研究腺苷的年龄依赖性终止早期关键期的分子机制 生产在目标3中，我们将确定门控机制的时间尺度。使用快速扫描循环 在清醒小鼠的伏安法中，我们发现腺苷在听觉丘脑中瞬时释放， 大脑皮层对声音的反应我们建议阐明这种声音诱发的机制和动力学 腺苷释放之前和之后的早期关键期，并确定它如何影响尖峰在丘脑 中继和皮层神经元在声音刺激。从这些研究中获得的知识将提供 为将来阐明听觉记忆的细胞和分子机制奠定了基础。

Abstract: Primary sensory cortices analyze sensory information and store information about learned sensory experiences. The auditory cortex (ACx) acquires and retains 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. In juvenile animals, cortical map plasticity in the ACx can be induced by passive environmental enrichment with a certain sound. In rodents, juvenile cortical map plasticity is limited to a few postnatal days (i.e., the early critical period). In mature animals, cortical map plasticity can be induced only if tones are behaviorally important or paired with the activation of modulatory (e.g., cholinergic, dopaminergic, noradrenergic) projections. During the previous funding period, we determined that cortical map plasticity is encoded by the same mechanisms as long-term potentiation (LTP) and long-term depression (LTD) at thalamocortical (TC) excitatory synapses. TC projections are the major sensory input to the neocortex and contribute to the formation of cortical maps. In brain slices, we showed that TC synaptic plasticity is not lost after the early critical period, instead a gating mechanism is acquired that can be released by activating cholinergic receptors on presynaptic terminals. Once gating is released, LTP/LTD at TC synapses and cortical map plasticity in vivo occur in animals aged beyond the early critical period. Adenosine machinery, consisting of adenosine-producing ecto-5'-nucleotidase (Nt5e) and A1 adenosine receptors (A1Rs), provides the gating. Juvenile plasticity can be reestablished in adults, if acoustic stimuli are paired with disruption of Nt5e or A1R signaling in the auditory thalamus. This plasticity occurs in cortical maps and individual ACx neurons of awake adult mice and is associated with long-term improvement in tone-discrimination abilities. In this competitive renewal, we propose to test our hypothesis that the adenosine machinery in the thalamus is the master mediator that transmits information from modulatory projections to the thalamus during ACx map plasticity in adults. In Aim 1, we will induce cortical map plasticity in adults by pairing sounds with activation of modulatory projections while activating or deactivating the gating mechanism. In Aim 2, we will explore the molecular mechanisms of terminating the early critical period by investigating age dependency of adenosine production. In Aim 3, we will determine time scales of the gating mechanisms. Using fast-scan cyclic voltammetry in awake mice, we found that adenosine is transiently released in the auditory thalamus and cortex in response to sound. We propose to elucidate the mechanisms and kinetics of this sound-evoked adenosine release before and after the early critical period and determine how it affects spiking in thalamic relay and cortical neurons during sound stimulation. Knowledge gained from these studies will provide the basis for future elucidation of the cellular and molecular mechanisms of auditory memory.