Changing strengths of learned associations: neuronal ensemble mechanism

改变学习关联的强度：神经元集成机制

• 批准号: BB/M009017/1
• 负责人: Eisuke Koya
• 金额: $ 56.69万
• 依托单位: University of Sussex
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM009017%2F1
• 关键词: Changing; strengths; learned; associations; neuronal

The ability to learn and remember the changing meanings about learned associations of biologically significant experiences and sensory stimuli is crucial for survival. For example, animals respond to external cues that predict the availability of natural rewards (e.g. food). However, they will learn to inhibit responding to these cues if the same cues fail to predict their availability. For many decades, a major goal of neuroscience has been to reveal the precise location and physiological nature of representations about these associations in the brain. Recent studies implicate the role of a minority of sparsely distributed, activated neurons called 'neuronal ensembles' in forming mental representations about learned associations about salient experiences and associated environmental cues. Although it is established that these ensembles play a causal role in mediating these associations, we do not fully understand the mechanisms that are involved in their formation. Also, little is known about what happens to these neurons once the original meaning of the learned associations change, such as when a cue no longer predicts food availability. A likely site where these changes occur to encode the meaning of these associations at neuronal ensembles is at the synapse, the key sites of neuronal communication. It is thought that enduring changes at the synapse akin to 'neuronal rewiring' underlie the formation of new associative representations. However, the precise nature of this rewiring process, especially with regards to how neuronal ensembles establish and maintain these associations, is largely unknown due to the technical challenges in identifying and recording from activated neurons. The aim of this grant is to elucidate the mechanisms that modulate the strength of learned associations between natural rewards and associated environmental cues at the synaptic and local circuit level in neuronal ensembles. We will accomplish this by using an animal model of associative learning, where a mouse learns how to associate a tone cue with sucrose delivery. Once this association forms, a tone cue elicits a conditioned approach response towards the sucrose delivery receptacle. Conversely, this response is inhibited following a procedure called 'extinction learning' when the animal learns that the cue does not predict sucrose delivery. It is widely believed for this type of learning that the original associative memory is not erased but rather suppressed, since exposure to sucrose can re-trigger the approach response. At the neuronal level, a sucrose predictive cue elicits activation of a minority of neurons in the prefrontal cortex. This brain area is important for motivated behaviours, such as securing food sources, and these activated neurons are believed to encode information about sucrose and its associated cues. We will selectively record from these neurons using transgenic mice in which these activated neurons can be identified and physiologically characterised. We will examine structural alterations at their synapses to reveal the changes in neuronal wiring, after mice have learned that the cue predicts or no longer predicts sucrose delivery. We will also examine changes in 'connectivity' or the ability of one ensemble member to communicate with another, a process that may facilitate activation of the entire ensemble representation. Finally, we will characterize the behavioural role of these neurons that undergo rewiring by silencing their activity and testing this effect on conditioned approach responses, and whether the mice can relearn the original conditioning task.Understanding these neuronal mechanisms will shed light on basic associative learning processes that are integral to healthy cognitive functioning. Moreover, it will reveal specific alterations at synapses on behaviourally relevant neurons and could potentially reveal new therapeutic targets.

学习和记住生物学上重要的经验和感官刺激的学习关联的变化意义的能力对生存至关重要。例如，动物对预测自然奖励（例如食物）可用性的外部线索做出反应。然而，如果同样的线索不能预测它们的可用性，他们将学会抑制对这些线索的反应。几十年来，神经科学的一个主要目标一直是揭示这些关联在大脑中的精确位置和生理性质。最近的研究表明，少数稀疏分布的激活的神经元（称为“神经元集合”）在形成关于显著经验和相关环境线索的学习关联的心理表征中发挥了作用。虽然它是建立，这些合奏发挥因果关系的作用，在调解这些协会，我们不完全了解的机制，参与其形成。此外，我们对这些神经元的情况知之甚少，一旦习得关联的原始意义发生变化，比如当一个线索不再预测食物的供应时。这些变化发生的一个可能的位置是在突触，神经元通信的关键部位，以编码这些关联在神经元集合中的意义。人们认为，突触的持久变化类似于“神经元重新布线”，这是新的联想表征形成的基础。然而，由于识别和记录激活神经元的技术挑战，这种重新布线过程的确切性质，特别是关于神经元集合如何建立和维持这些关联，在很大程度上是未知的。这项资助的目的是阐明在神经元集合的突触和局部回路水平上调节自然奖励和相关环境线索之间习得关联强度的机制。我们将通过使用联想学习的动物模型来实现这一点，其中小鼠学习如何将音调提示与蔗糖递送相关联。一旦这种联系形成，一个音调提示就会激发一种对蔗糖传递容器的条件性接近反应。相反，当动物得知提示不能预测蔗糖的传递时，这种反应会在一个称为“消退学习”的过程中被抑制。人们普遍认为，对于这种类型的学习，原始的联想记忆并没有被抹去，而是被抑制，因为接触蔗糖会重新触发接近反应。在神经元水平上，蔗糖预测线索会激活前额叶皮层中的少数神经元。这个大脑区域对于有动机的行为很重要，例如确保食物来源，这些激活的神经元被认为编码有关蔗糖及其相关线索的信息。我们将使用转基因小鼠选择性地记录这些神经元，其中这些激活的神经元可以被识别和生理特征。我们将检查其突触的结构变化，以揭示神经元布线的变化，在小鼠已经了解到，该线索预测或不再预测蔗糖输送。我们还将研究“连通性”或一个合奏成员与另一个成员沟通的能力的变化，这一过程可能有助于激活整个合奏表示。最后，我们将描述这些神经元的行为作用，通过沉默他们的活动，并测试这种影响的条件反射的方法rewiring，以及小鼠是否可以重新学习原来的conditioningtask.Understanding这些神经元的机制将阐明基本的联想学习过程是不可或缺的健康的认知功能。此外，它将揭示行为相关神经元突触的特定改变，并可能揭示新的治疗靶点。

项目成果

Extinction of cue-evoked food-seeking recruits a GABAergic interneuron ensemble in the dorsal medial prefrontal cortex of mice.

线索诱发的食物寻求消失会在小鼠背内侧前额叶皮层中招募 GABA 能中间神经元群。

• DOI: 10.1111/ejn.14754
• 发表时间: 2020
• 期刊: The European journal of neuroscience
• 作者: Brebner LS

Sound of silent synapses from the addicted hippocampus.

沉迷的海马体发出无声的突触声。

• DOI: 10.1038/s41386-018-0142-5
• 发表时间: 2018
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
• 作者: Koya,Eisuke;Dong,Yan
• 通讯作者: Dong,Yan

Acute, but not longer-term, exposure to environmental enrichment attenuates Pavlovian cue-evoked conditioned approach and Fos expression in the prefrontal cortex in mice.

• DOI: 10.1111/ejn.15146
• 发表时间: 2021-04
• 期刊: The European journal of neuroscience
• 作者: Margetts-Smith G;Macnaghten AI;Brebner LS;Ziminski JJ;Sieburg MC;Grimm JW;Crombag HS;Koya E
• 通讯作者: Koya E

Reversing Cocaine-Induced Adaptations and Reducing Relapse: An Opportunity for Repurposing Riluzole.

逆转可卡因引起的适应并减少复发：重新利用利鲁唑的机会。

• DOI: 10.1038/npp.2017.300
• 发表时间: 2018
• 期刊: official publication of the American College of Neuropsychopharmacology
• 作者: Ziminski JJ

Changes in Appetitive Associative Strength Modulates Nucleus Accumbens, But Not Orbitofrontal Cortex Neuronal Ensemble Excitability.

食欲联想强度的变化调节伏核，但不调节眶额皮层神经元整体的兴奋性。

• DOI: 10.1523/jneurosci.3766-16.2017
• 发表时间: 2017
• 期刊: the official journal of the Society for Neuroscience
• 作者: Ziminski JJ