The role of parvalbumin positive interneuron activity and plasticity in the prefrontal cortex for movement control

运动准备和抑制是成功与环境互动的关键技能。作为执行中枢，内侧前额叶皮层（mPFC）在学习，记忆和执行这项技能中起着重要作用。锥体细胞中的结构和突触可塑性已被证明是mPFC中学习、执行和记忆学习技能的关键组成部分（Frankland等人，2004; Restivo等人，2009;尤斯顿等人，2012年）。然而，GABA能抑制性中间神经元（INs）如何有助于mPFC中运动准备的微调以及抑制性信号在技能学习过程中如何变化仍然是一个未知数。在这里，我们假设，兴奋性神经递质输入的疗效的变化，针对INs，类似于在初级运动皮层（M1，TP 6）和海马（TP 1，TP 7）的观察可能在控制运动准备中发挥作用。我们进一步提出，在各种IN类型中，表达小清蛋白（PV）的、快速尖峰的、核周抑制性IN（PVIs）在该技能中特别相关（Kvitsiani等人，2013，平托& Dan，2015，Lagler等人，2016）。之前，我们已经建立了一种结合体内光遗传学和电生理学的行为运动方案，以研究啮齿动物运动控制的神经元基础，并发现PFC的特定子部分差异性地促成这种行为（Hardung et al.，2017 a; Hardung等人，2017年b）。在这里，我们将重点关注PVI在学习和执行行为任务中的作用。我们的目的是（1）确定mPFC-PVI在运动控制和学习过程中的放电活动，（2）使用体内光遗传学和电生理学的组合来确定mPFC-PVI神经元活动对运动启动和抑制的影响。这将通过我们的合作伙伴（TP 6 Poulet，TP 7 Csicsvari）在M1和海马体中的比较实验来验证。 (3)我们将进一步确定PVI活动对局部神经网络振荡的影响，并与TP 6（Poulet）合作，确定与下游运动皮层活动的假定通信。(4)最后，通过与Bartos（TP 1）合作应用离体研究，我们将测量PVIs中自发和诱发兴奋信号的振幅，以检查PVIs输入是否发生了可塑性变化。将在训练和未训练的小鼠之间比较数据。通过这四种并行方法，拟议的项目将提供有关PVI特异性突触可塑性和PVI活动对认知运动控制和学习的影响的详细信息，从而弥合突触可塑性、神经元活动和行为之间的差距。

Movement preparation and inhibition is a crucial skill-set for successfully interacting with the environment. As the executive hub, the medial prefrontal cortex (mPFC) plays a major role in learning, memorizing and executing this skill. Structural and synaptic plasticity in pyramidal cells have been shown to be a key component of learning, executing and recall of learned skills in the mPFC (Frankland et al., 2004; Restivo et al., 2009; Euston et al., 2012). However, how GABAergic inhibitory interneurons (INs) may contribute to the fine-tuning of movement preparation in the mPFC and how inhibitory signaling is changed during skill learning remains far of being understood. Here we hypothesize that changes in the efficacy of excitatory glutamatergic inputs targeting INs, similar to observations in the primary motor cortex (M1, TP6) and the hippocampus (TP1, TP7) may play a role in controlling movement preparation. We further propose that among the various IN types, parvalbumin (PV)-expressing, fast-spiking, perisomatic-inhibitory INs (PVIs) are particularly relevant in this skill (Kvitsiani et al., 2013, Pinto & Dan, 2015, Lagler et al., 2016). Previously, we have established a behavioural movement protocol combined with in vivo optogenetics and electrophysiology to investigate the neuronal underpinnings of movement control in rodents and found that specific subsections of the PFC differentially contribute to this behaviour (Hardung et al., 2017a; Hardung et al., 2017b). Here, we will focus on the role of PVIs in learning and executing the behavioural task. We aim (1) to define discharge activity of mPFC-PVIs during motor control and learning and (2) to identify the impact of mPFC-PVI neuronal activity on movement initiation and inhibition using a combination of in vivo optogenetics and electrophysiology. This will be paralleled by comparative experiments in M1 and the hippocampus by our partners (TP6 Poulet, TP7 Csicsvari). (3) We will further determine the effect of PVI activity on local neural network oscillations and – in collaboration with TP6 (Poulet) – on the putative communication with downstream motor cortex activity. (4) Finally, by applying ex vivo investigations in collaboration with Bartos (TP1), we will measure amplitudes of spontaneous and evoked excitatory signals in PVIs to examine whether PVIs inputs underwent plastic changes. Data will be compared between trained and untrained mice. With these four parallel approaches, the proposed project will provide detailed information on the impact of PVI-specific synaptic plasticity and PVI activity on cognitive movement control and learning and thereby bridge the gap between synaptic plasticity, neuronal activity, and behaviour.