Role of VGF in cortical PV+ interneuron interconnectivity

大脑的特殊之处在于，与计算机不同，它通过修改其连接来适应变化或损伤，基本上是重新布线。如果没有这种被称为大脑可塑性的能力，我们就无法从婴儿期发育到成年期，也无法从脑损伤中恢复过来。神经网络通常由兴奋性和抑制性细胞组成，维持兴奋性和抑制性之间的适当平衡对正常的大脑功能至关重要。从正常的发育变化到病理变化，许多力量不断地扰乱兴奋和抑制之间的平衡。即使是学习的过程也会改变这种平衡。尽管有这些压力，我们的大脑在大部分时间里都能补偿这些变化并保持稳定的功能。在单个神经元和网络的水平上，这是由于一种称为稳态可塑性的大脑可塑性，它基于一个简单的规则：增加神经元的活动导致其连接或电特性的变化，旨在减少这种活动，反之亦然，这确保神经元在最佳范围内发挥作用。在这个项目中，我们的目的是研究机制调节稳态可塑性在小鼠大脑皮层的主要群体的抑制性神经元。这些细胞可以通过表达钙结合蛋白小白蛋白（PV）与其他神经元区分开来，它们保护皮质网络免受失控的兴奋，使兴奋性神经元同步，并在学习中发挥重要作用。我们最近发现，PV中间神经元通过重塑它们从其他PV中间神经元接收的抑制性连接来响应它们的活性变化。这个过程需要神经肽编码基因Vgf的功能。在这个项目中，我们将：（1）研究突触数量变化背后的细胞动力学，（2）确定参与突触重塑的特异性VEGF衍生肽，以及（3）鉴定在PV+中介导VEGF衍生肽功能的假定受体。我们预期，阐明调节皮质PV抑制性神经元的稳态可塑性的机制将增加我们对它们在学习和记忆及其参与神经发育障碍的病理生理学。

What makes the brain special is that, unlike a computer, it adapts to changes or damage by modifying its connections, essentially re-wiring itself. Without this ability, known as brain plasticity, we would not be able to develop from infancy through to adulthood or recover from brain injury.Neural networks typically consist of excitatory and inhibitory cells, and maintaining a proper balance between excitation and inhibition is critical for normal brain function. Many forces continuously perturb the balance between excitation and inhibition, from regular developmental changes to pathological alterations. Even the process of learning is known to alter this balance. Despite all these pressures, our brains manage - most of the time - to compensate for these changes and maintain a stable function. At the level of individual neurons and networks, this is due to a form of brain plasticity known as homeostatic plasticity, which is based on a simple rule: increasing a neuron's activity leads to changes in its connections or electrical properties aiming to reduce this activity and vice-versa, which ensures that neurons function within an optimal range. In this project, we aim to investigate the mechanisms regulating homeostatic plasticity in the mouse cerebral cortex's main population of inhibitory neurons. These cells, which can be distinguished from other neurons by the expression of the calcium-binding protein parvalbumin (PV), guard cortical networks against runaway excitation, synchronise excitatory neurons, and are critically involved in learning. We have recently found that PV interneurons respond to changes in their activity by remodelling the inhibitory connections they receive from other PV interneurons. This process requires the function of the neuropeptide-encoding gene Vgf. In this project, we will: (1) study the cellular dynamics underlying the change in the number of synapses, (2) determine the specific VGF-derived peptides involved in synapse remodelling, and (3) identify the putative receptor mediating the function of VGF-derived peptides in PV+ interneurons.We anticipate that elucidating the mechanisms modulating homeostatic plasticity in cortical PV inhibitory neurons will increase our understanding of their role in learning and memory and their involvement in the pathophysiology of neurodevelopmental disorders.