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Plasticity of inhibitory synaptic transmission in the hippocampus

海马抑制性突触传递的可塑性

基本信息

批准号：
BB/N013956/1
负责人：
Jack Mellor
金额：
$ 72.79万
依托单位：
University of Bristol
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FN013956%2F1
关键词：
Plasticity inhibitory synaptic transmission hippocampus

项目摘要

The building blocks of the brain are nerves cells, also called neurons, connected to each other by synapses. Neurons form two categories: excitatory neurons promote activity in their connected neurons, whereas inhibitory neurons depress activity. Even though inhibitory neurons are less numerous than excitatory neurons (20%), they play a central role in brain function and computation. Disruption of inhibitory neurons leads to an imbalance in excitation and inhibition that can, in turn, lead to diseases such as epilepsy, schizophrenia and autism spectrum disorders. Thus, understanding what regulates the strength of excitatory and inhibitory synapses is an important research goal. Interestingly, although there has been much focus on plasticity of excitatory synapses, plasticity of inhibitory synapses has been largely neglected. In this BBSRC project, we aim to investigate the phenomenology and function of inhibitory synaptic plasticity. The hippocampus is a brain area that plays an important role in episodic memory and spatial navigation. Neuronal network activity in the hippocampus exhibits multiple discrete states that are identified by rhythmic oscillations and perform distinct computational functions. Memories are initially encoded during exploration when theta (5-12Hz) and gamma (30-120Hz) frequency oscillations are prevalent whereas consolidation of memories occurs offline in periods of transient sharp wave ripple (~200Hz) activity during rest or sleep. Specific subtypes of inhibitory neurons have been found to be active in these distinct behavioural states and, intriguingly, inhibitory plasticity has been shown to depend on the precise co-ordination of inhibitory and excitatory neuron firing and on the state of the neural network. This indicates that different behavioural states are likely to trigger distinct forms of inhibitory plasticity at specific inhibitory synapses. However, there is very limited evidence for the role of inhibitory plasticity in the hippocampus.Our hypotheses are that plasticity of inhibitory synapses: a) can regulate network computations, b) is specific to the inhibitory neurons subtypes and c) determines input selectivity for excitatory neurons in a behavioural state dependent manner. We propose a joint effort from an experimental team, which has expertise in synaptic plasticity in the hippocampus, with a computational team that recently proposed a theoretical model of inhibitory plasticity. By a tight interaction allowing the computational model to be informed by and to guide experiments and experiments to refine the model, we aim to investigate how neural activity engages inhibitory plasticity depending on the inhibitory neuron subtype, and how inhibitory plasticity shapes network computations in the hippocampus. This work will provide important information on the mechanisms and function of inhibitory plasticity that will ultimately improve our understanding of how inhibition may be modified in disease states potentially leading to new therapies.

大脑的组成部分是神经细胞，也称为神经元，通过突触相互连接。神经元分为两类：兴奋性神经元促进其连接的神经元的活动，而抑制性神经元抑制活动。尽管抑制性神经元的数量少于兴奋性神经元（20%），但它们在大脑功能和计算中发挥着核心作用。抑制性神经元的破坏导致兴奋和抑制的不平衡，这反过来会导致癫痫、精神分裂症和自闭症谱系障碍等疾病。因此，了解是什么调节兴奋性和抑制性突触的强度是一个重要的研究目标。有趣的是，尽管人们对兴奋性突触的可塑性有很多关注，但抑制性突触的可塑性却在很大程度上被忽视了。在这个BBSRC项目中，我们的目的是研究抑制性突触可塑性的现象学和功能。海马体是在情景记忆和空间导航中起重要作用的大脑区域。海马体中的神经元网络活动表现出多个离散状态，这些状态通过节律性振荡来识别，并执行不同的计算功能。当θ（5- 12 Hz）和γ（30- 120 Hz）频率振荡普遍时，记忆最初在探索期间被编码，而记忆的巩固在休息或睡眠期间的瞬时尖波涟漪（~ 200 Hz）活动期间离线发生。已经发现抑制性神经元的特定亚型在这些不同的行为状态中是活跃的，有趣的是，抑制性可塑性已经被证明取决于抑制性和兴奋性神经元放电的精确协调以及神经网络的状态。这表明不同的行为状态可能会在特定的抑制性突触上触发不同形式的抑制可塑性。然而，关于抑制性可塑性在海马中的作用的证据非常有限，我们的假设是抑制性突触的可塑性：a）可以调节网络计算，B）是抑制性神经元亚型所特有的，c）以行为状态依赖的方式决定兴奋性神经元的输入选择性。我们提出了一个共同的努力，从一个实验小组，在海马突触可塑性的专业知识，与计算团队，最近提出了一个理论模型的抑制可塑性。通过紧密的相互作用，允许计算模型了解并指导实验和实验来完善模型，我们的目标是研究神经活动如何根据抑制性神经元亚型参与抑制可塑性，以及抑制可塑性如何塑造海马中的网络计算。这项工作将提供有关抑制可塑性机制和功能的重要信息，最终将提高我们对疾病状态下如何改变抑制作用的理解，从而可能导致新的疗法。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Modeling somatic and dendritic spike mediated plasticity at the single neuron and network level.

DOI：
10.1038/s41467-017-00740-z
发表时间：
2017-09-26
期刊：
Nature communications
影响因子：
16.6
作者：
Bono J;Clopath C
通讯作者：
Clopath C

The functional role of sequentially neuromodulated synaptic plasticity in behavioural learning.

DOI：
10.1371/journal.pcbi.1009017
发表时间：
2021-06
期刊：
PLoS computational biology
影响因子：
4.3
作者：
Ang GWY;Tang CS;Hay YA;Zannone S;Paulsen O;Clopath C
通讯作者：
Clopath C

Free recall scaling laws and short-term memory effects in a latching attractor network.

锁定吸引子网络中的自由回忆缩放定律和短期记忆效应。

DOI：
10.1073/pnas.2026092118
发表时间：
2021
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Boboeva V
通讯作者：
Boboeva V

Assessment of Methods for the Intracellular Blockade of GABAA Receptors.