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Disinhibition-assisted LTP as a method for testing role of neuronal circuits in behavior

去抑制辅助 LTP 作为测试神经元回路在行为中的作用的方法

基本信息

批准号：
9903868
负责人：
Alexei Morozov
金额：
$ 12.46万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-20 至 2019-11-30
项目状态：
已结题

项目摘要

Project Summary During development, learning or progression towards disease, the brain undergoes plastic changes characterized by gradual increases or decreases in synaptic transmission. Modeling such changes by artificial means is necessary for understanding their functional role. Recently developed optogenetic and chemogenetic techniques allow neuronal activation or suppression, but they act in the all-or-none manner and do not allow modeling of gradual synaptic changes. Meanwhile, such gradual changes can be obtained by inducing long-term potentiation (LTP) or depression, but these techniques do not work reliably in all areas of the brain, particularly in the areas with a strong inhibitory control, which include the basolateral amygdala. In the pilot experiments, we found that a transient chemogenetic or optogenetic suppression of the somatostatin- but not parvalbumin-positive interneurons enables LTP induction in the prefrontal- amygdala pathway. Based on these findings and published data, we hypothesize that a transient suppression of certain classes of the local GABAergic neurons, combined with stimulation of synapses of interest, will provide a universal means for inducing LTP in the remote inputs to the local principal neurons in vivo. We will test this hypothesis in Aim 1 using the prefrontal-amygdala circuit, because its artificial synaptic modulation has been especially difficult to achieve, while the need for such modulation is high given the role of this circuit in the behavioral traits relevant to mental disease. In Aim 2, we will test predictions that synaptic efficacy in the dmPFC-BLA loop determines oscillatory synchronization between the two structures and influences anxiety- like behaviors. These predictions are based on findings that theta oscillations synchrony between BLA and dmPFC increase with innate anxiety in the open field, and photostimulation of BLA axonal terminals in dmPFC acutely increase anxiety-like behaviors in the elevated plus maze and open field. The study is expected to produce techniques for obtaining LTP of a desirable magnitude in glutamatergic synapses connecting principal neurons of dmPFC and BLA. The classes of GABAergic neurons that gate LTP in these pathways will be identified, and methods for their transient suppression to aid LTP induction will be developed. This LTP optimization process will provide a template for developing analogous LTP protocols for other brain areas. The role of synaptic efficacy of the dmPFC-BLA reciprocal projections in oscillatory synchronization and anxiety-relevant traits will be determined, which will inform about potential methods for targeted manipulation of that pathway in emotional disorders.

项目摘要在发育、学习或疾病进展过程中，大脑会经历可塑性，以突触传递的逐渐增加或减少为特征的变化。建模这种人为的改变对于理解它们的功能作用是必要的。最近开发的光遗传学和化学遗传学技术允许神经元激活或抑制，但它们以全有或全无的方式起作用，并且不允许对逐渐的突触变化进行建模。同时，这种逐渐变化可以通过诱导长时程增强（LTP）或抑郁症，但这些技术并不能在大脑的所有区域都可靠地工作，特别是在大脑中。具有强烈抑制控制的区域，包括基底外侧杏仁核。试点实验中，我们发现，一个短暂的化学遗传或光遗传抑制，生长抑素-而不是小清蛋白阳性的中间神经元能够在前额叶诱导LTP，杏仁核通路基于这些发现和已发表的数据，我们假设，抑制某些类别的局部GABA能神经元，结合刺激感兴趣的突触，将提供一个通用的手段，诱导LTP的远程输入到体内局部主要神经元。我们将在目标1中使用前额叶杏仁核来检验这一假设电路，因为它的人工突触调制一直特别难以实现，而考虑到该回路在相关行为特征中的作用，精神疾病在目标2中，我们将测试dmPFC-BLA中突触功效的预测，环决定了两个结构之间的振荡同步，并影响焦虑- 比如行为这些预测是基于以下发现，即θ振荡同步 BLA和dmPFC之间的关系随着开放视野中的先天焦虑而增加， dmPFC中的BLA轴突终末急性增加了升高的+ 迷宫和开阔地。这项研究有望产生获得LTP的技术，连接dmPFC主要神经元和 BLA.将识别在这些通路中门控LTP的GABA能神经元的类别，将开发用于其瞬态抑制以辅助LTP诱导的方法。这个LTP 优化过程将为开发类似的LTP协议提供模板，大脑区域dmPFC-BLA相互投射的突触效能在振荡神经元中的作用同步和焦虑相关的特征将被确定，这将告知潜在的有针对性地操纵情绪障碍中该通路的方法。