Functional heterogeneity of vasoactive intestinal peptide-expressing interneurons in the anterior cingulate cortex

前扣带皮层表达血管活性肠肽的中间神经元的功能异质性

基本信息

批准号：
10612970
负责人：
Alberto Cruz-Martin
金额：
$ 41.25万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612970
关键词：
3D Print Acute Adaptive Behaviors Address Anterior Anterior Nuclear Group Anti-Anxiety Agents Anxiety Area Automobile Driving Behavior Behavior monitoring Behavioral Behavioral trial Biological Assay Brain Calcium Categories Cells Cerebral cortex Classification Complex Contralateral Data Decision Making Dependovirus Electrophysiology (science)Emotional Enterobacteria phage P1 Cre recombinase Exhibits Goals Heterogeneity Image Implant Individual Injections Interneurons Label Light Maps Methods Microscope Modeling Molecular Monitor Morphology Mus Neurons Parvalbumins Pattern Population Positioning Attribute Probability Process Property Pyramidal Cells Rabies Reporter Resolution Rodent Role Slice Social Behavior Somatostatin Source Specificity Stimulus Synapses Testing Thalamic Nuclei Transgenic Mice Vasoactive Intestinal Peptide Viral Work anxiety-like behavior cingulate cortex classification algorithm cognitive function emotion regulation emotional behavior excitatory neuron implantation in vivo individual response insight miniaturize molecular marker neural neuronal cell body optogenetics presynaptic response social social cognition

项目摘要

PROJECT SUMMARY Cortical subregions are often implicated in a variety of behavioral functions, but it is not well understood how these areas encode such diverse information. The anterior cingulate cortex (ACC) is necessary for emotional processing and social cognition, but how it encodes stimuli relevant to both processes is unknown. The goal of this proposal is to understand the functional heterogeneity of ACC circuits, and how this impacts encoding of diverse stimuli and cognitive function. In Aim 1, we will determine the functional heterogeneity of ACC inhibitory circuits during social and anxiety-like behaviors. To monitor interneuron activity, we will first inject an adeno- associated virus (AAV) that expresses GCaMP6f, a fluorescent Ca2+ indicator, in a Cre-dependent manner into the ACC of somatostatin (SST)- or parvalbumin (PV)-cre transgenic mice. Next, we will use the 3D-printed miniature miniscopes to perform in vivo single-cell resolution calcium imaging in either somatostatin or parvalbumin interneurons in the ACC to investigate their functional heterogeneity while mice performed tasks to assay anxiety-like behaviors, general sociability and social novelty. In Aim 2, we will determine whether specific populations of excitatory pyramidal cells (Pyr) in the ACC encode particular behavioral stimuli. First, to target specific populations of Pyr in the ACC, we will inject an AAV that expresses Cre recombinase and can retrogradely label cells into either the contralateral ACC, anterior thalamic nucleus, or the retrosplenial cortex. Next, we will inject an AAV that expresses GCaMP6 in a cre-dependent manner to label Pyr in the ACC and project to either the contralateral ACC, anterior thalamic nucleus or retrosplenial cortex. Three weeks later, we will use approaches described in Aim 1 to monitor the activity of specific populations of Pyr during particular behaviors. We will also determine the laminar sources of synaptic input to VIP interneurons in the ACC. To test this, we will first cross VIP-cre mice to a cre-dependent fluorescent reporter line. Next, we will inject an AAV expressing ChETA, a light-activated channel, into the contralateral ACC, anterior thalamic nucleus or retrosplenial cortex. Four weeks after viral injections, we will combine electrophysiological recordings in acute brain slices with optogenetic stimulation to characterize the laminar organization of specific projections unto VIP interneurons in the ACC. In addition to determining the connectivity probability of these inputs, we will correlate the cortical depth of the soma to morphological, and electrophysiological properties and molecular markers. While reductionist and simplified models of cortical networks have established a framework to understand their function, it is now evident that to understand the role of cortical networks in complex, adaptive behavior, optimized models will need to incorporate the functional heterogeneity of these circuits. Completion of these aims will dissect the functional heterogeneity of inhibitory circuits in the ACC.

项目摘要皮质子区域通常与各种行为功能有关，但尚不清楚如何了解这些领域编码如此多样化的信息。前扣带回皮层（ACC）对于情感是必需的处理和社会认知，但是它如何编码与这两个过程相关的刺激。目标该建议是了解ACC电路的功能异质性，以及这如何影响编码多样化的刺激和认知功能。在AIM 1中，我们将确定ACC抑制的功能异质性社交和类似焦虑行为的电路。为了监视中间神经元的活动，我们将首先注入腺相关病毒（AAV）以CRE依赖性方式表达GCAMP6F，荧光Ca2+指示器生长抑素（SST） - 或白蛋白（PV）-CRE转基因小鼠的ACC。接下来，我们将使用3D打印在生长抑素或 ACC中的白蛋白中间神经元研究其功能异质性，而小鼠执行任务测定类似焦虑的行为，一般的社交和社会新颖性。在AIM 2中，我们将确定是否具体 ACC中特定行为刺激中的兴奋性锥体细胞（PYR）的种群。首先，目标 ACC中PYR的特定群体，我们将注入一种表达CRE重组酶的AAV，并且可以将细胞逆行标记为对侧ACC，前丘脑前核或后泛胞外皮质。接下来，我们将以CRE依赖性方式表达GCAMP6的AAV，以标记ACC中的PYR和投影到对侧ACC，前丘脑前核或泛胞外皮层。三周后，我们将使用AIM 1中描述的方法来监视特定特定PYR的特定人群的活动行为。我们还将确定ACC中VIP中间神经元的突触输入的层流源。测试这，我们将首先将VIP-CRE小鼠交叉至CRE依赖性荧光报告系。接下来，我们将注入AAV 表达cheta，一种光激活的通道，向对侧ACC，前丘脑前核或肾上腺皮质。注射病毒后四个星期，我们将在急性中结合电生理记录带有光遗传刺激的大脑切片，以表征特定投影的层流组织 ACC中的中间神经元。除了确定这些输入的连通性概率外，我们还将关联躯体的皮质深度，形态学，电生理特性和分子标记。虽然还原主义和简化的皮质网络模型已经建立了一个框架，以了解其功能，现在很明显，要了解皮质网络在复杂，适应性行为中的作用，优化的模型将需要结合这些电路的功能异质性。这些完成 AIMS将剖析ACC中抑制回路的功能异质性。