这个项目是由美国国立卫生研究院拨款DA19112（DGW）和DA026994（CMO）的支持。插图提供了由凯瑟琳Louderback。实验是在范德比尔特鼠的神经行为实验室。

1。作为增强剂使用不同的视觉和听觉刺激编写程序来运行操作性测试会议<ol><li>对于固定比率（FR）的会议：使长度为一小时的会议，在会议房子的光线和风扇打开。累进比率会议，会议两个小时的长度。有两个杠杆杆跨动物（杠杆分配对每个动物永远不会改变）“积极”与“不活跃”的会议和制衡的持续时间延长。 </li><li>程序代码在这样一个根据以下参数的方式是多种多样的，每个增强剂： <ul><li>每个增强剂随机选择以下工期：2，4，6，或8秒。 </li><li>每个增强剂随机选择下列刺激灯闪率：0.625，1.25，2.5，或与50％的占空比为5 Hz，每个。 </li><li>每个刺激灯闪是随机在左侧或右侧室。 </li><li>提供听觉刺激增强剂时间，在我们的实验室中，我们触发输液泵提供上述背景噪音的声音在会议厅内约3分贝。 </li></ul></li><li>代码程序，实时显示以下值：1。积极杠杆压力机，2的数量。数无效杆压力机，3。强化4的数量。时间（以0.1秒的增量）。 </li></ol> 2。处理动物（3天的程序） <ol><li>经过驯化的动物设施，开始处理的动物。这将habituate被拾起和运输的动物。 </li><li>放入笼戴手套的手，让他们坐在90秒开始。如果每个鼠标都还没有调查在那个时候你的手，轻轻地走向小鼠的手，等待每一个嗅探和/或联系你的手，然后再继续。 </li><li>小心地拿起一个尾巴的基地之一每个鼠标放在你的手，迅速解除了它，并把它背下来，让鼠标走你的手入笼。 </li><li>重复每个鼠标的5-10倍，根据鼠标的风采。这是最后一次，按住鼠标高（与它站在你的手）一段时间，取决于一天。第1天：5秒，第2天：10秒，第3天：15秒。确保每个鼠标符合这个标准的一天。在第1天，变化之间的笼子里手套。 </li><li>第2天开始，中风的动物的回当鼠标在你的手。同样在第2天，开始每天称量动物。马克每个动物的尾巴与Sharpie表示数为准。 </li><li>如果注射将在实验过程中，开始habituating小鼠注射2天。这项工作应在笼子里的所有老鼠后已处理，并会见了一天的标准。 </li></ol> 3。清洁和测试设备<ol><li>用热水底盘。 </li><li>操作性室墙壁和地板的清洁，用30％乙醇。 </li><li>运行一个测试程序，房子光，风扇，和刺激灯亮起，延伸杆，并记录杠杆压力机。 </li><li>确保所有的灯和风扇正常运行和测试程序，以确保所有杠杆压力机记录。 </li><li>用30％乙醇的清洁杠杆。 </li></ol> 4。执行操作性会议（会议应在每天的同一时间5-6天/周） <ol><li>称量每个鼠标。 </li><li>加载到每个分庭的程序和适当注释实验。活动的杠杆应平衡与动物之间（即积极杠杆是小鼠的一半分配到左边的拉杆;正确的杠杆激活另一半），但从未改变一次鼠标鼠标已经活跃杆端分配。 </li><li>每个鼠标运输到其指定的室，接近香港总商会，并启动会议。 </li><li>会议结束后，及时清除鼠标和重新标记的尾巴。 </li><li>清洁商会作为第3节中描述。 </li><li>分析活动和非活动的杠杆压力机数量的数据。强化和/或杆的精度（％活跃杆印刷机）的数量也可以报告。如果老鼠对开放源码软件的处理效果进行测试，确保所有被测试的小鼠已达到收购标准（例如，&gt; 20活跃杆压力机和&gt; 65％的积极杠杆压力机最后三个FR - 1会议）之前开始治疗。 </li><li>收购后的FR - 1响应，加固的时间表是可以改变的（例如，固定的比例较高的，渐进的比例，随机比例等）。 </li></ol> 5。代表性的成果雄性C57BL/6J小鼠的OSS收购的例子显示在图1（23日转载） 。对照组小鼠进行了相同的条件下，要么杆，杆压力机除外没有conse序列。小鼠的另一个队列如图2所示。在这个实验中，一组老鼠接受的OSS加固，而另一组接受食品加固。我们发现，随意获取食物的条件下，固定和进步的比例，响应OSS和响应为10％，确保（图2，A和B）之间的相似。这使得操纵的有效比较两种不同的加固类型（感官和食品），避免饥饿状态或反应率的差异所造成的潜在困惑。 <img src="/files/ftp_upload/2292/2292fig1.jpg" alt="图1" /> 图1：OSS小鼠和控制杠杆机 OSS的小鼠接受不同的视觉和听觉刺激，下面的每一个活动的杠杆压（FR - 1钢筋的时间表），而无效的杠杆压力机没有结果。对照组小鼠接受同样的条件，但没有按要么杆（杆为1和2，动物之间平衡以同样的方式，活动和非活动的杠杆平衡的OSS小鼠）的后果。主动杆紧迫的OSS小鼠增加相对不活跃的杠杆，按（* P &lt;0.05，** P &lt;0.01）和非增强的杠杆控制按下（N = 7 8元，P &lt;0.05，$ $ P &lt;0.01 ）。图23日转载。 <img src="/files/ftp_upload/2292/2292fig2.jpg" alt="图2" /> 图2：A.食物响应OSS小鼠和小鼠的杠杆机）小鼠回应FR - 1用于OSS的刺激或食品强化剂（10％保证）加固的时间表。所有小鼠在实验期间的广告食品 libidum访问。 B），FR - 1会议后，小鼠先进五天一个渐进的比率（PR）加固的时间表。数据代表值四天，并为每个动物5。报道最后完成的比例是在右边的Y轴和需要获得相应的增强剂（即30的答复是需要获得此前赢得九个强化增强剂10日）的响应。

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操作性感觉寻求是一个有用的替代静脉注射毒品的自我管理，当鼠标选择动物。既不能手术或导管维护是必需的，其实是有利的，因为这些都是鼠标中的重大技术障碍。开放源码软件也有吸引力，因为它可能是测量有别于其他天然食品，如强化加固方面。 它是有用的注意，在小鼠的行为措施可以在不同的环境条件 24的高度可变。这个问题已经出现在我们自己的实验室...

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<td>Drug self-administration test package for mouse: extra-wide chamber and retractable levers</td>
<td>&nbsp;</td>
<td><a href="http://www.med-associates.com/">Med Associates, Inc</a></td>
<td>MED-307W-CT-D1</td>
<td>Levers are ultra-sensitive (require ~2 grams force) and are mounted 2.2 cm above the floor. Yellow stimulus lamps are mounted 2 cm above each lever.</td>
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<td>Interface and software package</td>
<td>&nbsp;</td>
<td><a href="http://www.med-associates.com/">Med Associates, Inc</a></td>
<td>MED-SYST-16</td>
<td>This is the package for up to 16 chambers.</td>
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operant sensation seeking in the mouse

操作性的方法是强大的行为动机行为的研究工具。这些“自我管理”的方法已被广泛用于吸毒成瘾的研究，由于其高的结构效度。操作性研究，提供研究人员成瘾过程的几个方面的临床前研究的工具。例如，急性加固（包括药物和非药物）的机制，可以使用药物或遗传的工具进行测试，以确定一个分子的目标的能力 ，影响自我管理行为1-6。此外，药物或食物寻求行为可以在主增强剂的情况下进行研究，药理化合物能够破坏这个过程是一个发现的可能有用的治疗网瘾3的分子靶标和化合物的临床前模型， 7-9。用鼠标在执行静脉注射毒品的自我管理研究的一个问题是技术上的困难，保持尿管通畅。在这些实验中的流失率很高，可以达到40％或更高的 10-15 。一般药物自我管理的另一个问题是雪亮的增强剂药物诱导效应产生特定的行为。例如，加强和神经系统的影响的精神兴奋剂的测量，可以混淆他们的心理活动的影响。操作性使用食品加固的方法能够避免这些缺陷，虽然他们在研究药物成瘾的实用工具是有限的事实，改变药物的自我管理的一些操作，对粮食的自我管理的影响微乎其微。例如，中脑边缘多巴胺病变或D1多巴胺受体基因敲除减少，而无需一个重大影响粮食自给行政12,16可卡因的自我管理。 感官刺激被形容为自己的能力，以支持操作性作为主要强化（即没有空调的强化）17-22响应。听觉和视觉刺激是自我管理18,21,23几个品种，虽然少得惊人，是已知的神经机制有关这项加固。操作性的感觉寻求（OSS）的模式是获得鼠标的感觉自我管理的强大的模型，允许的神经机制的研究，在重要的感官加固24。开放源码软件的另一个优势是屏幕操作行为的差异，可能会上瘾有关的基因突变小鼠的能力。我们曾报道，多巴胺D1受体基因敲除小鼠，以前证明是缺乏自我管理精神兴奋剂，也无法获取的OSS 24的。这是一个独特的发现，这些老鼠都能够学习操作性的任务，当食物用来作为增强剂。使用食品加固操作性的研究虽然可以在一般的动机的行为和的内在机制，食品加固，上述研究的有用，这些研究是有限的在他们的应用研究药物成瘾的分子机制。因此，可能有类似的神经基础调解食品加固，这将使开放源码软件为吸毒过程的研究，特别是有吸引力的模式不同的感觉和精神兴奋剂加固。 OSS和药物强化其他的分子靶点之间的重叠程度尚不清楚，但是，我们目前追求的一个主题。虽然成瘾，如抵抗灭绝的某些方面可能与OSS观察，我们发现，在这个模型 24中观察到升级25。有趣的是，升级的摄入量和成瘾的一些其他方面的观察与自我管理蔗糖26。因此，当非药物的操作性程序所需的研究毒瘾有关的过程，食物或感官强化，可以选择最适合于特定的问题被要求。 总之，粮食的自我管理和鼠标OSS不需要静脉留置针，允许更高的吞吐量是指研究药物或遗传操纵的参与动机的神经目标的影响的优势。虽然操作性测试作为增强剂使用的食品是调节食物摄入量的研究，特别是在有用的，开放源码软件，特别是对研究感官刺激的加固机制apt和求新求和成瘾可能有广泛的适用性。

Watch this Scientific Journal Video about Operant Sensation Seeking in the Mouse at JoVE.com

Operant Sensation Seeking in the Mouse

在这个协议中，我们描述了一个操作性的学习方法，使用鼠标增强剂作为感官刺激。它不需要事先培训或食品的限制，以及允许在不使用药物或天然增强剂，如食品的动机行为的研究。

在鼠标的操作性感觉寻求

Operant methods are powerful behavioral tools for the study of motivated behavior.  These 'self-administration' methods have been used extensively in drug ...

Research

JoVE Journal

Neuroscience

12.9K 次观看.  Vanderbilt University Medical Center. 在这个协议中，我们描述了一个操作性的学习方法，使用鼠标增强剂作为感官刺激。它不需要事先培训或食品的限制，以及允许在不使用药物或天然增强剂，如食品的动机行为的研究。

视频: Operant Sensation Seeking in the Mouse

A Procedure for Studying the Footshock-Induced Reinstatement of Cocaine Seeking in Laboratory Rats

The most insidious aspect of drug addiction is the high propensity for relapse. Animal models of relapse, known as reinstatement procedures, have been used extensively to study the neurobiology and phenomenology of relapse to drug use. Although procedural variations have emerged over the past several decades, the most conventional reinstatement procedures are based on the drug self-administration (SA) model. In this model, an animal is trained to perform an operant response to obtain drug. Subsequently, the behavior is extinguished by withholding response-contingent reinforcement. Reinstatement of drug seeking is then triggered by a discrete event, such as an injection of the training drug, re-exposure to drug-associated cues, or exposure to a stressor 1.
Reinstatement procedures were originally developed to study the ability of acute non-contingent exposure to the training drug to reinstate drug seeking in rats and monkeys 1, 2. Reinstatement procedures have since been modified to study the role of environmental stimuli, including drug-associated cues and exposure to various forms of stress, in relapse to drug seeking 1, 3, 4.
Over the past 15 years, a major focus of the reinstatement literature has been on the role of stress in drug relapse. One of the most commonly used forms of stress for studying this relationship is acute exposures to mild, intermittent, electric footshocks. The ability of footshock stress to induce reinstatement of drug seeking was originally demonstrated by Shaham and colleagues (1995) in rats with a history of intravenous heroin SA5. Subsequently, the effect was generalized to rats with histories of intravenous cocaine, methamphetamine, and nicotine SA, as well as oral ethanol SA 3, 6.
Although footshock-induced reinstatement of drug seeking can be achieved reliably and robustly, it is an effect that tends to be sensitive to certain parametrical variables. These include the arrangement of extinction and reinstatement test sessions, the intensity and duration of footshock stress, and the presence of drug-associated cues during extinction and testing for reinstatement. Here we present a protocol for footshock-induced reinstatement of cocaine seeking that we have used with consistent success to study the relationship between stress and cocaine seeking.

Animal models of relapse, known as reinstatement procedures, have been used extensively to study the role of stress in relapse to drug seeking. Here, we report on a method for inducing the reinstatement of cocaine seeking in laboratory rats via acute exposures to mild, intermittent electric footshock.

在实验室老鼠研究求可卡因电击诱导恢复原状的程序

The most insidious aspect of drug addiction is the high propensity for relapse.  Animal models of relapse, known as reinstatement procedures, have been ...

科研

神经科学

Multiple-mouse Neuroanatomical Magnetic Resonance Imaging

The field of mouse phenotyping with magnetic resonance imaging (MRI) is rapidly growing, motivated by the need for improved tools for characterizing and evaluating mouse models of human disease. MRI is an excellent modality for investigating genetically altered animals. It is capable of whole brain coverage, can be used in vivo, and provides multiple contrast mechanisms for investigating different aspects of neuranatomy and physiology. The advent of high-field scanners along with the ability to scan multiple mice simultaneously allows for rapid phenotyping of novel mutations.
Effective mouse MRI studies require attention to many aspects of experiment design. In this article, we will describe general methods to acquire quality images for mouse phenotyping using a system that images mice concurrently in shielded transmit/receive radio frequency (RF) coils in a common magnet (Bock et al., 2003). We focus particularly on anatomical phenotyping, an important and accessible application that has shown a high potential for impact in many mouse models at our imaging centre. Before we can provide the detailed steps to acquire such images, there are important practical considerations for both in vivo brain imaging (Dazai et al., 2004) and ex vivo brain imaging (Spring et al., 2007) that should be noted. These are discussed below.

Magnetic resonance imaging (MRI) has become an increasingly popular tool for examining the phenotype of genetically altered mice. This article illustrates the methods necessary to achieve high-throughput phenotyping of genetically altered mice using multiple-mouse MRI.

多鼠神经解剖学磁共振成像

The field of mouse phenotyping with magnetic resonance imaging (MRI) is rapidly growing, motivated by the need for improved tools for characterizing and ...

Detection of Neuritic Plaques in Alzheimer's Disease Mouse Model

Alzheimer's disease (AD) is the most common neurodegenerative disorder leading to dementia. Neuritic plaque formation is one of the pathological hallmarks of Alzheimer's disease. The central component of neuritic plaques is a small filamentous protein called amyloid &beta; protein (A&beta;)1, which is derived from sequential proteolytic cleavage of the beta-amyloid precursor protein (APP) by &beta;-secretase and &gamma;-secretase. The amyloid hypothesis entails that A&gamma;-containing plaques as the underlying toxic mechanism in AD pathology2. The postmortem analysis of the presence of neuritic plaque confirms the diagnosis of AD. To further our understanding of A&gamma; neurobiology in AD pathogenesis, various mouse strains expressing AD-related mutations in the human APP genes were generated. Depending on the severity of the disease, these mice will develop neuritic plaques at different ages. These mice serve as invaluable tools for studying the pathogenesis and drug development that could affect the APP processing pathway and neuritic plaque formation. In this protocol, we employ an immunohistochemical method for specific detection of neuritic plaques in AD model mice. We will specifically discuss the preparation from extracting the half brain, paraformaldehyde fixation, cryosectioning, and two methods to detect neurotic plaques in AD transgenic mice: immunohistochemical detection using the ABC and DAB method and fluorescent detection using thiofalvin S staining method.

Detection of Neuritic Plaques in Alzheimer&#039;s Disease Mouse Model

One of the pathological characteristics of AD is the formation of Amyloid &#x03B2; protein positive neuritic plaques. In this protocol we describe two methods to detect neuritic plaques in transgenic AD model mice: immunohistochemical detection using the ABC and DAB method and fluorescent detection using thioflavin S staining method.

在阿尔茨海默氏症小鼠模型神经炎斑检测

Alzheimer's disease (AD) is the most common neurodegenerative disorder leading to dementia. Neuritic plaque formation is one of the pathological hallmarks ...

The Mouse Forced Swim Test

The forced swim test is a rodent behavioral test used for evaluation of antidepressant drugs, antidepressant efficacy of new compounds, and experimental manipulations that are aimed at rendering or preventing depressive-like states. Mice are placed in an inescapable transparent tank that is filled with water and their escape related mobility behavior is measured. The forced swim test is straightforward to conduct reliably and it requires minimal specialized equipment. Successful implementation of the forced swim test requires adherence to certain procedural details and minimization of unwarranted stress to the mice. In the protocol description and the accompanying video, we explain how to conduct the mouse version of this test with emphasis on potential pitfalls that may be detrimental to interpretation of results and how to avoid them. Additionally, we explain how the behaviors manifested in the test are assessed.

The forced swim test is validated as an experimental approach to assess potential antidepressant efficacy in rodents. Experimental animals are placed in a tank of water and escape-related mobility behavior is quantified. The common procedures for the mouse version of this test are described.

小鼠强迫游泳实验

The forced swim test is a rodent behavioral test used for evaluation of antidepressant drugs, antidepressant efficacy of new compounds, and experimental ...

Microdialysis of Ethanol During Operant Ethanol Self-administration and Ethanol Determination by Gas Chromatography

Operant self-administration methods are commonly used to study the behavioral and pharmacological effects of many drugs of abuse, including ethanol. However, ethanol is typically self-administered orally, rather than intravenously like many other drugs of abuse. The pharmacokinetics of orally administered drugs are more complex than intravenously administered drugs. Because understanding the relationship between the pharmacological and behavioral effects of ethanol requires knowledge of the time course of ethanol reaching the brain during and after drinking, we use in vivo microdialysis and gas chromatography with flame ionization detection to monitor brain dialysate ethanol concentrations over time. 
Combined microdialysis-behavioral experiments involve the use of several techniques. In this article, stereotaxic surgery, behavioral training and microdialysis, which can be adapted to test a multitude of self-administration and neurochemical centered hypotheses, are included only to illustrate how they relate to the subsequent phases of sample collection and dialysate ethanol analysis. Dialysate ethanol concentration analysis via gas chromatography with flame-ionization detection, which is specific to ethanol studies, is described in detail. Data produced by these methods reveal the pattern of ethanol reaching the brain during the self-administration procedure, and when paired with neurochemical analysis of the same dialysate samples, allows conclusions to be made regarding the pharmacological and behavioral effects of ethanol.

A method to determine the time course of ethanol concentration in the brains of rats during operant ethanol self-administration is described. Gas chromatography with flame ionization detection is used to quantify ethanol in the dialysate samples, because it has the sensitivity required for the small volumes that are generated.

微透析的乙醇操作性乙醇的自我管理和乙醇的测定气相色谱

Operant self-administration methods are commonly used to study the behavioral and pharmacological effects of many drugs of abuse, including ethanol.  ...

A Simple Way to Measure Alterations in Reward-seeking Behavior Using Drosophila melanogaster

We describe a protocol for measuring ethanol self-administration in fruit flies (Drosophila melanogaster) as a proxy for changes in reward states. We demonstrate a simple way to tap into the fly reward system, modify experiences related to natural reward, and use voluntary ethanol consumption as a measure for changes in reward states. The approach serves as a relevant tool to study the neurons and genes that play a role in experience-mediated changes of internal state. The protocol is composed of two discrete parts: exposing the flies to rewarding and nonrewarding experiences, and assaying voluntary ethanol consumption as a measure of the motivation to obtain a drug reward. The two parts can be used independently to induce the modulation of experience as an initial step for further downstream assays or as an independent two-choice feeding assay, respectively. The protocol does not require a complicated setup and can therefore be applied in any laboratory with basic fly culture tools.

A Simple Way to Measure Alterations in Reward-seeking Behavior Using Drosophila melanogaster

We describe a protocol for inducing rewarding and nonrewarding experiences in fruit flies (Drosophila melanogaster) using voluntary ethanol consumption as a measure for changes in reward states.

一个简单的方法来衡量在改建悬赏寻求行为使用<em&gt;果蝇</em

We describe a protocol for measuring ethanol self-administration in fruit flies (Drosophila melanogaster) as a proxy for changes in reward states. We ...

Operant Protocols for Assessing the Cost-benefit Analysis During Reinforced Decision Making by Rodents

Reinforcement-guided decision making is the ability to choose between competing courses of action based on the relative value of the benefits and their consequences. This process is integral to the normal human behavior and has been shown to be disrupted by neurological and psychiatric disorders such as addiction, schizophrenia, and depression. Rodents have long been used to uncover the neurobiology of human cognition. To this end, several behavioral tasks have been developed; however, most are non-automated and are labor-intensive. The recent development of the open-source microcontroller has enabled researchers to automate operant-based tasks for assessing a variety of cognitive tasks, standardizing the stimulus presentation, improving the data recording and consequently, improving the research output. Here, we describe an automated delay-based reinforcement-guided decision-making task, using an operant T-maze controlled by custom-written software programs. Using these decision-making tasks, we show the changes in the local field potential activities in the anterior cingulate cortex of a rat whilst it performs a delay-based cost-and-benefit decision-making task.

A cost-benefit analysis is a weighing-scale approach that the brain performs during the course of decision making. Here, we propose a protocol to train rats on an operant-based decision-making paradigm where rats choose higher rewards at the expense of waiting for 15 s to receive them.

啮齿动物强化决策中成本效益分析的操作协议

Reinforcement-guided decision making is the ability to choose between competing courses of action based on the relative value of the benefits and their ...

Transpupillary Two-Photon In Vivo Imaging of the Mouse Retina

The retina transforms light signals from the environment into electrical signals that are propagated to the brain. Diseases of the retina are prevalent and cause visual impairment and blindness. Understanding how such diseases progress is critical to formulating new treatments. In vivo&#160;microscopy in animal models of disease is a powerful tool for understanding neurodegeneration and has led to important progress towards treatments of conditions ranging from Alzheimer&#39;s disease to stroke. Given that the retina is the only central nervous system structure inherently accessible by optical approaches, it naturally lends itself towards in vivo imaging. However, the native optics of the lens and cornea present some challenges for effective imaging access.
This protocol outlines methods for in vivo two-photon imaging of cellular cohorts and structures in the mouse retina at cellular resolution, applicable for both acute- and chronic-duration imaging experiments. It presents examples of retinal ganglion cell (RGC), amacrine cell, microglial, and vascular imaging using a suite of labeling techniques including adeno-associated virus (AAV) vectors, transgenic mice, and inorganic dyes. Importantly, these techniques extend to all cell types of the retina, and suggested methods for accessing other cellular populations of interest are described. Also detailed are example strategies for manual image postprocessing for display and quantification. These techniques are directly applicable to studies of retinal function in health and disease.

In vivo imaging is a powerful tool for the study of biology in health and disease. This protocol describes transpupillary imaging of the mouse retina with a standard two-photon microscope. It also demonstrates different in vivoimaging methods to fluorescently label multiple cellular cohorts of the retina.

小鼠视网膜的经瞳双光子体内成像

The retina transforms light signals from the environment into electrical signals that are propagated to the brain. Diseases of the retina are prevalent ...

In vivo Calcium Imaging in Mouse Inferior Olive

Inferior olive (IO), a nucleus in the ventral medulla, is the only source of climbing fibers that form one of the two input pathways entering the cerebellum. IO has long been proposed to be crucial for motor control and its activity is currently considered to be at the center of many hypotheses of both motor and cognitive functions of the cerebellum. While its physiology and function have been relatively well studied on single-cell level in vitro, presently there are no reports on the organization of the IO network activity in living animals. This is largely due to the extremely challenging anatomical location of the IO, making it difficult to subject to conventional fluorescent imaging methods, where an optic path must be created through the entire brain located dorsally to the region of interest.
Here we describe an alternative method for obtaining state-of-the-art -level calcium imaging data from the IO network. The method takes advantage of the extreme ventral location of the IO and involves a surgical procedure for inserting a gradient-refractive index (GRIN) lens through the neck viscera to come into contact with the ventral surface of the calcium sensor GCaMP6s-expressing IO in anesthetized mice. A representative calcium imaging recording is shown to demonstrate the feasibility to record IO neuron activity after the surgery. While this is a non-survival surgery and the recordings must be conducted under anesthesia, it avoids damage to life-critical brainstem nuclei and allows conducting large variety of experiments investigating spatiotemporal activity patterns and input integration in the IO. This procedure with modifications could be used for recordings in other, adjacent regions of the ventral brainstem.

In vivo Calcium Imaging in Mouse Inferior Olive

We present a protocol to expose the brainstem of adult mouse from the ventral side. By using a gradient-refractive index lens with a miniature microscope, calcium imaging can be used to examine the activity of inferior olive neural somata in vivo.

在体内 小鼠劣质橄榄中的钙成像

Inferior olive (IO), a nucleus in the ventral medulla, is the only source of climbing fibers that form one of the two input pathways entering the ...

Using Optogenetics to Reverse Neuroplasticity and Inhibit Cocaine Seeking in Rats

This protocol demonstrates the steps needed to use optogenetic tools to reverse cocaine-induced plasticity at thalamo-amygdala circuits to reduce subsequent cocaine seeking behaviors in the rat. In our research, we had found that when rats self-administer intravenous cocaine paired with an audiovisual cue, synapses formed at inputs from the medial geniculate nucleus of the thalamus (MGN) onto principal neurons of the lateral amygdala (LA) become stronger as the cue-cocaine association is learned. We hypothesized that reversal of the cocaine-induced plasticity at these synapses would reduce cue-motivated cocaine seeking behavior. In order to accomplish this type of neuromodulation in vivo, we wanted to induce synaptic long-term depression (LTD), which decreases the strength of MGN-LA synapses. To this end, we used optogenetics, which allows neuromodulation of brain circuits using light. The excitatory opsin oChiEF was expressed on presynaptic MGN terminals in the LA by infusing an AAV containing oChiEF into the MGN. Optical fibers were then implanted in the LA and 473 nm laser light was pulsed at a frequency of 1 Hz for 15 minutes to induce LTD and reverse cocaine induced plasticity. This manipulation produces a long-lasting reduction in the ability of cues associated with cocaine to induce drug seeking actions.

The methods described here outline a procedure used to optogenetically reverse cocaine-induced plasticity in a behaviorally-relevant circuit in rats. Sustained low-frequency optical stimulation of thalamo-amygdala synapses induces long-term depression (LTD). In vivo optogenetically-induced LTD in cocaine-experienced rats resulted in the subsequent attenuation of cue-motivated drug seeking.