在注意定势转移任务：测量小鼠认知的灵活性
Summary
该协议的目的是为了执行行为分析，如注意力集转移任务（AST），以评估在小鼠中前额叶皮层介导的认知灵活性。
Abstract
Cognitive impairment, particularly involving dysfunction of circuitry within the prefrontal cortex (PFC), represents a core feature of many neuropsychiatric and neurodevelopmental disorders, including depression, post-traumatic stress disorder, schizophrenia and autism spectrum disorder. Deficits in cognitive function also represent the most difficult symptom domain to successfully treat, as serotonin reuptake inhibitors and tricyclic antidepressants have only modest effects. Functional neuroimaging studies and postmortem analysis of human brain tissue implicate the PFC as being a primary region of dysregulation in patients with these disorders. However, preclinical behavioral assays used to assess these deficits in mouse models which can be readily manipulated genetically and could provide the basis for studies of new treatment avenues have been underutilized. Here we describe the adaptation of a behavioral assay, the attentional set shifting task (AST), to be performed in mice to assess prefrontal cortex mediated cognitive deficits. The neural circuits underlying behavior during the AST are highly conserved across humans, nonhuman primates and rodents, providing excellent face, construct and predictive validity.
Introduction
在注意力集中转移任务（AST）前1,2是发展成为人们关注和认知弹性的大鼠了十多年。剑桥神经心理测试自动化电池（CANTAB），其被用于识别认知功能障碍的人类和非人类灵长类3,4的intradimensional /异次元分量后的AST被建模。同时学习简单的规则的能力保持不变，在学习赤字修改时，规则已经改变被发现在患者从各种神经精神障碍（如精神分裂症，强迫症，抑郁症）的痛苦，神经退行性疾病的响应（ 即，帕金森氏病）和患者的病灶，以预额叶皮层5。更一般地，这些患者被描述为具有在认知灵活性缺陷。类似的赤字在这两个非人类灵长类动物和啮齿动物时，病变吨被证明澳前额叶皮质已被诱导1,6-8。这些赤字表明认知僵化的状态或转移注意力集中的能力受损。
形成有注意力集当受试者得知的一组规则可应用于复杂的刺激，以从不相干线索分化有关。例如，在AST，动物将学习关注并给有关的提示（ 即，挖掘介质）响应，而忽略不相关的线索（ 即气味），通过配对食物奖励与介质。此关联随后在后续的任务，其中钢筋挖掘介质和气味的变化的类型，但介质和收益之间的配对关联保持。这种增强的规则形成了认知集。逆转和额外维的转变：在认知灵活性 AST协议的措施方面的两个阶段。在逆转的阶段，在一个dimensio先前负面刺激N（介质在本实施例）现在是肯定的，挑战动物忽略来自前一阶段的正面刺激。例如，如果感觉挖介质是在前一阶段的积极的刺激和纸是负的刺激，现在的情况正好相反。这种挑战，它必须保持注意力集中的动物的灵活性（ 即介质相关的尺寸），而改变规则，学会了一个维度内的刺激和奖励对。一个所注意的集合的形成在额外维移阶段，当不相关的维度（气味在这个例子中）成为相关的尺寸受到了挑战。一个固着的反应，通过使用以前学过的规则持续选择所示，在任一阶段，反映了认知灵活性的赤字。
在两个非人类灵长类动物和啮齿类动物损伤的研究显示前额叶皮层的特定区域可以归因于为PErF能力ORM的AST 1,9特定阶段。病变的眶额皮层（OFC），前额皮层（PFC）的次区域，已被证明是导致学习上的AST 8赤字逆转。此外，病变的内侧前额叶皮质（MPFC），导致在执行额外的维度转变的具体困难。
同时使用的AST许多研究在大鼠和非人灵长类动物被执行时，相对较少的已利用的AST如小鼠认知功能的量度。鉴于遗传操作的易用性小鼠，以及迫切需要测量前额叶皮质功能在研究各种障碍，适应和验证小鼠这种行为的措施是一个重要的除了研究与PFC功能障碍相关的疾病。这里详述的方案是由比勒尔和Brown 1被应用在小鼠中优化和过程的修改反映了许多小鼠- specifi的之前已经报道2,6,10-13Ç适应。
Protocol
Representative Results
Discussion
由PFC介导的在认知灵活性赤字表示与各种神经学和神经精神病学障碍有关的一个显著残疾，并且可以对结果和个人从这些疾病痛苦的生活质量产生重大的影响。在小鼠的AST使用的优化是研究遗传基础的连接到前额皮层介导的认知功能障碍的疾病至关重要。我们已发现，上述的方法是一个具体的认知缺陷，认知灵活性的可靠量度，并且近似于使用该任务在大鼠和非人灵长类动物中获得的结果。描述?…
Divulgazioni
The authors have nothing to disclose.
Acknowledgements
这项研究是由赠款R01-MH090127，P30-MH089868从心理健康国家研究所和获奖数量UL1TR001120从国家中心推进转化科学的支持。内容完全是作者的责任，并不一定代表NIMH或NCATS的官方意见。此外，我们想衷心感谢大卫Morilak博士为他宝贵的专业知识指导早期方法开发。
Materials
| Name of Material/ Equipment | Company | Catalog Number | Comments/Description | |
| Testing Chamber | Fabricated in-house, specifications can be found in protocol | |||
| 3 0z. Ramekins | BIA Cordon Bleu | 900002S12 | Purchased on amazon.com | |
| Essential Oils: | Fronteir Natural Products Co-Op | Purchased on http://www.frontiercoop.com/prodlist.php?ct=anpceoeo | ||
| Clove Bud | 191114 | |||
| Red Thyme | 191140 | |||
| Lemon | 190810 | |||
| Cinnamon Leaf | 191111 | |||
| Rosemary | 191133 | |||
| Citronella Java | 191112 | |||
| Vanilla in jojoba oil | 191231 | |||
| Anise Seed | 191102 | |||
| Ginger | 191121 | |||
| Nutmeg | 191161 | |||
| Filter Paper, 9.0 cm diameter | VWR International | 28310-048 | Purchased on https://us.vwr.com/ | |
| Digging Media | ||||
| Raffia | Ashland 8 oz Raffia | n/a | Purchased on http://www.michaels.com/ Cut into 1/2" to 1" strips |
|
| Green Felt | Creatology Basic Felt Forest/Dark Green 36 in x 36 in | n/a | Purchased on http://www.michaels.com/ cut into 1 cm x 1 cm squares |
|
| Brown foam | Creatology Fun Foam 18 x 12 in sheets (light brown/tan) | n/a | Purchased on http://www.michaels.com/ cut into 1/2 cm x 2 cm rectangles |
|
| Crepe paper (yellow) | Celebrate It Paper Crinkle 4 oz yellow jumbo | n/a | Purchased on http://www.michaels.com/ Cut into 1/2" to 1" strips |
|
| Ribbon (turqoise) | Celebrate It Wide Ribbon 4 in x 10 yd 100% polyester | n/a | Purchased on http://www.michaels.com/ cut into 1 cm x 1 cm squares |
|
| Metallic | Celebrate It Metallic Crinkle Gold 2 oz | n/a | Purchased on http://www.michaels.com/ Cut into 1/2" to 1" strips |
|
| Googly Eyes, 4 mm | ME4144 | Purchased on http://factorydirectcraft.com/index.php | ||
| Black Sequins, 3 mm | 8780BK | |||
| Pink Pom Poms, 1/4 inch | 1018221 | |||
| Pipe Cleaners, red | 108430 | |||
| Bedding material/sawdust | Obtained from in-house animal resources | |||
| Timer | Control Company | 5000 | Purchased on http://www.control3.com/5000p.htm | |
| Lightly sweetened dry breakfast cereal loops | HEB | Honey nut toasted oats used in the protocol described, any lightly sweet coated breakfast cereal is recommended | ||
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