Cerebellar associative sensory learning defects in five mouse autism models.
Cerebellar associative sensory learning defects in five mouse autism models.
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DOI：
10.7554/elife.06085
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发表时间：
2015-07-09
期刊：
影响因子：
7.7
通讯作者：
Wang SS
中科院分区：
文献类型：
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作者：
Kloth AD;Badura A;Li A;Cherskov A;Connolly SG;Giovannucci A;Bangash MA;Grasselli G;Peñagarikano O;Piochon C;Tsai PT;Geschwind DH;Hansel C;Sahin M;Takumi T;Worley PF;Wang SS
感觉统合困难已被报道在自闭症，但其潜在的脑回路机制是探索不足。使用5个自闭症相关小鼠模型，Shank 3 +/ΔC，Mecp 2 R308/Y，Cntnap 2 −/−，L7-Tsc 1（L7/Pcp 2Cre：：Tsc 1flox/+）和patDp（15 q11 -13）/+，我们报告了延迟眨眼条件反射的特定扰动，这是一种需要小脑可塑性的联合感觉学习形式。通过区分学习反应的概率和特征的扰动，我们发现与浦肯野细胞/深核基因表达相关的Cntnap 2 −/−、patDp（15 q11 -13）/+和L7/Pcp 2Cre：：Tsc 1flox/+的概率降低，沿着的还有Shank 3 +/ΔC。L7/Pcp 2Cre：：Tsc 1flox/+以及Shank 3 +/ΔC和Mecp 2 R308/Y中的振幅较小，这与颗粒细胞途径表达有关。Shank 3 +/ΔC和Mecp 2 R308/Y也表现出异常的反应时间和降低的浦肯野细胞树突棘密度。总的来说，我们的观察结果可能是由于橄榄小脑环路中的指示学习和颗粒细胞通路中的反应表征存在缺陷。我们的研究结果表明，在自闭症小鼠模型中，感觉事件的关联时间绑定的缺陷是普遍存在的。DOI：http://dx.doi.org/10.7554/eLife.06085.001在刮风的日子里，听到风的声音会让许多人眯着眼睛期待，以保护他们的眼睛。将两种在瞬间到达的感觉联系起来，比如声音和风的感觉，是一种需要小脑的学习，小脑是大脑底部的一个区域。当在实验室环境中进行时，这种特殊的学习形式被称为眨眼条件反射。患有自闭症的人往往难以适当地匹配不同的感官。例如，他们很难识别一个与语音配乐相匹配的视频。他们也不像其他人那样学习眨眼条件反射。然而，目前还不知道大脑中的哪些回路负责他们的困难。Kloth等人现在通过询问增加人类自闭症风险的基因版本是否也会破坏小鼠的眨眼条件反射来研究这个问题。他们测试了五种类型的小鼠模型，每一种都有一种不同的基因突变，这种突变以前被认为与自闭症有关。所有这五种突变都会导致小脑不同类型细胞的缺陷，所有小鼠都有异常的社会和习惯行为，类似于自闭症患者。测试包括向小鼠照射明亮的光线，一秒钟后，一股空气总是会使小鼠眨眼。这种情况发生了几十次之后，老鼠们开始眨眼，当光线出现时，期待着那股空气。为了测试老鼠是否已经成功地学会了只对强光做出反应，灯光偶尔也会在没有一股空气的情况下闪烁。Kloth等人发现，小鼠在眨眼条件反射中通常表现不佳，尽管根据小脑的哪些细胞类型受到基因突变的影响而以不同的方式表现。有些老鼠在灯光出现后眨眼过早或过晚;有些眨眼微弱或不太频繁;还有一些根本不眨眼。这表明自闭症可以以不同的方式影响小脑对感觉信息的处理。这项工作很重要，因为它证明了一种瞬间多感官学习的形式通常会被自闭症基因破坏。如果小脑学习的缺陷在生命的早期就存在，他们可能会阻止自闭症儿童学习周围的世界，并使他们的大脑发育偏离轨道。人们已经发现了数百个自闭症基因，将这些基因与大脑的一个区域联系起来，可以确定小脑是未来诊断和干预的一个重要解剖学靶点。DOI：http://dx.doi.org/10.7554/eLife.06085.002网站
Sensory integration difficulties have been reported in autism, but their underlying brain-circuit mechanisms are underexplored. Using five autism-related mouse models, Shank3+/ΔC, Mecp2R308/Y, Cntnap2−/−, L7-Tsc1 (L7/Pcp2Cre::Tsc1flox/+), and patDp(15q11-13)/+, we report specific perturbations in delay eyeblink conditioning, a form of associative sensory learning requiring cerebellar plasticity. By distinguishing perturbations in the probability and characteristics of learned responses, we found that probability was reduced in Cntnap2−/−, patDp(15q11-13)/+, and L7/Pcp2Cre::Tsc1flox/+, which are associated with Purkinje-cell/deep-nuclear gene expression, along with Shank3+/ΔC. Amplitudes were smaller in L7/Pcp2Cre::Tsc1flox/+ as well as Shank3+/ΔC and Mecp2R308/Y, which are associated with granule cell pathway expression. Shank3+/ΔC and Mecp2R308/Y also showed aberrant response timing and reduced Purkinje-cell dendritic spine density. Overall, our observations are potentially accounted for by defects in instructed learning in the olivocerebellar loop and response representation in the granule cell pathway. Our findings indicate that defects in associative temporal binding of sensory events are widespread in autism mouse models. DOI: http://dx.doi.org/10.7554/eLife.06085.001 On a windy day, hearing the sound of wind makes many individuals squint in anticipation in order to protect their eyes. Linking two sensations that arrive within a split second of one another, such as sound and the feeling of wind, is a type of learning that requires the cerebellum, a region found at the base of the brain. When done in a laboratory setting, this particular form of learning has been dubbed eyeblink conditioning. Individuals with autism tend to have difficulties with appropriate matching of different senses. For example, they have trouble identifying a video that goes with a spoken soundtrack. They also do not learn eyeblink conditioning the same way that other individuals do. However, it is not known which circuits in the brain are responsible for their difficulty. Kloth et al. now investigate this issue by asking whether versions of genes that increase the risk of autism in humans also disrupt eyeblink conditioning in mice. They tested five types of mouse model, each with a different genetic mutation that has previously been linked to autism. All five of these mutations cause defects in different cell types of the cerebellum, and all mice have abnormal social and habitual behaviors, similar to autistic people. The tests involved shining a bright light at the mice, which was followed, a split second later, by a puff of air that always causes the mice to blink. After this had occurred dozens of times, the mice started to blink earlier, as soon as the light appeared, in anticipation of the puff of air. To test whether the mice had successfully learned to respond to just the bright light, the light was also occasionally flashed without a puff of air. Kloth et al. found that the mice generally performed poorly in eyeblink conditioning, although in different ways depending on which cell types of the cerebellum were affected by the genetic mutations. Some mice blinked too soon or too late after the light appeared; others blinked weakly or less frequently; and some did not blink at all. This suggests that autism can affect the processing of sensory information in the cerebellum in different ways. This work is important because it demonstrates that a form of split-second multisensory learning is generally disrupted by autism genes. If defects in cerebellar learning are present early in life, they could keep autistic children from learning about the world around them, and drive their developing brains off track. Hundreds of autism genes have been found. Linking these genes to a single brain region identifies the cerebellum as an important anatomical target for future diagnosis and intervention. DOI: http://dx.doi.org/10.7554/eLife.06085.002