Using Genetic Mutations to Study the Neural Basis of Behavior
Using Genetic Mutations to Study the Neural Basis of Behavior
复制标题
利用基因突变研究行为的神经基础
DOI：
10.1016/s0092-8674(00)81712-2
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发表时间：
1998
期刊：
影响因子：
64.5
通讯作者：
M. Mauk
中科院分区：
文献类型：
--
作者：
Philip M. Steele;J. Medina;William L. Nores;M. Mauk
神经生物学的进步往往是由突触传递缺失的进步推动的。在技术上，很难想象先进的靶向突变似乎提供了巨大的希望，因为它吸引了比靶向基因成分特异性更多的关注，但它们在小鼠中遭受相同的突变(Chen和Tonegawa，1997；Silva et困难)。从好的方面来看，通常只有一个(1997年)。原则上，这个概念很简单：研究野生型和突变小鼠之间的基因差异。分子通过消除其对行为的贡献此外，已知的细胞特异性前基因的不断增加，或通过引入其产物干扰运动的基因，意味着突变的主要影响可以通过某种方式与分子有关(见Capecchi，1989，日益限于单一细胞类型)。然而，1994年；齐默尔，1992年)。但是，系统级神经科学家的突变不仅受到与知道使用分子或解剖学损伤的可能的代偿性变化有关的批评，而且还受到对大脑的担忧是一件棘手的事情。毕竟，这是在研究大脑的发育异常。因此，就像打破它的部件一样。现在，由于最初的常规损伤已经尘埃落定，人们可能很容易得出这样的结论：踩踏可能正在某种程度上稳定下来，缺乏一个分子似乎是有用的，因为它直接负责将基因靶向作为一种研究工具--用于观察到的行为缺陷，但这种关于行为的神经基础，特别是机制的结论几乎总是相对不令人满意。学习和记忆的缺陷。我们将考虑突变与突变方法的优缺点总而言之，组件特异性从根本上影响到旧的和不那么奇异的方法，我们将建议使用突变，但一些因素共同作用使其具有可能使突变的使用甚至非常难以实现和验证的特征。然而，对神经系统功能的研究更有效。在许多例子中，通过脑桥(细胞、突触等)识别了调节Behaviorsaregeneratedbycollectionsofneuralcom-特定行为的神经组件。相互作用的方式使损伤。这一明显矛盾的解决constituteasystemwithcertaininput/outputproperties.源于限制之间的区别，因此，确定基本组件列表是每个单个病变实验以及分析系统的关键第一步。然而具有讽刺意味的是，由于多年来可能存在的相互作用，即使是饱受这种演变而来的“病变方法”，也变得极其困难。这种方法的两个基石是组件之间的谨慎。亚伯拉罕系统就像一组实验上有利的行为生态系统--如果没有仔细的行为研究，几乎总是会复制通过病变的其余时间控制的级联效应，就很难影响一个组件。我们相信这个系统。因此，分析总是受到一个潜在问题的困扰，一个成功的“突变方法”可能伴随着一个平行的困惑：行为缺陷是否表明特定的发育，因此考虑被移除成分的临时贡献的重要性，或者它是相对的和行为的特异性。其余组件之间奇怪的交互作用的时间专一性的非信息性后果？使突变变得可诱导或可逆的技术正在迅速改进，克服这些困难的能力与成人大脑中的相关(例如，参见…的大部分内容
Progress in neurobiology is often driven by advances absence of synaptic transmission. in technology, and it is hard to imagine an advance Targeted mutations appear to offer great promise for that has captured more attention than targeted genetic component specificity, but they suffer from the same mutations in mice (Chen and Tonegawa, 1997; Silva et difficulties. On the plus side, there is generally only one al., 1997). In principle the concept is simple: study the gene that differs between wild-type and mutant mice. contributions of a molecule to behavior by eliminating its Moreover, the growing list of known cell-specific progene, or by introducing a gene whose product interferes moters means that the primary effects of mutations can with the molecule in some way (see Capecchi, 1989, increasingly be limited to a single cell type. However, 1994; Zimmer, 1992). But systems-level neuroscientists mutations are not only subject to criticisms related to know that using molecular or anatomical lesions of the possible compensatory changes, but also to concerns brain is a tricky business. It is, after all, studying the brain regarding developmental abnormalities. Thus, as with by breaking its parts. Now that the dust from the initial conventional lesions, it may be tempting to conclude stampede may be settling somewhat, it seems useful that the absence of a molecule is directly responsible to take a close look at gene targeting as a tool for study- for observed behavioral deficits, but such conclusions ing the neural basis of behavior, particularly the mecha- are almost always relatively unsatisfying. nisms of learning and memory. We will consider the Mutations Versus a Mutation Approach strengths and weaknesses of genetic mutations relative In sum, component specificity is fundamentally importo older and less exotic methods, and we will suggest tant, but a number of factors conspire to make it exfeatures that could make the use of mutations even tremely difficult to achieve and to verify. Yet there are more effective for the study of neural system function. many examples in which neural components mediating Behaviorsaregeneratedbycollectionsofneuralcom- particular behaviors have been identified using brain ponents (cells, synapses, etc.) interacting in ways that lesions. The resolution of this apparent contradiction constituteasystemwithcertaininput/outputproperties. stems from the distinction between the limitations of As such, identifying the list of essential components is each single lesion experiment and what can be accoma key first step in analyzing a system. Yet ironically, even plished with a “lesion approach” that has evolved over this is made extremely difficult by possible interactions the years. Two cornerstones of this approach are careful betweencomponents. Abrainsystemisalittlebitlikean selection of experimentally advantageous behaviors ecosystem—it’s hard to affect one component without and careful behavioral studies that almost always reproducing effects that cascade through the rest of the quire temporal control over the lesions. We believe that system. Thus, analysis is always plagued by a potential a successful “mutation approach” could follow a parallel confound: does a behavioral deficit indicate a specific development, thus the importance of considering temcontribution of the removed component, or is it a rela- poral and behavioral specificity. tively uninformative consequence of odd interactions Temporal Specificity between the remaining components? Techniques for making mutations inducible or reversible The ability to overcome these difficulties is related in in the adult brain are improving rapidly (see for example, large part to thoughtful …