Responses to Selective Breeding for High Voluntary Activity in House Mice

生物有机体是极其复杂的。研究生物多样性的简单原子论方法导致了对复杂特征进化方式的理解不足。这项拟议研究的总体目标是用一种整体的方法来阐明复杂的行为(自愿活动水平)如何在基因上改变，以响应受控和复制的跨代选择性繁殖。我们将检验两个普遍的假设。首先，自愿活动水平的增加将与大脑结构和功能的可识别变化相关，这些变化会导致高活动动机的增强。其次，活动量的增加将伴随着从属特征的变化(例如，肌肉收缩特性)，这些特征通过增强机体的表现能力(例如，运动耐力或能量效率)来支持行为。因此，可以假设，出色的运动成绩需要“脑力”和“体力”。在之前NSF的支持下，对一群杂交的实验室小鼠进行了人工选择，以进行高自愿的轮子跑。在第41代，4个重复选择(S)系的小鼠奔跑的速度几乎是4个随机育种对照(C)系的3倍(雌性为15.3vs.5.3公里/天；雄性为12.2vs.4.1公里/天)。在拟议的研究中，将继续进行选择性育种，并对S和C系进行比较，以阐明运动适应的形态、生理、生化和遗传基础，以及高自愿活动的神经生物学基础。对选择的一般(一致)反应将通过对所有4个S品系和所有4个C品系的统计比较来确定。通过比较4个S品系，将识别特定(唯一)响应(多个自适应解决方案)。先前工作的一个关键发现是在S的一个品系中被选择并被固定的“强大的微型肌肉”等位基因。这种常染色体隐性基因导致后肢肌肉质量减少50%，同时使比质量有氧能力翻了一番，并改变了收缩特性，这些方式被认为是为了增强耐力跑和运动的能量效率，但损害了短跑能力。这项研究将阐明S眼线和小肌与正常人相比，最大耗氧量升高的生理基础，最大耗氧量是持续运动的动力来源。小鼠将在跑步机上进行运动测试，然后接受生化和分子分析。该项目包括对微型肌肉表现出更高的收缩效率以及这种表型会降低整个动物的运输成本和最大冲刺速度的假设进行测试。研究人员将把假定的微型肌肉基因定位到染色体上，并确定可能的候选基因(结合原位杂交和微阵列数据)。最后，研究人员将检验假设，即S小鼠在轮子上跑步的动机更强，在轮子被剥夺时表现出生理戒断症状，并改变了大脑奖励系统关键区域的多巴胺生理。这项拟议的研究将对如何从综合和多学科的角度研究复杂现象具有普遍意义。它将确定与人类健康具有重大相关性的基因定义的自愿行为的生物学决定因素。选择性培育的小鼠品系是一种独特的遗传资源，将提供给其他研究人员用于其他几个项目。这些研究将有助于发展和推广所选品系作为研究运动对身体健康、体重调节和衰老影响的重要模型。研究将强调对本科生(包括女性和代表性不足的群体)和研究生(将有四名继续攻读博士学位的学生参加)的培训，并将涉及与其他八名教职员工和其他六所大学的合作。

Living organisms are exceedingly complex. Simple, atomistic approaches to studying biological diversity have led to an inadequate understanding of the ways in which complex traits evolve. The general goal of the proposed research is to use a holistic approach to elucidate how a complex behavior (voluntary activity level) changes genetically in response to controlled and replicated cross-generational selective breeding. Two general hypotheses will be tested. First, increases in voluntary activity level will be associated with identifiable changes in brain structure and function that cause increased motivation for high activity. Second, increases in activity will be accompanied by changes in subordinate traits (e.g., muscle contractile properties) that support the behavior by enhancing organismal performance abilities (e.g., locomotor endurance or energetic efficiency). Thus, it is hypothesized that exceptional athletic performance requires both "brains" and "brawn." With previous NSF support, artificial selection for high voluntary wheel running was applied to an outbred population of laboratory mice. At generation 41, mice in the 4 replicate selected (S) lines ran almost three times as much as the 4 randombred control (C) lines (for females, 15.3 vs. 5.3 km/day; for males, 12.2 vs. 4.1). In the proposed research, selective breeding will continue and the S and C lines will be compared to elucidate the morphological, physiological, biochemical, and genetic bases of locomotor adaptations, as well as the neurobiological underpinnings high voluntary activity. General (consistent) responses to selection will be determined by statistical comparisons of all 4 S lines with all 4 C lines. Specific (unique) responses (multiple adaptive solutions) will be identified by comparing the 4 S lines. A key discovery of previous work is the "mighty mini-muscle" allele that has been favored by selection and gone to fixation in one of the S lines. This autosomal recessive causes a 50% reduction in hindlimb muscle mass, while doubling mass-specific aerobic capacity and altering contractile characteristics in ways that are hypothesized to enhance endurance running and the energetic efficiency of locomotion, but compromise sprinting abilities. This research will elucidate the physiological underpinnings of elevated maximal oxygen consumption, the power source for sustained locomotion, in the S lines and in mini-muscle vs. normal individuals. Mice will be exercise-tested on a treadmill and then submitted to biochemical and molecular analyses. The project includes tests of hypotheses that mini-muscles exhibit higher contractile efficiency and that this phenotype leads to reduced whole-animal costs of transport and reduced maximal sprint speeds. The investigators will map the putative mini-muscle locus to a chromosome, and identify possible candidate genes (in conjunction with in situ hybridizations and micro-array data). Finally, the researchers will test the hypotheses that S mice possess higher motivation to run on wheels, exhibit physiological withdrawal symptoms when wheel-deprived, and have altered dopamine physiology in key regions of the brain reward system. The proposed research will have general implications for how to study complex phenomena from an integrative and multidisciplinary perspective. It will identify biological determinants of a genetically defined, voluntary behavior that has major relevance for human health. The selectively bred lines of mice are a unique genetic resource and will be made available to other researchers for several additional projects. These studies will help to develop and promote the selected lines as an important model for studying effects of exercise on physical fitness, body-weight regulation, and aging. Research will emphasize training of undergraduates (including women and under-represented groups) and graduate students (four continuing Ph.D. students will participate), and will involve collaborations with eight other faculty and six other universities.