Responses to Selective Breeding for High Voluntary Activity in House Mice

生物体是极其复杂的。 研究生物多样性的简单的原子论方法导致了对复杂特征进化方式的不充分理解。 拟议研究的总体目标是使用整体方法来阐明复杂行为（自愿活动水平）如何在控制和复制的跨代选择性育种中发生遗传变化。 将检验两个一般假设。 首先，自主活动水平的增加将与大脑结构和功能的可识别变化相关，这些变化导致高活动的动机增加。 其次，活动的增加将伴随着从属特征的变化（例如，肌肉收缩特性），其通过增强生物体的表现能力来支持行为（例如，运动耐力或能量效率）。 因此，有人假设，卓越的运动表现需要“头脑”和“肌肉”。“在先前NSF的支持下，对高自愿轮跑的人工选择被应用于实验室小鼠的远系繁殖种群。 在第41代，4个重复选择的（S）品系中的小鼠跑的距离几乎是4个随机繁殖的对照（C）品系的3倍（雌性，15.3 vs. 5.3 km/天;雄性，12.2 vs. 4.1 km/天）。 在拟议的研究中，选择性育种将继续进行，S和C系将进行比较，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。 通过对所有4个S系与所有4个C系进行统计学比较，确定对选择的一般（一致）反应。 将通过比较4条S线来识别特定（独特）响应（多种适应性解决方案）。 先前工作的一个关键发现是“强大的迷你肌肉”等位基因，该等位基因受到选择的青睐，并固定在一个S系中。 这种常染色体隐性遗传导致后肢肌肉质量减少50%，同时使质量特异性有氧能力加倍，并以假设增强耐力跑步和运动的能量效率的方式改变收缩特征，但会损害短跑能力。这项研究将阐明S线和迷你肌肉与正常个体相比最大耗氧量升高的生理基础，这是持续运动的动力源。 小鼠将在跑步机上进行运动测试，然后进行生化和分子分析。该项目包括测试假设，即迷你肌肉表现出更高的收缩效率，这种表型导致整个动物运输成本降低，最大冲刺速度降低。研究人员将把假定的小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，研究人员将测试以下假设：S小鼠具有更高的动力在轮子上跑步，当轮子被剥夺时表现出生理性戒断症状，并且改变了大脑奖励系统关键区域的多巴胺生理学。拟议的研究将具有一般性的影响，如何从综合和多学科的角度研究复杂的现象。 它将确定与人类健康有重大关系的基因定义的自愿行为的生物决定因素。 选择性繁殖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素质、体重调节和衰老影响的重要模型。 研究将强调对本科生（包括妇女和代表性不足的群体）和研究生（四名继续攻读博士学位的学生）的培训。学生将参与），并将涉及与其他八个教师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.