Mice selectively bred for high voluntary wheel running have larger midbrains: support for the mosaic model of brain evolution.

Increased brain size, relative to body mass, is a primary characteristic distinguishing the mammalian lineage. This greater encephalization has come with increased behavioral complexity and, accordingly, it has been suggested that selection on behavioral traits has been a significant factor leading to the evolution of larger whole-brain mass. In addition, brains may evolve in a mosaic fashion, with functional components having some freedom to evolve independently from other components, irrespective of, or in addition to, changes in size of the whole brain. We tested whether long-term selective breeding for high voluntary wheel running in laboratory house mice results in changes in brain size, and whether those changes have occurred in a concerted or mosaic fashion. We measured wet and dry brain mass via dissections and brain volume with ex vivo magnetic resonance imaging of brains that distinguished the caudate-putamen, hippocampus, midbrain, cerebellum and forebrain. Adjusting for body mass as a covariate, mice from the four replicate high-runner (HR) lines had statistically larger non-cerebellar wet and dry brain masses than those from four non-selected control lines, with no differences in cerebellum wet or dry mass or volume. Moreover, the midbrain volume in HR mice was ~13% larger (P<0.05), while volumes of the caudate-putamen, hippocampus, cerebellum and forebrain did not differ statistically between HR and control lines. We hypothesize that the enlarged midbrain of HR mice is related to altered neurophysiological function in their dopaminergic system. To our knowledge, this is the first example in which selection for a particular mammalian behavior has been shown to result in a change in size of a specific brain region.

Erythropoietin elevates VO2,max but not voluntary wheel running in mice.

Voluntary activity is a complex trait, comprising both behavioral (motivation, reward) and anatomical/physiological (ability) elements. In the present study, oxygen transport was investigated as a possible limitation to further increases in running by four replicate lines of mice that have been selectively bred for high voluntary wheel running and have reached an apparent selection limit. To increase oxygen transport capacity, erythrocyte density was elevated by the administration of an erythropoietin (EPO) analogue. Mice were given two EPO injections, two days apart, at one of two dose levels (100 or 300 microg kg(-1)). Hemoglobin concentration ([Hb]), maximal aerobic capacity during forced treadmill exercise (VO2,max) and voluntary wheel running were measured. [Hb] did not differ between high runner (HR) and non-selected control (C) lines without EPO treatment. Both doses of EPO significantly (P<0.0001) increased [Hb] as compared with sham-injected animals, with no difference in [Hb] between the 100 microg kg(-1) and 300 microg kg(-1) dose levels (overall mean of 4.5 g dl(-1) increase). EPO treatment significantly increased VO2,max by approximately 5% in both the HR and C lines, with no dosexline type interaction. However, wheel running (revolutions per day) did not increase with EPO treatment in either the HR or C lines, and in fact significantly decreased at the higher dose in both line types. These results suggest that neither [Hb] per se nor VO2,max is limiting voluntary wheel running in the HR lines. Moreover, we hypothesize that the decrease in wheel running at the higher dose of EPO may reflect direct action on the reward pathway of the brain.

Preliminary in vitro efficacy and toxicities studies of the herpes simplex thymidine kinase gene system for the treatment of breast cancer.

A novel gene therapy strategy is the use of suicide genes that transfer a drug sensitivity to cancer cells. We present preliminary in vitro efficacy data and in vivo toxicity data using the herpes simplex thymidine kinase (HStk) gene for breast cancer. The long-term objective of this project is to develop novel approaches for the treatment of breast cancer using in vivo retroviral gene transfer. Intraductal breast cancer cell line HTB126 transduced by an HStk retroviral vector is efficiently inhibited in vitro after GCV exposure. Further analysis revealed a bystander effect through which nontransduced HTB126 cells were also inhibited by GCV when cocultured with HStk-transduced HTB126 cells. In cell mixture experiments if only 1% of the cells in culture contained the HStk gene, 83% of the culture could be destroyed. Next safety studies were performed. Vector producer cells (VPC) were implanted into the mammary fat pads of athymic nude mice. The mice were then treated with GCV and monitored for regression of the VPC. The injected VPC regressed rapidly in response to the GCV therapy and produced no evidence of local or systemic toxicity in the animals. These in vitro efficacy data and in vivo toxicity studies lend support to the further development of an in vivo therapy model to treat breast cancer.