Ph.D. in Zoology, December 2002
The neural basis of hyperactive wheel running in mice
iv + 170 pp.
(Assistant Professor Stephen C. Gammie served as Justin's major professor during the final semester, as Ted Garland had moved to U.C., Riverside)
Abstract
The neural basis of genetic hyperactivity was studied
in four replicate lines of mice selectively bred for increased voluntary
wheel running (S mice) along with four randombred control lines (C mice).
S mice ran approximately 10 km/day compared to 4 km/day in C mice, and
were hyperactive in photobeam cages without wheels, suggesting they may
represent a useful model of attention deficit hyperactivity disorder (ADHD).
Dopamine reuptake blockers Ritalin, cocaine, and GBR 12909 reduced wheel
running in S mice, whereas they had either no effect or increased running
in C mice. The non-specific dopamine receptor agonist apomorphine
and the specific D1-like receptor antagonist SCH 23390 reduced wheel running
more in C than S mice. The specific D2-like receptor antagonist raclopride
and the serotonin reuptake blocker Prozac reduced running to a similar
extent in S and C mice. S and C mice did not differ in tissue concentrations
of dopamine, serotonin or catabolites (as measured by high performance
liquid chromatography) in the nucleus accumbens or at rest or after 20
min of treadmill running at 0.5, 1.0 or 1.5 km/hr. Taken together,
these results suggest that dopamine function is altered in S mice via a
D1-like receptor. To identify brain regions implicated in the hyperactive
wheel running, neuronal activity (as measured by Fos immunohistochemistry)
was compared between S and C mice allowed to run or blocked from running
to induce craving. Fos activity in the lateral hypothalamus, nucleus
accumbens, prefrontal cortex, and striatum was associated with craving
to run, whereas Fos activity in the hippocampus and entorhinal cortex reflected
actual locomotion. To test the hypothesis that exercise, hippocampal
neurogenesis (as measured by the BrdU technique), and spatial learning
(Morris water maze) are positively associated, S and C mice housed with
and without running wheels were compared. C mice showed a positive
correlation between running distance and new cell number, as well as improved
learning. In S mice, wheel running increased neurogenesis to maximal
levels but no improvement in learning occurred. Exercise-induced
hippocampal neurogenesis may contribute to motor programming and thus the
newly generated cells may not be expected to improve learning.