1 Born to Run: Experimental Evolution of High Voluntar y Exercise Mice Professor Theodore Garland,...

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Born to Run:Born to Run:Experimental Evolution of Experimental Evolution of

High VoluntarHigh Voluntar y Exercise Micey Exercise Mice

Professor Theodore Garland, Jr., Ph.D.Professor Theodore Garland, Jr., Ph.D.

Depar tment of Biology

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Collaborators in Our LabCollaborators in Our Labor at U.C., Riverside:or at U.C., Riverside:

Collaborators ElsewhereCollaborators Elsewhere(partial list):(partial list):

Wendy AcostaWendy AcostaDoug AltshulerDoug AltshulerAnne M. BronikowskiAnne M. BronikowskiVincent CareauVincent CareauPatrick A. CarterPatrick A. CarterMark A. ChappellMark A. ChappellGerald C. ClaghornGerald C. ClaghornMark A. ColemanMark A. ColemanElizabeth DlugoszElizabeth DlugoszIsabelle GirardIsabelle GirardFernando R. GomesFernando R. GomesRobert M. HannonRobert M. HannonBrooke K. KeeneyBrooke K. KeeneyScott A. KellyScott A. KellyErik M. KolbErik M. Kolb

Terry BelkeTerry BelkeAbel Bult-ItoAbel Bult-ItoHannah CareyHannah CareyGreg CarteeGreg CarteeLynn CopesLynn CopesSerge DaanSerge DaanBrigitte DemesBrigitte DemesGary DiffeeGary DiffeeCynthia DownsCynthia DownsJoey C. EisenmannJoey C. EisenmannPatricia A. FreemanPatricia A. FreemanFred H. (Rusty) GageFred H. (Rusty) GageStephen C. GammieStephen C. GammieHelga GuderleyHelga GuderleyRuss HeppleRuss HepplePeter HurdPeter HurdAaron M. JanowskyAaron M. JanowskyDenis JoanisseDenis Joanisse

Isabella JonasIsabella JonasGrant McClellandGrant McClellandKevin M. MiddletonKevin M. MiddletonGordon S. MitchellGordon S. MitchellAndy ObenausAndy ObenausMark OlfertMark OlfertSteve F. PerrySteve F. PerryDaniel PompDaniel PompThomas A. ProllaThomas A. ProllaGary SieckGary SieckSharon SwartzSharon SwartzDoug SymeDoug SymeNicole TemplemanNicole TemplemanLobke M. VaanholtLobke M. VaanholtGertjan van DijkGertjan van DijkHenriette van PraagHenriette van PraagG. Henk VisserG. Henk VisserBen B. Yaspelkis IIIBen B. Yaspelkis III

This selection experiment began in 1993,This selection experiment began in 1993,> 100 publications.> 100 publications.

Pawel KotejaPawel KotejaGuo LiGuo LiChris LytleChris LytleJessica L. MalischJessica L. MalischMorris & Gina MaduroMorris & Gina MaduroThomas H. MeekThomas H. MeekKevin MiddletonKevin MiddletonTricia RadojcicTricia RadojcicEnrico L. RezendeEnrico L. RezendeJustin S. RhodesJustin S. RhodesDerek RoffDerek RoffHeidi SchutzHeidi SchutzJohn ShyyJohn ShyyJohn G. SwallowJohn G. SwallowShizhong XuShizhong XuMany UndergradsMany Undergrads

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BackgroundBackground&&

IntroductionIntroduction

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EvolutionaryEvolutionary PhysiologyPhysiologyHow do organisms work?

How can we use "model organisms" to understand how organisms work?

Where is the line between "normal" individual variation and pathology?

How do we promote health and cure disease?

How do populations change over time?

How can we use "model organisms" to understand how evolution and genetics work?

How important is natural selection in shaping biological diversity?

How does the way organisms How does the way organisms workwork influence the way they influence the way they evolveevolve??

Copyright by Theodore Garland, Jr. May 2007

We are studying:

Animal Locomotion

from the perspective of

Evolutionary Physiology

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An Observation about Behavior:An Observation about Behavior:Animals exhibit tremendous diversity in locomotor behavior (e.g., home range size).

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An Observation about Behavior:An Observation about Behavior:Animals are diverse in locomotor behavior (e.g., home range size).

"Motivation" vs. per"Motivation" vs. per formance ability?formance ability?

Evolutionary causes:

Why has this diversity evolved?Natural selection: what is the benefit?

Physiological causes:

How do animals work?Body structure and physiology: what is the limit?

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Diversity in Locomotor Behavior

49 Species of Mammals

But, even for different animals that are the same size, home ranges are very diverse and can be 100-times different.

Large animals tend to have large home ranges.

Note the logarithmic axes.

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Carnivores tend to have larger home ranges than herbivores.

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Physiological causes:Physiological causes:

HowHow do animals work? do animals work?Body structure and physiology: Body structure and physiology: what is the limit?what is the limit?

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CarnivoraCarnivoraEat Eat HerbivoresHerbivores

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Might the kind of diet be a Might the kind of diet be a reason for the diversity?reason for the diversity?

Garland, T., Jr., A. W. Dickerman, C. M. Janis, and J. A. Jones. 1993. Phylogenetic analysis of covariance by computer simulation. Systematic Biology 42:265-292.

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Possibly just a direct Possibly just a direct environmental effect?environmental effect?

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Physiological causes:

How do animals work?Body structure and physiology: what is the limit?

We can attempt to answer these questions with experimentation.

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Lions, and tigers, and bearsLions, and tigers, and bears(oh my!) are great, but not the most (oh my!) are great, but not the most convenientconvenient organisms to study … organisms to study …

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"…research in which populations are studied across multiple generations under defined and reproducible conditions, whether in the laboratoryor in nature."

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Charles Darwin did not recognize this as a way to study evolution because he thought the process was too slow.

Humans can also showdiversity in locomotor behavior.

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● Individual differences in voluntary activity levels are large in both human beings and other animals (both in the lab and in the wild).

Locomotion & Activity Levels

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Evolutionary causes:Evolutionary causes:

WhyWhy has this diversity evolved? has this diversity evolved?Natural selection: Natural selection: what is the benefit?what is the benefit?

PhysiologicalPhysiological causes: causes:

HowHow do animals work? do animals work?Body structure and physiology: Body structure and physiology: what is the limit?what is the limit?

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● Individual differences in voluntary activity Individual differences in voluntary activity levels are large in both human beings and levels are large in both human beings and other animals (both in the lab and in the wild).other animals (both in the lab and in the wild).

● Physiology: what are the causes of these individual differences?

●may be related to variation in both motivation and ability to per form physical activity (brain & brawn);

●may also be part of the homeostatic mechanisms for energy balance and body composition.


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● Both motivation & ability must be affected by1) multiple alleles (genes),2) numerous environmental factors,3) interactions of genes and environment.

You can lead a horse to water, but you can't make him drink!


Genetic Factors in Locomotion and Activity Levels

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● Both motivation & ability must be affected byBoth motivation & ability must be affected by1) alleles (genes) segregating at multiple loci,1) alleles (genes) segregating at multiple loci,2) numerous environmental factors,2) numerous environmental factors,3) interactions of genes and environment.3) interactions of genes and environment.

● Except in cer tain pathological conditions,we should not expect to find "the gene for activity," but we can hope to find genes (polygenes) that account for an important fraction of the variation in activity levels.


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● Both motivation & ability must be affected byBoth motivation & ability must be affected by1) alleles (genes) segregating at multiple loci,1) alleles (genes) segregating at multiple loci,2) numerous environmental factors,2) numerous environmental factors,3) interactions of genes and environment.3) interactions of genes and environment.

● Except in cerExcept in cer tain pathological conditions,tain pathological conditions,we should not expect to find we should not expect to find ""thethe genegene forfor activityactivity,"," but we can hope to find genes but we can hope to find genes (polygenes) that account for an important (polygenes) that account for an important fraction of the variation in activity levels.fraction of the variation in activity levels.

● Understanding how such genes work could lead to therapeutic strategies for low-activity individuals.


Experimental Evolution

• Evolution: – Can we cause activity levels to change across

generations by selective breeding?– Are genes important in determining activity levels?

• Physiology: – How is body structure affected? Bones, muscles,

circulatory system?– What is the role of motivation? Brain structure?– What is the role of metabolism?

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MethodsMethods

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Why Select on Wheel-Running?Why Select on Wheel-Running?

http://school.discovery.com/clipart/clip/ani-mouse.html

1. potentially physiologically taxing - did you ever have a pet hamster?

2. individual dif ferences are highly repeatable (consistent) from day-to-day

3. genetically inherited to some extent

4. easy to automate measurement

5. an important regulator ofbody mass and composition

6. analogous to human voluntary activity? (e.g., Eikelboom, 1999)

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Star ting (Base) Population: 112 male & 112 female outbred mice

Design: 8 lines: 4 Selected for High Running

(HR lines), 4 non-selected Control 10 mating pairs in each (lit ter size ~10) Within-family selection

Selection Criterion: Wheel revolutions on days 5 + 6 This is a completely "voluntary" behavior.

Experimental DesignExperimental Design

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Impor tant point!

● We did not select for low voluntary running because it might not be the same trait as high wheel running.

●For example, selection for low running might simply increase fear of entering the wheels.

● For humans, active behaviors may not be opposites of sedentary behaviors.

●Jogging is not the opposite of playing a video game.

● Also, selection for low per formance might be accomplished by increasing frequency of “harmful” alleles (deleterious recessives), thus leading to sickly mice from a variety of causes.

31 Wheels are Attached to Standard Housing Cages

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200 total wheels,100 in each of two rooms

Food and water are always available.

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ResultsResults

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Selected run almost 3X more than control

Our lab moved from U. Wisconsin to U. Calif.

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Males always tend to run less than females, but the fold difference between selected and control lines is the same as in females.

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How How dodo Mice from Mice from the Selected Linesthe Selected Lines

Run More?Run More?

Data are collected about the wheel revolutions logged by the mice.

• Selected mice run more revolutions/day than controls

• Selected mice do not run for longer time period than controls

• Selected mice do run faster than controls

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>1 means selected is higher than control

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Show movie that accompanies:Show movie that accompanies:

Girard, I., M. W. McAleer, J. S. Rhodes, and T. Garland, Jr. 2001. Selection for high voluntary wheel running increases intermittency in house mice (Mus domesticus).Journal of Experimental Biology 204:4311-4320.

http://www.biology.ucr.edu/people/faculty/Garland/Girard01.mov

Mice from the selected lines mainly run faster than those from control lines.

42HCA_sensors_and_computer_2_shrunk.jpg

What about activity in ordinary cages?What about activity in ordinary cages?

Force plates detect any movement in the cage.

43g44_circadian_hca.xls

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How Else do theHow Else do theSelected and Selected and Control Lines Control Lines

Differ?Differ?

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Something to considerSomething to consider

What makes an What makes an individual a good individual a good distance runner?distance runner?

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Mice from the Selected lines:

• are smaller in body size

• have less body fat,even when housed without wheels

• eat more for their body weight,even when housed without wheels

• show no statistically significant difference from the Control lines in basal or resting metabolic rate

Body Size and Composition

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ExerciseExercise Adaptations? Adaptations?

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Using Oxygen =Using Oxygen =Maximal Aerobic CapacityMaximal Aerobic Capacity

http://nyvelocity.com/files/old/pictures/image/cadence/collete3.jpghttp://farm4.staticflickr.com/3108/2325682863_f41a385d5c.jpg

Single best indicator of cardiopulmonary functionSingle best indicator of cardiopulmonary functionSets upper limit to exercise intensity you can sustain for a long timeSets upper limit to exercise intensity you can sustain for a long time

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Maximal Maximal Aerobic Aerobic CapacityCapacity ororVOVO22maxmax

Mice generally won’t cooperate to wear a mask …Mice generally won’t cooperate to wear a mask …

.

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VO2max of Males at Generation 32Body-mass adjusted Mean and Standard Error (average) (a measure of uncertainty)

0.00

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= 33% higher

Rezende, E. L., S. A. Kelly, F. R. Gomes, M. A. Chappell, and T. Garland, Jr. 2006. Effects of size, sex, and voluntary running speeds on costs of locomotion in lines of laboratory mice selectively bred for high wheel-running activity. Physiological and Biochemical Zoology 79:83-99.

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Treadmill Endurance CapacityTreadmill Endurance Capacity

Meek, T. H., B. P. Lonquich, R. M. Hannon, and T. Garland, Jr. 2009. Endurance capacity of mice selectively bred for high voluntary wheel running. Journal of Experimental Biology 212: 2908-2917.

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Treadmill Endurance Treadmill Endurance (gen. 49)(gen. 49)

Means Endurance Time (minutes) Female Male S/C

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Mice from the Selected lines have higher endurance capacity.

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Increased Insulin-Stimulated Glucose Uptake of Isolated Extensor Digitorum Longus Muscles(extends toes 2-5 and dorsiflexes ankle)

Gen. 17 Males Wheels & No wheels for 2 months

Dumke et al. 2001. Journal of Applied Physiology 91:1289-1297.

Exercise AdaptationsExercise Adaptations

Mice from the Selected lines are better able to utilize some of the energy stores in their muscles.

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Larger Femoral Heads

Also truefor humans!

Garland, T., Jr., and P. A. Freeman. 2005. Selective breeding for high endurance running increases hindlimb symmetry. Evolution 59:1851-1854.Kelly, S. A., P. P. Czech, J. T. Wight, K. M. Blank, and T. Garland, Jr. 2006. Experimental evolution and phenotypic plasticity of hindlimb bones in high-activity house mice. Journal of Morphology 267:360-374.

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Thicker Femurs andTibiafibulas

(but not longer)

Gen. 21B Males Wheels & No Wheels for 2 months

Kelly, S. A., P. P. Czech, J. T. Wight, K. M. Blank, and T. Garland, Jr. 2006.Experimental evolution and phenotypic plasticity of hindlimb bonesin high-activity house mice. Journal of Morphology 267:360-374.

Maybe you expected the Selected lines to have evolved longer legs?

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More Symmetrical HindlimbBone Lengths Also truefor Englishthoroughbredhorses!

Garland, T., Jr., and P. A. Freeman. 2005. Selective breeding for high endurance running increases hindlimb symmetry. Evolution 59:1851-1854.

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Increased Hear t Mass(adjusted for differences in body mass)

Gen. 35 Females 5 days of Wheel Access Gomes et al. 2004. SICB Talk.

Gen. 37 Females Wheels & No Wheels for 3 months Kelly et al. HVR In preparation.

Gen. 49 Females Wheels & No Wheels for 2 months Kelly et al. Cotman In preparation.


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Reduced HindlimbMuscle Mass

This difference is similar to what we see for human marathon runners.

Garland, T., Jr., M. T. Morgan, J. G. Swallow, J. S. Rhodes, I. Girard, J. G. Belter, and P. A. Carter. 2002. Evolution of a small-muscle polymorphism in lines of house mice selected for high activity levels. Evolution 56:1267-1275.

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The BrainThe Brain& Motivation& Motivation

red: caudate-putamenpurple: ventriclesblue:blue: hippocampus hippocampusyellow: midbrainorange: cerebellum

Mice from the Selected lines have larger brains, Mice from the Selected lines have larger brains, but not the cerebellum.but not the cerebellum.

MRI scan done at Loma Linda University

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What neurotransmitters (brain What neurotransmitters (brain chemicals) are involved in chemicals) are involved in motivation?motivation? Dopamine is a logical candidate.Dopamine is a logical candidate.

Initial Experimental Test:Initial Experimental Test: compare response tocompare response to drugs that target drugs that target dopaminergic function. dopaminergic function.

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Dopamine Transporter Blockers Ritalin, GBR 12909, Cocaine (also serotonin) Receptor Agonist Apomorphine (non-selective) Receptor Antagonists Raclopride (D-2), SCH23390 (D-1)

Serotonin Transporter Blocker Prozac

Endogenous Opioids Receptor Antagonists Naloxone Naltrexone Rhodes, J. S., S. C. Gammie, and T. Garland, Jr. 2005. Neurobiology of mice selected for

high voluntary wheel-running activity. Integrative and Comparative Biology 45:438-455.

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Results: Pharmacology

Several dopamine drugs had dif ferential ef fects on C and S lines.

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For example, Ritalin increased running in C lines, but decreased it in S lines, almost down to level of controls.

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Therefore, the Selected

lines are a potentially

useful model for

studying human ADHD.

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For example, Ritalin increased running in C lines, but decreased it in S lines, down to level of controls.

No drug increased wheel running in the selected lines.

Therefore, motivation and/or abilityTherefore, motivation and/or ability to run may be at a physiological limit. to run may be at a physiological limit.

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ConclusionsConclusions&&

Future DirectionsFuture Directions

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● Experimental evolution can be a rapid and effective way to alter the characteristics of organisms and increase our understanding of both physiology and evolution.

● Evolutionary increases in voluntary activity levels entail increases in both motivation and ability to per form physical activity.

● Some traits that have changed seem to represent clear adaptations to support high locomotor activity (e.g., higher VO2max).

● Others might be maladaptive byproducts (not discussed today).

ConclusionsConclusions

.

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Future DirectionsFuture Directions

● Figure out what is limiting further increases Figure out what is limiting further increases in wheel running.in wheel running. Exercise ability vs. motivation?

● Unravel the neural and psychological Unravel the neural and psychological mechanisms of motivation for exercise.mechanisms of motivation for exercise. Is this like an addiction?

● Find the genes that cause higher running.Find the genes that cause higher running. What are they doing?

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● Consider translation to human beings.Consider translation to human beings.Might we develop drugs that make it

more pleasurablefor people to exercise?

Or lesspleasurableto besedentary?

And Maybe Even …And Maybe Even …

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ResourcesResources

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ResourcesResources

● The scientific papers on Dr. Garland's mice The scientific papers on Dr. Garland's mice can be found as PDF files at his website:can be found as PDF files at his website: http://www.biology.ucr.edu/people/faculty/Garland.html

● 1-hour lecture on the mouse experiment:1-hour lecture on the mouse experiment: http://cnas.ucr.edu/sciencelectures/garlandlecture.htmlhttp://cnas.ucr.edu/sciencelectures/garlandlecture.html

● Wikipedia has various relevant sites:Wikipedia has various relevant sites:http://en.wikipedia.org/wiki/Experimental_evolutionhttp://en.wikipedia.org/wiki/Evolutionary_physiologyhttp://en.wikipedia.org/wiki/Exercise_physiologyhttp://en.wikipedia.org/wiki/Evolution

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Extra Extra Slides Slides FollowFollow

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The Real "Wild Type"

This is the average wheel running for selected females divided by the average Wheel running in control females per generation

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This is a This is a substantial substantial evolutionary evolutionary difference.difference.

But the Selected lines But the Selected lines are are notnot "abnormal" "abnormal"

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Daily PatDaily Pat tern Does Not Diftern Does Not Dif fer Much ...fer Much ...

Given that we keep selecting, why don’t they also run for more minutes per night?

Selected

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Why a Selection Limit?

Functional Answers: Motivation or Reward at a Maximum Ability to Run at a Maximum Energetic Cost is too High

Not mutually exclusive,May elucidate mechanismsof evolutionary “constraints”

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Treadmill Endurance CapacityTreadmill Endurance Capacity

The selected lines have greater endurance than the control lines

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Maximal Sprint Maximal Sprint Speed on aSpeed on a6-meter Photocell-6-meter Photocell-timed Racetracktimed Racetrack

Generation 48, Meek et al.,Generation 48, Meek et al.,unpublished resultsunpublished results

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But there is no difference in sprinting ability

Generation 48, Meek et al., unpublished resultsGeneration 48, Meek et al., unpublished results

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Increased GLUT- 4 Glucose Transporter Concentration in Gastrocnemius Muscles (af ter wheel access)(extends ankle)

Gen. 35 Females5 days of Wheel AccessSampled in Afternoon

Gomes et al. 2009


Gastroc-nemius

82Tim Noakes

Nature 2006 444:1000-1001

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Hypothesis from the Hypothesis from the business world:business world:

ExceptionalExceptionalperper formance isformance is50% attitude &50% attitude &50% aptitude.50% aptitude.

"What separates high per formers from lesser competitors isn’t just talent. It's the way they fuse their capability and mindset."

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ConstConst ant ant DarkDark

ConstConst ant ant LightLight

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It occurs when the wheel is harder to turn.

If wheels are locked to prevent rotation, selected mice climb more.

Based on these behavioral data, Based on these behavioral data, we hypothesize that selected mice we hypothesize that selected mice possess possess higherhigher motivationmotivation toto runrun..

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The Increased Wheel Running The Increased Wheel Running Lasts for Much of the LifespanLasts for Much of the Lifespan

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k)

Females

ControlSelected

5 15 25 35 45 55 65 75 85

Age (weeks)

10

20

30

40

50

60

70

Wh

eel R

un

nin

g(k

m/w

eek)

Males

ControlSelected

and is Quite General:and is Quite General:

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Does the brain show evidence of Does the brain show evidence of increased motivation for running?increased motivation for running?

Mice from both Control and Selected lines were given wheel access Mice from both Control and Selected lines were given wheel access

for 6 days. for 6 days. On day 7, two hours before lights off, wheels were blocked

for 1/2 of the mice.

14 of 23 brain regions showed higher activity in mice with blocked wheels, which may indicate motivationmotivation, stress, anticipation, frustration, anxiety or depression.

The data also showed an interaction between wheel type(blocked and free) and line type (control and selected), suggestinggreater motivation in selected micegreater motivation in selected mice.

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c-fos Immunoreactivity in Striatum (CPu)c-fos Immunoreactivity in Striatum (CPu)

0

100

200

300

400

500

Fos

Cel

l cou

nt

Interaction P = 0.03

Fo

s C

ell

Co

un

t

Control Selected Control Selected

Blocked Free

Selected withBlocked Wheel

Selected withFree Wheel

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The Effects of The Effects of DietDiet

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Effects of a "Western" DietMales from generation 52Males from generation 52

Weaned at 21 days of age,Weaned at 21 days of age,housed individuallyhoused individually

At 25 days of age, divided into:At 25 days of age, divided into:

Sedentary Sedentary Wheel AccessWheel Access

Standard DietStandard Diet 50 50 5050

Western Diet Western Diet 50 50 5050 42% kcal from fat42% kcal from fat plus added sucrose plus added sucrose

Analyses of blood and tissue samples are currently in progress …Analyses of blood and tissue samples are currently in progress …

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Control Selected

Wheel WheelNo Wheel No Wheel

S W S W S W S W

Ret

rope

riton

eal F

at P

ad M

ass

(g)

Least Squares Means ± SE

Retroperitoneal Fat: 82 days old

Diet

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0

2,000

4,000

6,000

8,000

10,000

12,000

14,000

Control,Normal

Control, HighFat

Selected,Normal

Selected,High Fat

Rev

olu

tions/

Day

Control Selected Std. Western Std. Western

Days 17-30 of wheel access

Rev

olu

tio

ns/

Day

52% Increase

Adjusted Means + Standard Errors

+36% Time

+18% Speed

These mice These mice are unique!are unique!

Effects of a "Western" Diet

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Introduction,version 1.0

(more evolutionary)

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From either perspective, as Darwin wrote:

"The whole organism is so tied together that when slight variations in one par t occur, and are accumulated through natural selection, other par ts become modified."

Charles Dar win (1859) The Origin of Species

"This is a very important subject,most imper fectly understood."

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Future Directions 1Future Directions 1

● Figure out what "Western" diet is doing to Figure out what "Western" diet is doing to the selected lines.the selected lines.

Are they protected from its adverse effects(development of metabolic syndrome,

etc.)?

● Unravel the neural and psychological Unravel the neural and psychological mechanisms of motivation for exercise.mechanisms of motivation for exercise.

Is this like an addiction?

● Find the genes that cause higher running.Find the genes that cause higher running.What is their mechanism of action?

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Future Directions 2Future Directions 2

● Consider translation to human beings.Consider translation to human beings.Might we develop drugs that make it more pleasurable for people to exercise?

1 Born to Run: Experimental Evolution of High Voluntar y Exercise Mice Professor Theodore Garland,...

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Transcript of 1 Born to Run: Experimental Evolution of High Voluntar y Exercise Mice Professor Theodore Garland,...