Steven B. HammerPh. D. Candidate

Department of Biomedical SciencesKent State University

Circadian Rhythms

Examples

•Core body temperature

•Peak muscle performance

•Hormone levels

•Digestion

•Child Birth

Circadian System Input

Photic Light flash

Non-photic Drugs Sound Exercise

Processing SCN

Cyclic transcription/translation feedback loops

Output Hypothalamus Thalamus Effector Organs

IGL

MRN

RHT

GHT

Light

DRN

5-HT 5-HT

GlutamatePACAP

NPYGABA

Evolution of Phase Shifting

Adjust for seasonal changesHibernation, short and long days

Man made “Daylight Savings Time”Farmers

TravelEast or West bound?

Workshifts

Basic leveldaily changes

Phase Response Curve

ZT 6.0Peak Phase advance (non-photic stimulus)

ZT 18.5 Phase advance from light pulse

Dead

Zone

ZT 14Phase delay from light pulse

Hormone/Receptor Increase Decrease No Change

Dopamine - + -

Dopamine Receptor 1 + - +

Dopamine Receptor 2 - + -

MAO A - + +

MAO B + - -

Noradrenaline - + -

Serotonin - + +

GABA - + -

Muscarinic Receptor - + -

Choline Acyltransferase

- + -

Beta Endorphin - + -

Alpha MSH - + -

ACTH - + -

Beta Lipotropin - + -

Hormone/Receptor Increase Decrease No Change

FSH + - -

LH + - -

Inhibin - + -

Testosterone - + +

LHrh - + -

Aldosterone - + -

GH - + -

TSH - + +

Thyroxin - - +

Tri-iodothyronine - - +

ADH + - +

Oxytocin - + -

Prolactin + + +

Melatonin - + -

Alcohol Consumption

Baby BoomersRetirementEtOH consumption

Shift WorkDrinking to unwind/relax after night shift

Delay onset of activity

Death

Addiction

Late For Work

Decreased Ability To Perform ADL’s

Increase Stress

Increased Addiction

Increase in Family, Social, and Family

Problems

Increased Cost On Society

Increase Morbidity And Mortality Rates

Females MalesDrinking Category*

Disease I II III I II IIIMalignant neoplasms               Mouth and oropharynx cancers 1.45 1.85 5.39 1.45 1.85 5.39  Esophagus cancer 1.80 2.38 4.36 1.80 2.38 4.36  Liver cancer 1.45 3.03 3.60 1.45 3.03 3.60  Breast cancer 1.14 1.41 1.59           Under 45 years of age 1.15 1.41 1.46           45 years and over 1.14 1.38 1.62         Other neoplasms 1.10 1.30 1.70 1.10 1.30 1.70  Diabetes mellitus 0.92 0.87 1.13 1.00 0.57 0.73Neuropsychiatric conditions               Epilepsy 1.34 7.22 7.52 1.23 7.52 6.83Cardiovascular diseases (CVD)               Hypertensive disease 1.40 2.00 2.00 1.40 2.00 4.10  Coronary heart disease 0.82 0.83 1.12 0.82 0.83 1.00  Cerebrovascular disease                 Ischemic stroke 0.52 0.64 1.06 0.94 1.33 1.65    Hemorrhagic stroke 0.59 0.65 7.98 1.27 2.19 2.38  Other CVD causes 1.50 2.20 2.20 1.50 2.20 2.20Digestive diseases               Cirrhosis of the liver 1.26 9.54 9.54 1.26 9.54 9.54

Effects of Exercise

Increased fitness results in Increased blood flow Lean muscle mass Enzyme system/Biochemical pathways Substrate utilization

Decrease Depression by increasing NPY Serotonin Dopamine Norepinephrine

Improved Sleep Longer life? Quality of Life Increase adaptive ability to time changes Increased ability to deal with shift work

Bupropion

Interactions of Aging, EtOH and Exercise

Biochemical changes seen with agingSimilar to those seen with depression and EtOH abuse

Exercise decreases morbidity and mortality ratesAttenuates many of the biochemical changes associated

with agingReplacement of one addiction for another

“Ended my streak of consecutive days running on Sunday at 178. It was bittersweet but for the best. As my mileage got higher I really felt my body needed it. And a friend convinced me that the whole "On the seventh day God rested" thing may be in the Bible for a reason. :) Good luck to all of you as you try to balance determination and perseverance with what's best for you and your body”.(Endurance Planet web site, Unknown Author, June 30 2009 )

Specific Aims

AIM 1: To determine if exercise, either forced or voluntary, affects photic and or non-photic phase shifting in the Syrian hamster

AIM 2: To determine if aging, combined with exercise, affect non-photic phase shifting in the Syrian hamster

AIM 3: To determine if exercise and aging affect activity onset when measured by infrared versus wheel sensors

AIM 4: To determine if exercise affects the consumption of ethanol, and if there are interaction between aging, exercise, and ethanol consumption

General Methods

Syrian hamsters (Mesocricetus auratus)Individually housedLights (LD 14:10, DD and LL)1 to 26 months of agePassive IR sensors mounted above each cageMagnetic wheel sensors to measure wheel

running5mg (8-OH-DPAT)/kg (body mass)/ml (DMSO) EtOH 20%

Experiment Series OneTreadmill Running

(1A) Forced running Young

Runners (5 months, n=6) Controls (5 months, n=6)

Old Runners (19 months, n=7) Controls (19 months, n=7)

1 hour per day 4 weeks (LD, 14:10) 30 minute light pulse

(ZT 18.5)

Treadmill Running (1B)

Forced running Young

Runners (5 months, n=5) Controls (5 months, n=5)

Old Runners (19 months, n=9) Controls (19 months, n=10)

1 hour per day 13 weeks (LD, 14:10) 8-OH-DPAT (CT 6.0)

Experiment Series One

Wheel Running(1C)

Voluntary runners Young

Runners (6 months, n=6) Controls (6 months, n=6)

Old Runners (24 months, n=6) Controls (24 months, n=6)

13 weeks (LD, 14:10) Continuous running 8-OH-DPAT (CT 6.0)

Wheel Running(1D)

Voluntary runners Three age groups

6 months (n=6) 9 months (n=6) 14 months (n=6)

28 weeks (DD) Continuous running 1 injection per month for 4

months; 8-OH-DAPT at (CT 6.0)

Photic Phase Shift Comparison After Four Weeks of Forced Treadmill Running

Phot

ic Ph

ase A

dvan

ce (h

ours

)

Young Old1.6

1.7

1.8

1.9

2.0

2.1

2.2

2.3

2.4

2.5

Young Old

Non-running Running

*

Fig. 2: Non-P hotic phas e s hift after 13 week s of forc ed treadm ill running (1 hour/day ); 8-O H-DP A T (5m g/k g) and DM S O (vehic le)

DP A T DM S O M e a n M e a n ± S E

No

n-P

ho

tic P

hase A

dvan

ce (

ho

urs

)

Young Old0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

Young Old0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

a

aa

a

b

bb b

Control Running

Treadmill Running

The Effects of 13 Weeks of Wheel Running on The Non-photic Phase Shifting of Young and Old Syrian hamsters

Effects of Aging on Non-photic Shifting and Running Distance

Revolutions per Day Non-Photic Phase Shift

40 45 49 52 55 57 66 787461 83 88 40 45 49 52 55 57 66 787461 83 88

Weeks of Age

Experiment TwoActivity Onsets

Wheel Running(3B)

Voluntary runners Young (3-4 months,

n=18) 60 days Half of the animals have

access to 20% EtOH half do not

Wheel Running(1C)

Voluntary runners Young

Runners (6 months, n=6) Controls (6 months, n=6)

Old Runners (24 months, n=6) Controls (24 months, n=6)

13 weeks (LD, 14:10) Continuous running 8-OH-DPAT (CT 6.0)

Effects of Running and Age on Non-photic shifting

Onsets of Activity between IR and WS grouped by EtOH and Water

Experiment Series Three

Access to 20% EtOH and Water (3A)

LD (14:10) Young (2 months, n=18)

Runners (n=9) (Phase 2) Controls (n=9)

Old (24 months, n=15) Runners (n=8) (Phase 2) Controls (n=7)

Three Phases Phase 1 (10 days)

all wheels locked Phase 2 (30 days)

half wheels locked half unlocked

Phase 3 (20 days) all wheels locked

Voluntary Running (3B)

LD (14:10) Young (3-4 months, n=18) 60 days EtOH drinkers (n=9) Controls (water) (n=9)

(3C) LL (Constant Light) Same animals as experiment

(3B)

1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58 61

Da ys

-20

0

20

40

60

80

100

120

140

160

180

Wat

er C

on

sum

pti

on

(g

/kg

/day

) Control Tre a tm e nt

P ha se I P ha se II P ha se III

Treatmen t C o n tro l

40

60

80

100

120

140

160

180

200

**

#

#

Ph ase I Ph ase I I Ph ase I I I Ph ase I Ph ase I I Ph ase I I I

* #

Da ys

1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58 61

0

2

4

6

8

10

12

14

16

EtO

H C

on

sum

pti

on

(g

/kg

/day

)

Treatm ent

Control

Treatmen t C o n tro l

11.011.512.012.513.013.514.014.515.015.516.016.5

Ph ase I I Ph ase I I IPh ase IPh ase I Ph ase I IPh ase I I I

*

*

P ha se I P ha se II P ha se III*1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58

Da ys

0

2

4

6

8

10

12

14

16

18

20

EtO

H C

on

sum

pti

on

(g

/kg

/day

)

Tre a tm e nt Control

1 11 21 31 41 51 61 71 81 92 0

*

*

#

#

P ha s e I P ha s e IP ha s e III P ha s e IIIP ha s e II P ha s e II

Tre a tm e nt Control

Pha se I Pha se II Pha se III* #

1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58 61

Da ys

-30

-20

-10

0

10

20

30

40

50

60

Wat

er C

on

sum

pti

on

(g

/kg

/day

)

Control Tre a tm e nt

P ha se I P ha se II P ha se III

Treatmen t C o n tro l

15

20

25

30

35

40

45

50

55

Ph ase I Ph ase I I Ph ase I I I Ph ase I Ph ase I I Ph ase I I I

Young Old

Consumption and RunningEtOH Water

EtOH and Water Groups, Comprehensive Charts

Water, EtOH and Sum Correlations with Distance Run

LL Effects

Split Rhythms

Discussion

Exercise decrease fragmentation?Decrease phase shifting in the aged combined with

exerciseChange in activity onset with aging, with comparison

between IR and wheel onsets. Decrease EtOH consumption with running, competitive

reward pathway?Increase water consumption in aged animals combined

with runningExercise and aging:

Decrease in biochemical and neurological pathway substrates?

Inability to quickly replenish depleted substances?Ergogenic aids ?Chronic training; Lessons from Dean?

Conclusions

Further Research is Needed

Questions?

IGL

MRN

RHT

GHT

Light

DRN

Glutamate

NMDA(AMPA

Kainate) receptors

Ca++

PACAPPAC1

VPAC2receptors

Mg++

2nd messengerpathways

c-fosPer1Per2

5-HT 5-HT

NPYGABA

GlutamatePACAP