1. Exercise – an addiction or a cure?
A search for exercise-induced plasticity in the striatum…relief from anxiety?

2. Several Questions: Does exercise create changes to reward circuitry?
Does exercise help combat the effects of aversive stimuli?
What are the likely targets of exercise- induced neuroplasticity (if it exists)?
Are there benefits for preventing disorders (like anxiety)?

3. Rewarding? +
X Days

4. Reward is not bad
Could an exercise reward combat the ill- effects of stress and anxiety without the risk of ? or

5. Striatum Dorsal striatum Ventral striatum (includes nucleus accumbens)
Control of movement
Motor learning processes
Dorsal striatum is further broken down:
DMS
Goal directed motor behavior
DLS
Habit learning
Ventral striatum (includes nucleus accumbens)
Motivation
Reinforcement

6. Striatum (continued)
Medium spiny neurons accept the signals coming into the striatum

7. Striatum (continued)
Involved in a series of complex circuits

8. Striatum (continued)

9. Striatum (continued)

10. Striatum (continued) Striatal defects Huntington’s disease
Parkinson’s disease
Schizophrenia
Drug abuse
Depression
Anxiety

11. Striatum (continued)

12. Striatum (continued)

13. Adenosine

14. Adenosine (continued)
Receptor types (4 in humans) A1
A2A
A2B A3

15. Adenosine (continued)
Adenosine vs. Dopamine

16. Adenosine (continued)
Common pathways of adenosine

17. Dworak et al
Intense exercise increases adenosine concetrations in the rat brain: implications for a homeostatic sleep drive
Hypotheses:
Physical exercise and sleep deprivation (SD) decrease phosphocreatine (PCr) and ATP levels in the rat brain.
Physical exercise and SD increase adenosine levels in the rat brain.
Duration and intensity of exercise can effect the extent to which previously mentioned levels increase or decrease.
Duration of sleep and SD sessions can also effect the described levels.

18. Methods 70 day old Wistar rats Groups: Control (n = 18) SD (n = 12)
3hr
5hr
Exercised (n = 12) - treadmill
Moderate exercise (mEX)
Intense exercise (iEX)

19. Methods (continued)
HPLC/UV to measure levels of inosine, adenosine, AMP, ADP, ATP, Cr and PCr

20. Results
Adenosine levels significantly different in iEX group compared to control

21. Results
Inosine levels significantly different in iEX and mEX compared to control

22. Discussion
Greatly elevated levels of inosine and adenosine after intense exercise
Increased adenosine suggest a state of bioenergetic stress?

23. Adenosine (revisited)
How does adenosine accumulate in the brain?

24. Greenwood et al
Long-term voluntary wheel running is rewarding and produces plasticity in the mesolimbic reward pathway
Hypothesis:
Long-term voluntary exercise is rewarding and produces plastic changes in gene transcription factors capable of modulating dopaminergic and opoidergic neurotransmission in the mesolimbic reward pathway
Does exercise create changes to reward circuitry?
What are the likely targets of exercise-induced neuroplasticity (if it exists)?

25. Methods Fischer rats Groups: Sedentary (locked running wheels)
CPP training (n = 8)
Immunohistochemistry (n = 8)
In situ hybridization (n = 9)
Voluntary exercise for 6 weeks
CPP training (n = 8)
In situ hybridization (n = 10)

26. Methods (continued) Conditioned Place Preference (CPP) training
CPP extinction training

27. Results
Voluntary exercise behavior (between experimental groups)

28. Results
CPP Behavioral Testing

29. Results
ΔFosB/FosB protein expression in the nucleus accumbens

30. Results
Neuroplasticity in the Mesolimbic Reward Pathway

31. Results
Neuroplasticity in the Mesolimbic Reward Pathway

32. Results
Neuroplasticity in the Mesolimbic Reward Pathway

33. Discussion Rats develop CPP to the rewarding effects of exercise
Strength of exercise reward seems comparable to other rewarding stimuli (as seen through extinction tests)
However, 2 weeks – No CPP

34. Discussion
Neuroplasiticity in the mesolimbic reward circuit seems to be a result of exercise
↑ ΔFosB/FosB in the nucleus accumbens
↑ TH mRNA in the VTA
↓ D2R mRNA in the nucleus accumbens core
↑ DOR mRNA in the nucleus accumbens shell
↑ KOR mRNA in the nucleus accumbens core

35. Clark et al Hypothesis:
Long-term voluntary exercise is rewarding and produces plastic changes in gene transcription factors capable of modulating dopaminergic and opoidergic neurotransmission in the mesolimbic reward pathway
Wheel running alters patterns of uncontrollable stress-induced cfos mRNA expression in rat dorsal striatum direct and indirect pathways: A possible role for plasticity in adenosine receptors
Does exercise create changes to reward circuitry?
Does exercise help combat the effects of aversive stimuli?
What are the likely targets of exercise-induced neuroplasticity (if it exists)?
Are there benefits for preventing disorders (like anxiety)?

36. Methods 32 male Fischer rats Groups: Sedentary (locked running wheels)
No stress (n = 8)
Uncontrollable tail shock (n = 8)
Voluntary exercise for 6 weeks

37. Methods (continued) Plasma corticosterone measured
Radioactive in situ hybridization
A1R mRNA
A2AR mRNA
D1R mRNA
D2R mRNA

38. Methods (continued) Double fluorescent in situ hybridization
Detect cfos producing neurons
Dynorphin (direct pathway)
Enkephalin (indirect pathway)

39. Results Corticosterone levels
No significant difference to suggest exercise affects stress
Sedentary control: 1.9 μg/dl (± 0.4 SE)
Running control: 1.4 μg/dl (± 0.4 SE)
Sedentary stress: μg/dl (± 1.8 SE)
Running stress: μg/dl (± 6.5 SE)

40. Results
Gene Expression in DMS

41. Results
Gene Expression in DLS

42. Results
Gene Expression in AcbC

43. Results
Gene Expression in AcbShM

44. Results
Gene Expression in AcbShL

45. Result
Total cfos Expressing Neurons Between Groups

46. Results
Dynorphin Cells with cfos Expression

47. Results
Enkephalin Cells with cfos Expression

48. Discussion Running changes A1R and A2AR mRNA levels in the striatum
Effect adenosine vs. dopamine outcomes
Neuroplasticity of adenosine system following exercise
Reduced AR mRNA
Contribute to stress-buffering

49. Discussion Mechanism for reduction in AR? Exercise-induced
Stress-induced – not representative of time afterward tail shock?

50. Discussion Activation and deactivation of MSN ↑ Direct Pathway
↓ Indirect Pathway
Stress is more aversive for sedentary rats?

51. Putting it all together
Striatal Responses to Exercise
Adenosine levels
↑ ΔFosB/FosB in the nucleus accumbens
↑ TH mRNA in the VTA
↓ D2R mRNA in the nucleus accumbens core
↑ DOR mRNA in the nucleus accumbens shell
↑ KOR mRNA in the nucleus accumbens core
↓ A1R and A2AR mRNA
↑ D2R mRNA
↑ cfos in direct pathway (dynorphin)
↓ cfos in indirect pathway (enkephalin)

52. Putting it all together

53. Putting it all together

54. Where does the brain on exercise fit in?