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

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)?

Rewarding? + X Days

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

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

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

Striatum (continued) Involved in a series of complex circuits

Striatum (continued)

Striatum (continued)

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

Striatum (continued)

Striatum (continued)

Adenosine

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

Adenosine (continued) Adenosine vs. Dopamine

Adenosine (continued) Common pathways of adenosine

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.

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)

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

Results Adenosine levels significantly different in iEX group compared to control

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

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

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

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)?

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)

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

Results Voluntary exercise behavior (between experimental groups)

Results CPP Behavioral Testing

Results ΔFosB/FosB protein expression in the nucleus accumbens

Results Neuroplasticity in the Mesolimbic Reward Pathway

Results Neuroplasticity in the Mesolimbic Reward Pathway

Results Neuroplasticity in the Mesolimbic Reward Pathway

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

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

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)?

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

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

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

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: 61.4 μg/dl (± 1.8 SE) Running stress: 72.3 μg/dl (± 6.5 SE)

Results Gene Expression in DMS

Results Gene Expression in DLS

Results Gene Expression in AcbC

Results Gene Expression in AcbShM

Results Gene Expression in AcbShL

Result Total cfos Expressing Neurons Between Groups

Results Dynorphin Cells with cfos Expression

Results Enkephalin Cells with cfos Expression

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

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

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

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)

Putting it all together

Putting it all together

Where does the brain on exercise fit in?