Benefits of exercise on brain health are well-established. These include better memory, happier mood, decreased anxiety, and improved motor performance. Pursuing the mechanistic underpinnings of benefits for brain heath is important because these could point to new therapeutic targets for a range of neurological and psychiatric disorders, including disorders of movement like Parkinson’s disease. Despite the well-documented benefits of exercise, few mechanistic studies have identified underlying contributing factors.

Through an affiliation between the laboratory of Margaret E. Rice, PhD, and NYU Langone’s Marlene and Paolo Fresco Institute for Parkinson’s and Movement Disorders, we became interested in investigating factors that might contribute to the motor improvements seen in patients with Parkinson’s disease who exercise. Given that the motor impairments of Parkinson’s are alleviated by dopamine replacement using the dopamine precursor L-DOPA, we hypothesized that exercise might increase dopamine levels or release in brain regions affected by Parkinson’s.

The primary dopamine neurons that degenerate in Parkinson’s are those of the substantia nigra pars compacta (SNc), which project primarily to the dorsal striatum (dStr). Comparatively, the dopamine neurons in the adjacent ventral tegmental area (VTA), which project to the nucleus accumbens core and shell, are relatively spared. Although the dStr is primarily associated with motor control and the NAc is primarily associated with reward center, both contribute to movement and motivation.

We tested the influence of exercise on striatal dopamine content and release dynamics using a model of voluntary exercise in which mice were singly housed with a freely rotating wheel (runners), or with a locked wheel (controls), for 30 days (Bastioli et al., 2022). Mice are nocturnal and are most active during the initial hours of the dark phase; all tissue was collected and striatal slices prepared in this time window. Most of our experiments involved young adult male mice. We first determined striatal dopamine using high-performance liquid chromatography. We found no difference in total tissue levels of dopamine between runners versus controls in either dStr or NAc. We then assessed possible effects on dynamic dopamine release using local electrical stimulation in ex vivo striatal slices to stimulate release, which was detected using carbon-fiber microelectrodes with fast-scan cyclic voltammetry. Striatal dopamine release levels can vary widely between release sites; to mitigate this, we recorded stimulated dopamine release from multiple sites in each region in each slice, then compared the population responses in runners versus controls.

Consistent with our hypothesis that exercise might increase dopamine release, evoked increases in extracellular dopamine concentration ([DA]_o) were 30 to 40 percent higher in the dStr, NAc core, and NAc shell in male runners vs. controls, with similar results obtained in a cohort of females. Notably, dopamine release enhancement was still seen after a week of rest, showing that the effect of exercise extends beyond the exercise period, which is good news for those who do not exercise every day!

Given that dopamine release can be increased by acetylcholine (ACh) from striatal cholinergic interneurons via nicotinic ACh receptors (nAChRs) on dopamine axons, one explanation for enhanced dopamine release might be an amplification of ACh release or nAChR signaling. We tested this by comparing dopamine release in slices from runners and controls when nAChRs were blocked. The increase in evoked [DA]_o persisted under these conditions, implying a cell-autonomous effect of exercise on dopamine axons.

What other factors might be involved? Previous studies provide a clue: brain-derived neurotrophic factor (BDNF), a growth factor family member, has been shown to contribute to exercise-enhanced excitatory transmission in the hippocampus, as well as to the cognitive benefits of exercise.

We used three different approaches to examine a role for BDNF in the striatum. First, we quantified striatal BDNF in dStr and NAc using Western blotting and found significantly higher BDNF levels in the dStr of runners vs. controls, with no difference in NAc at the 30-day time point. Second, we examined dopamine release in striatal slices from heterozygous BDNF knockout mice (BDNF^+/-). Runner BDNF^+/- mice logged similar daily distances to wildtype mice, albeit with a slightly different running pattern. As expected, striatal BDNF levels in BDNF^+/- mice were less than half of those in wildtype, with no effect of exercise on BDNF levels in either dStr or NAc. More important mechanistically, the enhancing effect of exercise on dopamine release was absent in the dStr and NAc core of BDNF^+/- mice, although enhanced dopamine release remained in the NAc shell. Third, we monitored evoked [DA]_o in striatal slices while applying an agonist of the primary receptor for BDNF, TrkB (tropomyosin receptor kinase B). The TrkB agonist indeed caused a significant increase in evoked [DA]_o in all three striatal regions vs. time-matched controls. Like the increase in evoked [DA]_o seen with exercise, TrkB agonist-induced enhancement was ACh-independent.

Overall, our data show that exercise can increase dynamic dopamine release throughout the striatum. This is not from higher dopamine content, which was unaltered by exercise, and does not involve ACh acting at nAChRs. Instead, we find a necessary and sufficient role for BDNF/TrkB signaling in exercise-enhanced dopamine release in dStr and NAc core, which receive nigrostriatal input. Although dopamine release was enhanced in the NAc shell by exercise and by TrkB receptor activation, BDNF is apparently not required, implying involvement of other factors.

Our discovery that exercise leads to an enduring increase in dopamine release provides an explanation for motor improvements in patients with Parkinson’s disease who exercise, as well as for the decreased requirement for dopamine replacement therapy in some of these patients. Boosting of dopamine also provides insight into the beneficial effects of exercise on mood in healthy individuals, as well as the documented alleviation of symptoms in individuals with neuropsychiatric disorders, including depression and anxiety. In ongoing studies, our next step is to determine the influence of exercise on dopamine release and motor behavior in older mice of both sexes, and in wildtype and Parkinson’s model mice. Given our lab’s focus on factors that regulate dopamine release, we are delving deeper into the mechanisms by which BDNF boosts release, with support from the Parkinson’s Foundation.

Support for the work reported in Bastioli et al., 2022, came primarily from the Marlene and Paolo Fresco Institute for Parkinson’s and Movement Disorders at NYU Langone. In addition to funding our research, this support provided a unique opportunity for young scientists from Italy to conduct research related to movement and movement disorders at NYU Langone Health, including co-authors Guendalina Bastioli, PhD, and Maria Mancini, PhD, who were Fresco Institute Research Fellows. The program continues to foster collaboration between labs at NYU and in Italy, including connections between basic and clinical researchers.

—Guendalina Bastioli, PhD, and Margaret E. Rice, PhD

Read the paper “Voluntary exercise boosts striatal dopamine release: evidence for the necessary and sufficient role of BDNF” in The Journal of Neuroscience, published June 8, 2022.