Engaging cognitive circuits to promote motor recovery in degenerative disorders. exercise as a learning modality

Abstract

Exercise and physical activity are fundamental components of a lifestyle essential in maintaining a healthy brain. This is primarily due to the fact that the adult brain maintains a high degree of plasticity and activity is essential for homeostasis throughout life. Plasticity is not lost even in the context of a neurodegenerative disorder, but could be maladaptive thus promoting disease onset and progression. A major breakthrough in treating brain disorders such as Parkinson's disease is to drive neuroplasticity in a direction to improve motor and cognitive dysfunction. The purpose of this short review is to present the evidence from our laboratories that supports neuroplasticity as a potential therapeutic target in treating brain disorders. We consider that the enhancement of motor recovery in both animal models of dopamine depletion and in patients with Parkinson's disease is optimized when cognitive circuits are engaged; in other words, the brain is engaged in a learning modality. Therefore, we propose that to be effective in treating Parkinson's disease, physical therapy must employ both skill-based exercise (to drive specific circuits) and aerobic exercise (to drive the expression of molecules required to strengthen synaptic connections) components to select those neuronal circuits, such as the corticostriatal pathway, necessary to restore proper motor and cognitive behaviors. In the wide spectrum of different forms of exercise, learning as the fundamental modality likely links interventions used to treat patients with Parkinson's disease and may be necessary to drive beneficial neuroplasticity resulting in symptomatic improvement and possible disease modification.

Keywords: Parkinson’s disease; cognition; dopamine; neuroplasticity; physical activity.

Figure 1

Some of the “Fathers” of Neuroplasticity. The conceptualization of interactions between the brain and its environment has a long history based on scientific observation and experimentation going back several centuries. Some of the scientific luminaries are highlighted, but there are many others who are noteworthy.

Figure 2

Treadmill exercise enhances the restoration of motor behavior in the MPTP-lesioned mouse model of PD. Mice were administered MPTP in a series of 4 injections (total 80 mg/kg free-base) and subjected to treadmill running 5 days after the last injection. Panel A: The treadmill for mouse exercise. Panel B: Running velocity showing that MPTP parkinsonian mice (dark bars) achieve running behavior similar to saline (normal) mice after 3 weeks. Panel C: Analysis of striatal dopamine shows that parkinsonian mice do not have elevated levels of dopamine despite behavioral recovery. Panel D: Immunostaining for the striatal dopamine transporter (DAT) shows that exercised and recovered parkinsonian mice do not have elevated expression of DAT. Panel E: Fast-scan cyclic voltammetry shows increased dopamine release of remaining stores with exercise. Panel F: Dopamine D2 receptor ligand binding to [¹⁸F-fallypride] is restored with exercise in both mice (upper right image) and patients with Parkinson’s disease (lower panel).

Figure 3

Comparing skill-based and aerobic exercise in a rodent model of dopamine depletion implicates Cognitive Circuits. Rats lesioned with 6-OHDA were exercised on a skilled wheel where selective rungs were removed or an aerobic wheel with a smooth insert. During exercise rats were exposed to the radiotracer [¹⁴C]-iodoantipyrine, brains were removed, subjected to autoradiography and mapping/functional connectivity analysis. Results show elevated rCBF in the PFC and motor cortex with skill-based exercise compared to aerobic exercise. Images from Wang and Holschneider.