Basal Ganglia in Health and Disease

National Institute Of Environmental Health Sciences

Investigators

Linked publications, trials & patents

Abstract

Study 1: Silencing dopamine neurons during sleep slows the progression of Parkinson's disease in mice. Summary: Parkinson's disease (PD) is a highly debilitating neurodegenerative disorder featured with the progressive loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Currently, there are no disease-modifying treatments that can slow or stop the progression of PD. Though the etiology of PD still remains elusive, it has been suggested that SNc DA neurons are more vulnerable than other neurons because of their high bioenergetic demand. In this study, we first compare the energy status of different neuronal types and find that SNc DA neurons have the lowest energy reserve, measured by the ATP/ADP ratio using genetically encoded fluorescent indicator PercevalHR. This finding provide direct evidence to support the selective vulnerability hypothesis of PD. We then test whether reducing the energy expenditure in DA neurons by silencing them during sleep, when DA is not needed for voluntary movement, can protect DA neurons and slow the progression of PD. We show that silencing DA neurons for 6-8 hours daily improves motor and cognitive functions, ameliorates sleep disturbances, and reduces the loss of SNc DA neurons in MitoPark mice, a genetic murine model for PD. We further confirm the protective effect of DA neuron silencing in a 6-OHDA lesion PD model. Moreover, silencing DA neurons does not cause adverse motor or cognitive side effects. These results suggest that reducing energy expenditure by silencing DA neurons during sleep can be an effective and practical treatment to slow the progression of PD. Study 2: DBS-based chemogenetic gene-therapy rescues motor deficits in mice with advanced Parkinson's disease. Summary: Deep brain stimulation (DBS) is currently the most effective treatment for alleviating motor symptoms in patients with advanced Parkinson's Disease (PD). However, the mechanisms underlying its therapeutic effects remain elusive. In this study, using fiber photometry and genetically encoded fluorescent sensors, we measured DBS-induced changes in pre- and postsynaptic neural activities and neurotransmitter release in the subthalamic nucleus (STN), the most commonly selected target in therapeutic DBS for PD. We found that DBS caused persistent elevation in the presynaptic neural activity from afferent axonal terminals while inhibiting the postsynaptic neural activity after a brief initial excitation in local STN neurons. DBS also caused a decrease in both glutamate and GABA release in STN, with a larger decrease observed in glutamate release than GABA when measured simultaneously. Based on these results, we hypothesized that during high-frequency DBS, prolonged activation of presynaptic terminals may disproportionally deplete glutamate and GABA from the releasable pools, leading to a decrease in the excitation/inhibition ratio of synaptic inputs into STN, which in turn results in a decrease in the neural activity in STN neurons. To further test this hypothesis and to develop a less invasive alternative treatment, we used viral vectors to express GiDREADD in STN neurons bilaterally in MitoPark mice, a progressive mouse PD model. We found that a single i.p. injection of 3mg/kg CNO, which inhibits GiDREADD-expressing neurons, completely rescued the motor deficits in open field and rotarod tests in MitoPark mice injected with GiDREADD. The therapeutic effects lasted for at least 5 hours after a single injection. To further test the therapeutic effect of this new treatment after chronic use, the MitoPark mice were treated with CNO daily for 4 weeks their motor functions were evaluated at 29 weeks old. The efficiency of CNO treatment maintained at the same level. Finally, we directly compared the therapeutic effects of electrical DBS and chemogenetic DBS in the same MitoPark mice treated with either CNO or STN-DBS, and found that CNO treatment and DBS stimulation showed comparable effects inhibiting STN neurons and improving motor functions. Taken together, we have revealed the neural mechanisms underlying the therapeutic effects of DBS, and have developed a novel chemogenetic gene-therapy that may become an alternative treatment for patients with advanced PD. Study 3: Dietary nicotinamide riboside alleviates motor symptoms in parkinsonian mice. Summary: In this study, we tested whether nicotinamide riboside (NR), a NAD+ precursor, can produce beneficial effects in PD mouse models. We have found that daily treatment with NR significantly alleviates motor deficits in an alpha-synuclein and benomyl double-hit PD mouse model. Surprisingly, the behavioral rescue effects were not associated with a reduction in cell loss of dopamine neurons. Instead, we have found that NR intake boosts the APT/ADP ratio in neurons and facilitates dopamine release in the striatum. These results suggest that supplementation with dietary NR may provide beneficial effects in PD. Study 4: Co-administration of D1 receptor PAM prevents L-DOPA-induced dyskinesia in parkinsonian mice. Summary: Parkinsons disease (PD) is the second most common neurodegenerative disorder and the most common movement disorder featuring the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. L-DOPA is currently the most effective medication to mitigate the PD symptoms. However, most of patients will develop dyskinesia after prolonged use of L-DOPA. L-DOPA-induced dyskinesias (LIDs) in PD is still one of the most debilitating complications in PD treatment. In this study, we tested whether D1 receptor positive allosteric modulators (D1-PAMs), which enhances the function of D1 receptors, could lower the dose of L-DOPA and prevent the development of LIDs. In the behavioral tests, we found that MLS6585, a D1-PAM discovered at NIH, did not improve the PD symptoms when given alone in MitoPark PD mice, a mouse PD model with progressive loss of dopamine neurons and age-dependent motor deficits. However, when co-administered, MLS6585 significantly lowers the dose of L-DOPA required to alleviate the motor deficits. In addition, to see whether the low dose of L-DOPA in combination with D1-PAM can relieve LIDs in PD. We treated MitoPark mice at 30-week-old for 10 weeks with daily i.p. injection of L-DOPA alone at high dose (4 mg/kg), low dose (2 mg/kg) and low dose (2 mg/kg) L-DOPA combined with MLS6585. Dyskinesia symptoms are evaluated weekly in these mice. The results show that dyskinesia symptom induced by L-DOPA treatment is dose dependent and all these treatments prolong the survival of mice. Furthermore, compared to high dose L-DOPA, repeated combination of L-DOPA and D1-PAM treatment remarkably improved dyskinesia symptoms in MitoPark mice and had the best survival rate. Taken together, these results suggest that co-administration of D1R PAM effectively lowers dose of L-DOPA in treating PD and prevents LIDs, providing a new strategy in PD treatments in humans. Study 5: Impact of physical excise on the progression of Parkinson's disease. Exercise is clinically proven to help alleviate the symptoms in Parkinson's disease (PD) patients. However, it is debatable whether exercise can slow the disease progression. In this study, we test whether long-term voluntary exercise can improve PD motor symptoms and slow the loss of nigral dopaminergic neurons in MitoPark parkinsonian mice. We place the running wheels in the home cages of individually housed MitoPark and littermate control mice when they are 10 weeks of age, and monitor their daily wheel-running distance until they are sacrificed for brain tissue collection at the age of 25 weeks of age. We find that chronic exercise significantly improved the performance of MitoPark and littermate control mice in open field and rotarod tests. We are currently evaluating the PD pathology.