Basal Ganglia in Health and Disease

National Institute Of Environmental Health Sciences

Investigators

Linked publications & trials

Abstract

Accomplished study: Spectrally resolved fiber photometry for multi-component analysis of brain circuits. Simultaneous measurement of multiple cellular processes is a long-sought-after approach to study the interactions between different components in local brain circuits during behavior. Toward this endeavor, we designed a novel fiber photometry system that can capture high resolution fluorescence spectra from UV to IR range. In doing so, we have created a highly flexible optical system that can be used with all current and future fluorescent sensors to assess a broad range of cellular and molecular events in vivo. The unique feature of the system, that is, the capability of acquiring high resolution spectra, allows for precise signal unmixing even when fluorophores with highly overlapped emission spectra are used together. To demonstrate the functionality of the method, we sought to reveal the relationship between two parallel striatal projection pathways, the so-called direct and indirect pathways in movement control. To simultaneously record the neural activity from direct- and indirect-pathway neurons, we used Cre-on and Cre-off viral vectors to differentially express green and red genetically encoded Ca2+ indicators GCaMP6f and jRGECO1a in these two populations of neurons. We now show for the first time that the activities of direct- and indirect-pathway neurons in the same hemisphere are highly synchronized during movement, and that the activation in one striatum is accompanied by the lack of activation in the contralateral striatum. These biological findings obtained using the new method provide a valuable platform for directly testing the classical model of the basal ganglia function and the pathophysiology of Parkinsons disease. A manuscript describing this study has been submitted. Ongoing study 1: Dopaminergic modulation of striatal direct and indirect pathways. The predominant model of the basal ganglia function suggests that dopamine enhances the activity in direct-pathway striatal neurons through activation of D1 dopamine receptors while inhibits the activity of indirect-pathway neurons via D2 dopamine receptors. However, there has been no direct evidence to support or disprove this hypothesis in awake behaving animals. Using spectrally resolved fiber photometry method we have recently developed, we are able to simultaneously monitor the neural activity in striatal direct- and indirect-pathway neurons in freely moving animals. We administered dopamine receptor antagonists to block dopamine transmission and amphetamine to enhance dopamine release. Our results show that dopamine is required for activation in both direct and indirect pathway neurons. These results challenged our current view on the role of dopamine in regulating the basal ganglia function. Ongoing study 2: Pathophysiological changes in striatal direct and indirect pathways during Parkinson's disease. In parallel with our study using pharmacological methods to manipulate dopamine transmission, we created a Parkinsons disease model in mice using unilateral intranigral injection of neurotoxin 6OHDA to selectively lesion dopamine neurons, and investigated the neural activity changes in the striatal direct and indirect pathways. Our initial results suggest that neural activities in both pathways diminished after the loss of dopamine neurons, further challenging the classical model. Ongoing study 3: 'Drug-induced silencing' as a novel therapeutic strategy to stop the progression of Parkinson's disease. Based on the selective vulnerability hypothesis of Parkinsons disease, we sought to protect dopamine neurons by pharmacologically silence them to reduce the energy consumption in these neurons in mouse models of Parkinsons disease. Our initial data from 32 mice suggest that a cocktail of silencing agents are effective in protecting dopamine neurons in 6OHDA-induced Parkinsons disease model. Ongoing study 4: High density fiber photometry for large scale brain activity mapping. We have designed and built a high density fiber array photometry system for simultaneous recording from multiple brain regions in freely moving animals. The system can either acquire signals from 12 spectrally resolved channels or up to 48 channels with simultaneous dual color capability.