Optogenetic stimulation of nigral astrocytes is neuroprotective in a 6-OHDA model of neurodegeneration

Highlights

• Optogenetic stimulation of nigral astrocytes attenuates motor deficits & Th+ cell loss in a 6-OHDA model of neurodegeneration

• Bulk RNA-seq analysis reveals optogenetic stimulation of nigral astrocytes induces early changes in microglia

• snRNA-seq shows 6-OHDA alone induces extensive gene expression changes across all cell populations within the SN

• Oligodendrocytes within the SNc express Th, which is upregulated with DA neuron loss

Parkinson’s disease is characterized by the loss of dopaminergic neurons in the substantia nigra. Glial-glial crosstalk is essential for maintaining the regional milieu, and appears to be particularly important in modulating neuroinflammation and many aspects of neurodegeneration. In particular, astrocytes are critical for maintaining dopamine neuronal integrity and survival, and astroglial dysfunction is prominent in Parkinson’s disease. As such, astrocytes represent a potentially critical therapeutic target in neurodegeneration. In this study, in vivo optogenetics were used to selectively stimulate astrocytes in the substantia nigra following a striatal 6-OHDA lesion. Remarkably, a single bout of optogenetic stimulation was sufficient to attenuate motor deficits and dopamine neuron loss induced by the neurotoxin. Furthermore, bulk RNA-seq and snRNA-seq analysis of the substantia nigra revealed extensive changes in both microglia and oligodendrocytes, suggesting that the neuroprotective effects of stimulating astrocytes may be mediated through alterations in glia-glia crosstalk. Altogether, this work demonstrates the importance of understanding glia-glia interactions in neurodegeneration.