Oldham, B. | Search bioRxiv

bioRxiv2022

Striosomes constrain locomotor vigor with respect to an innate valence differential

Survival demands that safe and unsafe contexts are met with different locomotor profiles, yet whether striatal microcircuitry links contextual valence to spontaneous locomotor vigor is unresolved. Here we test for striosome contributions to spontaneous locomotion using ablation, calcium imaging and chemogenetics in the context of a modified Light/Dark box test. We found that locomotor speed reflects the unlearned, external valence differential present in this test, and that striosomes gate valence-oriented speed selection. Our data suggest that striosomes dampen motor vigor associated with lesser valence, or elevated anxiety. HighlightsO_LIMice explore the light and dark zones in Light/Dark box with different walk speed C_LIO_LIStriosome ablation reduces restful slowing and elevates speed relative to zone C_LIO_LIMany striosome neurons exhibit light-zone preference and speed related activity C_LIO_LIStriosome enhancement slows mice and blunts zone discrimination by speed C_LI

neuroscience↗

bioRxiv2021

Deficiency in endocannabinoid synthase DAGLB contributes to Parkinson's disease and dopaminergic neuron dysfunction

2-arachidonoyl-glycerol (2-AG), the most abundant endocannabinoid (eCB) in the brain, regulates diverse neural functions. However, whether 2-AG deficiency contributes to Parkinsons disease (PD) and nigral dopaminergic neurons (DANs) dysfunction is unclear. Diacylglycerol lipase and {beta} (DAGLA and DAGLB) mediate the biosynthesis of 2-AG. Using homozygosity mapping and whole-exome sequencing, we linked multiple homozygous loss-of-function mutations in DAGLB to a form of early-onset autosomal recessive PD. We then used RNA sequencing and fiber photometry with genetically encoded eCB sensors to demonstrate that DAGLB is the main 2-AG synthase in nigral DANs. Genetic knockdown of Daglb by CRISPR/Cas9 in mouse nigral DANs substantially reduces 2-AG levels in the substantia nigra (SN). The SN 2-AG levels are markedly correlated with the vigor of movement during the acquisition of motor skills, while Daglb-deficiency impairs motor learning. Conversely, pharmacological enhancement of 2-AG levels increases nigral DAN activity and dopamine release and improves motor learning. Together, we demonstrate that DAGLB-deficiency contributes to the etiopathogenesis of PD, reveal the importance of DAGLB-mediated 2-AG biosynthesis in nigral DANs in regulating neural activity and dopamine release, and provide preclinical evidence for the beneficial effects of 2-AG augmentation in PD treatment.

neuroscience↗