Lipid metabolism in dopaminergic neurons influences light entrainment

Abstract

Dietary lipids, particularly omega‐3 polyunsaturated fatty acids, are speculated to impact behaviors linked to the dopaminergic system, such as movement and control of circadian rhythms. However, the ability to draw a direct link between dopaminergic omega‐3 fatty acid metabolism and behavioral outcomes has been limited to the use of diet‐based approaches, which are confounded by systemic effects. Here, neuronal lipid metabolism was targeted in a diet‐independent manner by manipulation of long‐chain acyl‐CoA synthetase 6 (ACSL6) expression. ACSL6 performs the initial reaction for cellular fatty acid metabolism and prefers the omega‐3 polyunsaturated fatty acid, docosahexaenoic acid (DHA). The loss of Acsl6 in mice (Acsl6−/−) depletes neuronal membranes of DHA content and results in phenotypes linked to dopaminergic control, such as hyperlocomotion, impaired short‐term spatial memory, and imbalances in dopamine neurochemistry. To investigate the role of dopaminergic ACSL6 on these outcomes, a dopaminergic neuron‐specific ACSL6 knockout mouse was generated (Acsl6DA−/−). Acsl6DA−/− mice demonstrated hyperlocomotion and imbalances in striatal dopamine neurochemistry. Circadian rhythms of both the Acsl6−/− and the Acsl6DA−/− mice were similar to control mice under basal conditions. However, upon light entrainment, a mimetic of jet lag, both the complete knockout of ACSL6 and the dopaminergic‐neuron‐specific loss of ACSL6 resulted in a longer recovery to entrainment compared to control mice. In conclusion, these data demonstrate that ACSL6 in dopaminergic neurons alters dopamine metabolism and regulation of light entrainment suggesting that DHA metabolism mediated by ACSL6 plays a role in dopamine neuron biology.

Long chain acyl‐CoA synthetase 6 facilitates the local distribution of di‐docosahexaenoic acid‐ and ultra‐long‐chain‐PUFA‐containing phospholipids in the retina to support normal visual function in mice

“…ACSL6 is abundantly expressed in the testis, brain, and eyes. We and others previously demonstrated that ACSL6‐deficient mice develop male infertility and impaired brain function associated with a significant reduction of DHA‐containing lipids 11–15 . Here, we found that Acsl6 mRNA is highly expressed in the retina and is involved in the selective enrichment of di‐DHA‐ and ULC‐PUFA‐containing phospholipids, which supports normal visual function in mice.…”