Lipid metabolism in dopaminergic neurons influences light entrainment. Issue 3 (9th March 2023)

• Record Type: Journal Article
• Authors: Fernandez, Regina F.; Wilson, Emily S.; Diaz, Victoria; Martínez‐Gardeazabal, Jonatan; Foguth, Rachel; Cannon, Jason R.; Jackson, Shelley N.; Hermann, Brian P.; Eells, Jeffrey B.; Ellis, Jessica M.
• Is Part Of: Journal of neurochemistry. Volume 165:Issue 3(2023)
• Page Start: 379
• Page End: 390
• Publication Date: 2023-03-09
• Subjects: acyl‐CoA synthetase -- docosahexaenoic acid -- dopaminergic neurons -- light entrainment -- lipid metabolism; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.15793
• Languages: English
• ISSNs: 0022-3042

Abstract

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 ( Acsl6 DA−/− ). Acsl6 DA−/− mice demonstrated hyperlocomotion and imbalances in striatal dopamine neurochemistry. Circadian rhythms of both the Acsl6 −/− and the Acsl6 DA−/− 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. 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. In the present study, long‐chain acyl‐CoA synthetase 6 (ACSL6), a lipid metabolizing enzyme responsible for channeling the omega‐3 polyunsaturated fatty acid docosahexaenoic acid (DHA) into neuronal membranes, was deleted exclusively in mouse dopaminergic neurons. ACSL6 loss in dopaminergic neurons results in hyperactive movement and impaired response to light entrainment, a circadian challenge mimicking jet lag. These data demonstrate that lipid metabolic derangements within dopaminergic neurons alone are sufficient to drive hyperactive behavior and defects in recovery from jet lag.